Palladium-catalyzed intermolecular dehydrogenative aminohalogenation of alkenes under molecular oxygen: An approach to brominated enamines

Article abstract of DOI:10.1021/ja401034g

A novel and efficient palladium-catalyzed dehydrogenative aminohalogenation of alkenes with molecular oxygen as the sole oxidant has been developed. This protocol provides a valuable synthetic tool for the assembly of a wide range of brominated enamines under mild conditions, with unprecedented stereoselectivity and exceptional functional group tolerance. This attractive route for the synthesis of brominated enamines is of great significance due to the products' versatile reactivity for further transformations.

Full text of DOI:10.1021/ja401034g

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Communication
Palladium-Catalyzed Intermolecular Dehydrogenative Aminohalogenation
of Alkenes under Molecular Oxygen: An Approach to Brominated Enamines
Xiaochen Ji, Huawen Huang, Wanqing Wu, and Huanfeng Jiang
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja401034g • Publication Date (Web): 25 Mar 2013
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Palladium-Catalyzed Intermolecular Dehydrogenative Aminohalo-
genation of Alkenes under Molecular Oxygen: An Approach to Bro-
minated Enamines
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Xiaochen Ji, Huawen Huang, Wanqing Wu, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R.
China
Supporting Information Placeholder
nitrogen sources and more importantly provides highly con-
ABSTRACT: A novel and efficient palladium-catalyzed de-
hydrogenative aminohalogenation of alkenes with molecular
oxygen as the sole oxidant has been developed. This protocol
provides a valuable synthetic tool for the assembly of a wide
range of brominated enamines under mild conditions, with
unprecedented stereoselectivity and exceptional functional
venient access to halogenated enamine scaffold which was
difficult to prepare by traditional methodologies.11
Scheme 1. Difunctionalization and Dehydrogenative
Difunctionalization of Alkenes with Amines and
Halogens
group tolerance. This attractive route for the synthesis of
brominated enamines is of great significance due to the
products’ versatile reactivity for further transformations.
Alkene difunctionalization, involving the formation of two
new vicinal chemical bonds, exemplifies a class of reactions
with significant synthetic potential to rapidly increase mo-
lecular complexity.1-3 Among them, the aminohalogenation
of alkenes has attracted intensive attention over the years
particularly in developing regio- and stereoselective reaction
systems to provide multifunctional alkane products (Scheme
1a).4-8 Despite of the overall efficiency and versatility of this
We commenced our study by investigating the Pd-
catalyzed reaction of aniline 1a and methyl acrylate 2a in the
presence of bromine source with O2 as the oxidant (Table 1).
Fortunately, the desired product (Z)-3a was obtained in 62%
GC yield with LiBr12 (4 equiv) as bromine source and PdCl2 as
catalyst in acetonitrile under 5 atm O2 (entry 1). The use of
Pd(OAc)2 as the catalyst resulted in a decent boost in the
yield of (Z)-3a, while Pd(PPh3)2Cl2 and Pd(PPh3)4 gave de-
creased yields (entries 2-4). Further optimization showed
that the bromine source was critical for the success of this
reaction, and the desired product (Z)-3a was hardly obtained
with TBAB or NBS (entries 5-6). Screening of different sol-
vents revealed that using THF as solvent led to further in-
crease in the yield of (Z)-3a with excellent stereoselectivity
(>20:1) (entries 7-8). The reaction hardly proceeded to give
the desired product under 1 atm O2 (entry 9). Notably, no
reaction was observed using stoichiometric Pd(OAc)2 under
nitrogen atmosphere, suggesting that O2 is likely to be in-
volved in the product forming step rather than reoxidation of
Pd(0) (entry 10).
