Rhodium-catalyzed synthesis of diaryl sulfides using aryl fluorides and sulfur/organopolysulfides

Article abstract of DOI:10.1021/ol302497m

Substituted pentafluorobenzenes react with sulfur to give bis(4-substituted 2,3,5,6-tetrafluorophenyl) sulfides in the presence of RhH(PPh ₃)₄, 1,2-bis(diphenylphosphino)benzene (dppBz), and tributylsilane. The reaction proceeds efficiently between room temperature and 80 °C. A comparative study of the reactivities of an organic trisulfide and a tetrasulfide showed notable substrate specificity. Di-tert-butyl tetrasulfide reacted with reactive aryl monofluorides and substituted pentafluorobenzenes. Di-tert-butyl trisulfide reacted with aryl monofluorides. The reactivity was explained on the basis of the difference in S-S bond energy.

Full text of DOI:10.1021/ol302497m

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5318–5321
Rhodium-Catalyzed Synthesis of Diaryl
Sulfides Using Aryl Fluorides and
Sulfur/Organopolysulfides
Mieko Arisawa,* Takuya Ichikawa, and Masahiko Yamaguchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, Aoba, Sendai, 980-8578, Japan
yama@m.tohoku.ac.jp; arisawa@m.tohoku.ac.jp
Received September 10, 2012
ABSTRACT
Substituted pentafluorobenzenes react with sulfur to give bis(4-substituted 2,3,5,6-tetrafluorophenyl) sulfides in the presence of RhH(PPh3)4,
1,2-bis(diphenylphosphino)benzene (dppBz), and tributylsilane. The reaction proceeds efficiently between room temperature and 80 °C.
A comparative study of the reactivities of an organic trisulfide and a tetrasulfide showed notable substrate specificity. Di-tert-butyl
tetrasulfide reacted with reactive aryl monofluorides and substituted pentafluorobenzenes. Di-tert-butyl trisulfide reacted with aryl
monofluorides. The reactivity was explained on the basis of the difference in SÀS bond energy.
Diaryl sulfides have different properties from diaryl
ethers; they are used as biologically active substances1
and for high-temperature plastics.2 They are generally
synthesized by the substitution reaction of aromatic ha-
lides with inorganic sulfides3 or aromatic thiolates.4 The
utilization of sulfur in their synthesis is attractive because
sulfur is readily available, is easy to handle, and forms no
metal waste. Very few examples, however, have been
reported for the reaction of aryl halides and sulfur, which
proceeds at extremely high temperatures above 200 °C.5
Bis(pentafluorophenyl) sulfide is obtained by the reaction
of iodopentafluorobenzene and sulfur at 230 °C without a
solvent; the reaction of chloropentafluorobenzene and
sulfur is conducted at 350 °C in the presence of a stoichio-
metric amount of copper.
(1) (a) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen,
B.; Marsh, K. C.; Okasinski, G. F.; von Geldern, T. W.; Ormes, M.;
Fowler, K.; Gallatin, M. J. Med. Chem. 2000, 43, 4025. (b) Wang, Y.;
Chackalamannil, S.; Hu, Z.; Clader, J. W.; Greenlee, W.; Billard, W.;
Binch, H., III; Crosby, G.; Ruperto, V.; Duffy, R. A.; McQuade, R.;
Lachowicz, J. E. Bioorg. Med. Chem. Lett. 2000, 10, 2247. (c) Beard,
R. L.; Colon, D. F.; Song, T. K.; Davies, P. J. A.; Kochhar, D. M.;
Chandraratna, R. A. S. J. Med. Chem. 1996, 39, 3556. (d) Nagai, Y.; Irie,
A.; Nakamura, H.; Hino, K.; Uno, H.; Nishimura, H. J. Med. Chem.
1982, 25, 1065.
(2) (a) Fahey, D. R.; Hensley, H. D.; Ash, C. E.; Senn, D. R.
Macromolecules 1997, 30, 387. (b) Novi, M.; Petrillo, G.; Sartirana,
M. L. Tetrahedron Lett. 1986, 27, 6129. (c) Hawkins, R. T. Macro-
molecules 1976, 9, 189.
