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Asymmetric Tandem Reactions of N-Sulfonylimines and α,β-Unsaturated Aldehydes: An Alternative Reaction Pathway to That of Using Saturated Aldehydes Qianjin An,a Jing Li,a Jiefeng Shen,a Nicholas Butt,a Delong Liu,*,a Yangang Liua and Wanbin Zhang*,a,b

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An organocatalyzed asymmetric tandem reaction of cyclic Nsulfonylimines and α,β-unsaturated aldehydes was developed. These substrates follow an alternative reaction pathway to that of reactions involving saturated aldehydes, affording similar piperidine derivatives. Organocatalyzed asymmetric tandem reactions are extremely useful reactions because they can provide two or more bond-forming transformations concurrently in one reaction procedure.1 We have adopted this tactic utilizing easily accessible substrates to construct all-carbon cyclopentane ring systems with four contiguous stereocenters,2 using our recently developed trans-perhydroindolic acid as a chiral organocatalyst.3 With the same catalyst, asymmetric tandem reactions of amino aldehydes and aldehyde esters to β,γ-unsaturated α-keto esters were also developed, affording oxygen-containing pyran rings with excellent asymmetric results.3a,4 Following on from these promising results, we endeavored to use the asymmetric tandem reaction to construct chiral nitrogen-containing heterocyclic compounds, a backbone commonly found in natural products and biologically important molecules.5 Saccharin-derived cyclic sultam compounds (N-sulfonylimines) are an intriguing class of synthon, which have been used in several asymmetric reactions, such as Diels-Alder reactions,6 hydrogenations,7 and nucleophilic additions.8 During our studies with this synthon in asymmetric catalytic reactions,9 an asymmetric tandem reaction of cyclic Nsulfonylimines and simple aldehydes was developed using our catalyst mentioned above, providing piperidine derivatives containing three contiguous stereocenters in high yields and with excellent enantioselectivities (Scheme 1, Eq. 1).10 However, poor diastereoselectivities accompanied these promising results. A mechanistic study revealed the reaction proceeds via a condensation of N-sulfonylimine with one molecule of a simple

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aldehyde, followed by an aza-DA cycloaddition of the formed conjugated imine and another molecule of the simple aldehyde.10b This information prompted us to investigate whether a different pathway existed between the direct reaction of N-sulfonylimines and α,β-unsaturated aldehydes, and if so, whether or not the dr of the desired products could be improved. Bode and co-workers have investigated a related research topic using NHC-catalyzed annulations of N-sulfonylimines and α,β-unsaturated aldehydes to give γ or δ-lactams.11 Low ratios of cis- and anti-products, and low enantioselectivities were obtained. Chen reported a direct chiral iminium catalyzed Michael addition of saccharin-derived cyclic imines and α,β-unsaturated aldehydes with excellent enantioselectivities.12 However, an additional cyclization process was still required to prepare piperidine products in somewhat moderate yields and low diastereoselectivities. Herein, we wish to disclose an organocatalyzed asymmetric tandem reaction of Nsulfonylimines and α,β-unsaturated aldehydes in the presence of a basic additive, directly providing the chiral nitrogen-containing compounds in high yields and with excellent diastereo- and enantioselectivities (Scheme 1, Eq. 2). Previous work (Diels-Alder mechanism)

R'

O O S N +

O

O O S N

chiral catalyst R'

2 R

OH R R

CH3 up to 89% yield, 80:20 dr, 99% ee Current work (Michael addition mechanism)

R'

O O S N

+ R

O O S N

chiral catalyst O

CH3

OH (Eq. 2)

R' R

Scheme 1 Asymmetric tandem reaction Initially, we explored the asymmetric tandem reaction

