Copper-catalyzed nitrogen loss of sulfonylhydrazones: A reductive strategy for the synthesis of sulfones from carbonyl compounds

Article abstract of DOI:10.1021/ol101955x

Figure Presented. An efficient method for the synthesis of sulfones via nitrogen loss of sulfonyl hydrazones is described. The reaction was performed in the presence of simple copper salt and base by utilization of sulfonyl hydrazones, which were easily p

Full text of DOI:10.1021/ol101955x

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4408-4411
Copper-Catalyzed Nitrogen Loss of
Sulfonylhydrazones: A Reductive
Strategy for the Synthesis of Sulfones
from Carbonyl Compounds
Xing-Wen Feng, Jian Wang, Ji Zhang, Jing Yang, Na Wang, and Xiao-Qi Yu*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu, Sichaun 610064, P. R. China
xqyu@tfol.com
Received August 18, 2010
ABSTRACT
An efficient method for the synthesis of sulfones via nitrogen loss of sulfonyl hydrazones is described. The reaction was performed in the
presence of simple copper salt and base by utilization of sulfonyl hydrazones, which were easily prepared from carbonyl compounds. A wide
variety of aryl and alkyl sulfones were obtained in moderate to good yields.
The synthesis of sulfones has drawn much attention over
the years since they constitute useful building blocks in
natural products and pharmaceutical compounds. For
example, sulfone derivatives were found to be potent
inhibitors for several enzymes such as cyclooxygenase-
2, HIV-1 reverse transcriptase, matrix metalloproteinase,
and γ-secretase.1 On the other hand, sulfones exhibit
interesting chemical properties2 and are useful intermedi-
ates in organic synthesis.3 Therefore, sulfones have
emerged as important synthetic targets in recent years.
Known procedures for preparing sulfones are based on
the oxidation of corresponding sulfides4 or by displace-
ment reactions using sulfinate salts as nucleophiles
(Scheme 1).5 However, these methods generally involve
drawbacks such as limited substrate sources and sometimes
harsh reaction conditions.
Sulfonyl hydrazones are versatile synthetic intermediates
that have been used as an in situ source of diazo compounds
in different types of transition-metal-catalyzed reactions,6
such as XH (X ) C, N, O) insertion reactions,7 cyclopro-
(1) (a) Sakya, S. M.; Hou, X. J.; Minich, M. L.; Rast, B.; Shavnya, A.;
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C. F.; Seibel, S. B.; Haven, M. L. Bioorg. Med. Chem. Lett. 2007, 17, 1067.
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Chem 2006, 1, 82. (c) Kolodziej, S. A.; Hockerman, S. L.; DeCrescenzo,
G. A.; McDonald, J. J.; Mischke, D. A.; Munie, G. E.; Fletcher, T. R.;
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(4) (a) Schank, K. In The Chemistry of Sulfones and Sulfoxides; Patai,
S., Rappoport, Z., Stirling, C. J. M., Eds.; Wiley: New York, 1988; Chapter
7. (b) Aldea, R.; Alper, H. J. Org. Chem. 1995, 60, 8365. (c) Reddy, T. I.;
Varma, R. S. Chem. Commun. 1997, 471. (d) Rahimizadeh, M.; Rajabzadeh,
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323, 59. (e) Rostami, A.; Akradi, J. Tetrahedron Lett. 2010, 51, 3501.
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10.1021/ol101955x  2010 American Chemical Society
Published on Web 09/02/2010

