High yield thiolation of iodobenzene catalyzed by the phosphinite nickel PCP pincer complex: [NiCl{C6H3-2,6-(OPPh2)2}]

Article abstract of DOI:10.1016/j.tetlet.2006.05.094

[NiCl{C₆H₃-2,6-(OPPh₂)₂}] efficiently catalyzes the thiolation of iodobenzene with a broad scope of disulfides in the presence of zinc, the coupled products are obtained in excellent and in many cases nearly quantitative yields.

Full text of DOI:10.1016/j.tetlet.2006.05.094

Tetrahedron Letters 47 (2006) 5059–5062
High yield thiolation of iodobenzene catalyzed by the
phosphinite nickel PCP pincer complex:
[NiCl{C6H3-2,6-(OPPh2)2}]
´
´
´
´
Valente Gomez-Benıtez, Oscar Baldovino-Pantaleon, Cesar Herrera-Alvarez,
*
´
Ruben A. Toscano and David Morales-Morales
Instituto de Quı´mica, Universidad Nacional Auto´noma de Me´xico, Cd. Universitaria, Circuito Exterior,
Coyoaca´n, 04510 Me´xico DF, Me´xico
Received 5 April 2006; accepted 16 May 2006
Available online 6 June 2006
Abstract—[NiCl{C6H3-2,6-(OPPh2)2}] efficiently catalyzes the thiolation of iodobenzene with a broad scope of disulfides in the pres-
ence of zinc, the coupled products are obtained in excellent and in many cases nearly quantitative yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The increasing interest in the use and applications of
diarylthioethers and alkylarylthioethers has in recent
years lead to the design of efficient and high yield meth-
ods for their synthesis.1 Moreover, the scope and appli-
cation of organosulfur chemistry in organic synthetic
reactions has increased tremendously since sulfur-con-
taining groups serve as an important auxiliary function
in synthetic sequences,2 for instance, in the reversing of
the polarity (Umpolong), the enhancement of the acidity
of C–H bonds, and the transfer of chirality from sulfur
to carbon.3 Additionally, arylsulfides are a common
functionality found in a number of drugs commonly
used for the treatment of diabetes, Alzheimer’s, and Par-
kinson’s diseases.4 On the other hand, transition metal
complex-catalyzed reactions have made a great contri-
bution to the recent growth of organic synthesis.5 How-
ever, transition metal complex-catalyzed synthetic
reactions using sulfur-containing compounds remain a
fertile field of study, since this sort of complexes have
long been known to act as catalyst poisons often render-
ing the catalytic reaction totally ineffective.6 However, in
recent years several useful transformations of sulfur
containing compounds using transition metal catalysts
have been developed.7 In the particular case of arylsul-
fides, their metal-catalyzed synthesis has included the
cross coupling of thiols with aryl halides using copper
compounds under basic conditions or palladium cata-
lyst.8 Nevertheless, the metal catalyzed thiolation of
arylhalides with disulfides has been scarcely studied.9
We believe that a robust complex used as catalyst may
render a better performance in the alkyl and aryl thiol-
ation of halobenzenes. Thus we have previously reported
the use of fluorinated bis-imino nickel(II) NNN pincer
complexes [NiCl2{C5H3N-2,6-(CHNArf)2}] as efficient
and selective catalysts for the cross coupling of (RS)2
and halobenzenes attaining yields as high 90% of methyl
phenyl sulfide from the reaction of iodobenzene and
MeS–SMe.10 However this system affords lower yields
as the substituent in the disulfide increases in size, thus
the lower yields employing the diimino system were only
of 60% for di-tert-butyl disulfide.10 Additionally, we
have previously synthesized the PCP pincer ligand pre-
cursor [C6H4-1,3-(OPPri2)2] (1).11 And reported on the
use of its palladium PCP pincer complex [PdCl{C6H3-
2,6-(OPPri )2}] (2) for the efficient, high yield C–C cou-
2
pling reaction of a wide variety of chlorobenzenes.12 It
was therefore of interest to synthesize an analogous
nickel complex [NiCl{C6H3-2,6-(OPR2)2}] in an effort
to obtain an efficient, cheap, and easy to synthesize sys-
tem for the thiolation of iodobenzene using disulfides.
Hence, we synthesized the NiPCP phosphinite pincer
complex [NiCl{C6H3-2,6-(OPPh2)2}] (3). Complex 3
was obtained in a very facile manner and quantitative
yield as an olive green microcrystalline powder by
Keywords: C–S cross-coupling; Phosphinite ligands; Homogeneous
catalysis; Nickel; Pincer complexes; Thiolation.
*
Corresponding author. Tel.: +52 55 56224514; fax: +52 55
56162217; e-mail: damor@servidor.unam.mx
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.094

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V. Go´mez-Ben´ıtez et al. / Tetrahedron Letters 47 (2006) 5059–5062
Table 1. Alkyl- and arylthiolation of iodobenzene by [NiCl{C6H3-1,3-
(OPPh2)2}] (3)
C–H activation from the reaction of the ligand [C6H4-
1,3-OPPh2)2]13 and NiCl2.14
S
I
(PCP)NiCl/Zn
R
+
1/2 RS-SR
DMF, 110 oC, 4h.
O
PPh2
O
PPh2
toluene
reflux
Entry
1
RS–SR
Yielda (%)
>99
Ni Cl
NiCl2
+
S
S
S
O
PPh2
O
PPh2
(3)
2
3
>99
>99
S
Unlike 1,3-bis(phosphino)benzenes, the 1,3-bis(phosphi-
nite)benzene [C6H4-1,3-OPPh2)2] can be conveniently
prepared in 95% yield from the reaction of inexpensive
precursors (resorcinol and chlorodiphenylphosphine)13
and more important, this ligand is not sensitive to
oxygen, thus it can be easily handled in the open air.
Crystals of 3 suitable for single crystal X-ray diffraction
analysis were obtained from a CH2Cl2/MeOH solvent
system, showing the nickel center to be into a slightly
distorted square planar environment with the phosphi-
nite ligand being coordinated in a tridentate PCP pincer
fashion having one chloride completing the coordina-
tion sphere (Fig. 1).15
S
S
4
>99
S
S
5
6
49b
S
S
The results of our studies on the catalytic activity of 3
are summarized in Table 1. In order to optimize the effi-
ciency of the catalytic system, we initially examined the
coupling reaction of iodobenzene and MeS–SMe by 3
under a variety of reaction conditions19 and analyzed
the product mixtures through GC–MS techniques. We
found the reactions uniformly affording >99% yields of
the corresponding asymmetric sulfide when carried out
86c
S
S
a Yields were determined by GC–MS and related to C6H5I.
b Formation of biphenyl is observed with a 35% yield.
c Formation of biphenyl is observed with an 8% yield.
in DMF, in the presence of zinc powder as a necessary
ingredient. Using the same combination of reagents in
a preparative scale experiment, we were able to isolate
the coupled product in nearly quantitative yield. At
110 °C, a reaction time of 24 h is required to achieve this
high conversion.
The reactivities of a variety of disulfides were examined
under the optimized conditions and uniformly showed
>99% selective for the corresponding asymmetric sul-
fide, except for the cases of di-tert-butyldisulfide and
diphenyldisulfide (entries 5 and 6, respectively, in Table
1) where the yields for the desired product are reduced
by the formation of biphenyl, product of the C–C
homo-coupling of iodobenzene. This fact, being proba-
bly due to steric effects due to the larger size of the sub-
stituents in these disulfides.
In order to verify that the high catalytic activity of the
present system requires the presence of both the phosph-
inite PCP pincer complex [NiCl{C6H3-2,6-(OPPh2)2}]
(3) and zinc, we carried out control experiments exclud-
ing complex 3 and zinc powder, respectively, obtaining
no conversion at all in both experiments. Similarly,
other reducing agents such as magnesium and tin pow-
der were employed under the same reaction conditions,
however the effect of both metals is negligible in compar-
ison with that of zinc.
Figure 1. Thermal ellipsoid (50% probability) drawing of NiCl{C6H3-
2,6-(OPPh2)2} (3). Hydrogen atoms have been omitted for clarity.
˚
Selected bond distances (A) and angles (°): Ni(1)–C(2) 1.879(2), Ni(1)–
P(1) 2.1556(6), Ni(1)–P(2) 2.1582(7), Ni(1)–Cl(1) 2.1880(6), C(2)–
Ni(1)–P(1) 81.98(7), C(2)–Ni(1)–P(2) 82.31(7), P(1)–Ni(1)–P(2)
164.16(2), C(2)–Ni(1)–Cl(1) 178.43(7), P(1)–Ni(1)–Cl(1) 97.24(2),
P(2)–Ni(1)–Cl(1) 98.51(3).

