# Chiral Phosphoric Acid-Catalyzed Enantioselective Formal [4+2] Cycloaddition Between Dienecarbamates and 2-Benzothioazolimines

Wei-yang Ma, Emeric Montinho-inacio, Bogdan Iorga, Pascal Retailleau, Xavier Moreau, Luc Neuville, Geraldine Masson

► To cite this version:

Wei-yang Ma, Emeric Montinho-inacio, Bogdan Iorga, Pascal Retailleau, Xavier Moreau, et al.. Chiral Phosphoric Acid-Catalyzed Enantioselective Formal [4+2] Cycloaddition Between Dienecarbamates and 2-Benzothioazolimines. Advanced Synthesis and Catalysis, 2022, 364 (10), pp.1708-1715. 10.1002/adsc.202200161. hal-03660600

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Distributed under a Creative Commons Attribution 4.0 International License
Chiral Phosphoric Acid–Catalyzed Enantioselective Formal
[4+2] Cycloaddition between Dienecarbamates and 2–
Benzothioazolimines

Wei-Yang Ma,ª Emeric Montinho-Inacio,ª Bogdan I. Iorga,ª Pascal Retailleau,ª Xavier Moreau,ᵇ Luc Neuville,ª,c and Géraldine Massonª,a,c,\*

a Institut de Chimie des Substances Naturelles CNRS UPR 2301,
Université Paris–Saclay
1, avenue de la Terrasse, 91198 Gif–sur–Yvette Cedex, France
Fax: (+33)1–6907–7247
E–mail: Geraldine.masson@cnrs.fr
Homepage: https://massongroup.wixsite.com/power

b Institut Lavoisier de Versailles (ILV) UMR CNRS 8180,
Université Versailles–St–Quentin–en–Yvelines, Université Paris–Saclay,
45 avenue des États–Unis, Bâtiment Lavoisier, 78035 Versailles Cedex, France

c Labcom HITCAT, joint lab CNRS-SEQENS
ZI de Limay 2, 8 rue de Rouen, 78440 Porcheville, France

**Abstract.** An enantioselective chiral phosphoric acid catalyzed formal [4+2] cycloaddition between 2-benzothiazolimines and N-H-1,3-dienecarbamates is described. A divergence in reaction pathways was observed depending on the dienes employed. The reaction performed with 4-substituted dienes produced benzothiazolopyrimidines as major product in yields ranging from 42 to 67%, as single diastereoisomer and with enantioselectivity between 93 and 99%. The same reaction performed with 3-substituted dienes, however, gave highly enantioenriched 1,2,3,4-tetrahydroquinolines as the major products albeit with moderate diastereoselectivity.

**Keywords:** Dienecarbamate; Chiral phosphoric acid; cycloaddition; Heterocycle; Aza–Diels–Alder reaction

Tetrahydropyridines (THP)[1] and benzothiazolopyrimidines[2] have been heavily targeted since these two heterocyclic motifs provide an entry to various medicinally relevant products. In addition, benzothiazolopyrimidines, also referred to as isothioureas (ITU), have been found to be excellent Lewis base organocatalysts.[3] Therefore, a tremendous amount of effort has been devoted to develop efficient enantioselective catalytic methods for construction of both type of heterocycles. Among them, [4 + 2] cycloaddition strategies are one of the most efficient and direct ways to synthesize these corresponding heterocycles.[4] In this context, our group reported an enantioselective synthesis of tetrahydropyridines through chiral phosphoric acid catalyzed enantioselective Diels–Alder reaction between enecarbamates and unsaturated imine (Scheme 1a, left).[5] More recently, we disclosed a chiral phosphoric acid catalyzed [4 + 2] cycloaddition of enecarbamates with 2-benzothiazolimines leading to diverse benzothiazolopyrimidines with excellent diastereo- and enantioselectivities (Scheme 1a, right).

[6] Due to the important biological activities of both type of azacycles and since they carry some common structural element, developing of a divergent synthetic strategy would be particularly attractive.[7] As such, we became interested in further exploring enantioselective [4 + 2] cycloaddition strategies in this direction.

