Efficient synthesis of unsymmetrical diaryl thioethers via TBAF-mediated denitrative substitution of nitroarenes with PhSTMS under mild and neutral conditions

Article abstract of DOI:10.1016/j.cclet.2013.04.011

Tetrabutylammonium fluoride (TBAF) effectively facilitated a denitrative substitution reaction of electron-deficient nitroarenes with phenylthiotrimethylsilane (PhSTMS) under mild and base-free neutral conditions at room temperature, providing a practical and efficient synthesis of useful unsymmetrical diaryl thioethers. Nitroarenes bearing ortho- and para-positioned electron-withdrawing groups are the most reactive substrates, indicating that this reaction most possibly proceeded via the nucleophilic aromatic substitution (S_NAr) mechanism.

Full text of DOI:10.1016/j.cclet.2013.04.011

Chinese Chemical Letters 24 (2013) 605–608
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Chinese Chemical Letters
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Original article
Efficient synthesis of unsymmetrical diaryl thioethers via TBAF-mediated
denitrative substitution of nitroarenes with PhSTMS under mild and neutral
conditions
*
Xiao-Chun Yu, Bo Li, Bao-Hua Yu, Qing Xu
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Tetrabutylammonium fluoride (TBAF) effectively facilitated a denitrative substitution reaction of
electron-deficient nitroarenes with phenylthiotrimethylsilane (PhSTMS) under mild and base-free
neutral conditions at room temperature, providing a practical and efficient synthesis of useful
unsymmetrical diaryl thioethers. Nitroarenes bearing ortho- and para-positioned electron-withdrawing
groups are the most reactive substrates, indicating that this reaction most possibly proceeded via the
nucleophilic aromatic substitution (SNAr) mechanism.
Received 23 January 2013
Received in revised form 28 March 2013
Accepted 8 April 2013
Available online 17 May 2013
Keywords:
ß 2013 Qing Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Phenylthiotrimethylsilane
Nitroarenes
Denitrative substitution
Unsymmetrical diaryl thioethers
Nucleophilic aromatic substitution
1. Introduction
tures of the reactions [13–16]. In comparison with the reactions
of the corresponding aryl halides, the C-heteroatom bond
The formation of carbon-heteroatom bonds via arylation
reactions has attracted much interest in recent years. These
methods have also been applied in diaryl thioether synthesis
since they are also a class of useful intermediates in synthesis and
key building blocks in natural products and biologically and
pharmaceutically active compounds [1,2]. One common method
for diaryl thioether preparation is the classic, copper-assisted
Ullmann reactions [3–5]. However, this method usually requires
a high reaction temperature and large amounts of copper
reagent, which may lead to the generation of undesirable wastes
and other problems upon scaling-up of the reactions. Thus, in
recent years to overcome these limitations, various new methods
have been developed for the reactions of aryl halides and sulfur
nucleophiles, such as the palladium-catalyzed reactions [6,7],
improved copper-catalyzed Ullmann reactions [4,5,8–10], as
well as iron [11], nickel [12] and other transition metal-catalyzed
methods. Despite the advances in metal-catalyzed methods,
nucleophilic aromatic substitution (SNAr) reactions of electron-
deficient aryl halides are still attractive alternatives in synthesis
of thioethers and other C-heteroatom compounds due to the
relatively milder conditions and environmentally benign fea-
formation via SNAr reactions of the readily available nitroarenes
by displacement of the nitro groups were much less known
processes [17]. Recently, Oshima [18], Beier [19], and Wu [20]
independently reported C–O, C–S and C–C coupling reactions of
electron-deficient nitroarenes with thiols, alkali alkoxides,
alkane thiolates, and arylboronic acids. However, drawbacks
still remain because these methods usually use excess amounts
of nucleophiles, large amounts of base resulting in strong basic
conditions, high reaction temperatures, and the generation of
large amounts of wastes. In our previous studies, we have
developed a mild and efficient method for the synthesis of diaryl
thioethers by tetrabutylammonium fluoride (TBAF)-catalyzed
SNAr reactions of aryl fluorides and phenylthiotrimethylsilane
(PhSTMS) under base-free neutral conditions [21,22]. In com-
parison with conventional SNAr reactions [13–16], the advan-
tages of using TBAF as the catalyst and trimethylsilyl-activated
PhSTMS as the sulfur nucleophile include comparatively lower
reaction temperatures (e.g., at room temperature), base-free
neutral conditions, and high tolerance of the reactive functional
groups, which also implied that this method may have broader
applications in synthesis. Herein we continue to report on a mild
and efficient TBAF-mediated denitrative substitution reaction of
electron-deficient nitroarenes with PhSTMS, providing a simple
and practical alternative for the synthesis of useful unsymme-
trical diaryl thioethers.
