A simple one-pot and transition metal-free synthesis of diaryl- and dialkyl sulfides via grignard reaction/deoxygenation

Full text of DOI:10.1002/bkcs.10762

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DOI: 10.1002/bkcs.10762
BULLETIN OF THE
H. S. Jung et al.
KOREAN CHEMICAL SOCIETY
A Simple One-Pot and Transition Metal-free Synthesis of Diaryl- and
Dialkyl Sulfides via Grignard Reaction/Deoxygenation
*
Hee Seon Jung, Nuri Suh, and Heung Bae Jeon
Department of Chemistry, Kwangwoon University, Seoul 139-701, Republic of Korea.
*E-mail: hbj@kw.ac.kr
Received December 2, 2015, Accepted February 27, 2016, Published online April 7, 2016
Keywords: Diaryl sulfide synthesis, Grignard reaction, Deoxygenation, Thionyl chloride,
Arylmagnesium halide
Sulfur-containing organic compounds are a highly attractive
Regarding the Grignard reaction and deoxygenation in
one pot, initial experiments were performed with phenyl-
magnesium bromide (2 equiv) and thionyl chloride (1 equiv)
at various reaction temperatures for the Grignard reaction.
Although no great difference was shown for the synthesis
of diphenyl sulfoxide when the reactions were performed
motif. In particular, diaryl sulfides and their derivatives
have been recognized as significant molecules because of
their potent biological activities1 and material interests.2
Increasing interest in and applications of diaryl sulfides
have prompted investigations of novel methodologies for
the preparation of these compounds.
ꢀ
below 0 C, we found that the best result was afforded by a
ꢀ
For the last few decades, many types of methods have
been developed to construct the thioether linkage for the
conversion of aryl halides to diaryl sulfides.3 Among them,
a variety of transition-metals such as palladium (Pd),4 cop-
per (Cu),5 nickel (Ni),6 cobalt (Co),7 and iron (Fe)8 have
been widely employed as catalysts for the coupling reaction
between aryl halides and thiols as the most general method.
Less general synthetic methods have used thiourea,9
thiocyanate,10 xanthate,11 or thioacetate12 as a sulfur source
with aryl halides and transition-metal catalysts for the syn-
thesis of diaryl sulfides. However, the formation of aryl-
sulfur bond including diaryl sulfides by the coupling of
aryllithium or Grignard reagents with phenyldisulfide, thio-
sulfonates, sulfur, or sulfenyl chlorides without the use of
transition metals has only been reported in a few articles13
and still requires the preparation of disulfides or the use of
aryl or alkyl thiols in certain cases. For these reasons, a
need remains for alternative efficient and reliable methods
that utilize readily available reagents under mild reaction
conditions for the synthesis of aryl sulfides from aryl
halides.
In our recent endeavors, sulfoxides were readily reduced
to sulfides with thionyl chloride and triphenylphosphine.14
In our continuing effort to develop a method for the synthe-
sis of diaryl sulfides from aryl halides using our method of
sulfoxide deoxygenation, we envisioned that diaryl
sulfides would be prepared using arylmagnesium halide and
thionyl chloride15 by the Grignard reaction followed by our
deoxygenation reaction (two steps in one pot). The treat-
ment of arylmagnesium halide 1 with thionyl chloride
would provide the corresponding diaryl sulfoxide
2 (Scheme 1). The deoxygenation of 2 by additional thionyl
chloride and triphenylphosphine would afford the desired
diaryl sulfides 3.
slow increase from 0 C to room temperature. Then, the
deoxygenation reaction provided different results for the
use of various amounts of additional thionyl chloride and
triphenylphosphine, as shown in Table 1, when the reac-
tions were performed for 6 h. The best yield of diphenyl
sulfide was obtained when 2 equiv of each reagent
was used.
Next, the generality of this method for the direct synthe-
sis of diaryl sulfides from aryl Grignard reagents and thio-
nyl chloride was investigated, as shown in Table 2. First, a
variety of arylmagnesium halides (2 equiv) were added to
ꢀ
thionyl chloride (1 equiv) in THF (tetrahydrofuran) at 0 C,
and the reaction temperature was slowly increased to room
temperature for 2 h. Then, triphenylphosphine (2 equiv)
and additional thionyl chloride (2 equiv) were subsequently
added to the reaction mixture at room temperature. All aryl-
magnesium bromides investigated gave the corresponding
diaryl sulfides in moderate to excellent yields. The reaction
proceeded smoothly and tolerated various functional groups
such as 4-chloro- (entry 2), 4-fluoro- (entry 3), 4-
methylthio- (entry 4), 4-methoxy- (entry 5), 3,5-di(trifluoro-
methyl)- (entry 8), and 4-phenyl- (entry 9) to afford the
Scheme 1. Synthetic route of diaryl sulfides
Bull. Korean Chem. Soc. 2016, Vol. 37, 779–782
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KOREAN CHEMICAL SOCIETY
Table 1. Optimization of the amounts of SOCl2 and PPh3
Table 2. One-pot sulfide synthesis using various Grignard
reagents with SOCl2 and PPh3
.
.