of catalytic methodology.17 Drawing from recent experiences
in the field of copper-catalyzed diazo metallocarbene reac-
tions,18 we herein disclose a Cu-catalyzed decomposition of
sulfonyl hydrazone (Scheme 1). A wide variety of sulfones
were obtained in moderate to good yields.
Scheme 1. Methods toward the Preparation of Sulfones
First, the decomposition of tosyl hydrazone 1a, which was
derived from benzophenone, was chosen as a model system
for optimization of the reaction conditions (Table 1). Initially,
Table 1. Optimization of the Reaction Conditionsa
panations,8 epoxidations,9 and aziridinations.10 Recently,
Valde´s and co-workers have reported metal-free coupling
of tosylhydrazones with boronic acids11 or hydroxylic
compounds,12 which significantly improved the application
of sulfonyl hydrazones.
entry
catalyst
base
solvent
yieldb (%)
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMSO
toluene
dioxane
dioxane
dioxane
dioxane
trace
83
75
78
84
trace
46
trace
14
47
63
CuI/Pro
CuI/bpy
CuI/TMEDA
CuI
CuI
CuI
CuI
CuI
CuI
As early as 1952, Bamford and Stevens described that
thermal decomposition of tosylhydrazones under basic media
gave rise to diazo compounds, which went through a carbene
intermediate to elimination and dimerization compounds
(Bamford-Stevens reaction).13 To our delight, we observed
the formation of corresponding sulfones in good yields when
tosyl hydrazones were heated in the presence of copper salt
and base. Although pyrolysis14 and photolysis15 of tosyl
hydrazones have been reported to obtain sulfones, these
results were not satisfactory, and very poor yields were
observed with limited substrate scope. Che and co-workers
have reported that sulfones were formed as byproducts in
ruthenium(II) porphyrin-catalyzed cyclopropanation of alk-
enes with tosylhydrazones.16 Nevertheless, only some special
substrates can provide sulfones, and precious metal Ru was
used. In recent years, copper salts as economical metal
compounds led to remarkable progress in the development
NaOMe
KOtBu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
9
10
11
12
13c
14d
Cu(OAc)2. H2O
CuCl2
CuI
55
36
84
CuI
a Reaction conditions: 1a (0.3 mmol), [Cu] (20 mol %), ligand (20 mol
%), base (2 equiv), solvent (2 mL), 110 °C, 2 h, under air. b Isolated yields.
c 80 °C. d Under N2.
copper(I) iodide was used as copper source, and a variety
of ligands, bases, and solvents were then screened. Reactions
were inhibited to some extent after the addition of ligand
(proline, bipyridine, or TMEDA, entries 2-4). CuI alone
gave the best results, in which the yield was up to 84% (entry
5). Only a trace amount of target product 2a was observed
in the absence of either copper salt or base (entries 1 and
6). Thus, both copper salt and base are crucial for this
transformation. Increase of the basicity of basic salts led to
a harsh decrease of yields. When NaOMe and KOtBu were
used as bases, decreased yields of 46% and trace were
obtained, respectively (entries 7 and 8). The employment of
some alternate solvents (DMSO and toluene, entries 9 and
10) and copper salts (Cu(II) acetate and Cu(II) chloride,
(7) (a) Cheung, W. H.; Zheng, S. L.; Yu, W. Y.; Zhou, G. C.; Che,
C. M. Org. Lett. 2003, 5, 2535. (b) Cuevas-Yanez, E.; Serrano, J. M.; Huerta,
G.; Muchowski, J. M.; Cruz-Almanza, R. Tetrahedron 2004, 60, 9391. (c)
Aller, E.; Brown, D. S.; Cox, G. G.; Miller, D. J.; Moody, C. J. J. Org.
Chem. 1995, 60, 4449.
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Cox, R. J.; Shepherd, J.; de Vicente, J.; Walter, M.; Whittingham, W. G.;
Winn, C. L. J. Org. Chem. 2003, 68, 9433.
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Soc. 2002, 124, 5747. (b) Aggarwal, V. K.; Bae, I.; Lee, H. Y.; Richardson,
J.; Williams, D. T. Angew. Chem., Int. Ed. 2003, 42, 3274. (c) Aggarwal,
V. K.; Charmant, J.; Dudin, L.; Porcelloni, M.; Richardson, J. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5467. (d) Aggarwal, V. K.; Winn, C. L. Acc.
Chem. Res. 2004, 37, 611.
(10) (a) Aggarwal, V. K.; Ferrara, M.; O’Brien, C. J.; Thompson, A.;
Jones, R. V. H.; Fieldhouse, R. J. Chem. Soc., Perkin Trans. 1 2001, 1635.
(b) Aggarwal, V. K.; Alonso, E.; Fang, G. Y.; Ferrara, M.; Hynd, G.;
Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433. (c) Aggarwal, V. K.;
Vasse, J. L. Org. Lett. 2003, 5, 3987.
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J. Am. Chem. Soc. 2001, 123, 4480. (b) Chen, X.; Hao, X. S.; Goodhue,
C. E.; Yu, J. Q. J. Am. Chem. Soc. 2006, 128, 6790. (c) Ma, D. W.; Cai,
Q. A. Acc. Chem. Res. 2008, 41, 1450. (d) Shibasaki, M.; Kanai, M. Chem.
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2009, 1, 433.
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Org. Lett., Vol. 12, No. 19, 2010
4409

