# Thiazolium Salts: From Thiamine to Cutting-Edge Organocatalysts

Ilan Garcin, Ludovic Maillard, Jean-Marc Campagne, Renata Marcia de Figueiredo

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Ilan Garcin, Ludovic Maillard, Jean-Marc Campagne, Renata Marcia de Figueiredo. Thiazolium Salts: From Thiamine to Cutting-Edge Organocatalysts. Advanced Synthesis and Catalysis, 2025, pp.e70087. 10.1002/adsc.70087. hal-05337000

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# Thiazolium Salts: From Thiamine to Cutting-Edge Organocatalysts

Ilan Garcin,ª Ludovic Maillard,ᵇ Jean-Marc Campagne,ª and Renata Marcia de Figueiredoª,\*

ªICGM, Univ. Montpellier, CNRS, ENSCM, 34293 Montpellier, France
E-mail: renata.marcia_de_figueiredo@enscm.fr

ᵇIBMM, Univ. Montpellier, CNRS, ENSCM, 34293 Montpellier, France

**Abstract:** In this comprehensive review, the history of thiazolium salts as N-Heterocyclic Carbenes (NHC) in organocatalytic reactions is intended to be presented. Although the subject (i.e., NHC in organocatalysis) has been covered in several reviews in past years, the idea here stands on the exclusive use of thiazolium salts in such transformations. Indeed, thiazoliums and their related NHCs are the first identified as efficient mediators for the C—C bond formation through its peculiar ability to reverse the classical reactivity (umpolung) of carbonyl groups. However, they are relatively quickly overtaken by other classes of NHCs generated from imidazolium and triazolium salts. Even though, thiazolylidenes are still better catalysts in some particular reactions affording outstanding

results in terms of conversion and selectivity. Owing to the remarkably high number of reactions that are made possible thanks to the very characteristic properties of such NHCs, the aim of this review is to provide a full account on the discovery and evolution of thiazolium salts and thiazolylidenes in NHC organocatalysis. Information is first provided on their synthesis, structural evolution, physicochemical and electronic properties, and then reactivity and application in various organocatalytic methodologies.

**Keywords:** C—C bond formation, carbenes, organocatalysis, thiazolium salts, umpolung concept

## 1. Introduction

Catalysis is essential to organic chemistry and physio-logical processes.[1] It plays a central role in modern chemistry as well as industrial and biological processes. Overall, catalysts provide enhanced reaction kinetics and efficiency, atom economy, selectivity, and economic benefits when associated with industrial processes. In this context, enzymes,[2] transition metals,[3] organometallic complexes,[4] and organocatalysts[5] are powerful and essential tools for the efficient and selective synthesis of chiral molecules. Each of the aforementioned categories of catalysts has its own pros and cons, and chemists/biologists find the best one suited to their synthetic and strategic objectives. Enzymes offer both excellent catalytic activity and reaction specificity, thanks to conformational control within the active site that creates excellent substrate recognition (i.e., 3D structure defines catalytic activity). However, in many cases, their use is limited by high production costs or problems of instability in the chemical synthetic processes. Also, enzymes are very substrate dependent,

which detracts from scope generalization. These points have led to the development of new organometallic and organic catalysts, which have broader substrate scope and affordable production costs. From this time on, the use of enzymes in catalysis has given way to more practical small organic molecules or organometallic complexes, which enables a wider range of transformations. However, although enzymes instigate most of them, these bio-inspired models do not always offer the same remarkable level of selectivity. Indeed, chemists and biologists apply continuous efforts in designing and developing novel biomimetic catalysts that keep enzyme specificity without their complex scaffold.[6]

Transketolase enzymes supported by coenzyme thiamine 1 (vitamin B₁) (Figure 1), which bears a thiazole ring in its structure, were among the first templates to support the design of metal-free bio-inspired catalysts. Many studies carried out by several groups have focused on the elucidation of the mechanism of action of these enzymes[7] in order to transpose their catalytic effect by using azole rings alone. Since then, and with the seminal publications on
<figure><img src="image_2.png" /><figcaption>**Figure 1.** Coenzyme thiamine 1 (vitamin B₁).</figcaption></figure>

stable nucleophilic carbenes by Bertrand[8] and Arduengo[9]
in the late 1980s, thiazolium salts have been the source of
inspiration for the design of new organocatalysts for the
C—C bond formation using umpolung reactivity.

This review will thus focus on the discovery and
evolution of thiazolium salts as precatalysts in the
field of N-heterocyclic carbenes (NHC) catalysis.
Organocatalysis by NHC is a huge and important field
of research, which has been covered and often updated
in many excellent reviews.[10,11b] Here, we intend to
focus this vast field by giving a comprehensive
account of thiazolium salts through their evolution
over time in terms of synthesis, structural modifica-
tions, and physicochemical and electronic properties.
Then, their application in various organocatalytic
methodologies will be described. Moreover, where
appropriate, discussions on the advantages and/or
limitations of thiazolium salts as well as future
prospects for their use in NHC-organocatalysis will be
presented.

**2. Enzymes as Inspiration: From Thiamine to Thiazoliums**

In Nature, the unusual reactivity conferred by NHCs is
used by transketolase enzymes, which take advantage of
coenzyme thiamine 1 (vitamin B₁—a natural thiazolium
salt) (Figure 1), to catalyze numerous relevant and
complex biochemical transformations such as nucleo-
philic acylations. One example is the decarboxylation
of pyruvate where thiamine acts as a Lewis base catalyst
(Scheme 1).

The structure of vitamin B₁ was elucidated in 1936 by
Williams,[¹²] whereas in the 1990s, Schneider described
the X-ray structure of transketolase enzyme from
*Saccharomyces cerevisiae*. [¹³] A great deal of research

<figure><img src="image_3.png" /><figcaption>**Scheme 1.** Enzymatic pyruvate decarboxylation.</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>**Scheme 2.** a) Langenbeck's proposition on thiamine-pyruvic acid decarboxylation. b) Karrer's supposed open-chain intermediate from 1.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Scheme 3.** Mizuhara's suggestion on a "pseudo-base" formation in alkaline solution (1954).</figcaption></figure>

has been carried out to identify the active catalytic species in these reactions.[7,14] Among the first suggestions, in 1935, Langenbeck supported the participation of the amino group of **1** via condensation with pyruvic acid in order to provide a first Schiff base **2** that after decarboxylation evolves into a second one **3** (Scheme 2a). Hydrolysis afforded free acetaldehyde and **1**.[15] An open-chain isomer **4** of thiazolium **1** was also alleged (without any further indications) as being the active catalyst (Scheme 2b).[16] These proposals were rapidly argued and soon discredited by other studies.[17]

The initial “active form” of **1** was originally proposed in the early 1950s by Mizuhara (Scheme 3).[18] He postulated the formation of a “pseudo-base” **5** with a hydroxyl group added at the C-2 position of the thiazolium during biological transformations, as for example, the synthesis of acetoin and acetate from acetaldehyde and diacetyl under alkaline conditions.

Nowadays, it is well stated that the catalysis by trans-
ketolase enzymes in association with cofactor **1** goes
through NHC reactivity: the active catalytic species
has been identified as a nucleophilic carbene formed
by deprotonation in the C-2 position of the thiazole ring
(Scheme 4). Since then, catalytic transformations relying
on carbonyl umpolung using simplified thiazolium salts
have been extensively investigated by numerous
researchers, with the aim of achieving substrate specific-
ity and reaction selectivity comparable to that of com-
plex enzymatic systems.

**3. Outset of Umpolung-Type Acylation Reaction**

**3.1. Benzoin Condensation History**

The first example of acylation reaction was described in
1832, when Wöhler and Liebig used cyanide anions to
catalyze the coupling reaction of benzaldehyde **6** to
benzoin **7** (Scheme 5).[19] This seminal work was pub-
lished even before umpolung's concept of reverse acyl
reactivity was discovered. Seventy years later, Lapworth
proposed a mechanism for this reaction.[20] based on
the formation of an "active aldehyde" intermediate **8**
(Scheme 6) that illustrates the concept of umpolung
reactivity first proposed by Wittig[11] in 1951 and
<figure><img src="image_6.png" /><figcaption>**Scheme 4.** Mechanism of the enzymatic pyruvate decarboxylation.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Scheme 5.** Benzoin condensation by Wöhler and Liebig (1832).</figcaption></figure>

formalized by Seebach[21] in the late 1970s. Thereafter, the umpolung concept has become a powerful method in organic synthesis, and associated with organocatalysis, NHCs offer a plethora of opportunities in catalytic reactions.[11b]

Following these pivotal works, Ukai published in 1943 a study that has definitely marked the entry of thiazolylidenes into the field of organocatalysis. Indeed, Ukai and coworkers reported the first benzoin condensation that avoided either transketolase enzymes/thiamine combination or cyanide by simply using thiazolium salts (Scheme 7).[22] Interestingly to note, during the transformation, the authors expected to observe a similar reactivity for thiazolium salts as the one experienced for pyridines,[23] that can react with aldehydes via ylide formation (Scheme 7a). Nevertheless, expected products 9 were never observed (Scheme 7b). Instead, benzoin 7 was obtained showing that thiazolium salts might act as a catalyst and not as a substrate for the reaction (Scheme 7c).

## 3.2. Benzoin Condensation and Evolution of Mechanistic Aspects

With early reports on the mechanism of action of thiamine 1, and based on the works of Mizuhara[18] and

<figure><img src="image_8.png" /><figcaption>**Scheme 6.** Benzoin condensation mechanism proposed by Lapworth (1903).[20]</figcaption></figure>

Lapworth,[20] as well as hydrogen isotope exchange at C-2 of the thiazolium rings, Breslow postulated a mechanism for this transformation in 1958 (Scheme 8).[24] It is assumed that in situ deprotonation of thiazolium salt at the more acidic C-2 position affords the nucleophilic carbene 10 (i.e., thiazol-2-ylidene) which behaves as the
<figure><img src="image_9.png" /><figcaption>**Scheme 7.** Ukai discovery of benzoin condensation with thiazolium salts (1943); a) rationalized by analogy with pyridinium compounds; b) expected products **9** and some selected thiazolium salts used; c) observed benzoin condensation.</figcaption></figure>

NHC catalyst. Addition of the NHC to an aldehyde leads to the so-called primary intermediate, which after proton transfer, provides the Breslow intermediate **11** (i.e., hydroxy-enamine-type intermediate or **BI**). This neutral species functions as acyl-anion equivalent and in the presence of an electrophilic substrate (e.g., another aldehyde molecule) provides the condensation product (e.g., α-hydroxy ketone) and the NHC catalyst is regenerated.

Based on the work by Wanzlick in the early 1960s on the dissociation of NHC dimers into monomers (Scheme 10a),[25] an alternative pathway involving the formation of dimers **12** has been proposed by Lemał[26,27] in 1964 (Scheme 9) and supported later by López-Calahorra.[28] Two possible mechanisms for the benzoin condensation via dimers were thus advocated: one via dimer dissociation into **BI** and a free carbene after reaction with the substrate, and another one where the dimer structure is kept during the whole transformation (Scheme 10b). Nevertheless, none of these proposals was subsequently supported; the Breslow mechanism being the most likely.[29]

In 2015, Rehbein proposed the formation of radical intermediates that involve both the **BI** and the aldehyde substrate.[30] This alternative radical pathway, based on EPR-spectroscopic and computational experiments,

supports a single-electron transfer (SET) from **11** to the aldehyde to afford a radical pair **13** that collapses into carbene and benzoin product (Scheme 11). In 2019, Martin and Bertrand evidenced that **11** cannot undergo SET in the presence of mild oxidants.[31] They demonstrated that SET of **11** leads to a subsequent deprotonation affording neutral capto-dative radicals **14** (i.e., acylum radicals) which are more likely than **13** (Scheme 11). The authors pointed out, however, that although radicals have been observed in NHC-catalyzed reactions, it is not certain that they are true intermediates. Redox properties are going to be further discussed in Section 4.4.

Recently, Hollóczki has brought some new fundamentals on the mechanism of umpolung acylation reaction.[32] These studies were carried out in order to better understand some still unclear points of the mechanism established by Breslow, such as the absence of catalyst decomposition and the fact that reactions take place at broad pKa differences between carbene and base or even in acidic media.

Through computational studies, Hollóczki was able to identify an alternative pathway which skips the formation of “free” NHC carbenes as described by Breslow (i.e., dissociative mechanism). He proposes that under particular reaction conditions (e.g., base and solvent) and based on the nature of azolium salts (e.g., counterion, ring substituents), an associative mechanism is plausible. In this particular case, deprotonation of the C-2 position of azolium salts is sidestepped in favor of a concerted pathway via concomitant proton transfer and catalyst-substrate bond formation (intermediate 15; Scheme 12). In other words, the proton transfer and the substrate binding to the catalyst occur simultaneously in a single reaction step, without passing through a carbene-type intermediate. This associative alternative mechanism displays a lower energy barrier compared to the classical Breslow mechanism involving a free carbene. Interestingly, depending on the reaction parameters and the structure of azolium salts, transformations may follow either the associative or the dissociative mechanism, and the selectivity of the reaction may be influenced. Thus, through a judicious choice of the reaction components, the reaction pathway can be either the one via carbene formation (dissociative Breslow mechanism) or the associative mechanism proposed by Hollóczki.[32]

Soon after, Sunoj compiled the results of computational studies carried out in order to explain the 1,2-proton transfer that is responsible for the **BI** formation from the zwitterionic intermediate **16** (Scheme 13).[33] In this interesting review, it has been shown that this proton/hydride transfer needs very high kinetic barriers, being thus not practicable. Thus, to avoid the strained geometries involved in the possible pathways (e.g., three- and four-membered transition states) for the 1,2-proton transfer step, the participation of other molecules (e.g., additives such as alcohols, H₂O, bases and
<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /><figcaption>**Scheme 8.** Breslow's catalytic cycle for the benzoin condensation (1958).</figcaption></figure>

<figure><img src="image_12.png" /><figcaption>**Scheme 9.** Equilibrium between thiazolylidene NHCs and Wanzlick-type dimers.</figcaption></figure>

acids) has been proposed. DFT studies on representative reactions have shown that assisted hydrogen atom transfer (HAT) by these additives has lower barrier values compared to the unassisted pathways and is a much more plausible alternative.[34–36]

### 3.3. Efforts to Isolate/Characterize Breslow Intermediates

Over the years, despite the inherent high reactivity of NHCs and the fleeting nature of the associated intermediates, numerous research groups have undertaken significant efforts to isolate and characterize these elusive species. As a result, stable **BIs** and related analogs have been successfully observed or synthesized.[37]

The first ¹H NMR spectroscopic characterization of O-protected thiazole-based **BIs** from thiazoles dates back to 1987 when Jordan described their generation in pyridine-d5.[38] Three years later, Bordwell and Jordan characterize by NMR and cyclic voltammetry the acid-base equilibrium between primary intermediates and Breslow-type enamines.[39] They demonstrated that the pK<sub>AH+/A</sub> ranging from 9.75 to 14.3 in DMSO was highly dependent on the substitution pattern at the C-2-α.

A breakthrough came in 2012, when Mayr successfully published the first isolation of stable thiazolylidene-containing O-methylated **BIs**.[40] The synthesis starts
<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /><figcaption>**Scheme 10.** Mechanism via dimer **12** formation by Castells and López-Calahorra (1988). a) Dimers' dissociation into carbene and Breslow intermediate. b) Dimers' connection is maintained.</figcaption></figure>

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /><figcaption>**Scheme 11.** Radical intermediates on benzoin condensation by Rehbein and Martin. a) Postulated SET of **11** to give a radical pair **13** (2015); b) SET/deprotonation of **11** to give acylium radical **14** (2019).</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>**Scheme 12.** Alternative associative mechanism by Hollóczki.</figcaption></figure>

with the deprotonation of the thiazole substrates at the C-2 position with nBuLi, followed by the addition of benzaldehyde 6. Subsequent protection of the hydroxyl group with MeI and NaH and quaternization of the nitrogen atom using MeOTf provides the N-alkylated thiazolium 17 (Scheme 14). In the presence of NaH and catalytic amounts of KO/Bu in anhydrous THF, thiazolium salts 17 led to the O-methylated BIs 18a and 18b which remain stable for several weeks at -30 °C in an argon glove box.

<figure><img src="image_18.png" /><figcaption>**Scheme 13.** General accepted mechanism for the formation of the BI according to the review by Sunoj.[33]</figcaption></figure>

<figure><img src="image_19.png" /><figcaption>**Scheme 14.** Synthesis of O-methylated BIs 18 by Mayr.</figcaption></figure>

For both **18a** and **18b**, NOESY experiments in C₆D₆ revealed a preference for the Z-enolate geometry with a 2:1 Z/E ratio,[38] in striking contrast to the triazole analogs, which exhibited the reversed stereochemistry with a 1:10 Z/E ratio. X-Ray crystallographic analysis of **18a** showed a planar geometry for the exocyclic double bond with a bond length (134.9 pm).[37c] The major Z isomer configuration observed in the solid state could be explained by the S—O distance (258.0 pm), shorter than the addition of the corresponding van der Waals radii
<figure><img src="image_20.png" /><figcaption>**Scheme 15.** ¹³C NMR identification of **BI 22** by Berkessel.[42]</figcaption></figure>

(332.0 pm), which supports an intramolecular nonbonding 1,4-S···O interaction. The OMe group is almost perpendicular to the exocyclic double bond, an observation that corroborates the chemically calculated structure of analog **18a-OH**.

