A regioselective synthesis of 3-benzazepinones via intramolecular hydroamidation of acetylenes

Article abstract of DOI:10.1016/j.tetlet.2006.03.198

Synthesis of 3-benzazepinones by palladium-catalyzed intramolecular addition of amides to alkynes is achieved. Phenyl acetylenes substituted in the ortho-position with tethered amide functionality were prepared in a few steps from readily available starti

Full text of DOI:10.1016/j.tetlet.2006.03.198

Tetrahedron Letters 47 (2006) 3811–3814
A regioselective synthesis of 3-benzazepinones via intramolecular
hydroamidation of acetylenes
Ying Yu, Gregory A. Stephenson and David Mitchell*
Chemical Product R&D, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 8 February 2006; revised 30 March 2006; accepted 31 March 2006
Available online 27 April 2006
Abstract—Synthesis of 3-benzazepinones by palladium-catalyzed intramolecular addition of amides to alkynes is achieved. Phenyl
acetylenes substituted in the ortho-position with tethered amide functionality were prepared in a few steps from readily available
starting materials. It was found that 5% Pd(OAc)2(PPh3)2 and KOH most effectively promoted cyclization. When the tethered group
is an acetamide and an alkyl substituent is on the acetylene unit, regioselective 3-benzazepinone synthesis could be achieved in good
yields.
Ó 2006 Elsevier Ltd. All rights reserved.
The benzazepine framework is frequently found in
important pharmaceuticals. In particular, the 3-benzaze-
pines exhibit biological activities related to their more
popular benzodiazepines.1 Each molecule presents
unique challenges for the seven-membered nitrogen
heterocyclic ring formation, especially in large scales.
For example, a common approach centers on lactam
formation using ammonium salts or Friedel–Crafts
alkylation.2 However, during our course of study, a
large excess of strong acids or Lewis acids was required
for the cyclization, which led to problematic workup
and hazardous waste generation.
tion such as pyrroles, indoles and isoindoles;3 however,
few applications have been reported on synthesizing
seven-membered ring analogs.4 We were also interested
in the potential regioselectivity of such a transformation
by examining catalyst and reaction conditions. As
depicted in Scheme 1, an endo addition of amide to
alkyne would provide benzazepinone (path a). An exo
addition (path b) would lead to isoquinolinone. Herein,
we report the development and general synthesis of
3-benzazepinone via palladium catalyzed addition of
tethered amides to phenyl acetylenes.
The requisite 2-alkynyl benzeneacetamides were
obtained by amidation of commercially available 2-iodo
phenylacetic acid followed by Sonogashira coupling5
with terminal alkynes. As shown in Scheme 2, benzene-
acetamides with different alkynyl and N-substitutions
were obtained in good yields after a single crystallization.
Our investigation of 3-benzazepinone synthesis involved
a metal catalyzed amide heteroannulation reaction of
acetylene for the ring construction. This strategy for
intramolecular nitrogen heterocyclic ring formation is
common for both five- and six-membered ring forma-
O
MLn
O
R
R
or
N
H
b
N
H
O
MLn
O
N
R
N
a
R
R'
R'
R'
R'
path a
path b
Scheme 1. endo and exo hydroamidation of alkynes.
*
Corresponding author. Tel.: +1 317 276 1384; fax: +1 317 276 4507; e-mail: dmit@lilly.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.198

