Microwave assisted palladium catalyzed intermolecular a-arylation of copper-amide enolate of benzazepine

Article abstract of DOI:10.1016/j.tetlet.2013.02.026

Intermolecular a-arylation of copper enolate of 3-benzazepin-2-one with aryl halides in the presence of palladium as catalyst is reported as a general method. To the best of our knowledge this is the first Letter of the use of copper enolates of amides for C-C bond formation. The scope of the base, solvent, ligand, and catalysts used has also been investigated.

Full text of DOI:10.1016/j.tetlet.2013.02.026

Tetrahedron Letters 54 (2013) 2029–2032
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted palladium catalyzed intermolecular
of copper-amide enolate of benzazepine
a-arylation
⇑
Amit Verma, Navneet Prajapati, Sujata Salecha, Rajani Giridhar, Mange Ram Yadav
Pharmacy Department, Faculty of Technology & Engineering, Kalabhavan, The M.S. University of Baroda, Vadodara 390001, Gujarat, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Intermolecular a-arylation of copper enolate of 3-benzazepin-2-one with aryl halides in the presence of
Received 8 October 2012
Revised 4 February 2013
Accepted 8 February 2013
Available online 16 February 2013
palladium as catalyst is reported as a general method. To the best of our knowledge this is the first Letter
of the use of copper enolates of amides for C–C bond formation. The scope of the base, solvent, ligand, and
catalysts used has also been investigated.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
a-Arylation
Palladium catalysis
Benzazepine
Copper catalysis
C–C bond formation
The palladium-catalyzed process has been sufficiently explored
as a mild catalytic method to form the C–C bond between an aryl
ring and the
carbonyl compounds has been considered a difficult transforma-
tion traditionally, but with palladium catalysis it is achieved with
simpler and milder methods.2 It has been shown that the palla-
dium-catalyzed intermolecular coupling of halides and keto-eno-
palladium as a catalyst source, combined with co-catalytic
amounts of Cu(I) in an amine. In another Letter Sulikowski and
co-workers10 have demonstrated the use of Cu(II) enolates of ace-
tates, generated in situ from that silyl enol ethers in the presence of
copper (II) fluoride for palladium catalyzed sp3–sp2 cross coupling
a a-Arylation of
-position of a carbonyl compound.1
to afford
a-aryl ketones. Considering the Letters of greater func-
tional group tolerance of the coupling of aryl and alkyl zinc re-
agents11 than the aryl and alkyl magnesium, sodium or lithium
reagents,12 and the successful use of copper as a co-catalyst in
Sonogashira coupling, we anticipated that the use of copper (I) as
a co-catalyst with sp3 carbon could work efficiently, offering
lates or ester-enolates is a useful method for synthesizing
ketones and -aryl esters. -Arylation of amides is comparatively
less common.3 The
-arylation of amide-enolate, with one excep-
a-aryl
a
a
a
tion,4 has been limited to the cyclization for obtaining lactams or
intramolecular reactions of acyclic amides.5 Amide requires a
stronger base than ketones and esters to generate the enolate,
and the use of strong base has several significant drawbacks.
To overcome these problems, reactions that occur with enolates
that are less basic than alkali metal enolates of amides need to be
developed. A few methods have emphasized the use of zinc metal
milder reaction conditions for the
a-arylation of amide enolates.
The coupling of copper enolates of amides could also address the
problem of functional group tolerance under a given set of reaction
conditions, additionally.
We were interested in the in situ generation of copper (I) eno-
lates of amides from the displacement of alkali metal enolates
and their cross-coupling with aryl halides by palladium catalysts.
as milder basic functionality for a
-arylation.6 To some extent zinc
enolates have demonstrated promising results, although zinc eno-
Herein, we report the palladium catalyzed a-arylation of benzo-
lates of lactams are not that common reagents because they need
fused cyclic amide, 3-benzazepin-2-one with co-catalyst copper
(I) iodide (Scheme 1). To the best of our knowledge this is the first
to be formed from the
a
-bromoamides7 or by quenching of alkali
metal amide enolates with zinc halides.8 On the other hand copper
(I) as a co-catalyst with palladium has been extensively used for
the coupling of sp and sp2 carbon–carbon bond formation. Sono-
gashira et al.9 discovered and reported a process of sp–sp2 coupling
that could be performed easily at room temperature using
Letter on the use of copper enolates of amides for
a-arylation.
a
-Arylation of compound (1) was first tried as per the previ-
ously reported process for esters.13 N-Methyl-3-benzazepin-
2-one (1.0 equiv) was taken in THF and BuLi (1.5 equiv) at À70 °C
was added to it followed by the addition of Pd2dba3 (5 mol %),
Xantphos, (7.5 mol %) and aryl bromide (1.5 equiv) at rt. No aryla-
tion product was obtained. To improve the process, the reaction
was repeated with the addition of Cu(I) iodide (1.1 equiv) (Process
⇑
Corresponding author. Tel.: +91 265 2434187; fax: +91 265 2418927.
E-mail addresses: rajanimsu@rediffmail.com (R. Giridhar), mryadav11@yahoo.
co.in (M.R. Yadav).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.026

