Palladium-catalyzed desulfitative cross-coupling reaction of sodium sulfinates with benzyl chlorides

Article abstract of DOI:10.1021/ol400295z

A palladium-catalyzed approach for the synthesis of diarylmethanes from sodium sulfinates and benzyl chlorides is described. Various aromatic sodium sulfinates were used as aryl sources via extrusion of SO₂ and gave the diarylmethanes in moderate to good yields.

Full text of DOI:10.1021/ol400295z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Palladium-Catalyzed Desulfitative
Cross-Coupling Reaction of Sodium
Sulfinates with Benzyl Chlorides
Feng Zhao, Qi Tan, Fuhong Xiao, Shufeng Zhang, and Guo-Jun Deng*
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China
gjdeng@xtu.edu.cn
Received February 1, 2013
ABSTRACT
A palladium-catalyzed approach for the synthesis of diarylmethanes from sodium sulfinates and benzyl chlorides is described. Various aromatic
sodium sulfinates were used as aryl sources via extrusion of SO2 and gave the diarylmethanes in moderate to good yields.
Diarylmethanes are versatile intermediates in the synthe-
sis of pharmaceuticals and biologically active compounds,1
and they are also employed as subunits in the design of
supramolecular structures.2 Consequently, development
of efficient methods for construction of diarylmethanes
has stimulated considerable interest. Traditionally, diaryl-
methanes are synthesized via FriedelÀCrafts benzylation of
benzylic electrophiles in the presence of Lewis acid.3 How-
ever, this approach is mainly suitable for electron-rich
arenes and often suffers from low regioselectivity. The
reduction of diaryl ketones could provide an alternative
approach for preparation of diarylmethanes.4 Recently,
the transition-metal-catalyzed cross-coupling reactions of
benzylic halides with arylmetals (or benzylmetals with aryl
halides)5,6 have been proven to be very powerful for con-
struction of these compounds. Among them, the most
promising transition-metal-catalyzed methods for diaryl-
methane synthesis have been the SuzukiÀMiyaura-type
coupling of benzylic electrophiles with arylboronic acids.7,8
Metal-catalyzed CÀH bond activation and subsequent
CÀC bond-forming reaction can provide an efficient
synthesis with a reduced number of synthetic operations.9
(5) (a) Liegault, B.; Renaud, J. L.; Bruneau, C. Chem. Soc. Rev. 2008,
37, 290. (b) Kuwano, R. Synthesis 2009, 7, 1049. (c) Metal Catalyzed
Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998. (d) Metal Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
(6) For an example on selective diarylmethane formation using
Grignard reagents with benzyl alcohols, see: Yu, D. G.; Wang, X.;
Zhu, R. Y.; Luo, S.; Zhang, X. B.; Wangm, B. Q.; Wang, L.; Shi, Z. J.
J. Am. Chem. Soc. 2012, 134, 14638.
(1) For selected examples, see: (a) McPhail, K. L.; Rivett, D. E. A.;
Lack, D. E.; Davis-Coleman, M. T. Tetrahedron 2000, 56, 9391. (b)
Graffner-Nordberg, M.; Kolmodin, K.; Aqvist, J.; Queener, S. F.;
Hallberg, A. J. Med. Chem. 2001, 44, 2391. (c) Forsch, R. A.; Queener,
S. F.; Rosowsky, A. Bioorg. Med. Chem. Lett. 2004, 14, 1811. (d) Howell,
A.; Dowsett, M. Breast Cancer Res. 2004, 6, 269. (e) Bentley, K. W. Nat.
Prod. Rep. 2005, 22, 249. (f) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.;
Beller, M. Adv. Synth. Catal. 2006, 348, 691.
(2) (a) Philp, D.; Stoddart, J. F. Angew. Chem., Int. Ed. 1996, 35,
1154. (b) Ma, J. C.; Dougherty, D. A. Chem. Rev. 1997, 97, 1303. (c)
Conn, M. M.; Rebek, J. Chem. Rev. 1997, 97, 1647. (d) Jasat, A.;
Sherman, J. C. Chem. Rev. 1999, 99, 931.
(7) For recent examples, see: (a) Singh, R.; Viciu, M. S.; Kramareva,
N.; Navarro, O.; Nolan, S. P. Org. Lett. 2005, 7, 1829. (b) Molander,
G. A.; Elia, M. D. J. Org. Chem. 2006, 71, 9198. (c) Burns, M. J.;
Fairlamb, I. J. S.; Kapdi, A. R.; Sehnal, P.; Taylor, R. J. K. Org. Lett.
2007, 9, 5397. (d) Srimani, D.; Sarkar, A. Tetrahedron Lett. 2008, 49,
ꢀ
6304. (e) Ines, B.; Moreno, I.; SanMartin, R.; Dominguez, E. J. Org.
ꢀ
(3) (a) Olah, G. A. FriedelÀCrafts and Related Reactions; Wiley-
Interscience: New York, 1964; Vol. II, Part 1. (b) Roberts, R. M.; Khalaf,
A. A. FriedelÀCrafts Alkylation Chemistry. A Century of Discovery;
Marcel Dekker: New York, 1984. (c) Bandini, M.; Melloni, A.; Umani-
Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550.
(4) (a) Olah, G. A.; Arvanaghi, M.; Ohannesian, L. Synthesis 1986,
770. (b) Popielarz, R.; Arnold, D. R. J. Am. Chem. Soc. 1990, 112, 3068.
(c) Esaki, H.; Aoki, F.; Umemura, M.; Kato, M.; Maegawa, T.;
Mouguchi, Y.; Sajiki, H. Chem.;Eur. J. 2007, 13, 4052.
Chem. 2008, 73, 8448. (f) Ines, B.; SanMartin, R.; Moure, M.; Dominguez,
E. Adv. Synth. Catal. 2009, 351, 2124. (g) Bedford, R. B.; Gower, N. J.;
Haddow, M. F.; Harvey, J. N.; Nunn, J.; Okopie, R. A.; Sankey, R. F.
Angew. Chem., Int. Ed. 2012, 51, 5435. (h) Yu, A. J.; Li, X. D.; Peng, D. P.;
Wu, Y. J.; Chang, J. B. Appl. Organometal. Chem. 2012, 26, 301. (i) Maity,
P.; Shacklady-McAtee, D. M.; Yap, G. P. A.; Siriann, E. R.; Watson, M. P.
J. Am. Chem. Soc. 2013, 135, 280.
(8) For a reaction using zinc in water, see: Duplais, C.; Krasovskiy,
A.; Wattenberg, A.; Lipshutz, B. H. Chem. Commun. 2010, 46, 562.
r
10.1021/ol400295z
XXXX American Chemical Society

Various methods have been developed using direct benzy-
lation of heteroarenes and directing-group containing
arenes under transition-metal catalysis.10 The Goossen
group and others developed various methods for decar-
boxylative coupling reactions using inexpensive and read-
ily available aromatic carboxylic acids as substrates.11 The
decarboxylative cross-coupling reactions with aryl halides
have proved to be very effective and powerful for biaryl
synthesis. However, this strategy requires ortho-function-
alized benzoic substrates and is not suitable for cross-
coupling reactions with benzyl halides due to the easy
formation of very stable benzyl benzoate derivatives.12
Meanwhile, we and others developed various palladium-
catalyzed desulfitative Heck-type reactions,13 addition
reactions,14 homocoupling reactions,15 and cross-coupling
reactions with CÀH bonds16 using sodium sulfinates as
substrates. Unlike the decarboxylative coupling reactions,
no electron-withdrawing or donating group ortho to the
sulfinic acids group is necessary. We also found that the
reaction of benzylic halides with sodium sulfinates gener-
ates stilbene derivatives in the absence of transition metals.