transformation, significant limitations still exist. For instance,
the nitrogen sources have been limited to sulfonamides,6
amides7 and carbamates8 so far. Simple aromatic amines
have not been successfully used as the nitrogen source in
such transformations yet.9
On the other hand, as for the final products compared
with traditional aminohalogenation of alkenes, dehydrogena-
tive aminohalogenation would be of great significance to
yield synthetically useful halogenated enamines, which are
versatile building blocks in organic synthesis and medicinal
chemistry, as well as valuable intermediates in the construc-
tion of biologically active natural products. To the best of our
knowledge, there are no reported examples dedicated to
dehydrogenative difunctionalization of alkenes to afford
multifunctional olefins. Herein we disclose the first example
of a highly regio- and stereoselective Pd-catalyzed dehydro-
genative aminohalogenation of activated alkenes with mo-
lecular oxygen as the sole oxidant (Scheme 1b).10 The present
protocol directly employs simple aromatic amines as the
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We next evaluated the substrate scope of this transfor-
mation. The optimized reaction conditions were found to be
applicable to a broad range of substrates (Scheme 1). As for
the aniline partner, various valuable functional groups such
as methoxyl, fluoro, chloro, bromo, ester, methyl, cyanide,
mesyl, and trifluoromethyl were reasonably well tolerated in
meta and para positions of the aromatic ring, providing am-
ple opportunity for further derivatization of the products
(3a-3k). The structure of 3j was further characterized by X-
ray crystal diffraction measurement.13,14 Besides, α-
naphthylamine and β-naphthylamine proceeded smoothly to
give the corresponding products in excellent yields (3p-3q).
The ortho substituted anilines retarded the reaction, possibly
due to the steric interference. Gratifyingly, good results were
obtained with longer reaction times. It is noteworthy that
coumarin 151 was also productive, leading to product 3r in
excellent yield. Unfortunately, benzylamine and N-
methylaniline could not undergo this dehydrogenative ami-
nohalogenation of alkenes in current reaction system.
3
4
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8
9
R
R
O
O
O
N
O
R
N
O
N
H
O
H
H
Br
Br
Br
3a, R = H, 81% (>20:1)
3b, R = OMe, 73% (>20:1)
3c, R = F, 71% (>20:1)
3d, R = Cl, 77% (>20:1)
3e, R = Br, 72% (>20:1)
3f, R = CO2Me, 80% (>20:1)
3g, R = SO2Me, 83% (>20:1)
3h,R = CN, 79% (>20:1)
3l, R = Me, 63% (12:1)b
3i
, R= OMe, 82% (>20:1)
3j, R = F, 80% (>20:1)
3k, R = CF3, 84% (>20:1)
b
3m
, R = OMe, 80% (>20:1)
3n, R = Br, 68% (>20:1)b
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3o, R = F, 85% (>20:1)
O
O
N
O
N
O
H
H
Br
Br
3q, 84% (>20:1)
F
3p, 81% (>20:1)
F
F
O
O
O
N
O
Br
O
O
N
O
N
O
H
H
H
Br
Br
3s, 79% (>20:1)
3r, 78% (>20:1)
3t, 83% (>20:1)
O
O
O
F
F
O
N
O
N
O
N
O
On the other hand, acrylates with various functional
groups, such as cyclohexyl, tetrahydrofuran, and trifluorome-
thyl, were successfully transformed into desired products in
good to excellent yields (3s-3w). Intriguingly, hydroxyl was
also tolerated well in this reaction system, with 3x obtained
in 80% yield. Other alkenes with electron-withdrawing
groups, including acrylamide and acrylonitrile, gave the cor-
responding products in good yields (3y-3z).
H
H
H
Br
Br
Br
F
3u, 86% (12:1)
3v, 82% (12:1)
3w, 87% (>20:1)
O
O
N
OH
N
O
N
NH2
N
H
H
H
Br
Br
Br
3x, 80% (>20:1)
3y, 71% (6:1)
3z, 85% (>20:1)
aReaction conditions: aromatic amine 1 (0.5 mmol), alkene 2
(0.8 mmol), LiBr (4 equiv), Pd(OAc)2 (10 mol %), 2 mL THF,
under 5 atm O2, 60 oC for 24 h. Yields of isolated products are
reported, Z/E ratio is reported in parentheses. The reaction
time was prolonged to 60 h.
