Carbene-catalyzed enantioselective oxidative coupling of enals and di(hetero)arylmethanes

Abstract

Di(hetero)arylmethane is a unique structural motif for natural and synthetic functional molecules. To date, it remains challenging to functionalize the diaryl methyl sp3 carbon–hydrogen bond directly in an enantioselective manner. This is likely due to the relatively inert nature of the carbon–hydrogen bond and the difficult enantiofacial discrimination of two sterically similar aryl substituents. Here we disclose an N-heterocyclic carbene-catalyzed direct oxidative coupling of enals and di(hetero)arylmethanes. Our method allows for highly enantioselective transformation of diaryl methanes and quick access to benzimidazole fused lactams.

---

Introduction

Diarylmethyl units are widely present in functional molecules and natural products. Examples of such molecules include the antidepressant drug Sertraline,¹ Bz–IB conjugates with anti-inflammatory activities² and the natural product voacamine³ with cannabinoid CB1 receptor antagonistic activity (Fig. 1a). Notably, the diaryl methyl sp3 carbon in these bioactive molecules is often present as a chiral center.⁴ To date, the most well-studied approach for the incorporation of diaryl methane unit relies on reactions between diarylmethyl carbocations and nucleophilic substrates⁵ (Fig. 1b). Diarylmethyl carbocation intermediates are typically generated in situ from their precursors such as diarylmethanols.⁶ In contrast, as a potentially more straightforward approach, direct modification of diarylmethanes is much less studied (Fig. 1c). This is in part due to the weak acidity of the methyl C–H and the difficult enantiofacial discrimination of two sterically similar aryl substituents. Deprotonation of such a benzylic C–H bond typically requires the use of a strong base such as ⁿBuLi or Na.⁷ As an alternative choice, oxidative transformations of diarylmethanes via benzylic organometallic species⁸ or benzylic radicals⁹ can be realized under milder conditions. However, in all these approaches, direct enantioselective modification of diarylmethane remains challenging. Limited examples in this direction include oxidative or photoredox transformations via o-quinone methides (o-QM)¹⁰ or o-quinodimethanes(o-QDM)¹¹ as the key intermediates, and recent Rh-mediated asymmetric C–H arylation of diarylmethane.¹²

Fig. 1 Diarylmethyl compounds and their enantioselective synthesis.

Herein we disclose an N-heterocyclic carbene (abbreviated as NHC or carbene) organic catalyst-mediated formal oxidative coupling of enal β-carbon and diarylmethanes (Fig. 1d). Our initial designing consideration is to generate a diarylmethyl radical from a diarylmethane substrate as a key intermediate under oxidative conditions (Fig. 1c). It is known that the tendency for deprotonation and radical formation of benzylic carbons can be well-tuned by altering the electronic properties of the aryl substituents¹³ (Fig. 1c). We therefore eventually introduce heterocyclic benzimidazole as one of the aryl units of the diarylmethane substrate in order to achieve suitable reactivity. The selection of benzimidazole units also provides two additional benefits: benzimidazole is a structural analogue of purine and a potential pharmacophore;¹⁴ the NH group in benzimidazole can facilitate the turnover of the NHC catalyst via the formation of a lactam product at the end of the catalytic cycle.¹⁵ Mechanistic studies suggest that some of our carbene-catalyzed reactions likely go through single-electron-transfer (SET) processes and radical intermediates in the key steps, although an electron pair pathway cannot be completely ruled out.

