Synthesis of functionalized γ-lactones via a three-component cascade reaction catalyzed by consecutive N-heterocyclic carbene systems

Abstract

Two consecutive N-heterocyclic carbene (NHC) catalytic systems were combined in a one-pot cascade reaction for the assembly of aromatic aldehydes and 2-haloenals into a structurally complex γ-lactone backbone. To our knowledge, this is the first report of NHC-catalyzed [3 + 2] annulation of α,β-unsaturated acylazoliums with 1,2-bisnucleophiles.

---

N-Heterocyclic carbene (NHC) catalysis, an elegant organocatalytic method for forming new bonds, is used broadly in organic synthesis.¹ A number of NHC catalytic multicomponent cascade reactions have been developed, but most rely on a single catalyst, to perform continuous operations.²

Combining two catalytic bond-forming tactics into a single cascade reaction can offer unique synthetic opportunities, as it can allow unprecedented transformations that would be impossible in the presence of either catalyst on its own. NHC catalysis has been successfully integrated with transition metal catalysis,³ Lewis acid catalysis⁴ or aminocatalysis.⁵ These combinations have opened up synthetic possibilities, but they are severely limited by self-quenching between NHCs and transition metals/Lewis acids and by mutual interference between NHCs and the acidic additive in aminocatalytic systems. Over the past decade, NHC-mediated HOMO/LUMO activation of carbonyl compounds at the ipso-, α-, β- or γ-position has become well established; these carbonyl compounds include aldehydes, ketones and esters, as well as their α,β unsaturated variants.¹ Despite these advances, few studies have explored the combination of two NHC-mediated activation modes in one multicomponent cascade reaction in a way that takes advantage of the inherent basicity and compatibility of both catalysts.

An efficient NHC-catalyzed activation mode that recently received immense attention is the generation of α,β-unsaturated acylazolium, which may be achieved from α,β-unsaturated acyl fluorides, enol esters, enals (under oxidative conditions), ynals, or 2-haloenals.^6–14 This reactive intermediate may serve as an analogue of 1,3-biselectrophiles and form the basis for novel domino reactions. In fact, the groups of Lupton,⁶ Bode,⁷ Studer,⁸ Biju,⁹ You,¹⁰ Ye,¹¹ Yao,¹² Chi¹³ and Xiao¹⁴ have independently described NHC-catalyzed [3 + 3] annulation of α,β-unsaturated acylazoliums with 1,3-bisnucleophiles, leading to the formation of dihydropyranone or dihydropyridinone derivatives (Scheme 1, eqn (a)). To the best of our knowledge, the analogous [3 + 2] cycloaddition with 1,2-bisnucleophiles to synthesize five-membered heterocycles has not been reported (Scheme 1, eqn (b)).

Scheme 1 Annulation based on NHC-catalyzed generation of α,β-unsaturated acylazoliums.

As part of our ongoing investigations aimed at assembling multiple substrates into synthetically important cyclic molecules,¹⁵ we envisaged a two-step organocatalytic relay cascade, beginning with NHC-catalyzed benzoin condensation,¹⁶ as a way to synthesize functionalized γ-lactones (Scheme 2). Condensation of aldehyde 1 generates an α-hydroxyketone intermediate 2, which then serves as the 1,2-bisnucleophile in the second NHC catalytic cycle. Subsequent [3 + 2] cyclization between the NHC-generated α,β-unsaturated acylazolium with α-hydroxyketone affords the desired γ-lactone 4. This approach, if successful, would provide an alternative method for preparing pharmacologically interesting γ-lactones or dihydrofuranones,¹⁷ and it would broaden the applications of sequential dual catalysis.¹⁸

Scheme 2 Combination of two NHC catalytic cycles to construct γ-lactone bearing a quaternary carbon center.

At the very first beginning, we wondered whether NHC-catalyzed [3 + 2] annulation of α,β-unsaturated acylazoliums with 1,2-bisnucleophiles could work. So we investigated the reaction of benzoin 2a and α-bromo cinnamaldehyde 3a in the presence of NHC precursor with cesium carbonate. Fortunately, we were able to isolate the desired 4a product in moderate yield (Scheme 3). Since NHCs are known to catalyze benzoin condensation, we also wondered whether benzoin 2a could be generated in situ. If successful, two sequential NHC catalytic systems could be combined.

Scheme 3 NHC-catalyzed [3 + 2] annulation of benzoin and 2-bromoenal.

To probe the feasibility of the proposed two-step cascade process, the preliminary experiment was carried out with precatalyst Ia and benzaldehyde 1a to afford benzoin 2a in situ, after which precatalyst IIa and α-bromocinnamic aldehyde 3a were added in the reaction mixture. To our delight, by performing the reaction in dichloromethane with Cs₂CO₃, we were able to isolate the desired product with good diastereoselectivity, albeit in moderate yield (Table 1, entry 1). Screening various catalyst combinations (entries 1–5) showed Id and IIa to be the most promising catalyst pair for the reaction (entry 4). Different bases led to different yields, with DBU giving the best results (entries 6–10). Replacing dichloromethane with other solvents did not improve yield or diastereoselectivity (entries 10–13). We wondered whether one NHC catalyst could be used in both catalytic cycles. Performing the cascade reaction in the absence of precatalyst Id furnished only a trace amount of the desired product (entry 14), as did the reaction with only precatalyst Id (entry 15). At the same time, α-hydroxyketone 2a was detected by ¹H NMR and HRMS of the crude reaction mixture (entry 15). These results suggest that different NHC catalysts are required in the two catalytic systems.

Table 1 Optimization of reaction conditions^a

Entry	Cat. I	Cat. II	Base	Solvent	Yield^b (%)	dr^c
a Unless otherwise noted, reactions were performed with precatalyst I (0.1 mmol), base (0.3 mmol) and 1a (1.6 mmol) in solvent (2 mL) at 50 °C for a specified reaction time until the sufficient benzoin 2a was generated (monitored by TLC), after which precatalyst II (0.1 mmol) and 3a (0.4 mmol) were added.b Isolated yield of pure diastereomer 4a.c Based on ^1H NMR analysis of the crude reaction mixture. Mes = 2,4,6-(CH3)3C6H2; Ar = 2,6-(CH3CHCH3)2C6H3.
1	Ia	IIa	Cs2CO3	CH2Cl2	41	85 : 15
2	Ib	IIa	Cs2CO3	CH2Cl2	37	80 : 20
3	Ic	IIa	Cs2CO3	CH2Cl2	49	85 : 15
4	Id	IIa	Cs2CO3	CH2Cl2	59	88 : 12
5	Id	IIb	Cs2CO3	CH2Cl2	52	88 : 12
6	Id	IIa	K2CO3	CH2Cl2	59	86 : 14
7	Id	IIa	tBuOK	CH2Cl2	54	78 : 22
8	Id	IIa	TEA	CH2Cl2	39	85 : 15
9	Id	IIa	DABCO	CH2Cl2	46	82 : 18
10	Id	IIa	DBU	CH2Cl2	64	90 : 10
11	Id	IIa	DBU	Toluene	48	85 : 15
12	Id	IIa	DBU	MeCN	59	86 : 14
13	Id	IIa	DBU	THF	34	80 : 20
14	IIa	IIa	DBU	CH2Cl2	<10	n.d.
15	Id	Id	DBU	CH2Cl2	<10	n.d.

---

With the optimal reaction conditions in hand, we explored the substrate scope of the procedure (Table 2). Annulation of α-bromo cinnamaldehyde 3a proceeded smoothly with a variety of aldehydes 1 to give moderate to high yield with good diastereoselectivity (entries 1–10). Most substituted aromatic aldehydes 1 bearing electron-withdrawing groups led to higher yield than those possessing electron-donating groups, and dr values for products varied in the trend ortho > meta and para. This implies that the substitution pattern on the phenyl rings affects the reaction to some extent. Heteroaryl aldehydes participated efficiently, giving even higher yields than aryl aldehydes but with slightly lower dr values (entries 9 and 10). We also evaluated the use of aliphatic aldehydes (such as octanal and 3-phenylpropanal) in the optimal reaction conditions, but no [3 + 2] annulation products were obtained.¹⁹ To extend the scope of the reaction further, we explored other 2-bromoenals 3. The position and electronic properties of substituents on the aromatic ring of aryl-substituted 2-bromoenals did not significantly affect reaction efficiency (entries 11–19). The transformation was rather sluggish in the case of 2-bromo-3-furanylacrylaldehyde, and the corresponding γ-butyrolactone was afforded in only 35% yield after prolonged reaction time (entry 20). The relative configuration of 4a was determined by X-ray crystallographic analysis.²⁰ Configurations of the other dihydrofuranones were tentatively assigned by analogy.