* Corresponding author.
E-mail address: qing-xu@wzu.edu.cn (Q. Xu).
1001-8417/$ – see front matter ß 2013 Qing Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.04.011

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X.-C. Yu et al. / Chinese Chemical Letters 24 (2013) 605–608
Table 1
2. Experimental
Condition optimization for denitrative substitution of 2-nitrobenzaldehyde with
PhSTMS.a
[DT$INLE]
Unless otherwise noted, reactants and catalyst were pur-
chased and used without further purification. In reactions
carried out under air, commercial solvents were directly used.
In reactions carried out under N2, degassed solvents were used.
The reactions were then monitored by TLC. Products were
purified by column chromatography on silica gel using petro-
leum ether and ethyl acetate as eluent. 1H NMR and 13C NMR
spectra were measured on a Bruker Avance-III 500 instrument
(500 MHz for 1H NMR and 125.4 MHz for 13C NMR spectroscopy)
or a Bruker Avance 300 instrument (300 MHz for 1H NMR and
75 MHz for 13C NMR spectroscopy) using CDCl3 as the solvent
with tetramethylsilane (TMS) as the internal standard. IR spectra
were recorded on a Bruker Vector-55 instrument. Mass spectra
were measured on a Shimadzu GC-MS-QP2010 Plus spectrome-
ter (EI). HRMS (EI) analysis was performed by the Analytical
Center at the Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences.
CHO
CHO
STMS
O2N
fluoride ion sources
solvent, r.t., N2, 2 h
S
+
1
3a
2a
b
Entry
Fluorides (equiv.)
PhSTMS (equiv.)
Solvent
Yield of 3a (%)
1c
2c
3
TBAF (1.2)
TBAF (2.0)
TBAF (1.2)
TBAF (1.2)
TBAF (1.2)
TBAF (1.2)
TBAF (1.2)
TBAF (1.2)
CsF (1.2)
1.2
2.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
CH3CN
CH3CN
CH3CN
Toluene
THF
73
83
95
4
Trace
Trace
Trace
55
5
6
Dioxane
DMF
7
8
DMSO
CH3CN
CH3CN
CH3CN
61
9
48
10
11
KF (1.2)
15
NaF (1.2)
trace
General procedure for the synthesis of unsymmetrical diaryl
thioethers (3) by denitrative substitution reaction of nitroarenes (2)
with PhSTMS (1): The mixture of nitroarene 2 (1.0 mmol), PhSTMS 1
(1.2 mmol, 1.2 equiv.), and TBAF (1.2 mmol, 1.2 equiv.) in degassed
acetonitrile (2 mL) was stirred at room temperature under N2 for
2 h and the reaction was monitored by TLC. After completion of the
reaction, the solvent was evaporated under reduced pressure and
the residue purified by flash column chromatography on silica gel
to give 3.
a
Unless otherwise specified, the reactions were carried out using 1, 2a (1 mmol),
and a fluoride source in a degassed solvent (2 mL) under N2 at room temperature
(25–30 8C). The reactions were monitored by TLC.
b
Isolated yields.
c
The reactions were conducted under air.
oxidize 1 to PhSSPh and 2a to the corresponding acid when
the reaction was conducted under air, we next performed the
reaction under nitrogen and degassed solvents. Thus, by
carrying out the reaction under nitrogen, 1.2 equiv. of 1 and
TBAF could successfully afford a high yield of target 3a (entry
3). To further optimize the reaction conditions, various
solvents such as toluene, THF, DMF, DMSO, dioxane (entries
4–8) and fluoride salts (entries 9–11) were screened under the
same condition, indicating acetonitrile was the best solvent
and TBAF the most effective fluoride salt for the reaction
(entry 3).
