Palladium-catalyzed conjugate addition of arylsulfonyl hydrazides to α,β-unsaturated ketones

Article abstract of DOI:10.1039/c3ob40518d

A palladium-catalyzed desulfitative-denitrogenative conjugate addition of arylsulfonyl hydrazides to α,β-unsaturated ketones is described. The reaction showed very good selectivity and tolerated a wide range of functionalities under an atmosphere of oxygen with or without the aid of a metal co-oxidant. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40518d

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Palladium-catalyzed conjugate addition of arylsulfonyl
hydrazides to α,β-unsaturated ketones†
Cite this: Org. Biomol. Chem., 2013, 11, 4295
Received 14th March 2013,
Accepted 13th May 2013
Wen Chen, Hui Chen, Fuhong Xiao and Guo-Jun Deng*
DOI: 10.1039/c3ob40518d
www.rsc.org/obc
A
palladium-catalyzed desulfitative–denitrogenative conjugate
addition of arylsulfonyl hydrazides to α,β-unsaturated ketones is
described. The reaction showed very good selectivity and toler-
ated a wide range of functionalities under an atmosphere of
oxygen with or without the aid of a metal co-oxidant.
The transition-metal-catalyzed addition reactions of aryl
organo–metallic reagents to electron-deficient olefins have
attracted much attention and have made great progress in the
construction of new C–C bonds.1 The use of copper catalysts
has been very successful for the conjugate addition of hard
organometallics such as organolithiums, Grignards, or organo-
zincs.2 However, this strategy sometimes is problematic for
conjugate 1,4-addition of α,β-unsaturated carbonyl compounds
due to its sensitivity to the carbonyl functional groups. In
recent years, the rhodium- and palladium-catalyzed conjugate
additions of soft organoboranes,3 -silicones,4 and -stannanes5
to α,β-unsaturated carbonyl compounds are attractive alter-
natives because of their insensitivity to the carbonyl functional
groups (Scheme 1a).
Since aryl organometallics are generally synthesized from
the corresponding aryl halides, the direct use of aryl halides
for conjugate addition reactions can circumvent the use of
stoichiometric amounts of metals. However, the Mizoroki–
Heck type reaction is a problem and always results in low
selectivity of the conjugate addition products.6 The groups of
de Vries and Minnaard developed a Pd–NHC catalytic system
which can selectively provide the conjugate product or
Mizoroki–Heck product by using different bases.7 Recently, the
use of other organic nucleophiles instead of organometallics
for conjugate reactions has attracted much attention. Zhao
et al. developed a rhodium-catalyzed decarboxylative conju-
gated addition of benzoic acids to α,β-unsaturated carbonyl
Scheme 1 Various routes for conjugate addition of unsaturated carbonyl
compounds.
compounds.8 In this transformation, benzoic acids acted as
the aryl nucleophiles via releasing CO2.9 However, this strategy
required ortho-functionalized benzoic substrates and thus
limited the scope. We and others developed various palla-
dium-catalyzed desulfitative Heck-type reactions,10 addition
reactions (Scheme 1b),11 and cross-coupling reactions12 using
sodium sulfinate as substrates. Unlike the decarboxylative
coupling reaction, no electron-withdrawing or donating group
ortho to the sulfinic acids group is necessary.13 Arylsulfonyl
hydrazides are stable in air and can be prepared in one step
from readily available arylsulfonyl chlorides and hydrazine
hydrates. In the presence of palladium catalysts and carbonyl
compounds, arylsulfonyl hydrazides can readily convert into
very active diazo compounds which are found to be very impor-
tant cross-coupling partners.14 Very recently, these compounds
have also successfully been used as aryl sources via desulfi-
tation–denitrogenation for Heck-type reaction15 and direct C–H
bond arylations.16 In continuing with our interest in using aryl
sulfinic acids and their related compounds as aryl sources,
herein we describe a palladium-catalyzed desulfitative–denitro-
genative conjugate addition of aryl–sulfonyl hydrazides to
α,β-unsaturated carbonyl compounds (Scheme 1c).
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of
Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
E-mail: gjdeng@xtu.edu.cn; Fax: (+86)-731-58292251; Tel: (+86)-731-58298601
We began our study by examining the reaction of benzyli-
†Electronic supplementary information (ESI)
available. See DOI:
dene–acetone (1a) with benzenesulfonyl hydrazide (2a) in 1,4-
10.1039/c3ob40518d
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Table 1 Screening for the optimal conditionsa
Table 2 Addition of 2a to various unsaturated ketonesa
Yieldb (%)
Entry
Unsaturated ketone
Product
Yieldb (%)
Entry Catalyst
Oxidant
Solvent
3a
4a
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(COD)Cl2 Ag2CO3/air
Pd2(dba)3
PdCl2
Ag2CO3/air
1,4-Dioxane–H2O
1,4-Dioxane–H2O
1,4-Dioxane–H2O 12
1,4-Dioxane–H2O 11
2
3
0
0
0
0
0
0
0
0
2
0
0
28
2
0
0
0
1
0
0
2
0
1
2
3
R1 = H
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
81
82 (3)
80
76 (2)
75
59
61 (2)
62
63 (6)
80 (5)
80
78 (3)
53
60
Ag2CO3/air
Ag2CO3/air
Ag2CO3/air
Ag2CO3/air
Air
R1 = 4-Me
R1 = 4-MeO
R1 = 4-t-Bu
R1 = 4-NMe2
R1 = 3,4,5-(MeO)3
R1 = 4-F
Pd(OH)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
Pd(acac)2
1,4-Dioxane–H2O
2
1,4-Dioxane–H2O 70
1,4-Dioxane–H2O 25
1,4-Dioxane–H2O 68
1,4-Dioxane–H2O 88
1,4-Dioxane–H2O 65
1,4-Dioxane–H2O 56
1,4-Dioxane–H2O 45
4
5c
6
O2
9
CuSO4/O2
CuCl2/O2
Cu(OAc)2/O2
CuO/O2
Cu(CF3CO2)2/O2 1,4-Dioxane–H2O 70
FeCl3/O2
DBP/O2
CuSO4/O2
CuSO4/O2
CuSO4/O2
CuSO4/O2
CuSO4/O2
O2
7
8c
9c
10
11
12
13c
14
R1 = 4-Cl
10
11
12
13
14
15
16
17
18
19
20
21c
R1 = 4-Br
R1 = 3-Me
R1 = 3-MeO
R1 = 2-MeO
R1 = 2-F
1,4-Dioxane–H2O
1,4-Dioxane–H2O 57
Toluene–H2O
NMP–H2O
DMF–H2O
H2O
4
R1 = 2-Cl
3
13
20
5
1,4-Dioxane
1,4-Dioxane–H2O 87
65
15
16
17
18
R2 = H
1o
1p
1q
1r
3o
3p
3q
3r
80
81
81
82
R2 = Me
R2 = MeO
R2 = F
a Conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (5 mol%), oxidant
(1.4 equiv.), organic solvent (0.6 mL), H2O (0.2 mL), 80 °C, 16 h under
air or oxygen. b GC yield based on 1a. c For 24 h.
a Conditions: 1 (0.2 mmol), 2a (0.3 mmol), Pd(acac)2 (5 mol%), 1,4-
dioxane–H2O (0.8 mL, 3 : 1), 80 °C, 24–32 h under oxygen; numbers in
parentheses denote the amount of Heck-type by-product (GC yield).
b Isolated yield. c CuSO4 (1.4 equiv.), 14 h, under oxygen.
dioxane–H2O (3 : 1) using palladium salt as the catalyst and
Ag2CO3 as the oxidant at 80 °C. When Pd(OAc)2 was used as
the catalyst in air, the desired product 3a was obtained in only
2% yield as determined by GC and 1H NMR methods (Table 1,
entry 1). When Pd2(dba)3 and PdCl2 were used, the desired
product could be obtained in 12% and 11% yields, respectively
(entries 3 and 4). Among the various palladium salts investi-
gated, Pd(acac)2 was the most efficient and the addition
product was obtained in 70% yield (entry 6). Only 25% yield
was obtained when the reaction was carried out in the absence
of Ag2CO3 (entry 7). However, the yield could be improved to
68% by using molecular oxygen as the sole oxidant (entry 8).
