Palladium/copper-catalyzed oxidative arylation of terminal alkenes with aroyl hydrazides

Article abstract of DOI:10.1002/chem.201304696

An unprecedented oxidative arylation reaction of terminal alkenes with simple aroyl hydrazides has been developed under aerobic conditions for the stereoselective synthesis of 1,2-disubstituted alkenes. A range of aroyl hydrazides underwent palladium/copper-catalyzed oxidative Mizoroki-Heck reaction with terminal alkenes open to air in a 1:1 mixture of dimethyl sulfoxide and acetonitrile to give structurally diverse 1,2-disubstituted alkenes in moderate to excellent yields with excellent regio- and E-selectivity. The reaction tolerated a wide variety of functional groups, such as alkoxy, hydroxy, amino, fluoro, chloro, bromo, cyano, nitro, ester, amide, imide, phosphine oxide, and sulfone groups, and, moreover, molecular oxygen and dimethyl sulfoxide were demonstrated to serve as terminal oxidants. This study provides a useful method for the stereoselective synthesis of 1,2-disubstituted alkenes through direct transformation of the vinylic Ci-H bonds in terminal alkenes. Cross-coupling: An oxidative arylation reaction of terminal alkenes with simple aroyl hydrazides has been developed in the presence of a PdCl₂/CuI catalyst under aerobic conditions to give a range of structurally diverse 1,2-disubstituted alkenes in moderate to excellent yields with excellent regio- and E-selectivity (see scheme; r.s.=regioselectivity).

Full text of DOI:10.1002/chem.201304696

DOI: 10.1002/chem.201304696
Communication
&
Organic Chemistry
Palladium/Copper-Catalyzed Oxidative Arylation of Terminal
Alkenes with Aroyl Hydrazides
Yong-Gang Zhang,[a] Xiang-Lei Liu,[a] Zeng-Yang He,[a] Xi-Ming Li,[a] Hong-Jian Kang,[a] and
Shi-Kai Tian*[a, b]
tions, but it still required ortho-substituents on benzoic acids
Abstract: An unprecedented oxidative arylation reaction
of terminal alkenes with simple aroyl hydrazides has been
and suffers from the use of excess terminal alkenes
(ꢀ1.5 equiv).[5] Although ortho-substituents are unnecessary for
developed under aerobic conditions for the stereoselec-
benzoic acid derivatives in the decarbonylative Mizoroki–Heck
tive synthesis of 1,2-disubstituted alkenes. A range of
reaction of acid chlorides,[6] anhydrides,[7] and active esters,[8]
aroyl hydrazides underwent palladium/copper-catalyzed
most of these carboxylic acid derivatives are sensitive to mois-
oxidative Mizoroki–Heck reaction with terminal alkenes
ture and the reaction frequently requires an elevated tempera-
open to air in a 1:1 mixture of dimethyl sulfoxide and ace-
ture up to 1608C.
tonitrile to give structurally diverse 1,2-disubstituted al-
In contrast to many other types of carboxylic acid deriva-
kenes in moderate to excellent yields with excellent regio-
tives, simple aroyl hydrazides (ArCONHNH2) are in general
and E-selectivity. The reaction tolerated a wide variety of
readily accessible solids that are compatible with moisture.
functional groups, such as alkoxy, hydroxy, amino, fluoro,
Prompted by our recent studies on the oxidative removal of
chloro, bromo, cyano, nitro, ester, amide, imide, phos-
the NHNH2 group from sulfonyl hydrazides[9] and carbazates,[10]
phine oxide, and sulfone groups, and, moreover, molecu-
together with our interest in alkene synthesis,[11] we envisioned
lar oxygen and dimethyl sulfoxide were demonstrated to
that simple aroyl hydrazides could lose the NHNH2 group in
serve as terminal oxidants. This study provides a useful
the presence of a palladium catalyst under oxidative condi-
method for the stereoselective synthesis of 1,2-disubstitut-
tions to generate certain aroylpalladium intermediates, extru-
ed alkenes through direct transformation of the vinylic CÀ
sion of carbon monoxide from which followed by coupling
with terminal alkenes would yield 1,2-disubstituted alkenes.[12]
H bonds in terminal alkenes.
