Synthesis of 4-azepanones and heteroaromatic-fused azepines

Article abstract of DOI:10.1016/j.tetlet.2011.11.129

Two syntheses of versatile intermediate azepinones 2 and 3 are described. A 6-step intramolecular Dieckmann cyclization and decarboxylation led to the intermediate 3 while an alternate 4-step synthesis of 2 was developed and used for scale-up. The highlight of the second synthesis is the one-step per-bromination/elimination protocol from readily available azepinone 13a to provide a versatile scaffold in vinyl bromide 5, which enables SAR around the aryl moiety. An example of the elaboration of the intermediate 2 toward a heteroaryl azepinone is also described.

Full text of DOI:10.1016/j.tetlet.2011.11.129

Tetrahedron Letters 53 (2012) 723–725
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 4-azepanones and heteroaromatic-fused azepines
Subas M. Sakya a, , Andrew C. Flick a, , Jotham W. Coe a, David L. Gray a, Sidney Liang a, Fabiola Ferri b,
⇑
⇑
Michel Van Den Berg b, Kees Pouwer b
a Pfizer Global Research & Development, Neurosciences Discovery Chemistry, Eastern Point Rd., Groton, CT 06340, USA
b Syncom BV, Kadijk, 9747AT Groningen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
Two syntheses of versatile intermediate azepinones 2 and 3 are described. A 6-step intramolecular Die-
ckmann cyclization and decarboxylation led to the intermediate 3 while an alternate 4-step synthesis of 2
was developed and used for scale-up. The highlight of the second synthesis is the one-step per-bromin-
ation/elimination protocol from readily available azepinone 13a to provide a versatile scaffold in vinyl
bromide 5, which enables SAR around the aryl moiety. An example of the elaboration of the intermediate
2 toward a heteroaryl azepinone is also described.
Received 12 November 2011
Accepted 23 November 2011
Available online 3 December 2011
Keywords:
Benzazepines
Dieckmann condensation
Suzuki coupling
Perbromination
Azepanone
Ó 2011 Elsevier Ltd. All rights reserved.
Azepine
Azepinone
Introduction
densation of an a,x
-diester.5 Condensation of methyl-2-phenylac-
etate (6, Scheme 1) with formaldehyde under basic conditions gave
methacrylate 7 in a 70% yield as reported.6 Exposure of Michael
acceptor 7 to benzylamine in methanol afforded aminoester 8.
Pharmacologically relevant benzo-fused heterocycles are
known in the literature for both exploratory and approved thera-
peutic agents.1 For example SKF-38393 (Fig. 1) has been exten-
sively studied for its potential to ameliorate positive and
negative symptoms of schizophrenia in preclinical models.2 A clo-
sely related compound Fenoldopam, a partial agonist of peripheral
HO
D1 receptors—gained approval as
a
treatment of severe
hypertension.3
HO
HO
HO
HO
NH
As such, benzazepines represent a promising platform for the
development of novel bioactive compounds. Although fused
hetero-benzazepines have been widely studied and their syntheses
well-documented,4 to our knowledge no 3-substituted heteroaryl
azepines have been described thus far (1, Fig. 2). We postulated
that general structures 1 could be constructed via azepinones 2
or 3, in turn derived from 4 or 5. We describe our efforts to prepare
2 and 3 en route to 3-substituted hetero-benzazepines.
NH
Cl
SKF-38393
Fenoldopam
Figure 1. Representative neuroactive benzazepines.
O
RO
1st Gen
2nd Gen
N
OR
Results and discussion
O
Boc Ph
4
Our first generation approach to hetero-benzazepines involved
modification of a known route to azepinone 3 via Dieckmann con-
3
O
R
Br
(N)
NBoc
NH
O
NBoc
1
2; R = CO2Et
EtO2C
⇑
Corresponding authors. Tel.: +1 860 715 0425; fax: +1 860 715 7312 (S.M.S.);
tel.: +1 860 715 0228 (A.C.F.).
Hetero-benzazepine
3
; R = H
5
E-mail addresses: subas.m.sakya@pfizer.com (S.M. Sakya), andrew.flick@pfizer.
com (A.C. Flick).
Figure 2. Approach to hetero-benzazepines via azepinones 6 and 7.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.129

724
S. M. Sakya et al. / Tetrahedron Letters 53 (2012) 723–725
O
O
O
O
O
O
Ph
N
Ph
N
Ph
Ph
CO2Me
Ph
O
O
O
Ph
O
MeO2C
b
a
c
b
a
O
R
Boc
Ph
+
Ph
O
O
Bn
25%
N
H
N
N
N
O
O
(from 10)
Boc
Boc
11a
Boc
O
O
10
11
3
6
7
8
9; R = Bn
d
10; R = Boc
Scheme 2. Reagents and conditions: (a) LHMDS, À78 °C to rt; (b) K2CO3, aq THF,
80 °C, 25% (two steps).
