Radical reduction of Passerini 3CR adducts by SmI2/HMPA

Hui Yu *, Tao Gai, Wen Liang Sun, Mei Su Zhang

Department of Chemistry, Tongji University, Shanghai 200092, China

Received 23 August 2010

Available online 17 January 2011

Abstract

The Passerini 3-CR adducts of substituted cinnamaldehydes, isocyanides and acetic acid were treated with SmI2/HMPA in dry

tetrahydrofuran (THF) at room temperature, and b,g-unsaturated amides were obtained in moderate yields. The reaction was

supposed involving a radical reduction procedure.

# 2010 Hui Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

Keywords: Passerini; Isocyanide; Modification; Amides; Samarium diiodide

As a classic isocyanide-based multicomponent reaction (MCR) [1], Passerini 3CR has already been applied

successfully to the synthesis of complicate compounds [2]. Recent years, to purchase higher molecular diversity, many

efforts were focused on the modification of functionalized Passerini 3CR adducts, and numerous synthetically useful

scaffolds were built up by such a strategy [3]. Combined with different post-condensation reactions, P-3CR could be

used to prepare peptide derivatives [4] and heterocycles [5] in high yield with short steps.

In our previous work, we reported the preparation of N- substituted b,g-unsaturated amides by radical reduction of

Ugi type compounds with SmI2/HMPA in dry THF [6]. In this paper, we found that such a reduction condition could

also be applied to the modification of P-3CR adducts, and same products were obtained. In contrast with Ugi-4CR,

here atom economy was increased because amines were avoided. Meanwhile, the P-3CR adducts need not to be

purified, which makes the reaction easier to carry out.

Different P-3CR adducts 1, which could be easily prepared by mixing equivalent cinnamaldehydes, isocyanides

and carbonic acids in DCM, could undergo a-cleavage when treated with SmI2/HMPA in THF to furnish b,g-

unsaturated amide 2 (Eq. (1)), and the results were listed below (Table 1). Change of the acids did not affect the result

greatly, and the yield was also acceptable when benzoic acid or formic acid was used instead of acetic acid (Table 1,

entries 2–3). Varies substituted cinnamaldehydes, and isocyanides such as t-butyl, cyclohexyl, and PMB (4-methoxy

benzyl) isocyanides were also examined and different N-substituted amides were isolated (Table 1, entries 4–8).

Unfortunately, croton aldehyde failed because of the rapid polymerization during the P- 3CR stage (Table 1, entry 9).

The conjugate double bond in the start aldehydes was necessary, and no expected product phenyl acetic amide was

detected when benzaldehyde was used instead of cinnamaldehyde. (Table 1, entry 10).

The reduction of a-heterosubstituted esters by SmI2 has been investigated, but the reduction of a-hetero-substituted

amides was not mentioned there [7]. We supposed that the reaction involved a monoelectronic transfer procedure [8].

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Chinese Chemical Letters 22 (2011) 379–381

* Corresponding author.

E-mail address: yuhui@tongji.edu.cn (H. Yu).

1001-8417/$ – see front matter # 2010 Hui Yu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.

doi:10.1016/j.cclet.2010.11.013

Here a radical anion intermediate 3 was generated when 1 was treated with SmI2, then 3 was reduced by another

molecule SmI2 to get anion 4, which could change to 5 after leaving an acetate anion. Finally 5 was hydrolyzed to the

product after worked up with diluted HCl (Scheme 1).

1. Experimental

General procedure for Passerini 3-CR reaction: A solution of cinnamaldehyde (1.5 mmol), acetic acid (1.5 mmol)

and isocyanide (1.5 mmol) in 2 mL CH2Cl2 was stirred for 24 h at room temperature until the reaction was completed

(indication by TLC). The solvent was moved and the residue was used in next step without further purification.

General procedure for SmI2 reduction: A mixture of samarium powder (75 mg, 0.5 mmol) and diiodomethane

(32 mL, 0.45 mmol) in THF (6 mL) was stirred at r.t. for 3 h to get a blue solution, then HMPA (0.6 mL, 3.4 mmol) was

added and the color changed to purple. The P-3CR adducts (0.2 mmol) dissolved in 1 mL dry THF was added and the

mixture was stirred for 2 h, then HCl (0.1 mol/L, 2 mL) was added. After stirred for an additional 15 min, the reaction

was diluted with water (15 mL) and extracted with AcOEt (3� 10 mL), then the organic layers was combined and

dried with anhydrous Na2SO4. The solvent is removed and the residue was purified by column chromatography on

silica gel (hexane/ethyl acetate = 4/1) to get the product. 2c: white solid, m.p. 106–108 8C, 1H NMR (300 MHz,

CDCl3): d 7.19–7.29 (m, 7H), 6.86 (d, 2H, J = 8.4 Hz), 6.54 (d, 1H, J = 16.0 Hz), 6.26–6.34 (m, 1H), 5.85 (br, 1H),

4.39 (d, J = 6.0 Hz, 2H), 3.79 (s, 3H), 3.18 (d, 2H, J = 7.5 Hz); 13C NMR (125 MHz, CDCl3): d 40.8, 43.1, 55.2, 114.0,

119.8, 122.2, 126.2, 127.7, 128.5, 128.8, 128.9, 129.1, 129.2, 130.2, 134.6, 136.5, 159.0, 170.4; IR (KBr) n: 2906,

1639, 1567, 1470, 1246, 1030, 913, 744 cm�1; HRMS-EI calcd. for C18H19NO2 181.1416, found 181.1413.

In conclusion, we explore a way to synthesize the b,g-unsaturated amides by radical reduction of P-3CR adducts,

the reaction is easy to handle and the yield is moderate to good.

Acknowledgment

We thank NSFC for the financial support (No. 20802053).

H. Yu et al. / Chinese Chemical Letters 22 (2011) 379–381380

Table 1

Synthesis of N-substituted b,g-unsaturated amides from P-3CR /SmI2 reduction sequence.

[TD$INLINE]

R1 OR2

R3NC

CH2Cl2, r.t. NHR3R1

O

2.2eq SmI2

THF/HMPA, r.t.R2

NHR3R1

OR2

2a-f1R4COOH

OCOR4

+

Entry R1 R2 R3 R4 Yield (%)a

1 C6H5 H t-Bu CH3 2a (75%)

2 C6H5 H t-Bu C6H5 2a (67%)

3 C6H5 H t-Bu H 2a (63%)

4 C6H5 H Cyclohexyl CH3 2b (65%)

5 C6H5 H p-MeOC6H5CH2 CH3 2c (61%)

6 p-MeC6H5 H t-Bu CH3 2d (72%)

7 m-ClC6H5 H t-Bu CH3 2e (68%)

8 C6H5 Me t-Bu CH3 2f (56%)

9 Me H t-Bu CH3 –

10 PhCHO t-Bu CH3 –

a Isolated yields for 2 steps.

[()TD$FIG]

NHt-BuPh

OSm

OAc

1SmI2 H3O

2

3

NHt-BuPh

OSm

OAc4

SmI2

NHt-BuPh

OSm

5

-OAc

Scheme 1. The supposed mechanism for the SmI2 reduction of P-3CR adducts.

References

[1] A. Domling, I. Ugi, Angew. Chem. Int. Ed. 39 (2000) 3168.

[2] (a) I. Lengyel, V. Cesare, T. Taldone, Tetrahedron 60 (2004) 1107;

(b) F. Vela, S. Venkatraman, W. Wu, et al. Org. Lett. 9 (2007) 3061.

[3] J. Zhu, H. Bienayme, Multicomponent Reactions, Wiley, Weinheim, 2005, Chapter 2, p. 37.

[4] B. Beck, M. Magnin-Lachaux, E. Herdtweck, A. Domling, Org. Lett. 3 (2001) 2875.

[5] (a) L. Banfi, G. Guanti, R. Riva, Chem. Commun. 37 (2000) 985;

(b) A.G. Neo, C. Polo, S. Marcaccini, et al. Tetrahedron Lett. 46 (2005) 23.

[6] H. Yu, W. Sun, R. Gao, et al. Chin. J. Org. Chem. 30 (2010) 890.

[7] (a) G.A. Molander, G.J. Hahn, J. Org. Chem. 51 (1986) 1135;

(b) T. Honda, F. Ishikawa, Chem. Commun. 36 (1999) 1065.

[8] (a) K. Lam, I.E. Marko, Org. Lett. 10 (2008) 2773;

(b) K. Lam, I.E. Marko, Org. Lett. 11 (2009) 2752.

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