Reactions of lithiated alkynes and allenes with isothiocyanates: A simple and efficient synthesis of new aryl- or hetaryl-substituted 3H-azepines and 4,5-dihydro-3H-azepines

Article abstract of DOI:10.1055/s-0030-1260084

A novel synthetic approach to the preparation of a wide range of 3H-azepines and 4,5-dihydro-3H-azepines bearing various aryl, hetaryl, alkyl, and heteroalkyl substituents from readily accessible starting materials (aryl- and hetaryl-substituted alkynes o

Full text of DOI:10.1055/s-0030-1260084

2192
FEATURE ARTICLE
Reactions of Lithiated Alkynes and Allenes with Isothiocyanates: A Simple
and Efficient Synthesis of New Aryl- or Hetaryl-Substituted 3H-Azepines and
4,5-Dihydro-3H-azepines
N
ew
3
H
-Azepines
i
and 4,
n
5-Dihydro-
3
a
H
-azepines A. Nedolya,* Ol’ga A. Tarasova, Ol’ga G. Volostnykh, Alexander I. Albanov, Ludmila V. Klyba,
Boris A. Trofimov*
A. E. Favorsky Irkutsk Institute of Chemistry of the Russian Academy of Sciences, Siberian Branch, Favorsky Street 1, 664033 Irkutsk,
Russian Federation
Fax +7(3952)419346; E-mail: nina@irioch.irk.ru
Received 4 April 2011; revised 5 May 2011
ry impairment, alcoholism, senile dementia, Alzheimer’s
Abstract: A novel synthetic approach to the preparation of a wide
disease).1,10–13 Many natural azepines, including azepine
range of 3H-azepines and 4,5-dihydro-3H-azepines bearing various
alkaloids and their synthetic congeners, are used or re-
aryl, hetaryl, alkyl, and heteroalkyl substituents from readily acces-
sible starting materials (aryl- and hetaryl-substituted alkynes or al-
garded as a potential anticancer, antibacterial, anti-HIV,
lenes, sec-alkyl isothiocyanates, and alkyl halides) has been and other types of drugs.14
developed. The methodology is based on a fast and smooth conver-
Therefore, the search for and the development of novel
sion of conjugated 2-aza-1,3,5-trienes derived from 1-aza-1,3,4-
trienes, S-alkylated adducts of isopropyl isothiocyanate and allenic
or acetylenic carbanions, into seven-membered azaheterocycles,
3H-azepines and 4,5-dihydro-3H-azepines, using potassium tert-
butoxide (THF–DMSO, ca. –30 °C, 30 min). The ratio of the het-
erocycles depends on the nature of the substituent on the allene or
alkyne and on the 2-aza-1,3,5-triene derived therefrom.
and efficient synthetic approaches to seven-membered
azaheterocycles providing access to new representatives
is of high interest to both heterocyclic chemistry and med-
icine.
In the past few years it has been well documented that aza-
trienic systems, readily available by simple and efficient
one-pot synthesis from isothiocyanates and acetylenic or
dienic carbanions,15 can be utilized in heterocyclic synthe-
sis as unique common precursors of abundance funda-
mental four-, five-, and six-membered aza- and
thiaheterocycles (pyrroles, cyclobuta[1,2-b]pyrroles, py-
ridines, dihydropyridines, dihydropyridinones, pyridi-
Key words: 3H-azepines, 4,5-dihydro-3H-azepines, azatrienes,
allenes, alkynes, isothiocyanate, metalation, electrocyclization
Seven-membered azaheterocycles, azepines and their de-
rivatives, represent an important class of heterocyclic
compounds1 and they are the focus of numerous synthetic,
theoretical, and medical investigations, primarily due to
their peculiar structure, high reactivity (notably in pericy-
clic reactions), and wide variety of bioactivity.2 In theoret-
ical studies of azepines, considerable interest has been
directed towards various stereochemical and thermody-
namic aspects, including tautomerism,3 valence isomer-
ism,4 sigmatropic rearrangements,3b,5 the transannular
effect of the nitrogen lone pair,2a aromaticity/anti-aroma-
ticity,2b,c,6 and intramolecular hydrogen bonds.7 Azepine
derivatives, especially partially or fully reduced
azepines,1d–i benzazepines,8 and diazepines9 are widely
used in pharmacology and medicine, first of all, as
psychotropic, antidepressant, and anticonvulsant drugs
[Carbamazepine (synonyms: Amizepin, Carbagretil, Car-
bazep, Finlepsin, Mazetol, Neurotol, Simonil, Stazepin,
Tegretal, Tegretol, Temporal, Zeptol, etc.),10 Insidon
(synonyms: Dinsidon, Opipramol, Opramol, Oprimol,
etc.),11 Imipramine and its derivatives and analogues
(Clomipramine, Desimipramine, Melipramin, etc.)12] for
the treatment of trigeminal neuralgia, diverse forms of ep-
ilepsy, schizophrenia, and other mental disorders (memo-
nethiones,
quinolines,
thietanes,
thiophenes,
dihydrothiopyrans, etc.), including bi- and polycyclic ar-
chitectures.15,16
Recently, we found that conjugated 2-aza-1,3,5-trienes 2,
products of a sigmatropic [1,5]-H shift in the correspond-
ing 1-aza-1,3,4-trienes 1, derived from readily accessible
allenic ether or allenic acetals and isopropyl isothiocyan-
ate, by treatment with potassium tert-butoxide in tetrahy-
drofuran
or
dimethyl
sulfoxide–tetrahydrofuran
undergoes an unprecedented transformation to 6-alkoxy-
2-methyl-3H-azepines 3 and 3-alkoxy-7-methyl-2-(meth-
ylsulfanyl)-4,5-dihydro-3H-azepines 4, the product ratio
being markedly dependent on the alkoxy substituent and
reaction conditions (Scheme 1).17
In particular, treatment of methoxy-substituted 2-aza-
1,3,5-triene 2a with potassium tert-butoxide in dimethyl
sulfoxide–tetrahydrofuran at ca. –30 °C for 30 minutes
(Method A) gave the corresponding 3H-azepine 3a and
4,5-dihydro-3H-azepine 4a in a ratio of ~1:1 (Table 1, en-
try 1).17a However, acetal analogues 2b,c, in contrast to
2a, react with potassium tert-butoxide under similar con-
ditions yielding mainly 4,5-dihydro-3H-azepines 4b,c
(88–92% along with 3H-azepines 3b,c) (entries 3–5).17b
3H-Azepine 3a and 4,5-dihydro-3H-azepine 4a were ob-
tained from 2-aza-1,3,5-triene 2a in a ratio of ~1:3 when
the reaction was carried out in tetrahydrofuran (in the ab-
SYNTHESIS 2011, No. 14, pp 2192–2204
x
x.
x
x
.
2
0
1
1
Advanced online publication: 21.06.2011
DOI: 10.1055/s-0030-1260084; Art ID: Z35211SS
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Biographical Sketches
New 3H-Azepines and 4,5-Dihydro-3H-azepines
2193
Nina A. Nedolya is currently
Head of the Research Group of
Chemistry of Heterocyclic Com-
pounds at the A. E. Favorsky
Irkutsk Institute of Chemistry
(Russia). She received her Ph.D.
(1982) and D.Sc. (1998) in
Chemistry from Irkutsk State
University. From 1995 to 1999
she was associated with Prof. L.
Brandsma at Utrecht University
(The Netherlands). In 1999 she
obtained her second Ph.D. in
chemistry from Utrecht Univer-
sity. She is the author of over 240
research papers and various re-
view articles. She is also one of
the inventors for over 110 pat-
ents. Her current scientific inter-
ests are focused on the chemistry
of unsaturated heteroatom sys-
tems (vinyl, allenyl, and alkynyl
ethers and their derivatives, het-
eropolyenes, heterocumulenes)
and heterocyclic synthesis (par-
ticularly, the synthesis of pyr-
roles, thiophenes, thiazoles,
imidazoles, dihydropyridines,
pyridines, quinolines, dihy-
droazepines, azepines, etc.),
based on metalated 1,2- and 1,3-
dienes, alkynes, and/or heterocu-
mulenes.
Ol’ga A. Tarasova received her
diploma from Irkutsk Polytech-
nic Institute (Russia) in 1971 and
her Ph.D. in Chemistry from the
Irkutsk Institute of Organic
Chemistry in 1975. She is now a
Senior Staff Scientist at the A. E.
Favorsky Irkutsk Institute of
Chemistry. Her research inter-
ests are the chemistry of acety-
lene and allene systems in
superbasic medium. She is the
author of over 130 papers and 23
author’s certificates and patents.
Ol’ga G. Volostnykh was born
in 1986 in Irkutsk (Russia). She
studied chemistry at Irkutsk State
Technical University and ob-
tained her diploma in 2008. Cur-
rently she is completing her
Ph.D. in chemistry under the su-
pervision of Dr. Nina A. Nedolya
at the A. E. Favorsky Irkutsk In-
stitute of Chemistry. Her re-
search focuses on the synthesis
of conjugated azatriene systems
and their transformations under
the action of superbases.
Alexander I. Albanov received
his Ph.D. in chemistry from the
Irkutsk Institute of Organic
Chemistry (Russia) in 1984. He
is now a Senior Staff Scientist at
the A. E. Favorsky Irkutsk Insti-
tute of Chemistry. His research
interests include the investiga-
tion of hetero-organic com-
pounds by multinuclear NMR
spectroscopy methods. A. I.
Albanov has over 340 publica-
tions in refereed journals.
Lyudmila V. Klyba received
her Ph.D. in chemistry from the
Irkutsk Institute of Organic
Chemistry (Russia) in 1987 with-
in the field of mass spectrometry
of pentacoordinated silicon com-
pounds. Her current research in-
terests cover the study of
rearrangement processes of un-
solvated ions of organic hetero-
cyclic compounds in the gas
phase by mass spectrometry.
Boris A. Trofimov was born in
Tchita, Russia in 1938. He re-
ceived his diploma in 1961, his
Ph.D. in 1964, and his D.Sc. in
1970. He became a Professor in
1974 and in 1990 a Correspond-
ing Member of the Academy of
Sciences (USSR). He became a
Full Member (Academician) of
the Russian Academy of Scien-
ces in 2000. He is currently Direc-
tor of the A. E. Favorsky Irkutsk
Institute of Chemistry, Head of
the Laboratory of Unsaturated
Heteroatomic Compounds. Boris
Trofimov is a member of the ed-
itorial board of the Russian Jour-
nal of Organic Chemistry,
Russian Journal of Heterocyclic
Compounds, and Journal of Sul-
fur Chemistry. He was awarded
the Butlerov Prize of the Russian
Academy of Science in 1997 and
the Medal and Diploma of a
Mendeleev Reader (St. Peters-
burg) in 2003. In 2011 he was
elected Professor Emeritus of the
Chemical Faculty of Saint-Pe-
tersburg State University. He is
the author and co-author of over
2000 papers, 60 reviews, and 21
monographs. His current scien-
tific interests are focused on:
organic synthesis based on
acetylene and its derivatives; het-
erocyclic chemistry, particularly,
the chemistry of pyrroles, in-
doles, imidazoles, pyridines, and
furans; organic chemistry of
phosphorus (halogen-free syn-
thesis), sulfur, selenium, telluri-
um; addition reactions to
multiple bonds; and superbase
catalysts and reagents.