N-H 1,3-Dienecarbamates are valuable building blocks in organic synthesis. Introduced by Overman in 1978,[8] they have since been found to be valuable units enabling the synthesis of several natural products such as perhydrogephyrotoxin, gephyrotoxin, pumiliotoxin C or amiclenomycin.[9] As electron rich dienes, they were used as partner in various enantioselective normal electron demand [4+2] cycloadditions leading to 6-membered cyclic amines, for which chiral phosphoric acid catalysis[10] proved to be particularly effective (Scheme 1b, left). Indeed, when opposed to dienophiles such as alkenes, quinones, nitroso or diazo compounds, they give access to valuable cyclohexenes amines or related azacycles.[11] Interestingly, while these dienes have been essentially used a dienes in [4+2] cycloadditions (Scheme 1b, left), including in enantioselective ones, N-H 1,3-dienecarbamates can also act as simple ene unit. As such, Bernardi et al. reported the use of simple unsubstituted dienecarbamates[12] in Povarov reaction leading to the synthesis of 1,2,3,4-tetrahydroquinolines (Scheme 1b, right).[13]
<figure><img src="image_2.png" /><figcaption>**Scheme 1.** Catalytic enantioselective cycloaddition involving dienecarbamates and present work.</figcaption></figure>

In continuation of our research program in catalytic asymmetric reactions with dienecarbamates,[14] we decided to explore their reactivities in connection with 2-benzothiazolimines. Indeed, these imines are versatile synthetic intermediates used for the syntheses of various heterocycles[15] and they have been embedded in direct catalytic asymmetric annulation strategies.[2e-h] With two latent nucleophiles (N and N'), we reasoned that they could be ideal linchpin for divergent pathways,[7] as a common intermediate generated upon addition of a dienecarbamate onto the imine, could eventually lead by ring closure either to a tetrahydropyridine motive or benzothiazolopyrimidine skeleton (Scheme 1c). Herein, we report our findings uncovering a substrate-controlled behavior, allowing developing a highly enantioselective chiral phosphoric acid catalyzed aza-Diels-Alder for the synthesis of both, chiral benzothiazolopyrimidines or chiral tetrahydropyridines.

We initiated our work by evaluating the reaction between imine **1a** and dienecarbamate **2a** in dichloroethane at 50 °C in presence of various catalysts (Table 1). We were delighted to identify compound **4a** as the main isolable product in nearly each attempt. Careful NMR analyses lead to the conclusion that compound **4a**, isolated as a single diastereoisomer, had a 3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimidine core in which the terminal double bound of the dienecarbamate **2a** was embedded in the cyclisation.[16] While most chiral phosphoric acids were poorly effective, TRIP (**3e**) stood out as essentially the sole effective catalyst able to promote a reaction. Further investigation of the conditions leads to the following observations: heating the reaction at 50 °C was mandatory as no reaction occurred at RT but further increase of temperature was deleterious. 1,2-dichloroethane (DCE) proved to be a superior solvent compared to toluene.[17] The reaction

was only marginally affected by the presence of molecular sieves (entry 5 vs 11) contrary to the relative stoichiometry of reagents that was best when using 3 equivalents of dienecarbamate **2a** (entry 5 vs 13,14). Overall, conditions established in entry 5 delivered product **4a** in 60% yield with 99% enantiomeric excess.