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between cyclic N-sulfonylimines (1a) and trans-2-hexenal (2c) catalyzed by organocatalysts (I to V) in DCM at 25 ℃ in the presence of DMAP (1 equiv.). To our delight, all reactions provided excellent dr (>20 : 1, Table 1). Proline (I) was first used for the reaction, however only a low yield and enantioselectivity were obtained. To improve the catalytic behavior, some prolinelike organocatalysts were also examined. Trans-perhydroindolic acid (II) provided only 23% yield and 59% ee. Cisperhydroindolic acid (III) was comparable to I. A trace amount of the desired product was obtained when using (S)-indoline-2carboxylic acid (IV) as an organocatalyst, and the product with the opposite configuration was formed. The use of a proline derivative, (S)-diphenylprolinol O-TMS ether (V-a), was subsequently examined. To our delight, the desired product was obtained in 85% yield and with 86% ee. Encouraged by this promising result, other proline derivatives were screened (V-b to V-g). Better results could be obtained by utilizing a catalyst possessing a bulkier O-substituent (i.e. R2 = TES, V-b). Further increasing the steric hindrance of R2 from TES to TBS (V-c) had little effect on the asymmetric catalysis. Replacing the R1 group with a methyl group led to a similar result (V-d to V-f). V-e, which possessed an O-TES group provided the most promising result (93% yield, > 20 : 1 dr and 93% ee). Finally, the R2 group of the catalyst was changed to an electronwithdrawing group CF3 (V-g) resulting in poor reaction activity. Table 1 Catalyst screeninga

Journal Name DOI: 10.1039/C4CC07051H Table 2 Solvent and additive screeninga

Entry 1 2 3 4

6 7 8 9 10

Solvent DCM toluene CH3CN DMSO 1,4dioxane EtOH DCM DCM DCM DCM

11

DCM

12 13 14 15 16d

DCM DCM DCM DCM DCM

5

Additive (equiv.) DMAP (1.0) DMAP (1.0) DMAP (1.0) DMAP (1.0)

Yieldb (%) 93 18 31 40

eec (%) 93 88 78 70

DMAP (1.0)

20

90

DMAP (1.0) DABCO (1.0) Et3N (1.0) DIPEA (1.0) TMEDA (1.0) cinchonidine (1.0) Na2CO3 (1.0) DMAP (0.1) DMAP (0.5) DMAP (2.0) DMAP (1.0)

25 73 45 89 60

76 89 76 91 60

29

88

55 78 82 90 66

92 91 92 92 92

a

The reactions of 1a (0.1 mmol) and 2c (0.12 mmol, 1.2 equiv.) were carried out under the catalysis of V-e (10 mol%) in the presence of additive at 25 °C in 24 h and all the reactions afforded > 20:1 dr which were determined by 1H NMR spectra of the crude product. b Isolated yield. c Determined by a chiral HPLC with the major diastereomers. d at 0 °C.

The effect of basic additives on the reaction was also tested with the aim of improving reaction activity (entries 1, 7-12). DMAP proved to be the best addiditive according to a combination of reaction activity and stereoselectivity (entry 1). The amount of DMAP also had an effect on the reaction. The lower the DMAP loading, the lower the reaction activity (entries 13, 14). Significantly increasing the amount of DMAP had no obvious effect on the reaction outcome (entries 1, 15). Temperature also had an effect on reaction activity. Decreasing the temperature to 0 ℃ led to a reduction in yield (entries 1, 16). The optimal reaction conditions were therefore found to be the following: 10 mol% V-e in DCM in the presence of 1.0 equiv. DMAP at 25 ℃. Table 3 Scope screeninga a

The reactions of 1a (0.1 mmol) and 2c (0.12 mmol, 1.2 equiv.) were carried out under the catalysis of different catalysts (10 mol%) in the presence of DMAP (1 equiv.) at 25 °C in 24 hours and all the reactions afforded > 20:1 dr which were determined by 1H NMR spectra of the crude product. b Isolated yield. c Determined by a chiral HPLC with the major diastereomers.

We next investigated the influence of solvent on the reaction (Table 2). Several commonly used solvents, such as DCM, toluene, CH3CN, DMSO and 1,4-dioxane, were examined and DCM was found to be the best solvent according to chemical yield and enantioselectivity (entries 1-5). As a comparison, the protic alcohol EtOH was tested, and the desired product was only obtained in 25% yield with 76% ee (entry 6).

