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NH4I-Promoted and H2O-Controlled Intermolecular Bis-sulfenylation and Hydroxysulfenylation of Alkenes via a Radical Process Runfa He, Xiuwen Chen, Yibiao Li, Qiang Liu, Chunshu Liao, Lu Chen, and Yubing Huang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01047 • Publication Date (Web): 11 Jun 2019 Downloaded from http://pubs.acs.org on June 11, 2019
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The Journal of Organic Chemistry
NH4I-Promoted and H2O-Controlled Intermolecular Bis-sulfenylation and Hydroxysulfenylation of Alkenes via a Radical Process
Runfa Hea, Xiuwen Chena, Yibiao Lia*, Qiang Liua,b, Chunshu Liaoa, Lu Chen*, Yubing Huang aSchool
of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong Province
529090, China; bCenter of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100084, China E-mail:
[email protected];
[email protected] R
+ DMSO
SMe
NH4I R
H2O-Controlled
SMe
15 examples Up to 86% yield
OH
or R
SMe
or R
15 examples Up to 89% yield
O
SMe
6 examples Up to 92% yield
ABSTRACT: An NH4I-promoted and H2O-controlled intermolecular difunctionalization of alkenes for the synthesis of bis-methylsulfane and β-hydroxysulfides is presented. Mechanistic investigation revealed the reaction proceeds via methylthiyl radical addition to C=C double bond of alkenes to give a carbon-centered radical and immediately cyclize to a thiiranium ion, followed by combination with H2O to afford β-hydroxysulfides in 52–89% yield with chemo- and regioselectivity. In the absence of the water, 1,2-disulfenylation takes place to give bis-methylsulfane in moderate to good yields. In recent decades, the difunctionalization of olefins has become one of the most practical methods for synthesizing functional molecules or organic synthons bearing two vicinal carbon−carbon bonds or carbon−heteroatom bonds.[1] Among them, the bis-sulfenylation[2] and hydroxysulfenylation[3] of allylbenzene derivatives to prepare synthetically useful vicinal
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dithioethers is attracting increasing attention due to their synthetic utility in drug development[4] and fine chemical synthesis[5]. Previously reported sulfur etherification reagents mainly focused on alkyl and aromatic sulphides, such as thiol,[6] sulfonyl hydrazides,[7]
disulfides,[8]
sulfonamides,[9]
sulfenyl
halides,[10]
sulfenate
esters,[11]
(methylthio)-sulfonium salts[12] and sodium methanethiolate.[13] In particular, Lei and co-workers developed that the first efficiently electrocatalytic dehydrogenative C−H/S−H cross-coupling construct C-S bond, which was use the aryl/heteroaryl thiols and electron-rich arenes as reaction substrates.[14] Simultaneously, Jiang and co-workers use the organic thiosulfate salts to adjust the nature of free radicals by using the “masked strategy” and achieve selective sulphoxide and thioetherification.[15] However, these systems involve unpleasant odors, expensive catalysts and reagents, low chemo- and regio-selectivity and harsh conditions. There are hardly any reports of the use of dimethyl sulfoxide (DMSO) as a sulfur etherification reagent in bis-sulfenylation and hydroxysulfenylation reactions of alkenes. DMSO, however, has been used as source of groups such as –C1, –CH2–, =CH–, – CH3, –CHO, –CN, –SMe, –SO2Me group and as an oxygen source[16] in various organic synthesis methodology over recent decades. In addition, most bis-sulfenylation reactions are generally initiated through an episulfonium ion intermediate, with nucleophilic attack ultimately leading to vicinal dithioethers (Scheme 1a)[2a-e ,17]. In contrast, the bis-sulfenylation of alkenes to give vicinal dithioethers via a radical approach has rarely been explored. When the bis-sulfenylation reaction was initiated through a CH3S• radical originating from DMSO, a subsequent carbon radical intermediate was formed. Herein, we report the realization of this
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The Journal of Organic Chemistry
hypothesis via an NH4I-promoted and H2O-controlled intermolecular bis-sulfenylation and hydroxysulfenylation reaction of alkenes with DMSO as a MeS radical surrogate (Scheme 1b). Reported work:
R1
+
R1
S
R 2S (from RSSR) This work:
R1
R2
R1
R1
cationic intermediate
R R
+
R 2S
R SMe
radical intermediate
R1
(a)
SMe
CH3S (from DMSO)
SR2
SMe
or OH
R
(b)
SMe
Scheme 1. Outline for the Bis-sulfenylation and Hydroxysulfenylation of Alkenes In order to test the above bis-sulfenylation hypothesis, we screened reaction conditions using allylbenzene 1a, NH4I and anhydrous DMSO as a model reaction. The DMSO was used as both solvent and a MeS radical surrogate. To our delight, at a reaction temperature of 100 °C, the bis-sulfenylation reaction proceeded to afford the vicinal dithioether product 2a in 19% yield, along with a small amount of the hydroxysulfenylation product 3a in the presence of 2 equiv. NH4I (Table 1, entry 1). Further studies demonstrated that the yield was significantly improved upon increasing the reaction temperature (Table 1, entries 2−4). When the reaction temperature was increased to 140 °C, the yield of the bis-sulfenylation product 2a was slightly lower, and the yield of the hydroxysulfenylation product 3a was slightly increased to 15% (Table 1, entry 5). Increasing or decreasing the amount of NH4I did not improve the yield of the bis-sulfenylation reaction (Table 1, entries 6-7). It is noteworthy that H2O concentration had a significant effect on the yield of 2a and 3a (Table 1, entries 8−12). The yield of the hydroxysulfenylation product 3a was greatly improved if DMSO and H2O
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were used as the reaction solvent. We observed that when the ratio of DMSO: H2O was 1:1, the hydroxysulfenylation product was afforded in 87% yield and the yield of the bis-sulfenylation reaction did not exceed 5% (Table 1, entries 8-12). Subsequently, we investigated various halide sources, such as Et4NI, NH4Br and HI (Table 1, entries 15-17). None
of
these
promoted
the
reaction
well,
and
only
I2
generated
the
1-(methylthio)-3-phenylpropan-2-ol 3a in 53% yield (Table 1, entry 18). When 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or butylated hydroxytoluene (BHT) were added as radical scavengers, the sulfenylation reaction was completely inhibited (Table 1, entries 19-20). This indicates that the current intermolecular difunctionalization reaction proceeds via a radical pathway. Table 1. Optimization of Reaction Conditionsa
+
O S
OH
SMe
NH4I
+
SMe
SMe
1a
2a
3a
Entry Halide (equiv.) Solvent(v/v)
Temp (oC)
1
NH4I (2 eq)
DMSO
100
Yieldb (%) 2a 3a 19