Scheme 1. Reagents and conditions: (a) 30% aq formaldehyde, K2CO3, cat TBAI,
DMF, 80 °C, 70%; (b) BnNH2, MeOH, rt, 67%; (c) methyl 4-bromobutanoate, K2CO3,
cat KI, dioxane, 100 °C, 4 days, 70%; (d) H2, Pd(OH)2, Boc2O, EtOH, 90%.
O
O
O
O
Br
CO2Et
CO2Et
CO2Et
Br
Br
Br
c
a
b
Subsequent alkylation with methyl-4-bromobutanoate gave dies-
ter 9. With an aim to accelerate Dieckmann cyclization rates
through Thorpe-Ingold interactions while reducing retro-Michael
derived by-products, we converted to the t-butoxy carbamate
group as N-substitution.7 Hydrogenolytic debenzylation in the
presence of Boc-anhydride converted amine 9 directly to the key
cyclization precursor 10, furnishing the Dieckmann substrate in a
27% overall yield from 6.
N
R
N
R
N
R
N
Boc
12a
13a
14a
5
; R = Boc
; R = Boc
; Boc
12b; R = Troc
13b; R = Troc
14b; Troc
Scheme 3. Reagents and conditions: (a) ethyl diazoacetate, BF3ÁOEt2, Et2O, À25 to
0 °C (12a, 90%; 12b, 84%); (b) 3 equiv NBS, 11 mol % NH2OAc, CCl4, h
m, reflux; (c) aq
Na2S2O3, EtOH, rt, (20–25% from 13).
After considerable optimization, we found that LHMDS-induced
cyclization of carbamate 10 at low temperatures followed by
immediate potassium carbonate-promoted decarboxylation deliv-
ered azepinone 3 in reproducible purities and yields as shown in
Scheme 2. Although both intermediate ketoesters 11 and 11a were
detected in crude reaction mixtures by mass spectrometry (accom-
panied by several by-products), attempts to purify either of these
compounds failed as these keto-esters were not stable to silica
chromatography. We presume retro-Michael products formed
and may be responsible for diminished yields of 3 from 10 (25%).
With yields comparable to Dahmann (28%), we proceeded with this
result.5
O
O
O
CO2Et
CO2Et
Ph
R
Ph
b
c
N
Boc
3
N
N
Boc
Boc
5; R = Br
15; R = Ph
2
a
Scheme 4. Reagents and conditions: (a) PhB(OH)2, Pd(PPh3)4, Na2CO3, tol/EtOH/
H2O, reflux, ꢀ69% to 74%; (b) H2, 1 atm, Pd/C, MeOH, 78%; (c) NaOH, EtOH, reflux,
99%.
Although this route (Schemes 1 and 2) delivered synthetically
useful quantities of azepinone 3, the approach suffered from low
yields and an early commitment to the 3-position substituent
(Fig. 2). This compromised the route’s utility, prompting develop-
ment of an alternate and more versatile route to intermediates 2
and 3. Starting with commercial 4-piperidones 12a and 12b
(Scheme 3), Lewis acid-catalyzed ring expansion with ethyl diazo-
acetate furnished the 3-unsubstituted azepinone core in a 90%
yield (13) irrespective of the protecting group.8,9
Perbromination of either azepinone 13a or 13b with 3 equiv of
N-bromosuccinimide (NBS) and catalytic ammonium acetate in
refluxing CCl4 under a 300 W lamp provided the putative tribro-
mide intermediates 14. Although detected by mass spec analysis
of crude reactions, these transient materials were unstable to puri-
fication conditions.10 For the N-Boc protected material derived
from 13a, workup with sodium thiosulfate in aqueous ethanol pre-
sumably induced bromide reduction and elimination of hydrobro-
mic acid to provide the desired vinylogous amide 5.11 This
sequence reproducibly constructed the desired enaminoketone in
ꢀ20% to 25% yield for both steps. Purification of vinyl bromide 5
was straightforward enabling production of 100 g quantities of this
intermediate as described. Conversion of the Troc-protected (2,2,2-
trichloroethoxycarbonyl) substrate 13b to the corresponding vinyl
bromide (e.g., 5) failed, possibly due to competitive dehalogenation
reactions, and this protecting group was no longer studied.
Assembly of an aryl substituent onto enone 5 (Scheme 4) was
accomplished via Suzuki coupling as exemplified by the conversion
of 5 to styrene 15.