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

2194
N. A. Nedolya et al.
FEATURE ARTICLE
RO
i
ii
RO
H
RO
i
ii
MeS
RO
N
N
MeS
N
MeS
N
MeS
1a–c
2a–c
6
5
iii
RO
+
iii
N
N
MeS
+
N
N
4a–c
MeS
3a–c
7
8
Scheme 1 Reagents and conditions: (i) 1. n-BuLi (1 equiv), THF–
hexane; 2. i-PrNCS; 3. MeI; (ii) [1,5]-H shift: 65–67 °C, 10–15 min
(for 1a) or r.t., 4 h (for 1b,c); (iii) t-BuOK (1.0–1.2 equiv), THF–
DMSO (4.3–5:1), ca. –30 °C, 30 min (Method A) or THF, 0 °C, 10
min (Method B).
Scheme 2 Reagents and conditions: (i) 1. n-BuLi (2 equiv), THF–
hexane; 2. i-PrNCS; 3. t-BuOH; 4. MeI; (ii) [1,5]-H shift (see Table
2); (iii) t-BuOK (1 equiv), THF, 15 °C, 30 min (Method C).
and 8 was 74% (after flash chromatography on silica gel,
PE–Et2O, 3:1).
Table 1 Transformation of 2-Aza-1,3,5-trienes 2 into 3H-Azepines
3 and 4,5-Dihydro-3H-azepines 4 (Scheme 1)
Methoda Yield (%) Ratio 3/4b
Unlike
phenyl-substituted
2-aza-1,3,5-triene
6
Entry Substrate
R
(Scheme 2),18 when thienyl-substituted 2-aza-1,3,5-triene
10, derived from dilithiated 5-methyl-2-(2-propy-
nyl)thiophene, isopropyl isothiocyanate, and methyl io-
dide (via 1-aza-1,3,4-triene 9), was treated with potassium
tert-butoxide (by Method A), only the previously un-
known 2-methyl-6-(5-methyl-2-thienyl)-3H-azepine (11)
was isolated in 45% yield (Scheme 3).19 The correspond-
ing 4,5-dihydro-3H-azepine was not detected in this case
even in the crude product (1H NMR).
1
2
3
4
5
2a
2a
2b
2b
2c
Me
A
B
A
B
A
71
71
89
82
89
~1:1
Me
~1:3
CH(Me)OEt
CH(Me)OEt
CH(Me)OBu
~1:12.5
~1:12.5
~1:11.5
a For Methods A and B see Scheme 1.
b In the crude product (by 1H NMR).
i
sence of DMSO) at 0 °C for 10 minutes (Method B, entry
2).17a
S
ii
MeS
N
S
The whole process, from lithiation of the allene with bu-
tyllithium to formation of the azepine nucleus, was ac-
complished in three preparative steps: (1) one-pot
synthesis of 1-aza-1,3,4-triene 1 (by nucleophilic addition
of allenic carbanion, generated in situ from the corre-
sponding allene, to isothiocyanate, followed by S-meth-
ylation of the adduct with MeI); (2) thermally induced
isomerization of azatriene 1 into 2-aza-1,3,5-triene 2
(through a sigmatropic [1,5]-H shift); (3) rapid transfor-
mation of 2-aza-1,3,5-triene 2 into 3H-azepine 3 and 4,5-
dihydro-3H-azepine 4 under the action of potassium tert-
butoxide (via deprotonation of azatriene 2 and spontane-
ous [1,7]-electrocyclization of the emerging carbanion).
9
iii
S
S
N
MeS
N
10
11
Scheme 3 Reagents and conditions: (i) 1. n-BuLi (2 equiv), THF–
hexane; 2. i-PrNCS; 3. t-BuOH; 4. MeI; (ii) [1,5]-H shift (see Table
2); (iii) t-BuOK (1.2 equiv), THF–DMSO (4.5:1), ca. –30 °C, 30 min
(45%).
Apparently, the application in these reactions of others
alkynes or allenes, bearing aromatic and heteroaromatic
substituents, provides an effective synthetic approach to
new bicyclic azepine and dihydroazepine assemblies,
promising scaffolds for the design of new medicinal
agents and materials for various objectives, particularly
having in mind that so far, general and efficient methods
for their preparation are not known.
We have also found that this procedure can be successful-
ly applied to aryl- or hetaryl-substituted azatrienic sys-
tems to give azepines and dihydroazepines containing an
aryl or hetaryl substituent. Thus, phenyl-substituted 2-
aza-1,3,5-triene 6, prepared from dilithiated 1-(2-propy-
nyl)benzene and isopropyl isothiocyanate via one-pot
synthesis and isomerization of 1-aza-1,3,4-triene 5, under
the action of an equimolar amount of potassium tert-bu-
toxide in tetrahydrofuran at 15 °C for 30 minutes (Method
C) was easily converted into the previously unknown 2-
methyl-6-phenyl-3H-azepine (7) and 7-methyl-2-(meth-
ylsulfanyl)-3-phenyl-4,5-dihydro-3H-azepine (8) (ratio
~1:1 by 1H NMR) (Scheme 2).18 Total yield of products 7
With the aim to obtain a new range of aryl- and hetaryl-
substituted 3H-azepines and 4,5-dihydro-3H-azepines, as
well as to investigate the scope and limitations this ap-
proach to their preparation, we synthesized a wide number
of their precursors, earlier unknown and unavailable aryl-
and hetaryl-substituted conjugated 2-aza-1,3,5-trienes 13,
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

FEATURE ARTICLE
New 3H-Azepines and 4,5-Dihydro-3H-azepines
2195
and studied their reactions upon treatment with potassium Then, compounds 12 were easily transformed into the cor-
tert-butoxide.
responding 2-aza-1,3,5-trienes 13 via [1,5]-sigmatropic
hydrogen shift. The conditions of thermal isomerization
of 1-aza-1,3,4-trienes 12 and the values of their conver-
sion are summarized in Table 2. For comparison, the data
on isomerization of phenyl- 5 and thienyl-substituted 1-
aza-1,3,4-trienes 9 into 2-aza-1,3,5-trienes 6 and 10, re-
spectively, are also included (entries 1 and 6). As seen
from Table 2, the transformation of neat azatrienes 12 into
13 occurs at 55–84 °C for ~20 minutes (entries 2–5, 7, and
8), the conversion of 1-aza-1,3,4-trienes being ~100%,
except for compounds 12a (~88%) and 12c (90%).
1-Aza-1,3,4-trienes 12, precursors of 2-aza-1,3,5-trienes
13, were obtained in turn from dilithiated with butyllithi-
um in tetrahydrofuran–hexane aryl- or hetaryl-substituted
alkynes [1-(2-propynyl)benzenes and 1-methyl-2-(2-pro-
pynyl)-1H-pyrrole] (Scheme 4) or lithiated 1-(1,2-propa-
dienyl)-1H-pyrrole (Scheme 5), isopropyl isothiocyanate,
and methyl iodide in one preparative step (yields 63–95%
by 1H NMR).
Li
Li
R
2-Aza-1,3,5-trienes 13a–f, synthesized in this way, with-
out further purification were smoothly converted into the
earlier unknown aryl- or hetaryl-substituted 3H-azepines
14a–f and 4,5-dihydro-3H-azepines 15a–f upon treatment
with potassium tert-butoxide (Scheme 6, Table 3). The
reaction was performed in dry dimethyl sulfoxide–tetra-
hydrofuran (1:4.5–6.0) at ca. –30 °C with slight excess
(1.1–1.5 equiv) of potassium tert-butoxide and was com-
plete in 30 minutes. After aqueous workup, compounds 14
and 15 were obtained as a mixture in moderate to good
yields. Deprotonation of phenyl-substituted 2-aza-1,3,5-
triene 6 was also carried out under these conditions
(Method A). The total yield of compounds 7 and 8 was
comparable to this obtained by Method C (Scheme 2),18
but their ratio changed from ~1:1 to ~2:1; a similar ten-
dency to that observed for the transformations of meth-
oxy-substituted 2-aza-1,3,5-triene 2a into 3H-azepine 3a
and 4,5-dihydro-3H-azepine 4a by Methods A and B
(Scheme 1, Table 1, entries 1 and 2).17a
i
ii
iii
R
R
Li
LiS
N
R
R
R
v
iv
N
LiS
N
MeS
N
MeS
12a–e
13a–e
Scheme 4 Reagents and conditions: (i) n-BuLi (2 equiv), THF–
hexane, 10–15 °C, 20 min; (ii) i-PrNCS, ca. –30 °C, 20 min; (iii) t-
BuOH; (iv) MeI; (v) [1,5]-H shift (see Table 2).
In the case of 1-(1,2-propadienyl)-1H-pyrrole, the first (i)
or second (ii) stage was not completed under the investi-
gated conditions and some unreacted starting compound
was recovered (Scheme 5).
N
i
ii
iii
N
Similar to the synthesis of the above-mentioned 3H-
azepines 3, 7, 11 and 4,5-dihydro-3H-azepines 4 and 8,17–19
the reaction is thought to proceed through the deprotona-
tion of a methyl group from the azomethine moiety
(N=CMe2) of the 2-aza-1,3,5-trienic system 13 with po-
tassium tert-butoxide, followed by isomerization of the
initially formed carbanion A and spontaneous [1,7]-elec-
trocyclization of isomerized anion resulting in the forma-
N
LiS
N
Li
N
N
iv
MeS
N
N
MeS
12f
13f
tion of azacycloheptadienyl anionic species
B
Scheme 5 Reagents and conditions: (i) n-BuLi (1 equiv), THF–
hexane, –70 to –60 °C, 10 min; (ii) i-PrNCS, –35 to –30 °C, 20 min;
(iii) MeI; (iv) [1,5]-H shift (see Table 2).
(Scheme 6). The unprecedented elimination of the sulfide
anion from anionic intermediate B under the reaction con-
Table 2 Conditions for Isomerization of 1-Aza-1,3,4-trienes 5, 9, and 12 into 2-Aza-1,3,5-trienes 6, 10, and 13 (Schemes 2–5)
Entry
R
1-Aza-1,3,4-triene Temp (°C)
Time (min)
2-Aza-1,3,5-triene Conv. (%)
1
2
3
4
5
6
7
8
Ph
518
12a
12b
12c
12d
919
80–85
79–82
80–84
80–82
79–82
74–82
55–62
60–65
30
20
20
20
20
10
20
20
618
13a
13b
13c
13d
1019
13e
13f
100
88
4-MeC6H4
4-t-BuC6H4
4-MeOC6H4
4-FC6H4
100
90
100
100
100
100
5-methyl-2-thienyl
1-methyl-1H-pyrrol-2-yl
1H-pyrrol-1-yl
12e
12f
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

2196
N. A. Nedolya et al.
FEATURE ARTICLE
R
– MeS–
N
K+
i
ii
R
–
R
14a–f
–
13a–f
N
N
MeS
MeS
H+
R
B
A
N
MeS
15a–f
Scheme 6 Reagents and conditions: (i) deprotonation with t-BuOK in THF–DMSO (Method A); (ii) isomerization and [1,7]-electrocycliza-
tion; yields: 14–74% for 3H-azepines 14a–f and 8–56% for 4,5-dihydro-3H-azepines 15a–f.
Table 3 Ratio and Total Yield of 3H-Azepines 7, 11, 14a–f and 4,5-Dihydro-3H-azepines 8, 15a–f
Entry
3H-Azepine
4,5-Dihydro-3H-azepine
Ratioa
70:30
Total yieldb (%)
1
66
N
N
MeS
718
818
2
3
90:10
75:25
56
99
N
N
MeS
14a
15a
N
N
MeS
14b
15b
MeO
MeO
4
5
75:25
55:45
72
65
N
N
MeS
14c
15c
F
F
N
N
MeS
14d
15d
S
6
–
100:0
56
N
1119
Me
N
Me
N
7
8
22:78
13:87
76
52
N
N
MeS
14e
15e
N
N
N
N
MeS
14f
15f
a Ratio of azepine/dihydroazepine in crude product (by 1H NMR).
b After rough separation of products by column chromatography on alumina.