Moreover, we planned to use molecular oxygen as a terminal
oxidant for the proposed arylation of terminal alkenes with
Direct transformation of the vinylic CÀH bonds in terminal al-
simple aroyl hydrazides, and consequently, water, molecular ni-
kenes constitutes one of the most ideal methods for the ste-
reoselective synthesis of 1,2-disubstituted alkenes. In this
regard, terminal alkenes have been widely employed in the
palladium-catalyzed Mizoroki–Heck reaction to couple with aryl
sources, such as aryl halides and sulfonates.[1] Moreover, the
scope of aryl sources has been significantly expanded by per-
forming the Mizoroki–Heck-type reaction under oxidative con-
ditions.[2] In 2002, Myers and co-workers disclosed an interest-
ing palladium-catalyzed Mizoroki–Heck-type reaction using
arenecarboxylic acids as aryl sources and Ag2CO3 as an oxidant
at 1208C.[3,4] Later on this decarboxylative Mizoroki–Heck reac-
tion was subjected to a few modifications on reaction condi-
trogen, and carbon monoxide were speculated to be generat-
ed as byproducts [Eq. (1)]. Hopefully, the reaction would pro-
ceed at lower temperature and exhibit broader substrate
scope relative to that for the reaction with arenecarboxylic
acids and their derivatives.[3–5,7,8]
To test the aforementioned hypothesis, we treated benzoyl
hydrazide (1a) (1.1 equiv) with styrene (2a) and 5 mol% PdCl2
in dimethyl sulfoxide open to air at 1008C (oil bath) and found
that alkene 3a was formed in 10% yield with exclusive E selec-
tivity (Table 1, entry 1). Subsequently, a range of solvents were
examined and a slightly better yield was achieved from the re-
action performed in a 1:1 mixture of dimethyl sulfoxide and
acetonitrile (entry 7). Replacing PdCl2 with Pd(OAc)2 or
[Pd(PPh3)4] failed to promote the desired oxidative Mizoroki–
Heck reaction (entries 8 and 9). To accelerate the possible
switch between PdII and Pd0 species that might be involved in
the reaction (see below), we examined a few copper sources
and found that the use of 1 mol% CuI improved the yield to
17% (entry 12). To our delight, the catalytic ability of PdCl2/CuI
(5:1) was dramatically enhanced by Brønsted acids and the ad-
[a] Y.-G. Zhang, X.-L. Liu, Z.-Y. He, X.-M. Li, H.-J. Kang, Prof. Dr. S.-K. Tian
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (P. R. China)
Fax: (+86)551-63601592
E-mail: tiansk@ustc.edu.cn
[b] Prof. Dr. S.-K. Tian
Key Laboratory of Synthetic Chemistry of Natural Substances
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Shanghai 200032 (P. R. China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304696.
Chem. Eur. J. 2014, 20, 2765 – 2769
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
In sharp contrast to benzoyl hydrazide (1a), an N’-substitut-
ed aroyl hydrazide, such as PhCONHNHBn (5a) failed to under-
go oxidative Mizoroki–Heck reaction with styrene (2a) to give
alkene 3a under the standard conditions. This result indicates
that the NHNH2 group is essential for the oxidative Mizoroki–
Heck reaction of terminal alkenes with aroyl hydrazides.
Control experiments indicated that the desired reaction did
not occur in the absence of PdCl2 and a much lower yield was
obtained from the reaction without CuI (Table 3, entries 1 and
2). Furthermore, we examined the catalytic ability of [Pd(OTs)2-
(MeCN)2], which might be generated from PdCl2 and p-tolu-
enesulfonic acid, and found that the corresponding reaction
gave only 16% yield (entry 3). These results suggest that PdCl2
serves as the major active PdII catalyst, which can be regenerat-
ed through copper-mediated aerobic oxidation after being re-
duced to Pd0 during the reaction (see below). The PdCl2/CuI
(5:1) catalyst system was also responsible for a minor side reac-
tion, the Wacker oxidation of styrene (2a),[14] wherein a trace
amount of acetophenone was generated and condensed with
benzoyl hydrazide (1a) to give Ph(Me)C=NHNHCOPh (6a) that
was tentatively assigned by electrospray ionization (ESI) mass
spectrometric analysis of the reaction mixture.[15] Moreover, the
ESI mass spectrometric analysis allowed tentative assignment
of two other byproducts, PhCONHNHCOPh (7a) and PhCOCH=
CHPh (8a),[16] which lend substantial support to the formation
of the proposed key aroylpalladium intermediate during the
reaction (see below).