6-(Phenylthio)benzo-[1,3]dioxole-5-carbaldehyde (3c): 1H NMR
(300 MHz, CDCl3):
6.67 (s, 1H), 5.95 (s, 1H); 13C NMR (75 MHz, CDCl3):
148.2, 135.6, 135.5, 130.7, 129.5, 127.5, 112.9, 108.3, 102.4; IR
d
10.30 (s, 1H), 7.29 (s, 1H), 7.23–7.18 (m, 5H),
d
189.7, 152.9,
(KBr, cmÀ1):
n 3717, 2910, 1683, 1582, 1472, 1252, 1037; MS (EI):
m/z (%) 258 (M+), 241, 199, 171, 148, 120, 95, 69, 51; HRMS Calcd.
for C14H10O3S: 258.0351; found: 258.0353. 2,4-Bis(phenylthio)-
benzaldehyde (3d): 1H NMR (300 MHz, CDCl3):
d
10.22 (s, 1H), 7.68
(d, 1H, J = 8.2 Hz), 7.38–7.28 (m, 10H), 7.00 (d, 1H, J = 8.2 Hz), 6.61
(s, 1H); 13C NMR (125 MHz, CDCl3):
190.4, 147.6, 143.3, 134.7,
134.1, 132.7, 131.6, 130.1, 129.8, 129.4, 128.9, 125.9, 123.4; IR
d
The optimized condition was then employed to investigate
the utility of the method. As shown in Table 2, the reaction of
nitroarene analogs bearing EWGs, such as formyl, acetyl,
benzoyl, and cyano groups at ortho- or para-positions similar
to 2a (entry 1), usually proceeded efficiently to give high yields
of the nitro-displaced, unsymmetrical diaryl thioethers (entries
2–11). However, ortho-acetyl- and ortho-benzoyl nitrobenzenes
2 g and 2i did not react under this condition (entries 7 and 9).
Since the para-isomers of 2g and 2i (2f and 2h in entries 6 and 8)
and another ortho-substituted nitrobenzene 2j (entry 10)
bearing the smaller cyano group, all reacted efficiently to give
high yields of the corresponding products, the reason for the
failure of 2g and 2i to react may be attributed to steric
hindrance of the ortho-acetyl and -benzoyl groups, because
these bulky groups may prevent the similarly bulky phenylthio
group from approaching the ortho-nitro groups. In the case of 5-
fluoro-2-nitrobenzaldehyde 2b, the fluoro is usually regarded as
a better leaving group than nitro group [13,17,28], possibly
because the nitro group is activated by both the ortho-formyl
and para-fluoro groups while the fluoro is only activated by the
para-nitro group, the nitro group, another good leaving group,
accordingly become more reactive than fluoro, and thus the
reaction finally gave the fluorine-retained, but nitro-replaced
product 5-fluoro-2-(phenylthio)benzaldehyde 3b (entry 2). For
dinitrobenzene 2d, a double-sulfenylated product 3d could
result as the major product in high yield when an excess of
2.4 equiv. of 1 and TBAF was used (entry 4). As shown in Table 2,
the reactions under nitrogen (results outside the parentheses)
were always more efficient than those under air (results in
(KBr, cmÀ1):
n 3747, 3430, 2801, 1683, 1575, 1205, 752, 691; MS
(EI): m/z (%) 322 (M+), 244, 212, 184, 152, 109, 77, 51; HRMS Calcd.
for C19H14OS2: 322.0486; found: 322.0483.
For the known products, their spectral data are in agreement
with the literature [21–27].