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

FEATURE ARTICLE
New 3H-Azepines and 4,5-Dihydro-3H-azepines
2197
ditions affords 3H-azepines 14. The protonation of cyclic diary azacycloheptadienyl anionic species B (Scheme 6)
anion B upon aqueous workup gives (directly or after hy- on the ratio of azacycloheptadienes and -trienes is puz-
drogen shift) 4,5-dihydro-3H-azepines 15.
Apart from our own previous work,17–19 there is no meth-
zling. Therefore, additional studies will be necessary to
obtain a correct explanation for these results.
odology in the literature that allows the construction of The 3H-azepines and 4,5-dihydro-3H-azepines synthe-
both azepine and dihydroazepine rings from a common sized were isolated and purified by rough separation on
precursor, namely 2-aza-1,3,5-triene, under the same re- alumina, followed by treatment with diluted hydrochloric
action conditions. Würthwein et al.20 reported the synthe- acid and final purification by column chromatography on
sis of N-acyl-2,3-dihydro-1H-azepines and N-substituted alumina or by recrystallization (for solids).22 Microanaly-
4,5-dihydro-1H-azepines from 1-phenyl-7-(4-tolyl)-2- ses of the compounds gave satisfactory results.
azaheptatriene, 4-MePhCH=CHCH=CHCH=NCH2Ph,
The structures of the products have been assigned using
and
N-allyl-N-(3-phenyl-
or
3-thienylprop-2-
13
1H, 13C,
C
, homo-, and heteronuclear 2D (1H–1H
jmod
enylidene)amines, ArCH=CHCH=NCH2CH=CH2, re-
spectively, via deprotonation with lithium diisopropyl-
amide and subsequent trapping of anionic intermediates
with various electrophiles. But in this case, deprotonation
occurred on an azamethylene fragment activated by a phe-
nyl or vinyl group to furnish the only N-substituted dihy-
dro-1H-azepines. To the best of our knowledge, the use of
potassium tert-butoxide for the metalation of aldimines
and ketimines has also not been previously reported; the
reagent generally used for this objective is lithium diiso-
propylamide.21
1
1
COSY-45, H–13C HSQC, and HMBC, H–15N HMBC)
NMR and IR spectroscopy and mass spectrometry.
In conclusion, the methodology developed represents a
novel general synthetic protocol for the preparation of
new aryl- and hetaryl-substituted 3H-azepines and 4,5-di-
hydro-3H-azepines from isothiocyanates and propynes or
allenes which are otherwise not easily available by other
approaches. The procedure involves three very simple
preparative operations: one-pot synthesis of 1-aza-1,3,4-
trienes (through S-alkylation of the adduct of isothiocyan-
ate with allenic or acetylenic carbanion), their thermally
induced isomerization into 2-aza-1,3,5-trienes, and rapid
transformation of the latter into the corresponding 3H-
azepines and 4,5-dihydro-3H-azepines in the presence of
potassium tert-butoxide under mild reaction conditions.
The novel representatives of the seven-membered azahet-
erocycles combining the properties of both azepines and
fundamental substituents, such as benzenes, pyrroles,
thiophenes, and sulfides, can be of considerable theoreti-
cal, synthetic, and practical interest, including their poten-
tial application as promising precursors for drug design.
In the present study, we have found that, in analogy to
methoxy- and acetal-substituted derivatives 2 (Scheme 1),
the ratio of 3H-azepine/4,5-dihydro-3H-azepine is criti-
cally dependent on the nature of the substituent at the 2-
position of starting 2-aza-1,3,5-triene (Table 3). But, in
contrast to acetal-substituted 2-aza-1,3,5-trienes 2b,c
which under similar conditions (Method A) yield mainly
4,5-dihydro-3H-azepines 4b,c (ratio of 4b,c/3b,c 11.5–
12.5:1) (Table 1, entries 3 and 5),17b aryl- and hetaryl-sub-
stituted 2-aza-1,3,5-trienes 6, 10, and 13 in the most of
cases afforded 3H-azepines as the main product.
Thus, deprotonation of 4-methylphenyl- 13a, 4-tert-bu-
tylphenyl- 13b, and 4-methoxyphenyl-substituted 2-aza-
1,3,5-trienes 13c led to a mixtures of the corresponding
3H-azepines and 4,5-dihydro-3H-azepines in a ratio of
90:10 to 75:25 (Table 3, entries 2–4). 4-Fluorophenyl-
substituted 2-aza-1,3,5-triene 13d also gave a mixture of
3H-azepine 14d and 4,5-dihydro-3H-azepine 15d but
with slight predominance of azepine (~55% in mixture)
(entry 5). Thienyl-substituted azatriene 10, as already
mentioned, gave exclusively 3H-azepine 11 (entry 6).
Meanwhile the replacement of the 5-methyl-2-thienyl
substituent in the initial 2-aza-1,3,5-triene with another
five-membered aromatic heterocycle, namely the 1-meth-
yl-1H-pyrrol-2-yl substituent surprisingly led to preferen-
tial formation of 4,5-dihydro-3H-azepine 15e (~78% in a
mixture with 3H-azepine 14e) (entry 7). The same effect
gives the 1H-pyrrol-1-yl substituent in 2-aza-1,3,5-triene
13f (entry 8). In this case, the content of 4,5-dihydro-3H-
azepine 15f in a mixture with azepine 14f was ~87%.
1-(1,2-Propadienyl)-1H-pyrrole, 1-(2-propynyl)benzenes, 1-meth-
yl-2-(2-propynyl)-1H-pyrrole, 5-methyl-2-(2-propynyl)thiophene,
and i-PrNCS were prepared as described in the literature.15a,23
n-BuLi (2.5 M soln in hexane), t-BuOK, and solvents are commer-
cially available. All solvents were purified according to standard
procedures. All reactions (with the exception of isomerization of 1-
aza-1,3,4-trienes into 2-aza-1,3,5-trienes) were performed under
anhydrous conditions and under an argon atmosphere. For all reac-
tions at low temperatures a cooling bath with liquid N2 was used.
All reactions were monitored by TLC on precoated with Merck sil-
ica gel 60 F254 plates, were visualized by exposure to I2 vapor. PE
refers to light petroleum.
IR spectra were measured neat or as KBr pellets on a Bruker Vertex-
70 infrared spectrophotometer. 1H (400.13 MHz), 13C (100.62
MHz), and 15N (40.55 MHz) NMR spectra were recorded on Bruker
DPX-400 and Bruker AV-400 spectrometers in CDCl3 soln at r.t.,
referenced to HMDS (for 1H and 13C) and MeNO2 (for 15N) as inter-
nal standards. Assignments of spectra were carried out using 2D ex-
periments. The mass spectra (EI, 70 eV) were recorded on a
Shimadzu GCMS-QP5050A instrument. The microanalyses were
performed on a Flash EA 1112 Series elemental analyzer. Melting
points were determined using a Kofler micro hot stage.
The nature of such a strong and unpredictable (from the
point of view of stereoelectronic effects) influence of the
substituent [methoxy, 1-(alkoxy)ethoxy, phenyl, thienyl,
pyrrolyl] in the starting 2-aza-1,3,5-triene and/or interme-
Full spectral data for all novel compounds are given below, all pre-
viously characterized compounds gave spectra consistent with the
literature.
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

2198
N. A. Nedolya et al.
FEATURE ARTICLE
1-Aza-1,3,4-trienes 5, 9, 12a–e; General Procedure
tet, 3J = 6.2 Hz, 1 H, NCH(CH3)2], 5.23 (s, 2 H, CH2=), 7.21, 7.33
(2 d, 3J = 8.4 Hz, 4 H, H-o,m); d (minor isomer) = 1.25 [d, 3J = 6.2
Hz, 6 H, NCH(CH3)2], 1.28 [s, 9 H, C(CH3)3], 2.24 (s, 3 H, SMe),
To a stirred soln of corresponding alkyne (50 mmol) in THF (115
mL) under argon, at –95 °C, n-BuLi (40 mL, 100 mmol) was added.
After stirring for an additional 20 min at 10–15 °C, the soln was
cooled to –90 °C and a mixture of i-PrNCS (5.05 g, 50 mmol) and
THF (5 mL) was added in one portion. The temperature of the mix-
ture was allowed to rise to ca. –30 °C, and maintained at this tem-
perature for an additional 20–30 min. Then a mixture of t-BuOH
(3.7 g, 50 mmol) and Et2O (3 mL) was added at –55 °C. The tem-
perature was allowed to rise to –40 °C, the mixture was cooled to
–80 °C, and MeI (20 g, 141 mmol, excess) was then added in one
portion, after which the temperature was allowed to rise to r.t. for ~1
h. The mixture was cooled to –80 °C, and then quenched with sat.
aq NH4Cl soln (100 mL) and extracted with Et2O (3 × 30 mL). The
combined organic extracts were washed with H2O (3 × 15 mL),
dried (MgSO4), and concentrated under reduced pressure at a bath
temperature of 20 °C to give a residue consisting of corresponding
1-aza-1,3,4-triene as a mixture of syn- and anti-isomers. 1-Aza-
1,3,4-trienes 12a and 12d were obtained on a scale of 26 and 29
mmol, respectively. The crude products were purified by flash col-
umn chromatography on neutral alumina (PE). Yields and charac-
teristic data of 1-aza-1,3,4-trienes 5, 9, 12a–e are reported below.
3
3.95 [septet, J = 6.2 Hz, 1 H, NCH(CH3)2], 5.31 (s, 2 H, CH2=),
7.38, 7.46 (2 d, 3J = 8.4 Hz, 4 H, H-o,m).
13
C
NMR: d (major isomer) = 13.30 (SMe), 23.84
jmod
[NCH(CH3)2], 31.21 [C(CH3)3], 34.51 [C(CH3)3], 54.09
[NCH(CH3)2], 79.95 (CH2=), 104.25 (C2), 125.54, 125.66 (4 C-
o,m), 129.24 (C-i), 150.53 (C-p), 157.14 (C=N), 205.90 (=C=);
d (minor isomer) = 15.11 (SMe), 22.68 [NCH(CH3)2], 31.26
[C(CH3)3], 34.48 [C(CH3)3], 53.59 [NCH(CH3)2], 80.43 (CH2=),
105.90 (C2), 125.54, 125.76 (4 C-o,m), 130.33 (C-i), 150.37 (C-p),
157.86 (C=N), 207.88 (=C=).
The 1H–13C HMBC 2D experiment provided additional support for
the proposed structure.
Methyl N-Isopropyl-2-(4-methoxyphenyl)-2,3-butadienimido-
thioate (12c)
Yellow solid; yield: 95% (1H NMR), 8.30 g (64%); ratio major/mi-
nor (1H NMR) ~70:30; mp 38–40 °C.
IR (KBr): 1937 cm–1 (C=C=C).
1H NMR: d (major isomer) = 1.05 [d, 3J = 6.0 Hz, 6 H,
Methyl N-Isopropyl-2-phenyl-2,3-butadienimidothioate (5)
Yellow solid; yield: 90% (1H NMR), 8.16 g (71%); ratio major/
minor (1H NMR) ~70:30; mp 46–48 °C.
IR (KBr): 1937 cm–1 (C=C=C).
3
NCH(CH3)2], 2.35 (s, 3 H, SMe), 3.76 [septet, J = 6.0 Hz, 1 H,
NCH(CH3)2], 3.77 (s, 3 H, OMe), 5.23 (s, 2 H, CH2=), 6.84, 7.21 (2
d, 3J = 8.4 Hz, 4 H, H-o,m); d (minor isomer) = 1.24 [d, 3J = 6.4 Hz,
6 H, NCH(CH3)2], 2.23 (s, 3 H, SMe), 3.75 (s, 3 H, OMe), 3.94 [sep-
tet, 3J = 6.4 Hz, 1 H, NCH(CH3)2], 5.30 (s, 2 H, CH2=), 6.84, 7.30
(2 d, 3J = 8.5 Hz, 4 H, H-o,m).