2030
A. Verma et al. / Tetrahedron Letters 54 (2013) 2029–2032
Cu2I2
enolate of 1 with NaH in DMF:dioxane mixture (1:5), treatment
(1.1 equiv)
of sodium enolate with cuprous iodide and transmetallation with
palladium in the presence of microwaves afforded the best results
among all of the tried methods, and the yields improved up to 95%
(Table 2); so it was used as a general method (Method E) for the
rest of the reactions. The microwave irradiation method was well
tolerated by the substituents present on ArBr (2). The coupling of
copper enolate generated by compound (1) occurred in high yield
at 100 °C under microwave irradiation with a variety of aryl bro-
mides, including those with electron-rich, electron-deficient, and
electroneutral groups. Previous studies6b have reported steric hin-
drance in ArBr as a major stumbling block in not offering these hin-
dered products; the microwave-assisted method proved to be a big
success for the sterically hindered products (Table 2, entries 3e, 3f,
3k). It is noteworthy that electron-donating groups in the ortho
and/or para positions increased the yields (Table 2, entries 3d, 3e,
3m) and the presence of an electron-donating group in the meta
position decreased the yield slightly (Table 2, entry 3a). But the
presence of electron-withdrawing groups at meta and para posi-
tions always decreased the yields of the products remarkably (en-
tries 3c, 3h, 3i).
N
Me
ArBr
N
Me
Pd (0)
(1.5 equiv)
Ligand (L)
Base
O
O
(2)
(1)
Ar
(3)
Scheme 1.
a-Arylation of 3-benzazepin-2-one.
A). Reaction proceeded and an arylated product was obtained in
about 25–35% yield (Tables 1 and 2).
In 1979, Orito et al.14 studied and reported
a-alkylation of
N-methyl-3-benzazepin-2-one with the help of sodium hydride
and alkyl halides. In this study NaH emerged as the most appropri-
ate base in different solvents at different temperatures to generate
the enolate ion and improve the yields. To an obvious extension of
this observation to improve the a-arylation yields of our products
BuLi was replaced with NaH as the base. Simultaneously we
worked on the use of different solvents and a mixture of solvents
that were more suitable for the generation of amidic enolate ion.
Best results were obtained with 1:5 ratio of DMF:dioxane mixture
for the generation of enolate ion with NaH (2.5 equiv) as a base at
100 °C. Replacing BuLi with NaH plus Pd2dba3 and Xantphos in
DMF:dioxane (1:5) improved the yields upto 70% for different aryl
halides (Process B) (Table 2). It is noteworthy that much better
yields were obtained with the copper enolate of 1 than with its
lithium or sodium enolates. The formation of the copper enolate
with Cu2I2 is crucial, as the arylated product (2) was not obtained
at all when the reaction was performed in the presence of Cu(II)
acetate in place of Cu2I2. Generation of carbanion also proved very
critical for the reaction as the use of KTB, Cs2CO3, or K2CO3 yielded
back the starting material (1) only even in the presence of cuprous
iodide. To examine the effect of counter ion in alkali metal bases,
LiH and KH were also used apart from NaH for the generation of
enolate ion. The yields of the products were reduced in the case
of LiH but KH was as effective as NaH or slightly better in some
experiments.
The
a-arylation of N-methyl-3-benzazepin-2-one can be ex-
plained by a mechanism similar to the one proposed previously
for the Sonogashira cross-coupling reaction, except that the copper
acetylide is replaced by a copper (I) enolate of the amide (Scheme
2). The active palladium catalyst complex Pd(0)Ln (A) reacts with
