Approach to 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines

Article abstract of DOI:10.1016/j.tetlet.2017.04.030

An approach to 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines via the cyclization of 1-(2-(3-azidopropyl)pyridin-3-yl)alkanones under Staudinger–aza-Wittig reaction conditions is described. The overall reaction sequence includes eight steps and allows for the preparation of gram quantities of the title products. In some cases, the formation of 5,7,8,9-tetrahydrooxepino[4,3-b]pyridine derivatives was observed.

Full text of DOI:10.1016/j.tetlet.2017.04.030

Accepted Manuscript
Approach to 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines
Andrii I. Subota, Oleksiy S. Artamonov, Alina Gorlova, Dmitriy M.
Volochnyuk, Oleksandr O. Grygorenko
PII:
S0040-4039(17)30460-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.030
TETL 48822
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 March 2017
3 April 2017
7 April 2017
Please cite this article as: Subota, A.I., Artamonov, O.S., Gorlova, A., Volochnyuk, D.M., Grygorenko, O.O.,
Approach to 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.04.030
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Graphical Abstract
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Approach to 5-substituted 6,7,8,9-
tetrahydro-5H-pyrido[3,2-c]azepines
Andrii I. Subota, Oleksiy S. Artamonov, Alina Gorlova, Dmitriy M. Volochnyuk, Oleksandr O. Grygorenko∗

1
Tetrahedron Letters
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Approach to 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines
Andrii I. Subota,a Oleksiy S. Artamonov,a Alina Gorlova,a Dmitriy M. Volochnyuk,a
Oleksandr O. Grygorenkob∗
aInstitute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
bNational Taras Shevchenko University of Kyiv, Volodymyrska Street, 64, Kyiv 01601, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
An approach to 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines via the cyclization of
1-(2-(3-azidopropyl)pyridin-3-yl)alkanones under Staudinger–aza-Wittig reaction conditions is
described. The overall reaction sequence includes eight steps and allows for the preparation of
gram quantities of the title products. In some cases, the formation of 5,7,8,9-
tetrahydrooxepino[4,3-b]pyridine derivatives was observed.
Received in revised form
Accepted
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Nitrogen heterocycles
Fused azepanes
Pyridine
Aza-Wittig reaction
Lead-oriented synthesis
The quest for lead-oriented synthesis proposed by medicinal
chemistry in early 2010s has prompted the design and study of
low-molecular-weight, hydrophilic, conformationally restricted,
and sp3-enriched molecular scaffolds.1 Fused azepanes are
promising chemotypes which comply with these criteria and in
most cases possess sufficient novelty;2 moreover, the azepane
motif is in the top 100 most frequently used ring systems for
small molecule drugs.3 6,7,8,9-Tetrahydro-5H-pyrido[3,2-
c]azepines (1), which contain fused azepane and pyridine rings,
were evaluated as cannabinoid (CB2) receptor modulators (2),4
H1-antihistamines (3),5 or serotonin (5HT2c) receptor agonists (4)6
(Fig. 1).
or the Heck reaction9 as key steps. Recently, the microwave-
assisted condensation of azepan-4-ones with 3,5-dinitro-1-
methylpyridin-2-one was reported, leading to the formation of 7-
nitro-substituted derivatives of 1.10 The method which allowed
the preparation of 5-phenyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-
c]azepine (5a), relied on a five-step reaction sequence illustrated
in Scheme 1.11 The latter method had a low overall yield (3.7%)
and in our hands, was not amenable to scale-up to gram
quantities.
Figure 1. 6,7,8,9-Tetrahydro-5H-pyrido[3,2-c]azepine (1) and its biologically
active derivatives4–6
Most known methods for the construction of bicyclic ring
system 1 result in the formation of 3- or 5-oxo derivatives.5, 7
Other approaches furnishing 1-substituted 6,7,8,9-tetrahydro-5H-
pyrido[3,2-c]azepines include intramolecular enolate arylation8
Scheme 1. Synthesis of compound 5a reported in the literature11
———
∗ Corresponding author. Tel.: +38-044-239-3315; fax: +38-044-573-2643; e-mail: gregor@univ.kiev.ua

2
Tetrahedron Letters
Herein, we report an alternative approach to 5-substituted
quenching intermediate 10 with DMF (Scheme 3). For the
synthesis of 3-acetylpyridine derivative 13d (R = Me), compound
13e was reacted with MeMgCl to give product 12d, which was
subsequently oxidized with CrO3 to give the target ketone 13d in
75% yield. The Sonogashira coupling of 13a–e with O-THP-
propargyl alcohol (14) gave 15a–e in good yields (68–74%),
which were transformed into alkane derivatives 16a–e (80–99%)
via catalytic hydrogenation. Deprotection of compounds 16a–c
(R = Aryl, i-Pr) occurred in the expected manner, leading to the
formation of the key intermediates 8a–c in 73–92% yield. In the
case of 8c, by-product 17c was also isolated in 18% yield.
Unfortunately, the method did not work with the smallest
aliphatic substituents (R = H, Me): only products 17d,e were
isolated in 48–53% yield upon the attempted deprotection of
16d,e.
6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepines of the general
structure 5, which also relies on the formation of imines 6 as the
key step (Scheme 2). Contrary to the literature method, our
strategy relied on the cyclization of azides 7, in turn prepared
from alcohols 8. Further retrosynthetic disconnections led us to
2-bromopyridine (9) as a readily available starting material.
Scheme 2. Retrosynthetic analysis of 6,7,8,9-tetrahydro-5H-pyrido[3,2-
c]azepines 5
Scheme 3. Synthesis of compounds 13e and 12d. Reagents and Conditions:
(i) LDA (1.2 eq), THF, –78 °C, 90 min; (ii) 11 (3 eq), THF, –78 °C, 80 min,
56% (from 9); (iii) MeMgCl (1.1 eq), THF, 0–5 °C, 0.5 h, 95%
Table 1. Synthesis of key intermediates 8a–ca
Table 2. Synthesis of target products 5a–ca
R
O
R
(i) or (ii)
O
OH
N+
N
8
18
(iii)
2Cl-
R
R
R
(iv)
(v, vi)
+
N
NH2
O
N3
N
N
N
H+
5.
2HCl
7
6
Yield (%)
Entry Product
R
Yield (%)
12
13
15
16
8
17
Overall yield (%)
(8 steps)
Entry Product
R
7
5b
1
2
8a
8b
8c
8d
8e
Ph
71
67
82
95
74
77
98
99
90
92
0
0
4-F-C6H4
1
2
5a
5b
5c
Ph
35
37
67
64
8.9
4-F-C6H4
10.6
i-Pr
Me
H
60
94
84
72
71
68
99
87
80
73
0
18
53
48
3
4
b
i-Pr
33
64
6.2
3
–
b
aReagents and Conditions: (i) MsCl (1.05 eq), Et3N (1.5 eq), CH2Cl2, 0 °C to
rt, 24 h; (ii) phthalimide (1.5 eq), DIAD (1.5 eq), PPh3 (1.5 eq), THF, –30 °C
to rt, 24 h; (iii) DIAD (1.5 eq), PPh3 (1.5 eq), NaHCO3 (3 mol%), THF,
(PhO)2P(O)N3 (1.5 eq), –30 to 20 °C, 3 h; (iv) PMe3 (1.4 eq), THF, rt, 6 h; (v)
NaBH4 (3 eq), MeOH, 0 °C to rt, 8 h; (vi) sat. HCl in Et2O, rt
5
–
–
0
aReagents and Conditions: (i) LDA (1.2 eq), THF, –78 °C, 90 min; (ii) 11
(1.13 eq), THF, –78 °C, 80 min; (iii) CrO3⋅2Py (3 eq), CH2Cl2, rt, 24 h
(13a,b) or CrO3 (3 eq), acetone, rt, 18
h (13c,d); (iv) 2-prop-2-
ynyloxytetrahydropyran (14) (1.5 eq), Pd(OAc)2 (1 mol%), PPh3 (2 mol%),
CuI (0.19 mol%), Et3N, 80 °C, 16 h; (v) H2 (1 atm), 10% Pd-C (4 mol%),
MeOH, rt, monitored by TLC; (vi) TsOH⋅H2O (1.05 eq), MeOH, rt, 12 h.
bIsolated as dihydrochloride. Yield for two steps (from 7)
The attempted mesylation of compounds 8 proved to be
unfruitful, as was the reaction with phthalimide under Mitsunobu
conditions (DIAD, PPh3). In our opinion, this was due to the
formation of dihydroindolizinium derivatives 18 (Table 2).
Presumably, this heterocyclization was still a problem in the
Mitsunobu reaction of 8 using diphenylphosphoryl azide (DPPA)
since the target products 7 were obtained in only moderate yields
(33–37%), and the formation of 18 was observed in the reaction
mixtures by LCMS. Nevertheless, the isolation of 7a–c and
bSee Scheme 3 for the synthesis of 12d and 13e
The synthesis began with the lithiation of 9, followed by
quenching the organolithium intermediate 10 with aldehydes
11a–c to give alcohols 12a–c in 60–71% yield (Table 1).12 The
oxidation of 12a–c was performed using CrO3–py in CH2Cl2 or
CrO3 in acetone to give ketones 13a–c in 82–95% yield.
Aldehyde 13e (R = H) was obtained directly from 9 by