Table 2 Scope of the cascade reaction^a

Entry	R^1	R^2	Product	Yield^b (%)	dr^c
a See entry 13 and footnote a in Table 1.b Isolated yield of pure diastereomer 4.c Based on ^1H NMR analysis of the crude reaction mixture.
1	Ph	Ph	4a	64	90 : 10
2	2-ClC6H4	Ph	4b	65	95 : 5
3	4-ClC6H4	Ph	4c	68	88 : 15
4	3-BrC6H4	Ph	4d	65	92 : 8
5	4-BrC6H4	Ph	4e	70	85 : 15
6	4-FC6H4	Ph	4f	65	87 : 13
7	2,4-Cl2C6H3	Ph	4g	70	92 : 8
8	4-i-PrC6H4	Ph	4h	54	86 : 14
9	2-Furyl	Ph	4i	72	80 : 20
10	2-Thienyl	Ph	4j	71	75 : 25
11	Ph	2-ClC6H4	4k	60	92 : 8
12	Ph	4-ClC6H4	4l	61	86 : 14
13	Ph	4-BrC6H4	4m	66	85 : 15
14	Ph	2-FC6H4	4n	57	90 : 10
15	Ph	3-FC6H4	4o	61	85 : 15
16	Ph	4-FC6H4	4p	68	82 : 18
17	Ph	4-NO2C6H4	4q	63	84 : 16
18	Ph	4-MeC6H4	4r	54	80 : 20
19	Ph	2-OCH3C6H4	4s	50	87 : 13
20	Ph	2-Furyl	4t	35	80 : 20

---

We also performed experiments on the asymmetric version of this [3 + 2] annulation (Scheme 4). We envisioned that treatment of benzoin 2a and 2-bromoenal 3a in the presence of chiral triazolium salts IIc and IId, which has proven effective in many asymmetric [3 + 3] cycloadditions involving activation of α,β-unsaturated acylazolium, might furnish the desired chiral product. Unfortunately, numerous attempts were unsuccessful, with only the α,β-unsaturated ester product 5a obtained in nearly quantitative yield. This linear product presumably formed via direct intermolecular O-acylation of the benzoin to the chiral α,β-unsaturated acylazolium intermediate (Scheme 4). Notably, the final product 5a was a racemic mixture, suggesting no kinetic or dynamic kinetic resolution during the conversion.

Scheme 4 Studies on the enantioselectivity of the annulation process.

Based on these results, we were puzzled by what the reaction mechanism might be. We reasoned that the γ-butyrolactone might form either by tandem 1,4-addition followed by intramolecular acylation (Scheme 5, path A) or by tandem intermolecular acylation followed by 2,3-wittig rearrangement-acylation (Scheme 4, path B). Importantly, the product 5a (generated in Scheme 4) did not undergo cyclization under various alkaline conditions,²¹ suggesting that pathway A is more reasonable to describe this α,β-unsaturated acylazolium-mediated [3 + 2] annulation.

Scheme 5 Two possible pathways for [3 + 2] annulation mediated by α,β-unsaturated acylazolium.

Conclusions

In summary, we have developed a flexible and simple organocatalytic cascade reaction involving two sequential NHC catalytic cycles, and we have used it to assemble a functionalized γ-lactone (or dihydrofuranone) scaffold bearing a quaternary carbon center. Starting from aromatic aldehydes and 2-haloenals, we obtained the desired products in moderate to good yield with high diastereoselectivity. The present work is the first report of NHC-catalyzed [3 + 2] annulation of α,β-unsaturated acylazoliums with 1,2-bisnucleophiles. Studies are under way in our laboratory to clarify the detailed reaction mechanism and explore whether this method can be applied to asymmetric domino reactions.

Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (21302016 and 81303208), the Science & Technology Department of Sichuan Province (2014JQ0020) and the Foundation for the Author of National Excellent Doctoral Dissertation of PR China.

Notes and references

1. For recent reviews on NHC catalysis, see: (a) D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007, 107, 5606; (b) V. Nair, S. Vellalath and B. P. Babu, Chem. Soc. Rev., 2008, 37, 2691; (c) E. M. Phillips, A. Chan and K. A. Scheidt, Aldrichimica Acta, 2009, 42, 55; (d) J. L. Moore and T. Rovis, Top. Curr. Chem., 2010, 291, 77; (e) A. T. Biju, N. Kuhl and F. Glorius, Acc. Chem. Res., 2011, 44, 1182; (f) V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu, R. R. Paul, A. Jose and V. Sreekumar, Chem. Soc. Rev., 2011, 40, 5336; (g) H. U. Vora and T. Rovis, Aldrichimica Acta, 2011, 44, 3; (h) J. Izquierdo, G. E. Hutson, D. T. Cohen and K. A. Scheidt, Angew. Chem., Int. Ed., 2012, 51, 11686; (i) H. U. Vora, P. Wheeler and T. Rovis, Adv. Synth. Catal., 2012, 354, 1617; (j) X. Bugaut and F. Glorius, Chem. Soc. Rev., 2012, 41, 3511; (k) M. Fèvre, J. Pinaud, Y. Gnanou, J. Vignolle and D. Taton, Chem. Soc. Rev., 2013, 42, 2142; (l) S. J. Ryan, L. Candish and D. W. Lupton, Chem. Soc. Rev., 2013, 42, 4906; (m) J. Mahatthananchai and J. W. Bode, Acc. Chem. Res., 2014, 47, 696; (n) M. N. Hopkinson, C. Richter, M. Schedler and F. Glorius, Nature, 2014, 510, 485.
2. For a comprehensive review, see: A. Grossmann and D. Enders, Angew. Chem., Int. Ed., 2012, 51, 314.
3. (a) K. Hirano, I. Piel and F. Glorius, Chem. Lett., 2011, 40, 786; (b) N. T. Patil, Angew. Chem., Int. Ed., 2011, 50, 1759.
4. D. T. Cohen and K. A. Scheidt, Chem. Sci., 2012, 3, 53.
5. (a) S. P. Lathrop and T. Rovis, J. Am. Chem. Soc., 2009, 131, 13628; (b) B.-C. Hong, N. S. Dange, C.-S. Hsu and J.-H. Liao, Org. Lett., 2010, 12, 4812; (c) B.-C. Hong, N. S. Dange, C.-S. Hsu, J.-H. Liao and G.-H. Lee, Org. Lett., 2011, 13, 1338; (d) K. E. Ozboya and T. Rovis, Chem. Sci., 2011, 2, 1835; (e) C. B. Jacobsen, K. L. Jensen, J. Udmark and K. A. Jørgensen, Org. Lett., 2011, 13, 4790; (f) D. Enders, A. Grossmann, H. Huang and G. Raabe, Eur. J. Org. Chem., 2011, 4298; (g) Y.-Z. Liu, J. Zhang, P.-F. Xu and Y.-C. Luo, J. Org. Chem., 2011, 76, 7551; (h) Y. Liu, M. Nappi, E. C. Escudero-Adán and P. Melchiorre, Org. Lett., 2012, 14, 1310; (i) G. He, F. Wu, W. Huang, R. Zhou, L. Ouyang and B. Han, Adv. Synth. Catal., 2014, 356, 2311.
6. (a) S. J. Ryan, L. Candish and D. W. Lupton, J. Am. Chem. Soc., 2009, 131, 14176; (b) S. J. Ryan, L. Candish and D. W. Lupton, J. Am. Chem. Soc., 2011, 133, 4694; (c) L. Candisha and D. W. Lupton, J. Am. Chem. Soc., 2013, 135, 58; (d) L. Candish, C. M. Forsyth and D. W. Lupton, Angew. Chem., Int. Ed., 2013, 52, 9149.
7. (a) A. G. Kravina, J. Mahatthananchai and J. W. Bode, Angew. Chem., Int. Ed., 2012, 51, 9433; (b) J. Mahatthananchai, J. Kaeobamrung and J. W. Bode, ACS Catal., 2012, 2, 494; (c) E. Lyngvi, J. W. Bode and F. Schoenebeck, Chem. Sci., 2012, 3, 2346; (d) J. Mahatthananchai, P. Zheng and J. W. Bode, Angew. Chem., Int. Ed., 2011, 50, 1673; (e) B. Wanner, J. Mahatthananchai and J. W. Bode, Org. Lett., 2011, 13, 5378; (f) J. Kaeobamrung, J. Mahatthananchai, P. Zheng and J. W. Bode, J. Am. Chem. Soc., 2010, 132, 8810.
8. (a) R. C. Samanta, S. De Sarkar, R. Frøhlich, S. Grimme and A. Studer, Chem. Sci., 2013, 4, 2177; (b) R. C. Samanta, B. Maji, S. De Sarkar, K. Bergander, R. Fröhlich, C. Mück-Lichtenfeld, H. Mayr and A. Studer, Angew. Chem., Int. Ed., 2012, 51, 5234; (c) A. Biswas, S. De Sarkar, R. Fröhlich and A. Studer, Org. Lett., 2011, 13, 4966; (d) S. De Sarkar and A. Studer, Angew. Chem., Int. Ed., 2010, 49, 9266.
9. (a) S. R. Yetra, T. Kaicharla, S. S. Kunte, R. G. Gonnade and A. T. Biju, Org. Lett., 2013, 15, 5202; (b) S. R. Yetra, A. Bhunia, A. Patra, M. V. Mane, K. Vanka and A. T. Biju, Adv. Synth. Catal., 2013, 355, 1089; (c) S. R. Yetra, T. Roy, A. Bhunia, D. Porwal and A. T. Biju, J. Org. Chem., 2014, 79, 4245.
10. Z.-Q. Rong, M.-Q. Jia and S.-L. You, Org. Lett., 2011, 13, 4080.
11. F.-G. Sun, L.-H. Sun and S. Ye, Adv. Synth. Catal., 2011, 353, 3134.
12. (a) C. Yao, W. Jiao, Z. Xiao, R. Liu, T. Li and C. Yu, Tetrahedron, 2013, 69, 1133; (b) C. Yao, D. Wang, J. Lu, T. Li, W. Jiao and C. Yu, Chem.–Eur. J., 2012, 18, 1914.
13. J. Cheng, Z. Huang and Y. R. Chi, Angew. Chem., Int. Ed., 2013, 52, 8592.
14. (a) Z.-Q. Zhu, X.-L. Zheng, N.-F. Jiang, X. Wan and J.-C. Xiao, Chem. Commun., 2011, 47, 8670; (b) Z.-Q. Zhu and J.-C. Xiao, Adv. Synth. Catal., 2010, 352, 2455.
15. (a) X. Xie, C. Peng, G. He, H.-J. Leng, B. Wang, W. Huang and B. Han, Chem. Commun., 2012, 48, 10487; (b) X. Li, L. Yang, C. Peng, X. Xie, H.-J. Leng, B. Wang, Z.-W. Tang, G. He, L. Ouyang, W. Huang and B. Han, Chem. Commun., 2013, 49, 8692; (c) B. Han, X. Xie, W. Huang, X. Li, L. Yang and C. Peng, Adv. Synth. Catal., 2014, 356, 3676.
16. For selected examples, see: (a) Y. Shimakawa, T. Morikawa and S. Sakaguchi, Tetrahedron Lett., 2010, 51, 1786; (b) D. Enders and A. Henseler, Adv. Synth. Catal., 2009, 351, 1749.
17. Several groups have reported the synthesis of the analogous γ-lactone derivatives via benzoin-triggered multicomponent tandem reactions, see: (a) O. Winkelmann, C. Näther and U. Lüning, Org. Biomol. Chem., 2009, 7, 553; (b) M. Yoshida, N. Terai and K. Shishido, Tetrahedron, 2010, 66, 8922; (c) W. Ye, G. Cai, Z. Zhuang, X. Jia and H. Zhai, Org. Lett., 2005, 7, 3769.
18. For recent reviews on dual catalysis, see: (a) C. C. J. Loh and D. Enders, Chem.–Eur. J., 2012, 18, 10212; (b) Z. Du and Z. Shao, Chem. Soc. Rev., 2013, 42, 1337; (c) M. Rueping, R. M. Koenigs and I. Atodiresei, Chem.–Eur. J., 2010, 16, 9350; (d) J. M. R. Narayanam and C. R. J. Stephenson, Chem. Soc. Rev., 2011, 40, 102; (e) C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167; (f) Ł. Albrecht, H. Jiang and K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50, 8492; (g) J. Zhou, Chem.–Asian J., 2010, 5, 422; (h) S. Piovesana, D. M. ScarpinoSchietroma and M. Bella, Angew. Chem., Int. Ed., 2011, 50, 6216; (i) A. E. Allen and D. W. C. MacMillan, Chem. Sci., 2012, 3, 633; (j) N. T. Patil, V. S. Shinde and B. Gajula, Org. Biomol. Chem., 2012, 10, 211; (k) H. Pellissier, Tetrahedron, 2013, 69, 7171.
19. The mixture of the aliphatic α-hydroxyketone and the aldol condensation product could be detected.
20. ESI.†.
21. We screened Cs₂CO₃, K₂CO₃, tBuOK, TEA, DABCO and DBU.

---

Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data for new compounds. CCDC 958885. For ESI and crystallographic data in CIF or other electronic formats see: DOI: 10.1039/c5ra01254f

‡ These authors contributed equally to this work.

---