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Entry

R'

R

3b (%)

drc

eed (%)

1 2 3 4 5 6 7 8 9 10

H H H H H H H H H H

methyl ethyl propyl iso-propyl Ph 2-ClC6H4 3-ClC6H4 4-ClC6H4 2-FC6H4 3-FC6H4

3a, 90 3b, 92 3c, 93 3d, 82 3e, 84 3f, 85 3g, 80 3h, 82 3i, 90 3j, 85

83:17 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

83 91 93 98 94 95 98 99 99.7 99.5

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11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26

H H H H H H H H H H H H Me t-Bu OCH3 CF3

COMMUNICATION DOI: 10.1039/C4CC07051H 4-FC6H4 4-BrC6H4 4-CF3C6H4 4-CH3OC6H4 2-CH3OC6H4

2-CH3C6H4 3-CH3C6H4 4-CH3C6H4 1-naphthyl 2-naphthyl 2-furyl 2-thienyl 2-FC6H4 2-FC6H4 2-FC6H4 2-FC6H4

3k, 87 3l, 78 3m, 88 3n, 73 3o, 80 3p, 88 3q, 84 3r, 85 3s, 80 3t, 85 3u, 70 3v, 80 3w, 82 3x, 80 3y, 85 3z, 75

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 75:25 78:22 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

99 99 96 99 99 94 99 97 94 96 94 89 99.5 95 97 98

a

The reactions of 1 (0.1 mmol) with 2 (0.12 mmol, 1.2 equiv.) were carried out under the catalysis of V-e (10 mol%) in the presence of DMAP (1 equiv.) at 25 °C for 24 h. b Isolated yields of the major products; for 3a, 3s and 3t, the whole yields of two isomers. c Determined by 1H NMR of the crude product. d ee values of major isomers were determined by chiral HPLC. e A scale of 1 g 1a was used.

With the optimal reaction conditions in hand, the applicability of the asymmetric tandem reaction to different substrates was evaluated (Table 3). Several aliphatic α,βunsaturated aldehydes were examined first (entries 1-4). When crotonaldehyde was used as a substrate, low diastereo and good enantioselectivities were obtained (entry 1). Substrates possessing an ethyl or propyl R-group gave good yields, and excellent diastereo- and enantioselectivities (entries 2, 3). When an iso-propyl R-group was introduced, an improved enantioselectivity was obtained but with a somewhat low yield (entry 4). Electron-withdrawing and electron-donating aromatic α,β-unsaturated aldehydes were next investigated (entries 5-18). These substrates provided the desired products in high yields and with excellent diastereo- and enantioselectivities (up to 99.7% ee, entry 9). The asymmetric catalytic results were not affected by the steric hindrance of different substituents located on the phenyl ring of the aldehyde substrates. When the phenyl ring was replaced by a naphthalene, high yields and excellent enantioselectivities were also obtained but with low dr (entries 19, 20). The phenyl ring could also be replaced by a furan or thiophene ring with no detrimental effect on catalytic activity (entries 21, 22). Finally, different substituted cyclic Nsulfonylimines were examined in the reaction. Excellent asymmetric catalytic results were obtained for both electrondonating and electron-withdrawing substituted substrates (entries 23-26). In addition, the large scale asymmetric transformation of Nsulfonyl imine 1a (1 g) with (E)-3-(2-chlorophenyl)acrylaldehyde 2f was carried out successfully, providing the desired product 3f in 70% yield, > 20 : 1 dr and 98% ee. To determine the absolute configuration of the asymmetric tandem reaction products, an X-ray crystallography study was performed. A single crystal of the product 3f could be obtained via recrystallization from ethyl acetate. X-ray crystal analysis

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showed that the hydroxyl group lies under the six-membered piperidine ring, while the 2-ClC6H4 group points in the opposite direction (Figure 1).13

Figure 1 X-ray of compound 3f We believe the tandem reaction between N-sulfonylimines and α,β-unsaturated aldehydes may proceed through a different pathway compared to that of reactions involving Nsulfonylimines and simple aldehydes. Thus, we propose the following pathway based on the absolute configuration of the product 3 (Scheme 2). Firstly, a conjugated imine intermediate A is formed via a condensation reaction between the aldehyde and catalyst. The sulfonyl enamine subsequently attacks the C=C bond of A from below the double bond to yield the enamine species B. Hydrolysis of B leads to the formation of the aldehyde functionality C, which subsequently undergoes a cyclization in the presence of base to afford the resulting piperidine 3 (the product with the thermodynamically stable configuration).

Scheme 2 Proposed reaction pathway The desired nitrogen-containing heterocyclic products could be easily converted into other valuable compounds. With 3f, for

Scheme 3 The transformation of 3f example, the hydroxyl group can be removed in the presence of Et3SiH / BF3‧Et2O at -78 ℃ to give chiral piperidine molecule 4.12 3f can also be oxidized with IBX to give the corresponding lactam 5 in the absence of any racemization (Scheme 3).14 These transformations show that the current asymmetric methodology

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provides an efficient pathway to the synthesis of a diverse array of nitrogen-containing heterocyclic compounds. To summarize, we have developed an efficient organocatalyzed asymmetric tandem reaction of cyclic Nsulfonylimines with α,β-unsaturated aldehydes for the synthesis of medicinally interesting and synthetically challenging piperidine ring intermediates containing two stereocenters. It appears that the reaction proceeds via a different pathway compared to that involving N-sulfonylimines and simple aldehydes. The desired products were obtained in good yields (up to 93%) and with excellent diastereoselectivities (up to >20:1) and enantioselectivities (up to 99.7%).

1781; (e) F. X. Felpin and J. Lebreton, Eur. J. Org. Chem. 2003, 19, 3693; (f) M. G. P. Buffat, Tetrahedron 2004, 60, 1701; (g) J. W. Daly, T. F. Spande and H. M. Garraffo, J. Nat. Prod. 2005, 68, 1556; (h) C. Escolano, M. Amat and J. Bosch, Chem. Eur. J. 2006, 12, 8198; (i) M. Terada, K. Machioka and K. Sorimachi, J. Am. Chem. Soc. 2007, 129, 10336; (j) C. De Risi, G. Fanton, G. P. Pollini, C. Trapella, F. Valente and V. Zanirato, Tetrahedron: Asymmetry 2008, 19, 131; (k) D. Cao, Z. Chai, J. Zhang, Z. Ye, H. Xiao, H. Wang, J. Chen, X. Wu and G. Zhao, Chem. Commun. 2013, 49, 5972; (l) X.-L. Meng, T. Liu, Z.-W. Sun, J.-C. Wang, F.-Z. Peng and Z.-H. Shao, Org. Lett. 2014, 16, 3044. 6 (a) X. Feng, Z. Zhou, C. Ma, X. Yin, R. Li, L. Dong and Y.-C. Notes and references Chen, Angew. Chem. Int. Ed. 2013, 52, 14173; (b) Q.-R. a School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Zhang, J.-R. Huang, W. Zhang and L. Dong, Org. Lett. 2014, Road, Shanghai 200240, P. R. China. 16, 1684; (c) J. Gu, C. Ma, Q.-Z. Li, W. Du and Y.-C. Chen, b School of Chemistry and Chemical Engineering, Shanghai Jiao Tong Org. Lett. 2014, 16, 3986. University, 800 Dongchuan Road, Shanghai 200240, P. R. China. Fax: 21 7 (a) Q. A. Chen, Z. S. Ye, Y. Duan and Y. G. Zhou, Chem. 5474 3265; Tel: 21 5474 3265; E-mail: [email protected]; Soc. Rev. 2013, 42, 497, and the literatures cited in; (b) L. [email protected]. Wang, Q. Zhou, C. H. Qu, Q. W. Wang, L. F. Cun, J. Zhu † This work was partially supported by the National Natural Science and J. G. Deng, Tetrahedron 2013, 69, 6500; (c) H. Sugie, Y. Foundation of China (No. 21172143, 21172145, 21372152 and Hashimoto, N. Haraguchi and S. Itsuno, J. Organomet. Chem. 21232004), Nippon Chemical Industrial Co., Ltd and Shanghai Jiao Tong 2014, 751, 711. University (SJTU). We thank the Instrumental Analysis Center of SJTU 8 (a) B. H. Zhu, J. C. Zheng, C. B. Yu, X. L. Sun, Y. G. Zhou, for HRMS analysis. We also thank Prof. Tsuneo Imamoto and Dr. Q. Shen and Y. Tang, Org. Lett. 2010, 12, 504; (b) T. Masashi Sugiya of Nippon Chemical Industrial Co., Ltd. for helpful Nishimura, A. Noishiki, G. C. Tsui and T. Hayashi, J. Am. discussions. Chem. Soc. 2012, 134, 5056; (c) H. Wang, T. Jiang and M.