3. Results and discussion
In previous studies [21,22], we noticed that contrary to the
usual behavior of halo-substituted nitroarenes, those nitroar-
enes bearing electron-withdrawing groups (EWGs), such as
formyl, as substrate, the formyl-retained and nitro-displaced
product could be obtained under similar conditions. This
interesting result encouraged us to further explore the
denitrative reactions of nitroarenes with PhSTMS in detail.
Thus, the reaction of PhSTMS (1) and 2-nitrobenzaldehyde
(2a) was investigated to optimize the reaction conditions
(Table 1). As in the previous studies, the reaction was initially
carried out under atmospheric conditions using 1.2 equiv. of
both
1 and TBAF in acetonitrile. The reaction proceeded
rapidly even at room temperature (2 h), but only with a
moderate yield of product 3a (entry 1). No higher yield of the
product could be achieved despite large excessive amounts of
1 and TBAF (2 equiv.) under the identical condition (entry 2).
During the study, we noticed that variant amounts of diphenyl
disulfide (PhSSPh) and other unidentified byproducts were
detected in the reactions under air. Realizing that oxygen may

X.-C. Yu et al. / Chinese Chemical Letters 24 (2013) 605–608
607
Table 2
TBAF-mediated denitrative substitution reactions of various nitroarenes with PhSTMS
[DT$INLE]
STMS
S
O2N
TBAF (1.2 equiv.)
CH3CN, r.t., N2, 2 h
+
EWG
EWG
3
1
2
Entry
Nitroarenes
Products
Yield %a
1
2
o-NO2C6H4CHO (2a)
o-PhSC6H4CHO (3a)
95 (73)
98 (74)
NO2
SPh
[DT$INLE]
[TD$INLINE]
F
CHO
F
CHO
CHO
(3b)
(2b)
(2c)
3
93 (23)
93 (30)
CHO
O
O
O
O
[DT$INLE]
[TD$INLINE]
NO2
SPh
(3c)
4b
PhS
SPh
NO2
NO2
[DT$INLE]
[TD$INLINE]
CHO
(3d)
CHO
(2d)
5
6
p-NO2C6H4CHO (2e)
p-NO2C6H4COCH3 (2f)
o-NO2C6H4COCH3 (2g)
p-NO2C6H4COPh (2h)
o-NO2C6H4COPh (2i)
o-NO2C6H4CN (2j)
p-PhSC6H4CHO (3e)
p-PhSC6H4COCH3 (3f)
o-PhSC6H4COCH3 (3g)
p-PhSC6H4COPh (3h)
o-PhSC6H4COPh (3i)
o-PhSC6H4CN (3j)
91 (31)
94 (91)
–
7
8
89 (50)
–
9
10
11
12c
13c
14
15
16
96 (85)
95 (81)
34 (27)
37 (35)
–
p-NO2C6H4CN (2k)
p-PhSC6H4CN (3k)
p-NO2C6H4CO2CH3 (2l)
p-PhSC6H4CO2CH3 (3l)
p-NO2C6H4CO2C2H5 (2m)
m-NO2C6H4CHO (2n)
C6H5NO2 (2o)
p-PhSC6H4CO2C2H5 (3m)
m-PhSC6H4CHO (3n)
C6H5SPh (3o)
–
p-NO2C6H4CH3 (2p)
p-PhSC6H4CH3 (3p)
–
a
Isolated yield from reactions under nitrogen were shown outside the parentheses (yields obtained from reactions under air were shown in the parentheses).
b
c
2.4 equiv. of 1 and TBAF were used.
The reaction was conducted at 75 8C.
parentheses) (entries 1–11), especially in the case of 2c–e
4. Conclusion
(entries 3–5), which afforded much higher product yields under
nitrogen. Worth noting is that, under the current mild, TBAF-
mediated, base-free neutral conditions, the reactive formyl,
acetyl, benzoyl, and cyano groups can be retained. For
comparison, under conventional strong basic conditions using
less reactive protonic nucleophiles, side reactions of these
reactive functional groups usually occur to give undesired
byproducts.
In contrast with above efficient reactions, the reactions of
methyl- and ethyl-4-nitrobenzoates were ineffective under the
standard conditions. When heated at an elevated temperature of
75 8C, low yields of the target products were obtained, and the
reactions under nitrogen failed to yield much better results
(entries 12–13). In these reactions, some unidentified byproducts
were observed both under air and under nitrogen, but the reasons
are still not clear at present.