The formation of benzyl sulfone intermediate plays an
important role in this transformation.17 In continuing with
our interest in using aryl sodium sulfinates as aryl sources,
herein we describe a palladium-catalyzed desulfitative
cross-coupling reactions of sodium sulfinates with benzyl
chlorides, affording diarylmethanes in moderate to good
yields.18
Table 1. Optimization of the Reaction Conditionsa
(9) For recent reviews on CÀH functionalization, see: (a) Dyker, G.
Handbook of CÀH Transformations: Applications in Organic Synthesis;
Wiley-VCH: Weinheim, 2005. (b) Yu, J.; Shi, Z. CÀH Activation; Springer:
Berlin, 2010. (c) Goldberg, K. I.; Goldman, A. S. Activation and Function-
alization of CÀH Bond; ACS Symposium Series 885; American Chemical
ꢀ
Society: Washington, DC, 2004. (d) Diaz-Requejo, M.; Perez, P. Chem. Rev.
2008, 108, 3379. (e) Hartwig, J. Nature 2008, 455, 314. (f) Giri, R.; Shi, B.;
Engle, K.; Maugel, N.; Yu, J. Q. Chem. Soc. Rev. 2009, 38, 3242. (g) Li,
C. J. Acc. Chem. Res. 2009, 42, 335. (h) Coperet, C. Chem. Rev. 2010,
110, 656. (i) Mkhalid, I.; Barnard, J.; Marder, T.; Murphy, J.; Hartwig,
J. Chem. Rev. 2010, 110, 890. (j) Colby, D. A.; Bergman, R. G.; Ellman,
J. A. Chem. Rev. 2010, 110, 624. (k) Lyons, T. W.; Sanford, M. S. Chem.
Rev. 2010, 110, 1147.
entry
catalyst
ligand
PPh3
base
solvent
yieldb (%)
ꢀ
1
Pd(OAc)2
PdCl2
Na2CO3 dioxane
Na2CO3 dioxane
Na2CO3 dioxane
Na2CO3 dioxane
Na2CO3 dioxane
Na2CO3 dioxane
Na2CO3 dioxane
Na2CO3 dioxane
45
2
PPh3
PPh3
PPh3
PPh3
40
3
PdBr2
24
4
Pd(OH)2
Pd(acac)2
trace
25
(10) (a) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev.
2012, 112, 5879. (b) Jaouhari, R.; Dixneuf, P. H. Inorg. Chim. Acta 1988,
145, 179. (c) Kuwano, R.; Kondo, Y.; Matsuyama, Y. J. Am. Chem. Soc.
2003, 125, 12104. (d) Mertins, K.; Iovel, I.; Kischel, J.; Zapf, A.; Beller,
M. Angew. Chem., Int. Ed. 2005, 44, 238. (e) Dong, C. G.; Hu, Q. S.
Angew. Chem., Int. Ed. 2006, 45, 2289. (f) Ren, H. J.; Knochel, P. Angew.
Chem., Int. Ed. 2006, 45, 3462. (g) Kuwano, R.; Shige, T. J. Am. Chem.
Soc. 2007, 129, 3802. (h) Yu, J. Y.; Kuwano, R. Org. Lett. 2008, 10, 973.
(i) Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc. 2008, 130,
16158. (j) Lapointe, D.; Fagnou, K. Org. Lett. 2009, 11, 4160. (k)
5
6
Pd(COD)Cl2 PPh3
44
7
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
dppe
20
8
50
9
DPEphos Na2CO3 dioxane
21
10
11
12
13
14
15
16
17
18
19
p-Tol3P
Na2CO3 dioxane
Na2CO3 dioxane
58
o-Tol3P
trace
57
m-Tol3P Na2CO3 dioxane
ꢀ
Ackermann, L.; Novak, P. Org. Lett. 2009, 11, 4966. (l) Verrier, C.;
Hoarau, C.; Marsair, F. Org. Biomol. Chem. 2009, 7, 647. (m) Ueno, S.;
Ohtsubo, M.; Kuwano, R. J. Am. Chem. Soc. 2009, 131, 12904. (n)
p-Tol3P
p-Tol3P
p-Tol3P
p-Tol3P
p-Tol3P
p-Tol3P
p-Tol3P
p-Tol3P
NaHCO3 dioxane
t-BuOK dioxane
CH3ONa dioxane
CH3ONa anisole
CH3ONa toluene
CH3ONa DMSO
60
62
ꢀ
Ackermann, L.; Novak, P.; Vicente, R.; Hofmann, N. Angew. Chem.,
65
Int. Ed. 2009, 48, 6045. (o) Deng, G. J.; Li, C. J. Org. Lett. 2009, 11, 1171.
(p) Mukai, T.; Hirno, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12, 1360.
66
€
(q) Ackermann, L.; Barfussser, S.; Pospech, J. Org. Lett. 2010, 12, 724.
64
(r) Yi, C. S.; Lee, D. W. Organometallics 2010, 29, 1883. (s) Ackermann,
L.; Hofmann, N.; Vicente, R. Org. Lett. 2011, 13, 1875.
trace
72
CH3ONa cyclohexane
CH3ONa cyclohexane
(11) For recent reviews, see: (a) Goossen, L. J.; Ridrıguez, N.;
Goossen, K. Angew. Chem., Int. Ed. 2008, 47, 3100. (b) Rodrıguez, N.;
Goossen, L. J. Chem. Soc. Rev. 2011, 40, 5030. For selected examples on
decarboxylative cross-coupling reactions, see: (c) Goossen, L. J.; Deng,
G. J.; Levy, L. M. Science. 2006, 313, 662. (d) Goossen, L. J.; Rodriguez,
N.; Bettina, M.; Linder, C.; Deng, G. J.; Levy, L. M. J. Am. Chem. Soc.
2007, 129, 4824. (e) Forgione, P.; Brochu, M.; St-Onge, M.; Thesen, K.;
Bailey, M.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
(12) Otera, J.; Nishikido, J. Esterification: Methods, Reactions and
Applications; Wiley-VCH: Weinheim, 2010.
20c Pd(OAc)2
88
a Conditions: 1a (0.2 mmol), 2a (0.2 mmol), catalyst (5 mol %),
ligand (10 mol %), base (0.3 mmol), solvent (0.6 mL), 120 °C, 4 h under
air unless otherwise noted. b GC yield. c 160 °C.
We began our study by examining the reaction of benzyl
chloride (1a) with p-toluenesulfinic acid sodium salt (2a) in
dioxane by using Pd(OAc)2/PPh3 as catalyst and Na2CO3
as base. When benzyl chloride reacted with an equal
amount of 2a under air, the desired product was obtained
in 45% yield as detected by GCÀMS and 1H NMR
methods (Table 1, entry 1). Then various palladium salts
were investigated for this reaction under similar reaction
(13) (a) Zhou, X. Y.; Luo, J. Y.; Liu, J.; Peng, S. M.; Deng, G. J. Org.
Lett. 2011, 13, 1432. (b) Wang, G.; Miao, T. Chem.;Eur. J. 2011, 17,
5787.
(14) (a) Liu, J.; Zhou, X.; Rao, H.; Xiao, F.; Li, C. J.; Deng, G. J.
Chem.;Eur. J. 2011, 17, 7996. (b) Yao, H.; Yang, L.; Shuai, Q.; Li, C. J.
Adv. Synth. Catal. 2011, 353, 1701. (c) Miao, T.; Wang, G. W. Chem.
€
€
Commun. 2011, 47, 9501. (d) Behrends, M.; Savmarker, J.; Sjoberg, P.;
Larhed, M. ACS Catal. 2011, 1, 1455. (e) Wang, H.; Li, Y.; Zhang, R.;
Jin, K.; Zhao, D.; Duan, C. Y. J. Org. Chem. 2012, 77, 4849. (f) Chen,
W.; Zhou, X.; Xiao, F.; Luo, J.; Deng, G. J. Tetrahedron Lett. 2012, 53,
4347.
(15) Rao, B.; Zhang, W.; Hu, L.; Luo, M. M. Green Chem. 2012, 14,
3436.
(17) Zhao, F.; Luo, J. Y.; Tan, Q.; Liao, Y. F.; Peng, S. M.; Deng,
G. J. Adv. Synth. Catal. 2012, 354, 1914.
(16) (a) Chen, R.; Liu, S.; Liu, X.; Yang, L.; Deng, G. J. Org. Biomol.
Chem. 2011, 9, 7675. (b) Wu, M.; Luo, J.; Xiao, F.; Zhang, S.; Deng,
G. J.; Luo, H. A. Adv. Synth. Catal. 2012, 354, 335. (c) Liu, B.; Guo, Q.;
Cheng, Y.; Lan, J.; You, J. S. Chem.;Eur. J. 2011, 17, 13415. (d) Wang,
M.; Li, D.; Zhou, W.; Wang, L. Tetrahedron 2012, 68, 1926.
(18) Diarylmethanes can be formed using sulfonyl chlorides with
organometals: (a) Dubbaka, S. R.; Vogel, P. J. Am. Chem. Soc. 2003,
125, 15292. (b) Dubbaka, S. R.; Vogel, P. Org. Lett. 2004, 6, 95. (c)
Dubbaka, S.; Vogel, P. Angew. Chem., Int. Ed. 2005, 44, 7674. (d) Rao
Volla, C.; Vogel, P. Angew. Chem., Int. Ed. 2008, 47, 1305.
B
Org. Lett., Vol. XX, No. XX, XXXX

conditions. Similar yields were observed when PdCl2 and
Pd(COD)Cl2 were used as the catalysts (entries 2 and 6).
Other palladium salts such as PdBr2, Pd(OH)2, Pd(acac)2,
and Pd(TFA)2 were less effective (entries 3À5 and 7). With
Pd(OAc)2 asthe catalyst, the effectofligand on the reaction
yield was investigated by screening various phosphine
ligands. Among them, p-Tol3P (tri-p-toluenephosphine)
showed the best reactivity, and the desired product was
obtained in 58% yield (entry 10), whereas the use of o-Tol3P
completely inhibited the reaction (entry 11). Base also affected
the reaction yields slightly. The use of CH3ONa can further
improve the reaction yield to 65% (entry 15). The choice of
solvents was crucial for this reaction. The reaction in DMSO
did not give any desired product (entry 18). Other solvents
such as anisole, toluene, and cyclohexane were proved to be
also good reaction media (entries 16, 17 and 19). When the
reaction temperature increased to 160 °C, the reaction yield
was improved to 88% using cyclohexane as solvent (entry 20).
proceeded smoothly to give the desired products in moderate
to good yields. The position of the substituents did not affect
the reaction yields, and o-, m-, and p-methylbenzyl chlorides
all gave the desired products in good yields (entries 2À4).
However, the use of 4-methoxybenzyl chloride and 4-nitro-
benzyl chloride both decreased the reaction yields signifi-
cantly. Notably, replacement of benzyl chloride with benzyl
bromide dramatically decreased the reaction yield under
similar reaction conditions partly due to the much higher
reactivity of benzyl bromide.
Table 3. Reaction of 1d with Various Sodium Sulfinates (2)a
Table 2. Reaction of 2a with Various Benzyl Chloridesa
a Conditions: 1d (0.2 mmol), 2 (0.2 mmol), Pd(OAc)2 (5 mol %),
p-Tol3P (10 mol %), CH3ONa (0.3 mmol), cyclohexane (0.6 mL), 160 °C,
4 h under air. b Isolated yield.
a Conditions: 1 (0.2 mmol), 2a (0.2 mmol), Pd(OAc)2 (5 mol %),
p-Tol3P (10 mol %), CH3ONa (0.3 mmol), cyclohexane (0.6 mL), 160 °C,
4 h under air. b Isolated yield.
Under the optimized reaction conditions, the substituent
effect on the reaction yield was investigated and the results
are presented in Table 3. In general, alkyl substituents on
the para position of sulfinic acid group did not affect the
reaction yield significantly (entries 2À4). However, a
methoxy substituent profoundly decreased the reaction
yield, and the corresponding product 3m was obtained in
52% yield (entry 5). Halogen substituents such as fluoro,
chloro, and trifluoromethyl were tolerated under the
With the optimized reaction conditions established, the
scope of the reaction with respect to p-toluenesulfinic acid
sodium salt (2a) and various benzyl chlorides (1) was inves-
tigated (Table 2). The reactions with benzyl chlorides bearing
electron-donating groups (entries 2À5) and electron-with-
drawing substituents (entries 6À8) at the aromatic ring
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Control Experiments
Scheme 2. Proposed Mechanism
optimal reaction conditions, and the desired products were
obtained in moderate to good yields (entries 6À8). An
electron-withdrawing group such as nitro on the aromatic
ring of sulfinic acid dramatically decreased the reaction
yield, and only a trace amount of product was obseved
when (4-nitrophenyl)sulfinic acid sodium salt (2j) reacted
with 1d (entry 9). In all cases, cross-coupled diaryl-
into intermediate C via extrusion of SO2. A reductive
elimination of C affords the final product and regenerates
Pd(0) species, thus closing the catalytic cycle.
In conclusion, we have demonstrated a palladium-catalyzed
approach for the synthesis of diarylmethanes via desulfitative
benzylation of aromatic sulfinic acid sodium salts with
benzyl chlorides. The reaction showed good selectivity and
tolerated various functional groups. This method provides
an alternative route for the synthesis of diarylmethanes
from benzyl chlorides. The scope, mechanism, and syn-
thetic applications of this reaction are being explored in
our laboratory.
1
methanes were the major products as determined by H
NMR method.19
To get more information about the reaction mechanism,
several control experiments were set up under the standard
conditions. When the reaction of 1a with 2a was set up at
60 °C under air, 1-(benzylsulfonyl)-4-methylbenzene (4a)
was obtainedin 83% yield, and no corresponding ester (5a)
was observed (scheme 1).17 Treatment of 4a under the
standard reaction conditions did not afford the final pro-
duct 3a. This means the product was not generated from 4a
or 5a via extrusion of SO2. Based on these observations, a
tentative mechanism to rationalize the transformation is
illustrated in Scheme 2. Oxidative addition of Pd(0) species
with 1a generates an intermediate Bn-Pd(II)-Cl (A).20,21,5a
The replacement of chloride with arylsulfinic acid sodium
salt forms an intermediate B, which can be further converted
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (21172185),
the Hunan Provincial Natural Science Foundation of
China (11JJ1003, 12JJ7002), the New Century Excellent
Talents in University from Ministry of Education of China
(NCET-11-0974), and the Hunan Provincial Innovative Foun-
dation for Postgraduate (CX2012B250) and Undergraduate.
(19) The use of o-toluenesulfinic acid sodium salt significantly de-
creased the reaction yield to 20% as determined by GC.
(20) For an early example on insertion of Pd(0) into a benzylic
carbonÀhalogen bond, see: Fitton, P.; MeKeon, J. E.; Ream, B. C.
J. Chem. Soc. D. 1969, 370.
(21) For an example of palladium-catalyzed cross-coupling of benzyl
chlorides with olefins involving radical mechanism, see: Pan, Y.; Zhang,
Z. Y.; Hu, H. W. Synth. Commun. 1992, 22, 2019.
Supporting Information Available. General experimen-
tal procedure and characterization data of the products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX