Alkyl- or arylthiolation of aryl iodide via cleavage of the S-S bond of disulfide compound by nickel catalyst and zinc

Article abstract of DOI:10.1021/jo040184q

Various aryl sulfides can be synthesized by nickel-catalyzed alkyl- or arylthiolation of aryl iodide with a disulfide compound. This reaction produces Ni(0) from NiBr₂-bpy by the reduction with zinc, and this generated complex works as an activating species to convert ArI into ArSR under neutral conditions. Furthermore, this system enables the use of two RS groups in (RS)₂.

Full text of DOI:10.1021/jo040184q

Alk yl- or Ar ylth iola tion of Ar yl Iod id e via
Clea va ge of th e S-S Bon d of Disu lfid e
Com p ou n d by Nick el Ca ta lyst a n d Zin c
Nobukazu Taniguchi
F IGURE 1. Strategy for the synthesis of ArSR from ArI and
Department of Chemistry, Fukushima Medical University,
Fukushima 960-1295, J apan
(RS)2.
problem, it is necessary for (RY)2M to be reduced into a
mono(organochalcogenide)-metal complex RYM (Figure
1).
Recently, we found that the addition of magnesium
stimulates the copper-catalyzed synthesis of diaryl chal-
cogenide from diphenyl dichalcogenide and aryl iodide.6
Two points are noted in this reaction: (1) the copper
catalyst is reduced by magnesium and (2) it is possible
to use two PhY (Y ) S or Se) groups in diphenyl
dichalcogenide under neutral conditions.
taniguti@fmu.ac.jp
Received April 23, 2004
Abstr a ct: Various aryl sulfides can be synthesized by
nickel-catalyzed alkyl- or arylthiolation of aryl iodide with
a disulfide compound. This reaction produces Ni(0) from
NiBr2-bpy by the reduction with zinc, and this generated
complex works as an activating species to convert ArI into
ArSR under neutral conditions. Furthermore, this system
enables the use of two RS groups in (RS)2.
On the other hand, the above-described method has
been limited to the case of a Cu(I)-Mg system, and in
the use of dialkyl dichalcogenide, a lowering of the
reactivity is often observed.
The transition metal-catalyzed thiolation of aryl halide
is an important reaction in the synthesis of miscellaneous
unsymmetrical aryl sulfides.1 These aryl sulfides have
interesting characteristics in organic compounds and are
often used as effective reagents or convenient intermedi-
ates in organic synthesis.2 Usually, in methods for the
metal-catalyzed preparation of aryl sulfides, the cross-
coupling of thiol with aryl halide, using a copper or
palladium catalyst under basic conditions, is used.3
However, the metal-catalyzed thiolation of aryl halide
with a disulfide compound has rarely been done, despite
of the fact that the efficient use of (RS)2 in the catalytic
thiolation of alkyl halide has been published.4
In the present Note, we report a nickel-catalyzed
synthesis of unsymmetrical aryl sulfide from aryl iodide
and dialkyl- or diaryl-disulfide using zinc.
The nickel-catalyzed thiolation of aryl halide with thiol
under basic conditions has been well studied.7 Similarly,
in the presence of polymer-supported borohydride, the
phenylselenation of aryl halide with diselenide is re-
ported by Millois and Diaz.8 Ni-catalyzed thiolation that
uses disulfide is briefly described in their Note. Their
-
method involved the generation of PhSe- (PhSeB(OEt)3
)
by the reduction of (PhSe)2 using borohydride in EtOH-
THF.9 However, a catalytic system that uses a property
that nickel metal inserts into the disulfide bond has not
been researched. To carry out the reaction with the nickel
catalyst and disulfide, we first investigated the addition
of various metals as reductive reagents of nickel (Table
1).
As a rule, a transition metal rapidly inserts into a
disulfide bond,5 and the formed complex (RY)2M prevents
the reaction, such as the thiolation of aryl halide, owing
to the stability of a metal-chalcogen bond. To solve this
From many experimental results, it was obvious that
the addition of zinc gave a respectable yield (Table 1,
entries 5, 6, and 7), but no other metals (Mg, Al, and Sn)
showed any effect (Table 1, entries 2, 3, and 4). When
iodobenzene (1a ) (0.3 mmol) and diphenyl disulfide (2a )
(0.15 mmol) were treated with NiBr2-bpy (1:1, 10 mol
%) and zinc (0.6 mmol) in DMF (0.5 mL) at 110 °C for 18
h, diphenyl sulfide (3a a ) could be obtained in 90% yield
(Table 1, entry 5). When the use of NiCl2 or NiI2 was
examined, the yield of 3a a was slightly lower (Table 1,
entries 6 and 7). Accordingly, the employment of zinc as
(1) (a) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205-3220.
(b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400-
5449.