<figure><img src="image_3.png" /><figcaption>**Table 1.** Synthesis of ITU: a survey of reaction conditions.[a]</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Cat</th><th>Solvent</th><th>Temp.</th><th>Yield<br>[%]<sup>b)</sup></th><th>ee<br>[%]<sup>c)</sup></th></tr></thead><tbody><tr><td>1</td><td><b>3a</b></td><td>DCE</td><td>50 °C</td><td>4</td><td>—</td></tr><tr><td>2</td><td><b>3b</b></td><td>DCE</td><td>50 °C</td><td>5</td><td>—</td></tr><tr><td>3</td><td><b>3c</b></td><td>DCE</td><td>50 °C</td><td>14</td><td>—</td></tr><tr><td>4</td><td><b>3d</b></td><td>DCE</td><td>50 °C</td><td>Low</td><td>—</td></tr><tr><td>5</td><td><b>3e</b></td><td>DCE</td><td>50 °C</td><td>60</td><td>99</td></tr><tr><td>6</td><td><b>3f</b></td><td>DCE</td><td>50 °C</td><td>7</td><td>—</td></tr><tr><td>7</td><td><b>3g</b></td><td>DCE</td><td>50 °C</td><td>20</td><td>—</td></tr><tr><td>8</td><td><b>3e</b></td><td>Toluene</td><td>50 °C</td><td>Low</td><td>—</td></tr><tr><td>9</td><td><b>3e</b></td><td>Toluene</td><td>reflux</td><td>0%</td><td>—</td></tr><tr><td>10<sup>d)</sup></td><td><b>3e</b></td><td>DCE</td><td>RT</td><td>Trace</td><td>—</td></tr><tr><td>11<sup>e)</sup></td><td><b>3e</b></td><td>DCE</td><td>50 °C</td><td>61</td><td>98</td></tr><tr><td>12</td><td><b>3e</b></td><td>DCE</td><td>reflux</td><td>39</td><td>98</td></tr><tr><td>13<sup>f)</sup></td><td><b>3e</b></td><td>DCE</td><td>50 °C</td><td>&lt;30</td><td>—</td></tr><tr><td>14<sup>d)</sup></td><td><b>3e</b></td><td>DCE</td><td>50 °C</td><td>38</td><td>—</td></tr></tbody></table>

a) General conditions: Cat **3** (0.01 mmol), **1a** (0.2 mmol), **2a** (0.6 mmol) in solvent (1 mL), temperature, 24h. b) ¹H NMR yields, determined with 1,3,5-trimethoxybenzene as internal standard. d.r. > 98:2 in all cases, determined by ¹H NMR analysis. c) Enantiomeric excess determined by HPLC on a chiral stationary phase; see the Supporting Information for details. d) **2a** (0.4 mmol). e) 0.2g molecular sieve (4Å). f) **2a** (0.3 mmol).

With the optimal reaction conditions established, we next investigated the substrate scope of the reaction by employing various imines **1** and **1,3-dien-1-yl** carbamate **2**. As can be seen in table 2, imines tolerated various substituents such as methoxy, methyl, cyanide or halogens either at the benzo[d]thiazol-2-yl or at the aromatic ring. However, incorporation of *ortho* substitution at either aromatic end of imines ((o-tolyl)methanimine or 4-methylbenzo[d]thiazol-2-yl) was not tolerated. Presence of electron withdrawing group seems beneficial in terms of yield (compounds **4d** and **4e**), but overall, the reaction proceeded with acceptable yields in each case and importantly with excellent enantioselectivity (up to 99%).
Heteroaromatic thiophene was also fully compatible allowing building compound **4g** in 67% yield with near perfect enantioselectivity.

<figure><img src="image_4.png" /><figcaption>**Table 2.** Scope of the organocatalytic enantioselective regioselective [4+2] cyclization for the synthesis of ITU.[a]</figcaption></figure>

a) General conditions: table 1 entry 5; yields refer chromatographically pure products; absolute configuration is speculative.