3812
Y. Yu et al. / Tetrahedron Letters 47 (2006) 3811–3814
R
4: R=n-Bu, R'=Me, 72%
5: R=n-Bu, R'=Ph, 71%
6: R=n-Bu, R'=H, 82%
7: R=CH2OMe, R'=Me, 72%
8: R=CH2CH(CH3)2, R'=Me, 75%
9: R=(CH2)3CO2Me, R'=Me, 78%
10: R=SiMe3, R'=Me, 70%
11: R=Ph, R'=Me, 76%
I
1. SOCl2, 40 oC, 2 h
I
H
R
2. R'NH2, EtOAc
5% Pd(PPh3)2(OAc)2,
10% CuI, Et3N,
K2CO3/H2O, rt, 1 h
O
OH
O
NHR'
55 oC, 5~16 h
O
NHR'
1: R'=Me, 96%
2: R'=Ph, 97%
3: R'=H, 91%
Scheme 2. Synthesis of o-alkynyl benzeneacetamides.
In pursuing the desired nucleophilic addition of amide
to the triple bond in o-alkynyl benzeneacetamides, we
reasoned that the activation of both the triple bond
and the amide proton might be essential. Exploration
of benzazepinone formation was probed by heating o-
(1-hexynyl)-N-methyl benzeneacetamide (4), a base and
a metal additive in DMF for 16 h. As shown in Table
basicity would also lead to fast deprotonation of the
benzylic position and formation of five-membered ring
indene byproduct in moderate yields. A Pd catalyst
would facilitate the hydroamidation process;10 there-
fore, a weaker base could be utilized and the formation
of indene byproduct was minimized.
6
1, bases such as Et3N, Cs2CO3, and LiN(TMS)2 failed
Further optimization of the reaction conditions showed
that Pd(PPh3)2(OAc)2, Pd(PPh3)2Cl2, and Pd(Ph-
CN)2Cl2 were superior than Pd(OAc)2. Although both
Pd(II) and Pd(0) have been reported as efficient in cata-
lyzing hydroamidation/amination of acetylenes, in our
cases Pd2dba3 was not effective.11 The optimal condition
was found to be DMF or DMA as solvent at 50–60 °C.
Solvents such as THF, DMSO, acetonitrile and toluene
resulted in lower yields. Benzazepinone 12 was obtained
to provide any desired product (entries 1–3). Alternate
basic conditions involving NaOH or KOH afforded
the desired seven-membered ring compound 1,3-dihy-
dro-3-methyl-4-butyl-2H-3-benzazepin-2-one 12 in low
yields (entries 4–6). An indene compound 13 was identi-
fied as a byproduct, generated from the nucleophilic
addition of the benzylic CH2 to the triple bond followed
by isomerization.7 In the case of KO(t-Bu) as base, the
yield of 13 was comparable with benzazepinone 12 (en-
try 6). Metal additives Cu(OTf)2, AgOTf and ZnCl2
were applied thereafter along with KOH for the activa-
tion of the triple bond as Lewis acids.8 However, 12 was
still obtained in <40% yield (entries 7–9). Fortunately,
the yield of 12 was improved to >80% with ꢀ5%
byproduct 13 in the presence of KOH or NaOEt and
5% Pd(OAc)2(PPh3)2 (entries 10–11). The above obser-
vations indicated that hydroamidation of acetylene
could be achieved by using strong bases which would
directly deprotonate the amide proton;9 however, high
1
as a white crystalline solid and its H NMR spectrum
exhibited certain unique characters: a singlet for the ole-
fin proton (H-5) at 6.5 ppm and two broad peaks for the
benzylic CH2.12 Interestingly, hydroamidation of the tri-
ple bond occurred exclusively at the endo position in the
cyclization of benzeneacetamide 4 and no 6-exo product
was observed.
The methodology has been successfully applied in syn-
thesizing various 4-alkyl-2H-3-benzazepin-2-one com-
pounds. As illustrated in Table 2, benzazepinones with
Table 1. Formation of benzazepinone 12 from benzeneacetamide 4
5% catalyst, base
DMF, 60 oC, 16 h
+
N
Me
O
NHMe
O
O
NHMe
4
13
12
Entry
Catalyst
Base (equiv)
Recovered 4a (%)
12a (%)
13a (%)
1
2
3
4
5
6
7
8
9
None
None
None
None
None
None
Cu(OTf)2
AgOTf
ZnCl2
Pd(PPh3)2(OAc)2
Pd(PPh3)2(OAc)2
Et3N (2)
100
100
Traceb
75
62
0
58
64
57
Trace
0b
0
0
0
0
0
0
Cs2CO3 (2)
LiN(TMS)2 (1)
NaOH (2)
KOH (2)
KO(t-Bu) (1)
KOH (2)
KOH (2)
KOH (2)
KOH (2)
NaOEt (2)
20
35
55
34
30
38
82c
80c
Trace
Trace
45
4
Trace
0
6
5
10
11
a LC/MS yield.
b Decomposition observed.
c Isolated yield.