(2) (a) Metzner, P.; Thuillier, A. Sulfur Reagents in Organic
Synthesis; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Academic
Press: San Diego, CA, 1994. (b) Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press Ltd.: New York, 1991;
Vol. 6.
(3) (a) Kosugi, M.; Shimizu, T.; Migita, T. Chem. Lett. 1978, 13-14.
(b) Suzuki, H.; Abe, H.; Osuka, A. Chem. Lett. 1980, 1363-1369. (c)
Bowman, W. R.; Heaney, H.; Smith, P. H. G. Tetrahedron Lett. 1984,
25, 5821-5824. (d) Yamamoto, T.; Sekine, Y. Can. J . Chem. 1984, 62,
1544-1547. (e) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1995, 36, 4133-4136. (f) Hartwig, J . F.; Barran˜ano, D. J . Am. Chem.
Soc. 1995, 117, 2937-2938. (g) Zheng, N.; McWilliams, J . C.; Fleitz,
F. J .; Armstrong, J . D., III; Volante, R. P. J . Org. Chem. 1998, 63,
9606-9607. (h) Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org.
Lett. 2002, 4, 2803-2806. (i) Kwong, F. Y.; Buchwald, S. L. Org. Lett.
2002, 4, 3517-3520.
(4) (a) Chowdhury, S.; Roy, S. Tetrahedron Lett. 1997, 38, 2149-
2152. Examples of the use of diselenide: (b) Nishino, T.; Okada, M.;
Kuroki, T.; Watanabe, T.; Nishiyama, Y.; Sonoda, N. J . Org. Chem.
2002, 67, 8696-8698. (c) Nishino, T.; Nishiyama, Y.; Sonoda, N. Chem.
Lett. 2003, 32, 928-929.
(6) (a) Taniguchi, N.; Onami, T. Synlett 2003, 829-832. (b) Tan-
iguchi, N.; Onami, T. J . Org. Chem. 2004, 69, 915-920.
(7) (a) Cristau, H. J .; Chabaud, B.; Christol, C. H. Synthesis 1981,
892-894. (b) Takagi, K. Chem. Lett. 1985, 1307-1308. (c) Yamamoto,
T.; Sekine, Y. Inorg. Chim. Acta 1984, 83, 47-53. (d) Takagi, K. Chem.
Lett. 1987, 2221-2224. (e) Kuethe, J . T.; Cochran, J . E.; Padwa, A. J .
Org. Chem. 1995, 60, 7082-7083. Example of phenylselenation of
ArI: (f) Cristau, H.; Chabaud, B.; Labaudiniere, R.; Christol, H.
Organometallics 1985, 4, 657-661.
(5) (a) Zanella, R.; Ros, R.; Graziani, M. Inorg. Chem. 1973, 12,
2736-2738. (b) Lam, C, T.; Senoff, C. V. Can. J . Chem. 1973, 51, 3790-
3794. (c) Canich, J . A. M.; Cotton, F. A.; Dunbar, K. R.; Falvello, L. R.
Inorg. Chem. 1988, 27, 804-811.
(8) Millois, C.; Diaz, P. Org. Lett. 2000, 2, 1705-1708.
(9) (a) Wirth, T., Ed. Organoselenium Chemistry; Topics in Current
Chemistry No. 208; Springer-Verlag: Heidelberg, Germany, 2000. (b)
Sharpless, K. B.; Lauer, R. F. J . Am. Chem. Soc. 1973, 95, 2697-2699.
10.1021/jo040184q CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/27/2004
6904
J . Org. Chem. 2004, 69, 6904-6906

TABLE 1. Nick el-Ca ta lyzed P h en ylth iola tion of 1a
TABLE 3. Nick el-Ca ta lyzed Cou p lin g of Ar I a n d
(n Bu S)2
entry
[Ni]
additive
3a a (%)a
1
2
3
4
5
6
7
NiBr2
NiBr2
NiBr2
NiBr2
NiBr2
NiCl2
NiI2
none
Mg
Al
Sn
Zn
0
0
0
entry
ArI (1)
C6H5I (1a )
2-MeC6H4I (1b)
2-MeOC6H4I (1c)
2-H2NC6H4I (1d )
2-HOC6H4I (1e)
4-MeC6H4I (1f)
4-MeOC6H4I (1g)
4-BrC6H4I (1h )
4-ClC6H4I (1i)
4-F3CC6H4I (1j)
4-H2NC6H4I (1k )
4-HOC6H4I (1l)
4-HO2CC6H4I (1m )
4-MeO2CC6H4I (1n )
4-AcC6H4I (1o)
ArSnBu
3 (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16b
17c
3a d
3bd
3cd
3d d
3ed
3fd
3gd
3h d
3id
3jd
3k d
3ld
3m d
3n d
3od
3p d
3qd
81
76
92
85
80
85
75
76
80
77
74
73
61
87
72
78
0
0
90
67
85
Zn
Zn
a
Isolated yields after silica gel chromatography.
