Ligand-free Ni-catalyzed reductive cleavage of inert carbon - Sulfur bonds

Article abstract of DOI:10.1021/ol2033306

A catalytic reductive cleavage of C(sp²) - and C(sp³) - SMe bonds under ligandless conditions is presented. The method is characterized by its wide scope and high chemoselectivity profile including challenging substrate combinations, allowing the design of orthogonal and site-selectivity approaches.

Full text of DOI:10.1021/ol2033306

ORGANIC
LETTERS
2012
Vol. 14, No. 3
796–799
Ligand-Free Ni-Catalyzed Reductive
Cleavage of Inert CarbonꢀSulfur Bonds
Nekane Barbero and Ruben Martin*
Institute of Chemical Research of Catalonia (ICIQ), Av Paısos Catalans 16, 43007,
¨
Tarragona, Spain
rmartinromo@iciq.es
Received December 13, 2011
ABSTRACT
A catalytic reductive cleavage of C(sp2)ꢀ and C(sp3)ꢀSMe bonds under ligandless conditions is presented. The method is characterized by its
wide scope and high chemoselectivity profile including challenging substrate combinations, allowing the design of orthogonal and site-selectivity
approaches.
The discovery of new catalytic methods for activating
inert molecular bonds constitutes one of the most active
areas of research in modern organic chemistry.1 These
methods provide unique strategies for converting rather
ubiquitous and unreactive motifs into valuable molecules.
Despite recent advances, particularly in the field of CꢀH
bond functionalization, the development of procedures for
Cꢀheteroatom bond functionalization has received much
less attention.2,3
Although carbonꢀsulfur bonds are inherently disposed
to cross-coupling reactions, the strong affinity of sulfur
atoms to metal centers constitutes a significant barrier for
further functionalization.3,4 Among all aryl sulfides, the
use of aryl methyl thioethers (ArSMe) would be especially
attractive as coupling counterparts due to the fact that (a)
ArSMe are the simplest derivatives from thiophenols
(ArSH) and (b) the use of ArSMe electrophiles is much
more atom economical than other ArSR motifs (R¼Me)
describedin the literature.5 Still, however, the development
of coupling reactions with unactivated CꢀSMe bonds6 has
been less explored, and few examples have been reported in
this regard.7
Particularly interesting would be the development of a
catalytic reductive cleavage of unactivated CꢀSMe bonds,
thus opening up the possibility of using aryl sulfides as
temporary removable directing groups8 in organic synthe-
sis (Scheme 1). To the best of our knowledge, such a
procedure can only be carried out with stoichiometric
amounts of highly reactive Grignard reagents possess-
ing β-hydrogens9 or with a large excess of Raney Nickel10
as reducing agents (Scheme 1, path a), thus drastically
(1) Murai, S. Activation of unreactive bonds and organic synthesis.
Topics in Organometallic Chemistry; Springer-Verlag: Berlin, 1999.
(2) For recent reviews on CꢀO bond activation: (a) Rosen, B. M.;
Quasdorf, K. W.; Wilson, D. A.; Zhang, N.; Resmerita, A.-M.; Garg,
N. K.; Percec, V. Chem. Rev. 2011, 111, 1346. (b) Li, B.-J.; Yu, D.-G.;
Sun, C.-L.; Shi, Z.-J. Chem.;Eur. J. 2011, 17, 1728. (c) McGlacken,
G. P.; Clarke, S. L. ChemCatChem 2011, 3, 1260. (d) Tobisu, M.;
Chatani, N. ChemCatChem 2011, 3, 1410.
(6) For selected coupling reactions of activated CꢀSMe bonds: (a)
Graham, T. H.; Liu, W.; Shen, D.-M. Org. Lett. 2011, 13, 6232. (b)
Melzig, L.; Metzger, A.; Knochel, P. Chem.;Eur. J. 2011, 17, 2948. (c)
Melzig, L.; Metzger, A.; Knochel, P. J. Org. Chem. 2010, 75, 2131. (d)
Begouin, J.-M.; Rivard, M.; Gosmini, C. Chem. Commun. 2010, 5972.