Table 1. Optimization of reaction conditions.[a,b]
Entry
[Pd]
[Cu]
Acid
Solvent
Yield [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13[d]
14
15
16[e]
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
[Pd(PPh3)4]
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
none
none
none
none
none
none
none
none
none
CuCl
CuBr
CuI
none
none
none
none
none
none
none
none
none
none
none
none
TsOH
TsOH
H2SO4
TsOH
DMSO
DMF
MeCN
dioxane
toluene
propanol
DMSO/MeCN (1:1)
DMSO/MeCN (1:1)
DMSO/MeCN (1:1)
DMSO/MeCN (1:1)
DMSO/MeCN (1:1)
DMSO/MeCN (1:1)
DMSO/MeCN (1:1)
DMSO/MeCN (1:1)
DMSO/MeCN (1:1)
DMSO/MeCN (1:1)
10
trace
trace
0
0
0
11
0
0
9
11
17
19
86
43
77
CuI
CuI
CuI
CuI
[a] Reaction conditions: hydrazide 1a (0.44 mmol), alkene 2a (0.40 mmol),
[Pd] (5 mol%), [Cu] (if any, 1 mol%), acid (if any, 1.2 equiv), air (1 atm.),
solvent (1.0 mL), 1008C (oil bath), 3 h. [b] In all cases alkene 3a was ob-
tained as a single regioisomer with >99:1 E/Z selectivity. [c] Isolated
yield. [d] 20 mol% TsOH was used. [e] The reaction was run at 808C (oil
bath). Ac=acetyl, Ts=p-toluenesulfonyl.
dition of 1.2 equivalents of p-toluenesulfonic acid improved
the yield to 86% (entry 14). Whereas the reaction did take
place at a lower temperature, the desired product was ob-
tained in a lower yield (entry 16).
For comparison, the reaction of benzoyl hydrazide (1a) with
styrene (2a) was performed under an oxygen atmosphere to
give alkene 3a in 65% yield (Table 3, entry 4). The higher con-
centration of molecular oxygen led to a lower yield probably
by accelerating the decomposition of the hydrazide (see
below). Much to our surprise, the reaction did take place in
the absence of an oxygen atmosphere albeit that the desired
product was obtained in a much lower yield (entry 5). Further-
more, CuI proved to be irrelevant to the reaction without
oxygen (entry 6). These results allow us to conclude that the
solvent, dimethyl sulfoxide, is capable of serving as an oxidant
to convert Pd0 to PdII (see below).[17] To our delight, this conclu-
sion was unambiguously confirmed by the experiment shown
in Equation (2). When dibenzyl sulfoxide (9a) rather than di-
methyl sulfoxide was used as the cosolvent for the reaction of
benzoyl hydrazide (1a) with styrene (2a) in the presence of
5 mol% PdCl2 and 1.2 equivalents of p-toluenesulfonic acid
under a nitrogen atmosphere, a significant amount of dibenzyl
sulfoxide (9a) was found to be reduced to give dibenzyl sul-
fide (10a).
In the presence of 5 mol% PdCl2, 1 mol% CuI, and 1.2 equiv-
alents of p-toluenesulfonic acid and open to air, a range of
aroyl hydrazides smoothly underwent oxidative Mizoroki–Heck
reaction with arylethenes at 1008C (oil bath) to give structural-
ly diverse 1,2-diaryl alkenes in moderate to good yields with
excellent regio- and E-selectivity (Table 2, entries 1–25).[13] It is
noteworthy that both electron-withdrawing and -donating
groups were successfully introduced into the aromatic rings of
the products by employing the aroyl hydrazides or the aryle-
thenes bearing such groups and that the oxidative conditions
were mild enough to be compatible with very electron-rich
aryl groups, such as hydroxyphenyl, aminophenyl, and thienyl
groups (entries 3, 4, 14, and 17). This chemistry was successful-
ly extended to a variety of terminal alkenes, such as acrylates,
acrylamides, N-protected allylamines, allylphosphine oxides,
and allyl sulfones, and a range of functionalized 1,2-disubstitut-
ed alkenes were obtained in moderate to excellent yields with
extremely high regio- and E-selectivity (entries 26–31). When
compared to previously reported Mizoroki–Heck-type reactions
of arenecarboxylic acids and their derivatives,[3–8] the reaction
exhibited broader scope with regard to terminal alkenes
through oxidative arylation of the vinylic CÀH bonds in the N-
allyl, S-allyl, and P-allyl groups. In addition, as demonstrated by
the results summarized in Table 2, the reaction tolerated
a wide variety of functional groups, such as alkoxy, hydroxy,
amino, fluoro, chloro, bromo, cyano, nitro, ester, amide, imide,
phosphine oxide, and sulfone groups.