3
chromatographic purification was simple even on a gram scale.
Formation of the seven-membered ring under Staudinger–aza-
Wittig reaction conditions (treatment of 7 with PMe3) smoothly
gave the bicyclic products 6. It should be noted that using PMe3
to promote the cyclization step was essential, since with PPh3
cyclization of the corresponding phosphazene intermediate did
not occur, presumably due to sterics. The final step of the
reaction sequence – reduction of 6 with NaBH4 – gave the
10. Schultz, T.; Turner, S. C.; Braje, W. M. Synthesis 2010, 1339–
1343.
11. Hussenether, T.; Troschuetz, R. J. Heterocycl. Chem. 2004, 41,
857–865.
12. Subota, A. I.; Grygorenko, O. O.; Valter, Y. B.; Tairov, M. A.;
Artamonov, O. S.; Volochnyuk, D. M.; Ryabukhin, S. V. Synlett
2015, 26, 408–411.
targeted
c]azepines 5, isolated as dihydrochlorides, in 64–67% yield.
5-substituted
6,7,8,9-tetrahydro-5H-pyrido[3,2-
In conclusion, a reaction sequence was developed for the
preparation of 5-substituted 6,7,8,9-tetrahydro-5H-pyrido[3,2-
c]azepines, proceeding over eight steps to give the title products
in 6.2–10.6% overall yield on a gram scale (up to 10 g). The
method relied on cyclization of the corresponding azidoketones 7
under mild Staudinger–aza-Wittig reaction conditions as the key
step. The approach was limited to the preparation of 6,7,8,9-
tetrahydro-5H-pyrido[3,2-c]azepines containing
a
relatively
hindered substituent at the C-5 position (i. e. aryl or i-Pr). In
other cases, formation of 5,7,8,9-tetrahydrooxepino[4,3-
b]pyridines 17 did not allow the preparation of target products.
Acknowledgments
The work was supported by Ukrainian Government Funding
(state registry No. 0114U003956) and Life Chemicals Group.
References and notes
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McGaughey, G. B.; Sheridan, R. P.; Good, A. C.; Warren, G. ;
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3862–3886. (d) Kingwell, K. Nature Rev. Drug Discov. 2009, 8,
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(a) Zhukauskaite, L. N.; Stankevichyus, A. P.; Kost, A. N. Chem.
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4
Tetrahedron Letters
Highlights
• Approach to 5-substituted 6,7,8,9-
tetrahydro-5H-pyrido[3,2-c]azepines is
reported
• The products were prepared in 8 steps,
in up to 10% total yield, and on up to a
10 g scale
• Staudinger–aza-Wittig reaction was used
for the azepane ring construction
• Only products with relatively hindered
groups at the C-5 position were obtained
• In
some
tetrahydrooxepino[4,3-b]pyridines were
cases,
5,7,8,9-
isolated