Hydrogenation of olefin 15 gave the ketoester intermediate 2 in
a 78% yield, which was accompanied by a readily separable by-
product arising from over-reduction of ketone 2 to the correspond-
ing alcohol (<10%). Base-induced decarboxylation of 2 furnished
3-substituted azepinone 3 in near-quantitative yield. This route
Figure 3. ORTEP representation of crystalline intermediate 2.
(Schemes 3 and 4) provided the key hetero-benzazepine precursor
3 on 50 g scale.

S. M. Sakya et al. / Tetrahedron Letters 53 (2012) 723–725
725
Bailey, J. M.; Scott, J. S.; Basilla, J. B.; Bolton, V. J.; Boyfield, I.; Evans, D. G.;
Fleury, E.; Heightman, T. D.; Jarvie, E. M.; Lawless, K.; Matthews, K. L.; McKay,
F.; Mok, H.; Muir, A.; Orlek, B. S.; Sanger, G. J.; Stemp, G.; Stevens, A. J.;
Thompson, M.; Ward, J.; Vaidya, K.; Westaway, S. M. Bioorg. Med. Chem. Lett.
2009, 19, 6452–6458; (c) Brioni Jorge, D.; Esbenshade, T. A.; Garrison, T. R.;
Bitner, S. R.; Cowart, M. D. J. Pharmacol. Exp. Ther. 2011, 336, 38–46; (d) Coe, J.
W.; Rollema, H.; O’Neill, B. T. Ann. Rep. Med. Chem. 2009, 336, 71–101; (e) Ghali
Jalal, K.; Hamad, B.; Yasothan, U.; Kirkpatrick, P.; Tolvaptan Nat. Rev. Drug Disc.
2009, 8, 611–612; (f) O’Neill, M. J.; Astles, P.; Dell, C. P.; Keenan, M.; Murray, T.
K.; Lakics, V.; Visanji, N. P.; Duty, S. Med. Chem. Rev. Online 2005, 2, 455–470; (g)
Zhao, H.; Guo, Z. Drug Discovery Today 2009, 14, 516–522; (h) Zhen, X.;
Goswami, S.; Friedman, E. Pharmacol. Biochem. Behav. 2005, 80,
597–601.
O
N
O
Ph
Ph
Ph
a
b
HO
NC
N
N
Boc
N
N
Boc
Boc
3
16
17
Scheme 5. Reagents and conditions: (a) (CH3)3COCH(N(CH3)2)2, DME, 65 °C, 99%;
(b) 2-cyanoacetamide, NaOMe, DMF, 70 °C, 21%.
A single crystal X-ray structure of compound 2 confirmed our
NMR characterization, with the expected diequatorial anti-3,5-
phenyl-ester stereorelationship (Fig. 3).
2. (a) Al-Fulaij, M. A.; Ren, Y.; Beinborn, M.; Kopin, A. S. J. Mol. Neurosci. 2008, 34,
211–223; (b) Dall’Olio, R.; Gandolfi, O.; Gaggi, R. Behav. Pharmacol. 2000, 11,
29–36; (c) Fletcher, P. J.; Tenn, C. C.; Rizos, Z.; Lovic, V.; Kapur, S.
Psychopharmacology (Berlin, Germany) 2005, 183, 190–200; (d) Lambe, E. K.;
Aghajanian, G. K. Neuroscience (San Diego, CA, United States) 2007, 145, 900–
910; (e) Mamelak, M.; Chiu, S.; Mishra, R. K. Eur. J. Pharmacol. 1993, 233, 175–
176; (f) McLean, S. L.; Idris, N. F.; Woolley, M. L.; Neill, J. C. Eur.
Neuropsychopharmacol. 2009, 19, 440–450; (g) Rosengarten, H.; Bartoszyk, G.
D.; Quartermain, D.; Lin, Y. Prog. Neuropsychopharmacol. Biol. Psych. 2006, 30,
273–279; (h) Zhang, L.; Yang, H.; Zhao, H.; Zhao, C. Neurochem. Int. 2011, 58,
281–294.
3. (a) Monnier, Le.; de Gouville, A. C.; Lawson, K.; Thiry, C.; Cavero, I. J. Pharmacol.
Exp. Ther. 1991, 256, 1049–1056; (b) Polakowski, J. S.; Segreti, J. A.; Cox, B. F.;
Hsieh, G. C.; Kolasa, T.; Moreland, R. B.; Brioni, J. D. Clin. Exp. Pharmacol. Phys.