In summary, we have developed a mild and efficient TBAF-
mediated denitrative substitution reaction of electron-deficient
nitroarenes with PhSTMS for the synthesis of useful unsymme-
trical diaryl thioethers. Due to the wide availability of the
nitroarenes, high tolerance of the reactive functional groups under
the base-free neutral conditions, fast transformation under the
mild conditions, and higher efficiency of the reactions than those of
the corresponding aryl halides [21,22], the present method may
provide a potentially useful alternative for the synthesis of
unsymmetrical diaryl thioether from nitroarenes.
Acknowledgments
We are grateful to the National Natural Science Foundation of
China (No. 20902070), Natural Science Foundation of Zhejiang
Province (No. Y4100579), and Qianjiang Talents Program of
Zhejiang Province (No. QJD0902004) for financial supports.
In addition, meta-formyl nitrobenzene (2n), unsubstituted
nitrobenzene (2o), and
a substituted nitrobenzene with an
electron-donating group at the para-position (2p) were also
investigated (Table 2, entries 14–16). However, no reaction
occurred at all and no target product could be detected under
the standard condition. Based on the great difference of these inert
substrates to the previous reactive ones, it can be concluded that
the present reaction is a nucleophilic aromatic substitution (SNAr)
reaction, in which the leaving nitro group is activated by the para-
or ortho-EWGs, as with the aryl halides in our previous systems.
Therefore, the present reactions most possibly proceeded via a
typical SNAr mechanism.
References
[1] L. Liu, J.E. Stelmach, S.R. Natarajan, et al., SAR of 3,4-dihydropyrido[3,2-d]pyr-
imidone p38 inhibitors, Bioorg. Med. Chem. Lett. 13 (2003) 3979–3982.
[2] G. Liu, J.R. Huth, E.T. Olejniczak, et al., Novel p-arylthio cinnamides as antagonists
of leukocyte function-Associated antigen-1/intracellular adhesion molecule-1
interaction. 2. Mechanism of inhibition and structure-based improvement of
pharmaceutical properties, J. Med. Chem. 44 (2001) 1202–1210.
[3] F. Ullmann, Ueber eine neue Darstellungsweise von Phenyla¨thersalicylsa¨ure,
Chem. Ber. 37 (1904) 853–854.

608
X.-C. Yu et al. / Chinese Chemical Letters 24 (2013) 605–608
[17] J.R. Beck, Nucleophilic displacement of aromatic nitro groups, Tetrahedron 34
[4] S.V. Ley, A.W. Thomas, Modern synthetic methods for copper-mediated C(aryl)-O,
C(aryl)-N, and C(aryl)-S bond formation, Angew. Chem. Int. Ed. 42 (2003) 5400–
5449.
(1978) 2057–2068.
[18] A. Kondoh, H. Yorimitsu, K. Oshima, Nucleophilic aromatic substitution reaction
of nitroarenes with alkyl- or aryl-thio groups in dimethyl sulfoxide by means of
cesium carbonate, Tetrahedron 62 (2006) 2357–2360.
[5] I.P. Beletskaya, A.V. Cheprakov, Copper in cross-coupling reactions. The post-
Ullmann chemistry, Coord. Chem. Rev. 248 (2004) 2337–2364.
[6] D. Prim, J. Campagne, D. Joseph, B. Andrioletti, Palladium-catalysed reactions of
aryl halides with soft, non-organometallic nucleophiles, Tetrahedron 58 (2002)
2041–2075.
ˇ´
´
[19] P. Beier, T. Pasty´rıkova, N. Vida, G. Iakobson, SNAr reactions of nitro-(pentafluor-
osulfanyl)bnezenes to generate SF5 aryl ethers and sulfides, Org. Lett 13 (2011)
1466–1469.
[7] J.F. Hartwig, Evolution of a fourth generation catalyst for the amination and
thioetherification of aryl halides, Acc. Chem. Res. 41 (2008) 1534–1544.