the aryl halide in an oxidative addition manner to produce a Pd(II)
intermediate complex (B). In a transmetallation reaction, complex
B reacts with the copper enolate of amide complex (E), which is
produced after quenching of the alkali metal enolate with copper(I)
iodide, to give complex C. Compound E continues to react with the
palladium intermediate B with elimination of the copper(I) halide.
In the final step, complex C undergoes reductive elimination to
produce the 1-aryl-N-methyl-3-benzazepin-2-one, with the regen-
eration of the palladium catalyst.
An interesting observation was made when the reactions were
carried out using aryl bromides having electron withdrawing
groups (Cl, F, CF3) at ortho- position or with highly hindered
2,6-dimethylphenyl bromide. Instead of the normal products, an
abnormal product in low yield was always obtained. The abnormal
The influence of palladium catalyst was also studied. Since
PdCl2 is the most commonly used reagent in Sonogashira reaction,
we thought of using PdCl2 in place of Pd2dba3. To further explore
the reactivity of Pd catalysts, Pd(OAc)2 was also used. Both the cat-
alysts were used in the presence of
L (triphenylphosphine)
product was identified as the a-methylated benzazepinone deriva-
(5.0 mol %) in DMF:dioxane (1:5) mixture at 100 °C. Both of these
catalysts improved the yields but Pd(OAc)2 along with triphenyl-
phosphine offered higher yields especially for the hindered aryl ha-
lides (Table 2).
To widen the scope of the developed method, other aryl halides
like chloro and iodo derivatives were also used (Table 2). Aryl io-
dides yielded the best results while aryl chlorides did not offer
the products at all even for the most reactive substituents (3d
and 3e). Although aryl iodides offer higher yields over the aryl bro-
mides, considering the availability and the cost of aryl halides, bro-
mo derivatives were used in rest of the study.
tive (5). As N,N-dimethylformamide (DMF) along with dioxane was
used as an ideal solvent system for all these reactions, DMF was
suspected to be acting as methyl donor in these reactions. If that
was the case then an equivalent amount of N-methylformamide
(NMF) should have also been formed during the reaction. The reac-
tion mixture after suitable dilution with water was submitted for
HPLC analysis. To our surprise in addition to NMF, formamide
was also detected in the reaction mixture. Formamide, NMF, and
DMF were characterized by their retention times in HPLC analysis
which were further confirmed by spiking the analyte samples with
formamide, NMF, and DMF. Moreover, formamide was existing in a
greater concentration in the reaction mixture than expected. That
means NMF was more actively participating as methyl donor in
the reaction than DMF. To further strengthen this observation a
Since microwave irradiation has been used for improving the
yields of endothermic reactions, it was thought of inducting micro-
waves in this cross coupling reaction. The generation of amidic
Table 1
Processes explored for obtaining products (3)
Process
Conditions
Base (equiv)
Source of energy (rean. temp.)
Rean. time
A
B
C
D
E
BuLi, Pd2dba3 (5 mol %), (L) Xantphos (7.5 mol %)
NaH, Pd2dba3 (5 mol %), (L) Xantphos (7.5 mol %)
NaH, PdCl2 (5 mol %), (L) TPPa (5 mol %)
NaH, Pd(OAc)2 (3 mol %), (L) TPPa (5 mol %)
–do–
BuLi (1.5)
NaH (2.5)
NaH (2.5)
NaH (2.5)
–do–
Mechanical stirring (RT)
24 h
12 h
12 h
8 h
Conventional heating (100 °C)
Conventional heating (100 °C)
Conventional heating (100 °C)
Microwave, 100 W (100 °C)
10–25 min
a
Triphenylphosphine.