In 2014, Lee used ESI-MS to track the benzoin condensation and identified the intermediate formed by the addition of benzaldehyde to the thiazolium NHC.[41] In 2018, using thiazolium salt labeled with ¹³C at C-2 and pentafluorobenzaldehyde labeled with ¹³C at the aldehyde function, Berkessel characterized by ¹³C NMR the first thiazolin-2-ylidene-based **BI**.[42] First attempts using N-Dipp [i.e., 2,6-di-(2-propyl) phenyl] substituted thiazolium failed. Moving to sterically less encumbered trimethylthiazolium salt **19**, that gives stable Wanzlick dimer **20** which is more likely to accumulate than free carbenes in reaction media,[29c,43] and by using an excess of the extremely electrophilic aldehyde partner **21**, the authors could follow the reaction by NMR in THF-d8 at -10 °C (Scheme 15). Over the course of 2 h, the authors clearly observed the gradual disappearance of the NMR signals corresponding to dimer **20** and aldehyde **21**, accompanied by the emergence of new resonances attributed to the ¹³C-labeled carbons of the enol C≡C double bond in **BI 22**. After 2 h of reaction monitoring, two additional species were detected: the more stable ketone **23**, formed by tautomerization of **22**, and the enediol **24**, identified as the major tautomeric form of the final benzoin-type product.

One year later, **BI 26**, derived from N-Dipp substituted thiazolin-2-ylidene **25**, and a related protonated primary intermediate **27** were successfully synthesized and characterized by both NMR and X-ray diffraction (XRD) (Scheme 16).[44] Moreover, intermediate **29**,

<figure><img src="image_21.png" /><figcaption>**Scheme 16.** XRD and NMR characterization of Dipp-based **BI 26**, protonated analog **27**, and CF₃ analog **29** by Berkessel.[44]</figcaption></figure>

<figure><img src="image_22.png" /><figcaption>**Scheme 17.** Carbene **25** and benzaldehyde for NMR characterization of Dipp-based **BI 30**.</figcaption></figure>

generated from an aliphatic aldehyde (i.e., polymeric trifluoroacetaldehyde **28**), was also prepared and characterized by ¹³C NMR.

Moving to the combination of **25** with benzaldehyde, NMR monitoring in THF-d8 showed a rapid formation of **30**, followed by its keto tautomer **31** (Scheme 17). The latter could be crystallized when the reaction was run in benzene.[44]

In another context, Biju and Das developed a method for the analysis of free carbenes present in the reaction flask after NHC-organocatalyzed transformations.[45] The idea was to trap the free NHCs after reactions that take place under the transient formation of an α,β-unsaturated acylazolium intermediate by addition of elemental sulfur and consequent isolation of the thiourea/thione derivatives. In the case of thiazolium precatalyst **32**, the technique has been used for the analysis of free NHCs after benzoin and Stetter reactions with the isolation of the corresponding thione **33** (Scheme 18).
**Benzoin reaction**

<figure><img src="image_23.png" /></figure>

**Intramolecular Stetter reaction**

<figure><img src="image_24.png" /><figcaption>**Scheme 18.** Analysis of free thiazolium precatalysts outcome by trapping with elemental sulfur.[45]</figcaption></figure>

# 4. Fundamentals of Thiazolium Salts NHCs

The impact of organocatalytic umpolung via NHCs has prompted several research groups to study their physicochemical properties in deep.[46] Previous reviews have efficiently compiled data on azolium salts, with imidazoliums and triazoliums being more commonly documented.[10b,32b] However, valuable insights into thiazolium rings are available in studies on the electronic mechanisms of thiamine-catalyzed reactions.[47]

## 4.1. pKa

The key reactivity of thiazolium salts in organocatalyzed NHC transformations lies in their ability to be deprotected at the C-2 position.[48] The subject has received sustained attention over the years.[49] Overall, thiazolium salts ($pKa$ = 17–19 in $H_2O$) are more acidic than imidazoliums ($pKa$ = 19–24 in $H_2O$) (**Scheme 19**). The oxazolium salt, containing a more electronegative oxygen atom, exhibits an even lower $pKa$ of 16.9. Similarly, incorporating a third electronegative nitrogen atom into the ring, as in triazolium salts, further decreases the $pKa$ to almost 16–17.[46] A voltammetric analysis, made in 2016 by Feroci, confirms this tendency in organic medium [values of $pKa$ in DMSO: imidazolium salts = 20–22, thiazolium salts = 16–19 (versus acetic

<figure><img src="image_25.png" /><figcaption>**Scheme 19.** Acidity of thiazolium-salts.</figcaption></figure>

acid = 12)].[50] It should be emphasized that $pKa$ values are directly linked to the nature of substituent groups on the heterocycle, while little is known on the counterions part. Thiamine **1**, for which many studies concerning $pKa$ have been carried out,[51] the precise value ($pKa$ = 18 in $H_2O$), was determined in 1988.[52]

Although Ukai's first report on benzoin condensation[22] and Breslow's studies on the mechanism elucidation[24] were experimentally run in the presence of strong alkali hydroxide bases, the greater acidity of thiazolium salts compared to imidazolium salts allows organocatalytic reactions involving these NHCs to be carried out with milder bases. This was further proved by Breslow, who demonstrated by infrared spectroscopy and NMR that thiazoliums exchange rapidly with deuterium, under very mild conditions (e.g., neutral $D_2O$ at room temperature in a few hours) (**Scheme 20**).

Breslow proposed that the stability of the zwitterion resulting from the facile C-2 deprotonation of **1** could arise from an overlap between the C-2 anion and an unfilled d orbital of sulfur.[24] Pullman and Spanjaard, on their side, when studying the electronic aspects of the mechanism of thiamine-catalyzed reactions, ascribed

<figure><img src="image_26.png" /><figcaption>**Scheme 20.** C-2 proton exchanges with $D_2O$ by Breslow (1958).</figcaption></figure>
<figure><img src="image_27.png" /><figcaption>**Scheme 21.** Distribution of electronic charges as calculated by Pullmann and Spanjaard; selection of examples.[47a]</figcaption></figure>

to the sulfur atom the fact that carbon C-2, between N and S atoms, is a center of very high electronic density even at its unionized form (Scheme 21).[47a] The stabilization role of sulfur in the formation of the carbene species was supported by the observation that substitution of the sulfur atom with oxygen, both in thiamine (yielding O-heterothiamine) and in related model compounds, results in a complete loss of activity. While calculations show that the C-2 position in thiazolium derivatives bears a significant negative charge of -0.11e, this is not the case in analogous oxazolium ions. In the 4,5-dimethyloxazolium cation, for instance, the electronic

charge at C-2 drops significantly and corresponds to an effective positive partial charge of +0.256e, reflecting a deficiency of electron density on this atom. In accordance with this hypothesis, Olofson and Landesberg observed on thiazole and other sulfur-containing azoles that base-promoted deuterium exchange occurs faster at carbon atoms adjacent to sulfur (C-2 or C-5) than other positions (Table 1).[47b] It has been found that deprotonation is consequently enhanced on carbon next to the sulfur atom, pointing out indeed that the d-σ overlap is probably a major factor in stabilizing these C-2 anions. More recently, DuPré and Wong, using quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses, demonstrated that the stabilization of the thiazolium C-2 anion does not arise from a hyperconjugative interaction involving sulfur d orbitals, nor from resonance stabilization through the adjacent quaternary nitrogen acting as an electron sink.[53] Instead, their studies revealed that the π-system plays a critical role in accommodating the developing negative charge at C-2 during deprotonation. Thiazolium salts were found to offer the best capacity for carbanion electron delocalization among related azolium systems. According to their conclusions, sulfur provides optimal orbital contributions to both the LUMO of the transition state and the HOMO of the resulting thiazol-2-ylidene, owing to its moderate atomic size and lower electronegativity compared to oxygen, nitrogen, or selenium (Scheme 22).[47c]

## 4.2. Steric Factors and Electronic Properties

From a strictly structural point of view, replacing a nitrogen in imidazol-2-ylidene systems with sulfur to form thiazol-2-ylidenes introduces a significant difference as ring symmetry is interrupted due to the lack of substitution on the sulfur atom.

<table><caption>**Table 1.** Rates of H-D exchange by Olofson.[47b]</caption><thead><tr><th rowspan="2">Compound</th><th rowspan="2">Proton</th><th colspan="2">K<sub>2</sub>, 1 mole<sup>-1</sup> s<sup>-1</sup></th><th colspan="2">Relative rate</th></tr><tr><th>-OMe in MeOD</th><th>-OD in D<sub>2</sub>O</th><th>MeOD</th><th>D<sub>2</sub>O</th></tr></thead><tbody><tr><td rowspan="3">H<sub>4</sub>N-S-H<sub>5</sub> thiazole</td><td>H<sup>2</sup></td><td>5.6 &times; 10<sup>-5</sup></td><td>5.8 &times; 10<sup>-5</sup></td><td>1.00</td><td>1.00</td></tr><tr><td>H<sup>4</sup></td><td>No exchange</td><td>No exchange</td><td>&lt;10<sup>-6</sup></td><td>&lt;10<sup>-6</sup></td></tr><tr><td>H<sup>5</sup></td><td>5.1 &times; 10<sup>-5</sup></td><td>4.3 &times; 10<sup>-5</sup></td><td>0.91</td><td>0.74</td></tr><tr><td rowspan="2">H<sub>3</sub>N-S-H<sub>5</sub> isothiazole</td><td>H<sup>3</sup></td><td>No exchange</td><td>Insoluble</td><td>&lt;10<sup>-7</sup></td><td>—</td></tr><tr><td>H<sup>5</sup></td><td>3.9 &times; 10<sup>-4</sup></td><td></td><td>7.00</td><td></td></tr><tr><td>H<sub>2</sub>N-S-H<sub>2</sub> 1,3,4-thiadiazole</td><td>H<sup>2</sup></td><td>—</td><td>0.36</td><td>—</td><td>6200</td></tr><tr><td rowspan="2">H<sub>4</sub>N-S-H<sub>5</sub> 1,2,3-thiadiazole</td><td>H<sup>4</sup></td><td>—</td><td>No exchange</td><td>—</td><td>&lt;10<sup>-2</sup></td></tr><tr><td>H<sup>5</sup></td><td></td><td>1.8</td><td></td><td>31.000</td></tr></tbody></table>
<figure><img src="image_28.png" /></figure>

<figure><img src="image_29.png" /><figcaption>**Scheme 22.** a) Thiazolium deprotonation toward an arbitrary base (B) to give TS and finally form the carbanion. b) Illustration of orbital contributions to the LUMO of the TS and the HOMO of the thiazol-2-ylidene.[47c]</figcaption></figure>

In organometallic catalysis, the metal-carbon bonds involving the C-2 position of azole rings are affected by this substitution. This structural change results in what has been termed an “umbrella-shaped” steric environment, as opposed to the “cone-shaped” profile typically associated with phosphine ligands. With imidazol-2-ylidene-based NHC ligands, this geometry yields a symmetrical umbrella-like coordination environment (system A). In contrast, thiazol-2-ylidene ligands generate an unsymmetric “half-umbrella” geometry (system B), as illustrated in Figure 2.

The percentage buried volume ($%V_{Bur}$) is an established ligand metric introduced in coordination chemistry in 2003 by Nolan and Cavallo,[54–56] to assess the steric demands of NHCs. A ligand-metal complex is modeled as a sphere of radius 3.5 Å, with the metal atom positioned at its center and a fixed metal-carbene bond length (typically 2.00 or 2.28 Å).[55] In this framework, the $%V_{Bur}$ corresponds to the fraction of the spherical volume occupied by the ligand (Figure 3). The

<figure><img src="image_30.png" /></figure>

$%V_{Bur}$ = percentage of sphere occupied by the ligand

[M]-carbene bond length d = 2.00 or 2.28 Å

Radius of sphere r = 3.5 Å

<caption>**Figure 3.** Reported model used to define the $%V_{Bur}$ of NHCs.</caption>

calculation, which relies on quantum mechanical methods such as DFT and/or XRD data analysis, provides a quantitative assessment of the steric hindrance exerted by the ligand around the metal center. For comparative purposes, $%V_{Bur}$ for several commonly used NHC classes (e.g., imidazol-2-ylidene, imidazol-4,5-dihydro-2-ylidene, and triazol-2-ylidene) have been calculated for many metallic complexes and are compiled in a feature article by Clavier and Nolan in 2010.[56,57] Depending on the substituent pattern, values range from 25% to 50%.

Initially developed for organometallic systems, this model has proven informative in rationalizing the behavior of NHCs in organocatalysis, particularly when comparing structurally distinct carbenes.[58] In the case of thiazol-2-ylidenes, the asymmetry and lower substitution degree of the sulfur atom reduce the spatial shielding near the reactive center, thus yielding lower $%V_{Bur}$ values compared to more substituted imidazol-2-ylidenes. For example, the CuCl complex of 3-(Dipp)thiazol-2-ylidene exhibits a $%V_{Bur}$ of 37.0%, which is markedly lower than the 47.6% observed for the corresponding 1,3-bis(Dipp)imidazol-2-ylidene complex.[59]

This steric openness may facilitate substrate access to the catalytic site or alter transition state stabilization, thereby contributing to the observed selectivity and reactivity patterns in NHC-mediated organocatalysis. In 2011, Glorius applied this model to thiazolium-derived carbenes.[60] As for other NHC ligands, $%V_{Bur}$ values are mostly related to the steric bulk of the N-substituent on the thiazole ring (e.g., Dipp vs Mes), as shown in Figure 4. Interestingly, variations at the C-4 and C-5 positions of the thiazolium backbone do not significantly impact the $%V_{Bur}$ values.

As we discussed in the previous section, one of the most characteristic properties of NHCs is their pronounced electron-richness. The characterization of the electronic properties of NHCs is once again addressed through the preparation and analysis of their corresponding metal complexes. These systems provide a robust platform to probe donor abilities via spectroscopic,

<figure><img src="image_31.png" /></figure>

Phosphine
cone-shaped

<figure><img src="image_32.png" /></figure>

A, NHC
umbrella-shaped

<figure><img src="image_33.png" /></figure>

B, Thiazole-like NHC
half-umbrella-shaped

<caption>**Figure 2.** Steric properties of NHCs and phosphines.</caption>
<figure><img src="image_34.png" /><figcaption>**Figure 4.** %V<sub>Bur</sub> for selected thiazolium salts by Glorius. Based on modified CIF files from X-ray crystals from perchlorate salts.[60] Mes = mesityl (2,4,6-trimethylphenyl) group. Dipp = 2,6-diisopropylphenyl group.</figcaption></figure>

<figure><img src="image_35.png" /><figcaption>**Figure 5.** TEP measurement with thiazole-based NHC as ligands.</figcaption></figure>

<figure><img src="image_36.png" /><figcaption>**Scheme 23.** Synthesis of complexes **34** by Glorius for TEP measurements.[60]</figcaption></figure>

electrochemical, and computational methods, thereby allowing a deeper understanding of how subtle structural changes in the carbene backbone or its substituents influence its electronic profile. Among these methods, the measurement of the electron-donating or electron-withdrawing ability of a ligand by infrared spectroscopy (IR),

commonly referred to as Tolman's Electronic Parameter (TEP), has been widely applied, including to NHCs. Following Tolman's original rationale developed for phosphine ligands,[61] an electron-rich NHC ligand enhances the electron density at the metal center, which in turn increases π-backdonation into the π* antibonding orbital of a coordinated carbonyl ligand (Figure 5). This effect can be observed by IR, with a decrease in the effective bond order of the carbonyl ligand (i.e., lower frequency A₁ vibration in the spectrum IR of the complex). Comparison of IR spectra of different NHC-metal complexes offers an indirect evaluation of the relative electron-donating capacity of NHC ligands. Reliable results are obtained through analysis of the CO stretching frequencies of [(L)Ni(CO)₃], [(L)Rh(CO)₂Cl], and [(L)Ir(CO)₂Cl].

