Efficient synthesis of the 3-benzazepine framework via intramolecular heck reductive cyclization

Article abstract of DOI:10.1021/ol071079g

A microwave-assisted protocol based on reductive Heck reaction was developed for regio- and stereoselective construction of the 3-benzazepine core.

Full text of DOI:10.1021/ol071079g

ORGANIC
LETTERS
2007
Vol. 9, No. 16
3017-3020
Efficient Synthesis of the 3-Benzazepine
Framework via Intramolecular Heck
Reductive Cyclization
Pavel A. Donets and Erik V. Van der Eycken*
Laboratory for Organic & MicrowaVe-Assisted Chemistry (LOMAC), Department of
Chemistry, UniVersity of LeuVen, Celestijnenlaan 200F, B-3001 LeuVen, Belgium
erik.Vandereycken@chem.kuleuVen.be
Received May 9, 2007
ABSTRACT
A microwave-assisted protocol based on reductive Heck reaction was developed for regio- and stereoselective construction of the 3-benzazepine
core.
The 3-benzazepine framework is widespread among natural
compounds and important pharmaceuticals. Considerable
efforts have been made toward the synthesis of alkaloids as
aphanorphine,1 lennoxamine,2 and cephalotaxine3 (Figure 1)
relates to the class of 1-substituted tetrahydro-3-benzazepines
and is a peripheral dopamine D1 receptor agonist.4 The
tetracyclic MK-801 (dizocilpine) represents a noncompetitive
NMDA receptor antagonist and has been extensively studied
for treatment of neurodegenerative diseases such as Hun-
tington’s, Alzheimer’s, and amyotrophic lateral sclerosis.5
Variously substituted at position 1, 3-benzazepine structure
1 has also been studied for the synthesis of potent NMDA
receptor antagonists.6
Most often the construction of the medium-sized ring of
the 3-benzazepine scaffold is achieved via intramolecular
(2) (a) Comins, D. L.; Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95.
(b) Couty, S.; Liegault, B.; Meyer, C.; Cossy, J. Tetrahedron 2006, 62,
3882 and references cited therein.
(3) (a) Worden, S. M.; Mapitse, R.; Hayes, C. J. Tetrahedron Lett. 2002,
43, 6011. (b) Tietze, L. F.; Modi, A. Med. Res. ReV. 2000, 20, 304 and
references cited therein.
Figure 1. Alkaloids containing the 3-benzazepine framework and
(4) (a) Ladd, D. L.; Weinstock, J.; Wise, M.; Gessner, G. W.; Sawyer,
J. L.; Flaim, K. E. J. Med. Chem. 1986, 29, 1904. (b) Weinstock, J.; Ladd,
D. L.; Wilson, J. W.; Brush, C. K.; Yim, N. C. F.; Galladher, G.; McCarthy,
M. E.; Silvestry, J.; Sarau, H. M.; Flaim, K. E.; Ackerman, D. M.; Setler,
P. E.; Tobia, A. J.; Hahn, R. A. J. Med. Chem. 1986, 29, 2315.
(5) (a) Ayala, G. X.; Tapia, R. Eur. J. Neurosci. 2005, 22, 3067. (b)
Kocaeli, H.; Korfali, E.; Ozturk, H.; Kahveci, N.; Yilmazlar, S. Surg. Neurol.
2005, 64, S22. (c) Mukhin, A. G.; Ivanova, S. A.; Knoblach, S. M.; Faden,
A. I. J. Neurotrauma 1997, 14, 651-63.
(6) (a) Krull, O.; Wunsch, B. Bioorg. Med. Chem. 2004, 12, 1439. (b)
Smith, B. M.; Smith, J. M.; Tsai, J. H.; Schultz, J. A.; Gilson, C. A.; Estrada,
S. A.; Chen, R. R.; Park, D. M.; Prieto, E. B.; Gallardo, C. S.; Sengupta,
D.; Thomsen, W. J.; Saldana, H. Z.; Whelan, K. T.; Menzaghi, F.; Webb,
R. R.; Beeley, N. R. A. Bioorg. Med. Chem. Lett. 2005, 15, 1467.
NMDA receptor antagonists.
because of their challenging chemical structures and interest-
ing biological activity. The renal vasodilator fenoldopam
(1) (a) Bower, J. F.; Szeto, P.; Gallagher, T. Chem. Commun. 2005, 5793.
(b) Zhai, H.; Luo, S.; Ye, C.; Ma, Y. J. Org. Chem. 2003, 68, 8268. (c)
Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923. (d) Katoh, M.; Inoue,
H.; Suzuki, A.; Honda, T. Synlett 2005, 18, 2820. (e) Bower, J. F.; Szeto,
P.; Gallagher, T. J. Org. Biomol. Chem. 2007, 5, 143 and references cited
therein.
10.1021/ol071079g CCC: $37.00
© 2007 American Chemical Society
Published on Web 07/03/2007

Friedel-Crafts alkylation.1b-d,5b,7 However, this method
demands an excess of Lewis acid and lacks flexibility for
variation of substituents. Alternatively, ring closure is
accomplished upon formation of the C-N bond via intramo-
lecular reductive amination.6a Intramolecular radical cycliza-
tion was successfully applied for the synthesis of the
7-membered ring in aphanorphine.1a,e Particularly useful for
the syntheses of natural compounds and analogues is the cor-
responding 3-benzazepinone structure, as alkylation allows
further introduction of substituents, for example, giving rise
to bridged structures.1c,d,8
Transition-metal-catalyzed reactions were also used for
generating the 3-benzazepine scaffold. Thus, the Heck
reaction of olefins proved to be high yielding and reliable.3a,b,6b,9
Though this approach regioselectively leads to 7-membered
rings, a problem with the geometry and location of the
resulting double bond still remains, due to the unselective
elimination of palladium-hydrogen species at the final step
of the Heck reaction.1e,3a,9a A regioselective synthesis of
4-substituted 3-benzazepinones via intramolecular hydro-
amidation of the triple bond incorporated in the noncyclic
precursor has also recently been reported.10a,b
ously 3-substituted 2-propynoic acids, deliver the substrates
3 for intramolecular cyclization. Due to the syn-addition to
the triple bond during Heck reaction, our strategy provides
exclusively compounds possessing the Z-conformation of the
exocyclic double bond.
Moreover, the regioselectivity of the Heck reaction and,
as a result, the ring size of the generated medium-sized ring,
is also determined by the mechanism of the reaction. As the
initially generated arylpalladium π-complex 4 is transformed
into a σ-vinyl palladium complex 5 via simultaneous syn-
addition to the triple bond, endocyclization via a hypothetical
intermediate 7 is fairly unlikely due to the high strain exerted
by the trans geometry around the double bond in the
8-membered ring. The Pd(0) catalyst is regenerated with a
reducing agent present in the reaction mixture.
Our first attempts to find optimal conditions for the
reductive Heck reaction (Table 1) were carried out with the
Table 1. Optimization of the Reaction Conditionsa
We have elaborated a new pathway toward the synthesis
of 1-substituted 3-benzazepinones 6, based on a Heck
intramolecular reductive cyclization reaction (Scheme 1).
time
(h)
dilution yield
Scheme 1
entry
solvent (v/v)
catalyst
(mM)
(%)
1
2
3
12
12
3
DME/H2O (4:1) Pd(PPh3)4
DMF/H2O (3:1) Pd(PPh3)4
DMF/H2O (3:1) Pd(PPh3)4
170
170
70
70
70
60
67
80
81
79
4 (MW) 0.25 DMF/H2O (3:1) Pd(PPh3)4
5 (MW) 0.25 DMF/H2O (3:1) Pd(OAc)2 +
2Ph3P
6 (MW) 0.25 DMF/H2O (3:1) Hermann’s
70
81
palladacycle
a Reactions were run on a 0.4 mmol scale of 3a; for entries 1-3, the
mixture was heated at 100 °C (oil bath temperature) in a sealed vial; for
entries 4-6, MW irradiation at 110 °C and 300 W maximum power was
employed.
amide 3a, generated from the corresponding amine and
phenylpropiolic acid chloride. The reaction was run under
conventional heating in the presence of 3 mol % of Pd(PPh3)4
as the catalyst and sodium formate as the reducing agent.
The optimal solvent system for the cyclization was found to
be a DMF/water mixture. In the absence of water the reaction
failed, probably because of the ineffectiveness of the reducing
agent under anhydrous conditions.
Best yields for cyclization were found using high dilution
conditions. The structure of the obtained compound 6a was
fully confirmed with 2D-NMR spectroscopy. The Z-config-
uration of the resulting exocyclic double bond was assigned
on the basis of a NOE effect between the vinylic proton of
the double bond and the neighboring proton of the aryl ring.
Thus, having found appropriate conditions under conven-
tional heating for generating the medium-sized ring of model
compound 6a, we investigated the protocol applying micro-
The sequence starts with the readily available 2-bro-
mophenylethylamines 212a which, after coupling with vari-
(7) (a) Kawase, M.; Motohashi, N.; Niwa, M.; Nozaki, M. Heterocycles
1997, 45, 1121. (b) Weinstein, B.; Craig, A. R. J. Org. Chem. 1976, 41,
875.
(8) Wirt, U.; Frohlich, R.; Wunsch, B. Tetrahedron: Asymmetry 2005,
16, 2199.
(9) (a) Tietze, L.; Schimpf, R. Synthesis 1993, 876. (b) Tietze, L.;
Burkhardt, O.; Henrich, M. Liebigs Ann. 1997, 1407.
(10) (a) Yu, Y.; Stephenson, G. A.; Mitchell, D. Tetrahedron Lett. 2006,
47, 3811. (b) Tsubakiyama, M.; Sato, Y.; Mori, M. Heterocycles 2004, 64,
27.
(11) (a) Herrmann, W. A.; Brossmer, C.; Reisinger, C. P.; Riermeier,
T. H.; Ofele, K.; Beller, M. Chem. Eur. J. 1997, 3, 1357. (b) Herrmann,
W. A.; Brossmer, C.; Ofele, K.; Reisinger, C. P.; Priermeier, T.; Beller,
M.; Fischer, H. Angew. Chem. 1995, 107, 1989. (c) Herrmann, W. A.;
Brossmer, C.; Ofele, K.; Reisinger, C. P.; Priermeier, T.; Beller, M.; Fischer,
H. Angew. Chem., Int. Ed. 1995, 34, 1844.
3018
Org. Lett., Vol. 9, No. 16, 2007

wave irradiation. Experiments were carried out in a multi-
mode Milestone MicroSYNTH microwave reactor in a sealed
vial applying a maximum power level of 300 W. Under these
conditions, the reaction rate was dramatically increased, while
the yield remained satisfactorily high (81%; Table 1, entry
4) using otherwise the same conditions. While the reaction
required 3 h to reach completion upon conventional oil bath
heating, the microwave-assisted cyclization was finished after
a mere 15 min. Switching to other Pd catalysts (Table 1,
entries 5 and 6) as, for example, Pd(OAc)2-Ph3P combina-
tion or Hermann’s palladacycle,11 does not have any impor-
tant effect on the yield or the rate of the reaction. With this
optimized microwave-assisted protocol at hand, we started
to explore the scope and limitations of the procedure by
generating a small library of analogues.
Table 2. Heck Reductive Cyclization of the Amides 3a-oa
yield
(%)
entry
R1
R2
R3
1 (6a)
2 (6b)
3 (6c)
4 (6d)
5 (6e)
6 (6f)
7 (6g)
8 (6h)
9 (6i)
3-MeO, 4-MeO PMB Ph
3-MeO, 4-MeO PMB Me
3-MeO, 4-MeO PMB TMS
81
65
36
77
71
68
61
32
39
53
81
80
61
87
90
3-MeO, 4-MeO PMB p-methoxyphenyl
3-MeO, 4-MeO Me
3-MeO, 4-MeO Me
3-MeO, 4-MeO Me
3-MeO, 4-MeO Me
p-methoxyphenyl
Ph
Me
TMS
A number of propynoic acid amides 3a-o (Scheme 2)
was synthesized using a two-step, one-pot coupling procedure
3-MeO, 4-MeO
H
Ph
10 (6j)
11 (6k)
12 (6l)
13 (6m)
14 (6n)
15 (6o)
3-MeO, 4-MeO
H
Me
n-Pentyl
p-methoxyphenyl
Me
p-methoxyphenyl
3,4,5-trimethoxyphenyl
H
H
H
H
H
Me
Me
Me
i-Pr
i-Pr
Scheme 2
a All reactions were run on a 0.4 mmol scale; for all entries except 3
and 8, Pd(PPh3)4 (3 mol %), HCOONa (1.5 equiv), in 6 mL of solvent
DMF/H2O (3:1), at 110 °C, maximum power 300 W for 15 min. For entries
3 and 8,same conditions as for all other entries with the exception of
HCOONa (3 equiv), solvent DME/H2O (4:1), 120 °C.
of 2-bromophenylethylamines 212a with in situ generated
NHS derivatives of the corresponding 3-substituted propynoic
acids 8.
underwent degradation. However, when the reaction was run
upon microwave irradiation in DME/water (4:1) at a ceiling
temperature of 120 °C, with 3 equiv of sodium formate, the
desired compounds 6c,h could be obtained in 36 and 32%,
respectively (Table 3, entries 3 and 8) next to decomposed
Amides 3a-o were obtained in excellent yields mostly
as 1/1 mixtures of Z/E rotamers. Microwave-assisted cycli-
zation of the substrates 3a-o into the 3-benzazepinones
6a-o proceeded very smoothly with a complete conversion
of the starting material in a mere 15 min (Table 2). The
7-membered ring is formed in good yields with the exception
of compounds 6c,h-j (Table 2, entries 3, 8-10) where a
significant fall of the yield was observed. In the case of the
cyclization of the secondary amides 3i,j (entries 9 and 10),
this could presumably be ascribed to a competitive interaction
of the unprotected nitrogen with Pd in the catalytic inter-
mediate.
However, these 3-benzazepinones 6i,j may be alternatively
prepared in good overall yield using acid-catalyzed PMB
deprotection of the corresponding benzazepines 6a,b (entries
1 and 2).12b
On the other hand, the TMS-propynoic acid amides 3c,h
underwent hydrolysis of the TMS group in 15 min applying
the optimized conditions. The deprotected acetylenes could
be recovered in 75% yield. Unfortunately, during prolonged
reaction time these terminal acetylenes themselves were
found to be unstable under the described conditions and
Table 3. Double-Bond Hydrogenationa
yield
(%)
entry
R1
R2
R3
1 (9a)
2 (9b)
3 (9c)
15 (9d)
3-MeO, 4-MeO PMB Ph
90
96
96
95
3-MeO, 4-MeO Me
Me
Me
H
H
Me
i-Pr
3,4,5-trimethoxyphenyl
a Reactions were run on a 0.3-0.4 mmol scale under H2 atmosphere (1
atm), in 6-10 mL of THF/MeOH (1:1) with 10% Pd/C (5 mol %) at rt for
24 h.
material due to the competitive cleavage of the labile TMS-
protecting group. Attempts to run the reaction with the
terminal acetylenes under anhydrous conditions in DMF
using ammonium formate as the reducing agent,2b resulted
in recovery of the starting material.
(12) See the Supporting Information: (a) synthesized following known
procedures; (b) MW-assisted deprotection in acidic media proceeds with
80-84% yield; (c) synthesized in 75% yield from 2-bromo-4,5-dimethoxy-
cinnamic acid.
(13) Larock, R. C.; Tu, C.; Pace, P. J. Org. Chem. 1998, 63, 6859.
Org. Lett., Vol. 9, No. 16, 2007
3019

