CuI promoted sulfenylation of organozinc reagents with arylsulfonyl chlorides

Article abstract of DOI:10.1039/c6ra27201k

A CuI promoted sulfenylation of organozinc reagents with arylsulfonyl chlorides/PPh₃ has been explored. This reaction proceeded smoothly through an alkyl/aryl radical (generated from organometallics) under mild conditions and produced the desired sulfide products in excellent yields.

Full text of DOI:10.1039/c6ra27201k

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CuI promoted sulfenylation of organozinc reagents
with arylsulfonyl chlorides†
Cite this: RSC Adv., 2017, 7, 6018
*
Ying Fu, Yuhu Su, Qin-shan Xu, Zhengyin Du, Yulai Hu, Ke-Hu Wang
and Danfeng Huang
Received 23rd November 2016
Accepted 7th January 2017
A CuI promoted sulfenylation of organozinc reagents with arylsulfonyl chlorides/PPh3 has been explored.
This reaction proceeded smoothly through an alkyl/aryl radical (generated from organometallics) under
mild conditions and produced the desired sulfide products in excellent yields.
DOI: 10.1039/c6ra27201k
www.rsc.org/advances
Thioether is a very important structural motif in numerous
At the outset of this investigation, optimization of the reac-
natural products and bioactive molecules, and is widely used as tion parameters was performed using phenylzinc bromide 1a
a versatile building block in organic molecules. As a conse- and p-tolylsulfonyl chloride 2a as the model substrates
quence, novel synthetic protocols have been continuously (Table 1). When the reaction was conducted by adding p-tol-
developed1 and much of recent attention has focused on ylsulfonyl chloride 2a into phenylzinc bromide 1a in the pres-
exploitation environmental friendly, thiol-free materials such as ence of CuI (1.0 equiv.) and PPh3 (2.2 equiv.) in THF at room
Bunte Salts,2 potassium ethyl xanthogenate,3 NaS2O3,4 KSCN,5 temperature, phenyl p-tolyl sulfone was formed in 68% isolated
CS2,6 sulfonyl hydrazides,7 DMSO8 and N-(aryl/alkylthio)succi- yield without formation of any suldes product. Alternatively,
nimides9 etc. as the sulfur source.
when phenylzinc bromide 1a was added into a mixture of p-
Recently, arylsulfonyl chloride, considering its abundance tolylsulfonyl chloride 2a and PPh3 (2.2 equiv.) in the presence of
and inexpensiveness, has emerged as a promising thiol-free CuI (1.0 equiv.) in THF at room temperature, p-tolyl disulde 4a
sulfur source in thioether synthesis. In 2011, You et al. rst was obtained in nearly quantitative yield (95%, entry 1). The
demonstrated that arylsulfonyl chlorides can be employed as appearance of disulde 4a can be ascribed to immediate
sulfur source for sulfenylation of electron-rich arenes or heter- reduction of p-tolylsulfonyl chloride 2a by PPh3.19 However, this
oarenes.10 This promising sulfenylation protocol was quickly experimental result also illustrates the fact that organozinc
recognized and was further enlarged in sulfenylation of (hetero) reagents are inert organometallic species towards organo-
arenes in PEG-400,11 quinones12 and iodoarenes.13 However, disuldes. To further improve the reactivity of organozinc
these methodologies are limited to diaryl sulde synthesis and reagents, two equivalents of TMEDA (tetramethylethylenedi-
require high temperature.
amine, L1) was added and heating to reux overnight, the yield
Organozinc reagents are mild organometallics and were of 3a was improved to 35% (entry 2). Replacement of CuI with
used extensively in organic synthesis.14 However, these privi-
leged organometallics have rarely been employed in C–S bond
formation reactions unless a reactive sulfur electrophile such as
sulfenyl chlorides15 or SO2 (ref. 16) etc. were introduced as the
substrates. Previously, we developed a CuI catalyzed synthesis of
arylsulfones from organozinc reagents and arylsulfonyl chlo-
rides.17 During this study, we accidentally found that when PPh3
was employed as the ligand, thioether can be formed unex-
pectedly. Owing to our interests on the synthesis and applica-
tion of organozinc reagents in organic synthesis,18 we here
report an CuI promoted sulfenylation of organozinc reagents
employing commercially available arylsulfonyl chlorides as the
sulfur source under mild reaction (Scheme 1).
College of Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu 730070, P. R. China. E-mail: fuying@iccas.ac.cn; Fax: +86-931-
7971989; Tel: +86-931-7971533
† Electronic supplementary information (ESI) available. See DOI:
Scheme 1 Approaches toward transformation of sulfonyl chlorides
10.1039/c6ra27201k
into thioethers.
6018 | RSC Adv., 2017, 7, 6018–6022
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Table 1 Optimization of the reaction conditionsa
Table 2 Reaction of arylsulfonyl chlorides with arylzinc reagentsa,b
Entry
Solvent
Cat./ligand
Temp.
3ab [%]
4ab [%]
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
THF
THF
CuI/—
CuI/L1
RT
0
95
61
61
62
64
67
31
32
51
0
Reux
Reux
Reux
Reux
Reux
Reux
Reux
Reux
RT
35
29
32
28
31
63
56
42
88c
CuBr/L1
CuCl/L1
CuCN/L1
Cu(OAc)2/L1
CuI/L2
CuI/L3
CuI/L4
CuI/L2
THF
THF/DMF
10
a
Reaction conditions: 1a (2 mmol) in THF (4 mL) was added into a THF
(4 mL) solution containing catalyst (1.0 mmol), ligand (2.0 mmol), 2a
(1.0 mmol) and PPh3 (2.2 mmol) under argon atmosphere and was
then stirred overnight. b Isolated yields. c 1.0 mL of DMF was added.
a
Reaction conditions: 1 (2 mmol) in THF (4 mL) was added into a THF–
DMF (5 mL, 4 : 1, v/v) solution containing CuI (1.0 mmol), bpy (2.0
mmol), 2a (1.0 mmol) and PPh3 (2.2 mmol) under argon atmosphere
b
and was then stirred at room temperature overnight. Isolated yields.
other cuprous salts such as CuBr, CuCl, CuCN and Cu(OAc)2 are
all effective, albeit without obvious yield improvement (entries
3–6). Ligands L1–L4 screening showed that bipyridine (L2) was
the best one, enhancing the yield of 3a to 63% (entries 7–9).
Organozinc reagents exhibit enhanced reactivity in a polar
aprotic solvent, e.g. DMF.20 Gratifyingly, the use of THF–DMF
(8 : 1, v/v) as a solvent dramatically improved the yield of 3a to
88% yield and disuldes 4a was cleanly consumed at room
temperature aer 12 hours (entry 10).
Although classic reactive organometallics such as
Grignards,21 organolithium reagents22 and some mild organo-
metallic species such as aryltrimethoxysilanes23 and triar-
ylbismuthanes24 are able to convert disuldes into suldes,
there are some apparent problems relating to these protocols.
Grignards and organolithium reagents will simultaneously
cleave both C–S and S–S bonds of disuldes,25 thus are limited
in practical suldes synthesis. On the other hand, triar-
ylbismuthanes26 and aryltrimethoxysilanes27 themselves were
prepared from corresponding Grignards, therefore, precludes
existence of some important functional groups on these
reagents. In this respect, our organozinc protocol28 is advanta-
geous both on their structural diversity and wide spectrum of
functional groups tolerance.
c
Biszincation of ferrocene (1.0 mmol) was performed using n-
butyllithium (2.2 mmol) and ZnCl2 (2.0 mmol).
tolerated under this optimized reaction conditions. The steric
hindrance effect of this reaction was not obvious; 2,6-disubsti-
tuted arylsulfonyl chlorides could participate this trans-
formation, giving the sulde products (3g, 3h) in good yields.
Heteroaromatic suldes containing furan (3m–3o), thiophene
(3p) and ferrocene (3q–3s) moieties can be easily prepared from
corresponding organozinc bromides in good isolated yields.
The application of aliphatic organozinc reagents with
various aromatic sulfonyl chlorides was then investigated
(Table 3). Gratifyingly, a range of aliphatic organozinc reagents,
both commercial available dialkylzinc reagents (5a–c, 5h, 5k
and 5l) and aliphatic organozinc halides, prepared by ZnCl2
mediated transmetalation of Grignards or organolithium
reagents, were compatible with the developed conditions.
Notably, adamantyl thioether 5n was also successfully prepared
using adamantylzinc bromide in 45% yield. Allylic and benzylic
thioethers (5m, 5o–5q) were easily prepared using allyl or ben-
zylzinc bromides in good yields. Also of note are thioethers 5r
and 5s were readily prepared in high yields via Reformasky type
reaction. Zinc acetylides (in situ formed via zincation of
terminal akynes by Et2Zn) were successfully employed to form
alkynylsuldes in good yields (5t and 5u).
The scope and generality of this CuI promoted sulfenylation
of various aryl and heteroarylzinc bromides with aromatic
sulfonyl chlorides/PPh3 couple was investigated under the
optimized conditions (Table 2). To PhZnBr$LiCl 1a, arylsulfonyl
chlorides containing either electron-donating or electron-
withdrawing groups were smoothly converted into diaryl
suldes (3a–h) in good to excellent yields. A variety of important
functional groups, including nitro (3d) and cyano (3e) were well
The halogen/magnesium exchange reaction29 and the direct
deprotonative metalation30 of arenes or heteroarenes with
strong bases are now recognized as powerful method for highly
functionalized organometallic reagents preparation. In this
respect, iodobenzene bearing an electron-withdrawing CF3
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Table 3 Reaction of arylsulfonyl chlorides with aliphatic organozinc
reagentsa,b
Scheme
2
Reaction of organozinc reagents delivered via Mg/I
exchange reaction and deprotonation method.
a
1 (2 mmol) in THF (4 mL) was added into a THF–DMF (5 mL, 4 : 1, v/v)
solution containing CuI (1.0 mmol), bpy (2.0 mmol), 2a (1.0 mmol) and
PPh3 (2.2 mmol) under argon atmosphere and was then stirred at room
b
c
temperature overnight. Isolated yields. Me2Zn (4 mmol) was used.
d
e
1,6-Dibromozinc hexane (0.5 mmol) was used. Et2Zn (4 mmol)
was used.
substituent found difficulty in direct magnesium insertion.31 Scheme 3 Some control experiments.
Nevertheless, treatment of 4-iodotriuorobenzene 6 by turbo
Grignards (i-PrMgCl$LiCl)32 and then transmetalated with
ZnCl2 afforded the corresponding organozinc reagents, which
equiv.) gave suldes 3m and 5a in exactly 1 : 1 ratio along with
quantitative remaining of 12 according to crude H NMR anal-
1
reacted with 4-methoxybenzenesulfonyl chloride/PPh3, giving
sulde 7a in 74% yield (Scheme 2). Similarly, dimethyl 4,40-
thiodibenzoate 7b was prepared in 82% yield. Furthermore,
zincation of benzo[d]oxazole 8 with TMPZnCl$LiCl33 and then
reaction with 3,4,5-trimethoxybenzenesulfonyl chloride/PPh3
couple yielded the sulde 9 in 71% yield.
To illustrate a possible mechanism for this transformation,
some control experiments were conducted (Scheme 3). When p-
tolylsulfonyl chloride 2a was treated with PhZnBr$LiCl 1a at the
same reaction without PPh3, sulfone 10 was obtained in 63%
isolated yield and sulde 3a was not detected at all (Scheme 3a),
indicating that PPh3 was the only reductant. However, PPh3
could not reduce sulfone 10 at room temperature in THF/DMF
(5 : 1, v/v). When diphenyl disulde 11 (1 mmol) instead of
phenylsulfonyl chloride/PPh3 was used in reaction with 4-
methoxyphenylzinc bromide 1b, sulde 3c was obtained in 94%
isolated yield, indicating that diaryl disulde in situ formed by
reduction of sulfonyl chlorides and PPh3 were the reactive
intermediates (Scheme 3b). Interestingly, treatment of 4-chlor-
ophenylzinc iodide 1c (1 equiv.) with mixed disulde 12 (1
ysis, addressing a radical mechanism of this reaction as in
a nucleophilic displacement reaction, 3m and 5a will be formed
in different ratio owing to the unsymmetric structure nature of
the mixed disulde 12. The signicant difference between
organozinc reagents and Grignard reagents was also high-
lighted here as Grignards normally nucleophilically cleave S–S
bond of disuldes and leaving another part of disulde as thiol
by-product. Furthermore, when a radical scavenger, 2,2,6,6-
tetramethyl-1-piperidinyloxyl (TEMPO, 2 equivalent) was added
into the sulfenylation reaction of 4-methoxyphenylzinc bromide
1b (2 equiv.) with phenylsulfonyl chloride (1 equiv.), sulde 3c
was not produced (Scheme 3d). Meanwhile, adduct (13) of the
thiyl radical34 with TEMPO was also not obtained. TEMPO was
totally decomposed by organozinc reagents, leaving disulde 4a
untouched, whereas adduct (14) of 1b with TEMPO was ob-
tained in 23% yield (GC-MS analysis).
Based on aforementioned experimental facts, a plausible
mechanism was proposed (Scheme 4). Arylsulfonyl chloride (I)
was reduced by PPh3 to give diaryl disulde (II).19
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In summary, we have developed an efficient and practical
method for the preparation of aromatic suldes based on CuI
promoted reaction of organozinc reagents with aromatic
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