Various 1,3-dien-1-yl carbamates **2** were subsequently evaluated. Besides benzyl-protected carbamate (NHCbz), methylcarbamate or S-benzylcarbamothioate were well tolerated and the corresponding benzothiazolopyrimidines (**4h** and **4k**) were, isolated in good yields and excellent stereoselectivities. Pleasingly, 1,3-dien-1-yl carbamate **2** with more or less sterically demanding δ-substituted alkyl side chains such as methyl, isobutyl, isopropyl or 2,6-dimethylhept-5-enyl performed uneventfully (compounds **4j-1**). Of note, presence of an additional chiral center in the side chain of dienecarbamate does not affect the enantioselectivity as observed for **4l** ((S)-)-citronellal derived), obtained with equal enantiomeric excess compared to **4j** (>99% ee). Presence of δ-substituent on the dienecarbamate proved however to be mandatory for enantioselectivity, as use of benzyl (E)-buta-1,3-dien-1-ylcarbamate **2c** furnished the corresponding cycloadduct **4i** in descent yield (62%) but almost as racemate (ee: 10%). It is also worth noting that in general yields are moderate mainly due to the

difficulty to purify the relative polar products in presence of excess of carbamates.

Following this last result, we surmised that substitution on the diene could be a handle to modulate or diverge from the ITU-pathway and therefore decided to investigate the behavior of benzyl (E)-(3-methylbuta-1,3-dien-1-yl)carbamate **2g**, bearing a methyl substituted at the γ-position. To our delight, under the initially established conditions (Table 1, entry 5), this diene did not form any benzo[4,5]thiazolo[3,2-a]pyrimidine adduct, but instead, we were able to isolate the tetrahydropyridin-2-ylcarbamates adduct **5a** as single diastereoisomer. The modest yield (38%) and limited enantioselectivity (40%) prompted us to reinvestigate the conditions (Table 3).

<figure><img src="image_5.png" /><figcaption>**Table 3.** Synthesis of 4-aminotetrahydroquinoline: a survey of reaction conditions. a)</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Cat</th><th>Solvent</th><th>Temp</th><th>dr<sup>b)</sup></th><th>5a<br>Yield<br>[%]<sup>c)</sup><br>(ee [%]<sup>d)</sup>)</th><th>5a'<br>Yield<br>[%]<sup>c)</sup><br>(ee [%]<sup>d)</sup>)</th></tr></thead><tbody><tr><td>1<sup>d)</sup></td><td>3e</td><td>DCE</td><td>50 °C</td><td>-</td><td>38 (40)</td><td>(-)</td></tr><tr><td>2</td><td>3e</td><td>DCE</td><td>25 °C</td><td>-</td><td>40 (60)</td><td>trace</td></tr><tr><td>3</td><td>3e</td><td>DCE</td><td>0 °C</td><td>1.5:1</td><td>20 (90)</td><td>14 (nd)</td></tr><tr><td>4</td><td>3e</td><td>DCE</td><td>45 °C</td><td>-</td><td>&lt;10 (97)</td><td>nd</td></tr><tr><td>5</td><td>3e</td><td>CHCl<sub>3</sub></td><td>0 °C</td><td>2:1</td><td>40 (92)</td><td>21 (88)</td></tr><tr><td>6</td><td>3b</td><td>CHCl<sub>3</sub></td><td>0 °C</td><td>1.3:1</td><td>39 (46)</td><td>28 (10)</td></tr><tr><td>7</td><td>3c</td><td>CHCl<sub>3</sub></td><td>0 °C</td><td>1:1</td><td>27 (45)</td><td>18 (25)</td></tr><tr><td>8</td><td>3h</td><td>CHCl<sub>3</sub></td><td>0 °C</td><td>1:1.1.</td><td>36 (22)</td><td>28 (10)</td></tr></tbody></table>

a) General conditions: **3** (0.01 mmol), **1a** (0.2 mmol), **2g** (0.4 mmol) in solvent (1 mL), at a defined temperature, 24h. b) Estimated from crude ¹H NMR analysis. c) Yields refer to chromatographically pure products. d) Enantiomeric excess determined by HPLC on a chiral stationary phase: see the Supporting Information for details. e) **2a** (0.6 mmol).

