The homologous tert-amino effect: A route to fused 2-benzazepine derivatives

Article abstract of DOI:10.1016/j.tet.2010.11.101

2-Cyano- and 2-carbethoxy-3-[2-(pyrrolidin-1-ylmethyl)phenyl]acrylonitriles were prepared through either amination of appropriate 3-[2-(bromomethyl)phenyl] acrylonitriles with pyrrolidine or condensation of 2-(pyrrolidin-1-ylmethyl) benzaldehyde with malo

Full text of DOI:10.1016/j.tet.2010.11.101

Tetrahedron 67 (2011) 1030e1035
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The homologous tert-amino effect: a route to fused 2-benzazepine derivatives
,
a,
Alexander P. Gorulya a, Anton V. Tverdokhlebov a , Andrey A. Tolmachev b, Oleg V. Shishkin c,
*
Svetlana V. Shishkina c
a Enamine Ltd., Alexandra Matrosova str. 23, 01103 Kiev, Ukraine
b Kiev National Taras Shevchenko University, Volodimirska str. 62, 01033 Kiev, Ukraine
c STC ‘Institute for Single Crystals’, NAS of Ukraine, 60 Lenina ave., 61001, Kharkiv, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 July 2010
Received in revised form 12 November 2010
Accepted 30 November 2010
Available online 7 December 2010
2-Cyano- and 2-carbethoxy-3-[2-(pyrrolidin-1-ylmethyl)phenyl]acrylonitriles were prepared through
either amination of appropriate 3-[2-(bromomethyl)phenyl]acrylonitriles with pyrrolidine or condensa-
tion of 2-(pyrrolidin-1-ylmethyl)benzaldehyde with malononitrile and ethyl cyanoacetate. These acrylo-
nitrile derivatives were shown to undergo easy mutual interconversion with 1-(pyrrolidin-1-yl)indane-2-
carbonitriles driven by solvent polarity. Upon heating at 140e150 ꢀC both acrylonitrile and indane de-
rivatives were found to give 2,3,5,10,11,11a-hexahydro-1H-pyrrolo[1,2-b][2]benzazepine-11-carbonitriles.
All transformations observed were rationalized in the terms of reactions related to the tert-amino effect.
Furthermore, the corresponding piperidin-1-yl and azepan-1-yl analogs of the above acrylonitriles and
indanes were obtained similarly. By analogy their heating afforded 1,2,3,4,6,11,12,12a-octahydropyrido[1,2-
b][2]benzazepine-12-carbonitriles and 7,8,9,10,11,11a,12,13-octahydro-5H-azepino[1,2-b][2]benzazepine-
12-carbonitriles.
Keywords:
Benzazepine
Indane
Rearrangement
Sigmatropic reaction
Solvent effect
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
The stereochemical and kinetic aspects of the tert-amino effect
were thoroughly investigated3e6 and the mechanism was sug-
In the eighties Verboom and Reinhoudt developed an efficient
method1e6 for the preparation of fused tetrahydroquinolines using
the so-called tert-amino effect (Scheme 1). The term was specially
coined7,8 to describe this type and related cyclizations. Thus upon
heating the Knoevenagel adducts 1 in high-boiling polar solvents
the quinoline derivatives 2 were isolated in good yields.1e6
gested. Thus, the reaction was assumed to proceed through
a suprafacial sigmatropic hydrogen 1,5-shift occurring from the ca-
nonic structure 3 and further ringclosureof the bipolar intermediate
4.3e6 Later this cyclization was extensively studied varying the tert-
amine framework,9e12 the methylene component,13e15 and replac-
ing the benzene moiety with heteroaromatics.16e19 These efforts are
summarized in the recent reviews.20,21 Moreover, recently tert-
amino effect type reactions were reported for biphenyl,22 1,2-bis
(aryl)arene,23 and peri-naphthalene24 systems. In the course of our
research12,16 on the tert-amino effect we have taken an interest in
the compounds of type 8,9 (Scheme 2), the homologs of derivatives 1
with benzene and tertiary amine moieties separated by methylene
group. Are the tert-amino effect reactions possible for this system?
Since nothing was previously known we have studied the question
and report the results herein.
Y
X
Y
X
heating
N
2
( )n
N
-
1
( )n
X
Y
-
X
Y
H
H
1,5-[H]shift
N+
N+
2. Results and discussion
( )n
( )n
3
4
There are two possible approaches to the target compounds 8,9.
The first one (route A) includes amination of derivatives 5,6 available
through a bromination of the appropriate 2-methylcinnamoni-
triles.25 The second one (route B) is based on the condensation of
aldehydes 7aec with malononitrile or ethyl cyanoacetate. The
starting aldehydes 7 were prepared as reported.26,27 The both
Scheme 1. The typical tert-amino effect cyclization. n¼1, 2. X and Y are the electron-
withdrawing groups like CN, COOR etc.
* Corresponding author. Tel.: þ380 445373253; fax: þ380 445373253; e-mail
address: atver@univ.kiev.ua (A.V. Tverdokhlebov).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.101