1H NMR: d (major isomer) = 1.22 [d, 3J = 6.1 Hz,
6 H,
3
NCH(CH3)2], 2.39 (s, 3 H, SMe), 3.97 [septet, J = 6.1 Hz, 1 H,
NCH(CH3)2], 4.93 (s, 2 H, CH2=), 7.08 (m, 1 H, H-p), 7.20 (t,
3J = 7.7 Hz, 2 H, H-m), 7.52 (d, 2 H, H-o); d (minor isomer) = 1.40
[d, 3J = 6.1 Hz, 6 H, NCH(CH3)2], 2.01 (s, 3 H, SMe), 4.26 [septet,
3J = 6.1 Hz, 1 H, NCH(CH3)2], 4.95 (s, 2 H, CH2=), 7.11 (m, 1 H,
H-p), 7.30 (m, 2 H, H-m), 7.64 (m, 2 H, H-o).
13
C
NMR: d (major isomer) = 13.27 (SMe), 23.87
imod
[NCH(CH3)2], 55.23 (OMe), 54.06 [NCH(CH3)2], 80.10 (CH2=),
104.02 (C2), 114.16, 127.10 (4 C-o,m), 124.46 (C-i), 158.98 (C-p),
159.03 (N=C), 205.52 (=C=); d (minor isomer) = 15.02 (SMe),
22.69 [NCH(CH3)2], 53.52 [NCH(CH3)2], 55.18 (OMe), 80.51
(CH2=), 105.68 (C2), 114.09, 127.30 (4 C-o,m), 125.52 (C-i),
158.00 (C-p), 157.28 (N=C), 207.47 (=C=).
Methyl N-Isopropyl-2-(4-methylphenyl)-2,3-butadienimido-
thioate (12a)
Light yellow mobile liquid; yield: 76% (1H NMR), 2.16 g (34%);
ratio major/minor (1H NMR) ~70:30.
Methyl 2-(4-Fluorophenyl)-N-isopropyl-2,3-butadienimido-
thioate (12d)
Dark mobile liquid; yield: 76% (1H NMR), 2.55 g (35%); ratio ma-
jor/minor (1H NMR) ~70:30.
IR (neat): 1938 cm–1 (C=C=C).
1H NMR: d (major isomer) = 1.05 [d, 3J = 6.5 Hz,
6 H,
IR (neat): 1939 cm–1 (C=C=C).
NCH(CH3)2], 2.29 (br s, 3 H, Ph-4-CH3), 2.35 (s, 3 H, SMe), 3.75
3
1H NMR: d (major isomer) = 1.05 [d, 3J = 6.2 Hz, 6 H,
[septet, J = 6.5 Hz, 1 H, NCH(CH3)2], 5.22 (s, 2 H, CH2=), 7.11,
3
3
7.19 (2 d, J = 7.9 Hz, 4 H, H-o,m); d (minor isomer) = 1.24 [d,
NCH(CH3)2], 2.36 (s, 3 H, SMe), 3.72 [septet, J = 6.2 Hz, 1 H,
3J = 6.0 Hz, 6 H, NCH(CH3)2], 2.29 (br s, 3 H, Ph-4-CH3), 2.21 (s,
3 H, SMe), 3.83 [septet, 3J = 6.0 Hz, 1 H, NCH(CH3)2], 5.30 (s, 2
H, CH2=), 7.11, 7.28 (2 d, 3J = 8.1 Hz, 4 H, H-o,m).
13
NCH(CH3)2], 5.25 (s, 2 H, CH2=), 6.99 (t, 3JH-F ≈ 3JH-H = 8.6 Hz, 2
4
H, H-m), 7.25 (dd, JH-F = 5.3 Hz, 2 H, H-o); d (minor isomer) =
3
1.25 [d, J = 6.2 Hz, 6 H, NCH(CH3)2], 2.23 (s, 3 H, SMe), 3.94
[septet, 3J = 6.2 Hz, 1 H, NCH(CH3)2], 5.33 (s, 2 H, CH2=), 6.99 (t,
C
NMR: d (major isomer) = 13.20 (SMe), 23.77
jmod
3JH-F ≈ 3JH-H = 8.6 Hz, 2 H, H-m), 7.35 (dd, 4JH-F = 5.3 Hz, 2 H, H-o).
[NCH(CH3)2], 54.00 [NCH(CH3)2], 79.94 (CH2=), 104.32 (C2),
125.73, 129.36 (4 C-o,m), 137.22 (C-i), 157.05 (C=N), 136.83 (C-
p), 205.75 (=C=); d (minor isomer) = 14.96 (SMe), 22.65
[NCH(CH3)2], 53.49 [NCH(CH3)2], 80.36 (CH2=), 106.03 (C2),
125.94, 129.11 (4 C-o,m), 136.10 (C-p), 136.84 (C-i), 157.68
(C=N), 207.68 (=C=).
13
C
NMR: d (major isomer) = 13.18 (SMe), 23.74
jmod
[NCH(CH3)2], 54.07 [NCH(CH3)2], 80.23 (CH2=), 103.64 (C2),
115.62 (d, JF-C = 21.5 Hz, C-m), 127.53 (d, JC-F = 8.3 Hz, C-o),
128.42 (d, JC-F = 3.3 Hz, C-i), 156.65 (C=N), 162.11 (d, JC-F
2
3
4
1
=
247.4, C-p), 205.82 (=C=); d (minor isomer) = 14.97 (SMe), 22.63
1H–15N HMBC: d (major isomer) = –59.00; d (minor isomer) =
–40.04.
[NCH(CH3)2], 53.59 [NCH(CH3)2], 80.75 (CH2=), 105.33 (C2),
2
3
115.59 (d, JF-C = 22.0 Hz, C-m), 127.72 (d, JC-F = 8.1 Hz, C-o),
4
1
129.35 (d, JC-F = 2.8 Hz, C-i), 157.39 (C=N), 162.11 (d, JC-F
247.4 Hz, C-p), 207.80 (=C=).
=
Methyl 2-(4-tert-Butylphenyl)-N-isopropyl-2,3-butadienimido-
thioate (12b)
Red mobile liquid; yield: 90% (1H NMR), 11.36 g (79%); ratio
major/minor (1H NMR) ~70:30.
Methyl N-Isopropyl-2-(5-methyl-2-thienyl)-2,3-butadieneimi-
dothioate (9)
Transparent brown mobile liquid; yield: 90% (1H NMR), 7.41 g
(59%); ratio major/minor (1H NMR) ~60:40.
IR (neat): 1939 cm–1 (C=C=C).
1H NMR: d (major isomer) = 1.07 [d, 3J = 6.2 Hz,
6 H,
IR (neat): 1934 cm–1 (C=C=C).
NCH(CH3)2], 1.29 [s, 9 H, C(CH3)3], 2.36 (s, 3 H, SMe), 3.77 [sep-
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

FEATURE ARTICLE
New 3H-Azepines and 4,5-Dihydro-3H-azepines
2199
1H NMR: d (major isomer) = 1.08 [d, 3J = 6.2 Hz,
6
H,
NCH(CH3)2], 5.63 (s, 2 H, CH2=), 6.72 (m, 2 H, H3¢, H4¢), 6.74 (m,
2 H, H2¢, H5¢).
NCH(CH3)2], 2.35 (s, 3 H, SMe), 2.41 (s, 3 H, Me-5¢), 3.86 [septet,
3J = 6.2 Hz, 1 H, NCH(CH3)2], 5.21 (s, 2 H, CH2=), 6.58, 6.62 (2 d,
3J = 2.7 Hz, 2 H, H3¢, H4¢); d (minor isomer) = 1.23 [d, 3J = 6.2 Hz,
6 H, NCH(CH3)2], 2.33 (s, 3 H, SMe), 2.41 (s, 3 H, Me-5¢), 3.92
2-Aza-1,3,5-trienes 6, 10, 13a–f; General Procedure
The isomerization of 1-aza-1,3,4-trienes into 2-aza-1,3,5-trienes
was effected by rotating a sample on a rotary evaporator at a bath
temperature of 55–85 °C for 10–30 min. The bath temperatures, re-
action times, and conversions of 1-aza-1,3,4-trienes are reported in
Table 2; spectral data are reported below. 2-Aza-1,3,5-trienes were
used without further purification.
3
[septet, J = 6.2 Hz, 1 H, NCH(CH3)2], 5.31 (s, 2 H, CH2=), 6.58,
6.78 (2 d, 3J = 2.7 Hz, 2 H, H3¢, H4¢).
13C NMR: d = 13.29, 15.41 (SMe), 22.71 (Me-5¢), 23.93
[NCH(CH3)2], 53.71, 54.16 [NCH(CH3)2], 80.23, 80.98 (CH2=),
112.14 (C2), 124.87, 125.66 (C3¢, C4¢), 133.73 (C5¢), 140.35 (C2¢),
156.16, 156.71 (C=N), 204.11, 207.39 (=C=).
(1E)-N-(1-Methylethylidene)-1-(methylsulfanyl)-2-phenyl-1,3-
butadien-1-amine (6)
Dark mobile liquid.
Methyl N-Isopropyl-2-(1-methyl-1H-pyrrol-2-yl)-2,3-butadien-
imidothioate (12e)
Red mobile liquid; yield: 90% (1H NMR), 8.63 g (74%); ratio
major/minor (1H NMR) ~70:30.
IR (neat): 3079, 3055, 3025, 2966, 2924, 2866, 2164, 2146, 2099,
1971, 1944, 1876, 1653, 1602, 1596, 1553, 1491, 1440, 1367, 1301,
1244, 1171, 1107, 1072, 1031, 992, 965, 887, 863, 802, 766, 700,
644, 564 cm–1.
IR (neat): 1934 cm–1 (C=C=C).
1H NMR: d (major isomer) = 1.07 [d, 3J = 6.1 Hz,
6 H,
1H NMR: d = 1.95, 1.97 [2 s, 6 H, N=C(CH3)2], 2.21 (s, 3 H, SMe),
NCH(CH3)2], 2.33 (s, 3 H, SMe), 3.63 (s, 3 H, NMe), 3.89 [septet,
3J = 6.1 Hz, 1 H, NCH(CH3)2], 5.20 (s, 2 H, CH2=), 6.01 (m, 1 H,
H3¢), 6.07 (dd, 3J4,5 = 3.6 Hz, 3J4,3 = 2.8 Hz, 1 H, H4¢), 6.58 (m, 1 H,
3
2
4.46, 4.79 (2 dd, 3Jtrans = 17.4 Hz, Jcis = 10.5 Hz, Jgem = 1.8 Hz, 2
3
3
H, CH2=), 6.41 (dd, Jtrans = 17.4 Hz, Jcis = 10.5 Hz, 1 H, CH=),
7.20 (m, 2 H, H-o), 7.28 (m, 1 H, H-p), 7.34 (m, 2 H, H-m).
3
H5¢); d (minor isomer) = 1.22 [d, J = 6.4 Hz, 6 H, NCH(CH3)2],
2.29 (s, 3 H, SMe), 3.64 (s, 3 H, NMe), 3.90 [septet, 3J = 6.4 Hz, 1
13C NMR: d = 13.68 (SMe), 21.13, 27.39 [N=C(CH3)2], 112.05
(CH2=), 121.22 (C2), 126.83 (CH=), 127.98, 130.58 (4 C-o,m),
133.52 (C-p), 137.54 (C-i), 142.06 (C1), 172.28 (N=C).
H, NCH(CH3)2], 5.30 (s, 2 H, CH2=), 6.02 (m, 1 H, H3¢), 6.11 (m, 1
H, H4¢), 6.54 (m, 1 H, H5¢).
13
C
NMR: d (major isomer) = 13.40 (SMe), 23.86
jmod
(1E)-N-(1-Methylethylidene)-2-(4-methylphenyl)-1-(methylsul-
fanyl)-1,3-butadien-1-amine (13a)
Yellow mobile liquid.
[NCH(CH3)2], 35.72 (NMe), 53.80 [NCH(CH3)2], 80.00 (CH2=),
107.73 (C3¢), 110.02 (C4¢), 111.71 (C2), 124.91 (C5¢), 172.41
(C=N), 122.96 (C2¢), 205.98 (=C=); d (minor isomer) = 13.62
(SMe), 22.57 [NCH(CH3)2], 35.86 (NMe), 53.49 [NCH(CH3)2],
80.68 (CH2=), 107.76 (C3¢), 110.14 (C4¢), 133.22 (C5¢).
IR (neat): 3087, 3046, 3022, 3007, 2966, 2924, 2868, 2732, 2611,
2444, 2890, 2146, 2096, 2023, 2003, 1938, 1902, 1794, 1728, 1655,
1634, 1599, 1512, 1435, 1423, 1367, 1339, 1301, 1269, 1244, 1212,
1189, 1171, 1151, 1107, 1080, 1038, 1022, 992, 966, 886, 867, 819,
803, 789, 770, 749, 734, 725, 687, 669, 639, 614, 564, 550, 531,
502, 479, 450 cm–1.
Methyl N-Isopropyl-2-(1H-pyrrol-1-yl)-2,3-butadienimidothio-
ate (12f)
To a stirred soln of 1-(1,2-propadienyl)-1H-pyrrole (5.26 g, 50
mmol) in THF (50 mL) under argon, at –90 °C, n-BuLi (50 mmol,
20 mL) was added. After stirring for an additional 10 min at ca. –70
to –60 °C, the soln was cooled to –90 °C and a mixture of i-PrNCS
(5.05 g, 50 mmol) and THF (5 mL) was added in one portion. The
temperature of the mixture was allowed to rise to –35 to –30 °C, and
maintained at this temperature for an additional 20 min. The soln
was cooled to –80 °C and MeI (14 g, 100 mmol, excess) was then
added in one portion, after which the temperature was allowed to
rise to r.t. for 30 min. The mixture was cooled to –80 °C, and then
quenched with sat. aq NH4Cl soln (100 mL) and extracted with Et2O
(3 × 30 mL). The combined organic extracts were washed with H2O
(3 × 15 mL), dried (MgSO4), and concentrated under a reduced
pressure at a bath temperature of 20 °C to give a residue (10.40 g of
dark mobile liquid) consisting of 1-aza-1,3,4-triene 12f (~63%) as a
mixture of syn- and anti-isomers, 2-aza-1,3,5-triene 13f (~4%) and
1H NMR: d = 1.969, 1.976 [2 s, 6 H, N=C(CH3)2], 2.22 (s, 3 H,
3
SMe), 2.35 (s, 3 H, Ph-CH3-4), 4.48, 4.80 (2 d, Jtrans = 17.1 Hz,
3
3
3Jcis = 10.6 Hz, 2 H, CH2=), 6.40 (dd, Jtrans = 17.1 Hz, Jcis = 10.6
Hz, 1 H, CH=), 7.09, 7.18 (2 m, 4 H, H-o,m).
13
C
NMR: d = 13.86 (SMe), 21.25 (Ph-CH3-4), 21.29, 27.56
jmod
[N=C(CH3)2], 112.20 (CH2=), 121.27 (C2), 128.94, 130.53 (4 C-
o,m), 133.75 (CH=), 134.62 (C1), 136.57 (C-p), 136.83 (C-i),
172.34 (N=C).
(1E)-2-(4-tert-Butylphenyl)-N-(1-methylethylidene)-1-(methyl-
sulfanyl)-1,3-butadien-1-amine (13b)
Viscous red-brown liquid.
1H NMR: d = 1.32 [s, 9 H, C(CH3)3], 1.98, 1.99 [2 s, 6 H,
N=C(CH3)2], 2.23 (s, 3 H, SMe), 4.50, 4.80 (2 dd, 3Jtrans = 17.1 Hz,
1
2
3
3Jcis = 10.6 Hz, Jgem = 1.8 Hz, 2 H, CH2=), 6.40 (dd, Jtrans = 17.1
unreacted 1-(1,2-propadienyl)-1H-pyrrole (~33%) (by H NMR).
Hz, 3Jcis = 10.6 Hz, 1 H, CH=), 7.13, 7.38 (2 d, 3J = 8.3 Hz, 4 H, H-
The residue was purified by flash column chromatography (neutral
alumina, PE) to give a mixture (7.82 g) of 1-aza-1,3,4-triene 12f
(~58%), 2-aza-1,3,5-triene 13f (~15%), and starting allene (~27%).
o,m).
13
C
NMR: d = 13.95 (SMe), 21.36, 27.63 [N=C(CH3)2], 31.38
jmod
[C(CH3)3], 34.50 [C(CH3)3], 112.25 (CH2=), 121.20 (C2), 125.07,
130.26 (4 C-o,m), 133.81 (CH=), 134.51 (C-i), 141.92 (C1), 149.73
(C-p), 172.36 (N=C).
The 1H–13C HMBC 2D experiment provided additional support for
1-Aza-1,3,4-triene 12f
Transparent brown mobile liquid; yield: 63% (by 1H NMR), 5.71 g
(52%) after flash chromatography; ratio major/minor (1H NMR)
~50:50.
the structure 13b.
IR (neat): 1964 cm–1 (C=C=C).
1H NMR: d (major isomer) = 1.23 [d, 3J = 6.1 Hz,
6 H,
(1E)-2-(4-Methoxyphenyl)-N-(1-methylethylidene)-1-(methyl-
sulfanyl)-1,3-butadien-1-amine (13c)
Dark mobile liquid.
3
NCH(CH3)2], 2.34 (s, 3 H, SMe), 3.78 [septet, J = 6.1 Hz, 1 H,
NCH(CH3)2], 5.55 (s, 2 H, CH2=), 6.71 (m, 2 H, H3¢, H4¢), 6.73 (m,
2 H, H2¢, H5¢); d (minor isomer) = 1.05 [d, 3J = 6.1 Hz, 6 H,
3
NCH(CH3)2], 2.17 (s, 3 H, SMe), 3.91 [septet, J = 6.1 Hz, 1 H,
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

2200
N. A. Nedolya et al.
FEATURE ARTICLE
IR (neat): 3087, 3033, 2997, 2963, 2925, 2868, 2835, 2612, 2528,
2477, 2279, 2146, 2095, 2030, 1939, 1886, 1774, 1728, 1655, 1608,
1603, 1575, 1553, 1508, 1464, 1439, 1367, 1338, 1302, 1284, 1244,
1173, 1132, 1105, 1080, 1035, 992, 966, 936, 886, 831, 806, 789,
761, 742, 673, 636, 615, 565, 509 cm–1.
122.24 (C2), 128.25 (C2¢), 133.25 (CH=), 147.14 (C1), 172.44
(N=C).
(1E)-N-(1-Methylethylidene)-1-(methylsulfanyl)-2-(1H-pyrrol-
1-yl)-1,3-butadien-1-amine (13f)
Brown viscous liquid.
1H NMR: d = 1.98 [s, 6 H, N=C(CH3)2], 2.23 (s, 3 H, SMe), 3.80 (s,
3
3
3 H, OMe), 4.49, 4.80 (2 dd, Jtrans = 17.2 Hz, Jcis = 10.6 Hz,
IR (neat): 3099, 2968, 2926, 2868, 2630, 2454, 2147, 2098, 1965,
1656, 1606, 1577, 1522, 1493, 1484, 1432, 1369, 1332, 1281, 1247,
1202, 1171, 1136, 1103, 1078, 1066, 1048, 985, 967, 946, 890, 848,
825, 797, 756, 725, 674, 634, 611, 571 cm–1.
3
3
2Jgem = 1.5 Hz, 2 H, CH2=), 6.40 (dd, Jtrans = 17.2 Hz, Jcis = 10.6
Hz, 1 H, CH=), 6.91, 7.13 (2 d, 3J = 8.6 Hz, 4 H, H-o,m).
13
C
NMR: d = 13.86 (SMe), 21.29, 27.55 [N=C(CH3)2], 55.02
jmod
(OMe), 112.06 (CH2=), 113.61, 131.80 (4 C-o,m), 120.87 (C2),
129.83 (C-i), 133.93 (CH=), 142.22 (C1), 158.54 (C-p), 172.29
(N=C).
1H NMR: d = 1.98, 1.99 [2 s, 6 H, N=C(CH3)2], 2.23 (s, 3 H, SMe),
4.44, 4.80 (2 dd, 3Jtrans = 16.9 Hz, Jcis = 10.8 Hz, Jgem = 1.0 Hz, 2
H, CH2=), 6.23 (m, 3J = 2.3 Hz, 2 H, H3¢, H4¢), 6.26 (dd,
3Jtrans = 16.9 Hz, 3Jcis = 10.8 Hz, 1 H, CH=), 6.59 (t, 3J = 2.3 Hz, 2
H, H2¢, H5¢).
3
2
(1E)-2-(4-Fluorophenyl)-N-(1-methylethylidene)-1-(methylsul-
fanyl)-1,3-butadien-1-amine (13d)
Yellowish-orange liquid.
13C NMR: d = 13.19 (SMe), 21.57, 27.86 [N=C(CH3)2], 108.02
(C3¢, C4¢), 110.37 (CH2=), 120.06 (C2), 122.22 (C2¢, C5¢), 130.27
(CH=), 144.11 (C1), 173.80 (N=C).
IR (neat): 3088, 3042, 2990, 2965, 2926, 2869, 2721, 2612, 2449,
2098, 2028, 1970, 1941, 1891, 1770, 1727, 1687, 1656, 1634, 1599,
1553, 1506, 1465, 1435, 1367, 1303, 1272, 1241, 1220, 1194, 1172,
1156, 1105, 1091, 1037, 1016, 992, 967, 937, 888, 870, 836, 815,
797, 762, 740, 727, 672, 644, 634, 612, 582, 562, 532, 505, 470, 388
cm–1.
3H-Azepines 7, 11, 14a–f and 4,5-Dihydro-3H-azepines 8,
15a–f; General Procedure for Method A
To a stirred soln of the 2-aza-1,3,5-triene (27.4–31.5 mmol) (in the
case of 13a and 13d, 6.4 and 6.3 mmol, respectively) in THF (35–
55 mL), THF–DMSO (1:1, 20–30 mL) and t-BuOK (1.1–1.5 equiv)
were sequentially added at –65 °C. The mixture was warmed to –30
°C, stirred at this temperature for 30 min, then cooled to –60 °C,
quenched with H2O (~50 mL), and extracted with Et2O (3 × 30 mL).
The combined organic extracts were washed with H2O (3 × 15 mL),
dried (MgSO4), and concentrated under a reduced pressure at a bath
temperature of 20 °C. The products were purified and separated in
the following way. Initially, column chromatography (neutral alu-
mina, PE and PE–Et2O, 10:1, 3:1) gave 2 fractions consisting most-
ly of azepine and dihydroazepine. Then, the fraction containing
predominantly azepine was repetitively purified by column chroma-
tography or recrystallized (PE). The fraction enriched in dihy-
droazepine (the ethereal soln) was vigorously shaken for few
seconds with a calculated amount of ~3% HCl soln; the dihy-
droazepine remained in ethereal soln and the azepine, in the form of
its iminium salt, passed into aqueous phase from which, after neu-
tralization with a ~10% aq KOH soln, it was isolated by Et2O. Both
organic solns were dried (MgSO4). Concentration under reduced
pressure followed by column chromatography afforded pure dihy-
droazepine and an additional portion of azepine. The ratios and
yields are reported in Table 3; physical and spectral data are report-
ed below.
1H NMR: d = 1.983, 1.986 [2 s, 6 H, N=C(CH3)2], 2.23 (s, 3 H,
SMe), 4.42, 4.80 (2 dd, 3Jtrans = 17.3 Hz, 3Jcis = 10.6 Hz, 2Jgem = 1.6
3
3
Hz, 2 H, CH2=), 6.40 (dd, Jtrans = 17.3 Hz, Jcis = 10.6 Hz, 1 H,
CH=), 7.05 (t, 3JH,H = 8.8 Hz, 2 H, H-m), 7.17 (dd, 3JH,F = 5.6 Hz, 2
H, H-o).
13
C
NMR: d = 13.80 (SMe), 21.32, 27.57 [N=C(CH3)2], 112.16
3
jmod
(CH2=), 115.22 (d, JC-F = 21.3 Hz, C-m), 120.15 (C2), 132.43 (d,
3JC-F = 8.1 Hz, C-o), 133.48 (d, 4JC-F = 3.3 Hz, C-i), 133.70 (CH=),
142.65 (C1), 161.91 (d, 1JC-F = 246.0 Hz, C-p), 172.58 (N=C).
(1E)-N-(1-Methylethylidene)-1-(methylsulfanyl)-2-(5-methyl-2-
thienyl)-1,3-butadien-1-amine (10)
Dark mobile liquid.
IR (neat): 3086, 3059, 2966, 2923, 2864, 1656, 1602, 1533, 1481,
1464, 1434, 1367, 1338, 1317, 1273, 1244, 1212, 1159, 1135, 1078,
1035, 989, 967, 939, 889, 844, 796, 662, 616 cm–1.
1H NMR: d = 1.94, 2.01 [2 s, 6 H, N=C(CH3)2], 2.22 (s, 3 H, SMe),
3
2.48 (s, 3 H, Me-5¢), 4.77, 4.84 (2 dd, 3Jtrans = 17.0 Hz, Jcis = 10.6
2
3
Hz, Jgem = 1.4 Hz, 2 H, CH2=), 6.36 (dd, Jtrans = 17.0 Hz,
3Jcis = 10.6 Hz, 1 H, CH=), 6.68 (s, 2 H, H3¢, H4¢).
13C NMR: d = 13.94 (SMe), 15.44 (Me-5¢), 21.60, 27.57
[N=C(CH3)2], 112.13 (CH2=), 113.41 (C2), 124.82, 133.74 (C3¢,
C4¢), 128.66 (CH=), 135.81 (C1), 140.24 (C2¢), 145.61 (C5¢),
172.47 (N=C).
2-Methyl-6-phenyl-3H-azepine (7)
Scale: 31 mmol; THF–DMSO, 5.0:1; t-BuOK (1.2 equiv); dark
brown oil; yield: 2.44 g (43%) after rough separation on alumina;
1.50 g (26%) after separation with HCl.
(1E)-N-(1-Methylethylidene)-2-(1-methyl-1H-pyrrol-2-yl)-1-
(methylsulfanyl)-1,3-butadien-1-amine (13e)
Brown mobile liquid.
IR (neat): 3082, 3057, 3027, 2971, 2944, 2911, 2885, 2830, 1950,
1883, 1805, 1762, 1715, 1686, 1619, 1598, 1578, 1562, 1508, 1490,
1447, 1427, 1408, 1371, 1340, 1314, 1290, 1276, 1242, 1210, 1187,
1142, 1121, 1007, 1035, 1015, 1002, 957, 944, 894, 884, 817, 771,
750, 698, 647, 630, 616, 568, 510, 473, 415 cm–1.
IR (neat): 3098, 3039, 2966, 2925, 2867, 2811, 2708, 2614, 2456,
2147, 2099, 1941, 1656, 1599, 1569, 1523, 1482, 1469, 1430, 1409,
1368, 1314, 1259, 1246, 1215, 1168, 1132, 1106, 990, 965, 891,
852, 799, 780, 710, 651, 610, 557, 526, 505, 473, 439, 380 cm–1.
1H NMR (50 °C*): d = 2.18 (s, 3 H, Me-2), 2.54 (m, 2 H, CH2-3),
5.43 (dtd, 3J4,5 = 9.0 Hz, 3J4,3 = 7.0 Hz, 5J4,7 = 0.6 Hz, 1 H, H4), 6.43
(dd, 3J5,4 = 9.0 Hz, 4J5,7 = 1.8 Hz, 1 H, H5), 7.28 (m, 1 H, H-p), 7.36
1H NMR: d = 1.98, 1.99 [2 s, 6 H, N=C(CH3)2], 2.24 (s, 3 H, SMe),
3
3
4
3.43 (s, 3 H, NMe), 4.48, 4.80 (2 dd, Jtrans = 16.8 Hz, Jcis = 10.3
(m, 2 H, H-m), 7.44 (m, 2 H, H-o), 7.64 (ddq, J7,5 = 1.8 Hz,
Hz, 2Jgem = 1.6 Hz, 2 H, CH2=), 6.02 (dd, 3J3,4 = 3.2 Hz, 4J3,5 = 1.5
5J7,4 = 0.6 Hz, 1 H, H7); * CH2-3 signal is not visible at r.t.
3
Hz, 1 H, H3¢), 6.15 (dd, J4,5 = 2.8 Hz, 1 H, H4¢), 6.35 (dd,
13
C
jmod
NMR: d = 26.30 (Me-2), 38.42 (C3), 116.41 (C4), 127.08
3Jtrans = 16.8 Hz, 3Jcis = 10.3 Hz, 1 H, CH=), 6.67 (br t, 1 H, H5¢).
(C5), 127.52 (2 C-o), 128.21 (C-p), 128.47 (2 C-m), 129.14 (C6),
138.14 (C7), 140.57 (C-i), 149.92 (C2).
13C NMR: d = 13.66 (SMe), 21.63, 27.66 [N=C(CH3)2], 33.86
(NMe), 107.02 (C3¢), 109.94 (CH2=), 111.74 (C4¢), 121.59 (C5¢),
The 1H–1H COSY-45, 1H–13C HSQC, and HMBC 2D experiments
provided additional support for the structure 7.
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

FEATURE ARTICLE
New 3H-Azepines and 4,5-Dihydro-3H-azepines
2201
MS (EI): m/z (%) = 183 (100) [M]+, 182 (74) [M – 1]+, 168 (36),
(dd, 4J5,7 = 1.2 Hz, 1 H, H5), 7.39 (m, 4 H, H-o,m), 7.65 (br s, 1 H,
141 (93), 115 (53).
H7).
13
The data are consistent with those previously reported.18
C
jmod
NMR: d = 26.30 (Me-2), 31.33 [C(CH3)3], 34.48 [C(CH3)3],
38.37 (C3), 116.35 (C4), 125.43, 127.15 (4 C-o,m), 128.24 (C5),
128.93 (C-i), 137.65 (C6), 137.87 (C7), 149.85 (C2), 150.12 (C-p).
The 1H–13C HSQC 2D experiment provided additional support for
7-Methyl-2-(methylsulfanyl)-3-phenyl-4,5-dihydro-3H-azepine
(8)
Colorless viscous liquid; yield: 1.61 g (23%) after rough separation
the structure 14b.
on alumina; 1.30 g (18%) after separation with HCl; nD21 1.5866.
MS (EI): m/z (%) = 239 (99) [M]+, 240 (24) [M + 1]+, 238 (53) [M
IR (neat): 3105, 3086, 3060, 3028, 2972, 2940, 2921, 1947, 1883,
1803, 1633, 1614, 1603, 1561, 1495, 1450, 1408, 1375, 1336, 1312,
1236, 1209, 1173, 1121, 1080, 1030, 1004, 972, 919, 896, 882, 840,
794, 784, 758, 739, 698, 651, 620, 611, 591, 549, 513, 468 cm–1.
– 1]+, 224 (88), 182 (100), 115 (29), 77 (61).
3-(4-tert-Butylphenyl)-7-methyl-2-(methylsulfanyl)-4,5-dihy-
dro-3H-azepine (15b)
Yield: 2.22 g (25%) after rough separation on alumina.
1H NMR: d = 1.93 (s, 3 H, Me-7), 1.92, 2.00 (2 m, 2 H, CH2-4), 2.22
3
(s, 3 H, SMe), 2.28, 2.61 (2 m, 2 H, CH2-5), 4.08 (dd, J3,4 = 11.8
1H NMR: d = 1.28 [s, 9 H, C(CH3)3], 1.93 (s, 3 H, Me-7), 1.92, 2.00
Hz, 3J3,4¢ = 6.7 Hz, 1 H, H3), 5.27 (br t, 3J6,5 = 6.4 Hz, 1 H, H6), 7.26
(2 m, 2 H, CH2-4), 2.23 (s, 3 H, SMe), 2.28, 2.61 (2 m, 2 H, CH2-5),
(m, 5 H, H-o,m,p).
4.05 (dd, J3,4 = 11.8 Hz, 3J3,4¢ = 6.7 Hz, 1 H, H3), 5.28 (br t,
3
13
C
jmod
NMR: d = 13.24 (SMe), 22.50 (Me-7), 23.48 (C4), 40.27
3J6,5 = 6.4 Hz, 1 H, H6), 7.19 (m, 3JHm–Ho = 8.1 Hz, 2 H, H-o), 7.26
(m, 2 H, H-m).
(C5), 50.77 (C3), 110.29 (C6), 127.30 (C-p), 128.00 (2 C-o), 129.41
(2 C-m), 138.60 (C7), 146.99 (C-i), 173.02 (C2).
13C NMR: d = 13.32 (SMe), 22.53 (Me-7), 23.59 (C4), 31.30
[C(CH3)3], 34.44 [C(CH3)3], 40.54 (C5), 50.42 (C3), 110.35 (C6),
127.57 (C-p), 127.58 (2 C-m), 129.08 (2 C-o), 137.00 (C-i), 147.03
(C7), 173.02 (C2).
The 1H–1H COSY-45, 1H–13C HSQC, and HMBC 2D experiments
provided additional support for the structure 8.
MS (EI): m/z (%) = 231 (16) [M]+, 184 (100), 115 (50).
The data are consistent with those previously reported.18
6-(4-Methoxyphenyl)-2-methyl-3H-azepine (14c)
Scale: 28.5 mmol; THF–DMSO, 4.8:1; t-BuOK (1.2 equiv); yellow
solid; yield: 3.41 g (56%) after rough separation on alumina; 0.95 g
(16%) after separation with HCl, followed by purification on alumi-
na; mp 70–72 °C.
2-Methyl-6-(4-methylphenyl)-3H-azepine (14a)
Scale: 6.4 mmol; THF–DMSO, 6.0:1; t-BuOK (1.4 equiv); yellow
solid; yield: 0.60 g (48%) after rough separation on alumina; 0.50 g
(40%) after recrystallization (PE); mp 67–68 °C.
IR (KBr): 3096, 3069, 3026, 2997, 2981, 2960, 2933, 2907, 2892,
2834, 2033, 1971, 1912, 1848, 1780, 1764, 1724, 1676, 1656, 1619,
1607, 1572, 1512, 1499, 1450, 1439, 1423, 1399, 1367, 1341, 1313,
1283, 1246, 1215, 1179, 1147, 1114, 1035, 1015, 969, 958, 948,
898, 885, 834, 820, 790, 763, 727, 667, 648, 624, 605, 567, 531,
505, 449, 421, 405 cm–1.