Aroyl hydrazides were subjected to decomposition either by
PdCl2 or by CuI under the standard reaction conditions. Treat-
ment of benzoyl hydrazide (1a) with 1.1 equivalents of p-tolu-
Chem. Eur. J. 2014, 20, 2765 – 2769
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Communication
enesulfonic acid, excess air, and
5 mol% PdCl2 led to the forma-
tion of benzophenone (11 a) and
benzoic acid (12a) in 34 and
Table 2. Oxidative arylation of terminal alkenes with aroyl hydrazides.[a]
30%
yields,
respectively
Entry
1, Ar
2, R
3
Yield [%][b]
3/4[c]
E/Z[c]
(Scheme 1). On the other hand,
replacing 5 mol% PdCl2 with
1 mol% CuI only gave benzoic
acid (12a) in 45% yield.[18] How-
ever, neither benzophenone
(11 a) nor benzoic acid (12a)
could react with styrene (2a) to
give alkene 3a under the stan-
dard conditions.
1
2
3
4[d]
5
6
7
8
1a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
3a
3b
3c
3d
3e
3 f
3g
3h
3i
86
60
51
59
56
82
72
57
42
46
88
64
80
45
77
73
44
74
69
77
60
77
56
73
74
58
69
69
>99:1
96:4
>99:1
97:3
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
97:3
1b, 4-MeO-Ph
1c, 4-HO-Ph
1d, 4-H2N-Ph
1e, 4-F-Ph
1 f, 4-Cl-Ph
1g, 4-Br-Ph
1h, 4-F3C-Ph
1i, 4-NC-Ph
1j, 4-O2N-Ph
1k, 3-Cl-Ph
1l, 3-O2N-Ph
1m, 2-Me-Ph
1n, 2-HO-Ph
1o, 2-naphthyl
1p, 1-naphthyl
1q, 3-thienyl
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
1a, Ph
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
96:4
>99:1
>99:1
>99:1
>99:1
>99:1
91:9
9[e]
10[f]
11
12[f]
13
14[g]
15
16
17
18
19
20
21
22
23
24
25
26
27
28
3j
3k
3l
On the basis of the above ex-
perimental results, we propose
the following reaction pathways
for the palladium/copper-cata-
lyzed oxidative arylation of ter-
minal alkenes with aroyl hydra-
zides (Scheme 2). While hydra-
zide 1 can form a salt with p-tol-
uenesulfonic acid, reversal of the
salt-forming reaction allows hy-
drazide 1 to displace a PdII cata-
lyst, PdXY (X, Y=Cl, OTs, I), to
give hydrazide–PdII complex 13,
b-hydride elimination of which
results in the formation of dia-
zene 14 and HPdX.[9a,10] Displace-
ment of PdXY with diazene 14
followed by successive extrusion
of molecular nitrogen and
carbon monoxide leads to the
formation of arylpalladium 17,
which undergoes regioselective
alkene insertion followed by ste-
reoselective b-hydride elimina-
tion to give alkene 3 and release
3m
3n
3o
3p
3q
3b
3 f
3g
3k
3r
3s
3o
3p
3t
3u
3v
2a, Ph
2b, 4-MeO-Ph
2c, 4-Cl-Ph
2d, 4-Br-Ph
2e, 3-Cl-Ph
2 f, 2-MeO-Ph
2g, 2-O2N-Ph
2h, 2-naphthyl
2i, 1-naphthyl
2j, CO2nBu
2k, CONHBn
2l, CONHPh
2m,
>99:1
>99:1
93:7
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
1a, Ph
1a, Ph
29
1a, Ph
3w
91
>99:1
>99:1
30
31
1a, Ph
1a, Ph
2n, CH2POPh2
2o, CH2SO2Ph
3x
3y
89
70
>99:1
>99:1
>99:1
>99:1
[a] Reaction conditions: hydrazide 1 (0.44 mmol), alkene 2 (0.40 mmol), PdCl2 (5 mol%), CuI (1 mol%), TsOH
(0.48 mmol), air (1 atm), DMSO/MeCN (1:1, 1.0 mL), 1008C (oil bath), 3 h. [b] Isolated yield. [c] Determined by
1H NMR spectroscopic analysis. [d] TsOH (0.96 mmol) was used. [e] Hydrazide (0.60 mmol) and TsOH
(0.68 mmol) were used. [f] The reaction was run with 10 mol% PdCl2 under oxygen (1 atm.). [g] The reaction
was run at 1208C (oil bath) for 13 h. Bn=Benzyl.