2004, 31, 837–841; (c) Weinstock, J.; Ladd, D. L.; Wilson, J. W.; Brush, C. K.; Yim,
N. C.; Gallagher, G., Jr.; McCarthy, M. E.; Silvestri, J.; Sarau, H. M.; Flaim, K. E. J.
Med. Chem. 1986, 29, 2315–2325.
4. For reviews, see: (a) Kunick, C. Curr. Pharm. Des. 1999, 5, 181–194; (b)
McCarthy, K. E. Curr. Pharm. Des. 2000, 6, 1057–1083; (c) Meigh, J. P. K. Sci.
Synth. 2004, 17, 825–927; (d) Sano, T. Trends Heterocycl. Chem. 2001, 7, 117–
142; (e) Tymoshenko, D. O. Adv. Heterocycl. Chem. 2008, 96, 1–80.
5. Dahmann, G.; Himmelsbach, F.; Wittneben, H.; Pautsch, A.; Prokopowicz, A. S.;
Krist, B.; Schnapp, G.; Steegmaier, M.; Lenter, M.; Schoop, A.; Steurer, S.;
Spevak, W. 2002-EP11453 2003032997, 20021014., 2003.
Ketone
3 was used successfully to furnish a variety of
heteroaromatic-fused benzazepine derivatives (e.g., 1) for screen-
ing purposes, and one such reaction sequence is described in
Scheme 5. Condensation of 3 with Brederick’s reagent (tert-butoxy
bis(dimethylamino)methane) in warm DME gave enaminone 16,
which was subsequently treated with cyanoacetimide under basic
conditions to furnish pyridoazepine 17 in modest overall yield
(ꢀ21% from 3).
In conclusion, two distinct synthetic routes to azepinones 2 and
3 were developed, and these key intermediates were further elab-
orated to novel 3-aryl substituted fused heterocyclic benzazapines.
An in situ per-bromination/debromination of azepinone ketoester
13a generated vinyl bromide 5, a versatile intermediate for the
construction of hetereoazepinones such as 17. This route enabled
late-stage exploration around the 3-aryl group giving access to
additional heteroaromatic variants bearing structural similarities
to known bioactive phenylbenzazepines.
6. (a) Felpin, F.-X.; Miqueu, K.; Sotiropoulos, J.-M.; Fouquet, E.; Ibarguren, O.;
Laudien, J. Chem. -A Eur. J. 2010, 16, 5191–5204; (b) Grosjean, C.; Novakovic, K.;
Scott, S. K.; Whiting, A.; Willis, M. J.; Wright, A. R. J. Mol. Catal. A: Chem. 2008,
284, 33–39.
Acknowledgments
7. (a) Agami, C.; Couty, F.; Hamon, L.; Venier, O. Tetrahedron Lett. 1993, 34, 4509–
4512; (b) Agami, C.; Couty, F.; Hamon, L.; Venier, O. Bull. Soc. Chim. Fr. 1995,
132, 808–814.
8. (a) Roglans, A.; Marquet, J.; Moreno-Manas, M. Synth. Commun. 1992, 22, 1249;
(b) Finery, C. G.; Riley, T. N. J. Med. Chem. 1980, 23, 895.
We are grateful to Mark Bundesmann for HPLC studies on the
Troc bromination product, Brian Samas for X-ray crystallography
support, and Christopher O’Donnell for helpful discussions.
9. Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am. Chem. Soc. 2011, 133,
8834.
Supplementary data
10. For similar examples, see: (a) Edwards, O. E.; Rank, W. Can. J. Chem. 1990, 68,
1425–1436; (b) Sevenard, D. V.; Kazakova, O.; Chizhov, D. L.; Yachevskii, D. S.;
Lork, E.; Poveleit, J.; Charushin, V. N.; Roeschenthaler, G.-V. Helv. Chim. Acta
2007, 90, 369–384; (c) Sevenard, D. V.; Vorobyev, M.; Sosnovskikh, V. Y.;
Wessel, H.; Kazakova, O.; Vogel, V.; Shevchenko, N. E.; Nenajdenko, V. G.; Lork,
E.; Roeschenthaler, G.-V. Tetrahedron 2009, 65, 7538–7552.
11. (a) Tanemura, K.; Suzuki, T.; Nishida, Y.; Satsumabayashi, K.; Horaguchib, T.
Chem. Commun. 2004, 470; (b) Roglans, A.; Marquet, J.; Moreno-Mañas, M.
Synth. Commun. 1992, 22, 1249.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.129.
References and notes
1. (a) Becker, A.; Kohfeld, S.; Lader, A.; Preu, L.; Pies, T.; Wieking, K.; Ferandin, Y.;
Knockaert, M.; Meijer, L.; Kunick, C. Eur. J. Med. Chem. 2010, 45, 335–342; (b)