In view of generating 1-alkyl-substituted 3-benzazepino-
nes, which further may be reduced5b,8 to the corresponding
3-benzazepines, we explored the reduction of the double bond
of the enones 6a,g,m,o. Hydrogenation over Pd/C in THF/
MeOH (1:1) proceeded smoothly rendering the 1-alkyl-3-
benzazepinones 9a-d in excellent yields after 24 h under
atmospheric pressure of hydrogen (Table 3).
Table 4. Heck Reductive Cyclization of the Amides 10a,ba
To explore the general applicability of our strategy for
the synthesis of medium-sized rings, we evaluated the
protocol for the generation of 8-membered N-containing
rings. Similar tetrahydrobenzo[d]azocine structures have been
previously synthesized via palladium-catalyzed heteroannu-
lation of allenes.13 Howeve, this procedure renders the
compounds as an E/Z mixture of isomers of the exocyclic
double bond. On the contrary, our method should produce
only Z-isomers following the mechanism of ring closure. The
substrates 10a,b bearing an extended alkyl chain were
synthesized starting from [3-(2-bromo-4,5-dimethoxyphenyl)-
propyl]-(4-methoxybenzyl)amine.12c Applying our microwave-
assisted protocol cyclization of 10a,b occurred in 35 and
55% respectively next to the partial decomposition of the
starting material. As expected, the compounds were isolated
as single Z-isomers 11a,b (Table 4). The lower yields could
probably be ascribed to the higher conformational freedom
of the starting amides 10a,b.
entry
R3
yield (%)
1 (11a)
2 (11b)
Me
Ph
55
35
a Reactions were run on a 0.4 mmol scale in 6 mL of DMF/H2O (3:1)
under MW irradiation at 110 °C and 300 W maximum power for 15 min.
this strategy for the synthesis of some benzazepine alkaloids
and analogues is under current investigation.
Acknowledgment. We thank the F.W.O. [Fund for
Scientific Research - Flanders (Belgium)] and the Research
Fund of the University of Leuven for financial support to
the laboratory.
Supporting Information Available: Spectroscopic data
for all new compounds prepared, as well as detailed
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
In summary, we have developed an efficient new proce-
dure for the synthesis of 1-substituted 3-benzazepinones. The
medium-sized ring is constructed applying a microwave-
assisted reductive intramolecular Heck reaction, which occurs
with full regio- and stereoselectivity. The applicability of
OL071079G
3020
Org. Lett., Vol. 9, No. 16, 2007