V. Go´mez-Benı´tez et al. / Tetrahedron Letters 47 (2006) 5059–5062
5061
Ar-Ar
O
PPh2
O
PPh2
Ar
Ar
Ni(II) X
PPh2
Ni
X
O
O
PPh2
1/2 Zn
R-S-Ar
ArX
O
O
PPh2
O
O
PPh2
Ni
O
PPh2
Ni(I)
R
S
1/2 ZnX2
Ar
Ni(II) Ar
PPh2
1/2 ZnX2
1/2 Zn
X
ArX
PPh2
O
PPh2
1/2RS-SR
O
O
PPh2
O
PPh2
Ni(III)
PPh2
ArX
Ar
Ni(II) SR
PPh2
X
O
Scheme 1. Proposed reaction mechanism for the thiolation of iodobenzene with disulfides.
It has been proposed that these reactions using nickel
catalysts must proceed through a Ni(0)/Ni(II) interme-
Acknowledgments
diates.20 So, it is possible to conceive a similar mecha-
nism to be involved in the present case (Scheme 1),
although alternative routes cannot be ruled out. Thus,
one of the first steps would be the reduction of the com-
plex [NiIIPCP(Cl)] by metallic zinc, further activation by
this new complex [NiIPCP] of the disulfide RS–SR
would lead to the cleavage of the S–S bond by oxidative
addition to afford the thiolate species [NiIIPCP(SR)]. It
is worth to note, that as the size of the substituent in
the thiolate increases the complex [NiIIPCP(SR)] be-
comes more stable.21 This fact would explain the lower
yields attained with sterically hindered disulfides, since
the resulting intermediate would prefer to stay as a thio-
late species rather than react further. The nickel thiolate
complex [NiIIPCP(SR)] will then undergo, in a con-
certed manner, the addition of iodobenzene and further
elimination of the C–S cross coupled product Ar–S–R,
to yield the [NiIIPCP(X)] species that after a new reduc-
tion with more metallic zinc would restart the catalytic
cycle all over again (Scheme 1). Additionally, a parasite
side mechanism can be invoked to explain the formation
of biphenyl in the case of entries 5 and 6 in Table 1, this
side reaction must be favored due to the steric hindrance
of these particular disulfides (ButS–SBut and PhS–SPh
respectively) resulting easier the oxidative addition of
iodobenzene and thus eventually leading to the forma-
tion of the C–C coupling product. This theory is cur-
rently being investigated in our research group by
synthesizing analogous pincer ligands with larger byte
angles in order to evaluate the cavity size.
V.G.-B., O.B.-P., and C.H.-A. would like to thank
CONACYT for financial support. The support of this
research by CONACYT (J41206-Q), DGAPA-UNAM
(IN114605) is gratefully acknowledged.
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In summary, the relatively inexpensive, easy to prepare,
air, and moisture stable nickel phosphinite PCP pincer
complex [NiCl{C6H3-2,6-(OPPh2)2}] (3) catalyzes the
high yield C–S cross coupling (thiolation reaction) of a
broad scope of disulfides using zinc as a necessary reduc-
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catalytic system to the synthesis of commercially impor-
tant, structurally complex fine chemicals containing
thermally sensitive groups.

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distance of 4.837 cm from the crystal. A total of 1800
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˚
reflections to a maximum 2h angle of 56.00° (0.93 A
resolution), of which 6284 were independent (Rint
=
5.05%, Rsig = 5.47%) and 4566 were greater than
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9717 and anisotropic thermal parameters for all non-
hydrogen atoms. The numbering of the atoms is shown in
Figure 1 (ORTEP).18 Supplementary data for complex 3
has been deposited at the Cambridge Crystallographic
Data Centre. Copies of this information are available free
of charge on request from The Director, CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK (Fax: +44 1223
336033; e-mail: deposit@ccdc.cam.ac.uk or www: http://
www.ccdc.cam.ac.uk) quoting the deposition number
CCDC 298238.
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nitrogen, a solution of 4.9 mmol of iodobenzene,
2.45 mmol of methyl disulfide, 3.0 mg of catalyst 3
(0.0057 mmol) and 202 mg (0.924 mmol) of diethylene
glycol di-n-butylether (internal standard) in 3.0 mL of
DMF, was introduced into a Schlenk tube containing a
magnetic stir bar and charged with 4.9 mmol of zinc dust.
The tube was sealed and fully immersed in a 110 °C silicon
oil bath. After 4 h, the reaction mixture was cooled to
room temperature and, the organic phase analyzed by gas
chromatography (Quantitative analyses were performed
on a Agilent 6890N GC with a 30.0 m DB-1MS capillary
column coupled to an Agilent 5973 inert mass selective
detector).
´
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14. Synthesis of [NiCl{C6H3-2,6-(OPPh2)2}] (3). A solution of
toluene
(50 mL),
[C6H4-2,6-(OPPh2)2]
(907 mg,
1.89 mmol), and NiCl2 (450 mg, 1.89 mmol) were refluxed
for 24 h. The solvent was evaporated under vacuum and
the crude product isolated. Following recrystalization
from diethyl ether, the purified product was obtained
(yield 880 mg, 82%). 1H NMR (300 MHz, CDCl3):
3
3
d = 6.61 (d, JHH = 8.0 Hz, 2H, arom), 7.06 (t, JHH
=
20. Taniguchi, N. J. Org. Chem. 2004, 69, 6904–6906.
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M.; Mascharak, P. K. J. Am. Chem. Soc. 1995, 117, 1584–
1594.
7.7 Hz, 1H, arom), 7.45 (br m, 12H, arom), 7.99 (br m,
8H, arom); 31P{1H} NMR (121 MHz, CDCl3): d = 141.52
(s, 1P). Anal. calcd for C30H23ClO2P2Ni (571.60) C, 63.04;