# Electromediated alcohol-based Passerini type reaction

Alexandre Simon
Sylvestre Bachollet
Na Pan
Laurence Grimaud*
Maxime R. Vitale*

Laboratoire des biomolécules (LBM), Département de chimie,
École normale supérieure, PSL University, Sorbonne Université,
CNRS, 75005 Paris, France.

Laurence.grimaud@ens.psl.eu
maxime.vitale@ens.psl.eu

<figure><img src="image_1.png" /></figure>

23 examples
24-80% yield

**Abstract** A electrochemical variant of the alcohol-based oxidative Passerini reaction is reported here. It is based on an indirect anodic oxidation process followed by a 3-component coupling, in which TEMPO serves as a key redox mediator. This electrochemical approach permits to operate without the need for a metal catalyst, nor oxygen atmosphere, and allows the use of non-activated alcohols as reaction partners. It could be applied to the preparation of good variety of acyloxy-carboxamides in yields ranging from 24 to 80%.

**Key words** multicomponent reaction (MCR), Passerini type coupling, electrosynthesis, catalytic oxidation, isocyanides, TEMPO.

Multicomponent reactions (MCRs) are wonderful tools for the fast, efficient, and atom-economical preparation of organic compounds.¹ Under exceptionally green reaction conditions, they allow high chemical diversity to be achieved in a straightforward manner.²,³ For these reasons, MCRs have found numerous applications ranging from fine chemistry to materials science.⁴⁻⁷

Despite their undeniable practicality, MCRs may sometimes face technical difficulties, such as the use of an unstable or toxic partners. To circumvent such problems, "oxidative MCRs," MCRs in which one of the participating reactants is generated in situ via an oxidation event, have been developed and popularized.⁸,⁹

In this vein, Ngouansavanh and Zhu reported the first Passerini and the first Ugi-type multicomponent processes using an excess of 2-iodoxybenzoic acid (IBX) as the oxidant to in situ generate the required aldehydes or imines from relatively stable alcohols or amines.¹⁰,¹¹ Since then, much effort has been devoted to the development of more environmentally friendly oxidative isocyanide-based MCRs (IMCRs) exploring metal catalysis,¹²⁻¹⁵ photoredox catalysis,¹⁶⁻¹⁹ organo-catalysis²⁰ and electrosynthesis²¹,²² as means to promote Ugi-type processes.

In this area, we have previously demonstrated that the mild and safe electrochemical oxidation of cyclic secondary amines such as pyrrolidine can be realized in the presence of a carboxylic acid and an isocyanide, leading to the formation of the corresponding Ugi-type adducts in good yields (Scheme 1, (a)).²¹ This electrochemical process is based on an indirect anodic oxidation in which the (2,2,6,6-tetramethylpiperidin-1-yl)oxyl radical (TEMPO) acts as a redox mediator (i.e. catalyst).

As previously documented, this method allows for the transient formation of a potent oxoammonium oxidant that is constantly regenerated at the anode. In line with this initial study, we have

recently reported the first alcohol-based 4-component oxidative Ugi reaction, in which the electrochemical TEMPO-catalyzed strategy allowed the fully chemoselective oxidation of the alcohol over that of the amine (Scheme 1, (a)).²²

To the best of our knowledge, catalytic methods that enable an alcohol-based oxidative Passerini type process remain scarce. In 2010, Masson, Zhu *et coll.*²³ pioneered this field and reported a multicatalytic system based on a copper (II) salt, TEMPO, and sodium nitrite, which operates under oxygen atmosphere (Scheme 1, (b)). Since then, a very similar iron-catalyzed process was reported by Batra *et coll.*,²⁴ and Karimi and Farhangi developed a magnetically recyclable TEMPO derivative acting as a heterogenous catalyst.²⁵ Based on our expertise in electro-oxidative IMCRs, we decided to study the feasibility of a metal- and oxygen-free electrochemical alternative to such alcohol-based Passerini type coupling (Scheme 1, (c)).