(7) Isolated examples when coupling unactivated CꢀSMe bonds with
stoichiometric and highly reactive Grignard reagents have been de-
scribed: (a) Kanemura, S.; Kondoh, A.; Yorimitsu, H.; Oshima, K.
Synthesis 2008, 2659. (b) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L.
J. Chem. Soc., Chem. Commun. 1979, 637.
(8) Rousseau, G.; Breit, B. Angew. Chem., Int. Ed. 2011, 50, 2450.
(9) For desulfurative procedures of CꢀSMe bonds using stochio-
metric and highly reactive Grignard reagents as reducing agents: (a)
Wenkert, E.; Hanna, J. M.; Leftin, M. H.; Michelotti, E. L.; Potes, K. T.;
Usifer, D. J. Org. Chem. 1985, 50, 1125. (b) Wenkert, E.; Ferreira, T. W.
J. Chem. Soc., Chem. Commun. 1982, 840.
(3) For a recent review on CꢀS bond activation: Dubbaka, S. R.;
Vogel, P. Angew. Chem., Int. Ed. 2005, 44, 7674.
(4) For a review dealing with thioether coordination to transition
metals, see: Murray, S. G.; Hartley, F. R. Chem. Rev. 1981, 81, 365.
(5) For selected catalytic CꢀSR bond-activation reactions (R ¼ Me):
(a) Ishizuka, K.; Seike, H.; Hatakeyama, T.; Nakamura, M. J. Am.
Chem. Soc. 2010, 132, 13117. (b) Itami, K.; Higashi, S.; Mineno, M.;
Yoshida, J.-I. Org. Lett. 2005, 7, 1219. (c) Cho, C.-H.; Yun, H.-S.; Park,
K. J. Org. Chem. 2003, 68, 3017. (d) Srogl, J.; Liu, W.; Marshall, D.;
Liebeskind, L. S. J. Am. Chem. Soc. 1999, 121, 9449. (e) Tseng, H.-R.;
Lee, C.-F.; Yang, L.-M.; Luh, T.-Y. J. Org. Chem. 1999, 64, 8582.
(10) Mozingo, R.; Wolf, D. E.; Harris, S. A.; Folkers, K. J. Am.
Chem. Soc. 1943, 65, 1013.
r
10.1021/ol2033306
Published on Web 01/18/2012
2012 American Chemical Society

reducing the preparative scope of these transformations as
a powerful tool in organic synthesis. Furthermore, while
the use of supporting ligands is typically needed for pro-
moting CꢀS bond activation,3 ancillary ligands are elabo-
rate, difficult to modify, and can be significantly more
expensive than the metal they bind to; therefore, the devel-
opment of a flexible, orthogonal and general catalytic
protocol for promoting a catalytic reductive cleavage of
functionalized aryl methyl thioethers under ligandless con-
ditions in the presence of other reactive motifs would be
highly desirable.11
strong σ-donor ligands.3 At present, we believe that sulfur
atoms in 1a may serve as ancillary ligands16 facilitating the
oxidative addition step within the catalytic cycle. To the best
of our knowledge, these results represent the first catalytic,
“ligand-free”,13 reductive cleavage of CꢀS bonds reported
to date.
Scheme 1. Metal-Catalyzed Reduction of Unactivated CꢀS
bonds
As part of our ongoing interest in the field of inert bond
activation,12 we present herein the first metal-catalyzed
reductive cleavage of CꢀS bonds under “ligand-free”
conditions13 (Scheme 1, path b). Unlike related desulfura-
tive processes using Grignard reagents or Raney Nickel
(Scheme 1, path a),9,10 our protocol does not require the
use of stoichiometric amounts of metal complexes, tolerates
a wide range of functional groups, shows a broad substrate
scope, and exhibits excellent site selectivity and orthogonal
reactivity toward other reactive motifs (Scheme 1, path b).
