N-Heterocyclic carbene catalysed umpolung reactions of imines approaching enantioselective synthesis

Pankaj Chauhan
Department of Chemistry, Indian Institute of Technology Jammu, Jagti, NH 44, Nagrota Bypass, Jammu (J&K), 181221, India. E-mail: pankaj.chauhan@iitjammu.ac.in

Received 1st September 2019 , Accepted 19th October 2019

First published on 21st October 2019

N-Heterocyclic carbenes (NHCs) have emerged as efficient catalysts for promoting umpolung reactions of aldehydes and enals. To a certain extent, the NHC catalyzed umpolung reactions of Michael acceptors are also reported. Recently, the NHCs have been successfully used for catalysing the umpolung reactions of aldimines through the formation of aza-Breslow intermediates. The initial reports on the chiral NHC-catalysed enantioselective umpolung reactions of imines are turning out to be very promising to achieve a high level of enantio-induction. This highlight article focuses on the NHC catalysed umpolung reactions of aldimines, with a special emphasis on the corresponding enantioselective transformations.

N-Heterocyclic carbene (NHC) catalysis is instrumental for promoting interesting and useful transformations ranging from one carbon–carbon or carbon–heteroatom bond formation to multiple bond forming domino/cascade reactions.1 One of the widely explored aspects of NHC catalysis is the polarity inversion of the reactants by forming some special intermediates. This reactivity reversal is termed umpolung, which was introduced around four decades ago.2 However, the concept of reactivity reversal was first observed in 1832, when the famous cyanide catalysed benzoin condensation was discovered by Wöhler and Liebig.3 Later, it was found that cyanide can be replaced by NHCs for the umpolung reactions of aldehydes via the formation of Breslow intermediates 1, which not only facilitate the benzoin condensation, but also promote the Stetter reactions (Scheme 1).4 In 2004, the seminal and independent studies from the research groups of Glorius5 and Bode6 disclosed the umpolung reactions of enals via the NHC generated homoenolate intermediates 2. Until 2006, the majority of NHC catalysed reactions were only limited to the umpolung reactions of aldehydes and their unsaturated analogues; however, Fu and co-workers extended the concept of NHC catalysed umpolung reactions to other Michael acceptors via the generation of deoxy-Breslow intermediates 3.7
image file: c9qo01074b-s1.tif
Scheme 1 NHC-catalysed umpolung strategies.

Imines are privileged electrophilic substrates involved in several organic transformations for procuring nitrogen containing compounds. Similar to aldehydes, aldimines can be potential substrates for the NHC mediated umpolung reactions via the formation of aza-Breslow intermediates 4. In this context, Douthwaite and co-workers realized the stoichiometric formation of aza-Breslow intermediates via the intramolecular addition of in situ generated NHCs to the aldimines.8 This work was followed by the isolation of aza-Breslow intermediates from NHCs and iminium salts by the research group of Rovis.9 However, NHC-catalysed reactivity reversal in imines has not been well explored until recently.

This highlight article aims to provide a concise overview on the NHC mediated imine umpolung reactions and also emphasizes the latest contributions in the aza-Breslow intermediate mediated enantioselective umpolung reactions of imines.10

The polarity inversion reactions through NHC catalysis involving aza-Breslow intermediates remained unexplored until 2017, when the research group of Biju disclosed the NHC catalysed intramolecular cyclization reaction of aldimines 5 bearing unsaturated acceptors (Scheme 2).11 This type of imino-Stetter reaction leads to the formation of 2-substituted indole 3-acetic acid derivatives 6. In order to understand the reaction mechanism and involvement of aza-Breslow intermediates instead of deoxy-Breslow intermediates, new reactions have been designed. It was observed that the NHC catalysed cyclization reaction of imines derived from the aldehydes bearing electron-withdrawing groups did not afford the expected products. This observation indicates the generation of weakly nucleophilic aza-Breslow intermediates, which did not lead to the addition to the conjugate acceptor. This reaction route was further supported by the failure of NHC catalysed reactions of various weakly electrophilic α,β-unsaturated amides and by 100% deuterium incorporation into product 8 derived from imine 7. In the proposed catalytic cycle, the initial addition of NHC (generated from triazolium salt C1) to the C[double bond, length as m-dash]N of 5 generates a tetrahedral intermediate 9, which after proton transfer provides the aza-Breslow intermediate 10. This intermediate undergoes an intramolecular conjugate addition to generate enolate species 11, which eventually release the desired indole products 6 with the regeneration of NHC.

image file: c9qo01074b-s2.tif
Scheme 2 Synthesis of 2-substituted indole 3-acetic acid derivatives via NHC-catalysed imine umpolung reaction.

Simultaneously with Biju's work, Suresh and co-workers presented a similar NHC catalysed strategy to afford the same class of 2-substituted indole 3-acetic acid derivatives from the in situ generated ortho-imino cinnamates.12 However, no clear evidence was provided for the mechanism of the reaction whether operating through aza-Breslow or deoxy-Breslow intermediates.