(a) Our previous work - Electro-induced oxidative Ugi-type processes

<figure><img src="image_2.png" /></figure>

(b) Masson, Zhu *et al.* - Copper catalyzed Oxidative Passerini process

<figure><img src="image_3.png" /></figure>

(c) This work - Electro-induced oxidative Passerini process

<figure><img src="image_4.png" /></figure>

Scheme 1 Background and aim of this work

Due to relative difficulty to directly electro-oxidize alcohols, we opted for an indirect anodic oxidation process based on the use of aminoxyl redox mediators.²⁶,²⁸a This type of alcohol oxidation process has been extensively studied in the past and has been
proven to be favoured under basic conditions.²⁶⁻²⁹ In the electro-induced Ugi reaction that we previously developed,²² the presence of an amine ensured a "buffered" reaction medium, facilitating the rapid oxidation of alcohol by the in situ generated oxoammonium. However, it remained very uncertain whether the electro-induced Passerini reaction could proceed under similar conditions, especially because the activation of the carbonyl group for nucleophilic addition of the isocyanide requires acidic conditions.³⁰ To get some insights into this, we performed some preliminary cyclic voltammetry (CV) studies. As expected, the gradual addition of up to 200 equivalents of MeOH to a 2 mM solution of TEMPO in acetonitrile did not reveal any catalytic effect, as detected by cyclic voltammetry (CV) at a slow scan rate of 50 mV/s (Figure 1, red plot).²⁶,²⁸ This observation held true under "acidic conditions" in the presence of 25 equivalents of acetic acid (Figure 1, blue plot). However, we confirmed that in the presence of a 1:1 mixture of AcOH (25 eq) and 2,6-lutidine (25 eq),²⁸ the electrogenerated oxoammonium TEMPO⁺ is consumed, as evidenced by the absence of a reverse reduction peak on the corresponding CV trace (Figure 1, green plot).

<figure><img src="image_5.png" /><figcaption>**Figure 1** Cyclic Voltammetry studies performed on a glassy carbon electrode in a solution of TBABF₄ (0.1 M in acetonitrile), using a platinum wire as counter electrode and an Ag/AgCl (NaCl 3M) as reference electrode. TEMPO (2 mM) (black plot). TEMPO (2 mM) + MeOH (200 eq) (red plot). TEMPO (2 mM) + MeOH (200 eq) + AcOH (25 eq) (blue plot). TEMPO (2 mM) + MeOH (200 eq) + AcOH (25 eq) + 2,6-lutidine (25 eq) (green plot).</figcaption></figure>

Optimizing the entire process involved a delicate balance between promoting efficient alcohol oxidation under buffered conditions and facilitating rapid nucleophilic addition of isocyanide to the activated aldehyde in acidic conditions. Therefore, we tested the reaction under both buffered and acidic conditions. The first trials were performed in acetonitrile using methanol **1a** (3 eq), *tert*-butyl isocyanide **3a** (1 eq, 1 M), and AcOH **2a** (2.5 eq) in the presence of TEMPO (10 mol%) with and without 2,6-lutidine (25 eq). The electrosynthesis was performed at constant current (20 mA cm⁻²) in an undivided cell, in the presence of a small amount of tetra-*n*-butylammonium tetrafluoroborate (TBABF₄, 0.25 eq) as supporting electrolyte, using a carbon graphite anode (Cg) and a stainless steel (SS) cathode. Unexpectedly, the reaction in acidic conditions (Table 1, entry 1) outperformed that in buffered conditions, where no

desired product could be detected (Table 1, entry 2). It led us to conclude that, even though "buffered" reaction conditions seemed beneficial for the oxidation event, they probably impeded the activation of the carbonyl derivative which is key for the isocyanide addition step.³⁰ Pleasingly, in the absence of the base, the targeted 3-component Passerini adduct **4aaa** was isolated in 77% yield after a total charge of 2.7 F per mol of methanol (Table 1, entry 1).

Other solvents including DCM, THF and DMF (Table 1, entries 3-5) were tested but none outperformed the use of acetonitrile. Testing other cathode materials, including nickel, carbon graphite, zinc, and magnesium, resulted in reduced yields (Table 1, entries 6-9).³² Notably, the lowest yield (13%) was observed when using carbon graphite (Table 1, entry 7), likely due to a more significant overpotential for proton reduction.³² Additionally, we observed reproducibility issues with nickel, for reasons that still remain unclear. Tetra-*n*-butylammonium tosylate (TBAOTs) and lithium hexafluorophosphate (LiPF₆) could be used, albeit lower yields were obtained (Table 1, entries 10-11). Considering the significant hygroscopic properties of these two salts, we speculate that the reduced yield may be due to the reaction's poor tolerance towards water. As Stahl and coworkers established that 4-NHAc-TEMPO demonstrated superior efficiency for 1-butanol oxidation than TEMPO,³³ we also tested it. However, no significant improvement was observed (Table 1, entry 12).