We initiated our study with 2-(methylthio)naphthalene
1a as the model substrate, and the effects of Ni precatalyst,
ligand, reducing agent, solvent and temperature were system-
atically examined. Although structurally related larger alkyl
groups on sulfur such as ethyl, propyl, isopropyl, or pivaloyl
groups could also be employed,14 we found that CꢀSMe
motifs provided the best yields. Intriguingly, the inclusion of a
supporting ligand had a deleterious effect, resulting in low
yields of 2a. After some experimentation, we found that the
use of dimethylethylsilane as a reducing agent under ligand-
free conditions13 provided the best results, affording 2a in
87% isolated yield.15 This is particularly noteworthy as CꢀS
bond cleavage has typically been achieved in the presence of
Figure 1. Ni-catalyzed reductive cleavage of CꢀSMe bonds.
aArSMe (0.50 mmol), Ni(COD)2 (10 mol %), EtMe2SiH
(1.0 mmol), PhMe (0.5 M) at 90 °C; isolated yields, average of at
least two independent runs. bNi(COD)2 (20 mol %). cEtMe2SiH
(2.50 mmol) at 130 °C. dEtMe2SiH (1.50 mmol) at 130 °C.
f
eEtMe2SiH (2.00 mmol) at 130 °C. EtMe2SiH (2.50 mmol) at
110 °C. gNi(COD)2 (5 mol %). hProduct was volatile; GC yield
using decane as internal standard. i140 °C.
Encouraged by these findings, we turned our attention
to the scope of the reaction (Figure 1). The Ni-catalyzed
reductive cleavage of aryl methyl thioethers shows an
excellent chemoselectivity profile, as heterocycles (2g, 2i,
and 2k), amines (2f), amides (2h), and even ketones (2n)
were all tolerated under our reaction conditions. The
ability to furnish 2g indicated that the active nickel species
were not deactivated by the presence of strong nitrogen
(11) Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang,
P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998.
ꢀ
(12) (a) Novak, P.; Correa, A.; Gallardo-Donaire, J.; Martin, R.
Angew. Chem., Int. Ed. 2011, 50, 12236. (b) Flores-Gaspar, A.; Martin,
ꢀ
R. Adv. Synth. Catal. 2011, 353, 1223. (c) Alvarez-Bercedo, P.; Martin,
ꢀ
R. J. Am. Chem. Soc. 2010, 132, 17352. (d) Alvarez-Bercedo, P.;
Flores-Gaspar, A.; Correa, A.; Martin, R. J. Am. Chem. Soc. 2010, 132,
466. (e) Correa, A.; Martin, R. J. Am. Chem. Soc. 2009, 131, 15974.
(13) By “ligand-free”, we mean that typical σ-donor ligands such as
phosphines, nitrogen-containing heterocycles, or N-heterocyclic car-
benes are not present.
(16) Lam, F. L.; Kwong, F. Y.; Chang, A. S. C. Chem. Commun.
2010, 4649.
(17) The reactions of 1d, 1e, and 1j initially afforded O-silylated
compounds, as judged by NMR spectroscopy of the crude reaction
mixtures. A simple acidic workup gave 2d, 2e, and 2j in pure form.
(14) For more details, see Supporting Information.
(15) No conversion was observed in the absence of Ni(COD)2
Org. Lett., Vol. 14, No. 3, 2012
797

donors. Unprotected alcohols (2e) and even carboxylic
acids (2d and 2j) could be efficiently coupled in high
yields.17 This is quite interesting taking into account that
the classical use of Grignard reagents as reducing agents
results in the undesired addition to the carboxylic acid
moiety.9 Interestingly, ortho-substitution did not hinder
the reaction (2l and 2t). In sharp contrast to other catalysts
used for hydrogenolysis of CꢀOMe bonds,12c,18 no ortho-
directing groups are necessary to facilitate CꢀSMe bond
cleavage in simple thiophenol derivatives with different
electronic environments and substitution patterns (2jꢀ2o).