entries 11 and 12) also led to dereased yields. The chemical
yield was dramatically decreased to only 36% when the
reaction temperature was lowered to 80 °C (entry 13). The
reaction was also carried out under nitrogen atmosphere, and
same yield was found, indicating that oxygen is not necessary
for this reaction (entry 14).
Scheme 2
.
Decomposition of Tosylhydrazones Derived from
Various Carbonyl Compoundsa
Under optimized conditions, studies on the development
of substrate scope were then carried out. Various substituted
sulfonyl hydrazones, which were prepared from benzophe-
none and relative sulfonyl hydrazides, were used as sub-
strates. Table 2 summarizes the results. This method was
Table 2. Decomposition of Sulfonylhydrazones Prepared from
Benzophenone with Relative Sulfonyl Hydrazidesa
entry
R1
1
2
yieldb (%)
1
2
3
4
5
6
7
8
9
4-Tol
4-MeO-C6H4
Ph
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
2h
2i
84
77
80
75
80
84
90
60
85
a Reaction conditions:1 (0.3 mmol), CuI (20 mol %), K2CO3 (2 equiv),
dioxane (2 mL), all yields given are isolated yields. b 4 h reaction time was
needed.
2-Nap
4-NO2-C6H4
4-Br-C6H4
Bn
Me
n-Bu
As sulfonyl hydrazones could be simply prepared by
mixing relative sulfonyl hydrazides and the carbonyl com-
pounds, we investigated whether the reaction could be carried
out in a one-pot fashion directly from carbonyl compounds
without the isolation of sulfonyl hydrazone intermediates.
We were pleased to achieve positive results. After heating
the carbonyl compound 3 and sulfonyl hydrazide 4 for 2 h
at 110 °C, we added the base and catalyst CuI, and then the
mixture was heated for another 4 h. The product sulfone 2
was isolated with a slight decrease in the yield (Scheme 3).19
a Reaction conditions: 1 (0.3 mmol), CuI (20 mol %), K2CO3 (2 equiv),
dioxane 2 mL. b Isolated yields.
proven to be general and efficient to prepare aryl and alkyl
sulfones. Sulfonyl hydrazones derived from both electron-
rich (entries 1 and 2) or electron-deficient (entries 5 and 6)
sulfonyl hydrazides could afford the corresponding sulfones
in good yields. It is worth mentioning that alkyl sulfones
could also be produced from the corresponding sulfonyl
hydrazones in moderate to good yields (entries 7-9).
Further, various carbonyl compounds were investigated
for this type of reaction. These carbonyl compounds,
including aldehydes and ketones with aromatic or heteroaro-
matic substituents, were used to prepare tosyl hydrazone
substrates with tosyl hydrazide. These tosyl hydrazones 1j-p
could give target sulfones through the same reaction with
moderate to good yields (Scheme 2). Tosyl hydrazone
derivatives of diaryl ketones gave sulfone products with
better yields than those derived from other carbonyl com-
pounds. We speculated that this result might be ascribed to
the more stable metallocarbene intermediates. Product 2m
was formed in lower yield, probably due to its rigid structure
that was unfavorable to the transformation. Various benzal-
dehydes with electron-deficient or electron-donating substi-
tutents were also investigated. Relative products were
obtained in poor to moderate yields (data not shown), and
electron-donating substituents could facilitate the reaction
(2p).
Scheme 3
.
One-Pot Synthesis of Sulfones from Carbonyl
Compounds
Scheme 4 showed the supposed reaction mechanism. First,
diazo compound III and sulfinate salt IV were formed by
decomposition of the hydrazone salt II. Subsequently, in the
presence of copper salt, III released nitrogen and led to
metallocarbene V. For the gemini nucleophile IV, we
(19) Diarylketones were also tested. As the sulfonyl hydrazones derived
from diaryl ketones were more difficult to prepare, the results were not
satisfactory.
4410
Org. Lett., Vol. 12, No. 19, 2010

oxygen, so intermediate VI could be formed directly. The
final product was then formed through loss of copper and
proton exchange.
Scheme 4. Possible Reaction Mechanism
In conclusion, we have developed a simple and efficient
method for the synthesis of sulfones. The reaction used
sulfonyl hydrazones, which were easily prepared from
carbonyl compounds, to provide corresponding target prod-
ucts in moderate to good yields. Further applications of this
methodology are now in progress.
Acknowledgment. This work was financially supported
by the National Science Foundation of China (Nos. 20725206
and 20732004), Program for Changjiang Scholars and
Innovative Research Team in University, the Key Project
of Chinese Ministry of Educationin China, and Scientific
Fund of Sichuan Province for Outstanding Young Scientists.
Supporting Information Available: General experimental
procedures and spectroscopic data (1H NMR and 13C NMR)
for the corresponding products. This material is available
free of charge via the Internet at http://pubs.acs.org.
considered that the sulfur would act as the attack atom
because of its higher nucleophilicity compared to that of
OL101955X
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