TABLE 2. Nick el-Ca ta lyzed Cou p lin g of 1a w ith (RS)2
trans-PhCHdCHBr (1p )
4-O2NC6H4I (1q)
entry
(RS)2 (2)
(PhS)2 (2a )
(4-MeC6H4S)2 (2b)
(MeS)2 (2c)
(nBuS)2 (2d )
(iPrS)2 (2e)
(tBuS)2 (2f)
time (h)
PhSR
3 (%)a
a
b
Isolated yields after silica gel chromatography. nBu4NI was
added, 10 mol %. c 1q was recovered in 96% yield.
1
2
3
4
5
6
18
18
72
48
72
48
3a a
3a b
3a c
3a d
3a e
3a f
90
87
80
81
68
trace
SCHEME 1. Effect of Nick el Br om id e a n d Zin c
a
Isolated yields after silica gel chromatography.
the reductant was the most suitable for the nickel-
catalyzed thiolation of aryl iodide.
The thiolation of 1a with different disulfides 2 was
then examined. As shown in Table 2, a mixture of 1a , 2,
NiBr2-bpy catalyst, and zinc in DMF was treated at 110
°C. In the reaction of diaryl disulfides, the corresponding
sulfides 3 were available in good yields (Table 2, entries
1 and 2). Similarly, this coupling can also take advantage
of the use of dialkyl disulfides (Table 2, entries 3, 4, and
5). For instance, the case of di-n-butyl disulfide (2d )
provides 3a d in 81% yield (Table 2, entry 4). Regrettably,
when di-tert-butyl disulfide (2f) was used, the reactivity
was significantly decreased (Table 2, entry 6).
Next, the coupling of ortho- or para-substituted aryl
iodides with di-n-butyl disulfide (2d ) was carried out
according to established methods. The results of the
preparation of aryl n-butyl sulfides are presented in Table
3. The desired sulfides 3 could be produced in 61-92%
yields by aryl iodides 1 having various functional groups,
and di-n-butyl disulfides (2d ) were treated with NiBr2-
bpy catalyst and zinc in DMF at 110 °C for 48 h (Table
3, entries 1-15). Moreover, this reaction could result in
n-butyl styryl sulfide (3p d ) in 78% yield from trans-2-
bromostyrene (1p ) by the addition of n-Bu4NI (10 mol
%) (Table 3, entry 16).12a Unfortunately, 4-nitro-1-iodo-
benezene (1q) could not convert into the corresponding
product, and 1q was recovered in 96% yield (Table 3,
entry 17). Thus, the combination of the nickel catalyst
and zinc enabled the synthesis of the unsymmetrical
sulfide from aryl iodide and dialkyl disulfide under
neutral conditions.
This catalytic process requires a nickel salt and zinc,
and it is clear that neither Ni(II)Br2-bpy nor zinc itself
had the ability to insert into S-S or Ar-I (Scheme 1).10
On the contrary, Ni(0) can insert into these bonds.11,12
The reaction of 2-iodoanisole (1c) in the system of the
nickel-catalyst and zinc affords the biaryl and anisole
in yields of 12% and 41%, respectively (Scheme 2). In
addition, it has been reported widely that the Ni(II)(SR)2
complex is produced by Ni(0) insertion into the disulfide
bond.11
These facts show that, in the thiolation of aryl iodide,
at the first step, an Ni(0)-species is formed by the
reduction by zinc. At the next step, this Ni(0)-species
(12) (a) Iyoda, M.; Otsuka, H.; Sato, K.; Nisato, N.; Oda, M. Bull.
Chem. Soc. J pn. 1990, 63, 80-87. (b) Organometallic Mechanisms And
Catalysis; Kochi, J . K., Ed.; Academic Press: London, UK, 1978. (c)
Takagi, K.; Hayama, N.; Sasaki, K. Bull. Chem. Soc. J pn. 1984, 57,
1887-1890. (d) Colon, I.; Kelsey, D. R. J . Org. Chem. 1986, 51, 2627-
2637. (e) J utand A.; Mosleh, A. J . Org. Chem. 1997, 62, 261-274.
(10) Kumar, R.; Mabrouk, E. H.; Tuck, D. G. J . Chem. Soc., Dalton
Trans. 1988, 1045-1047.
(11) (a) Hayter, R. G.; Humiec, F. S. J . Inorg. Nucl. Chem. 1964,
26, 807-810. (b) Schott, V. H.; Wilke, G. Angew. Chem. 1969, 81, 896.
J . Org. Chem, Vol. 69, No. 20, 2004 6905

SCHEME 2. Rea ction of 1c w ith NiBr 2-bp y
Ca ta lyst a n d Zin c
SCHEME 3. P h en ylth iola tion of 1b w ith
(P h S)2Ni(bp y)2
F IGURE 2. Plausible reaction mechanism.