To further evaluate the donor strength of thiazol-2-ylidene ligands, Glorius prepared a small collection of iridium(I) carbonyl complexes of the type [(NHC)Ir(CO)₂Cl] (34a-d), featuring various thiazol-2-ylidene scaffolds (Scheme 23).[60] IR analysis of these complexes provided the corresponding TEP values, which indicated that these ligands possess fairly similar electronic properties. While these thiazol-2-ylidenes can be considered relatively electron-rich, comparison with classical imidazol-2-ylidene ligands revealed a clear difference: their electron-donating ability is consistently lower. For instance, benchmark TEP values for IMes and IPr were reported at 2049.6 and 2050.2 cm⁻¹, respectively, whereas the thiazol-2-ylidenes showed systematically higher stretching frequencies, confirming that they are among the least electron-rich carbenes within the NHC family (Figure 6). These results are consistent with the calculations of Dupré and Wong who reported the higher electron delocalization among related imidazol-2-ylidenes.[47c]

Recently, by measuring the TEP values of N-aryl thiazol-2-ylidene and imidazol-2-ylidene complexes of Rh(I), Ag(I), and Cu(I), Zhang, Fang, and Szostak confirmed this trend.[59] For instance, the TEP of [(34b)Rh(CO)₂Cl] was determined to be 2053.6 cm⁻¹, slightly higher than that of its imidazol-2-ylidene analog [(IPr)Rh(CO)₂Cl] (2050.2 cm⁻¹), highlighting the slightly lower electron-donating ability of thiazol-2-ylidene ligands compared to imidazol-2-ylidenes. In contrast, they observed that thiazol-2-ylidenes are better π-accepting

<figure><img src="image_37.png" /><figcaption>**Figure 6.** Carbonyl stretching frequencies (TEP values) for IMes, IPr, and thiazolium-based NHCs **34**.</figcaption></figure>
<figure><img src="image_38.png" /><figcaption>**Figure 7.** a) σ and π interactions between a NHC ligand and a transition metal. b) σ and π interactions between a NHC and adjacent N and S atoms. c) LUMO/HOMO level comparison between thiazolylidene and imidazolylidene.</figcaption></figure>

ligands than the imidazol-2-ylidene carbenes. The reduced σ-donating and enhanced π-accepting character can be attributed to the lowering of both HOMO and LUMO energy levels (Figure 7c) relative to conventional imidazol-2-ylidene carbenes.[62,63] While these frontier orbital considerations are typically derived from coordination chemistry, they offer valuable insights into how thiazol-2-ylidenes may perform as organocatalysts. However, if N-aryl thiazol-2-ylidenes emerge as π-accepting, σ-donating, and sterically less demanding (“half-umbrella”-shaped) ligands, ideally suited to promote electrophilic catalysis in purely organic contexts (Figure 7), such properties alone cannot fully explain their behavior in organocatalyzed processes.[60] The π-donating ability of the carbene, particularly relevant in the formation and stabilization of the BI, must also be taken into account.

In 2021, Brimble published the synthesis, the stereochemical- and the electronic quantification, of novel (35-38) and known thiazole-based NHC organocatalysts (Figure 8).[64] By comparing the %V<sub>Bur</sub> values, the authors

<figure><img src="image_39.png" /><figcaption>**Figure 8.** Stereoelectronic quantification for comparison of NHC organocatalysts by Brimble.[64] For an application, see Section “Intermolecular Stetter Reaction.”</figcaption></figure>
were able to identify a clear trend in steric demand around the carbene center (37 >> 35 ≈ 36 > 38); precatalyst 38 being both the least sterically hindered and the least σ-donating among the new precatalysts (35-38). Despite the highly-encumbered N-mesityl group, the almost perpendicular orientation relative to the thiazole heterocycle results in low steric bulk near the active catalytic site.

The electronic quantification was performed using a ¹H NMR method developed by Szostak and Nolan for determining the σ-donor properties of NHCs.[65] The one-bond CH J-coupling value (¹J<sub>CH</sub>) is related to the hybridization of the carbon atom involved. The ¹J<sub>CH</sub> obtained from ¹³C satellites of the ¹H NMR spectrum provide good indication of the electronic properties of an NHC ligand, and higher ¹J<sub>CH</sub> constants correspond to poor σ-donating properties of NHC ligands. The four N-aryl thiazolylidenes synthesized (35-38) are stronger σ-donors compared to imidazolylidene and triazolylidene analogs. From these studies, N-mesityl thiazolylidene catalyst 38 (highlighted in blue in Figure 8) has been identified as an efficient catalyst for an aliphatic Stetter reaction (vide infra, Section “Intermolecular Stetter Reaction”).

### 4.3. Stability and Nucleophilicity of the Breslow Intermediate

Mayr and coworkers performed DFT calculations on the Lewis basicity of various NHCs, specifically, imidazole-, imidazoline-, and triazole-based carbenes, by evaluating their methyl cation affinities (MCAs).[66] These values revealed that all tested NHCs are substantially more Lewis basic than traditional Lewis bases such as PPh₃, DMAP, or DBU, which may partly account for their pronounced nucleophilic behavior in typical NHC-mediated transformations. However, in contrast to carbenes issued from imidazoles and triazoles, there is no experimental data on the intrinsic nucleophilicity of thiazolium-type NHCs. To the best of our knowledge, only the O-methylated **BIs 18a** and **18b** have been investigated using the stabilized benzhydrylium ion **39** as the reference electrophile (**Scheme 24**).[40] Compound **18a**, bearing two methyl groups, exhibits significantly higher nucleophilicity, with a reactivity increased by a factor of ≈2700 compared to its benzoannelated analog **18b**, in which electron density is delocalized over the extended aromatic system. This high reactivity places **18a** on a par with the imidazolylidene-derived enol ether **41** and markedly above that of the triazolylidene **42**. In the latter case, the reduced nucleophilicity is likely due to the electron-withdrawing effect of the additional nitrogen atom in the triazole ring, as well as the substitution of NMe groups with NPh moieties, both of which lower the electron density at the carbene center.

A computational comparison by DFT at the B3LYP/6-311+G* level of theory of imidazole-2-ylidene, triazol-3-ylidene, and thiazol-2-ylidene as catalysts for the benzoin condensation revealed that the **BI** derived from thiazol-2-ylidene is ≈10 kcal mol⁻¹ more stable

<figure><img src="image_40.png" /><figcaption>**Scheme 24.** Nucleophilicity of **18** toward **39** in THF at 20 °C.</figcaption></figure>

than those from the other two carbenes.[67] This enhanced thermodynamic stability increases the barrier for the coupling of the second aldehyde molecule, thereby extending the lifetime of the **BI**. This feature plays a key role in cross-benzoin reactions: while imidazole- and triazole-based carbenes tend to yield product distributions governed by statistical factors, the prolonged lifetime of the **BI** in the case of thiazolium-derived catalysts enables kinetic selectivity, favoring the formation of the most stable cross-benzoin product (see Section 6.1.2). This mechanistic rationale accounts for the high selectivities observed experimentally, sometimes up to 100%, in cross-benzoin condensations exclusively catalyzed by thiazol-2-ylidenes.

### 4.4. Redox Properties of Thiazolium-Based Breslow Intermediates

Since the seminal works of Studer[68] and Rovis,[69] NHC-catalyzed radical reactions have flourished (vide infra, Section 6.2), highlighting the unique redox properties of the **BIs** involved in these reactions. It has been shown that Breslow enol derivatives **I** are weak reductants, contrary to their enolate counterparts **II**.[31] These enolates can undergo two consecutive SET oxidations: the first leads to the persistent radical intermediate **III**, and the second to the acyl (thi)azolium salt **IV** (**Scheme 25a**). The persistent radical intermediate **III** is highly stabilized due to the heterocyclic mesomeric effects and was characterized by electron paramagnetic resonance (EPR) spectroscopy.[30a,70–72] EPR/computational data on radicals **III** have been described and discussed by Rehbein and Fuzukumi.[30a,70] Radicals **III** can also be prepared independently (and characterized) by in situ zinc reduction of acyl-azoliums obtained from acyl chlorides and NHCs (Scheme 25b).[73,74] It has also been suggested by DFT studies that both mesomeric forms **IIIa** and **IIIb** could differently react with a transient radical to give alkenes 1,2-diacylation products.[73]

The redox behavior of thiazolium-based Breslow enolates **II** was first investigated by Fukuzumi in 1998 using cyclic voltammetry.[70,71] Two successive and reversible
<figure><img src="image_41.png" /><figcaption>**Scheme 25.** a) Two SET steps for the oxidation of enolates II to the corresponding cations IV. b) Synthesis of type III radicals from acyl chlorides.</figcaption></figure>

one-electron oxidation peaks were recorded at approximately $E_1 = -0.9$ V and $E_2 = -0.4$ V (vs SCE, at 298 K). However, these values were later questioned in the context of NHC-catalyzed radical transformations, which often require reduction potentials more negative than -1.4 V. To clarify this, Tomás-Mendivil and Martin

reinvestigated the reduction potentials of the corresponding acyl thiazoliums IV (i.e., the oxidized form of the enolates), using isolated and well-characterized compounds.[72] In a comprehensive study involving more than 60 acyl thiazolium derivatives, two main reduction waves were identified at -0.6 and -1.4 V, respectively (Figure 9), thus consistent with a two-electron reduction pathway converging to the enolate species II. The apparent discrepancy between Fukuzumi's and Martin's data stems from the nature of the species analyzed and the experimental conditions. In Fukuzumi's work, redox potential values were recorded from enolates II generated in situ from thiazolium salts, aldehyde, and two equivalents of DBU. In contrast, Martin performed reduction measurements on isolated acyl azoliums IV (Scheme 26). Importantly, when two equivalents of DBU·HPF₆ were added to the acyl thiazoliums, the redox behavior matched Fukuzumi's data, illustrating the strong influence of the enolate counterion on the redox potentials.

Breslow enolates II thus appear stronger reducing agents than initially estimated and indeed Martin was able to observe the reaction of iodobenzene (-2.2 V versus SCE) with Breslow enolate IIa (in situ generated by electrolysis of the corresponding radical IIIa) (Scheme 27). Again, no reaction was observed when the reaction was carried out in the presence of DBU·HPF₆.

In 2021, supported by theoretical calculations, Yu reported that ionic and radical structures can coexist and that this is directly associated with the protonation state of the hydroxyl group in the BI.[75] In 2023, Bertrand, Baik, and Yan conducted an extensive computational study on the frontier orbitals and redox potentials of various enolate forms of BIs, derived from

<figure><img src="image_42.png" /><figcaption>**Figure 9.** 1st and 2nd reduction potentials of acyl thiazolium by Martin ($E_{1/2}$ in V vs SCE). *a*Partially irreversible EC process, even at 1 V s⁻¹ scan rate.[72]</figcaption></figure>
<figure><img src="image_43.png" /><figcaption>**Scheme 26.** Generation of enolates II by Fukuzumi and isolated acyl-azoliums IV by Martin.</figcaption></figure>

<figure><img src="image_44.png" /><figcaption>**Scheme 27.** Electrolysis of radical IIIa at -2.2 V versus SCE.</figcaption></figure>

10 different classes of carbenes.[62] By systematically analyzing the different stages of the SET pathway, they identified the key parameters governing each step of the catalytic cycle. Their results indicate that all investigated carbenes possess sufficient nucleophilicity to engage benzaldehyde and generate the corresponding **BI** species. As previously demonstrated, **BI** and its keto tautomer act as very weak oxidants and must be deprotonated, typically by a carbonate base, to generate the corresponding enolate, which is the actual redox-active species. Surprisingly, despite being among the most widely used in SET-based organocatalysis, thiazol-2-ylidenes and 1,2,4-triazolylidenes were found to exhibit the lowest redox potentials among the entire series. As a result, these carbenes are likely to participate in SET processes only in the presence of strong oxidants. However, since oxidation potentials are highly sensitive to reaction conditions, they can be modulated, for instance, by employing apolar solvents or choosing bases that generate large, weakly coordinating cations such as $Cs^+$, which tend to lower the oxidation threshold. Finally, the radical-radical coupling step appears to be the most kinetically challenging event in carbene-mediated oxidative catalysis, due to both electronic and steric constraints. In this regard, thiazol-2-ylidenes and 1,2,4-triazolylidenes outperform more sterically encumbered carbenes such as imidazol-2-ylidenes, as evidenced by their lower %$V_{Bur}$ and more accessible

**BI**' radicals, which facilitate productive radical coupling.

Given the potential for thiazolium carbene dimers **V** to play a role in the formation of **BIs** (vide supra, Section 3), and the recent growth in thiazolium-catalyzed radical reactions (vide infra, Section 6.2), Martin and Tomás-Mendivil have been interested in studying the redox potentials of these dimeric species.[76] Starting from isolated and fully characterized dimers **V** ($R$ = Dipp, Ph, $CH_2fBu$), two consecutive reversible oxidations attributed to the formation of the radical cation $V^{+}$ and dication $V^{2+}$ were observed by cyclic voltammetry (**Scheme 28**). If the observed redox potentials were indeed lower than those measured for Breslow enolates, thiazolium-derived carbene dimers may act as competitive reducing agents. Among them, the Dipp-substituted dimer **Va** exhibits a stronger reducing potential (-0.80 V) compared to its congeners **Vb** and **Vc** bearing Ph and $CH_2fBu$ substituents, respectively. This result was attributed to the importance of the Dipp substituent's hindrance, which enables the amine function to be blocked in a planar structure, thus reinforcing the +M donor character.

<figure><img src="image_45.png" /><figcaption>**Scheme 28.** Redox properties of dimers of thiazol-2-ylidenes by Martin and Tomás-Mendivil.</figcaption></figure>

<figure><img src="image_46.png" /><figcaption>**Scheme 29.** NHC-catalyzed oxindole 44 synthesis via single electron transfer by Martin and Tomás-Mendivil.</figcaption></figure>
Interestingly, these potentials can account for the previously described NHC-organocatalyzed oxindole synthesis described by Wang.[77] Using thiazolium 43 (10 mol%), the oxindole 44 was obtained in 62% yield and the carbene resulting from 43 was initially advocated by the authors to be the single-electron donor in the reaction. However, given that free carbenes remain very weak reducing species, Martin and Tomás-Mendivil proposed that the thiazolium carbene dimer is in fact the active redox NHC organocatalyst. Notably, when the same transformation was performed using the radical cation 43⁺ derived from thiazolium 43, a significantly higher yield (90%) was obtained, supporting the hypothesis that dimerization of the free carbene likely occurs under the reaction conditions (Scheme 29).[76]

In conclusion, the redox potentials of thiazolium-based Breslow enolates account for the observed reactivities in the NHC-catalyzed radical reactions that will be further disclosed (vide infra, Section 6.2).

## 5. Synthesis of Thiazolium Salts as Carbene Precursors

Synthesis of thiazolium-based carbene precursors has already been the subject of dedicated publications. A seminal one that encompasses synthetic routes to azoliums as precarbenes was published in 2011.[78] Some additional methods were subsequently reported in a review devoted to NHCs as organocatalysts.[10b] Here, we intend to give an overview of the main strategies that have been used to prepare thiazolium salts as carbene precursors. Up to date, two paths stand out: the condensation of N-substituted thioformamides with α-haloketones (Scheme 30a), and the intermediary formation of a cyclic thiazoline-2-thione followed by its oxidative conversion under acidic conditions to

<figure><img src="image_47.png" /></figure>

<figure><img src="image_48.png" /><figcaption>**Scheme 30.** Main routes, described to date, to thiazolium salts as carbene precursors. a) Condensation of N-substituted thioformamides with α-haloketones. b) Oxidation of thiazoline-2-thione to thiazolium salts.</figcaption></figure>

the cationic thiazolium (Scheme 30b). However, in special cases (see next section), other pathways have been employed in order to provide conformationally restricted thiazolium salts, by locking into a ring the rotation of the side chain between the nitrogen atom and the C-4 carbon. Some examples will be highlighted on the enantioselective benzoin reaction (vide infra, Section 6.1.1).

### 5.1. Condensation of N-Substituted Thioformamide with an α-Haloketone

First reported by Götze in 1938, the combination of α-chloroketones and N-substituted thioformamides has paved the way to several thiazolium salts.[79] Indeed, Sheehan and Hunneman have used this strategy in 1974, to provide compounds 50 in good yields.[80] The synthesis started with the formation of thioformamides 47 via the reaction between amines 45 with potassium dithioformate 46 (Scheme 31). From these intermediates, thiazolium salts 49 were isolated in moderate yields after a condensation reaction with α-chloroketone 48 followed by an ion-exchange step (Cl⁻ → BF₄⁻). The chloride-to-tetrafluoroborate exchange was crucial to facilitate purification, as recrystallization proved more efficient with BF₄⁻ salts. The strategy was later used by Tagaki to provide optically active thiazolium salts 54–56 derived from L-menthol (Scheme 32).[81]

<figure><img src="image_49.png" /></figure>

Selected examples

<figure><img src="image_50.png" /><figcaption>**Scheme 31.** Thiazolium salts 50 synthesized by Sheehan and Hunneman.[80]</figcaption></figure>
<figure><img src="image_51.png" /><figcaption>**Scheme 32.** Thiazolium salts 54–56 derived from L-menthol by Tagaki.[81] (*) = Stereochemistry not shown.</figcaption></figure>

A similar procedure involving N-formylation of anilines to yield formanilides **57** followed by reaction with phosphorus pentasulfide and 3-chloro-2-butanone **58** in dioxane was reported by Grubbs in 2008 to synthesize 3-aryl-4,5-dimethylthiazolium chlorides **59** (*Scheme 33*).[82] These thiazol-2-ylidene compounds were subsequently evaluated as ligands on ruthenium-based complexes as potential olefin metathesis catalysts.

## 5.2. Oxidation of Thiazoline-2-thione to Cationic Thiazolium Salts

Bach used this approach during the synthesis of N-arylthiazolium salts to study their viability in benzoin and intramolecular Stetter reactions (vide infra, Section 6.1).[83] The syntheses of acyclic and cyclic racemic thiones **62** and **65** started with the condensation of 2-(tert-butyl)aniline **60** with carbon disulfide (CS₂) and haloketones **61** and **64** under basic conditions in DMSO (*Scheme 34*). Then, acid-mediated condensation provided racemic thiazoline-2-thiones that have been further oxidized to the corresponding thiazolium chloride salts.[84] A final ion exchange step (Cl⁻ → ClO₄⁻) gave the expected *rac*-perchlorate salts **63** and **66**.