Described in this study is the rhodium-catalyzed synthe-
sis of diaryl sulfides from aryl fluorides and sulfur, which
proceeds at much lower temperatures (Scheme 1). Pre-
viously, we developed a method for the rhodium-catalyzed
synthesis of aryl sulfides from aryl fluorides and organic
disulfides.6 Here, we describe the extension of this metho-
dology to the reaction of sulfur.7 During our study to
(3) For examples using Na2S, see: (a) Li, Y.; Nie, C.; Wang, H.; Li,
X.; Verpoort, F.; Duan, C. Eur. J. Org. Chem. 2011, 7331. Also see ref 2a.
Using thioacetamide: (b) Tao, C.; Lv, A.; Zhao, N.; Yang, S.; Liu, X.;
Zhou, J.; Liu, W.; Zhao, J. Synlett 2011, 134. Using thiourea: (c)
€
~ꢀ~
Arguello, J. E.; Schmidt, L. C.; Penenory, A. B. Org. Lett. 2003, 5, 4133.
(4) For examples using palladium-catalyzed reactions, see: (a) Shi,
Y.; Cai, Z.; Guan, P.; Pang, G. Synlett. 2011, 2090. (b) Fernandez-
Rodriguez, M. A.; Shen, Q.; Hartwig, J. F. Chem.;Eur. J. 2006, 12,
7782. Using iron-catalyzed reaction: (c) Wu, J.-R.; Lin, C.-H.; Lee, C.-F.
Chem. Commun. 2009, 4450. (d) Correa, A.; Carril, M.; Bolm, C. Angew.
Chem., Int. Ed. 2008, 47, 2880. Using copper-catalyzed reaction: (e)
Zhang, X.-Y.; Zhang, X.-Y.; Guo, S.-R. J. Sulfur Chem. 2011, 32, 23.
Using nickel-catalyzed reaction: (f) Jammi, S.; Barua, P.; Rout, L.; Saha,
P.; Punniyamurthy, T. Tetrahedron Lett. 2008, 49, 1484. Using cobalt-
catalyzed reaction: (g) Lan, M.-T.; Wu, W.-Y.; Huang, S.-H.; Luo,
K.-L.; Tsai, F.-Y. RSC Adv. 2011, 1, 1751. (h) Wong, Y.-C.; Jayanth,
T. T.; Cheng, C.-H. Org. Lett. 2006, 8, 5613. Using rhodium-catalyzed
reaction: (i) Lai, C.-S.; Kao, H.-L.; Wang, Y.-J.; Lee, C.-F. Tetrahedron
Lett. 2012, 53, 4365and references cited therein.
(5) (a) Golloch, A.; Sartori, P. Synthesis 1973, 52. (b) Cohen, S. C.;
Reddy, M. L. N.; Massey, A. G. Chem. Commun. 1967, 451.
(6) Arisawa, M.; Suzuki, T.; Ishikawa, T.; Yamaguchi, M. J. Am.
Chem. Soc. 2008, 130, 12214.
(7) (a) Arisawa, M.; Tanaka, K.; Yamaguchi, M. Tetrahedron Lett.
2005, 46, 4797. (b) Arisawa, M.; Ashikawa, M.; Suwa, A.; Yamaguchi,
M. Tetrahedron Lett. 2005, 46, 1727.
r
10.1021/ol302497m
Published on Web 10/05/2012
2012 American Chemical Society

develop a sulfur reaction methodology, the reactivities of
an organic trisulfide and a tetrasulfide were compared,
which showed notable substrate specificity.
Table 1. Reaction of Pentafluorobenzenes and Sulfur
Scheme 1
yield (%)
entry
R
80 °Ca
rta
1
2
3
4
5
6
7
NO2 (a)
42
62
67
66
72
65
18
71
77
42
27
3
CN (b)
PhCO (c)
CH3CO (d)
PhS (e)
When (phenylthio)pentafluorobenzene 1e was reacted
with sulfur (0.9 equiv atom) in the presence of RhH(PPh3)4
(5 mol %), dppBz (10 mol %), and tributylsilane (1 equiv)
at 80 °C for 6 h, bis(4-phenylthio-2,3,5,6-tetrafluorophenyl)
sulfide 2e was obtained in 72% yield (Table 1, entry 5). The
reaction proceeded effectively using only a small excess of
sulfur. The added tributylsilane was converted to tributyl-
silyl fluoride in 59% yield, which was confirmed by 19F
NMR dÀ174.6 (quintet, J = 6.0 Hz) and HRMS 218.1852
(calcd for C12H27FSi 218.1866).8 A trace amount of 2e was
obtained without using tributylsilane. When triphenylpho-
sphine was used as the fluoride acceptor,6,9b the yield of 2e
decreased to 8%, accompanied by the formation of triphe-
nylphosphine sulfide (78%). The result indicated that
triphenylphosphine reacted with sulfur faster than fluo-
ride. The rhodium complex and dppBz ligand were both
essential for the reaction. No reaction occurred in the
absence of either substance. The reaction of p-fluorobenzo-
phenone 10a and p-fluorobenzonitrile 10c, however, did not
proceed under the conditions; as will be noted later, the use
of an organic trisulfide was essential for such a reaction.
