Palladium-catalyzed desulfitative addition of sodium sulfinates with α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2012.06.026

A palladium-catalyzed desulfitative conjugate addition of sodium sulfinates with α,β-unsaturated carbonyl compounds is described. The reaction showed very good selectivity and tolerated a wide range of functionalities under an atmosphere of argon.

Full text of DOI:10.1016/j.tetlet.2012.06.026

Tetrahedron Letters 53 (2012) 4347–4350
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Palladium-catalyzed desulfitative addition of sodium sulfinates with
a,b-unsaturated carbonyl compounds
⇑
Wen Chen, Xianya Zhou, Fuhong Xiao, Jiaying Luo, Guo-Jun Deng
Key Laboratory for Environmental Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed desulfitative conjugate addition of sodium sulfinates with
bonyl compounds is described. The reaction showed very good selectivity and tolerated a wide range
of functionalities under an atmosphere of argon.
a,b-unsaturated car-
Received 26 April 2012
Revised 30 May 2012
Accepted 5 June 2012
Available online 13 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Addition
Desulfination
Palladium
Sulfinic acids
Transition-metal-catalyzed conjugate addition to electron defi-
cient olefins is a powerful strategy for the construction of new C–C
bonds.1 The use of transition-metal catalysts in combination with
an organometallic reagent has been particularly effective in this re-
gard. The commonly used organometallic reagents for conjugate
addition reactions are relatively active organolithiums, organo-
magnesiums, or organozincs catalyzed by copper catalysts.2 How-
accessible preparatively from their corresponding sulfonyl chlo-
rides.9 Sulfinic acid sodium salts have the potential to serve as
the aryl sources for C–C bond forming reactions via releasing SO2
under relatively mild conditions.10 However, the current research
has been mainly focused on sulfonylation reagents.11 Research on
desulfitative C–C bond formation is rare.12,13 Very recently, we
and others developed various palladium-catalyzed desulfitative
Heck-type reactions,14 addition reactions,15 and cross-coupling
reactions with C–H bonds16 under relative mild conditions. Various
aromatic sulfinic acids were used as aryl sources without the
requirement of ortho substituents.17 In continuing with our
ever, this strategy is problematic for 1,4-addition of
a,b-
unsaturated carbonyl compounds due to its sensitivity to the car-
bonyl functional groups. In recent years, the rhodium-catalyzed
conjugate addition of organoboranes,3 -silicones,4 and -stannanes5
with a,b-unsaturated carbonyl compounds is as an attractive alter-
native because of their insensitivity to carbonyl functional groups
and the availability of various chiral ligands for rhodium catalysts
(Scheme 1, a).6 This strategy showed good selectivity and the car-
bonyl groups are well tolerated under the reaction conditions. Re-
cently, Zhao et al. developed a rhodium-catalyzed decarboxylative
R1
M
O
catalyst
R1
a
+
O
R2
R3
R2
R3
O
conjugated addition of benzoic acids to
a,b-unsaturated carbonyl
cat. = Cu, Rh, Pd
compounds (Scheme 1, b).7 In this transformation, benzoic acids
acted as the aryl nucleophiles via releasing of CO2.8 This strategy
showed good selectivity and provided an efficient synthetic route
for conjugate addition reactions. However, it required ortho-flu-
oro-substituted benzoic acid substrates and thus limited the scope.
Compared with the widely studied arylboronic acid and carbox-
ylic acid partners, aromatic sulfinic acid sodium salts are rarely
used as aryl sources via desulfination. Sulfinic acid sodium salts
are relatively stable, easy to handle, and when necessary, are
M = Mg, Zn, B(OH)2, Si, SnCl3, Ti
O
F
F
R2
COOH
F
Rh
R3
b
c
+
R1
R1
R2
R3
F
This work
R2
O
O
SO2Na
Pd
R3
+
R1
R1
R2
R3
⇑
Corresponding author.
E-mail address: gjdeng@xtu.edu.cn (G.-J. Deng).