Table 1. Optimization of the Reaction Conditionsa
b
The vinyl halide functionality and the free NH functionali-
ty in the product molecules enable them to be attractive and
versatile synthetic building blocks in a variety of chemical
transformations, leading to more complicated organic archi-
tectures by the formation of new C-C, C-N, etc. bonds. Thus
to demonstrate the synthetic utility of this protocol, the new-
ly formed brominated enamines were employed for further
transformations to prepare a series of functionalized prod-
ucts (Scheme 3). The Suzuki−Miyaura cross-coupling reac-
tions of 3a and 3b with phenylboronic acid delivered arylated
compounds 4a and 4b, respectively, in excellent yields.15
Brominated enamine 3a was successfully reduced to methyl
2-bromo-3-(phenylamino) propanoate (5) by NaBH4 (3 equiv)
in 91% yield.16 Intriguingly, 3a and 3d gave rise to the for-
mation of tertiary amine 6a and 6d, respectively, in excellent
yields with excessive NaBH4 (8 equiv) and prolonged reaction
time, probably resulting from the further reduction of the
corresponding amide compounds formed in situ from alkyl-
amines and acetic acid.
entry
[Br]
source
catalyst
solvent
yield(%)b
1
LiBr
LiBr
LiBr
LiBr
TBAB
NBS
LiBr
LiBr
LiBr
LiBr
PdCl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
62
2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
79
3
43
4
trace
trace
-
5
6
7
57
8
9d
10e
THF
87 c
trace
-
THF
THF
aReaction conditions: aniline 1a (0.5 mmol), methyl acry-
late 2a (0.8 mmol), [Br] Source (4 equiv), catalyst (10 mol %),
2 mL solvent, under 5 atm O2, 60 oC for 24 h. bGC yield based
Moreover, 3a was efficiently transfomed into aziridine
compound
7
in 85% overall yield via
a
reduc-
tion/intramolecular formation of C-N bond sequence with-
out purification of the reduced product 5. Aziridine com-
pounds have become useful synthons in organic synthesis
due to their diverse reactivities. Especially, the activated
aziridine compounds, such as aziridine-2-carboxylic acid
derivatives, have been widely investigated in ring-opening
reactions to produce a large number of functionalized prod-
ucts that are not easily accessible by other means.17 Thus, this
method also provides a novel and efficient access to the
c
d
on 1a. Z/E ratio >20:1. The reaction proceeded with an oxy-
gen balloon. eWith Pd(OAc)2 (1 equiv), under N2 atmosphere.
Scheme 2. Pd-Catalyzed Dehydrogenative Aminohal-
ogenation of Alkenesa
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aziridine compounds from readily available starting materi-
als under mild conditions.
conditions, gave a trace amount of 3a (Scheme 4b), indicat-
ing that 3a was not derived from simple bromination of 8.
We speculated that 3a might be formed through the oxida-
tion of methyl 2-bromo-3-(phenylamino) propanoate (5).
However, only trace 3a was detected by GC-MS when 5 was
subjected to the standard conditions (Scheme 4c). These
results described above suggested that neither 8 nor 5 was
possible intermediate of the transformation. Combining with
the fact that N-methylaniline could not undergo this trans-
formation, we speculated that the NH in the alkyl palladium
intermediate, formed by nucleopalladation of an alkene,
played an important role in the fomation of the final product.
The reaction is scalable and practical since a satisfactory
yield (73%) with excellent stereoselectivity (Z/E=21:1) was
obtained in the presence of just 0.5 mol % Pd(OAc)2 when
the reaction was performed on 5 mmol scale (eq 1).14
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Scheme 3. Selected Transformations of Brominated
Enaminesa,14
Scheme 4. Mechanistic Investigations of the dehy-
drogenative aminohalogenation process
In summary, we have developed a novel and efficient pal-
ladium-catalyzed dehydrogenative aminohalogenation of
activated alkenes with molecular oxygen as the oxidant, with
unprecedented stereoselectivity and exceptional functional
group tolerance. It represents an unprecedented example of
the dehydrogenative difunctionalization of alkenes to our
knowledge. In addition, this protocol provides a valuable
synthetic tool for the assembly of a wide range of brominated
enamines under mild conditions, which are expected to be
useful intermediates for the preparation of pharmaceutically
and biologically active compounds as well as functional ma-
terials. Moreover, the use of inexpensive and readily available
starting materials, as well as the environmentally benign
oxidant, makes this practical and atom-economy approach
particularly attractive. Further investigations toward the
scope of the reaction, a detailed mechanism, and applica-
tions in organic synthesis are currently ongoing in our labor-
atory.