Lowering the temperature was in this case possible and had a clear beneficial impact on enantioselectivity, delivering compound **5a** with 90% or 97% ee at 0°C or -45°C, respectively (entries 2-4). Yields remained however low and examination of reactions revealed the presence of a second compound **5a'**. Diastereomeric relationship between **5a** and **5a'** was established based on analytical data (see SI) and on the fact that **5a'** converted to **5a** at 50°C, but with substantial degradation. Solvent was found to be important for the overall yield of the transformation. Indeed, performing the reaction at 0°C but switching from DCE to CHCl<sub>3</sub> as supporting media allowed to isolate **5a** in 40% yield with 92% ee and 21% of **5a'**
with 88% ee. Finally, while other chiral phosphoric acid did promote the reaction, none was superior to TRIP catalyst (3e) (entries 5–8).

<figure><img src="image_6.png" /><figcaption>**Table 4.** Scope of the organocatalytic enantioselective [4+2] cyclization for the synthesis of THP.<sup>a)</sup></figcaption></figure>

a) General conditions: table 3, entry 5; dr is estimated from crude ¹H NMR analysis, yields refer chromatographically pure products; absolute configuration based on X-ray of compound 5b'.

Various N-(benzo[d]thiazol-2-yl)-1-phenylmethanimines **1** were subsequently engaged with diene **2g** under these novel conditions (Table 4). The reaction proved to be quite general furnishing in each case two separable diastereoisomers in a good overall yield (from 61% to 97%). Diverse functional groups such as methyl, OMe, CN, NO₂ or halides, positioned at the benzothiazole unit or at the terminal aryl of imine precursor, proved all compatible. Interestingly, compound **5f/5f'** and compound **5g/5g'** derived from sterically demanding 4-methylbenzo- or naphthalizoles, could also be isolated uneventfully. 2-Methylbenzaldehyde derived imine could be also used

as demonstrated with the synthesis of compounds **5i/5i'**; enantioselectivity (73% and 68%, respectively) was however reduced in that case probably for steric reason. **tert**-Butoxycarbonyl-protected diene carbamate **2h** was also a competent precursor, furnishing compounds **5h/5h'** in excellent yield. Overall, diastereoselection remained low but a few examples proved to be significant. As such, an almost equal amount of individual stereoisomers **5c** and **5c'** were produce in the reaction, contrary to compound **5f** and **5f'** isolated in 55% and 16%, respectively (d.r.: 3/1). Nevertheless, it should be mentioned that enantioselectivity was in each case high (>76%), reaching even 99% for compound **5b**. One diastereoisomer showed consistently a slightly lower enantioselectivity than the second one in pair of diastereoisomers. We also demonstrated that the reaction could be easily performed on a 1.0 mmol scale by synthetizing cycloadduct **5h/5h'**, obtained in comparable yields (90% vs 97% overall yield) and with equal selectivity, thus demonstrating the practicality of this process. In addition, use of (E)-N-(4-phenylbuta-1,3-dien-2-yl)acetamide **(6)** was also conducive to a tetrahydropyridin-2-yl framework. Conditions applied for ITU syntheses (Table 1, entry 5) were however required furnishing compound **7** in a modest 38% yield but as a single diastereoisomer with 90% enantiomeric excess.[18]