Scheme 1. Various routes for conjugate addition of
compound.
a,b-unsaturated carbonyl
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.026

4348
W. Chen et al. / Tetrahedron Letters 53 (2012) 4347–4350
Table 1
Optimization of the reaction conditionsa
O
SO2Na
catalyst
+
120 oC, argon
O
Ph
1a
2a
3a
Entry
Catalyst
Ligand
Additive
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14c
15c
16c
17c
18c
19d
PdCI2
2,20-Dipyridine
2,20-Dipyridine
2,20-Dipyridine
2,20-Dipyridine
2,20-Dipyridine
2,20-Dipyridine
1,10-Phen
2,20-Biquinoline
TMEDA
DMAP
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DMF
0
16
23
40
50
58
46
43
57
68
70
10
80
94
30
50
38
50
35
Pd2(dab)3
Pd(OAc)2
Pd(CH3CN)2CI2
Pd(CF3CO2)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
Pd(OH)2
TFA
TFA
TFA
TFA
TFA
TFA
TFA
Anisole
Toluene
1,4-Dioxane
a
Conditions: 1a (0.4 mmol), 2a (0.2 mmol), catalyst (5 mol %), ligand (10 mol %), additive (0.4 mL), solvent (0.2 mL), H2O (0.2 mL), 120 °C, 20 h under argon unless
otherwise noted.
b
GC yield based on 2a.
0.1 mL TFA was used.
Without water.
c
d
Table 2
Desulfitative addition 1a with various unsaturated compoundsa
O
O
p-Tolyl
Pd(OH)2
DABCO
120 oC, 20 h
R2
R2
1a
+
R1
R1
2
3
Entry
1
Substrate 2
Product
Yieldb (%)
80
O
3a
2a
Ph
O
2b
2
3
3b
3c
87
89
O
2c
MeO
tBu
F
O
2d
4
5
6
7
3d
3e
3f
70
53
80
79
O
2e
O
2f
Cl
O
2g
3g
Br

W. Chen et al. / Tetrahedron Letters 53 (2012) 4347–4350
4349
Table 2 (continued)
Entry
Substrate 2
Product
Yieldb (%)
55
O
2h
8
3h
Cl
O
2i
9
3i
60
64
85
O
10
3j
2j
Ph
H
O
2k
11
3k
a
Conditions: 1a (0.4 mmol), 2 (0.2 mmol), Pd(OH)2 (5 mol %), DABCO (10 mol %), TFA (0.1 mL), 1,4-dioxane (0.2 mL), H2O (0.2 mL),
120 °C, 20 h under argon.
b
Isolated yield based on 2.
PdII
Table 3
Ar-SO2Na
Desulfitative addition reaction of 2a with various sodium sulfinatesa
PdII
O
Entry Sodium Sulfinate
Product
Yieldb (%)
75
R2
SO2Na
O
O
Ph
Ar SO2 PdII
IV
1b
1c
Ar
R1
3l
1
I
SO2Na
Ph
Ph
Ph
Ph
Ph
Ph
SO2
Ar PdII
O
3m
2
3
4
5
60
88
80
74
MeO
Ar PdII
II
R2
OMe
tBu
F
SO2Na
O
O
O
O
O
R1
1d
1e
O
III
3n
3o
3p
3q
3r
tBu
F
R2
R1
SO2Na
Scheme 2. Proposed mechanism.
Pd(OAc)2 were used (entries 2 and 3). The reaction yield can be fur-
ther improved to 50% when Pd(CF3CO2)2 was employed (entry 5).
Among them, Pd(OH)2 was the most efficient catalyst and the addi-
tion product was obtained in 58% yield (entry 6). Various nitrogen-
containing ligands were also investigated using Pd(OH)2 as the cat-
alyst (entries 7–11). Phenanthroline (1,10-Phen), 1,2-bis(dimethyl-
amino)ethane (TMEDA), 4-dimethylaminopyrdine (DMAP) and
1,4-diazabicyclo[2.2.2]octane (DABCO) were efficient ligands for
the addition reaction. The acidic additive had an important impact
on the reaction yield. Only 10% yield was achieved in the absence
of acid additive (entry 12). The replacement of acetic acid with tri-
fluoroacetic acid (TFA) could improve the reaction yield slightly
(entry 13). Interestingly, 94% yield was obtained when the amount
of TFA was reduced to 0.1 mL (entry 14). The solvent also had a sig-
nificant impact on the reaction yield. The reaction yield decreased
when the reaction was run in other organic solvents or in the ab-
sence of water (entries 15–19).