-H. ‡ Electronic Supplementary Information (ESI) available: [details of any Xu, J. Am. Chem. Soc. 2013, 135, 971; (d) C. Jiang, Y. Lu supplementary information available should be included here]. See DOI: and T. Hayashi, Angew. Chem. Int. Ed. 2014, 53, 9936. 10.1039/b000000x/ 9 G. Yang and W. Zhang, Angew. Chem. Int. Ed. 2013, 52, 7540. 1 For selected reviews, see: (a) A.-N. Alba, X. Companyo, M. 10 (a) Q. An, J. Shen, N. Butt, D. Liu, Y. Liu and W. Zhang, Viciano and R. Rios, Curr. Org. Chem. 2009, 13, 1432; (b) H. Org. Lett. 2014, 16, 4496; (b) See the Supporting Information Pellissier, Adv. Synth. Catal. 2012, 354, 237; (c) C. M. of Ref. 10a. Marson, Chem. Soc. Rev. 2012, 41, 7712; for selected papers, 11 (a) M. He, J. R. Struble and J. W. Bode, J. Am. Chem. Soc. see: (d) J.-P. Wan, C. C. J. Loh, F. Pan and D. Enders, Chem. 2006, 128, 8418; (b) M. Rommel, T. Fukuzumi and J. W. Commun. 2012, 10049; (e) D. M. Rubush, M. A. Morges, B. J. Bode, J. Am. Chem. Soc. 2008, 130, 17266; (c) A. G. Kravina, Rose, D. H. Thamm and T. Rovis, J. Am. Chem. Soc. 2012, J. Mahatthananchai and J. W. Bode, Angew. Chem. Int. Ed. 134, 13554; (f) X. F. Zeng, Q. J. Ni, G. Raabe and D. Enders, 2012, 51, 9433. Angew. Chem. Int. Ed. 2013, 10, 2977; (g) C. C. J. Loh, D. 12 X. F. Xiong, H. Zhang, J. Peng and Y.-C. Chen, Chem. Eur. J. Hack and D. Enders, Chem. Commun. 2013, 10230; (h) P. 2011, 17, 2358. Chauhan and D. Enders, Angew. Chem. Int. Ed. 2014, 53, 13 CCDC 1015580 contains the supplementary crystallo-graphic 1485; (i) L. Caruana, M. Fochi, M. C. Franchini, S. Ranieri, data for this paper. These data can be obtained free of charge A. Mazzanti and L. Bernardi, Chem. Commun. 2014, 445. from The Cambridge Crystallographic Data Centre via 2 Q. An, J. Shen, D. Liu, N. Butt, Y. Liu and W. Zhang, www.ccdc.cam.ac.uk/data_request/cif. Synthesis 2013, 1612. 14 M. M. S. Duque, O. Baslé, N. Isambert, A. Gaudel-Siri, Y. 3 (a) J. Shen, D. Liu, Q. An, Y. Liu and W. Zhang, Adv. Synth. Genisson, J. C. Plaquevent, J. Rodriguez and T. Constantieux, Catal. 2012, 354, 3311; (b) T. Shi, J. Shen, Q. An, D. Liu, Y. Org. Lett. 2011, 13, 3296. Liu and W. Zhang, Chin. J. Org. Chem. 2013, 33, 1573. 4 J. Shen, Q. An, D. Liu, Y. Liu and W. Zhang, Chin. J. Chem. 2012, 30, 2681. 5 (a) G. M. Strunz and J. A. Findlay, in The Alkaloids, Vol. 26 (Ed.: A. Brossi), Academic Press, New York, 1985, 89; (b) P. D. Bailey, P. A. Millwood and P. D. Smith, Chem. Commun. 1998, 63; (c) P. S. Watson, B. Jiang and B. Scott, Org. Lett. 2000, 2, 3679; (d) S. Laschat and T. Dickner, Synthesis 2000,

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An organocatalyzed asymmetric tandem reaction of cyclic N-sulfonylimines and α,β-unsaturated aldehydes was developed. These substrates follow an alternative reaction pathway to that of reactions involving saturated aldehydes, affording similar piperidine derivatives with excellent asymmetric catalytic behavior.

Asymmetric tandem reactions of N-sulfonylimines and α,β-unsaturated aldehydes: an alternative reaction pathway to that of using saturated aldehydes.

An organocatalyzed asymmetric tandem reaction of cyclic N-sulfonylimines and α,β-unsaturated aldehydes was developed. These substrates follow an alter...
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