Three-component coupling reaction triggered by insertion of arynes into the S=O bond of DMSO

Article abstract of DOI:10.1021/ol501638x

An unprecedented three-component coupling reaction of arynes, α-bromo carbonyl compounds, and DMSO triggered by insertion of arynes into the S=O bond of DMSO has been developed. The reaction can generate a wide range of multisubstituted aryl methyl thioethers in good yields, wherein DMSO serves as both methylthiolation reagent and oxygen source.

Full text of DOI:10.1021/ol501638x

Letter
pubs.acs.org/OrgLett
Three-Component Coupling Reaction Triggered by Insertion of
Arynes into the SO Bond of DMSO
Feng-Lei Liu,† Jia-Rong Chen,*,† You-Quan Zou,† Qiang Wei,† and Wen-Jing Xiao*,†,‡
†Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan, Hubei 430079, China
‡Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 30072, China
S
* Supporting Information
ABSTRACT: An unprecedented three-component coupling
reaction of arynes, α-bromo carbonyl compounds, and DMSO
triggered by insertion of arynes into the SO bond of DMSO
has been developed. The reaction can generate a wide range of
multisubstituted aryl methyl thioethers in good yields, wherein
DMSO serves as both methylthiolation reagent and oxygen
source.
Scheme 1. Aryne-Based Three-Component Coupling
Reaction with Incorporation of Solvent
rynes represent a class of unique and highly versatile
Asynthetic intermediates, and the past decades have
witnessed a rapid revival in their application in organic
synthesis since the discovery of a mild generation of arynes
from o-silyl aryl triflate precursors by Kobayashi.1,2 Owing to
their high strain and low-lying LUMO, arynes could undergo
various transition-metal-free nucleophilic attack readily by a
wide range of neutral nucleophiles,3 such as isocyanides,4
aldehydes and ketones,5 N-heteroaromatic compounds,6
imines,7 amines,8 amides,9 and thioureas,10 to generate a
diverse variety of highly reactive and versatile zwitterions. The
resultant highly reactive 1,3- or 1,4-zwitterionic intermediates
have provided a powerful platform for identifying or engineer-
ing new multicomponent reactions (MCRs) by employing
appropriate electrophiles, thus leading to efficient construction
of diversely functionalized 1,2-disubstituted arenes and bio-
logically important carbo- and heterocycles.11 In particular, the
transition-metal-free three-component coupling reaction of
arynes has enjoyed considerable advances over the past several
years.12 Among them, solvent-participated (e.g., THF,4e
CH3CN,6a,8d and DMF9b−d) MCRs of arynes are particularly
intriguing and thus have attracted remarkable research effort,
wherein these solvents act not only as a reaction medium but
also as a reagent incorporated into the final products (Scheme
1). For example, the Cheng group pioneered a reaction of
arynes, isoquinolines, and nitriles (Scheme 1a),6a while Yoshida
and co-workers described an interesting three-component
coupling reaction of benzyne, THF, and alkynyl (or poly-
fluoroaryl) bromides to produce the corresponding alkyl aryl
ethers in moderate to high yields (Scheme 1b).4e Furthermore,
the Miyabe group disclosed another powerful transformation of
arynes, formamides and alkylzincs in a one-pot fashion for the
synthesis of ortho-disubstituted arenes (Scheme 1c).9b It was
found that the key to success for the desired reaction was the
formation of formal [2 + 2] adduct (benzoxetene) or ortho-
quinone methide via insertion of arynes into CO π-bond of
fomamides. Based on these elegant works, the third coupling
components were subsequently extended to active methylene
compounds,9c,d water,9e α-chlorinated methines,9f alcohols,9g,h
and aroyl cyanides,9i by the groups of Miyabe, Yoshida, Shi, and
Wang.
Despite these impressive advances, to our knowledge, there is
no report on the use of DMSO in MCRs of arynes for new
methodology developments.13 As part of our ongoing research
program in sulfur chemistry,14 we envisioned that the use of
cheap and commercially available DMSO as neutral nucleophile
instead of DMF might also lead to formation of highly reactive
formal [2 + 2] cycloaddition adduct through insertion of aryne
into the SO bond. Thus, exploration of such type of resultant
intermediate should provide a novel platform for incorporating
a S-containing moiety into valuable aromatic compounds.
Herein, we describe a transition-metal-free three-component
coupling reaction of arynes, α-bromo carbonyl compounds, and
DMSO, which is triggered by insertion of arynes into the SO
bond (Scheme 1d). The reaction furnished a wide range of
Received: June 6, 2014
© XXXX American Chemical Society
A
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Letter
biologically and synthetically important aryl methyl thioethers
in generally good yields.15,16
Table 2. Substrate Scope of α-Bromo Carbonyl Compounds
and Benzyl Bromide
a
Initially, we investigated the reaction by employing benzyne,
generated in situ from 2-(trimethylsilyl)aryl triflate 1a by
fluoride source and 2-bromo-1-phenylethanone 2a in DMSO at
room temperature.17 To our delight, the reaction resulted in
formation of the unexpected product 3aa in 53% yield in the
presence of KF and 18-crown-6 (Table 1, entry 1). The
a
Table 1. Optimization of Reaction Conditions
b
entry
temp (°C)
concn (M)
t (h)
yield (%)
1
2
3
4
rt
0.1
4
4
4
4
4
4
2
6
8
53
65
66
61
51
70
68
76
72
40
50
60
50
50
50
50
50
0.1
0.1
0.1
c
5
0.2
d
6
0.07
0.07
0.07
0.07
d
7
de
,
8
9
d
a
Unless noted, reactions were carried out with 1a (0.20 mmol), 2a
(0.40 mmol), KF (0.40 mmol), and 18-crown-6 (0.40 mmol) in
b
DMSO (2.0 mL). GC yield (using biphenyl as the internal standard).
c
d
e
DMSO (1.0 mL). DMSO (3.0 mL). Isolated yield = 68%.
structure of 3aa has been fully characterized by NMR and X-ray
crystallographic analysis.18 Notably, this novel and catalyst-free
process can generate two new C−O bonds and one C−S bond
through only one operation. Encouraged by this result, we
continued to screen reaction temperature and substrate
concentration to further improve the chemical yield. It was
found that increasing the reaction temperature to 50 °C
provided a 66% yield of 3aa (Table 1, entry 3). A brief survey
of substrate concentration showed that slightly diluted reaction
improved the yield to 70% (Table 1, entries 3, 5, and 6).
Moreover, somewhat prolonged reaction time resulted in a 76%
yield of 3aa (Table 1, entry 8 vs 9). Hence, the optimal reaction
conditions were established (Table 1, entry 8).
Under the optimized conditions, the scope of this reaction
was first examined by using a variety of α-bromo carbonyl
compounds, and the representative results are highlighted in
Table 2. In addition to 1a, various electron-donating and
electron-withdrawing groups at ortho-, meta-, or para-positions
of the phenyl ring of α-bromo carbonyl compounds were well-
tolerated, affording the corresponding products 3ab−3ak in
31−77% yields (entries 1−11). Note that the substrates bearing
electron-donating substituents generally give superior yields
over the ones with electron-withdrawing groups. Moreover,
reactions of α-bromo carbonyl compounds bearing a fused ring
(2l) or heterocycle (2m) can also result in the formation of the
corresponding products 3al and 3am in 55 and 61% yield,
respectively (entries 12 and 13). Importantly, an array of α-
bromoesters (2n−2q) with variable steric hindrance and α-
bromoamide (2r) have proved to be suitable for the reaction
with formation of products 3an−3ar in moderate to good
yields (51−76%) (entries 14−18). To our delight, the reaction
of alkyl-substituted α-bromoketone 2s, benzyne, and DMSO
proceeded smoothly to give the product 3as in 79% yield.
a
Unless noted, reactions were carried out with 1a (0.40 mmol), 2
(0.80 mmol), KF (0.80 mmol), and 18-crown-6 (0.80 mmol) in
DMSO (6.0 mL) at 50 °C for 6 h. Isolated yield.
b
Furthermore, 4-nitrobenzyl bromide 2t can successfully
participate in the reaction to furnish the desired product 3at
in 59% yield (entry 20). Notably, product 3ah was found to
B
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Letter
exhibit in vitro activities against intracellular Leishmania
amazonesis and Leishmania donovani amastigotes.19 Accordingly,
products 3aa−3at can provide a small library of candidates for
related biological studies.
On the basis of the above results and previous literature,9 we
proposed a possible mechanism to account for the formation of
aryl methyl thioethers (Scheme 3). First, the highly reactive
Encouraged by these results, we further investigated the
scope of this three-component reaction by using diversely
substituted aryne precursors under standard conditions (Table
3). In the case of symmetrical arynes, both 4,5-dimethyl- and
Scheme 3. Proposed Mechanism
a
Table 3. Substrate Scope of Arynes
benzyne intermediate A, generated in situ from precursor 1a by
fluoride source, underwent a nucleophilic attack by oxygen of
DMSO to generate the zwitterion B. Then, an intramolecular
cyclization of B formed the intermediate C, which isomerized
to α-carbonyl sulfur ylide D via a ring-opening process. The
zwitterion E is a resonance structure of α-carbonyl sulfur ylide
D. An intermolecular SN2 nucleophilic attack of oxygen anion
of zwitterion E to α-bromo carbonyl ketone 2a resulted in the
formation of intermediate F. Finally, the resultant bromine
anion from α-bromo carbonyl ketone 2a would abstract methyl
cation of intermediate F to give the product 3aa.17,20
In conclusion, we have developed a new three-component
coupling reaction of arynes, α-bromo carbonyl compounds, and
DMSO triggered by insertion of arynes into the SO bond of
DMSO. In this transformation, DMSO served as both
methylthiolation reagent and oxygen source. Remarkably, the
reaction allowed for an unusual construction of two new C−O
bonds and a C−S bond in a one-pot fashion, affording a variety
of synthetically and biologically important aryl methyl
thioethers in generally good yields.
a
Unless noted, reactions were carried out with 1b−e (0.40 mmol), 2a
(0.80 mmol), KF (0.80 mmol), 18-crown-6 (0.80 mmol) in DMSO
(6.0 mL) at 50 °C for 6 h. Isolated yield.
b
4,5-difluoro-substituted 2-(trimethylsilyl)phenyl triflates (1b
and 1c) can be tolerated in the reaction to afford the desired
product 3ba and 3ca in 35 and 52% yield, respectively (entries
1 and 2). In the case of 4-methyl-substituted benzyne precursor
1c, the reaction gave rise to a mixture in an almost 1:1
regioisomeric ratio (3da and 3da′) with 73% total yield (entry
3). We also carried out the reaction with benzyne precursor 1e
under the standard conditions (entry 4). The reaction with the
in situ-generated 3-methoxylbenzyne proceeded smoothly and
led to exclusive formation of 3ea in 72% yield, with the oxygen
moiety at the meta-position of the MeO group. This result
suggested that the reaction involves an initial nucleophilic
coupling process.7
In order to gain some insight into the mechanism, we carried
out a deuterium-labeling study in the reaction of 1a, 2a, and
DMSO-d6 (Scheme 2, eq 1). Complete deuterium incorpo-
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 2. Labeling Experiments
Experimental procedures, characterization data, NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chenjiarong@mail.ccnu.edu.cn.
*E-mail: wxiao@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ration at the carbon of methylthio moiety was observed by the
1H NMR analysis, which confirmed that DMSO served as the
source of the methylthio group. In addition, an O18-labeled
DMSO experiment with 1a and 2a was also performed, and
obvious detection of 18O-3aa by mass analysis suggested that
the oxygen of newly formed C−O bond originated from
DMSO (Scheme 2, eq 2).
ACKNOWLEDGMENTS
■
We are grateful to the National Science Foundation of China
(Nos. 21272087 and 21232003) and the National Basic
Research Program of China (2011CB808603) for support of
this research.
C
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Letter
(13) It has recently been found that DMSO could serve as efficient
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(17) Please see the Supporting Information for more details.
(18) CCDC 998873 (3aa) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
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proposed mechanism described in Scheme 3.
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