SO2Na
SO2Na
SO2Na
1f
Cl
Cl
1g
1h
6
7
70
89
Br
Br
a
Conditions: 1 (0.4 mmol), 2a (0.2 mmol), Pd(OH)2 (5 mol %), DABCO (10 mol %),
TFA (0.1 mL), 1,4-dioxane (0.2 mL), H2O (0.2 mL), 120 °C, 20 h under argon.
b
Isolated yield.
interest in using aromatic sulfinic acids (salts) as the aryl sources,
herein we describe a palladium-catalyzed desulfitative conjugate
With the optimized reaction conditions in hand, we then ex-
plored the scope and generality of this transformation. Various
addition of sodium sulfinates with
a,b-unsaturated carbonyl com-
pounds (Scheme 1, c).18
a
,b-unsaturated ketones bearing electron-withdrawing and donat-
We began our study by examining the reaction of p-toluene-
sulfinic acid sodium salt (1a) with benzylideneacetone (2a) in
1,4-dioxane/H2O (1:1) by using palladium salt as catalyst and
2,20-dipyridine as ligand in the presence of excess acetic acid. Var-
ious palladium salts were investigated for this transformation. No
desired product was observed when PdCl2 was used as determined
by GC and 1H NMR methods (Table 1, entry 1). The desired product
3a was obtained in 16% and 23% yields when Pd2(dba)3 and
ing substituents on the phenyl ring were investigated (Table 2).
(E)-4-p-Tolylbut-3-en-2-one (2b) and (E)-4-(4-methoxyphenyl)
but-3-en-2-one (2c) both smoothly reacted with 1a and gave the
desired conjugate addition products in 87% and 89% yields, respec-
tively (entries 2 and 3). A slightly lower yield was obtained when
2d reacted with 1a (entry 4). Halogen substituents such as fluoro,
chloro, and bromo were well tolerated under the optimized

4350
W. Chen et al. / Tetrahedron Letters 53 (2012) 4347–4350
Harutyunyan, S.; Hartog, T.; Geurts, K.; Minnaard, A.; Feringa, B. Chem. Rev.
2008, 108, 2824; (h) Alexakis, A.; Bäckvall, J.; Krause, N.; Diéguez, M. Chem. Rev.
2008, 108, 2796.
reaction conditions and the coupling of (E)-4-(4-bromophenyl)but-
3-en-2-one (2g) with 1a gave the product in 79% yield (entry 7).
The position of the substituents on the phenyl ring affects the reac-
tion yield significantly. The reaction yields decreased to 55% and
60% when 2h and 2i were used as substrates (entries 8 and 9).
Notably, the addition of cinnamaldehyde (2j) with 1a afforded
the desired product in 64% yield (entry 10). Aryl substituted enone
substrate (E)-chalcone (2k) also smoothly reacted with 1a and gave
the desired product in 85% yield (entry 11).
The reaction results of various arylsulfinic acid sodium salts
with benzylideneacetone 2a are presented in Table 3. A series of
functional groups including tert-butyl, methoxy, fluoro, chloro,
and bromo were tolerated under the optimal reaction conditions,
and the desired products were obtained in moderate to good yields
(entries 2–6). More bulky substrates such as 2-naphthylsulfinic
acid sodium salt (1h) also efficiently reacted with 2a and gave
the desired product in 89% yield (entry 7).
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A plausible mechanism to rationalize this transformation is
illustrated in Scheme 2. Similar to the Pd(II)-catalyzed conjugate
addition of arylboronic acids to
a,b-unsaturated carbonyl com-
8. For a recent reviews, see: (a) Goossen, L. J.; Ridríguez, N.; Goossen, K. Angew.
Chem., Int. Ed 2008, 47, 3100; b Rodríguez, 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; For other
examples on decarboxylative addition to imines and carbonyls, see: (f) Lindh,
J.; Sjöberg, P.; Larhed, M. Angew. Chem., Int. Ed. 2010, 49, 7733; (g) Luo, Y.; Wu, J.
Chem. Commun. 2010, 46, 3785; (h) Blaquiere, N.; Shore, D.; Rousseaux, S.;
Fagnou, K. J. Org. Chem. 2009, 74, 6190.
9. (a) Patai, S., Ed.The Chemistry of Sulfinic Acids, Esters, and Their Derivatives;
Wiley: NY, 1990; (b) Patai, S., Rappoport, Z., Eds.The Chemistry of Sulphonic
Acids, Esters, and Their Derivatives; Wiley: Chichester, NY, 1991; (c) Page, P.
Organosulfur Chemistry: Stereochemical Aspects; Academic Press Inc.: San Diego,
1998; (d) Simpkins, N. Sulfones in Organic Synthesis; Pergamon Press: Oxford,
1993.
pounds, the proposed mechanism involves the following 5 steps:
(1) coordination of aromatic sulfinic acid sodium salts to palla-
dium(II) to give complex I; (2) desulfitative reaction of the sulfinic
acid to generate the aryl-palladium complex II; (3) coordination of
the ketone group to form complex III; (4) migratory insertion of
the C@C bond with aryl-palladium complex to give complex IV;
(5) protonation of IV by the acid to give the final addition product
and a palladium(II) species.
In summary, we have demonstrated a palladium-catalyzed des-
ulfitative conjugate addition of sodium sulfinates with a,b-unsatu-
rated ketones (aldehydes). Various aromatic sulfinic acid sodium
salts with or without substituents selectively added with
a,b-unsaturated ketones and afforded the adducts in good yields.
10. Dubbaka, S.; Vogel, P. Angew. Chem., Int. Ed. 2005, 44, 7674.
11. For recent examples of sulfonylation using sulfinic acids or sodium sulfinates,
see: (a) Sandrinelli, F.; Perrio, S.; Beslin, P. Org. Lett. 1999, 1, 1177; (b) Yang, W.;
Berthelette, C. Tetrahedron Lett. 2002, 43, 4537; (c) Cacchi, S.; Fabrizi, G.;
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Ma, D. J. Org. Chem. 2005, 70, 2696; (e) Martin, C.; Sandrinelli, F.; Perrio, C.;
Perrio, S.; Lasne, M. J. Org. Chem. 2006, 71, 210; (f) Guan, Z.; Zuo, W.; Zhao, L.;
Ren, Z.; Liang, Y. Synthesis 2007, 1465; (g) Drabowicz, J.; Kaiatkowska, M.;
Kielbasinski, P. Synthesis 2008, 3563; (h) Sreedhar, B.; Reddy, M.; Reddy, P.
Synlett 2008, 1949; (i) Kim, H.; Kasper, A.; Park, Y.; Wooten, C.; Hong, J.; Moon,
E.; Dewhirst, M. Org. Lett. 2009, 11, 89; (j) Varela-Álvavez, A.; Markovic´, D.;
Vogel, P.; Sordo, J. J. Am. Chem. Soc. 2009, 131, 9547; (k) Liu, C.; Li, M.; Cheng, D.;
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Unlike the decarboxylative coupling reaction, no electron-
withdrawing or donating group ortho to the sulfinic acid group
was necessary to ensure the desulfitative addition. Functional
groups such as methyl, methoxy, fluoro, chloro, and bromo were
all well tolerated under the optimized reaction conditions. The
scope, mechanism, and synthetic applications of this reaction in
asymmetric version are under investigation.
Acknowledgements
This work was supported by the National Natural Science Foun-
dation of China (21172185, 20902076), the Hunan Provincial Nat-
ural Science Foundation of China (11JJ1003), the New Century
Excellent Talents in University from Ministry of Education of China
(NCET-11-0974) and the Scientific Research Foundation for Re-
turned Scholars, Ministry of Education of China (2011-1568).
12. For early investigations on desulfitative reaction using sulfinic acid (salt), see:
(a) Garves, K. J. Org. Chem. 1970, 35, 3273; (b) Selke, R.; Thiele, W. J. Prakt. Chem.
1971, 313, 875; (c) Wenkert, E.; Ferreira, T.; Michelotti, E. J. Chem. Soc., Chem.
Comm. 1979, 637.
13. For desulfitative biaryl synthesis in high yields, see: Sato, K.; Okoshi, T. Patent,
U.S. 5,159,082, 1992.
14. (a) Zhou, X.; Luo, J.; Liu, J.; Peng, S.; Deng, G. Org. Lett. 2011, 13, 1432; (b) Wang,
G.; Miao, T. Chem. Eur. J. 2011, 17, 5787.
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(b) Yao, H.; Yang, L.; Shuai, Q.; Li, C. Adv. Synth. Catal. 2011, 353, 1701; (c) Miao,
T.; Wang, G. Chem. Commun. 2011, 47, 9501; (d) Behrends, M.; Sävmarker, J.;
Sjöberg, P.; Larhed, M. ACS Catal. 2011, 1, 1455.
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,
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17. For a systematic investigation on reactivity comparison of desulfination and
decarboxylation, see: Sraj, L.; Khairallah, G.; Silva, G.; O’Hair, R. Organometallics
2012, 31, 1801.
18. During our preparation of this manuscript, Duan and his co-workers disclosed
a palladium-catalyzed desulfitative conjugate addition reaction using H2SO4 as
acid: Wang, H.; Li, Y.; Zhang, R.; Jin, K.; Zhao, D.; Duan, C. Y. J. Org. Chem 2012,
77, 4849.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.06.
026.
References and notes
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