A plausible reaction mechanism, accounting for both scaffolds, is depicted in Scheme 2. A two-step mechanism, reported for various (aza)-Diels-Alder reaction and in line with our previous study on benzothiazolopyrimidines, can be proposed.[6, 13b, 19] Presence of aldehyde traces in the crude reaction mixture possibly arising from the hydrolysis of intermediates (**B1/B2**) brings support to this 2-step mechanism. According to many precedents in phosphoric acid-catalyzed process, and in line with a bifunctional activation mode[10, 11a, 20] formation of a ternary complex **A** involving imine **1**, dienecarbamate **2** and phosphoric acid catalyst **3** could initiate the transformation. Within the spatially defined complex **A**, a dual activation mode will promote a stereoselective vinylogous Mannich reaction. This step could be reversible explaining the low enantioselectivity observed in the case of **4i**. The bond-forming event will be conducive to complex **B** containing the first enantio-defined bond and an unsaturated iminium. In a second event, intramolecular 1,2- or 1,4-addition of a defined nitrogen of the benzo[d]thiazol-2-amine residue onto the conjugated iminium will furnish either intermediate **C** or **D**. Configuration of the conjugated iminium in complex **B** could be advanced to justify individual pathways. Indeed, within the hydrogen bond network, an *E*-configured adduct (**B1**) could fold into a conformation where one nitrogen (Red) is in close proximity of the 4-position of the iminium and would cyclize to **C**. Presence of a substituent (R²) at the γ-position of the dienecarbamate will disfavor this *E*-configuration and probably slow down cyclisation. In this latter case, intermediate **B2** presenting a Z-
configuration could be favored and, based on
proximity, would cyclize through 1,2 addition.
Formation of individual B1/B2 complexes could be in
line with an initial s-trans or s-cis conformation of the
dienecarbamate. It should be noted E/Z stereochemical
arguments have been suggested from DFT-calculation
in related Mukaiyama-Mannich reaction involving γ-
substituted vinylketene silyl acetals.[21] Catalyst
control, through a chiral anchoring environment
present in complex B, could explain the high
diastereoselectivity observed for compound 4 (single
diastereoisomer). The same could hold for compound
5', which could subsequently epimerize to 5 under the
reaction condition. Indeed, partial conversion (≈20%)
of isolated 5a' to 5a was observed upon standing in
CDCl3 for 3 days. Catalyst decomplexation should
finally close the cycle. Because of the difference in
basicity of individual product, release of compound
5/5' can be performed at low temperature, contrary to
compound 4 for which more forcing condition (Heat,
excess reagent) will be beneficial.

<figure><img src="image_7.png" /><figcaption>**Scheme 2.** Mechanical proposal for the divergent enantioselective aza–DA reactions.</figcaption></figure>

We finally turned our attention to stereochemical
determination of compounds **4** and **5**. A suitable
crystal of compound **5b'** could be grown and
elucidated by X-ray analysis revealing a (2S,6S)
absolute configuration (scheme 3, a).[22] A *cis*
relationship was therefore assigned to the
corresponding diastereoisomer **5b** and in analogy, to
the entire series, with (2S,6R) absolute
configuration.[23] Despite considerable efforts, we
were not able to get suitable crystals from any
compound **4**. A combination of experimental and
computational approaches was there for adopted to
establish the relative configuration of the series.[24]
Extensive NMR studies were undertaken with a

representative isothiourea (4f). In parallel, we
performed a conformational search by restrained
molecular dynamics in explicit solvent on each
possible diastereoisomer of ITUs (cis/trans 8,
trans/trans 9, trans/cis 10, and cis/cis 11, Scheme 3, b)
considering pseudo axial or pseudo equatorial
arrangements, followed by DFT calculations for
geometry optimization of the most representative
conformers using Gaussian09 (see supporting
information). Comparison of information from
experimental data and computed structures allowed to
make several conclusions. Large set of cross peaks
experimentally observed in the NOESY spectra of
compound 4f were found to be compatible with all
possible configurations when considering both axial or
equatorial arrangements. However, an experimentally
observed signal assigned to hydrogens belonging to C2
and C1''/C2'' allowed excluding the cis-cis (11) and
trans-trans (9) configurations. Furthermore, two
coupling constants (J2–3= 3.6 Hz and J3–4= 6.2 Hz),
extracted from the ¹H NMR spectra of compound 4f,
furnished additional geometrical information: the first
value should be in line with a dihedral angle around
50°, while the second value would require a dihedral
angle close to 70°.[25] Such values were incompatible
with those found in 9 and 10, which therefore can also
be excluded. Overall, these results tend to indicate that
the cis-trans relationship of compound 8 presents the
best matching relative stereochemistry compared to
compound 4f. Further DFT calculations on additional
conformers of the enecarbamate side chain in
compound 8 allowed the identification of the most
stable conformers, representing more than 98.8% of
Boltzmann distribution, that were perfectly fitting with
all measured data. As such, considering that
compounds 5 and 4 share a common initial bond
forming event, a (2S,3R,4R) absolute configuration
can be suggested for this series of compounds.