The method has been successfully transposed to the preparation of the optically pure thiazolium salt **70** from α-bromomenthone **67** and 2-(tert-butyl)aniline **60** (*Scheme 35*). Contrary to the cyclohexanone-derived dithiocarbamate (see Scheme 34), **68** did not spontaneously cyclize to the N,O-acetal, and a

<figure><img src="image_52.png" /><figcaption>**Scheme 33.** Synthesis of 3-aryl-4,5-dimethylthiazolium chlorides **59** by Grubbs.[82]</figcaption></figure>

solvent exchange was mandatory (pentane versus EtOH). Dehydration under acidic conditions provided a mixture of two atropisomers (dr = 97:3), with the anti-isomer **69** as the major product. Oxidation of thione **69** to yield the diastereomerically pure compound **70** required careful optimization to prevent epimerization; the best outcome was achieved using *m*CPBA at low temperature.

The strategy was also employed by Glorius to synthesize mesityl **71** and diisopropylphenyl-derived **72** cycloheptathiazol-3-ium perchlorate salts (*Scheme 36*).[85] These encumbered NHC catalysts were compatible in a multicomponent coupling in the presence of palladium catalyst. Important to mention, mesityl-substituted NHC catalyst **71** was very efficient to promote several challenging transformations such as hydroacylation of unactivated double bonds (for other applications, see Section 6).[86,87] Inspired by the remarkable results of **71** in terms of reactivity, the same group next described the synthesis of many N-arylthiazolium salts **73-78** with variable backbone architectures based on the strategy developed by Bach by simply varying the starting arylamines and α-halo ketones (*Figure 10*).[60]

This remains the most conventional approach for reaching N-aryl substituted precatalysts, which have been used by several groups.[59,84b,88–90] However, reported overall yields are low to moderate, and the use of N-alkyl groups is barely described.
<figure><img src="image_53.png" /></figure>

<figure><img src="image_54.png" /></figure>

<figure><img src="image_55.png" /></figure>

<figure><img src="image_56.png" /><figcaption>**Scheme 34.** Synthesis of racemic thiazolium salts 63 and 66.[83]</figcaption></figure>

<figure><img src="image_57.png" /><figcaption>**Scheme 35.** Synthesis of diastereomerically pure thiazolium salt 70.[83]</figcaption></figure>

More recently, Tomás-Mendivil and Martin reported improved procedures that enabled higher yields, an expanded substrate scope with respect to primary amines, and successful scale-up of the reaction.[91]

<figure><img src="image_58.png" /><figcaption>**Scheme 36.** Thiazolium salts by Glorius.[85]</figcaption></figure>

<figure><img src="image_59.png" /><figcaption>**Figure 10.** Thiazolium salts 73-78 synthesized by Glorius. <sup>a</sup>Overall yields. Mes = [2,4,6-(CH<sub>3</sub>)<sub>3</sub>-C<sub>6</sub>H<sub>2</sub>]; Dipp = [2,6-(iPr)<sub>2</sub>-C<sub>6</sub>H<sub>3</sub>].[60]</figcaption></figure>

Key modifications included the isolation of dithiocarbamate intermediates 79, the substitution of strong bases such as KOH or NaOH by triethylamine (Et<sub>3</sub>N) during the amine-CS<sub>2</sub> condensation step, and the replacement of H<sub>2</sub>O<sub>2</sub>/AcOH by mCPBA for the final oxidation (Scheme 37). However, in the case of precatalysts bearing N-Mes and N-Dipp substituents, better yields were obtained using the previously reported one-pot procedure with NaOH, likely due to the difficulty in isolating the corresponding dithiocarbamate intermediates.[60] In these cases, oxidation in the presence of mCPBA remained the more effective.

The aforementioned methods are the most widely used for synthesizing thiazolium salts as NHC precatalysts. In practice, these procedures are either directly reproduced or slightly modified to accommodate specific reaction compatibility requirements. In any case, they appear to be sufficiently robust to guarantee not only reproducible synthesis, but also the structural diversity necessary to meet the demands of various organocatalytic transformations.
<figure><img src="image_60.png" /><figcaption>**Scheme 37.** Improved procedures for the synthesis of thiazolium salts by Tomás-Mendivil and Martin.[⁹¹] $^a$Overall yields. $^b$79 was scaled up to 5 g with overall yield of 56%. $^c$NR = no reaction.</figcaption></figure>

# 6. Organocatalytic Reactions Enabled by Thiazolium-Based NHCs

In this section, we intend to provide selected examples on key transformations allowed thanks to thiazolylidene NHCs rather than exhaustively describe their use in this field. As stated in the introduction, this class of NHC was the first one to be discovered as potential organic catalysts in umpolung acyl-anion catalysis by analogy with thiamine 1. However, over the years, efforts devoted to the field of NHC organocatalysis paved the way to the design and discovery of novel azolium precatalysts (e.g., imidazolium, imidazolidinium, and triazolium derivatives) that appear, in most cases, more powerful than thiazolium compounds. Nevertheless, thiazolium salts, by their unique structural, electronic, and physical properties, remain ubiquitous NHC precursors providing efficient catalysts for a variety of reactions, and in some cases, the catalyst of choice in dedicated transformations.

## 6.1. Umpolung Acyl-Anion Catalysis

### 6.1.1. Enantioselective Homo-Benzoin Reaction

While Section 3 outlined the historical development of the benzoin reaction, the present section focuses on the

structural evolution of thiazolium salts, alongside the optimization of reaction conditions, with the aim of achieving high yields and enantioselectivities.

In addition to creating a new C—C bond, the formation of a stereogenic center prompted interest in finding novel thiazolium salt precatalysts able to carry out benzoin reaction in an enantioselective manner. Soon after seminal works of Ukai and Breslow (see Section 3), Sheehan has proposed in 1966 the first asymmetric version using chiral precatalyst **87**, albeit with both low yield (9%) and enantioselectivity (22% ee) (**Scheme 38**).[⁸⁰a] A few years later, he described a modified thiazolium salt **88**, which provided better chiral induction (52% ee) but still in very low yield (6%).[⁸⁰b] These preliminary reports were the starting point for the design of second generation chiral thiazolium precatalysts (**54**, **89-94**).[⁸¹,⁹²⁻⁹⁴] Notably, Leeper and Rawal have surmised that the use of constrained chiral bicyclic thiazolium salts could provide a better stereocontrol.[⁹⁴⁻⁹⁶] Accordingly, precatalysts **92–94** were designed to restrict the free rotation of the carbon atom in the side chain directly bonded to the nitrogen atom, by introducing a ring connecting N-3 and C-4. The synthesis of these catalysts, which does not follow the classical methods previously described (vide supra, Section 5), is detailed in **Schemes 39 and 40**. Nevertheless, despite the considerable efforts devoted by this team and others, enantiomeric excesses and conversions remained disappointingly low.

Over the past four decades, the investigation of various thiazolium-based chiral precatalysts in the benzoin condensation has failed to identify a catalyst capable of delivering both high yields and enantioselectivities. The highest reported enantiomeric excess (52% ee) was achieved by Sheehan in 1974, albeit with a poor yield of 6%, using a PhCHO/88/Et₃N ratio of 10:1:≈0.95 equiv. in methanol at 30 °C over 24 h (Scheme 38). As later noticed by Rawal, a significantly improved conversion of 52% was obtained in only 8 h by adjusting the stoichiometry to 10:1:1.1 equiv. and switching to a MeOH/H₂O (1:2.5 v/v) solvent system at 20–23 °C, although the enantioselectivity dropped slightly to 48% ee. In general, the benzoin condensation has proven to be a particularly challenging transformation with thiazolium, being highly sensitive to both the structure of the catalyst and the reaction conditions. To date, triazolium salts remain by far the more effective for this reaction, providing up to 90% yield and >99% ee.[⁹⁷]

To gain deeper insight into the stereochemical outcomes of asymmetric benzoin condensations catalyzed by thiazolium and triazolium salts and to rationalize the discrepancies reported in the literature, some groups have undertaken kinetic, structure-activity, and theoretical studies. Kinetic studies, primarily focused on thiazolium-based systems, have yielded varied and sometimes conflicting data.[²⁹d,e] As highlighted by Leeper and White,[⁹⁸] these discrepancies may arise from
<figure><img src="image_61.png" /><figcaption>**Scheme 38.** Chiral thiazolium salts for enantioselective benzoin condensation.</figcaption></figure>

two key factors: 1) fluctuations in benzaldehyde concentration can influence the reaction order, 2) partial degradation of the catalyst during the reaction may lead to an unaccounted decrease in its effective concentration, 3) the assumption that the reaction proceeds irreversibly is not always justified, and 4) variations in base concentration, often due to the formation of side products such as benzoic acid, can also contribute to the observed

inconsistencies. Consequently, Leeper re-examined the kinetics of the thiazolium ion-catalyzed benzoin condensation.[98] Initial-rate studies were carefully conducted using different concentrations of benzaldehyde (0.1–1.7 M) while maintaining a constant concentration of catalyst **32** (0.03 M). From these studies, they concluded that the reaction is basically first order with respect to benzaldehyde. Further stoichiometric studies and deuterium
<figure><img src="image_62.png" /><figcaption>**Scheme 39.** Synthesis of chiral catalysts **92** and **93** by Leeper.[95]</figcaption></figure>

<figure><img src="image_63.png" /><figcaption>**Scheme 40.** Synthesis of chiral catalysts **94** by Rawal.[96]</figcaption></figure>

labeling allowed the determination of rate constants for each of the three key steps (i.e., formation of **95**, formation of **BI 96**, and attack of **96** to a second benzaldehyde) (**Scheme 41**). It seems that all of them are partially rate-determining. More recently, kinetic and structure-activity studies have been described by O'Donoghue for triazolium-catalyzed benzoin condensation.[99]

In addition, computational studies employing Morokuma's IMOMO-ONIOM method[100] were carried out by Houk and Dudding[101] to investigate the origins of the high stereoselectivity achieved with triazolium catalyst **97**,[102] developed by Enders, in contrast to the significantly lower efficiency observed with the bicyclic

<figure><img src="image_64.png" /><figcaption>**Scheme 41.** Kinetic model with catalyst **32** used by Leeper and White.[98]</figcaption></figure>

<figure><img src="image_65.png" /><figcaption>**Scheme 42.** Catalysts **97** and **98** for computational predictions of stereochemistry in asymmetric benzoin condensation.[101]</figcaption></figure>

thiazolium catalyst **98**,[95] previously synthesized by Leeper (**Scheme 42**). Transition state optimizations and single-point energy calculations showed good agreement between experimental outcomes and theoretical predictions. While the study successfully rationalized the origin of the high and modest stereoselectivities associated with catalysts **97** and **98**, respectively, it also underscored that the subtle energetic differences governing the stability of transition states and the facial selectivity of the incoming aldehyde are extremely delicate and difficult to predict with confidence.

### 6.1.2. Cross-Benzoin/Acyloin Reaction

**Aldehyde-Aldehyde Substrates:** The scope of the homo-benzoin reaction could be expanded by mixing two different aldehydes. Thus, the so-called cross-benzoin/acyloin reaction has also received intensive attention
and several papers on the topic have appeared over the years proposing the synthesis of a broader scope of α-hydroxy carbonyls.[103] However, as demonstrated by Cookson and Lane in 1976 with their report of the first intramolecular cross-benzoin condensation catalyzed by 3-benzyl-4-methylthiazolium chloride **99** (Scheme 43), achieving high chemo- and enantioselectivity in such transformations remains a significant challenge.[104]

Moving to the intermolecular version, controlling selectivity becomes even more difficult, as the use of non-equivalent aldehydes can provide eight products (e.g., four pairs of enantiomers) (Scheme 44).

To address this challenge, careful adjustment of structural and electronic features of both substrates and catalysts, as well as reaction conditions, must be considered. Stetter and Dämbkes provided the first chemoselective intermolecular cross-benzoin reaction by using a three-fold excess of a branched aliphatic aldehyde in combination with a sterically hindered aromatic counterpart.[105] This approach enabled complete selectivity toward α-hydroxy ketones **101** when using 2-chlorobenzaldehyde or 2-thiophenecarboxaldehyde (Scheme 45).

In a more recent work, Connon and Zeitler compared the relative performance of thiazolium **100** and triazolium **103** precatalysts in chemoselective cross-benzoin condensations.[106] While the thiazolium precatalyst proved effective, they demonstrated the superior

<figure><img src="image_66.png" /><figcaption>**Scheme 43.** First intramolecular cross-benzoin reaction by Cookson and Lane in 1976.[104]</figcaption></figure>

<figure><img src="image_67.png" /><figcaption>**Scheme 44.** Possible products formed during intermolecular cross-benzoin reaction.</figcaption></figure>

<figure><img src="image_68.png" /><figcaption>Selected examples</figcaption></figure>

<figure><img src="image_69.png" /><figcaption>**Scheme 45.** Intermolecular cross-benzoin by Stetter and Dämbkes. Chemoselectivity driven by steric factors and an excess of aliphatic aldehyde.</figcaption></figure>

reactivity and selectivity of the triazolium salt, particularly with 4-halo benzaldehydes and branched aliphatic aldehydes (Scheme 46).

Although initial strategies relied on sterically hindered or branched aliphatic aldehydes to ensure selectivity, it was soon realized that simpler aldehydes such as formaldehyde or acetaldehyde could also participate selectively in cross-benzoin condensations. Hydroxymethylation was first reported by Inoue in 1985 using a thiazolium salt.[107] In 2011, Glorius proposed the use of precatalyst **71** to synthesize hydroxymethyl ketones in moderate to high yields with remarkable selectivities and a broad substrate scope (Scheme 47).[108]

That same year, Han, Ryu, and Yang described a switch in regioselectivity in cross-benzoin condensations between aromatic aldehydes and acetaldehyde **105**, depending on the nature of the precatalyst, either a thiazolium salt **106** or a triazolium salt **103**.[109] They found that thiazolium **106** preferentially forms the Breslow intermediate with the aromatic aldehyde, whereas triazolium **103** favors the aliphatic substrate (Scheme 48), demonstrating that the regioselectivity of cross-acyloin condensations between aryl and aliphatic aldehydes can be effectively controlled through rational catalyst design.[110] However, in spite of these advances, enantioselective versions of reactions catalyzed by thiazolium-based NHCs remain scarcely reported in the literature, and as with the homo-benzoin
<figure><img src="image_70.png" /></figure>

<figure><img src="image_71.png" /></figure>

<figure><img src="image_72.png" /><figcaption>**Scheme 46.** Comparison between thiazolium and triazolium salts by Connon and Zeitler.</figcaption></figure>

<figure><img src="image_73.png" /><figcaption>**Scheme 48.** Regioselectivity on NHC-catalyzed cross-acyloin condensation.[109]</figcaption></figure>

<figure><img src="image_74.png" /></figure>

Selected examples:

<figure><img src="image_75.png" /></figure>

<figure><img src="image_76.png" /></figure>

<figure><img src="image_77.png" /></figure>

<figure><img src="image_78.png" /></figure>

<figure><img src="image_79.png" /><figcaption>**Scheme 47.** Hydroxymethylation by Glorius with precatalyst 71.</figcaption></figure>

condensation, triazolium-based precatalysts have proven more effective.[109,110]

Interestingly, high levels of chemoselectivity have also been achieved when both aldehyde partners are structurally similar. In 2001, Golding and Rétey demonstrated that cross-benzoin condensation can be successfully performed between two unhindered aliphatic aldehydes.[111] A decade later, Glorius showed that thiazolium salt **73b** is an efficient NHC catalyst for promoting chemoselective cross-benzoin condensations between benzaldehyde and its 2-substituted analogs (**Scheme 49**).[60] By carefully

fine-tuning the steric hindrance of both the substrates and the catalyst, high selectivity for the cross-coupled product could be attained.

**Keto-Aldehyde Substrates:** The development of selective cross-benzoin reaction between ketones and aldehydes as substrates is challenging as potential side compounds, such as aldol and dimeric benzoin products, can be concomitantly formed (**Scheme 50**). So far, only intramolecular versions have been explored with the aim of minimizing undesirable products.

The first example of a cross-benzoin condensation involving an aldehyde and a ketone was described in 2003 by Suzuki.[112] In this thiazolium-catalyzed intramolecular version, functionalized isoxazoles **109** served as starting materials to afford the cross-coupled products (**Scheme 51a**). Notably, the presence of the isoxazole motif was not essential for the transformation: the corresponding keto-aldehyde **110** lacking this functionality also delivered the expected product **111** in a respectable 65% yield, along with a competing intramolecular aldol product **112** (Scheme 51b). Later on, the scope of the transformation was broadened by using a wide variety of keto-aldehyde substrates.[113–115]

**Imine-Aldehyde Substrates (Aza-Benzoin Reaction):** The synthesis of α-amino- or α-amido-ketones via thiazolium-catalyzed cross-coupling of aldehydes with imines or acylimines was also studied. These transformations require careful selection of both substrates and reaction conditions to favor the desired cross-coupling over competing side reactions, particularly homo-benzoin condensation. In this context, the imine must be sufficiently electrophilic to compete effectively with the aldehyde, while also maintaining stability under the catalytic
<figure><img src="image_80.png" /><figcaption>**Scheme 49.** Chemoselective cross-benzoin condensation by Glorius with **73b**. <sup>a</sup>Isolated yield. <sup>b</sup>Based on <sup>1</sup>H NMR.</figcaption></figure>

<figure><img src="image_81.png" /><figcaption>**Scheme 50.** Different reaction directions and undesired possible side compounds.</figcaption></figure>

conditions. For example, imine substrates must be reactive enough to compete with undesirable benzoin condensation, and sufficiently stable under the reaction conditions and with respect to the catalyst.