Results and discussion

Key results in searching for suitable conditions by using cinnamaldehyde (1a) and diarylmethane 2 as model substrates are summarized in Table 1. We firstly used achiral triazolium salt A¹⁶ as the NHC pre-catalyst, DABCO as the base, and 3,3′,5,5′-tetra-tert-butyl-4,4′-diphenoquinone (DQ) as the oxidant.¹⁷ With 2-benzyl benzimidazole 2a as the substrate, the proposed lactam product was not observed in an appreciable amount under various conditions. We then introduced an electron-withdrawing nitro group into the phenyl ring of diarylmethane (using 2b as the substrate), and obtained the corresponding lactam product in 22% yield (entry 2). The use of amino indanol-derived triazolium carbene pre-catalyst B¹⁸ led to the lactam product in 36% yield with excellent ee (95% ee, entry 3). Several chiral NHC catalysts evaluated here did not provide better results in terms of both yields and ee values (entries 4–6). We then decided to use pre-catalyst B for further condition optimization (entries 7–12). The switch of the base from DABCO to DMAP significantly improved the yield from 36% (entry 3) to 60% (entry 7) with a slight increase of ee (from 95% to 98% ee) as well. Further optimization by using 1.5 equivalents of 1a and DQ and performing the reaction at 40 °C gave a better result of 84% yield and 98% ee (entry 8). Several oxidants (phenazine,¹⁹ hexachloroethane²⁰ and 4-nitro pyridine N-oxide²¹) previously used in oxidation and single-electron-transfer (SET) radical reactions could also mediate the reaction with low to moderate yields and excellent ee values (entries 9–11). Finally, the reaction outcome with B as the catalyst could be further improved by lowering the reaction concentration (entry 12).

Table 1 Screening of reaction conditions^a

Entry	2	NHC, base	Oxidant	Yield^b/%	ee^c/%
a Reaction conditions: 1a (0.06 mmol, 1.2 equiv.), 2 (0.05 mmol, 1.0 equiv.), NHC (20 mol%), base (0.5 equiv.) and oxidant (1.2 equiv.) in 0.5 mL THF at rt. b Determined by ^1H NMR, with 1,3,5-trimethoxybenzene as an internal standard. c Determined by chiral-phase HPLC analysis. d 1.5 equiv. of 1a and oxidant were used; reaction temperature was 40 °C. e In 1 mL THF. DABCO = 1,4-diazabicyclo[2.2.2]octane; DMAP = 4-dimethylaminopyridine.
1	2a	A, DABCO	DQ	Trace	—
2	2b	A, DABCO	DQ	22	—
3	2b	B, DABCO	DQ	36	95
4	2b	C, DABCO	DQ	27	−73
5	2b	D, DABCO	DQ	18	−77
6	2b	E, DABCO	DQ	25	−95
7	2b	B, DMAP	DQ	60	98
8^d	2b	B, DMAP	DQ	84	98
9^d	2b	B, DMAP	Phenazine	46	96
10^d	2b	B, DMAP	CCl3CCl3	7	nd
11^d	2b	B, DMAP	4-Nitropyridine N-oxide	40	98
12^d^,^e	2b	B, DMAP	DQ	92	98

---

With an acceptable condition in hand (Table 1, entry 12), we evaluated the scope of enals by using 2b as a model diarylmethane substrate (Table 2). Placing halogens, carboxylic esters, nitro groups, methyl, and methoxyl units as substituents at the para-position of the enal β-phenyl ring was well tolerated (3a–3h). The absolute configuration of 3c was unambiguously confirmed by single-crystal X-ray diffraction analysis (for details, see the ESI†). The use of enals with different substitution patterns on the phenyl ring all gave products with excellent yield, dr, and ee values (3i–3k). Heterocyclic, naphthalene, and alkene substituents were all tolerated in β-substitution of enals (3l–3o). Enal with a β-carboxylate substituent gave product 3p in moderate yield with excellent dr and good ee. The use of enals with a β-alkyl substituent led to products with low yields (around 10% yields as estimated via NMR).

Table 2 Examples of enal substrates^a

a Unless otherwise noted, all reactions were run on a 0.2 mmol scale under the standard conditions (Table 1, entry 12). Yield refers to isolated yield. b The reaction temperature was 80 °C.

---

We next studied the scope of diarylmethanes by using cinnamaldehyde 1a as the model enal substrate (Table 3). The nitro substituent in 2b can be replaced with other electron-withdrawing units such as CN, CO₂CH₃, SO₂CH₃, CF₃, and Br (4b–4f). Placing nitro groups at the ortho- or meta-position of the benzyl group of substrate 2 led to some decrease in reaction yields without affecting enantioselectivities (4g–4h). We also investigated the effect of substituents on the benzimidazole framework, and found that various substituents and substation patterns were well tolerated (4i–4o). When unsymmetrical benzimidazoles were used, the corresponding lactam products were obtained as a mixture of two regio-isomers (4k–4o, see the ESI† for details). This regio-isomer issue can be circumvented via one additional step in a one-pot operation: the lactam ring opened in acid alcohol in quantitative yield with ee and dr retained (as exemplified in 2k to 5, Table 3, one-pot procedure). Substrate bearing simple imidazolidine can also be used, giving product 4p in 69% yield, 10 : 1 dr, and 98% ee.