<table><caption>**Table 1** Influence of diverse reaction parameters over the reaction</caption><thead><tr><th colspan="3">MeOH + MeCOOH + <sup>1</sup>Bu-NC</th><th colspan="3">Cg + H + SS</th></tr><tr><th>1a</th><th>2a</th><th>3a</th><th colspan="3">J = 20 mA cm<sup>-2</sup><br>2.7 F per mol of 1a</th></tr><tr><th>3 eq</th><th>2.5 eq</th><th>1 eq<br>(c = 1M)</th><th colspan="3">TEMPO (10 mol%)<br>TBABF<sub>4</sub> (0.25 eq)<br>CH<sub>3</sub>CN</th></tr><tr><th>Entry</th><th colspan="2">Deviation from above</th><th colspan="3">Yield (%)<sup>a,b</sup></th></tr></thead><tbody><tr><td>1</td><td colspan="2">None</td><td colspan="3">77<sup>a</sup></td></tr><tr><td>2</td><td colspan="2">2,6-lutidine<sup>c</sup></td><td colspan="3">-</td></tr><tr><td>3</td><td colspan="2">CH<sub>2</sub>Cl<sub>2</sub> (DCM) as solvent</td><td colspan="3">50<sup>b</sup></td></tr><tr><td>4</td><td colspan="2">THF as solvent</td><td colspan="3">41<sup>b</sup></td></tr><tr><td>5</td><td colspan="2">DMF as solvent</td><td colspan="3">-</td></tr><tr><td>6</td><td colspan="2">Ni cathode</td><td colspan="3">41<sup>b</sup></td></tr><tr><td>7</td><td colspan="2">Cg cathode</td><td colspan="3">13<sup>b</sup></td></tr><tr><td>8</td><td colspan="2">Zn cathode</td><td colspan="3">68<sup>b</sup></td></tr><tr><td>9</td><td colspan="2">Mg cathode</td><td colspan="3">31<sup>b</sup></td></tr><tr><td>10</td><td colspan="2">TBAOTs as supporting electrolyte</td><td colspan="3">70<sup>b</sup></td></tr><tr><td>11</td><td colspan="2">LiPF<sub>6</sub> as supporting electrolyte</td><td colspan="3">50<sup>b</sup></td></tr><tr><td>12</td><td colspan="2">4-NHAc-TEMPO instead of TEMPO</td><td colspan="3">75<sup>b</sup></td></tr><tr><td>13</td><td colspan="2">TEMPO (5 mol%)</td><td colspan="3">57<sup>b</sup></td></tr><tr><td>14</td><td colspan="2">TEMPO (20 mol%)</td><td colspan="3">74<sup>b</sup></td></tr><tr><td>15</td><td colspan="2">no TEMPO</td><td colspan="3">-</td></tr><tr><td>16</td><td colspan="2">MeOH (1.5 eq)</td><td colspan="3">53<sup>b</sup></td></tr><tr><td>17</td><td colspan="2">1F per mol of 1a</td><td colspan="3">57<sup>b</sup></td></tr><tr><td>18</td><td colspan="2">[3a] = 0.3M</td><td colspan="3">46<sup>b</sup></td></tr></tbody></table>

Reaction conditions: Galvanostatic electrolysis of a solution of **1a** (3 eq), **2a** AcOH (2.5 eq.), **3a** <sup>1</sup>BuNC (1 eq, c = 1M), TEMPO (10 mol%), TBABF₄ (0.25 eq.) in acetonitrile in an undivided cell at a current density of 20 mA cm⁻² and a total charge of 2.7 F per mol of **1a**. <sup>a</sup> Isolated yields. <sup>b</sup> NMR yields determined using TBABF₄ as internal reference. <sup>c</sup> 2.5 eq of 2,6-lutidine.