The concept was first studied by Murry and Frantz in 2001 who used tosylamides **113** as practical precursors of acylimines.[116] Under optimized reaction conditions, and in the presence of thiazolium precatalysts, amido ketones **114** were isolated in good yields (**Scheme 52**). The mechanism involved is similar to the one proposed for benzoin

Selected examples:

<figure><img src="image_82.png" /><figcaption>**Scheme 51.** Intramolecular aldehyde-ketone benzoincondensation by Suzuki. a) With functionalized isoxazoles **109** and b) with keto-aldehyde **110**.</figcaption></figure>

condensation. The authors mentioned that the corresponding benzoin products were not observed suggesting that the process proceeds under kinetic rather than thermodynamic control. In 2007, You developed the cross-coupling of aromatic aldehydes with unactivated imines.[117] Experimental observations, by engaging benzoin substrate instead of benzaldehyde, suggested that this work was markedly different to the one reported by Murry as the expected product was obtained in comparable yields. In addition, α-amino-ketone formation was reversible in the conditions reported by You. Thus, the reaction in this case is likely to proceed, to some extent, under thermodynamic control. The work was illustrated with the synthesis of many α-aminoketones in moderate to good yields. The hypothesis about the reversibility of aza-benzoin reactions and the formation of aza-Breslow intermediates has also been studied by Bode and Rovis.[118,119]
<figure><img src="image_83.png" /></figure>

Selected examples:

<figure><img src="image_84.png" /><figcaption>**Scheme 52.** Thiazolium-catalyzed cross-coupling of aldehydes and acylimines derived from tosylamides.</figcaption></figure>

Building on the concept developed by Murry, an enantioselective version of the transformation was disclosed in 2005 by Miller, who employed a peptide-derived thiazolium salt **115** as precatalyst (**Scheme 53**).[120] Achieving high enantiocontrol required specific conditions to prevent racemization, notably the use of hindered bases and short reaction times. Interestingly, the authors observed an isotope effect associated with product enantioselectivity: when a deuterated tosylamide substrate was used, the enantiomeric excess of the product was significantly higher than with the nondeuterated analog, highlighting a subtle yet impactful role of the substrate structure on stereocontrol.

To rationalize the observed enantioselectivity, the authors proposed a bifunctional catalytic mechanism involving the formation of two putative transition states, **TS-116** and **TS-117**. Within the chiral environment provided by the peptide-derived catalyst, these transition states are believed to arise from a dual activation mode: while the acyl anion equivalent is generated through reaction of the aldehyde with the thiazolium catalyst, the *N*-acylimines, formed in situ from tosylamide precursors, are concurrently activated via hydrogen bonding within the catalyst's chiral pocket (**Scheme 54**).

The synthetic utility of the aza-benzoin reaction has also been showcased in more complex transformations. For instance, Massi and De Risi elegantly implemented it in a domino sequence combining aza-benzoin condensation/aza-acetalization providing access to functionalized imidazolidine-2-thiones **118** (**Scheme 55**).[121] In a complementary approach, Rovis proposed, in 2012, the use of versatile *N*-Boc protected imines as well-suited substrates

<figure><img src="image_85.png" /></figure>

Selected examples:

<figure><img src="image_86.png" /><figcaption>**Scheme 53.** Aza-benzoin reaction catalyzed by a peptide-derived thiazolium salt.</figcaption></figure>

<figure><img src="image_87.png" /><figcaption>**Scheme 54.** Putative transition states for the peptide catalyzed aza-benzoin reaction. $R_L$ = Lateral chain.</figcaption></figure>

for a highly enantioselective cross-aza-benzoin reaction with aliphatic aldehydes in the presence of triazolium salts.[122] For the use of acylsilanes as carbonyl anion precursors, see Section “Sila-Stetter Reaction”.

**Biocatalytic Homo- and Cross-Benzoin Condensations:** Beyond purely chemical strategies, lyases capable of forming or cleaving C—C bonds are attracting growing interest in biotechnology due to their potential for producing enantiomerically pure intermediates. In this context, ThDP-dependent lyases, such as acetolactate synthase and benzaldehyde lyase (BAL) are of particular interest. BAL was first isolated from *Pseudomonas* species capable of using benzoin as their only carbon source, where it catalyzes the reversible breakdown of benzoin into two benzaldehyde molecules.[123] Under conditions of benzaldehyde excess, BAL also promotes the stereoselective coupling of benzaldehyde to form
<figure><img src="image_88.png" /><figcaption>**Scheme 55.** Synthesis of imidazolidine-2-thiones **118** via aza-benzoin condensation/aza-acetalization domino reactions.</figcaption></figure>

(R)-benzoin, a valuable chiral building block in pharmaceutical synthesis.[124] Studies have expanded the known substrate range of BAL to other aldehydes.[125] Notably, aromatic as well as aliphatic aldehydes are accepted by the enzyme yielding either benzoins as products of self-condensation of the aromatic aldehydes or α-hydroxy ketones by carboligation of aromatic and aliphatic aldehydes.[126]

In such a context,[127,128] in 2017, Clapés explored an intramolecular version of benzoin condensation using the (ThDP)-dependent benzaldehyde lyase from *Pseudomonas fluorescens* biovar I.[129] In this study, several (pseudo-)dimeric benzaldehyde substrates **119** were investigated. As one can expect for enzymatic transformations, high yields and

<figure><img src="image_89.png" /><figcaption>Selected examples</figcaption></figure>

<table><caption>**Scheme 56.** BAL-catalyzed intramolecular benzoin condensation. ND = not determined.</caption><tr><td>X = Y = H</td><td><b>120a</b></td><td>77% yield (90% ee)</td></tr><tr><td>3-X = 3-Y = OMe</td><td><b>120b</b></td><td>67% yield (98% ee)</td></tr><tr><td>5-X = 5-Y = OMe</td><td><b>120c</b></td><td>84% yield (98% ee)</td></tr><tr><td>3-X = 3-Y = Cl</td><td><b>120d</b></td><td>61% yield (64% ee)</td></tr><tr><td>5-X = Cl; 5-Y = H</td><td><b>120e/121e</b> 2:3</td><td>58% yield (ND)</td></tr><tr><td>5-X = Br; 5-Y = H</td><td><b>120f/121f</b> 1:1</td><td>65% yield (ND)</td></tr></table>

<figure><img src="image_90.png" /><figcaption>**Scheme 57.** Kinetic resolution of rac-122 under enzymatic conditions.</figcaption></figure>

<figure><img src="image_91.png" /><figcaption>Selected examples:</figcaption></figure>

<figure><img src="image_92.png" /><figcaption>**Scheme 58.** α,β-Unsaturated aldehydes as donor partners in cross-benzoin reactions. <sup>a</sup>Yields according to GC-MS; reaction performed on an analytical scale (1.5 mL). <sup>b</sup>Isolated yields; reaction performed in preparative scale (100 mL). <sup>c</sup>Conversion according to NMR; reaction performed on an analytical scale (1.5 mL). <sup>d</sup>Reaction performed on a 50 mL scale.</figcaption></figure>
<figure><img src="image_93.png" /><figcaption>**Scheme 59.** One-pot, two-step enzymatic process involving hydroxymethylation and asymmetric reductive amination to reach 1,2-amino alcohols. IREDs = imine reductases.</figcaption></figure>

enantioselectivities were attained in the presence of symmetrical substrates (X = Y in **119**). In contrast, a mixture of regioisomers was observed with unsymmetric compounds (**Scheme 56**). The transformation is also very substrate dependent as no reaction was detected with phenylacetaldehyde, thiophene-2-carbaldehyde, 1- and 2-naphthaldehyde moieties, and compounds with modifications in the linker.

In 2018, Müller envisioned the use of BAL enzyme for the synthesis of chiral tetrol **124** by means of chemoenzymatic C—C bond formation followed by stereoselective reduction.[130] Kinetic resolution of the glyceraldehyde acetonide **122** was performed with a remarkable selectivity albeit in low yield (**Scheme 57**).

The same group has also developed a cross-benzoin reaction where α,β-unsaturated aldehydes react as donors in the presence of acetaldehyde, acetaldehyde derivatives, or formaldehyde as acceptors.[131] A perfect regioselectivity toward the 1,2-addition into the donor aldehydes is observed. Condensation between cyclohex-1-enecarbaldehyde and acetaldehyde derivatives provided the expected products **125** and **126** in low yields albeit in excellent enantioselectivities (**Scheme 58**).

Another elegant report on chemical diversity made possible thanks to biocatalytic processes was described by Zhu, Wu, and Yao in 2022.[132] They proposed an

asymmetric synthesis of N-substituted 1,2-amino alcohols starting from aldehydes and amines via a sequential hydroxymethylation (i.e., the cross-benzoin condensation of formaldehyde with other aldehydes) followed by an asymmetric reductive amination in the presence of imine reductases (IREDs) (**Scheme 59**). Even though the first step neither provides a new stereogenic center nor presents issues associated with chemoselectivity, this wise combination of enzymes renders the transformation quite appealing toward chiral 1,2-amino alcohols.

### 6.1.3. Stetter Reaction

Beyond the scope of imine and ketone electrophiles, the reactivity of the Breslow intermediate was further exploited by engaging alternative acceptors. Notably, by replacing the acceptor aldehyde of the benzoin condensation with an α,β-unsaturated compound, a novel C—C bond can be formed via a 1,4-addition (conjugate addition). This transformation, known as the Stetter reaction, involves the in situ generation of a nucleophilic **BI** and enables direct access to synthetically valuable 1,4-dicarbonyl compounds (**Scheme 60**). It has evolved in parallel to benzoin and cross-benzoin transformations, and countless reports have arisen since its discovery in 1973.[133] Many reviews and books appeared over the years devoted to the subject.[134,135] In the following section, we intend to provide a concise yet representative overview of the evolution of thiazolylidene-like NHCs on the Stetter reaction, highlighting key improvements in catalyst design, substrate scope, and asymmetric induction.

**Intermolecular Stetter Reaction:** First reported in 1973 under the catalytic stimulus of cyanide ions,[133a] the use of thiazolium salts as suitable precatalysts soon followed.[133b] Since then, this transformation has garnered considerable attention; nevertheless, to date, only one example of a chiral thiazolium precatalyst has been reported in an intermolecular version.[136] Notably, successful enantioselective versions of the intermolecular Stetter reaction typically require β-substituted Michael acceptors (see Scheme 60, group R⁶ ≠ H), which often exhibit diminished reactivity

<figure><img src="image_94.png" /><figcaption>**Scheme 60.** NHC-catalyzed Stetter reaction. EWG = electron-withdrawing group.</figcaption></figure>
due to steric hindrance and/or electronic deactivation. However, as observed in the benzoin reaction, triazolium salts have here also shown their superiority.[137]

The first enantioselective intermolecular Stetter reaction, and to date the only one with a chiral thiazolium precatalyst, was reported by Enders in 1993.[136] Enders showed that the combination of *n*-butanal **127** as donor substrate with chalcone **128** as the acceptor provides the expected 1,4-diketone product **130** in 30% isolated yield and 40% *ee* (Scheme 61). Soon after this seminal work, Enders and others have embarked on studies seeking to more powerful catalysts, including triazolium derivatives and broader substrate scope.[137]

Building on these early studies, a significant extension of the reaction scope was disclosed in 2006 by Scheidt, who reported the use of nitroalkenes as Michael acceptors in the Stetter reaction.[138,139] In this contribution, silyl-protected thiazolium carbinols reacted through nucleophilic addition into nitroalkenes promoted by a fluorine anion/thiourea combination to afford *β*-nitroketones (Scheme 62; for other Sila-Stetter reactions, see Section “Sila-Stetter Reaction”). Notably, in an effort to render the transformation enantioselective, the use of chiral thiourea **131** as an additive, intended to create a chiral environment around the nitroolefin, enabled the isolation of the optically active *β*-nitroketone **134** in 67% yield and 74% *ee* (Scheme 63).

Scheidt's work on the use of thiazolium carbinols as nucleophiles in conjugate addition to nitroolefins was the starting point for subsequent developments.[139] In 2009, You reported the combination of arylsulfonyl indoles as Michael acceptors with aldehydes, mainly aromatic ones, to give α-(3-indolyl) ketones in good yields through thiazolium-based NHC catalysis.[140] One enantioselective example, by using a chiral triazolium salt, was also described.

In 2010, Hong proposed a sequential organocatalytic Stetter and Michael-aldol condensation reaction giving access to entirely substituted cyclopentenes **135** (Scheme 64).[141] The transformation was ensured by merging thiazolium salt for the NHC-catalyzed Stetter reaction with Jørgensen-Hayashi catalyst to promote the subsequent Michael-aldol condensation step. The

<figure><img src="image_95.png" /><figcaption>**Scheme 61.** First asymmetric intermolecular Stetter reaction by Enders.[136]</figcaption></figure>

<figure><img src="image_96.png" /><figcaption>**Scheme 62.** Protected thiazolium carbinols on Stetter reactions with nitroalkenes by Scheidt.[138]</figcaption></figure>

<figure><img src="image_97.png" /><figcaption>**Scheme 63.** Enantioselective Stetter reactions with nitroalkene **133**, thiazolium carbinol **132**, and chiral urea **131** by Scheidt.[138]</figcaption></figure>

authors have shown that moving to heteroaromatic aldehydes as donor partners, it was possible to synthesize fully substituted cyclopentanols **136** bearing a tetrasubstituted stereocenter.[142]

Soon after, Liu reported a NHC-catalyzed C-glycosylation of 2-nitroglucal using **32**.[143] It has been observed that by changing the nature of the base used (DIPEA vs Cs₂CO₃), the transformation gives a selective *β*-addition or nitro-elimination (compounds **137** or products **138**, respectively) (Scheme 65). In 2016, Cheng proposed the combination of aromatic aldehydes with (*E*)-(2-nitrovinyl)cyclohexane as suitable substrates for intermolecular Stetter reaction.[144] As first introduced by Scheidt in 2006, the use of a thiourea in combination
<figure><img src="image_98.png" /></figure>

<figure><img src="image_99.png" /></figure>

<figure><img src="image_100.png" /><figcaption>**Scheme 64.** Sequential Stetter and Michael-aldol reactions with nitroalkenes for the synthesis of cyclopentenes **135** and cyclopentanols **136** fully substituted.[141,142]</figcaption></figure>

with a thiazolium salt provided *β*-nitro ketone products in moderate to good yields.

The use of *α*,*β*-unsaturated sulfones as Michael acceptors was successfully introduced by Biju in 2012.[145] Thanks to the combination of thiazolium **71** and tBuOK as base, γ-keto sulfones **139** were selectively prepared in good yields (**Scheme 66**). Catalyst **71** was also employed by Mhaske during the synthesis of succinimide derivatives by merging aromatic aldehydes with either N-substituted itaconimides[146] or maleimides.[147] In 2020, Desvergnes published a bio-inspired version under aqueous conditions where several aromatic and aliphatic aldehydes were condensed on chalcone, yielding the expected 1,4-diketones in moderate to good yields.[148]

<figure><img src="image_101.png" /></figure>

<figure><img src="image_102.png" /><figcaption>**Scheme 65.** Thiazolylidene-catalyzed C-glycosylation.[143]</figcaption></figure>

<figure><img src="image_103.png" /></figure>

<figure><img src="image_104.png" /><figcaption>**Scheme 66.** Intermolecular Stetter reaction with *α*,*β*-unsaturated sulfones as Michael acceptors.[145]</figcaption></figure>

The catalytic potential of catalyst **38** (for its steric and electronic properties, see Section 4.2, Figure 8) and thiamine analog **32** in an intermolecular Stetter reaction involving aliphatic aldehydes and sterically hindered unactivated *α*-quaternary enone acceptors was studied by Brimble in 2021 (**Scheme 67**).[64] Overall, catalyst **38** outperformed thiazolium **32** in terms of both reaction
kinetics and yields. These findings led to the conclusion that the remarkable reactivity of **38** in this transformation arises from a fine-tuned combination of steric and electronic properties.