IR (KBr): 3082, 3047, 3020, 2996, 2965, 2950, 2916, 2890, 2858,
1622, 1613, 1513, 1431, 1422, 1396, 1372, 1365, 1339, 1312, 1289,
1274, 1239, 1212, 1180, 1145, 1117, 1041, 1022, 1013, 1000, 965,
957, 946, 896, 886, 842, 822, 817, 760, 719, 670, 647, 631, 601,
563, 512, 460, 427, 413, 392 cm–1.
1H NMR: d = 2.18 (s, 3 H, Me-4¢), 2.35 (s, 3 H, Me-2), 2.55 (m, 2
H, CH2-3), 5.42 (dt, 2J4,5 = 9.0 Hz, 3J4,3 = 6.9 Hz, 1 H, H4), 6.41 (dd,
4J5,7 = 1.7 Hz, 1 H, H5), 7.17, 7.32 (2 d, 3J = 7.8 Hz, 4 H, H-o,m),
7.62 (br s, 1 H, H7).
1H NMR: d = 2.18 (s, 3 H, Me-2), 2.56 (m, 2 H, CH2-3), 3.81 (s, 3
H, OMe), 5.42 (dt, 3J4,5 = 8.8 Hz, 3J4,3 = 6.9 Hz, 1 H, H4), 5.39 (dd,
4J5,7 = 1.6 Hz, 1 H, H5), 6.90, 7.36 (2 d, 3J = 8.6 Hz, 4 H, H-o,m),
7.59 (br s, 1 H, H7).
13
13
C
NMR: d = 20.94 (Me-4¢), 26.17 (Me-2), 38.27 (C3), 116.15
jmod
C
NMR: d = 26.25 (Me-2), 38.32 (C3), 55.29 (OMe), 113.86
jmod
(C4), 127.28, 129.06 (4 C-o,m), 128.17 (C5), 128.88 (C-i), 136.72
(C-p), 137.63 (C6), 137.69 (C7), 149.57 (C2).
(2 C-o), 116.25 (C4), 128.29 (C5), 128.59 (2 C-m), 128.68 (C6),
133.20 (C-i), 137.45 (C7), 149.57 (C2), 158.97 (C-p).
MS (EI): m/z (%) = 197 (100) [M]+, 198 (31) [M + 1]+, 196 (90) [M
MS (EI): m/z (%) = 213 (99) [M]+, 214 (15) [M + 1]+, 212 (58) [M
– 1]+, 182 (78), 181 (36), 155 (42), 141 (73), 115 (67).
– 1]+, 128 (61).
7-Methyl-3-(4-methylphenyl)-2-(methylsulfanyl)-4,5-dihydro-
3H-azepine (15a)
Yield: 0.12 g (8%) after rough separation on alumina.
3-(4-Methoxyphenyl)-7-methyl-2-(methylsulfanyl)-4,5-dihy-
dro-3H-azepine (15c)
White solid; yield: 1.18 g (16%) after rough separation on alumina;
0.54 g (9%) after separation with HCl and purification on alumina;
mp 55–56 °C.
1H NMR: d = 1.93 (s, 3 H, Me-7), 1.92, 2.00 (2 m, 2 H, CH2-4), 2.19
(s, 3 H, Me-4¢), 2.22 (s, 3 H, SMe), 2.28, 2.61 (2 m, 2 H, CH2-5),
3
4.04 (dd, J3,4 = 11.6 Hz, 3J3,4¢ = 6.6 Hz, 1 H, H3), 5.27 (br t,
IR (KBr): 3046, 3030, 2969, 2959, 2936, 2921, 2908, 2881, 2843,
2044, 1910, 1889, 1767, 1664, 1632, 1611, 1567, 1548, 1514, 1459,
1442, 1371, 1349, 1314, 1306, 1291, 1278, 1253, 1204, 1183, 1165,
1153, 1121, 1083, 1028, 1004, 936, 909, 882, 832, 815, 802, 788,
781, 666, 632, 591, 576, 551, 517, 503, 473, 455 cm–1.
3J6,5 = 6.4 Hz, 1 H, H6), 7.17 (m, 2 H, H-m), 7.33 (m, 2 H, H-o).
6-(4-tert-Butylphenyl)-2-methyl-3H-azepine (14b)
Scale: 30.4 mmol; THF–DMSO, 4.6:1; t-BuOK (1.2 equiv); yellow
solid; yield: 5.37 g (74%) after rough separation on alumina; 2.16 g
(30%) after separation with HCl; mp 92–95 °C.
1H NMR: d = 1.93 (br s, 3 H, Me-7), 1.92, 2.00 (2 m, 2 H, CH2-4),
2.22 (s, 3 H, SMe), 2.26, 2.58 (2 m, 2 H, CH2-5), 3.77 (s, 3 H, OMe),
3
4.02 (dd, J3,4 = 12.0 Hz, 3J3,4¢ = 6.7 Hz, 1 H, H3), 5.28 (br t,
IR (KBr): 3030, 2960, 2894, 2865, 1619, 1561, 1511, 1473, 1458,
1425, 1414, 1392, 1363, 1337, 1287, 1275, 1266, 1210, 1187, 1116,
1109, 1023, 1012, 1000, 957, 945, 933, 896, 884, 843, 830, 821,
764, 745, 733, 659, 646, 586, 577, 543, 484, 417 cm–1.
3J6,5 = 6.0 Hz, 1 H, H6), 6.84, 7.16 (2 d, 3J = 8.8 Hz, 4 H, H-o,m).
13
C
NMR: d = 13.35 (SMe), 22.52 (Me-7), 23.56 (C4), 40.89
jmod
(C5), 49.96 (C3), 55.16 (OMe), 110.33 (C6), 113.45 (2 C-m),
130.52 (2 C-o), 130.67 (C-i), 147.17 (C7), 158.93 (C-p), 173.84
(C2).
1H NMR: d = 1.32 [s, 9 H, C(CH3)3], 2.19 (s, 3 H, Me-2), 2.55 (m,
2 H, CH2-3), 5.43 (dt, 3J4,5 = 8.8 Hz, 3J4,3 = 7.2 Hz, 1 H, H4), 6.43
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

2202
N. A. Nedolya et al.
FEATURE ARTICLE
MS (EI): m/z (%) = 261 (65) [M]+, 262 (9) [M + 1]+, 260 (9) [M –
MS (EI): m/z (%) = 203 (100) [M]+, 202 (73), 188 (28), 161 (20),
128 (22), 101 (20).
1]+, 214 (37), 172 (65), 121 (50), 112 (100).
The data are consistent with those previously reported.19
6-(4-Fluorophenyl)-2-methyl-3H-azepine (14d)
Scale: 6.3 mmol; THF–DMSO, 5.3:1; t-BuOK (1.2 equiv); yellow
solid; yield: 0.52 g (41%) after rough separation on alumina; 0.31 g
(24%) after recrystallization (PE); mp 66–67 °C.
2-Methyl-6-(1-methyl-1H-pyrrol-2-yl)-3H-azepine (14e)
Scale: 31.5 mmol; THF–DMSO, 4.6:1; t-BuOK (1.5 equiv); orange
liquid; yield: 1.2 g (20%) after rough separation on alumina; nD
21
IR (KBr): 3037, 3023, 3006, 2977, 2912, 2898, 1652, 1624, 1611,
1599, 1505, 1469, 1433, 1421, 1399, 1369, 1339, 1305, 1290, 1275,
1236, 1222, 1187, 1159, 1148, 1099, 1016, 971, 961, 952, 946, 897,
883, 836, 825, 806, 768, 722, 668, 648, 625, 601, 564, 523, 466,
443, 420, 404 cm–1.
1H NMR: d = 2.18 (s, 3 H, Me-2), 2.54 (m, 2 H, CH2-3), 5.42 (dt,
3J4,5 = 8.8 Hz, 3J4,3 = 7.2 Hz, 1 H, H4), 6.36 (dd, 4J5,7 = 1.9 Hz, 1 H,
H5), 7.03 (t, 3JH,H ≈ 3JH,F = 8.8 Hz, 2 H, H-m), 7.37 (dd, 4JH,F = 5.6
Hz, 2 H, H-o), 7.57 (br s, 1 H, H7).
1.5966.
IR (neat): 3099, 3024, 2971, 2944, 2910, 2880, 2830, 2718, 1615,
1573, 1542, 1500, 1484, 1470, 1427, 1406, 1370, 1332, 1307, 1284,
1238, 1210, 1183, 1141, 1090, 1056, 1021, 1002, 996, 954, 942,
898, 888, 872, 817, 783, 760, 713, 650, 631, 609, 557, 504, 405
cm–1.
1H NMR: d = 1.23, 2.55 (2 m, 2 H, CH2-3), 2.17 (s, 3 H, Me-2), 3.52
(s, 3 H, NMe), 5.33 (dt, 3J4,5 = 8.7 Hz, 3J4,3 = 7.2 Hz, 1 H, H4), 6.12
(dd, 3J4¢,3¢ = 3.6 Hz, 3J4¢,5¢ = 2.9 Hz, 1 H, H4¢), 6.21 (dd, 3J3¢,4¢ = 3.6
Hz, 4J3¢,5¢ = 1.8 Hz, 1 H, H3¢), 6.32 (dd, 4J5,7 = 1.3 Hz, 1 H, H5), 6.64
(t, 4J5¢,3¢ = 1.8 Hz, 1 H, H5¢), 7.48 (br s, 1 H, H7).
13
13
C
NMR: d = 26.25 (Me-2), 38.41 (C3), 115.22 (d, 3JC,F = 21.5
jmod
Hz, 2 C-m), 116.51 (C4), 128.04 (C5), 128.13 (C-i), 129.04 (d,
3JC,F = 7.9 Hz, 2 C-o), 136.66 (C6), 138.04 (C7), 149.88 (C2),
162.29 (d, 1JC,F = 245.3 Hz, C-p).
C
NMR: d = 26.05 (Me-2), 34.48 (NMe), 38.00 (C3), 107.08
jmod
(C4¢), 108.39 (C3¢), 114.57 (C4), 120.63 (C6), 123.54 (C5¢), 128.87
(C5), 133.75 (C2¢), 139.71 (C7), 149.11 (C2).
The 1H–13C HSQC and HMBC 2D experiments provided additional
support for the structure 14d.
The 1H–13C HSQC and HMBC 2D experiments provided additional
support for the structure 14e.
MS (EI): m/z (%) = 201 (97) [M]+, 202 (32) [M + 1]+, 200 (88) [M
– 1]+, 186 (44), 160 (59), 159 (100), 133 (88).
MS (EI): m/z (%) = 186 (100) [M]+, 187 (15) [M + 1]+, 185 (69) [M
– 1]+, 171 (23), 170 (20), 144 (39).
3-(4-Fluorophenyl)-7-methyl-2-(methylsulfanyl)-4,5-dihydro-
3H-azepine (15d)
Yellow viscous liquid; yield: 0.37 g (24%) after rough separation on
alumina followed by separation with HCl; 0.10 g (6%) after 2-fold
purification on alumina.
7-Methyl-3-(1-methyl-1H-pyrrol-2-yl)-2-(methylsulfanyl)-4,5-
dihydro-3H-azepine (15e)
White solid; yield: 4.16 g (56%) after rough separation on alumina;
2.51 g (34%) after purification on alumina, followed by separation
with HCl; mp 77–79 °C.
IR (neat): 3033, 2964, 2924, 2873, 1712, 1634, 1605, 1567, 1510,
1465, 1445, 1437, 1416, 1377, 1361, 1349, 1312, 1235, 1226, 1192,
1175, 1159, 1151, 1122, 1099, 1082, 1035, 1015, 1004, 991, 973,
936, 910, 883, 830, 814, 791, 761, 724, 663, 635, 611, 590, 572,
548, 512, 479, 463, 429 cm–1.
IR (KBr): 3108, 3027, 2992, 2969, 2947, 2937, 2923, 2911, 2893,
2864, 2853, 2808, 2725, 1631, 1611, 1607, 1567, 1533, 1493, 1464,
1443, 1430, 1413, 1377, 1364, 1347, 1326, 1302, 1283, 1245, 1231,
1191, 1173, 1152, 1123, 1081, 1059, 1049, 1039, 1006, 976, 911,
887, 861, 846, 803, 786, 778, 708, 692, 684, 670, 622, 609, 580,
535, 499, 476, 460 cm–1.
1H NMR: d = 1.88, 2.01 (2 m, 2 H, CH2-4), 1.94 (s, 3 H, Me-7), 2.24
(s, 3 H, SMe), 2.37, 2.60 (2 m, 2 H, CH2-5), 3.38 (s, 3 H, NMe), 4.02
(dd, 3J3,4 = 12.4 Hz, 3J3,4¢ = 7.0 Hz, 1 H, H3), 5.32 (t, 3J6,5 = 7.0 Hz,
1H NMR: d = 1.40, 1.63, 1.98 (3 m, 2 H, CH2-4), 1.93 (br s, 3 H,
Me-7), 2.24 (s, 3 H, SMe), 2.28, 2.57 (2 m, 2 H, CH2-5), 4.06 (dd,
3J3,4 = 11.8 Hz, 3J3,4¢ = 6.5 Hz, 1 H, H3), 5.28 (br t, 3J6,5 = 6.2 Hz, 1
3
H, H6), 6.99 (t, JH,H
≈
3JH,F = 8.6 Hz, 2 H, H-m), 7.21 (dd,
4JH,F = 5.6 Hz, 2 H, H-o).
13
3
3
C
NMR: d = 13.29 (SMe), 22.49 (Me-7), 23.46 (C4), 40.65
1 H, H6), 6.07 (m, 1 H, H3¢), 6.11 (dd, J4¢,3¢ = 3.3 Hz, J4¢,5¢ = 2.9
jmod
(C5), 50.04 (C3), 110.33 (C6), 114.92 (d, 3JC,F = 21.3 Hz, 2 C-m),
Hz, 1 H, H4¢), 6.61 (dd, 4J5¢,3¢ = 1.8 Hz, 1 H, H5¢).
4
4
130.94 (d, JC-F = 7.9 Hz, 2 C-o), 134.40 (d, JC,F = 2.9 Hz, C-i),
13
C
NMR: d = 19.93 (SMe), 22.14 (Me-7), 23.12 (C4), 33.38
jmod
162.13 (d, 1JC,F = 246.1 Hz, C-p), 147.10 (C7), 172.85 (C2).
(NMe), 40.98 (C5), 42.23 (C3), 106.75 (C4¢), 108.59 (C3¢), 110.43
(C6), 122.46 (C5¢), 130.13 (C2¢), 147.75 (C7), 174.48 (C2).
1H–15N HMBC: d = –230.7 (N-pyrrole), –73.6 (N-azepine).
MS (EI): m/z (%) = 234 (100) [M]+, 235 (17) [M + 1]+, 187 (40),
MS (EI): m/z (%) = 249 (67) [M]+, 250 (13) [M + 1]+, 248 (7) [M –
1]+, 202 (43), 201 (33), 200 (37), 161 (40), 160 (77), 159 (47), 133
(77), 112 (100).
186 (20), 145 (47), 112 (77).
2-Methyl-6-(5-methyl-2-thienyl)-3H-azepine (11)
Scale: 28 mmol; THF–DMSO, 4.5:1; t-BuOK (1.2 equiv); light-
brown solid; yield: 3.18 g (56%) after rough separation on alumina;
2.59 g (45%); mp ~56 °C.
2-Methyl-6-(1H-pyrrol-1-yl)-3H-azepine (14f)
Scale: 27.4 mmol; THF–DMSO, 5.0:1; t-BuOK (1.1 equiv); yel-
lowish-brown solid; yield: 0.67 g (14%) after rough separation on
alumina; 0.17 g (4%) after subsequent purification on alumina; mp
57–59 °C.
1H NMR: d = 2.15 (s, 3 H, Me-2), 2.39 (m, 2 H, CH2-3), 2.44 (s, 3
H, Me-5¢), 5.39 (dt, 3J4,5 = 8.8 Hz, 3J4,3 = 6.9 Hz, 1 H, H4), 6.45 (dd,
4
3
3J5,4 = 8.8 Hz, J5,7 = 1.7 Hz, 1 H, H5), 6.64 (dq, J4¢,3¢ = 3.6 Hz,
4J4¢,Me = 1.0 Hz, 1 H, H4¢), 6.81 (d, 3J3¢,4¢ = 3.6 Hz, 1 H, H3¢), 7.65
IR (KBr): 3093, 2977, 2910, 1699, 1619, 1571, 1547, 1534, 1512,
1484, 1428, 1389, 1369, 1315, 1308, 1286, 1263, 1254, 1220, 1212,
1191, 1146, 1108, 1075, 1071, 1018, 979, 955, 938, 914, 882, 865,
835, 819, 763, 741, 729, 714, 708, 667, 631, 622, 613, 569, 507,
432, 406 cm–1.
(br s, 1 H, H7).
13
C
NMR: d = 15.31 (Me-5¢), 26.21 (Me-2), 38.35 (C3), 116.61
jmod
(C4), 123.14 (C6), 123.62 (C3¢), 125.83 (C4¢), 127.00 (C5), 136.69
(C7), 138.76 (C5¢), 141.76 (C2¢), 149.90 (C2).
1H NMR: d = 1.25, 2.68 (2 m, 2 H, CH2-3), 2.18 (s, 3 H, Me-2), 5.47
The 1H–13C HMBC and HSQC 2D experiments provided additional
support for the structure 11.
(dt, 3J4,5 = 8.6 Hz, 3J4,3 = 7.3 Hz, 1 H, H4), 6.27 (br t, 3J3¢,2¢(4¢,5¢) = 1.8
Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York

FEATURE ARTICLE
New 3H-Azepines and 4,5-Dihydro-3H-azepines
2203
3
Hz, 2 H, H3¢, H4¢), 6.38 (d, J5,4 = 8.6 Hz, 1 H, H5), 6.89 (br t,
Academic Press: New York, 1969, 249. (c) Dardonville, C.;
Jimeno, M. L.; Alkorta, I.; Elgue, J. Org. Biomol. Chem.
2004, 2, 1587. (d) De Sousa, F. B.; Denadai, A. M. L.; Lula,
I. S.; Nascimento, C. S. Jr.; Neto, N. S. G. F.; Lima, A. C.;
De Almeida, W. B.; Sinisterra, R. D. J. Am. Chem. Soc.
2008, 130, 8426.
3J2¢,3¢(5¢,4¢) = 1.8 Hz, 2 H, H2¢, H5¢), 7.57 (br s, 1 H, H7).
13
C
jmod
NMR: d = 26.37 (Me-2), 38.45 (C3), 109.67 (C2¢, C5¢),
117.49 (C3¢, C4¢), 120.78 (C7), 125.25 (C5), 130.18 (C6), 132.87
(C4), 149.95 (C2).
MS (EI): m/z (%) = 172 (100) [M]+, 171 (34) [M – 1]+, 157 (27),
(3) (a) Hamprecht, D.; Josten, J.; Steglich, W. Tetrahedron
1996, 52, 10883. (b) Kubota, Y.; Satake, K.; Okamoto, H.;
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Y.; Okamoto, H.; Kimura, M. J. Chem. Soc., Perkin Trans.
1 1997, 2015. (c) Kassaee, M. Z.; Arshadi, S.; Haerizade, B.
N.; Vessally, E. THEOCHEM 2005, 731, 29.
156 (18), 130 (30).
7-Methyl-2-(methylsulfanyl)-3-(1H-pyrrol-1-yl)-4,5-dihydro-
3H-azepine (15f)
White solid; yield: 2.26 g (38%) after rough separation on alumina,
followed by separation with HCl; 0.68 g (11%) after subsequent pu-
rification on alumina; mp 30–32 °C.
(5) Cordonier, C. E. J.; Satake, K.; Okamoto, H.; Kimura, M.
Eur. J. Org. Chem. 2006, 3803.
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Commun. 2002, 642. (b) Karney, W. L.; Kastrup, C. J.;
Oldfield, S. P.; Rzepa, H. S. J. Chem. Soc., Perkin Trans. 2
2002, 388.
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423, 131. (b) Cabeza, A. J. C.; Day, G. M.; Motherwell, W.
D. S.; Jones, W. Cryst. Growth Des. 2007, 7, 100.
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Adapa, S. R. J. Braz. Chem. Soc. 2007, 18, 291.
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IR (KBr): 3101, 3095, 3028, 2964, 2951, 2923, 2888, 2870, 2850,
1714, 1687, 1629, 1574, 1542, 1515, 1487, 1447, 1438, 1431, 1408,
1376, 1351, 1327, 1314, 1294, 1280, 1256, 1229, 1184, 1134, 1095,
1076, 1062, 1045, 1036, 1007, 985, 966, 916, 891, 873, 840, 822,
790, 723, 678, 650, 626, 586, 531, 506, 469, 405 cm–1.
1H NMR: d = 1.93, 1.94 (2 d, 4JMe,6 = 1.22 Hz, 4JMe,6 = 1.19 Hz, 3 H,
Me-7), 1.97, 2.05 (2 m, 2 H, CH2-4), 2.22 (s, 3 H, SMe), 2.54 (tt,
2J5,2¢ ≈ 3J5,4 = 12.7 Hz, 3J5,3¢ ≈ 3J5,6 = 7.3 Hz, 1 H, CH2-5), 2.75 (tdd,
2J2¢,5 ≈ 3J2¢,3¢ = 12.7 Hz, 3J2¢,6 = 7.9 Hz, 3J2¢,4 = 2.2 Hz, 1 H, CH2-5),
3
5.00 (dd, J3,4 = 12.1 Hz, 3J3,3¢ = 7.1 Hz, 1 H, H3), 5.32 (ddq,
3
4
3J6,5 = 7.8 Hz, J6,2¢ = 5.6 Hz, J6,Me = 1.2 Hz, 1 H, H6), 6.21 (t,
3J3¢,2¢(4¢,5¢) = 2.1 Hz, 2 H, H3¢, H4¢), 6.70 (t, 3J2¢,3¢(5¢,4¢) = 2.1 Hz, 2 H,
H2¢, H5¢).
13
C
NMR: d = 12.49 (SMe), 21.86 (C4), 22.19 (Me-7), 40.89
jmod
(C5), 61.82 (C3), 108.46 (C3¢, C4¢), 110.08 (C6), 121.16 (C2¢, C5¢),
147.44 (C7), 172.44 (C2).
1H–15N HMBC: d = –219.2 (N-pyrrole), –74.9 (N-azepine).
MS (EI): m/z (%) = 220 (100) [M]+, 205 (64), 163 (43).
(11) Montserrat, S.; Ballus, C.; Pascual, B.; Prat, J.; Rom, J. Med.
Welt 1963, 38, 1937.
(12) (a) Monro, A. M.; Quinton, R. M.; Wrigley, T. I. J. Med.
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2008, 53, 2204. (b) Chieng, N.; Hubert, M.; Saville, D.;
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Acknowledgment
The authors are grateful for the financial support from the Russian
Foundation for Basic Research (Grant No. 09-03-00890a).
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(22) Very recently, we have found (unpublished data) that
excluding the purification stage of 1-aza-1,3,4-trienes
(column chromatography) and reversing the separation and
purification steps for azepines and dihydroazepines simplify
the reaction product separation and significantly increase
their yields.
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Synthesis 2011, No. 14, 2192–2204 © Thieme Stuttgart · New York