Y. Yu et al. / Tetrahedron Letters 47 (2006) 3811–3814
3813
Table 2. Synthesis of 4-alkyl-2H-3-benzazepin-2-ones from o-alkynyl benzeneacetamides
R
R
cat. Pd, base, DMF
N R'
O
NHR'
4-10
Conditions
O
Entry
1
Benzeneacetamide
3-Benzazepin-2-one (isolated yield)
4
5% Pd(OAc)2(PPh3)2, 2 equiv KOH, DMF, 60 °C, 16 h
N Me
O
12 (82%)
2
3
5
6
5% Pd(OAc)2(PPh3)2, 2 equiv KOH, DMF, 50 °C, 48 h
5% Pd(PhCN)2Cl2, 2 equiv NaH, DMF, 80 °C, 18 h
N
Ph
O
14 (61%)
15 (55%)
16 (42%)
N
H
O
OMe
N Me
O
4
5
7
8
5% Pd(OAc)2(PPh3)2, 1.2 equiv KOH, DMF, 55 °C, 15 h
5% Pd(OAc)2(PPh3)2, 3 equiv KOH, DMF, 60 °C, 16 h
N Me
O
17 (80%)
(CH2)3CO2Me
N Me
6
7
9
5% Pd(OAc)2(PPh3)2, 2 equiv NaOEt, DMF, 50 °C, 16 h;
then MeI, K2CO3, rt, 2 h
O
18 (71%)
10
5% Pd(OAc)2(PPh3)2, 2 equiv KOH, DMF, 50 °C, 4 h
— (Decomposition)
N-methyl, N-phenyl, and N-hydrogen substitutions
could all be synthesized in good yields. It is noted that
lower yields were obtained with N-Ph and N-H substitu-
tions (entries 2–3) due to weaker nucleophilicity of
amide substrates, and neither high temperature nor
strong basicity could improve the yields. Moderate yield
of 16 was obtained due to elimination of methyl propar-
gyl ether substrate in compound 7 (entry 4). Unfortu-
nately, cyclization of TMS-ethynyl benzeneacetamide
10 under the same condition was not successful and only
decomposition products were observed (entry 7).13
6.56 ppm (Z-isomer) and 6.41 (E-isomer) ppm for olefin
H, 2.93 ppm (Z-isomer) and 3.38 ppm (E-isomer) for
N-CH3 substitution (Scheme 3).15 However, 19 was
not stable and converted into multiple compounds upon
standing at room temperature.16 The formation of 6-exo
cyclization product supports the assumption that the
5% Pd(PPh3)2(OAc)2,
H
1.5 equiv NaH,
DMF, 60 oC, 5 h
Me
O
N
On the other hand, heating phenylethynyl benzeneacet-
amide 11 with 1.5 equiv NaH and 5% Pd(PPh3)2(OAc)2
in DMF at 60 °C gave 6-exo cyclization product 3-iso-
quinolinone derivative.14 1H NMR spectrum indicated
that the cyclization first yielded 19 as a mixture of E
and Z isomers: singlet of benzylic CH2 at 3.74 ppm,
O
NHMe
11
19, E and Z
based on 1H NMR
Scheme 3. Formation of isoquinolinone 19.