[8] F.Y. Kwong, S.L. Buchwald, A general, efficient, and inexpensive catalyst system for
the coupling of aryl iodides and thiols, Org. Lett. 4 (2002) 3420–3517.
[9] A.K. Verma, J. Singh, R. Chaudhary, A general and efficient CuI/BtH catalyzed
coupling of aryl halides with thiols, Tetrahedron Lett. 48 (2007) 7199–7202.
[10] S. Jammi, S. Sakthivel, L. Rout, et al., CuO nanoparticles catalyzed C–N, C–O, and C–S
cross-coupling reactions: scope and mechanism, J. Org. Chem. 74 (2009) 1971–1976.
[11] A. Correa, A. Carril, C. Bolm, Iron-catalyzed S-arylation of thiols with aryl iodides,
Angew. Chem. Int. Ed. 47 (2008) 2880–2883.
[20] X. Zheng, J. Ding, J. Chen, et al., The coupling of arylboronic acids with nitroarenes
catalyzed by rhodium, Org. Lett. 13 (2011) 1726–1729.
[21] B. Yu, X. Zang, X. Yu, Q. Xu, TBAF-catalysed facile synthesis of unsymmetrical
diaryl thioethers via mild SNAr reactions, J. Chem. Res. 34 (2010) 351–353.
[22] C. Liu, X. Zang, B. Yu, X. Yu, Q. Xu, Microwave-promoted TBAF-catalyzed SNAr
reaction of aryl fluorides and ArSTMS: an efficient synthesis of unsymmetrical
diaryl thioethers, Synlett (2011) 1143–1148.
[23] J.Y. Lee, P.H. Lee, Palladium-catalyzed carbon–ulfur cross-coupling reactions with
indium tri(organothiolate) and its application to sequential one-pot processes, J.
Org. Chem. 73 (2008) 7413–7416.
[12] S. Jammi, P. Barua, L. Rout, P. Saha, T. Punniyamurthy, Efficient ligand-free nickel-
catalyzed C–S cross-coupling of thiols with aryl iodides, Tetrahedron Lett. 49
(2008) 1484–1487.
[13] J.F. Bunnett, R.E. Zahler, Aromatic nucleophilic substitution reactions, Chem. Rev.
49 (1951) 273–412.
[14] J. Zhu, SNAr based macrocyclization via biaryl ether formation: application in
natural product synthesis, Synlett (1997) 133–144.
[15] J.S. Sawyer, Recent advances in diaryl ether synthesis, Tetrahedron 56 (2000)
5045–5065.
[24] Y.C. Wong, T.T. Jayanth, C.H. Cheng, Cobalt-catalyzed aryl–sulfur bond formation,
Org. Lett. 8 (2006) 5613–5616.
[25] H. Gilman, F.J. Webb, The metalation of some sulfur-containing organic com-
pounds, J. Am. Chem. Soc. 71 (1949) 4062–4066.
[26] H. Xu, X. Zhao, J. Deng, Y. Fu, Y. Feng, Efficient C–S cross coupling catalyzed by
Cu2O, Tetrahedron Lett. 50 (2009) 434–437.
[27] N. Taniguchi, Convenient synthesis of unsymmetrical organochalcogenides using
organoboronic acids with dichalcogenides via cleavage of the S–S, Se–Se, or Te–Te
bond by a copper catalyst, J. Org. Chem. 72 (2007) 1241–1245.
[28] R.E. Parker, T.O. Read, The mechanism of displacement reactions. Part III. Kinetics
of the reactions of the four 2-halogeno-1,3-dinitrobenzenes and 1,2,3-trinitro-
benzene with aniline in ethanol, J. Chem. Soc (1962) 3149–3153.
[16] J.S. Sawyer, E.A. Schmittling, J.A. Palkowitz, W.J. Smith III., Synthesis of diaryl ethers,
diaryl thioethers, and diarylamines mediated by potassium fluoride–alumina and
18-crown-6: expansion of scope and utility, J. Org. Chem. 63 (1998) 6338–6343.