A Facile and Efficient Approach to N‐Protected‐β‐Sulfinyl‐ enamines via C‐Sulfinylation of Enamides and Enecarbamates

Abstract

A practical method has been developed for the C-sulfinylation of enamides and enecarbam-A C H T U N G T R E N N U N G ates using sodium phenylsulfinate/methyltrichloro-A C H T U N G T R E N N U N G silane (PhSO 2 Na/MeSiCl 3 ) as the sulfinylating reagent and N,N-dimethylacetamide (DMAc) as the Lewis base promoter, which allows for the preparation of a variety of N-protected-b-sulfinylenamines in high yields and good stereoselectivities. The Lewis base is found to be important for both the in situ generation of the active sulfinylating species (PhSOCl) and the sulfinylation step.Keywords: enamides; enecarbamates; Lewis base; sodium phenylsulfinate/methyltrichlorosilane (PhSO 2 Na/MeSiCl 3 ); C-sulfinylation Organic sulfoxides are an important class of compounds that have found broad applications.[1] They serve as key structural components in some drug molecules.[2] Chiral sulfoxides are well known chiral auxiliaries and ligands for asymmetric synthesis.[3] Besides the oxidation of sulfides, [4] the sulfinylation of organometallic nucleophiles (Li, [5] Cu, [6] Zn, [7] and Mg [8] reagents) with sulfinates represents the most important method for the preparation of sulfoxides, which, however, suffers from limited practicality due to the use of relatively expensive organometallics that typically require low temperature and moisture-free conditions. Sulfinylation of organometallics-free carbon nucelophiles with sulfinyl chloride is in principle a more practical and cost-efficient method. Although the Osulfinylation [9] of alcohols and the N-sulfinylation [10] of amines with sulfinyl chloride are well-known and efficient approaches to sulfinates and sulfinamides, respectively, so far there have been no effective methods available for the C-sulfinylation of organic carbon nucleophiles to synthesize sulfoxides. Glaros [11] and Lavilla [12] have reported that ketones and dihydropyridines can be directly sulfinylated with sulfinyl chloride to produce sulfoxide derivatives which, however, only give low yields. Herein, we present the first highly effective method for C-sulfinylation of enamides and enecarbamates with in situ generated phenyl sulfinyl chloride (PhSOCl), which allows for the preparation of N-protected-b-sulfinylenamines in high yields (up to 99%) and good stereoselectivities.Recently, in an attempt to use in situ generated enecarbamate 1a from 1a' as the nucleophile for chlorosilane-promoted Mannich-type reactions, [13] a new compound 2a was obtained as a by-product (Scheme 1). We speculated that this side reaction should be due to the nucleophilic attack of the enecarbamate 1a to an active sulfinyl species. To explore if such a side reaction could be developed into a useful new method for the preparation of functionalized vinyl sulfoxides, we directly treated isolated 1a with sodium phenylsufinate (PhSO 2 Na) and SiCl 4 in the presence of DMF in dry CH 2 Cl 2 . To our delight, the desired product 2a was achieved in 92% yield in 1.5 h (entry 1, Table 1).Scheme 1. Observed C-sulfinylation of enecarbam...

Transition-metal-free regioselective and stereoselective C(sp2)–C(sp3) coupling of enamides with ethers or alkanes via photoredox-catalyzed cross-dehydrogenative coupling reactions

“…2 As a consequence, enormous efforts have been devoted to develop efficacious and robust synthetic platforms for the structural modification of enamides. Benefiting from a booming development on direct β-C(sp 2 )–H functionalization, a diverse range of synthetically prominent functional groups were incorporated into enamide skeletons via state-of-the-art methodologies including olefination, 3 arylation, 4 alkynylation, 5 fluoroalkylation, 6 acylation, 7 arylsulfonylation 8 and many other elegant transformations. 9 In particular, the regio- and stereoselective alkylation of enamides via transition-metal-catalyzed or photoredox-catalyzed C(sp 2 )–C(sp 3 ) cross-coupling reactions has been at the forefront of considerable attention.…”

Copper(I) Bromide Catalyzed Arylation of Cyclic Enamides and Naphthyl-1-acetamides Using Diaryliodonium Salts

“…In due course, Gigant et al, reported the first copper-catalyzed C3-arylation of cyclic enesulfonamide I using diaryliodonium salts in the presence of base at 80 °C. 15 Although, β-aryl cyclic enamides (4, 5) are important structural precursors for the synthesis of biologically important compounds, such as indole carboline ring systems (8,9,10), phenanthridine scaffolds (11), and 2-aryl-tetrahydronaphthylamines (12), 16−23 their preparation remains a challenge for the aforementioned reasons (Figure 1). The importance of β-aryl cyclic enamides 4 and drawbacks of existing methods stimulated us to develop an operationally simple and base/ additive-free C−H arylation of cyclic enamides at ambient temperature.…”

“…Enamides are prevalent intermediates for synthesis of valuable chiral amines and natural products. , Although acyclic enamides are well exploited in a number of interesting synthetic transformations with electrophiles, − exploration of cyclic enamides as nucleophiles is very limited. − Synthetic utility of cyclic enamides in forming a C–C bond was demonstrated by Zhou et al, , by synthesizing β-aryl cyclic enamides 4 through Suzuki–Hiyama-type coupling. These protocols rely on an expensive palladium(II) catalyst in conjunction with additives such as copper or silver salts/base at elevated temperature.…”

“…(10 mg, 20%). Melting Point: 224−227 °C; 1 H NMR (500 MHz, DMSO-d 6 ) δ: 9.55 (bs, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.35−7.32 (m, 3H), 7.26 (d, J = 8 Hz, 2H), 7.23−7.21 (dd, J = 8.5 Hz, J = 2.5 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 3.86 (s, 3H), 2.36 (s, 3H), 1.99 (s, 3H); 13 C NMR (125 MHz, DMSO-d 6 ) δ: 169.9, 158.4, 137.7, 137.5, 136.7, 132.9, 130.1, 130.1, 129.2, 129.1, 128.9, 127.4, 126.0, 118.6, 103.1, 55.6, 23.0, 21.2.…”

Stereoselective C(sp2)–H Alkylation of Enamides with Unactivated Aliphatic Carboxylic Acids via Decarboxylative Cross-Coupling Reactions

“…Enamides are particularly versatile and crucial building blocks in organic synthetic chemistry for the construction of pharmaceutically and biologically important molecules . Therefore, the regio- and stereoselective functionalization of enamides on their β-C­(sp 2 )–H bond have gathered increasing attention in the past few years, delivering a diverse array of β-functionalized enamides containing alkene, alkyne, aryl, trifluoro- or difluoromethyl, arylsulfonyl, carbonyl, and many other useful functionalities . Especially, the incorporation of alkyl groups into enamides via C­(sp 2 )–C­(sp 3 ) coupling reactions is of particular interest.…”