In 2011, Massi presented the use of 2,3-butanedione (biacetyl) as an effective substitute for acetaldehyde to be used as acyl anion in the Stetter reaction.[149] Thiazolylidene-NHC promoted scission of 2,3-butanedione and condensation with various α,β-unsaturated acceptors to give direct access to diketone products in moderate to good yields. The method effective under conventional heating (50 °C) was considerably accelerated under microwave activation (100 °C). Diketone-type substrates as acyl anion surrogates were thereafter extended with the publication of Takaki in 2014 who explored the behavior of benzils and enones under thiazolium-based NHC catalysis.[150] In aprotic solvents, double acylation products were obtained instead of the classical hydroacylation products, generally formed in the classical Stetter reaction. Later on, this extension of the Stetter reaction was transposed to the synthesis of triacylated alkenes by switching from enone to ynone acceptors (Scheme 68).[151]

The transformations take place under a mechanism involving the formation of monoacylated **BI 140** by addition of the catalyst to the benzil derivative. Migration of a first benzoyl group provides the nucleophilic species **141**, which is prone to react with either the enone or ynone substrate. A second benzoyl group migration to the α-position of enone or ynone derivative with concomitant elimination of the catalyst gives the expected triketones or triacylated alkenes (Scheme 69).

<figure><img src="image_105.png" /></figure>

Selected examples:

<figure><img src="image_106.png" /><figcaption>**Scheme 67.** Intermolecular Stetter reaction with catalysts **32** and **38**.[64]</figcaption></figure>

<figure><img src="image_107.png" /><figcaption>**Scheme 68.** Reaction of benzil derivatives with enones and ynones.[150,151]</figcaption></figure>

Polyether-substituted thiazolium ionic liquids were also synthesized and used as precatalysts in intermolecular Stetter reaction.[152] Moreover, the reactivity of thiazolium ionic liquids was also explored under electrochemistry.[153]

Given that the Stetter reaction provides efficient access to highly valuable 1,4-dicarbonyl compounds, it has inspired numerous research groups to develop cascade syntheses leading to heterocycles such as pyrroles, furans, and thiophenes. Kagan and Teo first demonstrated the use of the Stetter reaction to generate suitable 1,4-diones, which were subsequently employed as key intermediates in the synthesis of these heterocycles.[154] Due to the widespread occurrence of such heteroaromatic scaffolds in drug-like molecules and natural products, the cyclocondensation of 1,4-dicarbonyl compounds, readily obtained via the well-established Stetter reaction, has then been extensively explored. For instance, Hu and Ma published, in 2011, the synthesis of 2-aminofuran-3-carbonitriles **144** by combining aromatic aldehydes with acylidenemalonitriles **143** through a cascade reaction involving Stetter reaction and γ-ketonitrile cyclization (Scheme 70a).[155] A tricomponent version involving two distinct aromatic aldehydes and malononitrile **145** was thereafter reported by Yao (Scheme 70b).[156] Acylidenemalonitrile substrates **143** were in situ formed via a Knoevenagel condensation between one aromatic aldehyde and **145** under basic conditions. In 2005, Ma described a thiazolium-mediated multicomponent reaction for the preparation of functionalized 3-aminofurans.[157] The transformation involves over-stoichiometric amounts of thiazolium salts in the presence of aldehydes and dimethyl acetylenedicarboxylate (DMAD).

In 2013, Chi reported an original NHC-activation of biomass-based carbohydrates to generate a formaldehyde equivalent in the one-carbon acyl anion
<figure><img src="image_108.png" /><figcaption>**Scheme 69.** Proposed mechanism by Takaki for the synthesis of triketones.</figcaption></figure>

<figure><img src="image_109.png" /></figure>

<figure><img src="image_110.png" /><figcaption>**Scheme 70.** Synthesis of 2-aminofuran-3-carbonitriles [144]. [155,156]</figcaption></figure>

a) Hu and Ma in 2011; b) Yao in 2011.

intermediate **148** (Scheme **71**). [158] The formation of **148** involves a retro-benzoin-type process through a C—C bond cleavage of the carbohydrate precursor. Among the carbohydrates considered (e.g., glucose, fructose, galactose, ribose, xylose, cellobiose, sucrose, cellulose), arabinose **146** gave the best results. The β-formyl ketones **149** issued from this Stetter reaction were postfunctionalized as furans and pyrroles in good yields. Following on this work, Glorius reported a one-pot cascade reaction involving a NHC-catalyzed Stetter-type hydroformylation/Paal-Knorr reaction for

<figure><img src="image_111.png" /><figcaption>**Scheme 71.** Carbohydrates as one-carbon nucleophile precursors used in the Stetter reaction. [158]</figcaption></figure>

the synthesis of pyrroles among which a versatile ator-vastatin precursor.[159] In this work, glycolaldehyde dimer was used as acyl anion precursor.

Coelho proposed the synthesis of highly functionalized 1,4-dicarbonyl compounds via intermolecular Stetter reactions on Morita-Baylis-Hillman adducts in the presence of several aldehydes.[160] The products were used in the synthesis of tri-substituted 5-membered heterocycles as furans, pyrroles, and thiophenes. Likewise, 1,4-dicarbonyl substrates, issued from a Stetter reaction between chalcone and aldehydes, were also employed as starting point to the synthesis of triazole linked pyrrole derivatives as potent *Mycobacterium tuberculosis* inhibitors.[161] The synthesis of bi- and terthiophenes was proposed by Müller via a Stetter reaction into thienyl-substituted 1,4-diketones.[162] These compounds displayed significant blue and blue-green fluorescence upon UV light excitation. Müller also published a one-pot three-step three- or four-component method for the synthesis of highly substituted furan and pyrrole fluorophores via a coupling/isomerization/Stetter and coupling/isomerization/Stetter/Paal-Knorr sequences.[163] Kirschning introduced the use of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO) as suitable precursor for β-substituted α,β-unsaturated trifluoromethyl ketones that can be engaged on intermolecular Stetter reaction in the presence of aromatic aldehydes.[164] In addition to provide a good entry to trifluoromethyl-substituted heteroarenes, the method was illustrated with a short synthesis of the COX-2
inhibitor Celebrex (celecoxib). Other functionalized 1,4-diketone derivatives were also developed and studied on cyclization reactions toward heterocyclic compounds.[165] An example of biomimetic Stetter reaction was reported in 2018 combining sensitive nucleoside-type biomolecules as the donor partners with α,β-unsaturated ketones as the Michael acceptors.[166] Original nucleolipids, such as a pyrrole-triazole glycosynucleolipid suitable for biomedical purposes, were attained thanks to this bio-inspired approach.

The diastereoselective synthesis of highly functionalized indanes via a domino Stetter–Michael reaction was published in 2009 by Gravel.[167] The transformation relies on the combination of tethered α,β-unsaturated ketones **150** as acceptors with aromatic aldehydes as donors in the presence of precatalyst **151** (Scheme **72a**). Similarly, Ye described in 2010 the preparation of 3-substituted-4-hydroxytetralones by merging phthalaldehyde **153** and α,β-unsaturated ketones (Scheme 72b).[168] The transformation takes place via a cascade Stetter/aldol reaction catalyzed by thiazolium salt **32**. One year later, the same group published the diastereoselective synthesis of 2,2-disubstituted-3-hydroxyindanones via a [4 + 1] annulation of phthalaldehyde and 1,2-diactivated Michael acceptors, a tandem process involving a Stetter reaction/proton shift/aldol reaction.[169] In the same vein, Grabel reported the synthesis of bis-indanes via a domino Stetter/aldol/Michael and Stetter/aldol/aldol reaction.[170] This work provided the expected products with up to four contiguous stereogenic centers. In 2019, Sarkar and Maiti described thiazolium-based NHC catalyzed dual Stetter and Stetter-cascade reactions to give

<figure><img src="image_112.png" /></figure>

<figure><img src="image_113.png" /><figcaption>**Scheme 72.** Synthesis of indanes **152** and tetralones **154** involving intermolecular Stetter reactions.[167,168] a) Gravel in 2009. b) Ye in 2010.</figcaption></figure>

naphthoquinones, sugar-based naphthoquinones, and dihydroisoflavanones.[171] Two years later, Maiti published Stetter/aldol and imino-Stetter/aldol domino cyclizations to synthesize naphthalene-1(2H)-ones and isoquinolines.[172]

**Intramolecular Stetter Reaction:** The first example of intramolecular Stetter reaction was published in 1995 by Ciganek who reported the synthesis of esters of 2,3-dihydro-3-oxobenzofuran-2-acetic acid **155** and 2,3-dihydro-4-oxo-2H-1-benzopyran-3-acetic acid **156** (Scheme **73**).[173] The use of Et₃N as base, that is traditionally employed in Stetter reactions, was somehow deleterious in the presence of some substrates, likely due to product decomposition. Instead, reactions were generally conducted in refluxing dimethylformamide (DMF), which acted both as solvent and mild base, sufficient to initiate the reaction without compromising product stability. This early work paved the way for significant developments in intramolecular Stetter reactions, both in the achiral context, with the use of immobilized precatalysts,[174] fluorous thiazolium salts,[175] and alkylthiazolium-based ionic liquids,[176] and in the development of enantioselective variants relying on chiral NHC catalysts.[177]

In 2004, Bach evaluated the potential of axially chiral thiazolium salt **70** (see Scheme 35) to carry out this transformation (Scheme **74**).[83] A moderate 50% ee was attained for the preparation of the chromanone product. One year later, peptide-based thiazolium salts **115** and **157** were developed and tested by Miller, providing the expected chromanone in good yields and improved enantioselectivities (up to 80%) (Scheme 74).[178] In 2014, Shibasaki described the synthesis and catalytic evaluation of bis(hydroxyphenyl)diamide containing thiazolium salt **158** (Scheme 74).[179] As for the previously described transformations, thiazolium salts were soon replaced by more higher-performing triazolium NHC catalysts.[180]

<figure><img src="image_114.png" /><figcaption>**Scheme 73.** Intramolecular Stetter reaction by Ciganek.[173]</figcaption></figure>
<figure><img src="image_115.png" /><figcaption>**Scheme 74.** Chiral thiazolium-based NHC catalysts for enantioselective intramolecular Stetter reaction.</figcaption></figure>

Intramolecular Stetter reactions, in the presence of an aliphatic aldehyde and an acrylate group, were used in an iterative synthesis of the tricyclic compound **162** (Scheme 75).[181] In this particular case, thiazolium-based carbenes, used in over-stoichiometric amounts, displayed better results than triazoliums. A single diastereomer **160** was observed in the first Stetter reaction. This was ascribed to the fact that syn-pyranone is thermodynamically more stable than its *trans*-isomer. Given the basic nature of the reaction medium, the products formed may be converted into the more stable isomer. On the other hand, the *trans*,*syn*-fused bicyclic compound **160** is the kinetic product of the intramolecular Stetter reaction to the alkene *E*.

Xu published the synthesis of enantioselective Hajos-Wiechert ketone skeletons **166** bearing three contiguous stereogenic centers via a sequential, multiorganocatalytic relay sequence.[182] The regio-, diastereo-, and enantioselective vinylogous Michael addition was guaranteed by merging Jørgensen-Hayashi secondary amines **163** with *N*,*N'*-((1S,2S)-1,2-diphenylethane-1,2-diyl)bis(1,1,1-trifluoromethanesulfonamide) **164** catalysts (Scheme 76). Thus, intermediate **165**, which is the substrate for the intramolecular Stetter reaction, gave the expected products in the presence of thiazolium **32** in high yields and stereoselectivities.

The synthesis of spiro bis-indanes **167** and **168** was described by Gravel via domino transformations based on Stetter/aldol/Michael and Stetter/aldol/aldol reactions.[183] The work features the formation of polycyclic frameworks via three new C—C bonds formation and a quaternary spiro center (Scheme 77).

<figure><img src="image_116.png" /><figcaption>**Scheme 75.** Iterative intramolecular Stetter reaction for the synthesis of *trans*,*syn*,*trans*-fused polyether array **162**.[181]</figcaption></figure>

In 2019, Hsu and coworkers employed benzaldehyde-derived substrates tethered to a cyclic enone **169** to access spiro-fused tricyclic 1,4-diketones **170** via an intramolecular Stetter reaction (Scheme 78).[184] This strategy was successfully applied to the total synthesis of (±)-nidemone. For additional examples of the Stetter reaction in the total synthesis of natural products, see Section “Application of the Stetter Reaction in Total Synthesis”.[185,186]

The synthesis of 3-substituted 2,3-dihydroquinolin-4-ones **173** was described via a sequential multicatalytic
<figure><img src="image_117.png" /><figcaption>**Scheme 76.** Multicatalytic relay sequence involving Michael addition/intramolecular Stetter reaction.[182]</figcaption></figure>

process by combining Pd-catalyzed allylic amination/intramolecular Stetter reaction (Scheme 79).[187] Although the scope provided is quite narrow, the work represents an interesting route to dihydroquinolinones in excellent yields.

In 2013, McErlean reported an extension of the intramolecular Stetter reaction involving benzaldehyde tethers bearing α,β,γ,δ-unsaturated carbonyl moieties **174** as substrates (Scheme 80).[188] This vinylogous Stetter reaction proceeded efficiently in the presence of either thiazolium catalyst **32** or triazolium **103**. An enantioselective version was also proposed using a chiral triazolium salt. Recently, Suresh further expanded this strategy to access a broad range of phenanthrolyl derivatives **177** (Scheme 81).[189]

**Enzymatic and Biomimetic Stetter and Stetter-Like Reactions:** In the context of biomimetic catalysis, the development of Stetter-like transformations that proceed under aqueous conditions and via mechanisms reminiscent of thiamine-dependent enzymatic processes has attracted increasing interest.[190] In 2005, Scheidt reported a notable example of such a transformation: the catalytic conjugate addition of α-keto acids or α-keto carboxylate

<figure><img src="image_118.png" /><figcaption>**Scheme 77.** Synthesis of spiro bis-indanes described by Gravel.[183]</figcaption></figure>
salts **178** to α,β-unsaturated 2-acyl imidazoles **179** in water, under neutral conditions (**Scheme 82**). [191] This reaction mimics the biochemical activity of transketolases, wherein decarboxylation of the α-keto acid generates a nucleophilic acyl anion equivalent, formally a **BI**, through activation by thiazolium catalyst **32**.

<figure><img src="image_119.png" /><figcaption>**Scheme 78.** Synthesis of spirofused tricyclic 1,4-diketones **170**. [184–186]</figcaption></figure>

<figure><img src="image_120.png" /></figure>

Selected examples:

<figure><img src="image_121.png" /><figcaption>**Scheme 80.** Vinylogous intramolecular Stetter reaction. [188] $^a$CH$_2$Cl$_2$ as solvent. NR = no reaction.</figcaption></figure>

<figure><img src="image_122.png" /><figcaption>**Scheme 79.** Synthesis of 3-substituted 2,3-dihydroquinolin-4-ones **173**. [187]</figcaption></figure>
<figure><img src="image_123.png" /></figure>

<figure><img src="image_124.png" /></figure>

<figure><img src="image_125.png" /></figure>

>25 examples
82-96% yield

Selected examples:

<figure><img src="image_126.png" /></figure>

<figure><img src="image_127.png" /></figure>

<figure><img src="image_128.png" /></figure>

<figure><img src="image_129.png" /></figure>

<figure><img src="image_130.png" /></figure>

<figure><img src="image_131.png" /><figcaption>**Scheme 81.** Synthesis of phenanthroл derivatives 177 via vinylogous Stetter reaction.[189]</figcaption></figure>

The resulting intermediate then undergoes conjugate addition to Michael acceptors such as **179**, affording 1,4-dicarbonyl products **180**. The transformation is compatible with a wide pH range (pH 4–12), making it suitable for substrates sensitive to either acidic or basic conditions.

Building on these biomimetic strategies that emulate thiamine-dependent enzymatic pathways, recent advances have demonstrated that natural ThDP-dependent enzymes themselves can catalyze genuine Stetter-type reactions with remarkable selectivity and efficiency. In 2021, Chen, Xu, and Wu described an enantioselective intramolecular Stetter reaction catalyzed by benzaldehyde lyase from *Pseudomonas fluorescens* biovar I (*p*-BAL), an enzyme previously known to catalyze benzoin-type reactions (vide supra, Section “Biocatalytic Homo- and Cross-Benzoin Condensations”).[192] Catalyst screening of a series of ThDP-dependent enzymes was assisted by molecular dynamics (MD) simulations, leading to the identification of *p*-BAL as an efficient biocatalyst. The method allowed the synthesis of chromanones **181** in high yields and with excellent enantioselectivities (**Scheme 83**). Advantages of the process include mild

<figure><img src="image_132.png" /></figure>

<figure><img src="image_133.png" /></figure>

<figure><img src="image_134.png" /></figure>

>15 examples
72-96% yield

<figure><img src="image_135.png" /></figure>

Selected examples:

<figure><img src="image_136.png" /></figure>

$R^2 = 4-\text{MeOPh} (87\%)$

$R^2 = 4-\text{BrPh} (71\%)$

$R^2 = 2-\text{CF}_3\text{Ph} (76\%)$

$R^2 = 2-\text{ClPh} (95\%)$

$R^2 = 2-furyl (80\%)$

$R^2 = 2-thiophene (90\%)$

<figure><img src="image_137.png" /></figure>

<figure><img src="image_138.png" /></figure>

<figure><img src="image_139.png" /></figure>

<figure><img src="image_140.png" /></figure>

Proposed mechanism:

<figure><img src="image_141.png" /></figure>

Breslow intermediate

<figure><img src="image_142.png" /><figcaption>**Scheme 82.** Biomimetic conjugate addition of acyl anions in the presence of commercially available thiamin analog **32**.[191] NR = no reaction.</figcaption></figure>

10 examples
91-99% yields
up to 99:1 er

Selected examples:

<figure><img src="image_143.png" /></figure>

91%
98.2 er

<figure><img src="image_144.png" /></figure>

99%
90.10 er

<figure><img src="image_145.png" /></figure>

99%
93.7 er

<figure><img src="image_146.png" /></figure>

X = Cl or Me
NR

<figure><img src="image_147.png" /></figure>

NR

<figure><img src="image_148.png" /></figure>

99%
96.4 er

<caption>**Scheme 83.** Enzymatic enantioselective intramolecular Stetter reaction.[192]</caption>
reaction conditions, easy to implement, high performance (TON), and selectivities.