<figure><img src="image_8.png" /><figcaption>**Scheme 3.** Stereochemical considerations.</figcaption></figure>
Interestingly we could further transform ITU **4a** into 1,2-dihydropyridine[26] **12** (scheme 4, a). As such, treatment of enantioenriched **4a** (99% ee) with an excess of TFA (3 equiv) in DCM, followed by refluxing the crude salt in toluene furnished compound **12** in 72% yield and 90% ee. A slight decrease in enantioselectivity was observed during the reaction, but could be contained by rapidly stopping the reaction at full conversion (followed by TLC). Indeed, racemization of pure product **12** was found to occur upon prolonged heating. The mechanism transforming **4a** to **12** was not investigated, but could involve a ring opening, the formation of an intermediate tetrahydropyridine E and a 1,4-elimination of benzyl carbamate. We also demonstrated that tetrahydropyridines adduct **5** could be further derivatized by considering a diastereoselective dihydroxylation (scheme 4, b). Dioxygenated piperidines **13** could be cleanly synthesized from compound **5h** following an osmium mediated/diamine hydrolysis sequence and isolated in 95%.[27] Compound **13**, which bears four-controlled stereocenters, including a tetrasubstituted one, was isolated in 95% yield. It is of note that an enrichment took place during the process, probably through a Horeau amplification,[28] as starting from compound **5h** having 90% ee, compound **13** reached 95% ee. The relative stereochemistry between the substituents on C₂ and C₃ in **13** was tentatively assigned as *trans* based upon the presumed steric effect of the starting material.

<figure><img src="image_9.png" /><figcaption>**Scheme 4.** Post-transformations.</figcaption></figure>

In conclusion, we have explored enantioselective phosphoric acid-catalyzed aza-Diels-Alder processes involving diene carbamates and 2-benzothiazolimines. A divergent cycloaddition pathway, depending on the substitution of the diene carbamate has been uncovered, leading either to tetrahydropyridine or 3,4-dihydro-2H-benzo[4,5]thiazolo[3,2-a]pyrimidine scaffold. The transformation provides enantioselectivity ranging from 68 to 99% over a broad range of precursors.

# Experimental Section

**General procedure for the synthesis of Isothioureas 4:**
To a solution of imine **1** (1.0 equiv.) and catalyst **3e** (0.1 equiv.) in dry 1,2-DCE (0.1 M) was added dienecarbamate **2** (3.0 equiv.). The reaction mixture was heated to 50 °C and stirred for 24 h under argon. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and the crude was directly purified by flash chromatography (SiO₂, heptane/ethyl acetate mixture) as to afford pure product **4**.

**General procedure for the synthesis of 4-methyl-1,2,3,6-tetrahydropyridine 5 and 5':** To a solution of imine **1** (1.0 equiv.) and catalyst **3e** (0.1 equiv.) in dry CHCl₃ (0.1 M) was added dienecarbamate **2** (2.0 equiv.). The reaction mixture was cooled to 0 °C and stirred for 48 h under argon. The reaction mixture was warmed to room temperature, concentrated under reduced pressure and the crude was directly purified by flash chromatography (SiO₂, heptane/ethyl acetate mixture) to afford the two separable pure product **5** and **5'**.

# Acknowledgements

*Financial supports from ICSN and CNRS. W.-Y.M. thanks the China Scholarship Council for a doctoral fellowship, E.M.-I thanks Labex Charm3at for a financial support of Master.*

# References

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[17] Heating in CHCl₃ led essentially to degradation.

[18] CCDC 2120408 contain the supplementary crystallographic data for **compound 7** in this paper.
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www.ccdc.cam.ac.uk/data_request/cif.

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[22] CCDC 2120407 contain the supplementary crystallographic data for *compound 5'* in this paper. These data can be obtained free of charge from The

Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.

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[28] Recent review: Andrew M. Harned, *Tetrahedron*, **2018**, *74*, 3797-3841.