Several pentafluorobenzenes possessing cyano, benzoyl,
acetyl, and tolylthio groups reacted with sulfur in high
yields (Table 1, entries 2À6). Note that pentafluoroben-
zenes possessing electron-withdrawing groups such as
nitro, cyano, and benzoyl groups reacted even at room
temperature(entries1À3).10 All these reactions occurredat
the p-position of the substrates irrespective of the nature of
the substituents. The same tendency was previously ob-
served in the rhodium-catalyzed thiolation reactions of
polyfluorobenzenes with thioesters, the aryloxylation re-
action with aryl esters, and the CÀC bond-forming reac-
tion with 1,2-diphenylethanone.9
4-TolS (f)
Ph2N (g)
a Reaction temperature.
The synthesis of an unsymmetrical diaryl sulfide was
examined. When 1c and 1e (3 equiv) were reacted with sulfur
(1.8 equiv atom), 1-(4-phenylthio-2,3,5,6-tetrafluorophe-
nylthio)-4-benzoyl-2,3,5,6-tetrafluorobenzene 3 (44%) was
obtained, which was accompanied by the symmetric sulfides
2c (51%) and 2e (20%) (Scheme 2). The sulfur accepting
reactivity of 1c was slightly lower than that of 1e.
Scheme 2
Substituted pentafluorobenzenes react with sulfur to
give bis(4-substituted 2,3,5,6-tetrafluorophenyl) sulfides
under rhodium-catalyzed conditions. The reaction pro-
ceeds efficiently between room temperature and 80 °C,
unlike conventional methods, which proceed only above
200 °C.
The reactivity of sulfur was compared with those of
organic polysulfides. Since the reactivity of organic poly-
sulfides with a transition-metal catalyst has rarely been
examined,7 we considered it interesting to study the sub-
ject. When 1e was reacted with di-tert-butyl tetrasulfide 4
(0.9 equiv) in the presence of RhH(PPh3)4 (5 mol %),
dppBz (10 mol %), and tributylsilane (1 equiv) in DMF at
80 °C for 6 h, 2e was obtained in 80% yield along with di-
tert-butyl trisulfide 5 (41%) and the recovery of 4 (16%)
(Scheme 3). No di-tert-butyl disulfide was detected. No
reaction occurred in the absence of the rhodium complex.
(8) Engelhardt, G.; Licht, K. Z. Chem. 1970, 10, 266.
(9) (a) Arisawa, M.; Nakane, S.; Kuwajima, M.; Yamaguchi, M.
Heterocycles 2012in press. (b) Arisawa, M.; Igarashi, Y.; Kobayashi, H.;
Yamada, T.; Bando, K.; Ichikawa, T.; Yamaguchi, M. Tetrahedron 2011, 67,
7846.
(10) Typical Experimental Procedures. In
a two-necked flask
equipped with a reflux condenser were placed pentafluorobenzonitrile
1b (0.5 mmol, 61.6 μL), sulfur (0.45 mmol, 7.2 mg), RhH(PPh3)4
(5 mol%, 28.8 mg), 1,2-bis(diphenylphosphino)benzene (10 mol%,
22.3 mg), and tributylsilane (0.5 mmol, 129 μL) in DMF (0.5 mL) under
an argon atmosphere, and the solution was stirred at room temperature
for 6 h. The solvent was then removed under reduced pressure, and the
residue was purified by flash column chromatography on silica gel giving
bis(4-cyano-2,3,5,6-tetrafluorophenyl) sulfide 2b (73.1 mg, 77%).
Org. Lett., Vol. 14, No. 20, 2012
5319

These results showed that only one sulfur atom of 4 was
transferred to 1e, and accordingly, no reaction occurred
when 1e and 5 were reacted. The reactivity of the middle
sulfur in 4 is different from that in 5.
Table 2. Reaction of Pentafluorobenzenes and 4
Scheme 3
entry
R
yield/%
1
2
3
4a
5
6
7
8
NO2 (a)
CN (b)
14
20
71
40
66
80
89
82
PhCO (c)
CH3CO (d)
PhS (e)
4-TolS (f)
Ph2N (g)
Several pentafluorobenzenes possessing moderately
electron-donating groups (Ph2N and ArS) and electron-
withdrawing groups (PhCO and MeCO) reacted with 4 in
high yields (Table 2, entries 3À8). Note that 4 reacted with
1g possessing a diphenylamino group in a much higher
yield than sulfur (entry 8, also see Table 1 entry 7). The
yield decreased when 4 was reacted with 1a and 1b posses-
sing strong electron-withdrawing groups (entries 1 and 2).
The tetrasulfide 4 exhibited a slightly different reactivity
with pentafluorobenzenes from sulfur. A notable differ-
ence was observed in the reaction of aryl monofluo-
rides possessing two strong electron-withdrawing groups.
The reaction of 4 and 4-cyano-(3-trifluoromethyl)-
fluorobenzene 6a or 4-cyano-(2-trifluoromethyl)fluoro-
benzene 6b gave the sulfides in high yields (Scheme 4).
Trace amounts of the products were obtained with sulfur
for these substrates. 2-Fluorobenzothiazole 8 also reacted
with 4 (0.9 equiv) under the same conditions giving the
sulfide 9 in 67% yield. No reaction occurred using sulfur,
and the yield of 9 decreased to 13% using the di-tert-butyl
trisulfide 5 in place of 4. In contrast to these reactive aryl
fluorides, p-fluorobenzophenone 10a and p-fluorobenzo-
nitrile 10c gave no diaryl sulfides using 4. The difference
between the reactivities of 4 and sulfur may originate from
the difference in the nature of the middle sulfur, which will
be discussed later.
Observing the apparent difference between the reactiv-
ities of sulfur and tetrasulfide, it was considered interesting
to examine the reactivity of an organic trisulfide. It was
found that the reactivity of the middle sulfur in trisulfide
was different from those in sulfur and tetrasulfide. When
p-fluorobenzophenone 10a and di-tert-butyl trisulfide 5
(0.9 equiv) were reacted in DMF at 80 °C for 12 h in the
presence of RhH(PPh3)4 (10 mol %), dppBz (20 mol %),
and tributylsilane (100 mol %), bis(4-benzoylphenyl) sul-
fide 11a was obtained in 59% yield along with di-tert-butyl
disulfide (84%) and the recovery of 10a (35%) (Table 3,
entry 1). Using dibutyl trisulfide (0.25 equiv) in place of 5,
no 11a was detected, and p-benzoylphenyl butyl sulfide
(89%) was formed, which indicated the bulky substituent
of trisulfides to be critical for the selective transfer of the
middle sulfur atom in 5. As noted before, sulfur and the
a In air atmosphere.
Scheme 4
tetrasulfide 4 produced no 11a from 10a under the condi-
tions employed. Appropriate combinations of sulfurating
reagents and aryl fluorides are required for an effective
reaction.
The sulfuration of 5 could be applied to the synthesis of
aryl fluorides possessing p-benzoyl, o- or p-cyano, and
nitro groups (Table 3, entries 1À6). When triphenylpho-
sphine was used as the fluoride acceptor in the reaction of
o-nitrofluorobenzene 10d and 5, 11d was obtained in 43%
yield (entry 5). Since both triphenylphosphine and tribu-
tylsilane worked effectively, the formation of silyl sulfide
intermediates from trisulfide and silane reagent may not be
likely for the present reactions. 3,4-Difluorobenzonitrile
10g reacted at the p-fluoride atom (entry 8). No reaction of
m-cyanofluorobenzene and 4-fluorotoluene occurred. Di-
tert-butyl trisulfide reacted efficiently at 80 °C with aryl
monofluorides, which have electron-withdrawing groups
at the o- and p-positions.
A possible mechanism of the reaction of 4 follows
(Figure 1). The high-oxidation-state rhodium complex
A is formed by the oxidative addition of an aryl fluo-
ride and 4 at the SSÀSS bond. Then, a sulfur atom inserts
at the RhÀC bond with the liberation of 5. The result-
ing rhodium fluoride B reacts with another aryl fluo-
ride and transfers fluoride atoms to tributylsilane or
5320
Org. Lett., Vol. 14, No. 20, 2012

Table 3. Reaction of Aryl Monofluorides and 5
entry
R1
R2
yield (%)
1
2
3
4
5a
6
7
8
PhCO
H
H (a)
59
48
64
66
43
64
53
41
CN (b)
H (c)
CN
H
NO2 (d)
NO2
CN
H (e)
Cl (f)
F (g)
CN
Figure 1
a Using PPh3 in place of n-Bu3SiH.
groups and 2-fluorobenzothiazole > aryl monofluorides
with one electron-withdrawing group). These results sup-
port the idea that less reactive sulfurating reagents should
be used for less reactive substrates. Similar correlations
were previously observed in the thiolation reaction of
various organic compounds.13 The need for suitable com-
binations of substrates and sulfurating reagents is impor-
tant for the catalyzed sulfuration of organic compounds.
In summary, sulfur was reacted with substituted penta-
fluorobenzenes to give bis(4-substituted 2,3,5,6-tetra-
fluorophenyl) sulfidesin the presenceof a rhodium catalyst
and tributylsilane. The reaction proceeded efficiently be-
tween room temperature and 80 °C. The reactivities of
organic polysulfides under transition-metal catalyzed con-
ditions were compared, and these sulfur reagents showed
differences in reactivity between sulfur, trisulfide, and
tetrasulfide.
triphenylphosphine giving tributylsilyl fluoride or triphe-
nylphosphine difluoride. A diaryl disulfide is liberated by
reductive elimination, and the rhodium catalyst is regen-
erated by the oxidation of the rhodium dihydride C with a
trace amount of oxygen-forming water. It was previously
reported that the rhodium-catalyzed oxidation of thiols is
quite rapid, giving disulfides in an oxygen atmosphere.11
The reactionof1cand 4 gave2c(40%) in air atmosphere as
well as in argon atmosphere (Table 2, entry 4), indicating
that oxygen does not inhibit the catalytic cycle.
Sulfur, 4, and 5 showed different reactivities with aryl
fluorides. Trisulfide 5 sulfurated aryl monofluorides;
Tetrasulfide 4 sulfurated reactive aryl monofluorides and
substituted pentafluorobenzenes with moderately elec-
tron-donating and electron-withdrawing groups. Sulfur
reacted with only substituted pentafluorobenzenes. The
difference in reactivity may be due to the difference in SÀS
bond energy [trisulfide (46 kcal/mol) > tetrasulfide (37
kcal/mol) > sulfur (33 kcal/mol)]12 and the difference in
reactivity between the aryl fluorides (pentafluorobenzenes
> aryl monofluorides with two electron-withdrawing
Acknowledgment. This work was supported by a
Grant-in-Aid for Scientific Research (No. 21229001) from
JSPS and the GCOE program. M.A. expresses her thanks
for financial support from the Grant-in-Aid for Scien-
tific Research from MEXT (No. 22689001), Japan
Science Technology Agency, and also to the Asahi
Glass Foundation.
(11) Arisawa, M.; Sugata, C.; Yamaguchi, M. Tetrahedron Lett.
2005, 46, 6097.
(12) Pickering, T. L.; Saunders, K. J.; Tobolsky, A. V. Chem. Sulfides
1968, 61.
Supporting Information Available. General experimen-
tal procedures and characterization details. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(13) (a) Arisawa, M.; Nihei, Y.; Yamaguchi, M. Tetrahedron Lett.
2012, 53, 5729. (b) Arisawa, M.; Toriyama, F.; Yamaguchi, M. Heteroa-
tom Chem. 2011, 22, 18. (c) Arisawa, M.; Toriyama, F.; Yamaguchi, M.
Tetrahedron 2011, 67, 2305. (d) Arisawa, M.; Toriyama, F.; Yamaguchi,
M. Tetrahedron Lett. 2011, 52, 2344. (e) Arisawa, M.; Suwa, K.;
Yamaguchi, M. Org. Lett. 2009, 11, 625. (f) Arisawa, M.; Fujimoto, K.;
Morinaka, S.; Yamaguchi, M. J. Am. Chem. Soc. 2005, 127, 12226.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 20, 2012
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