In the same year, Planas and Himo computationally studied the mechanism of the enzymatic Stetter reaction involving 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylic acid (SEPHCHC) synthase (also known as MenD), a ThDP-dependent enzyme.[193] This enzyme catalyzes the formation of SEPHCHC from 2-ketoglutarate and isochorismate (Scheme 84) and displays potential as a biocatalyst for the preparation of 1,4-dicarbonyl compounds.

**Sila-Stetter Reaction:** Acylsilanes 182 have emerged as valuable alternatives to aldehydes in Stetter-type reactions, offering several practical and mechanistic advantages.[194] First, their enhanced oxidative stability makes them more convenient to handle and store, especially under aerobic conditions. Second, their reactivity can be more finely tuned under NHC catalysis, often reducing the risk of competing side reactions such as aldol condensations. Third, acylsilanes tend to exhibit better compatibility with sensitive substrates or functional groups, broadening the synthetic scope of Stetter-type transformations. Consequently, acylsilanes were introduced by Scheidt in 2004 as acyl anion equivalents in Stetter-type reactions,[195] taking advantage of a 1,2-silyl shift (Brook rearrangement) from the tetrahedral intermediate 183, which renders the acylsilane carbon nucleophilic (Scheme 85).

In the presence of an alcohol, desilylation takes place leading to a Breslow intermediate which subsequently undergoes conjugate addition leading 1,4-dicarbonyl

<figure><img src="image_149.png" /><figcaption>**Scheme 84.** Enzymatic Stetter reaction catalyzed by MenD.[193]</figcaption></figure>

<figure><img src="image_150.png" /><figcaption>**Scheme 85.** Acyl anion equivalent from acylsilanes.[195]</figcaption></figure>

<figure><img src="image_151.png" /><figcaption>Proposed mechanism</figcaption></figure>

<figure><img src="image_152.png" /><figcaption>Breslow intermediate</figcaption></figure>

<figure><img src="image_153.png" /><figcaption>**Scheme 87.** Thiazolium carbinols and silylated phenols for the synthesis of α-aryl ketones.[196]</figcaption></figure>

compounds 185, in the case of Stetter reaction, or reaction with other electrophiles (Scheme 86).[195]

Likewise, Scheidt prepared and isolated stable *O*-silyl thiazoliums that could act as acyl anions origina-
tors. As previously mentioned in Section “Intermolecular
Stetter Reaction,” this concept was first applied to the syn-
thesis of β-nitroketones via conjugate addition to nitroal-
kenes.[138] In 2007, it could be further extended to the
preparation of α-aryl ketones 187 via nucleophilic acyla-
tion of *o*-quinone methides 186 (Scheme 87)[196] and to
the synthesis of furans and pyrroles in a one-pot process.[197]

In 2004, Scheidt described the combination of acylsilanes **182** and *N*-diphenylphosphinoylimines **188** to access protected *α*-amino ketones **189** (*Scheme 88*).[198] The procedure is related to a “sila-aza-benzoin reaction” and the mechanism involved is similar to that observed for the sila-Stetter reaction (see Scheme 86), where the Michael acceptors have been replaced by imine electrophiles. For examples on classical aza-benzoin reaction, see Section “Imine-Aldehyde Substrates (Aza-Benzoin Reaction).”

In 2013, Landais published an intermolecular sila-Stetter reaction between aliphatic acylsilanes **182** and vinylketones **190** bearing silyl ether substituents (*Scheme 89*).[199] The 1,4-diketone products **191** so

<figure><img src="image_154.png" /><figcaption>**Scheme 89.** Intermolecular sila-Stetter reaction between aliphatic acylsilanes and vinylketones.[199]</figcaption></figure>

obtained were thus used as starting point to access bis-spiroacetals **192** via spiroacetalization under acidic conditions.

In another context, Otaka was interested in the synthesis of fluoroalkene dipeptide isosters (FDAIs) which are potential dipeptide mimetics having the fluoroalkene moiety as peptide bond surrogate.[200] To achieve these backbones, he relied on a sila-Stetter-type reaction using acylsilanes **193** as starting materials. The expected products **196** were isolated in higher yields compared to reactions using aldehyde substrates. This improved efficiency was attributed to the bulky TBS group, which likely hinders protonation of the silylated acyl anion intermediate **194** at the γ-position. As a result, the formation of defluorinated products **196** is favored (*Scheme 90*).

**Application of the Stetter Reaction in Total Synthesis:** The versatility of the products obtained by the Stetter reaction, combined with the operational simplicity of the transformation, has made it a valuable tool in the total synthesis of complex molecules.[135b] Selected examples will be highlighted to illustrate its strategic utility.

Trost published in 1979 the first stereocontrolled synthesis of (±)-hirsutic acid C, a sesquiterpene with antibiotic and antimitotic activities bearing seven stereocenters.[201] Among the key steps to achieve such a trick target, an intramolecular Stetter reaction was used to give the ketone **197** and install the polycyclic core of the natural product (*Scheme 91*).

In 1999, Townsend shed light on the origin of the *β*-lactam carbons in clavulanic acid.[202] It was
<figure><img src="image_155.png" /><figcaption>**Scheme 90.** γ,γ-Difluoro-α,β-enoylsilanes 193 for the synthesis of FADIs via a sila-Stetter reaction.[200]</figcaption></figure>

shown that thiamine pyrophosphate (TPP)-dependent enzyme is responsible for the formation of a α,β-unsaturated acylazolium ion **198** which is an intermediate formed during the biosynthesis of this potent naturally occurring inhibitor of β-lactamases in bacteria (**Scheme 92**).

Tius used an intermolecular Stetter reaction between exocyclic alkene **199** and 6-heptenal **200** for the synthesis of *trans*-cyclopentenone **201**, an important intermediate for the enantiospecific total synthesis of the alkaloid roseophilin, a cytotoxic antibiotic and antitumor natural product (**Scheme 93**).[203]

Dixon and Paton achieved the first enantioselective total synthesis of (-)-himalensine A, a pentacyclic *Daphniphyllum* alkaloid isolated from Himalayan evergreen *Daphniphyllum himalense*. With an extremely complex chemical structure, an intramolecular Stetter reaction, with concomitant base-induced alkene isomerization, was used as one of the final steps to access the cyclopentanone core **202** (**Scheme 94**).[204]

In 2023, Lei reported the first total syntheses of bis-β-carboline alkaloids, picrasidines G, S, R, and T.[205] While picrasidines G, S, and T possess an indolotetrahydroquinolizinium skeleton, picrasidine R features a 1,4-diketone linker between two β-carboline moieties. In order to install this dicarbonyl linker, a transformation that represents the final step in the total synthesis of picrasidine R, Lei used an intermolecular Stetter reaction between the vinyl ketone **203** and the aldehyde **204** (**Scheme 95**).

Latest, Deng described the asymmetric total synthesis of penicilfuranone A, a naturally occurring phytoxin isolated from *Penicillium* sp. Sh18.[206] The strategy calls for a key NHC-catalyzed intermolecular Stetter/aldol cascade reaction, merging a benzylaldehyde moiety **205** and an electron-deficient olefin fragment **206** (gregatin A) (**Scheme 96**). The combination of these two substrates made possible the synthesis of

<figure><img src="image_156.png" /><figcaption>**Scheme 91.** Hirsutic acid C total synthesis by Trost in 1979.[201]</figcaption></figure>

<figure><img src="image_157.png" /><figcaption>**Scheme 92.** Biomimetic origin of α,β-unsaturated acylazolium ions: biosynthesis of clavulanic acid.[202] Pi = inorganic phosphate.</figcaption></figure>

the 4-hydroxytetralone skeleton **207** via a formal [4 + 2] annulation, while attempts through Diels-Alder reactions failed. It is worth mentioning that this is the first example of an intermolecular Stetter/aldol domino reaction with a ketone as substrate. Moreover, imidazolylidene and triazolylidene catalysts were
<figure><img src="image_158.png" /><figcaption>**Scheme 93.** Total synthesis of roseophilin by Tius in 2001.[203]</figcaption></figure>

<figure><img src="image_159.png" /><figcaption>**Scheme 94.** Stetter reaction among the latest steps during the total synthesis of himalensine A.[204]</figcaption></figure>

ineffective, providing only homo-benzoin condensation product of 205.

### 6.1.4. Hydroacylation Reactions

Although hydroacylation reactions share a mechanistic foundation with the Stetter reaction (i.e., addition of acyl anions to Michael acceptors as electrophiles) this section focuses on transformations involving the insertion of carbonyl anions into suitable leaving groups or into both

activated and unactivated alkynes. A representative example of this reactivity was reported by She and Pan, who developed an intramolecular nucleophilic substitution reaction in order to provide benzopyrones **208** and benzofuranones **209**.[207] The process relies on the use of appropriately designed substrates bearing both a carbonyl, serving as the acyl anion precursor in the presence of an NHC catalyst, and a suitable leaving group (**Scheme 97**). Later on, the concept was transposed to the synthesis of benzofuranones via an intramolecular nucleophilic addition of carbonyl anion equivalents to enol ethers.[208]

In 2010, Glorius described the intramolecular hydroacylation of nonactivated alkynes followed by an intermolecular Stetter reaction to give chromanones (**Scheme 98**).[87] The transformation takes place under thiazolium **71** catalysis, which provided better results in terms of selectivity compared with other NHCs. Indeed, the unwanted benzoin and Stetter products were considerably suppressed in the presence of **71**. The synthesis of chromones was also reported by Liu and Shi starting from acetylenic substrates substituted with EWG such as an ethyl ester or phosphonates.

One year later, independently, Glorius and Zeitler developed a cascade approach involving the previous devised chromanone synthesis which was then transformed into benzofuranones via a subsequent retro-Michael/1,3-H shift/oxa-Michael sequence promoted by strong bases (**Scheme 99**).[209,210]

The synthesis of chromones from activated alkynes **210** and **212** was independently reported by Liu and Shi, respectively (**Scheme 100**).[211,212] In Shi's study involving
<figure><img src="image_160.png" /><figcaption>**Scheme 95.** Intermolecular Stetter reaction during the total synthesis of picrasidine R.[205]</figcaption></figure>

<figure><img src="image_161.png" /><figcaption>**Scheme 96.** Intermolecular Stetter/aldol cascade reaction for the synthesis of penicilfuranone A.[206]</figcaption></figure>

alkynylphosphonates **212**, the initially formed exocyclic olefins **214**, obtained under mild basic conditions ($K_2CO_3$, 17 °C), were shown to isomerize into the more stable endocyclic isomers **215** upon slight heating (30 °C). Building on this reactivity, Shi later designed a domino sequence combining the previously described intramolecular hydroacylation with an intermolecular Stetter reaction between salicyl alkynylphosphonates and aromatic aldehydes, affording chromanones bearing a phosphonate moiety.[213]

<figure><img src="image_162.png" /><figcaption>**Scheme 97.** Synthesis of benzopyrones and benzofuranones via NHC-catalyzed nucleophilic substitution.[207]</figcaption></figure>

<figure><img src="image_163.png" /><figcaption>**Scheme 98.** Synthesis of chromanones by Glorius.[87]</figcaption></figure>

The synthesis of 3-aminochromones **217** and 3-alkylchromones **219** was later described by Karvembu and Vedachalam involving the corresponding salicylaldehyde derived nitriles **216** and activated alkynes **218**, respectively.[214] The reactions take place with **32** as NHC-catalyst precursor under ionic liquids and microwave irradiation (**Scheme 101**).

In 2018, Chen and Zhou uncovered a procedure for building up symmetrical and unsymmetrical bisbenzopyrones **221** via a cascade approach involving intramolecular hydroacylation/Stetter reaction (**Scheme 102**).[215]

Whereas most hydroacylation processes described so far rely on intramolecular strategies, intermolecular variants remain scarce. In this context, Glorius reported a seminal example of intermolecular hydroacylation involving arynes, representing the first instance of combining NHC catalysis with arynes via formal insertion into $C_{formyl}$-H bonds (**Scheme 103**).[216]
## 6.2. Redox Reactions

Following on from the concepts introduced in Section 4.4 regarding redox properties of thiazolium-based Breslow intermediates, this section presents selected examples of redox transformations involving

<figure><img src="image_164.png" /></figure>

Glorius (2011):

* 71 (10 mol%)

* DBU (20 mol%)

* THF, 80 °C

* 24 min

* > 15 examples

* 37-90% yield

Zeitler (2011):

* i. 71 (5 mol%)

* K₂CO₃ (10 mol%)

* THF, 80 °C, 3 h

* ii. DBU (0.9 equiv)

* THF, 80 °C, 2 h

* 'one-pot'

* > 10 examples

* 20-98% yield

<figure><img src="image_165.png" /></figure>

71

Proposed mechanism

<figure><img src="image_166.png" /><figcaption>**Scheme 99.** Synthesis of benzofuranones by Glorius and Zeitler.[209,210]</figcaption></figure>

this class of NHCs. New insights are currently being disclosed on SET mechanisms involved in such NHC-mediated transformations, often involving persistent ketyl radical intermediates. Consequently, novel reactions are developed expanding the room for original applications.[217]

Among the first to harness the redox behavior of Breslow-type intermediates in synthetic transformations, Studer pioneered a biomimetic, transition-metal-free carbene-catalyzed oxidation of aldehydes under NHC catalysis.[68] In this work, three types of carbenes (i.e., imidazolylidene, thiazolylidene, and triazolylidene) (222-224) were evaluated in the presence of TEMPO 225 as oxidant, which did not inhibit catalytic activity. The mechanism assumed relies on the classical formation of **BI 226**, which undergoes SET to TEMPO, generating a radical cation **227**. Subsequent deprotonation affords radical species **228**, which after a second SET event produces activated ester **229**, ultimately leading to the oxidized product **230** and regeneration of the carbene. Direct hydrogen transfer from **226** to TEMPO to provide **228** cannot be excluded (**Scheme 104**).

Ohmiya described a decarboxylative coupling of aryl aldehydes and redox-active esters derived from alkyl carboxylic acids **231** to synthesize ketones (**Scheme 105**).[218,219] The reaction conditions are mild enough to allow functionalization of complex molecular architectures such as pharmaceutical drugs and natural products.

The proposed mechanism includes a SET from enolate intermediate **232** to the redox ester **231** (**Scheme 106**). The C—C bond formation to release

<figure><img src="image_167.png" /></figure>

<figure><img src="image_168.png" /><figcaption>**Scheme 100.** Synthesis of chromones by Liu and Shi.[211,212]</figcaption></figure>
<figure><img src="image_169.png" /></figure>

<figure><img src="image_170.png" /><figcaption>**Scheme 101.** Synthesis of amino- and alkyl-chromones by Karvembu and Vedachalam.[214]</figcaption></figure>

the ketone derivatives takes place via the recombination of the resulting radical pair **233** and **234**.

The concept was expanded to the vicinal alkylacylation of styrenes, acrylates, and acrylonitriles using aldehydes and **231** (**Scheme 107**).[220] The mechanism is almost similar to that depicted in Scheme 106, with

the only inclusion of the step which associates the alkyl radical **234**, derived from the activated carboxylic acid **231**, with the alkene, giving rise to a new secondary radical **235** through a NHC-catalyzed radical relay (**Scheme 108**).

In another context, Nagao and Ohmiya disclosed vicinal alkylacylation of olefins using aromatic aldehydes and tertiary α-bromo esters.[221] The transformation encompasses NHC-catalyzed radical relay and provides δ-keto esters **236** containing a quaternary carbon stereocenter (**Scheme 109**). In terms of reaction pathway, it follows similar considerations to those described above.

In the same year, Li and Han described the acylfluoroalkylation of alkenes in the presence of aromatic aldehydes and fluoroalkyl reagents.[222] The efficiency of the method was illustrated through the synthesis of more than thousand examples of functionalized ketones with fluorine substituents, and in the late-stage functionalization of Active Pharmaceutical Ingredients (APIs) (**Scheme 110**). The mechanism follows the same lines as the previous ones, where SET of the electron-rich Breslow enolate intermediate **232** to the fluoroalkyl reagent is responsible for the formation of radical **237** and the persistent ketyl radical **233**. Addition of **237** to the aromatic olefin yields the benzylic radical **238**.