aReaction conditions: (i) Pd(OAc)2 (5 mol %), Xphos (10 mol
%), PhB(OH)2 (3.0 equiv), K3PO4 (3.0 equiv), toluene, 110 oC,
10 h. (ii) NaBH4 (3 equiv), AcOH, rt, 2 h. (iii) NaBH4 (8
o
b
equiv), AcOH, rt, 8 h. (iv) K3PO4, toluene, 70 C, 36 h. The
stereoselectivity was 6:1.
To further highlight the versatility of this strategy, we next
attempted to other halide ions. A preliminary experiment
showed that the addition of 4 equiv of LiCl instead of LiBr
results in the expected chlorinated enamine product in 13%
GC yield under analogous conditions, with a stereoselectivity
(Z/E) of 5.2/1 (eq 2). This result provides extremely promising
precedent that palladium-catalyzed intermolecular dehydro-
genative aminochlorination of alkenes can be realized to give
chlorinated enamines under molecular oxygen.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data and spectra
of products, and X-ray crystal structures of 3j. This material
is available free of charge via the Internet at
http://pubs.acs.org.
To gain insight into the mechanism of the dehydrogena-
tive aminohalogenation process, several controlled experi-
ments were conducted. First, when the radical scavenger
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO; 1 equiv) was
added under the standard conditions, the reaction afforded
3a in 89% yield (Scheme 4a), indicating the transformation
might not proceed via a free-radical pathway. Subsequently,
methyl 3-(phenylamino) acrylate (8), a side product in some
cases, when treated with 4 equiv LiBr under the standard
AUTHOR INFORMATION
Corresponding Author
jianghf@scut.edu.cn
ACKNOWLEDGMENTS
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G.; Pan, Y. RSC Adv. 2011, 1, 429. (c) Ji, X.; Mei, H.; Qian, Y.; Han, J.;
Li, G.; Pan, Y. Synthesis 2011, 22, 3680. (d) Raghavan, S.; Mustafa, S.;
Sridhar, B. J. Org. Chem. 2009, 74, 4499.
We are grateful for financial support from the National Basic
Research Program of China (973 Program) (2011CB808600),
the National Nature Science Foundation of China (20932002,
21172076 and 21202046), the Guangdong Natural Science
Foundation (10351064101000000 and S2012040007088), and
the Fundamental Research Funds for the Central Universities
(2012ZP0003 and 2012ZB0011).
(9) An inherent challenge in transition metal catalyzed reactions
involving aromatic amines arises from the strong coordination of
nitrogen nucleophiles to the metal catalyst center, which reduces
the electrophilicity of metal catalyst and hence interferes with the
reactivity of the catalyst. See: (a) Zhao, H.; Wang, M.; Su, W.; Hong,
M. Adv. Synth. Catal. 2010, 352, 1301. (b) Obora, Y.; Shimizu Y.; Ishii,
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(10) For recent developments on transition metal catalyzed reac-
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halogenated enamines in the literature. For the only three refer-
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the reaction, but also can effectively inhibit the β-H elimination,
thus facilitating the dehydrogenative difunctionalization of alkenes.
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Palladium-Catalyzed Intermolecular Dehydrogenative Aminohalogenation of Alkenes
under Molecular Oxygen: AnApproach to Brominated Enamines
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Xiaochen Ji, Huawen Huang, Wanqing Wu, and Huanfeng Jiang*
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