Amount (equiv)
SOCl2 PPh3
Yield (%)a
Sulfoxide
Time
(h)
Yield
(%)a
Entry
Sulfide
Entry Substrate
1
Product
1
2
3
4
a
0.5
1.0
1.5
2.0
0.5
1.0
1.5
2.0
10
51
84
88
84
33
6
6
88
2
3
5.5
78
—
Isolated yield.
5
78
corresponding sulfides in good yields. With (2-methoxy-
phenyl)magnesium bromide (entry 6) and (2,4,6-trimethyl-
phenyl)magnesium bromide (entry 7), which have ortho-
substituent groups, to investigate the steric issue, the one-
pot reactions produced the corresponding sulfides in yields
of 82 and 93%, respectively, under the same reaction con-
ditions. These results indicate that our Grignard reaction
followed by deoxygenation for sulfide synthesis is not
affected by steric hindrance. In addition, 2-
naphthylmagnesium bromide was readily converted into
dinaphthyl sulfide in 92% yield (entry 10). On the other
hand, alkyl Grignard reagents such as benzylmagnesium
chloride (entry 11) and cyclohexylmagnesium chloride
(entry 12) were treated with thionyl chloride (1 equiv), and
the subsequent deoxygenation of the resulting dialkyl sulf-
oxides afforded better yields, 52 and 65%, respectively,
when treated with triphenylphosphine (1 equiv) and addi-
tional thionyl chloride (0.2 equiv) than with additional thio-
nyl chloride (1 equiv), as mentioned in our previous
report.14 Clearly, the Grignard reaction with thionyl chlo-
ride followed by deoxygenation with triphenylphosphine
and additional thionyl chloride produced the desired diaryl
and dialkyl sulfides from all types of Grignard reagents in
good yields.
4
5
6
4
7
4
97
80
82
7
8
8
96
56
7.5
9
4
8
81
92
10
11
12
a
2
3
52b
65b
In addition, we could find that diphenyl sulfide was pro-
duced in good yield when phenyllithium, instead of phenyl-
magnesium bromide, was treated under the same reaction
conditions, as shown in Scheme 2.
Isolated yield when SOCl2 (2 equiv) and PPh3 (2 equiv) were used
in second step.
Isolated yield when SOCl2 (0.2 equiv) and PPh3 (1 equiv) were
used in second step.
b
In conclusion, we obtained the desired symmetrical sul-
fides in good yields when aryl or alkylmagnesium halides
were treated with thionyl chloride and subsequently with
additional thionyl chloride and triphenylphosphine in one
pot at ambient temperature. Notably, aryl Grignard reagents
with ortho-substituent groups were also converted to the
corresponding diaryl sulfides in excellent yields under mild
reaction conditions, showing that the steric hindrance does
not hinder the reaction. Due to the ease of operation, mild
reaction conditions, absence of transition metal, and high
generality of the substrates, this protocol demonstrates
promise in broad applications in organic synthesis.
Experimental
Typical Procedure for Diaryl Sulfide. To a solution of
SOCl2 (1.5 mmol) in dry THF (10 mL) was added drop-
wise aryl magnesium halide (3.0 mmol in THF or Et2O) at
ꢀ
0 C. The resꢀulting solution was stirred for 2 h at a slow
rising from 0 C to room temperature. To the reaction mix-
ture were added dropwise a solution of PPh3 (3.0 mmol) in
Bull. Korean Chem. Soc. 2016, Vol. 37, 779–782
© 2016 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Scheme 2. Synthesis of diphenyl sulfide using phenyl lithium
dry THF (2 mL) via cannula and subsequently additional
SOCl2 (3.0 mmol) at room temperature. The resulting solu-
tion was stirred until the sulfoxide intermediate was con-
sumed completely by TLC (thin layer chromatography)
monitoring at room temperature and quenched with
H2O. The reaction mixture was extracted with Et2O and
H2O. The organic layer was separated, dried over Na2SO4,
and concentrated. The residue was subjected to column
chromatography with only hexanes or hexanes-EtOAc
(30:1 – 20:1) as eluent to afford the corresponding sulfide.
1,10-Bis[3,5-bis(trifluoromethyl)phenyl]sulfide (entry
1
8 in Table 2): H NMR (400 MHz, CDCl3) δ 7.85 (s, 2H),
7.79 (s, 4H); 13C NMR (100 MHz, CDCl3) δ 137.1, 133.3
(q, J = 34 Hz), 130.9 (q, J = 3 Hz), 122.7 (q, J = 272 Hz),
122.1 (sep, J = 3 Hz); ESI MS m/z 458 [M+].
1
Dicyclohexyl sulfide (entry 12 in Table 2): H NMR
(400 MHz, CDCl3) δ 2.76–2.69 (m, 2H), 1.97–1.91 (m,
4H), 1.79–1.74 (m, 4H), 1.63–1.60 (m, 2H), 1.37–1.21 (m,
10H); 13C NMR (100 MHz, CDCl3) δ 41.8, 34.2, 26.1,
25.8; ESI MS m/z 198 [M+].
Acknowledgments. We are grateful for support from a
research grant of Kwangwoon University in 2014 for
this work.
Supporting Information. Additional supporting informa-
tion (1H and 13C NMR of all compounds in Table 2) is
available in the online version of this article.
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