<figure><img src="image_171.png" /><figcaption>**Scheme 102.** Synthesis of bisbenzopyrones by Chen and Zhou.[216]</figcaption></figure>
<figure><img src="image_172.png" /></figure>

Selected examples:

<figure><img src="image_173.png" /></figure>

R = Br (92%)

R = tBu (69%)

R = CN (70%)

R = CO₂Me (77%)

R = CF₃ (88%)

<figure><img src="image_174.png" /></figure>

48%

<figure><img src="image_175.png" /></figure>

<figure><img src="image_176.png" /></figure>

<figure><img src="image_177.png" /></figure>

R = Ph (58%)

R = 2-furyl (43%)

<figure><img src="image_178.png" /><figcaption>**Scheme 104.** NHC-catalyzed oxidation of aldehydes via redox reaction in the presence of TEMPO.[68]</figcaption></figure>

<figure><img src="image_179.png" /></figure>

Selected examples:

<figure><img src="image_180.png" /><figcaption>**Scheme 105.** Decarboxylative alkylation of aldehydes by Ohmiya.[218]</figcaption></figure>

<figure><img src="image_181.png" /><figcaption>**Scheme 106.** Proposed mechanism by Ohmiya.[218]</figcaption></figure>

Recombination of **233** and **238** gives the expected fluoroketones and releases the NHC. The group of Yang and Wu published a similar procedure to synthesize α-aryl β-perfluoroalkyl ketones drawing together aromatic olefins, aromatic aldehydes, and perfluoroalkyl compounds.[223]
<figure><img src="image_182.png" /></figure>

Selected examples:

>35 examples
40-98% yields

<figure><img src="image_183.png" /></figure>

R = Me (85%)

R = Br (79%)

<figure><img src="image_184.png" /></figure>

83%

<figure><img src="image_185.png" /></figure>

86%

<figure><img src="image_186.png" /></figure>

67%

<figure><img src="image_187.png" /></figure>

45%

<figure><img src="image_188.png" /></figure>

79%

<figure><img src="image_189.png" /></figure>

60%

<figure><img src="image_190.png" /></figure>

53%

<figure><img src="image_191.png" /></figure>

83%

<figure><img src="image_192.png" /><figcaption>**Scheme 108.** Proposed mechanism for the vicinal alkylacylation of alkenes.[220]</figcaption></figure>

<caption>**Scheme 109.** Synthesis of *δ*-ketocarbonyl compounds bearing a quaternary carbon stereocenter.[221]</caption>

A new advance in NHC-catalyzed radical reactions was achieved by Ohmiya, who introduced the use of aryl radicals, so far unexplored in this type of transformation.[224] The aryl radical is generated

via a SET from the enolate form of **BI 232** to the aryl iodide derivative. Then, the catalytically generated aryl radical **239** was employed as an arylating agent for radical relay-type arylacylation of styrenes
<figure><img src="image_193.png" /><figcaption>**Scheme 110.** Acylfluoroalkylation of olefins and supposed mechanism.[222]</figcaption></figure>

<figure><img src="image_194.png" /><figcaption>**Scheme 111.** Arylacylation of styrenes by Ohmiya.[224]</figcaption></figure>

<figure><img src="image_195.png" /><figcaption>**Scheme 112.** C(sp³)-H acylation of secondary amides by Ohmiya.[224]</figcaption></figure>

(Scheme 111) and as a hydrogen atom abstraction reagent for α-amino C(sp³)-H acylation of secondary amides (241 → 242) (Scheme 112).

The three-component cyanoalkylacylation of alkenes with oxime esters 245 and aldehydes via radical relay was independently and simultaneously published by the groups of Li and Guo[225] and Feng and Du.[226] Both procedures displayed broad substrate scope and provided polyfunctionalized aliphatic keto nitriles 246 in good yields (Scheme 113). The overall proposed mechanism encompasses SET from the Breslow enolate intermediate 232 to the oxime ester 245. Homolytic single C—C bond cleavage of 247 generates cyanoalkyl radical 248, which reacts with
<figure><img src="image_196.png" /></figure>

Li and Guo (2021):

243/244/245 1:2:1:5

72 (10 mol%)

Cs₂CO₃ (1.5 equiv)

CH₂Cl₂, 60 °C

12 h, argon

>30 examples

10-88% yields

Feng and Du (2021):

243/244/245 1:5:1:5

72 (10 mol%)

Mg(OTf)₂ (5 mol%)

NaHCO₃ (1.5 equiv)

H₂O (2 equiv), DMAc

60 °C, 3 h, argon

>30 examples

20-85% yields

<figure><img src="image_197.png" /></figure>

72

<figure><img src="image_198.png" /><figcaption>**Scheme 114.** Mechanistic considerations for the cyanoalkylacylation of alkenes with oxime esters and aldehydes.[225,226]
a) Proposed catalytic cycle. b) Mg²⁺ matched Breslow/oxime ester EDA complex.</figcaption></figure>

the alkene substrate to deliver a secondary radical **249** (**Scheme 114**). The following steps involve transformations similar to those described by Ohmiya. A Mg/matched **BI**/oxime ester electron-donating acceptor (EDA) complex **250** is assumed to be responsible for the reactivity on the procedure

<figure><img src="image_199.png" /><figcaption>**Scheme 115.** Alkylacylation of unactivated alkenes via NHC and photoredox catalysis.[228] PCET = proton coupled electron transfer.</figcaption></figure>

<figure><img src="image_200.png" /></figure>

<figure><img src="image_201.png" /><figcaption>**Scheme 116.** Oxidative radical NHC catalysis via HAT for the synthesis of difunctionalized olefins.[230]</figcaption></figure>
<figure><img src="image_202.png" /><figcaption>**Scheme 117.** Mechanistic considerations for the oxidative NHC radical catalysis via HAT developed by Li.[230]</figcaption></figure>

<figure><img src="image_203.png" /></figure>

Selected examples:

<figure><img src="image_204.png" /><figcaption>**Scheme 118.** Cooperative NHC/Metal redox system for the synthesis of ketones by Tomás-Mendivil and Martin.[232]</figcaption></figure>

<figure><img src="image_205.png" /></figure>

(in situ formed during step 1 in conditions B)

Conditions A:

260 (1 equiv)
aldehyde (1.5 equiv)
Ir(ppy)₂dtbpy (5 mol %)
72 (10 mol %)
Cs₂CO₃ (1.5 equiv)
CH₃CN, blue LEDs
rt, 16 h

Conditions B:

1. Pht-OH (1.5 equiv)
   acid (1.5 equiv)
   DCC (1.5 equiv)
   DMF, rt, 1 h
2. aldehyde (1 equiv)
   DPAIPN (5 mol %)
   72 (10 mol %)

Na₂CO₃ (1.5 equiv)
DMF, white LEDs
rt, 16 h (one pot)

<figure><img src="image_206.png" /></figure>

Selected examples:

<figure><img src="image_207.png" /></figure>

<figure><img src="image_208.png" /></figure>

<figure><img src="image_209.png" /></figure>

<figure><img src="image_210.png" /></figure>

<figure><img src="image_211.png" /></figure>

**Scheme 119.** Synthesis of α-amino ketones from α-amino acids.[238] Pht = phthalimide.

described by Feng and Du. In the same year, Yang reported the acylation of cyclic oxime ester derivatives with aromatic aldehydes via a similar approach.[227]

The merging of NHC-organocatalysis and photocatalysis has enabled the development of a visible-light alkylacylation of unactivated alkenes in the presence of a diazo ester reagent **251** (**Scheme 115**).[228] The special feature of the method is the use of diazo derivative as radical source. Mechanistic aspects involve similar steps as the previous ones described in this section. However, a photoredox process is responsible for the generation of the primary alkyl radical **252** from **251**. Radical relay takes place in the presence of olefins to provide a more stable radical **253**.

Highly diastereoselective radical aminoacylations of olefins have been disclosed highlighting a radical–radical coupling of a NHC-Breslow radical (see **IIIb**, Scheme 25) and a prochiral C-centered radical (issued from the 5-*exo*-trig cyclization of an amidyl radical).[229] Very recently, strain-release-driven radical
<figure><img src="image_212.png" /><figcaption>**Scheme 120.** Mechanistic hypothesis.[238] Pht = phthalimide.</figcaption></figure>

acylfluoroalkylation of bicyclobutanes was described and the difunctionalization of the central C—C was achieved with high diastereoselectivities.[74]

In another study, oxidative radical NHC catalysis via HAT using peroxyesters as external single-electron oxidant was developed in order to realize difunctionalization of alkenes (Scheme 116).[230] A variety of substituted 1,4-diketones 256 were synthesized through the catalytically generated oxygen radicals, which trigger an intramolecular HAT process to activate otherwise inert C—H bonds, initiating an efficient radical relay mechanism (Scheme 117). Interestingly, when the reaction is performed in dichloromethane, hydrogen atom abstraction of dichloromethane in the presence of oxygen radicals provided a dichloromethyl radical affording 257 via dichloromethylacylation of olefins.

In 2011, Glorius reported a metal-free NHC-organocatalyzed alkylation reaction of aldehydes with activated alkyl bromides.[231] In 2024, Tomás-Mendivil and Martin uncovered a cooperative NHC/Ni catalytic methodology to reach ketones from alkyl iodides and aromatic aldehydes (Scheme 118).[232] Interestingly, by merging experimental, electrochemical, and spectroscopic studies, they showed the accumulation of the persistent Breslow-type radical 259. Moreover, single crystals of the persistent acyl radical were obtained, enabling X-ray diffraction studies of this elusive intermediate.

<figure><img src="image_213.png" /></figure>

<figure><img src="image_214.png" /><figcaption>**Scheme 121.** Enantioselective acyl-difluoroalkylation of alkenes by Cramer.[240]</figcaption></figure>
<figure><img src="image_215.png" /></figure>

Selected examples:

<figure><img src="image_216.png" /><figcaption>R = Et (89%, 13:1 dr)</figcaption></figure>

<caption>R = Bn (89%, >10:1 dr)</caption>

<figure><img src="image_217.png" /><figcaption>82%$^a$</figcaption></figure>

<figure><img src="image_218.png" /><figcaption>85%</figcaption></figure>

<figure><img src="image_219.png" /><figcaption>**Scheme 122.** NHC-catalyzed esterification of epoxyaldehydes.[243]</figcaption></figure>

Also, cooperative thiazolium-based NHC/Pd catalysis has been thoroughly studied by Ye and Zhang, who described alkylacylation of alkenes[233] and 1,3-dienes,[234] fluoroalkylacylation of alkynes,[235] alkylation of aldehydes,[236] and alkyl C(sp³)-H functionalization.[237]

Du, Shi, and Feng find out a method to prepare α-amino ketones through direct decarboxylative modification of α-amino acids or peptides with aldehydes, merging photoredox and NHC-catalysis (Scheme 119).[238] α-Amino-acid-derived NIPH esters 261, which are the key substrates of the transformation, can be either synthesized prior to the reaction (some problems associated with isolation and stability were observed) or in situ prepared via an activation step of the free-carboxylic acid 260 in the presence of N,N'-dicyclohexylcarbodiimide (DCC). Based on control experiments and literature, the authors propose a radical-polar crossover

<figure><img src="image_220.png" /></figure>

Selected examples:

<figure><img src="image_221.png" /><figcaption>87%</figcaption></figure>

<figure><img src="image_222.png" /><figcaption>79%</figcaption></figure>

<figure><img src="image_223.png" /><figcaption>79%</figcaption></figure>

<figure><img src="image_224.png" /><figcaption>**Scheme 123.** NHC-catalyzed reaction of alkynals for the synthesis of allenoates.[244]</figcaption></figure>

mechanism (Scheme 120).[239] First, α-amino-acid-derived NIPH esters 261 undergo decarboxylation in the presence of a photocatalyst. After another electron transfer, the resulting alkyl radicals 262 give rise to the α-aminoalkyl carbocations 263. Deprotonation of 263 led to imines 264 which then undergo an aza-benzoin condensation with BI 11, yielding the final products and liberating the NHC-carbene. It is noteworthy that some imine intermediates 264 can be trapped by the phthalimide anion or tautomerized to enamine byproducts 265 and 266, respectively.

One step further on the redox application of NHCs was published in 2024 by Cramer, who described enantioselective radical three-component dicarbofunctionalizations.[240] The work relied on the design and synthesis of tunable thiazolylidenes, with distinct steric and electronic effects on key positions to perfectly fit chiral induction requirements (Scheme 121). Catalyst 267 showed better results and was thus used on an enantioselective SET-type three-component acyl-difluoroalkylation of olefins providing the
expected products in high yields and selectivities (up to >99:1 *er*). On the basis of structural analysis, it has been proposed that elongating the aliphatic ring backbone increases the distance between the lower arene ring of the chiral aniline and the aliphatic moiety, while bringing the upper arene ring into closer proximity to the ketyl anion intermediate. This orientation results in a stable conformation and a better chiral environment.

It is important to mention that thiamine-centered photoenzymatic catalysis enables fine control of enantioselectivity in asymmetric synthesis, as recently evidenced.[241,242]

### 6.3. Miscellaneous Reactions Catalyzed by Thiazolium-Based NHCs

To conclude this overview, we will turn our attention to a selection of miscellaneous transformations catalyzed

<figure><img src="image_225.png" /><figcaption>**Scheme 124.** [4 + 2] cycloaddition of nitroolefins with oxodienes via NHC-catalysis.[245]</figcaption></figure>

by thiazolium-based NHCs. These diverse reactions, though less commonly classified under traditional categories, illustrate the remarkable versatility of this carbene family and its growing impact across various domains of organic synthesis.

In 2004, Bode reported a catalytic, diastereoselective synthesis of β-hydroxy esters **269** from α,β-epoxy aldehydes **268** through the catalytic formation of activated carboxylates.[243] The success of the transformation relies on the use of a 2-acyl thiazolium intermediate **276**, obtained from the oxidation of thiazolium-aldehyde species, which act as effective acyl donors (**Scheme 122**). Experimental observations and isotopic labeling suggest either a concerted elimination (**274** from **273**) or a stepwise process via a stabilized anion **272** for the epoxide-opening step. Approaches such as Favorskii rearrangement or hydride-shift from **271** or a hemiacetal were not considered.

Sun described, in 2012, a thiazolylidene-catalyzed strategy for the synthesis of allenoates **278** from alkynals **277** containing a good leaving group at the

<figure><img src="image_226.png" /><figcaption>**Scheme 125.** Regioselective allenylation of aldehydes with propargyl bromides.[246]</figcaption></figure>
γ-position.[244] Under the optimized reaction conditions, allene products **278** can be isolated via a cumulenol intermediate **279** that after tautomerization to 2-allenoyl thiazolium **280** can be thus trapped by a suitable nucleophile, in this particular case, a solvent molecule (**Scheme 123**). Important mentioning, preliminary studies on an enantioselective version were also carried out, and a chiral triazolium precatalyst developed by Rovis gave the expected allenoate in 73% yield with 30% ee.[180b]

Thiazolium salt **281** is an effective precatalyst for [4 + 2] cycloaddition of nitroalkenes and oxodienes providing dihydropyrans **282** in both good yields and diastereoselectivities.[245] Isotopic labeling indicates that the transformation appears to be initiated by the addition of the NHC-catalyst to the nitroolefin. Interestingly, by changing the N-substituent on the thiazolium precatalyst, reverse diastereoselectivity could be achieved (**281** versus **283**) (**Scheme 124**).

Recently, the regioselective allenylation of aldehydes with propargyl bromides was developed by Du and Gao to provide substituted allenones **284** (**Scheme 125**).[246] Based on DFT calculations, the approach relies on radical–radical coupling of allenyl radicals instead of propargyl radicals with the ketyl radicals **232**, enabling high regioselectivities to be achieved.

## 7. Conclusion and Outlook

It is undeniable that azolium-based NHC-organocatalysis has become an extremely powerful tool for modern organic chemistry to achieve great molecular diversity through unique transformations. Indeed, inspired by Nature, thanks to a thiamine pyrophosphate (TPP)-dependent enzyme which bears a thiazolium and is responsible for vital biological processes, C—C bond formation via unusual umpolung reactivity of carbonyl groups appears as a practical, mild, and greener alternative to the ones based on the use of transition metals. Initially, by analogy with thiamine, thiazolium salts were the first to be studied and marketed NHCs. This class of azolium pioneered traditional transformations such as benzoin condensation and Stetter reaction, demonstrating the power and selectivity of these precatalysts. As a result, other azolium salts, such as imidazoliums and triazoliums, have emerged together with chiral variants. Although thiazoliums were soon overtaken by other azolium salts, we cannot deny the role they played in the development of more powerful precatalysts. In this review, we have tried to tell a story about the evolution over time of thiazoliums in NHC-type organocatalysis. While more efficient catalysts have been developed, particularly for enantioselective transformations, it is beyond doubt that thiazoliums have yet to reveal their full catalytic potential. This can be seen in contemporary redox transformations, for which triazolium and

imidazolium salts are far less effective. The idea within this review was to demonstrate how thiazolium salts have played a crucial role in the development and evolution of NHC-organocatalysis. We are convinced that fine-tuning their physico-chemical properties, through the design and synthesis of novel thiazolium salt architectures, can lead to the discovery of new, as yet unexplored reactivities. Therefore, other transformations will follow, as thiazolylidenes have yet to reveal their full potential.

## Acknowledgements

The authors are grateful to the "Agence Nationale de la Recherche" (ANR PRC project ATzC_NHC: ANR-21-CE07-0039) for its financial support. The authors also thank the CNRS (Centre National de la Recherche Scientifique), the ENSCM (Ecole Nationale Supérieure de Chimie de Montpellier), and the Université de Montpellier for their support.

## Conflict of Interest

The authors declare no conflict of interest.

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