Gratifiyngly, our procedure could also be applied to the
reduction of benzylic C(sp3)ꢀSMe backbones with equal
efficiency (2pꢀ2t).
sharp contrast with the preferred cleavage of C(sp2)ꢀ
OMe bonds over benzylic C(sp3)ꢀOMe bonds.12c,20
Equally intriguing is the site selectivity achieved for the
C(sp2)ꢀSMe motif in 4d as there are many Ni-catalyzed
procedures reported in the literature for the activation of
CꢀS bonds within the benzo[b]thiophene backbone.21
Additionally, the preparation of 4e highlights that our
method can be used as a predictable synthetic tool for
performing selective functionalization among multiple
CꢀO or CꢀS bonds.
Scheme 2. Synthetic Applicability of Aryl Methyl Thioethers
a
Figure 2. Site selectivity in CꢀS bond cleavage. Same as for
Figure 1. bEtMe2SiH (2.0 mmol) at 130 °C. c110 °C. dEtMe2SiH
(0.90 mmol) at 130 °C. eEtMe2SiH (1.50 mmol) at 130 °C.
The orthogonality of the Ni-catalyzed reductive pro-
tocol is evident from the results compiled in Figure 2. As
can be seen, the selective reduction of CꢀSMe bonds has
been achieved in the presence of additional CꢀOMe
bonds (4a, 4b, and 4e), which remained untouched under
our catalytic conditions. The preparation of 4a is parti-
cularly noteworthy; all attempts to conduct either
CꢀSMe or CꢀOMe bond cleavage in 3a under the exact
conditions reported in the literature were completely
unsuccessful,9,10,12c,19 thus illustrating the potential of
our new catalytic reductive protocol. Site selectivity
could also be achieved among multiple CꢀS bonds
(4c, 4d, and 4e). While exhaustive reduction was observed
for simple substrates (Figure 1, 2a and 2p), benzylic C(sp3)ꢀ
SMe bonds could selectively be activated in the pre-
sence of C(sp2)ꢀSMe bonds (Figure 2, 4c). This is in
The results in Figures 1 and 2 suggest that we can turn
our orthogonal protocol into a strategic advantage
(Scheme 2). While the SuzukiꢀMiyaura reaction via
CꢀCl bond activation can selectively be achieved by Pd-
catalysts (6),22 CꢀSMe bond cleavageis preferred(7) when
employing our Ni-catalyzed, “ligand-free” reductive meth-
od (Scheme 2, top). These results are particularly interest-
ing as CꢀCl bonds are typically more reactive than
Cꢀheteroatom bonds in metal-catalyzed reactions.11 To
our knowledge, there are no reports of selective Ni-catalyzed
Cꢀheteroatombond-activationprocedures inthe presence of
aryl halides.23 Final reaction of 6 or 7 via the above-
mentioned Ni- or Pd-catalyzed procedures affords 8 in a
similar overall yield.
As shown in Scheme 2 (bottom), 10 could be selec-
tively prepared from benzenethiol in a few synthetic
steps using the ability of aryl thiols to direct function-
alization in the ortho- and para-positions of aromatic
(18) (a) Tobisu, M.; Yamakawa, K.; Shimasakia, T.; Chatani, N.
Chem. Commun. 2011, 2946. (b) Sergeev, A. G.; Hartwig, J. F. Science
2011, 332, 439.
(21) For selected references: (a) Hintermann, L.; Schmitz, M.; Chen,
ꢀ
´
(19) For CꢀN coupling: (a) Tobisu, M.; Shimasaki, T.; Chatani, N.
Chem. Lett. 2009, 38, 710. For SuzukiꢀMiyaura reaction:(b) Tobisu,
M.; Shimasaki, T.; Chatani, N. Angew. Chem., Int. Ed. 2008, 47, 4866.
For Kumada-type reaction:(c) Guan, B.-T.; Xiang, S.-K.; Wu, T.; Sun,
Z.-P.; Wang, B.-Q.; Zhao, K.-Q.; Shi, Z.-J. Chem. Commun. 2008, 1437.