3814
Y. Yu et al. / Tetrahedron Letters 47 (2006) 3811–3814
Hayashi, Y.; Shoji, M.; Yamaguchi, J.; Sato, K.; Yama-
guchi, S.; Mukaiyama, T.; Sakai, K.; Asami, Y.; Kakeya,
H.; Osada, H. J. Am. Chem. Soc. 2002, 124, 12078.
10. For examples of Pd-catalyzed hydroamidation of alkynes,
see Ref. 4 and (a) Khan, M. W.; Kundu, N. G. Synlett
1997, 1435; (b) Sashida, H.; Kawamukai, A. Synthesis
1999, 7, 1145; (c) Karstens, W. F. J.; Stol, M.; Rutjes, F. P.
J. T.; Kooijman, H.; Spek, A. L.; Hiemstra, H. J.
Organomet. Chem. 2001, 624, 244; (d) Kozawa, Y.; Mori,
M. J. Org. Chem. 2003, 68, 8068.
cyclization is electronically oriented by the acetylene
substrate.17
In summary, the synthesis of 3-benzazepinones has been
achieved from the palladium-catalyzed intramolecular
addition of amides to alkynes. Optimum conditions
were developed for the preparation of 3-benzazepinones.
It has been found that the regioselective transformation
is dependent on the amide, alkyne substitution or reac-
tion conditions. The utilization of this methodology in
the synthesis of isoquinolinones and indenes is currently
being explored.
11. Heating compound 4, 2 equiv KOH and 2.5% Pd2dba3 in
DMF at 60 °C for 16 h gave 12 in 32% LC/MS yield.
Usage of ligand dppb could improve the yield of 12 to
ꢀ60%.
12. General procedure for benzazepinone synthesis: 1.15 g
2-(1-hexynyl)-N-methyl benzeneacetamide
4 (5 mmol),
Acknowledgments
0.19 g Pd(OAc)2(PPh3)2 (0.25 mmol) and 0.66 g KOH
(10 mmol) were added to a flask and purged with N2.
25 mL DMF was then added and the mixture was stirred
at 50 °C for 16 h. The reaction mixture was concentrated
and the residue was partitioned between EtOAc and H2O.
EtOAc layer was washed with brine and dried with
MgSO4. The residue after evaporation was subjected to
silica gel plug chromatography (hexane–EtOAc = 1:1) to
give 1,3-dihydro-3-methyl-4-butyl-2H-3-benzazepin-2-one
12 as an off-white solid in 82% yield (0.94 g). Mp 57–
We would like to thank the LRL Physical Chemistry
Department and Dr. Thomas Zennie, for obtaining ana-
lytical data. Y.Y. gratefully acknowledges the CPR&D
management, for a postdoctoral fellowship in support
of this work.
1
References and notes
58 °C. H NMR (300 MHz, CDCl3) d 7.23–7.34 (m, 4H),
6.5 (s, 1H), 3.65 (br s, 1H), 3.44 (br s, 1H), 3.09 (s, 3H),
2.64 (br s, 1H), 2.44 (br s, 1H), 1.42–1.57 (m, 4H), 0.99 (t,
J = 7.2, 3H). 13C NMR (100 MHz, CDCl3) d 169.7, 142.5,
133.8, 133.2, 128.2, 128.1, 127.0, 126.8, 118.0, 43.0, 35.1,
31.8, 30.5, 22.2, 13.8. IR (KBr, cmÀ1): 2949, 2926, 2868,
1657, 1419, 1349, 1329, 1078, 931, 849, 765, 582. Anal.
Calcd for C15H19NO (MW 229.15): C, 78.56; H, 8.35; N,
6.11. Found: C, 78.49; H, 8.23; N, 6.17. N-Methyl 2-butyl-
3-indenecarboxamide 13 was isolated as a white solid. Mp
135–136 °C. 1H NMR (300 MHz, CDCl3) d 7.44 (d,
J = 7.8, 1H), 7.39 (d, J = 7.2, 1H), 7.27 (t, J = 7.5, 1H),
7.16 (t, J = 7.5, 1H), 5.77 (br s, 1H), 3.42 (s, 2H), 3.02 (d,
J = 4.5, 3H), 2.70 (t, J = 7.8, 2H), 1.53–1.63 (m, 2H), 1.38
(sext, J = 7.5, 2H), 0.93 (t, J = 7.5, 3H). 13C NMR
(75 MHz, CDCl3) d 166.8, 152.5, 143.2, 142.1, 134.5,
126.7, 124.8, 123.8, 120.0, 41.3, 32.1, 29.5, 26.4, 22.9, 14.1.
IR (KBr, cmÀ1): 3289, 2953, 2871, 1639, 1589, 1543, 1406,
1380, 1260, 1155, 945, 756, 709. Anal. Calcd for
C15H19NO (MW 229.15): C, 78.56; H, 8.35; N, 6.11.
Found: C, 78.61; H, 8.28; N, 6.06.
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13. The corresponding desilylated acetylene did not give any
benzazepinone product either.
14. It should be noted that heating NaH in DMF should be
handled with care because of safety issues. Thanks to a
reviewer’s suggestion to add this note.
15. The structure was proposed based on the reported data of
analogous compounds (Kubo, Y.; Suto, M.; Tojo, S.;
Araki, T. J. Chem. Soc., Perkin Trans. 1 1986, 771), 1-
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´
7. The structure of compound 13 was confirmed by NOE
NMR experiments.
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Vyas, D. M. Tetrahedron Lett. 1995, 36, 7841; (b) Hiroya,
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9. Amide proton pKa = 17 (March, J. Advanced Organic
Chemistry, 4th ed; 1992; pp 250–252). A base as strong as
NaH could promote direct hydroamidation of alkyne (a)
Nagarajan, A.; Balasubramanian, T. R. Indian J. Chem.,
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benzyl-2H-isoquinolin-3-one (Canepa, A. S.; Bravo, R. D.
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16. No further purification of the mixture was performed.
Possible subsequent reactions with 19 include tautomeri-
zation, oxidation, and dimerization.
17. Heating 2-[1-(4-methoxyphenyl)ethynyl]-N-methyl benzene-
acetamide with NaH in DMF at 60 °C; however, gave
6-exo cyclization products as well.