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Cite this: Org. Biomol. Chem., 2014, 12, 3423

Received 25th November 2013, Accepted 24th March 2014 DOI: 10.1039/c3ob42353k www.rsc.org/obc

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A multicomponent approach to the synthesis of N-sulfonyl β2,3-amino esters† Erwan Le Gall,* Stéphane Sengmany, Issa Samb, Sabrina Benakrour, Christopher Colin, Antoine Pignon and Eric Léonel The multicomponent synthesis of α,β-disubstituted N-sulfonyl β-amino esters is described. It involves a zinc-mediated, cobalt-catalyzed three-component reaction between sulfonylimines, acrylates and organic bromides. A possible mechanism is proposed, emphasizing the intermediate formation of an organocobalt as the initiator of a Mannich-like process.

Introduction Multicomponent reactions (MCRs)1 constitute straightforward processes for the simple and convenient generation of molecular diversity.2 In this context, Mannich-related reactions3 have drawn considerable attention from the organic chemistry community in the past few years by offering an efficient synthetic route to various β-aminocarbonyl compounds. Among the accessible scaffolds, β-amino esters are of particular interest, due to their important potential applications in biology such as their insertion in peptidomimetics, displaying significant properties compared to their α-peptide counterparts.4 However, while the design of new or improved methods for the synthesis of β-amino esters has been a subject of constant interest in the past few years,5 only limited examples of multicomponent reactions providing β-amino esters have been disclosed to date (Scheme 1).6 In addition, the synthesis of non-natural N-protected β-amino esters by a Mannich-like multicomponent reaction involving aryl and vinyl halides remains unexplored. In a previous report, we described the four-component synthesis of β-amino esters from amines, aldehydes, acrylates and organic halides.7 Although the scope of the reaction was demonstrated to be quite broad, primary amines or ammonia equivalents were unable to undergo the reaction. Consequently, as a part of our ongoing effort towards the development of more reliable and versatile multicomponent procedures, we describe herein a novel three-component reaction between sulfonylimines, acrylates and organic bromides, opening the way to one-step synthesis of non-natural primary α,β-disubstituted-

Électrochimie et Synthèse Organique, Institut de Chimie et des Matériaux Paris-Est, UMR 7182 CNRS – Université Paris-Est, 2-8 rue Henri Dunant, 94320 Thiais, France. E-mail: [email protected]; Fax: +33 149781148; Tel: +33 149781135 † Electronic supplementary information (ESI) available: Full experimental procedures, characterization data and copies of 1H, 13C and 19F NMR spectra. See DOI: 10.1039/c3ob42353k

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Scheme 1

Multicomponent reactions leading to β-amino esters.

β-amino esters (β2,3-amino esters) in their N-sulfonyl protected form.

Results and discussion Preliminary experiments were conducted under conditions similar to those already described for the in situ metallation of aryl or vinyl halides.7,8 N-Benzylidene-4-methylbenzenesulfonamide (1a) was reacted in acetonitrile with 4.5 equiv. of acrylate 2 and 2.4 equiv. of bromobenzene (3a) in the presence of a reducing metal (Zn, Mn) and a catalyst (cobalt- or nickel-based catalyst). Results are presented in Table 1. In a first series of experiments (Table 1, entries 1–4), a range of acrylates were evaluated in order to determine whether the alkyl chain linked to the oxygen has an influence on the reaction efficiency. Results indicated that similar yields are obtained with “linear” alkyl acrylates (Table 1, entries 1–3). Diastereoselectivity proved to be moderate, with diastereoisomeric ratios up to 74/26.9 The presence of a more hindering group on the acrylate resulted in a drop in the reaction yield, without a noticeable improvement of diastereoselectivity

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Table 1

Organic & Biomolecular Chemistry Optimization of the reaction conditionsa

Entry

R

Scaleb (mmol)

Reducer

Catalyst

T (°C)

Time (h)

Yieldc (%)

drd

1 2 3 4 5 6 7 8 9 10

Me Et nBu tBu nBu nBu nBu nBu nBu nBu

2.5 2.5 2.5 2.5 2.5 2.5 2.5 5e 2.5 2.5

Zn Zn Zn Zn Zn Zn Zn Zn Mn Zn

CoBr2 CoBr2 CoBr2 CoBr2 CoBr2 CoBr2 — CoBr2 CoBr2 NiBr2bpy

20 °C 20 °C 20 °C 20 °C 0 °C 60 °C 20 °C 20 °C 20 °C 20 °C

0.5 0.5 0.5 0.5 2 0.5 2 0.5 0.5 2

52 49 58 35 — 55 — 81 56 —

74/26 70/30 65/35 71/29 — 56/44 — 59/41 54/46 —

a Reactions were typically conducted with 5.0 mL of acetonitrile, 0.65 g (2.5 mmol) of imine 1a, 1.0 mL of the acrylate 2, 0.6 mL (6 mmol) of bromobenzene (3a), 0.2 g (0.9 mmol) of cobalt bromide, and 1.0 g (15 mmol) of zinc dust. b Reaction scale, corresponding to the amount of sulfonylimine used. c Isolated yield. d Diastereoisomeric ratio, determined by gas chromatography. e 3.2 mL of butyl acrylate, 1.2 mL (12 mmol) of bromobenzene (3a), 0.3 g (1.35 mmol) of cobalt bromide, and 1.5 g (23 mmol) of zinc dust were used.

(Table 1, entry 4). Consequently, as butyl acrylate furnished a comparable dr and a better reaction yield, this substrate was retained for the rest of the optimization process. Accordingly, it was noticed that the reaction works slightly better at room temperature than at 60 °C (Table 1, entry 6), while the reaction does not occur at 0 °C (Table 1, entry 5). The presence of a catalyst was mandatory, as attested by the absence of coupling

Table 2

when the reaction is conducted without cobalt salts (Table 1, entry 7). As the process proved to be moderately exothermic, it was figured out that the reaction scale could have a non-negligible impact on the reaction efficiency. Consequently, the imine 1a amount was modified from 2.5 mmol to 5 mmol,10 resulting in a spectacular increase (+23%) in the reaction yield (Table 1, entry 8). We could also notice that manganese can be

Scope of the reactiona

Entry

R1

R2

R3

R4

Product

Yieldb,c (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

4-Me–C6H4 4-Me–C6H4 4-Me–C6H4 4-Me–C6H4 4-Me–C6H4 4-Me–C6H4 4-Me–C6H4 4-Me–C6H4 4-Me–C6H4 4-Me–C6H4 Me Me Me Me Me Me Me Me Me Me

Ph Ph Ph Ph Ph 2-Thienyl 2-Thienyl 2-Thienyl 3-Furyl 4-MeO-C6H4 Ph Ph Ph Ph 2-Thienyl 2-Thienyl 2-Thienyl 4-F-C6H4 4-F-C6H4 4-MeO-C6H4

nBu nBu nBu Etd Etd nBu nBu nBu Etd Etd nBu nBu nBu nBu nBu nBu nBu nBu nBu Etd

Ph 4-MeO–C6H4 4-MeO2C–C6H4 3,4-(OCH2O)–C6H3 3-F3C–C6H4 Ph 4-MeO–C6H4 4-F–C6H4 4-Me–C6H4 (Z)-H3C–CHvCH Ph 4-Me–C6H4 4-iPr–C6H4 4-MeO–C6H4 Ph 4-MeO–C6H4 4-F–C6H4 Ph (Z)-H3C–CHvCH (Z)-H3C–CHvCH

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s 4t

81 61 57 66 53 55 56 62 52 50 70 66 65 68 63 52 60 55 56 54

a Reactions were typically conducted with 5.0 mL of acetonitrile, 5 mmol of imine 1, 3.2 mL of the acrylate 2, 12 mmol of the organic bromide 3, 0.3 g (1.35 mmol) of cobalt bromide, and 1.5 g (23 mmol) of zinc dust. b Isolated yield. c Diastereoisomeric ratios, ranging from 52/48 to 68/32, were determined by gas chromatography. d 2.5 mL of ethyl acrylate were used.

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between organic bromides, alkyl acrylates, and aromatic imines. The modular character of this multicomponent approach and the availability of the starting compounds make this process potentially attractive for diversity-oriented synthesis, using for instance build/couple/pair strategies.13 A reaction mechanism is proposed, emphasizing the key role of an organocobalt as the initiator of the Mannich-like process. Our future work will focus on the development of intramolecular and chiral versions of the reaction, the assessment of other protecting groups, as well as the use of the title compounds as molecular platforms in various post-condensation reactions. Scheme 2

Possible reaction mechanism for the investigated reaction.

Notes and references used as a reducer instead of zinc. However, in this case, a lower diastereoselectivity was observed (Table 1, entry 9). Finally, we could verify that a nickel-based catalyst is inefficient in the process (Table 1, entry 10). Given the significant improvement observed when working on the 5 mmol scale, the latter conditions were retained for the evaluation of the reaction scope. To this end, miscellaneous experiments were carried out using various sulfonylimines 1, alkyl acrylates 2 and vinylic or aromatic bromides 3. Results are presented in Table 2. It was noticed that either N-tosyl- (Table 2, entries 1–10) or N-mesylimines (Table 2, entries 11–20) can be successfully employed in the process. These results also indicated a significant functional compatibility for the reaction, which works with a satisfactory range of aromatic and heteroaromatic imines. Moreover, various aromatic bromides bearing either electron-withdrawing or electron-donating groups can be employed in the process. The modular character of the reaction was further established by the potential use of a vinyl bromide (Table 2, entries 10, 19 and 20). This constitutes a noteworthy result, given post-condensation strategies possibly involving the reaction products, especially the potential formation of small nitrogen-containing heterocycles. The possible use of manganese as a reducing metal instead of zinc (Table 1, entry 9) and the prevalent role of cobalt as a catalyst of the process allowed us to propose a possible reaction mechanism (Scheme 2).11 The first step would involve the formation of a key organocobalt I from aryl bromide 3, following a well described zincmediated redox process.12 This organometallic intermediate would then be involved in a conjugate addition to the acrylate 2, resulting in the formation of a zinc or cobalt enolate M, which would then undergo a Mannich-type addition to the activated imine 1 to yield the final product 4.

Conclusions In conclusion, the results presented in this study indicate that N-sulfonyl β2,3-amino esters can be obtained in satisfactory to good yields by a new straightforward three-component reaction

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1 (a) Multicomponent Reactions, ed. J. Zhu and H. Bienaymé, Wiley-VCH, Weinheim, 2005; (b) A. Dömling, Chem. Rev., 2006, 106, 17. 2 (a) J. D. Sunderhaus and S. F. Martin, Chem. – Eur. J., 2009, 15, 1300; (b) J. E. Biggs-Houck, A. Younai and J. T. Shaw, Curr. Opin. Chem. Biol., 2010, 14, 371. 3 For selected references, see: (a) M. Arend, B. Westermann and N. Risch, Angew. Chem., Int. Ed., 1998, 37, 1044; (b) H. Heaney, in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, vol. 2, pp. 953–973; (c) L. E. Overman and D. J. Ricca, in Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming, Pergamon Press, Oxford, 1991, vol. 2, pp. 1007–1046. 4 For an overview, see: (a) R. P. Cheng, S. H. Gellman and W. F. DeGrado, Chem. Rev., 2001, 101, 3219; (b) D. Seebach and J. Gardiner, Acc. Chem. Res., 2008, 41, 1366. 5 (a) T. Ye and M. A. McKervey, Chem. Rev., 1994, 94, 1091; (b) R. Moumne, S. Lavielle and P. Karoyan, J. Org. Chem., 2006, 71, 3332; (c) E. Juaristi, D. Quintana, B. Lamatsch and D. Seebach, J. Org. Chem., 1991, 56, 2553; (d) G. Nagula, V. J. Huber, C. Lum and B. A. Goodman, Org. Lett., 2000, 2, 3527; (e) M. P. Sibi and P. K. Deshpande, J. Chem. Soc., Perkin Trans. 1, 2000, 1461; (f ) H. S. Lee, J. S. Park, B. M. Kim and S. H. Gellman, J. Org. Chem., 2003, 68, 1575; (g) J. E. Beddow, S. G. Davies, A. D. Smith and A. J. Russell, Chem. Commun., 2004, 2778; (h) A. Rimkus and N. Sewald, Org. Lett., 2003, 5, 79; (i) A. Duursma, A. J. Minnaard and B. L. Feringa, J. Am. Chem. Soc., 2003, 125, 3700; ( j) W. Oppolzer, R. Moretti and S. Thomi, Tetrahedron Lett., 1989, 30, 5603; (k) K. Gademann, T. Kimmerlin, D. Hoyer and D. Seebach, J. Med. Chem., 2001, 44, 2460. 6 (a) M. Suginome, L. Uehlin and M. Murakami, J. Am. Chem. Soc., 2004, 126, 13196; (b) Y. Tanaka, T. Hasui and M. Suginome, Synlett, 2008, 1239. 7 E. Le Gall and E. Léonel, Chem. – Eur. J., 2013, 19, 5238. 8 For some recent references, see: (a) E. Le Gall, C. Haurena, S. Sengmany, T. Martens and M. Troupel, J. Org. Chem., 2009, 74, 7970; (b) C. Le Floch, E. Le Gall, E. Léonel, J. Koubaa, T. Martens and P. Retailleau, Eur. J. Org. Chem.,

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ate (0.1 equiv. per imine) did not show significant changes in the fate of the reaction, rather accounting for a nonradical mechanism. 12 S. Seka, O. Buriez, J.-Y. Nédélec and J. Périchon, Chem. – Eur. J., 2002, 8, 2534. 13 (a) W. R. J. D. Galloway, A. Isidro-Llobet and D. R. Spring, Nat. Commun., 2010, 1, 80; (b) N. Kumagai, G. Muncipinto and S. L. Schreiber, Angew. Chem., Int. Ed., 2006, 45, 3635.

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2010, 5279; (c) C. Le Floch, K. Laymand, E. Le Gall and E. Léonel, Adv. Synth. Catal., 2012, 354, 823. 9 In most cases, diastereoisomers proved to be easily separable by flash chromatography. 10 The amount of the other reagents and solvents was concomitantly increased to maintain similar concentrations. 11 Some experiments involving isopropenyl acetate (used as a co-solvent, 4 equiv. per imine) or 4-hydroxy-TEMPO benzo-

Organic & Biomolecular Chemistry

3426 | Org. Biomol. Chem., 2014, 12, 3423–3426

This journal is © The Royal Society of Chemistry 2014

A multicomponent approach to the synthesis of N-sulfonyl β(2,3)-amino esters.

The multicomponent synthesis of α,β-disubstituted N-sulfonyl β-amino esters is described. It involves a zinc-mediated, cobalt-catalyzed three-componen...
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