(20) For a Ni-catalyzed selective coupling of C(sp3)ꢀOMe over
C(sp2)ꢀOMe bonds: Guan, B.-T.; Xiang, B.-Q.; Wang, S.-K.; Sun,
Z. P.; Wang, Y.; Zhao, K.-Q.; Shi, Z.-J. J. Am. Chem. Soc. 2008, 130,
3268.
Y. Adv. Synth. Catal. 2010, 352, 2411. (b) Torres-Nieto, J.; Arevalo, A.;
Garcıa, J. J. Organometallics 2007, 26, 2228. (c) Cho, Y.-H.; Kina, A.;
Shimada, T.; Hayashi, T. J. Org. Chem. 2004, 69, 3811.
(22) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(23) It has specifically been described that Ni-catalyzed reaction of
Grignard reagents with chlorophenyl alkyl sulfides occurs with selective
cleavage of the CꢀCl bond, leaving the CꢀSMe backbone intact:Tiecco,
M.; Testaferri, L.; Tingoli, M.; Wenkert, E. Tetrahedron 1983, 39, 2289.
798
Org. Lett., Vol. 14, No. 3, 2012

rings14 and without the need for using ortho-directing
groups in the Ni-catalyzed reductive cleavage step. An
analogous sequence using 4-methoxy-3-methylbenzoic
acid (9-OMe) under the conditions reported in the
literature12c did not give rise to 10, thus showing the
striking differences when using CꢀOMe or CꢀSMe elec-
trophiles in Ni-catalyzed reductive cleavage reactions. We
strongly believe these results demonstrate the high versa-
tility of aryl methyl thioethers as synthetic intermediates,
illustrating the use of aryl sulfides as temporary directing
groups in organic synthesis.9
ments (Scheme 3). In line with our expectations, 2a and
2a-D were exclusively obtained when employing Et3-
SiH or Et3SiD.24 We believe these results rule out a
mechanistic pathway consisting of a β-hydride elim-
ination from preformed arylnickel(II)ꢀSMe intermediates.
Additionally, we did not observe Ni-hydride species by
NMR spectroscopy when Ni(COD)2 was reacted with
Et3SiH.25 At present, we propose a mechanistic pathway
consisting of CꢀSMe oxidative addition, σ-bond metathesis
with the SiꢀH bond,26 and reductive elimination from a
Ni(II) hydride intermediate.
In summary, a “ligand-free” Ni-catalyzed reductive
cleavage of CꢀS bonds has been achieved. The broad
scope, high chemoselectivity profile, mild reaction condi-
tions, and the excellent site selectivity achieved make this
method a new strategy for the ever-growing synthetic
arsenal.27 In further studies, we aim to unravel the me-
chanism and fully explore the potential of this and related
transformations.
Scheme 3. Mechanistic Considerations
Acknowledgment. We thank the ICIQ Foundation,
Consolider Ingenio 2010 (CSD2006-0003), and MICINN
(CTQ2009-13840) for financial support. Johnson Matthey,
Umicore, and Nippon Chemical Industrial are acknowl-
edged for a gift of metal and ligand sources. R.M. thanks
MICINN for a RyC fellowship.
To shed light onto the mechanism, we decided to gather
indirect evidencebyperformingdeuterium-labeling experi-
(24) Et3SiH (130 °C) gave comparable results to EtMe2SiH (90 °C)
(25) For related stoichiometric studies: Baxter, R. D.; Montgomery,
J. J. Am. Chem. Soc. 2011, 133, 5728.
(26) For a recent disclosure based on a σ-bond metathesis of CꢀS
bonds with R3SiH: Klare, H. F. T.; Oestreich, M.; Ito, J.-I.; Nishiyama,
H.; Ohki, Y.; Tatsumi, K. J. Am. Chem. Soc. 2011, 133, 3312.
(27) It is worth mentioning that, while the coupling of 3-(methylthio)
benzo[b]thiophene resulted in good yields of 4d (Figure 2), the use of
other heteroaromatics such as 3-(thiomethyl)quinoline gave no conver-
sion to products.
Supporting Information Available. Experimental pro-
cedures and spectral data for all compounds. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 14, No. 3, 2012
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