Addition of CuSO4 could improve the reaction yield slightly,
and the desired product could be obtained in 88% yield
together with 2% of Heck-type product (4a) when 1.4 equiv. of
CuSO4 was added (entry 9). Under similar reaction conditions,
other oxidants were less effective for this kind of transform-
ation (entries 10–15). The solvent had an important impact on
the reaction yield and the reaction yield decreased significantly
when the reaction was run in other organic or aqueous
media (entries 16–20). To our delight, the desired product 3a
could be obtained in 87% yield even in the absence of any
metal oxidant when the reaction time was extended to 24 h
(entry 21).
bearing electron-withdrawing and donating substituents on
the phenyl ring were investigated (Table 2). (E)-4-p-Tolylbut-
3-en-2-one (1b) and (E)-4-(4-methoxyphenyl)but-3-en-2-one (1c)
both smoothly reacted with 2a and gave the desired conjugate
addition products in 82% and 80% yields, respectively (entries
2 and 3). The reaction yields decreased slightly when 1d and
1e were used as substrates (entries 4 and 5). When (E)-4-(3,4,5-
trimethoxyphenyl)but-3-en-2-one (1f) was used, the desired
product 3f was obtained in moderate yield (entry 6). Halogen
substituents such as fluoro, chloro and bromo were well toler-
ated under the optimized reaction conditions (entries 7–9).
The position of the substituents on the phenyl ring did not
affect the reaction yield significantly (entries 10–14). Notably,
aryl substituted enone substrate (E)-chalcone (1o) also
smoothly reacted with 2a and gave the desired product in 80%
yield (entry 15). Substituents such as methyl, methoxy
and fluoro at the para position did not affect the conjugate
addition reactions (entries 16–18). In most cases, the reaction
showed good selectivity and only trace Heck-type reaction
product was detected. Unfortunately, olefins such as styrene
and acrylate were not suitable substrates for this kind of trans-
formation under the optimal conditions, and these substrates
mainly afforded the Heck-type by-products in low yields.
With the optimized reaction conditions in hand, we then
explored the scope and generality of this transformation with
or without the use of CuSO4. Various α,β-unsaturated ketones
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Table 3 Addition of 1a to arylsulfonyl hydrazidesa
Entry
1c
Sulfonyl hydrazide
Product
Yieldb (%)
87 (2)
2b
2c
3s
2
3t
85
3c
4
2d
2e
2f
3u
3v
3w
80 (3)
88 (4)
88
5c
Scheme 2 A tentative reaction mechanism.
a Conditions: 1a (0.2 mmol), 2 (0.3 mmol), 1,4-dioxane–H2O (0.8 mL,
3 : 1), 80 °C, 24–32 h under oxygen; numbers in parentheses denote
the amount of Heck-type by-product (GC yield). b Isolated yield.
c CuSO4 (1.4 equiv.), 14 h under oxygen.
conditions. The scope, mechanism, and synthetic applications
of this reaction in the asymmetric version are under
investigation.
The reaction results of various arylsulfonyl hydrazides with
benzylideneacetone 1a are presented in Table 3. A series of
functional groups including methyl, tert-butyl, methoxy and
fluoro were tolerated under the optimal reaction conditions,
and the desired products were obtained in high yields (entries
1–4). More bulky substrates such as naphthalene-2-sulfono-
hydrazide (2f) also efficiently reacted with 1a and gave the
desired product in 88% yield (entry 5).
Although the exact mechanism of the desulfitative–denitro-
genative addition of arylsulfonyl hydrazides to α,β-unsaturated
ketones is not very clear at present, we proposed a catalytic
cycle based on the experimental results and proposed mecha-
nisms reported in the literature (Scheme 2).15,16 The reaction
of PdII with arylsulfonyl hydrazide generates an active inter-
mediate I and Pd0 species through successive deprotonation
reactions. Meanwhile, PdII can be regenerated by the oxidation
of the Pd0 with oxygen. The liberation of N2 and SO2 from
intermediate I affords an ArPdII intermediate II. Coordination
of the ketone substrate forms a complex III, and subsequent
migratory insertion of the CvC bond with the aryl–palladium
complex gives complex IV. Protonation of IV by water will give
the final addition product and regenerate the reactive
palladium(II) species.11e
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21172185), the Hunan Provincial Natural
Science Foundation of China (11JJ1003 and 12JJ7002), the New
Century Excellent Talents in University from the Ministry of
Education of China (NCET-11-0974) and the Hunan Provincial
Innovative Foundation for Postgraduate (CX2012B250).
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