Table 3 Examples of di(hetero)arylmethane substrates^a

a Unless otherwise noted, all reactions were run on a 0.2 mmol scale under the standard conditions. Yield refers to isolated yield. b The reaction temperature was 80 °C. c The regio-isomer issues can be circumvented via one additional step in a one-pot operation.

---

To understand the reaction pathways, we performed several control experiments. We performed H/D exchange experiments for diarylmethane substrates 2b and 2f (Scheme 1a). With 2b as the substrate, deuterated adduct D-2b was observed in 50% yield (NMR yield, see the ESI† for details). However, when 2f (an effective substrate in our oxidative coupling reaction, Table 3, product 4f) was used, no H/D exchange was observed. This result suggested that the formation of an enamine intermediate was not necessary in our catalytic coupling reaction. When 2b was mixed with the radical scavenger BHT (butylated hydroxytoluene) in the presence of a DQ oxidant, adduct 7 could be obtained in 47% yield (Scheme 2b), suggesting the existence of benzylic radical intermediates. It is also worth noting that ketones 6 derived from 2via oxidation of the benzylic carbon were observed as the main side products in nearly all examples. 2q-dimer generated from homo-coupling of benzylic carbon was also observed when 2q was used as a substrate (Scheme 1c). This evidence suggested the presence of benzylic radical intermediates (see the ESI† for details of other mechanism study).

Scheme 1 Control test.

Scheme 2 Possible reaction pathways.

Two possible reaction pathways are illustrated in Scheme 2. In the 1st possible pathway (Scheme 2a), oxidation of 1a under NHC catalysis leads to α,β-unsaturated azolium ester intermediate I.²² Isomerization of 2 leads to an enamine intermediate II. Nucleophilic addition of II to Ivia an electron-pair pathway²³ (direct 1,4-addition²⁴ or Claisen rearrangement²⁵ route) leads to III. Cyclization of III leads to product 3a with regeneration of the NHC catalyst. In the 2nd possible pathway (Scheme 2b), NHC-bound radical cation intermediate V is formed via a SET oxidative process^21,26 starting from enal 1a. Under oxidative conditions, diarylmethane 2 is converted to a benzylic radical intermediate VI.⁹ Coupling of radical intermediates V and VIvia a SET process²⁷ leads to intermediate III, which is subsequently converted to product 3a. Ketones 6 derived from 2via oxidation of the benzylic carbon, as well as the homo-coupling generated 2-dimer (Scheme 1c), were observed as the main side products in nearly all examples, suggesting the presence of radical intermediate VI.⁹

The oxidative coupling products from our catalytic reactions can undergo further transformations under simple conditions (Scheme 3). For example, adduct 3a was reduced by DIBAL-H to N,O-acetal 8 in 84% yield. Nitro group reduction with simultaneously ring opening of lactam can also transform 3a to ester 9 in 86% yield. Reduction of adduct 4e with LiAlH₄ efficiently gave alcohol 10 (89% yield), which was further cyclized under MsCl to afford benzimidazole fused piperidine 11 in 98% yield. In all cases, the ee and dr of the molecules were completely retained during the transformations.

Scheme 3 Product Transformation.

Conclusions

In summary, we have developed an NHC-catalyzed highly enantioselective oxidative coupling of di(hetero)arylmethanes and enals to give benzimidazole fused lactams. Ongoing studies include the development of effective methods for enantioselective oxidative coupling of more challenging inactivated carbon–hydrogen bonds, application of this method for assembly or modification of pesticides and active components of Chinese medicines, and bioactivity evaluations of relevant molecules.

Conflicts of interest

There are no conflicts of interest to declare

Acknowledgements

We acknowledge financial support by the Singapore National Research Foundation (NRF-NRFI2016-06), Ministry of Education of Singapore (MOE2013-T2-2-003; MOE2016-T2-1-032; RG108/16), A*STAR Individual Research Grant (A1783c0008), Nanyang Technological University, Singapore; Guizhou Province First-Class Disciplines Project (YiLiu Xueke Jianshe Xiangmu)-GNYL(2017)008, and Guiyang College of Traditional Chinese Medicine, China.

Notes and references

1. D. Murdoch and D. McTavish, Drug, 1992, 44, 604.
2. Y. Bansal, M. Kaur and O. Silakari, Eur. J. Med. Chem., 2015, 89, 671.
3. M. Kitajima, M. Iwai, R. Kikura-Hanajiri, Y. Goda, M. Iida, H. Yabushita and H. Takayama, Bioorg. Med. Chem. Lett., 2011, 21, 1962.
4. D. Ameen and T. J. Snape, MedChemComm, 2013, 4, 893.
5. (a) Y. Li, F.-Q. Shi, Q.-L. He and S.-L. You, Org. Lett., 2009, 11, 3182; (b) F.-L. Sun, X.-J. Zheng, Q. Gu, Q.-L. He and S.-L. You, Eur. J. Org. Chem., 2010, 2010, 47; (c) M.-H. Zhuo, Y.-J. Jiang, Y.-S. Fan, Y. Gao, S. Liu and S. Zhang, Org. Lett., 2014, 16, 1096; (d) Y. Huang and T. Hayashi, J. Am. Chem. Soc., 2015, 137, 7556; (e) L. Caruana, M. Mondatori, V. Corti, S. Morales, A. Mazzanti, M. Fochi and L. Bernardi, Chem.–Eur. J., 2015, 21, 6037; (f) M. Nambo, Z. T. Ariki, D. Canseco-Gonzalez, D. D. Beattie and C. M. Crudden, Org. Lett., 2016, 18, 2339.
6. For selected examples, see: (a) G. Bergonzini, S. Vera and P. Melchiorre, Angew. Chem., Int. Ed., 2010, 49, 9685; (b) C. Xing, H. Sun, J. Zhang, G. Li and Y. R. Chi, Chem.–Eur. J., 2011, 17, 12272; (c) Z. Wang, Y. F. Wong and J. Sun, Angew. Chem., Int. Ed., 2015, 54, 13711; (d) H.-H. Liao, A. Chatupheeraphat, C.-C. Hsiao, I. Atodiresei and M. Rueping, Angew. Chem., Int. Ed., 2015, 54, 15540; (e) M. Chen and J. Sun, Angew. Chem., Int. Ed., 2017, 56, 4583.
7. (a) W. G. Kofron and J. Mathew, J. Org. Chem., 1976, 41, 114; (b) M. S. Hill and P. B. Hitchcock, Organometallics, 2002, 21, 220.
8. (a) H. Sterckx, J. D. Houwer, C. Mensch, I. Caretti, K. A. Tehrani, W. A. Herrebout, S. V. Doorslaer and B. U. W. Maes, Chem. Sci., 2016, 7, 346; (b) A. Vasilopoulos, S. L. Zultanski and S. S. Stahl, J. Am. Chem. Soc., 2017, 139, 7705.
9. (a) Y.-Z. Li, B.-J. Li, X.-Y. Lu, S. Lin and Z.-J. Shi, Angew. Chem., Int. Ed., 2009, 48, 3817; (b) S. Guo, Y. Li, Y. Wang, X. Guo, X. Meng and B. Chen, Adv. Synth. Catal., 2015, 357, 950; (c) L. Ren, L. Wang, Y. Lv, G. Li and S. Gao, Org. Lett., 2015, 17, 2078; (d) D. P. Hruszkewycz, K. C. Miles, O. R. Thiel and S. S. Stahl, Chem. Sci., 2017, 8, 1282; (e) E. Larionov, M. M. Mastandrea and M. A. Pericàs, ACS Catal., 2017, 7, 7008; (f) D. Uraguchi, M. Torii and T. Oii, ACS Catal., 2017, 7, 2765.
10. (a) K. Gebauer, F. Reuß, M. Spanka and C. Schneider, Org. Lett., 2017, 19, 4588; (b) B. Wu, X. Gao, Z. Yan, M.-W. Chen and Y.-G. Zhou, Org. Lett., 2015, 17, 6134.
11. (a) L. Dell'Amico, A. Vega-Peñaloza, S. Cuadros and P. Melchiorre, Angew. Chem., Int. Ed., 2016, 55, 3313; (b) L. Dell'Amico, V. M. Fernández-Alvarez, F. Maseras and P. Melchiorre, Angew. Chem., Int. Ed., 2017, 56, 3304; (c) X. Yuan, S. Dong, Z. Liu, G. Wu, C. Zou and J. Ye, Org. Lett., 2017, 19, 2322.
12. J. H. Kim, S. Freßies, M. Boultadakis-Arapinis, C. Daniliuc and F. Glorius, ACS Catal., 2016, 6, 7652.
13. F. G. Bordwell, J.-P. Cheng, M. J. Bausch and J. E. Bares, J. Phys. Org. Chem., 1988, 1, 209.
14. W. Akhtar, M. F. Khan, G. Verma, M. Shaquiquzzaman, M. A. Rizvi, S. H. Mehdi, M. Akhter and M. M. Alam, Eur. J. Med. Chem., 2017, 126, 705.
15. For selected examples, see: (a) D. E. A. Raup, B. Cardinal-David, D. Holte and K. A. Scheidt, Nat. Chem., 2010, 2, 766; (b) A. G. Kravina, J. Mahatthananchai and J. W. Bode, Angew. Chem., Int. Ed., 2012, 51, 9433; (c) P. Wheeler, H. U. Vora and T. Rovis, Chem. Sci., 2013, 4, 1674; (d) C. Guo, B. Sahoo, C. G. Daniliuc and F. Glorius, J. Am. Chem. Soc., 2014, 136, 17402; (e) L. Wang, S. Li, M. Blümel, A. R. Philipps, A. Wang, R. Puttreddy, K. Rissanen and D. Enders, Angew. Chem., Int. Ed., 2016, 55, 1110.
16. P.-C. Chiang, M. Rommel and J. W. Bode, J. Am. Chem. Soc., 2009, 131, 8714.
17. (a) S. D. Sarkar and A. Studer, Angew. Chem., Int. Ed., 2010, 49, 9266; (b) S. D. Sarkar, S. Grimme and A. Studer, J. Am. Chem. Soc., 2010, 132, 1190.
18. (a) M. He, J. R. Struble and J. W. Bode, J. Am. Chem. Soc., 2006, 128, 8418; (b) J. R. Struble and J. W. Bode, Org. Synth., 2010, 87, 362.
19. (a) C. Noonan, L. Baragwanath and S. J. Connon, Tetrahedron Lett., 2008, 49, 4003; (b) X. Zhao, K. E. Ruhl and T. Rovis, Angew. Chem., Int. Ed., 2012, 51, 12330.
20. X. Wu, B. Liu, Y. Zhang, M. Jeret, H. Wang, P. Zheng, S. Yang, B.-A. Song and Y. R. Chi, Angew. Chem., Int. Ed., 2016, 55, 12280.
21. (a) N. A. White and T. Rovis, J. Am. Chem. Soc., 2014, 136, 14674; (b) N. A. White and T. Rovis, J. Am. Chem. Soc., 2015, 137, 10112.
22. For recent review, see: C. Zhang, J. F. Hooper and D. W. Lupton, ACS Catal., 2017, 7, 2583.
23. (a) M. D. Greenhalgh, S. Qu, A. M. Z. Slawin and A. D. Smith, Chem. Sci., 2018, 9, 4909; (b) S. Vera, Y. Liu, M. Marigo and E. C. Escudero-Adán, Synlett, 2011, 4, 489.
24. R. C. Samantha, B. Maji, S. D. Sarkar, K. Bergander, R. Fröhlich, C. Mück-Lichtenfeld and H. Mayr, Angew. Chem., Int. Ed., 2012, 51, 5234.
25. J. Mahatthananchai, J. Kaeobamrung and J. W. Bode, ACS Catal., 2012, 2, 464.
26. Y. Zhang, Y. Du, Z. Huang, J. Xu, X. Wu, Y. Wang, M. Wang, S. Yang, R. D. Webster and Y. R. Chi, J. Am. Chem. Soc., 2015, 137, 2416.
27. H. Fischer, Chem. Rev., 2001, 101, 3581.

---

Footnotes

† Electronic supplementary information (ESI) available. CCDC 1843274 and 1843275. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8sc03480j

‡ Qiao Chen and Tingshun Zhu contributed equally.

§ Present address: School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, P. R. China.

---