On the other hand, in another cycle B, after the
intermediate 9 is reduced to ArNi(I)L (10) by zinc, Ar-
(RS)2Ni(III)L (11) is constructed by the oxidative addition
of disulfide to 10; at the next step, 11 provides ArSR and
7 by the reductive elimination. Finally, the complex 7
converts ArI into ArSR and also gives Ni(I)IL.
Therefore, this nickel-catalyzed thiolation of aryl iodide
with disulfide proceeds through two catalytic cycles.
In conclusion, we have developed a nickel-catalyzed
synthesis of unsymmetrical aryl sulfides from various
aryl iodides and dialkyl- or diaryl-disulfide by the addi-
tion of zinc in one pot using the insertion of a nickel
catalyst into the disulfide bond. This method can ef-
ficiently use two RS groups in the (RS)2 molecule and
can be carried out under neutral conditions.
inserts into S-S or Ar-I bonds, and (RS)2Ni(II)11 or ArNi-
(II)I12 is produced.
It is worth noting that (RS)2Ni(II) alone cannot trans-
form ArI to ArSR. Actually, (PhS)2Ni(II)(bpy)2 is unavail-
able for the synthesis of ArSR (Scheme 3).7c,13 However,
the addition of zinc as the reductive reagent, in the
presence of (PhS)2Ni(II)(bpy)2 (0.15 mmol), could afford
phenyl 2-tolyl sulfide (3ba ) in a 92% yield (Scheme 2).
Given these results, it is presumed that (RS)Ni(I) is an
activating species for the thiolation, and it is impossible
to promote the reaction under this condition by using
(RS)2Ni(II). Similarly, it appears that ArNi(II)I is also
reduced to ArNi(I) by zinc.12 Hence, it is anticipated that
the nickel-catalyzed thiolation of aryl iodide with disul-
fide is accelerated by (RS)Ni(I) or ArNi(I).
Exp er im en ta l Section
Typ ica l P r oced u r e. To a mixture of NiBr2 (6.6 mg, 0.03
mmol), bpy (4.7 mg, 0.03 mmol), zinc (dust) (39.2 mg, 0.6 mmol),
and DMF (0.5 mL) were added 2-iodotoluene (1b) (65.4 mg, 0.3
mmol) and di-n-butyl disulfide (2d ) (26.8 mg, 0.15 mmol), and
the mixture was stirred at 110 °C for 48 h. After evaporation of
the solvent, the residue was dissolved in Et2O, and the resulting
mixture was filtered through a Celite pad. The solution was
washed with H2O and saturated sodium chloride and dried over
anhydrous magnesium sulfate. Chromatography on silica gel
From these results, the reaction mechanism is consid-
ered as follows (Figure 2). After Ni(II)Br2L is reduced to
Ni(0)L (5) by zinc, (RS)2Ni(II)L (6) or ArNi(II)IL (9) is
produced via the insertion of 5 into S-S or Ar-I. It seems
that the generating proportion of 6 or 9 is different
according to the kind of substrate.
In catalytic cycle A, the reduction of 6 by zinc gives
(RS)Ni(I)L (7). Subsequently, the reaction of 7 and ArI
generates ArSR and Ni(I)IL via the formation of the
intermediate 8. Moreover, Zn(SR)2, which was formed
when 6 was reduced, yields 7 by a ligand exchange with
Ni(I)X. As a consequence, this process enables the
consumption of two RS groups in (RS)2.
1
(hexane) gave n-butyl 2-tolyl sulfide (3bd )3g (45.3 mg, 76%). H
NMR (CDCl3) δ 0.93 (t, J ) 7.2 Hz, 3H), 1.42-1.53 (m, 2H),
1.53-1.68 (m, 2H), 2.36 (s, 3H), 2.89 (t, J ) 7.4 Hz, 2H), 7.06-
7.26 (m, 4H); 13C NMR (CDCl3) δ 13.6, 20.3, 22.0, 31.0, 32.5,
125.2, 126.2, 127.3, 129.9, 136.3, 137.2.
Su p p or tin g In for m a tion Ava ila ble: Analytical data (1H
and 13C NMR spectra) and literature citations for known
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) (PhS)2Ni(II)(bpy)2 was prepared by the mixture of Ni(II)Cl2(bpy)
(4.2 mmol), bpy (8.8 mmol), and PhSNa (8.8 mmol) and was stirred in
dioxane (10 mL) at 80 °C for 1.5 h. (a) Uchino, M.; Asagi, K.; Yamamoto,
A.; Ikeda, S. J . Organomet. Chem. 1975, 84, 93-103.
J O040184Q
6906 J . Org. Chem., Vol. 69, No. 20, 2004