Theoretical investigations on the mechanism of the NHC-catalyzed synthesis of 2-substituted indole-3-acetic esters also disclosed that these transformations take place through the formation of aza-Breslow intermediates.13,14 DFT calculations revealed that the whole catalytic cycle comprises of the following steps: (1) nucleophilic addition of NHC to the imine to give a tetrahedral intermediate, (2) first [1,2]-proton transfer to provide an aza-Breslow intermediate, (3) intramolecular conjugate addition; (4) second [1,2]-proton transfer, and (5) release of NHC to deliver the desired products. The outcome of DFT studies is also consistent with the catalytic cycle proposed by Biju's group shown in Scheme 2.11

The application of NHC-catalysed umpolung reactions of aldimines was further extended for the synthesis of 4-difluoromethyl quinoline derivatives (Scheme 3).15 In the presence of NHC precursor triazolium salt C2 and DBU, the imino-Stetter type intramolecular cyclization of aldimines 12 bearing a trifluoromethylated double bond proceeds via aza-Breslow intermediates to achieve moderate to good yields of quinoline products 13.

image file: c9qo01074b-s3.tif
Scheme 3 Synthesis of 4-difluoromethyl quinolines via NHC-catalysed imine umpolung reaction.

Huang and co-workers reported the involvement of aza-Breslow intermediates in the formation of amides 15 from aldimines 14 (Scheme 4).16 This transformation occurs through the oxidative carbene catalysis assisted by cooperative Lewis acid catalysis with wide substrate scope tolerance. It was proposed that initially aldimine 17 activated by LiCl undergoes the addition of NHC (generated from the triazolium salt C3) to provide isomeric intermediates 18 and 19. These zwitter ionic intermediates after deprotonation with a base resulted in the formation of aza-Breslow intermediate 20, which then adds to dioxygen thus generating intermediate 21. This step is followed by the addition of an oxygen anion of intermediate 21 to the LiCl activated aldimine 17 to provide intermediate 22, which undergoes O–O bond cleavage under basic conditions to furnish two molecules of amide product 15 with the regeneration of NHC. Direct involvement of aza-Breslow intermediates was confirmed by X-ray diffraction analysis of the isolated compound 16, which could be converted to the desired amide product in 95% yield in the presence of K2CO3 in THF and air.

image file: c9qo01074b-s4.tif
Scheme 4 Synthesis of amides from aldimines through aerobic oxidative carbene catalysis.

After achieving initial success in non-enantioselective synthesis, the strategy of NHC-catalysed imine umpolung reaction has recently been applied in enantioselective synthesis. In this context, Lupton and co-workers have developed an intermolecular imino-Stetter reaction between aldimines 23 and 3-methylene-chroman-2-ones 24 (Scheme 5).17 This NHC-catalysed asymmetric umpolung reaction provides a new entry to the chromanone products 25 with an excellent level of enantioselectivity. Other Michael acceptors such as a chalcone, cyclohexan-2-one, 2-amino acrylates and methylmethacrylate were also tested, however all these substrates failed to couple with imines 23, instead self-condensation products after the aza-benzoin condensation of imines along with the Michael acceptor have been isolated. On the basis of mechanistic studies, a catalytic cycle was proposed, in which the initial addition of NHC to imine 23 forms intermediate 26, which undergoes t-BuOH mediated tautomerization to provide aza-Breslow intermediate 27. The conjugate addition of 27 to chromanone 24 provides enolate species 28, which after the diastereoselective protonation affords intermediate 29. Subsequent elimination of product 25 makes NHC available for the next catalytic cycle.

image file: c9qo01074b-s5.tif
Scheme 5 Enantioselective intermolecular imino-Stetter reaction between aldimines and 3-methylene-chroman-2-ones.

Simultaneously with Lupton's work, Biju's group devised a NHC-catalysed enantioselective umpolung reaction of aldimines to provide aza-heterocyclic compounds (Scheme 6).18 The intramolecular umpolung reaction of bisimines 29 in the presence of a chiral NHC catalyst derived from the triazolium salt C5 provides an efficient entry to dihydroquinoxalines 30 with low to high er values. The dihydroquinoxalines were projected as a sensor of various acids and bases through preliminary photo-physical studies. The reaction was proposed to proceed via the initial addition of NHC to imine 30 to form intermediate 31, which upon proton transfer generates the intramolecular H-bonded aza-Breslow intermediate 32. The role of –OH groups in stabilizing the aza-Breslow intermediates via intramolecular H-bonds was also supported by DFT studies. The activated imine portion of 32 undergoes enantioselective intramolecular addition to afford intermediate 33, which after proton transfer and NHC release, provides the desired products 30.

image file: c9qo01074b-s6.tif
Scheme 6 Enantioselective intramolecular umpolung reaction of bisimines.

In summary, NHC catalysis proved its potential to promote inter- and intramolecular imine umpolung reactions. With this strategy, useful heterocyclic molecules could readily be synthesized. Even a couple of initial asymmetric reports were also very successful. In my opinion, the key elements for the success of NHC-catalyzed imino-Benzoin/Stetter reactions include easy and broad availability as well as high reactivity of imine substrates. The NHC-catalysed imine umpolung reaction, especially the enantioselective version is still at the stage of infancy and there exists a wide possibility for further development in terms of applying different other imines and acceptors as substrates. It is expected that this imine umpolung strategy will be extended for the development of new asymmetric transformations via the generation of other intermediates such as aza-enolate, aza-homo-enolate, aza-dienolate intermediates, etc., analogous to the intermediates generated by aldehydes and enals with NHCs. After the umpolung reaction of aldehydes, enals, Michael acceptors and now imines, it will be interesting to know the next feat of NHCs in terms of catalysing umpolung reactions.

Conflicts of interest

There are no conflicts to declare.


Financial support from Indian Institute of Technology Jammu for providing a seed grant is gratefully acknowledged.


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