We also examined the impact of varying the amount of TEMPO. While employing only 5 mol% led to a substantial decrease in yield (Table 1, entry 13), using 20 mol% of this redox mediator gave no significant improvement (Table 1, entry 14). As
anticipated, the reaction was inoperative in its absence, providing support of a complete indirect anodic oxidation process (Table 1, entry 15) and completely ruling out a competitive direct oxidation of the alcohol partner at the anode.²⁵ The amount of methanol could be decreased down to 1.5 eq, although at the expense of reaction yield (Table 1, entry 16). In the same vein, lowering the total charge to 1F per mol of **1a** was detrimental (Table 1, entry 17). Finally, conducting the reaction under more diluted conditions (Table 1, entry 18) proved to be less efficient, in line with the classical concentrations required for efficient multicomponent reactions.

With these optimal conditions in hand, we assessed the scope of the reaction (Scheme 1). The reaction was tolerant to linear alcohols, affording 3-CR Passerini products in 60-80% yields (4aaa, 4baa, 4caa, 4daa). This result could be attributed to the low steric demand of these alcohols balanced with the good electrophilicities of the corresponding aldehydes. Conversely, more sterically hindered alcohols yielded the desired multicomponent products in moderate yields (4eaa, 4gaa). Terminal double bonds could be tolerated in a certain extent (33 %), albeit a concurrent anodic oxidation of the alkene moiety of

**4faa** could take place. Finally, the presence of a C-Cl bond on the alkyl chain reduced the efficiency of the reaction, giving a moderate 32 % yield of **4haa**, with uncomplete conversion of **1h** (0.40 eq recovered from starting 3.0 eq).

The scope of the carboxylic acids was then studied. Primary, secondary and tertiary aliphatic carboxylic acids afforded the adducts in good yields (**4aba**, **4aca**, **4ada**, **4aga**, **4aha**). Worthy of note, little influence of the steric hindrance was detected with only a small decrease in yield from **4aba** to **4aha** (from 72 % to 60 %). Internal double bonds and terminal triple bonds could also be tolerated albeit in lesser yields (**4aia**, **4aja**). Acrylic acids turned out to be efficient partners, affording the adduct **4aka** in a satisfactory 81% yield.

Finally, we investigated the scope of possible isocyanides for this reaction. Tertiary aliphatic or benzylic electron-rich isocyanides gave the products in excellent to good yields (**4aab**, **4aac**, **4aad**). However secondary and primary aliphatic isocyanides gave good to moderate yields (**4aac**, **4aaf**), in line with their lower nucleophilicity compared to tertiary ones.³⁴

<figure><img src="image_6.png" /></figure>

Alcohols

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

Acids

<figure><img src="image_9.png" /></figure>

<figure><img src="image_10.png" /></figure>

Isonitriles

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /><figcaption>Scheme 1 Scope of the Electro-oxidative TEMPO-catalyzed alcohol-based Passerini reaction</figcaption></figure>
<figure><img src="image_13.png" /><figcaption>Scheme 2 Mechanistic proposal for the electro-induced Passerini 3-CR.</figcaption></figure>

Consistently with the optimal conditions and the reaction scope, we propose a plausible reaction mechanism for this electro-oxidative Passerini reaction (Scheme 2). Initially TEMPO is oxidized at the anode to form the corresponding oxoammonium TEMPO+, which oxidizes the alcohol most likely through a bimolecular hydride transfer mechanism.²⁶⁻²⁹ The in-situ aldehyde A then undergoes an acid-catalysed addition of the isocyanide yielding the hydroxy-nitrilium B, which is trapped by the carboxylic acid, forming imidate C. The latter further rearranges via a Mumm rearrangement to form the desired Passerini adduct D.

In conclusion, we have developed the first alcohol-based electro-
induced Passerini 3-component reaction using TEMPO as the
electrocatalyst. This work is reminiscent of our previous work on
the electro-oxidative Ugi (4-CR)²² and further studies to broaden
this strategy to new electro-oxidative IMCR is currently
underway.

Funding Information

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Acknowledgment

The authors gratefully thank the ANR (ANR-20-CE07-0020, ELMER), the CNRS, the ENS and Sorbonne University for financial support. N. Pan thanks the China Scholarship Council (CSC) for funding her PhD studies.

Conflict of Interest

There are no conflicts of interest to declare.

Supporting Information

YES (this text will be updated with links prior to publication)

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