A. Verma et al. / Tetrahedron Letters 54 (2013) 2029–2032
2031
Table 2
Processes applied for obtaining the product (3)
N
Me
ArBr
Ar
N
Me
LnPd0
A
Entry
ArBr
Process
Rean. time
Yield (%)
O
NaH
A
B
C
D
E
24 h
12 h
12 h
8 h
10 min
35
58
70
68
86
Br
OMe
Me
O
Ar
(3)
N
Me
L
3a
Pd
L
Br
D
O
Cu2I2
Na
B
A
B
C
D
E
24 h
12 h
12 h
8 h
10 min
31
65
82
80
89
Br
Br
N
O
Me
L
3b
3c
N
Me
C
Pd
E
O
L
Cu
Ar
Cu
Br
A
B
24 h
12 h
12 h
8 h
20 min
25
40
55
60
72
CF3
Scheme 2.
a-Arylation of 3-benzazepin-2-one.
C
D
E
A
E
24 h
10 min
30
93
Br
Cl
Base
Cu2I2
O
H
N
Me
N
Me
N
Me
OMe
OMe
N
3d
Pd (0)
Me
R
(4)
Ligand (L)
Process E
15 Min
O
O
O
Me
Me
Me
E
25
0
(1)
(6)
Traces
(5)
R=Me
R=Me (35% isolated yield)
R=H (70% isolated yield)
R=
A
C
D
E
24 h
12 h
8 h
0
65
70
92
OMe
Br
I
Scheme 3. Mono-/di-alkylation of (1).
25 min
OMe
of product 5 doubled to almost 70%. LC–MS analysis of the reaction
mixture offered another interesting result. -Dimethyl derivative
6 was also detected in the reaction mixture although in trace
3e
E
E
E
E
20 min
25
93
0
a,a
OMe
Me
amounts (Scheme 3).
Cl
Br
Keeping the above discussed observations in mind a plausible
a-methylation of N-methyl-3-benzazepin-2-one
(1) involving DMF and/or NMF as carbon sources is depicted in
mechanism for
Scheme 4.
25 min
25
86
88
In the absence of a reactive aryl bromide the active palladium
catalyst [Pd(0)Ln] complex A activates the otherwise unreactive
DMF in an oxidative addition manner to produce a Pd–DMF com-
3f
Me
I
plex (F). Transfer of
p-electron density in DMF for the formation
of Pd–O bond eliminates one methyl group attached to N-atom
yielding an oxidative addition intermediate (G). In a transmetalla-
tion reaction, complex G reacts with the copper enolate of amide E
to afford complex H expelling the copper enolate (I) of NMF.
Quenching of the reaction mixture with water would obviously af-
Br
3g
3h
3i
E
E
E
15 min
15 min
15 min
93
79
72
Me
F
Br
Br
ford NMF. Complex H would offer the a-methylated product in the
normal reductive elimination step. On the other hand, in the
continuing catalytic process the [Pd(0)Ln] complex A can further
activate the copper enolate I of NMF to form the intermediates J
and K which on further reaction with E can form H by eliminating
L. Formamide would be formed from complex L when the reaction
F
Me
Br
3j
E
15 min
86
mixture is quenched with water. It may be noted that some
a-
Me
methylated 3-benzazepin-2-one (5) can also enter the catalytic
reaction cycle to offer the dimethylated product (6). This is possi-
ble because it has been reported14 that at elevated temperatures a
tertiary carbanion can be formed by abstraction of a proton by the
secondary carbanion through intermolecular reaction. In the case
of copper enolate of NMF (I), insertion between the N–Me bond
by the palladium catalyst seems to be more relevant as the N-atom
in NMF is well exposed unlike DMF wherein N-atom is highly hin-
dered and unapproachable.
Br
Br
3k
3l
E
E
10 min
10 min
93
92
Et
Br
3m
E
10 min
95
To summarize, a rapid and high yielding convenient process for
a
-arylation of 3-benzazepin-2-one has been developed with intro-
duction of Cu(I) as a co-catalyst and microwaves as energy source.
The process offers good to high yields of the -arylated products
a
reaction of compound 1 was performed under exactly the same
conditions as performed previously but in the presence of NMF
(1.5 equiv) and additional (1.5 equiv) quantity of NaH. The yield
using different type of aryl bromides. The aryl bromides possessing
electron withdrawing or donating groups either at para or meta
positions were active enough to offer the desired products.

2032
A. Verma et al. / Tetrahedron Letters 54 (2013) 2029–2032
H
O
Acknowledgments
Me
LnPd0
N
Me
N
Me
The authors thank the Director, SAIF-Division of Panjab
University for their help. Also, A.V thanks AICTE, New Delhi for
his NDF-fellowship.
A
δ+
O
H
L
L
O
Me
R
Pd
N
(5) R=H
(6) R=Me (5, 6)
F
Me
Me
N
Me
Pd
δ−
Supplementary data
H
N
O
L
L
R
H
L
L
O
Supplementary data (experimental procedures and character-
ization data of all the compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.02.026.
Pd
Me
Me
Me
G
H
N
N
Me
ICu2-O
References and notes
Me
N
I
O-Cu2I
R
H
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O-Cu2I
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Electron donors at ortho position of the aryl bromide yielded the
best results by offering highest yields of the desired products.
But hindered aryl bromides or those possessing electron with-
drawing groups at ortho- position offered abnormal a-methylated
product instead of the normal desired products. A plausible mech-
anism for the formation of the abnormal products (monomethylat-
ed and dimethylated) has been discussed.