Table 3. Control experiments.[a,b]
Entry
[Pd]
[Cu]
[O]
Yield [%][c]
1
2
3
4
5[d]
6[d]
none
PdCl2
Pd(OTs)2(MeCN)2
PdCl2
PdCl2
CuI
none
CuI
CuI
CuI
air
air
air
O2
none
none
0
53
16
65
49
49
PdCl2
none
Scheme 1. Decomposition of benzoyl hydrazide (1a).
[a] Reaction conditions: hydrazide 1a (0.44 mmol), alkene 2a (0.40 mmol),
[Pd] (if any, 5 mol%), CuI (if any, 1 mol%), TsOH (1.2 equiv), air or O2 (if
any, 1 atm.), DMSO/MeCN (1:1, 1.0 mL), 1008C (oil bath), 3 h. [b] In all
cases alkene 3a was obtained as a single regioisomer with >99:1 E/Z se-
lectivity. [c] Isolated yield. [d] The reaction was run under nitrogen (1
atm.).
HPdX. Reductive elimination of HPdX regenerates Pd0, which is
converted to PdXY either by copper-mediated aerobic oxida-
tion[14] or by oxidation with the solvent dimethyl sulfoxide.[17]
Chem. Eur. J. 2014, 20, 2765 – 2769
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ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
were demonstrated to serve as terminal oxidants for the palla-
dium/copper-catalyzed oxidative arylation of terminal alkenes
with aroyl hydrazides.
Experimental Section
General procedure for the oxidative arylation of terminal al-
kenes with aroyl hydrazides
PdCl2 (3.5 mg, 0.02 mmol), CuI (0.8 mg, 0.004 mmol), and TsOH·H2O
(91.3 mg, 0.48 mmol) were added to a solution of hydrazide
1 (0.44 mmol) in DMSO/MeCN (1:1, 1.0 mL) under an air atmos-
phere at room temperature. The mixture was stirred for 1 h, and
alkene 2 (0.40 mmol) was added. The mixture was heated at 1008C
(oil bath) for 3 h, cooled to room temperature, and directly purified
by silica gel chromatography, eluting with ethyl acetate/petroleum
ether (1:100~1:1), to give alkenes 3 and 4 (if any).
Scheme 2. Proposed reaction pathways.
Two of the intermediates proposed for the above reaction
pathways, diazene 14 and aroylpalladium 16, have been
speculated to account for the side reaction pathways depicted
in Scheme 3. Displacement of arylpalladium 17 with diazene
Acknowledgements
We are grateful for the financial support from the National Nat-
ural Science Foundation of China (21232007 and 21172206),
the National Key Basic Research Program of China (973 Pro-
gram 2014CB931803), and the Program for Changjiang Schol-
ars and Innovative Research Team in University (IRT1189).
Keywords: alkenes
· arylation · hydrazides · oxidation ·
palladium
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Scheme 3. Proposed side reaction pathways.
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14 followed by extrusion of molecular nitrogen results in the
formation of aroylpalladium 20, reductive elimination of which
gives ketone 11. Aroylpalladium 16 undergoes alkene insertion
followed by b-hydride elimination to give a,b-unsaturated
ketone 8. On the other hand, displacement of aroylpalladium
16 with hydrazide 1 followed by reductive elimination gives
diacyl hydrazide 7.
In summary, we have developed, for the first time, an oxida-
tive arylation reaction of terminal alkenes with simple aroyl hy-
drazides under aerobic conditions for the stereoselective syn-
thesis of 1,2-disubstituted alkenes. In the presence of 5 mol%
PdCl2, 1 mol% CuI, and 1.2 equivalents of p-toluenesulfonic
acid and open to air, a range of aroyl hydrazides smoothly un-
derwent oxidative Mizoroki–Heck reaction with terminal al-
kenes in a 1:1 mixture of dimethyl sulfoxide and acetonitrile to
give structurally diverse 1,2-disubstituted alkenes in moderate
to excellent yields with excellent region- and E-selectivity. No-
tably, the reaction tolerated a wide variety of functional
groups, such as alkoxy, hydroxy, amino, fluoro, chloro, bromo,
cyano, nitro, ester, amide, imide, phosphine oxide, and sulfone
groups. Moreover, molecular oxygen and dimethyl sulfoxide
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Received: November 30, 2013
Published online on February 5, 2014
Chem. Eur. J. 2014, 20, 2765 – 2769
www.chemeurj.org
2769
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim