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Synthesis of #-Sulfur-Substituted Ketones via Rh(II)/Sc(III) Cocatalyzed ThreeComponent Reaction of Diazo Compounds with Thiophenols and Enones Guolan Xiao, Chaoqun Ma, Xiang Wu, Dong Xing, and Wenhao Hu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03074 • Publication Date (Web): 22 Mar 2018 Downloaded from http://pubs.acs.org on March 22, 2018
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The Journal of Organic Chemistry
Synthesis of γ-Sulfur-Substituted Ketones via Rh(II)/Sc(III) Cocatalyzed Three-Component Reaction of Diazo Compounds with Thiophenols and Enones Guolan Xiao,† Chaoqun Ma,† Xiang Wu,† Dong Xing,*,† and Wenhao Hu*,†,‡ †
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering,
East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China. ‡
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
Abstract: A facile method for the synthesis of γ-sulfur-substituted ketones is developed via a Rh(II)/Sc(III) cocatalyzed three-component reaction of diazo compounds with thiophenols and enones. With this method, different γ-sulfur-substituted ketones were obtained in moderate to high yields with good diastereoselectivities.
Sulfur-containing compounds are widely existed in a large number of synthetic drugs, bioactive molecules and natural products.1 For example, all of the top 10 best-selling drugs in 2012 were sulfur-containing compounds.2 Among different types of sulfur-containing molecules, γ-sulfur substituted carbonyl compounds have drawn considerable synthetic attention owing to their roles in various biological systems. For example, methionine, one of the amino acids that contains γ-sulfur-substituted carbonyl moiety, plays an important role both in protein structure and in metabolism.3 The traditional ways for the synthesis of γ-sulfur carbonyl compounds include the conjugated addition of α-lithiosulphides or α-sulfur substituted alkylstannanes to α,β-unsaturated ketones (Scheme 1, part a),4,5 which require either the use of stoichiometric amount of organolithium reagents under harsh reaction conditions or the use of highly toxic organotin reagents. As a result, it would be highly desirable to develop more efficient and straightforward approaches to build γ-sulfur carbonyl compounds under mild reaction
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conditions.
(a) Traditional methods for the synthesis of -sulfur substituted carbonyl compounds 1
R S
R2
R
O
3
+
M
R2
R1S
R4
R5
R3
O
R4
R5
M = Li, Sn (b) Our previously developed electrophilic trapping approach of active sulfonium ylide with imines
R1SH
+
N2 R2
Ar CO2R3
+
Ar1
Rh(II) chiral PPA
1
N
NH
R1S
Ar2 3 R CO2R
Ar2
2
(c) This work: construction of -sulfur substituted ketones by trapping of sulfonium ylide with enones R1 SH
Rh(II)
R1HS
+ R2
N2 Ar1
ORhLn
O
OR3 R
CO2Me
R1S
Sc(III)
2
R2
Ar1 CO2Me O R3
3
R
Scheme 1 Synthesis of γ-Sulfur-Substituted Ketones via the Trapping of Sulfonium Ylide with Enones.
Over the past ten years, our research group has been devoted to the development of multicomponent reactions (MCRs) via electrophilic trapping of in situ generated active intermediates from metal carbenes, therefore establish a powerful strategy for the rapid construction of complex molecules.6-9 Within this context, we have recently developed the first example of MCR via electrophilic trapping of sulfonium ylide intermediates with imines by a Rh(II)/chiral phosphoric acid (CPA) cocatalyzed reaction system, to generate a series of α-sulfur-β-amino esters in good stereoselectivities (Scheme 1, part b).8 Based on this electrophilic trapping strategy, we envisioned whether α,β-unsaturated ketones could also be used as electrophiles to undergo a Michael-type trapping of the in situ generated sulfonium ylide intermediates, therefore established a rapid way for the synthesis of γ-sulfur substituted ketones. However, owing to the much lower electrophilic ability of α,β-unsaturated ketones as Michael acceptors, the proposed electrophilic interception might be difficult to realize and appropriate activation of this kind of electrophile is required. Herein, we reported our successful development of a Rh(II)/Sc(III) cocatalyzed system that allows an efficient three-component reaction of diazo compounds, thiophenols and enones for the efficient construction of γ-sulfur substituted ketones.
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The Journal of Organic Chemistry
Table 1. Catalyst Screening and Optimization of Reaction Conditionsa
entry
solvent
temp
additive
yield of 4a (%)b
drc (syn : anti)
1
CH2Cl2
rt
--