A.P. Gorulya et al. / Tetrahedron 67 (2011) 1030e1035
( )n
1031
CN
X
CN
X
X
polar solv.
N
H
CN
non-polar solv.
A
N
1,4-[H-]transfer
Br
5,6
( )n
N
X
CN
10a-c
11a-c
CN
H
H
X
-
( )n
8a-c
9a-c
CHO
B
N
N+
( )n
7a-c
( )n
12
Scheme 2. X¼5, 8, 10: CN; 6, 9, 11: COOEt. n¼a: 1; b: 2; c: 3.
approaches wereemployed yielding thesame compoundsidentified
as indanes 10aec,11aec on the basis of their 1H and 13C NMR spectra
recorded in DMSO-d6 or acetone-d6 solutions. Surprisingly, when
the spectra of these compounds were recorded in CDCl3 or C6D6
solutions they exhibited sets of signals corresponding to the Knoe-
venagel adducts structures 8aec, 9aec. So, the materials obtained
undergo easy mutual interconversion between cinnamonitrile 8,9
and indane 10,11 structures driven by the solvent polarity. Never-
theless derivatives 8,9 and 10,11 are rather the different substances
separated by a low energy barrier, than an equilibrium mixture.
Thus, we failed to record an equilibrium spectrum for the compound
8a (10a) in the mixtures of CDCl3 and DMSO-d6. Instead, when the
concentration of DMSO-d6 in CDCl3 solution increased up to 20% (by
volume) complete and instantaneous transformation of cinnamo-
nitrile 8a into indane 10a was observed.
We suppose the conversion of cinnamonitriles 8,9 into indanes
10,11 is the result of reversible tert-amino effect type reaction oc-
curring through the bipolar intermediate 12. The latter is formed
from the derivatives 8,9 by means of 1,4-hydride transfer. It should
be noted that preparation of close related indanes from the com-
pounds like 5,6 through the tandem process including Michael
addition to the double bond followed by intramolecular alkylation
was reported previously.25,28e31 However, formation of the same
derivatives 8e11 via the route B provides clear evidence of the tert-
amino effect (for other approaches to related indanes see 32ꢁ37).
Since typically the tert-amino effect (Scheme 1) is observed at
elevated temperatures,1e19 the thermal behavior of the prepared
compounds 8e11 was studied. It was found that heating derivatives
10a,11a (or 8a,9a) in DMSO at 140e150 ꢀC afforded pyrrolobenza-
zepines 14a,15a in good yields (65e80%, Scheme 3). Compounds
14a,15a were assumed to be formed at the expense of another
sigmatropic process. Thus, the initial bipolar intermediate 12 un-
derwent hydrogen 1,3-shift leading to further intermediate 13 with
endocyclic double bond. Its ring closure furnished derivatives
14a,15a. In the case of six and seven member amines 10b,c,11b,c (or
8b,c, 9b,c) the similar transformation appeared to occur signifi-
cantly worse. Nevertheless, the corresponding fused benzazepines
14b,c, 15b,c were obtained, but in poor yields (10e20%). Perhaps
enlarging of the ring size led to a less favorable endocyclic double
bond, thus increasing energy of the intermediate 13 comparing to
12 and hampering the reaction.
Formation of the fused benzazepines 14,15 can be considered as
the hitherto unknown formal homologous variant of the typical
tert-amino effect. Also it provides a facile route to pyrrolo[1,2-b][2]
benzazepines 14a,15a. The previously known approaches to this
heterocyclic core utilized intramolecular rearrangements of certain
azido and diazo compounds,38e40 intramolecular Heck reactions of
suitable pyrrolidine derivatives,41,42 and photochemical trans-
formations of N-(4-pentenyl)phthalimides.43e47 Furthermore,
a few less general methods have been reported.48e51
The structures of the prepared compounds 14,15 were con-
firmed by 1H and 13C NMR data. Moreover, in the case of the esters
11aec the reaction turned out to occur diastereoselectively yielding
the products 15aec with definite relative configuration of the two
neighboring stereocenters. So, in order to assign the relative ste-
reochemistry and to confirm the structure surely an X-ray crystal-
lographic study was performed for the derivative 15a (Fig. 1). It
revealed clearly the cis mutual arrangement of the bridgehead
hydrogen atom and the ester group. Following the analogy the
same relative configuration was assigned throughout the series of
compounds 15aec. Thus, they should be formulated as the race-
mates of the pair of enantiomeric structures A and B (Fig. 2).
According to the crystal data the azepine ring adopts a chair
conformation with the coplanar atoms C(1), N(1), C(8), and C(9)
DMSO, 140-150 oC
10a-c, 11a-c
[ 12 ]
(or 8a-c, 9a-c)
ꢀ
(with precision of 0.04 A) and the atoms C(2), C(7), and C(10) de-
1,3-[H]shift
ꢀ
ꢀ
ꢀ
viated from their plane at þ0.99 A,þ1.04 A, and ꢁ0.71 A, re-
spectively. Simultaneously the pyrrolidine ring has asymmetric
twist conformation with the N(1) and C(10) atoms deviated from
the least-squared plane of the rest of the atoms of the ring at
-
CN
H
X
X
CN
ꢀ
ꢀ
þ0.71 A and þ0.22 A, correspondingly.
H
To resume, the present investigation has resulted in discovery of
the novel type of the tert-amino effect reaction. Formally it looks
like the well known tert-amino effect process (Scheme 1) simply
extended to the homologous compounds 8,9. However, actually the
overall transformation of derivatives 8,9 into benzazepines 14,15
has been shown to include the sequence of two reactions pro-
ceeding through the bipolar intermediates 12 and 13. Character-
ization of the indanes 10,11 has provided sufficient proof for this
N
( )n
N+
14a-c
15a-c
( )n
13
Scheme 3. X¼14: CN; 15: COOEt. n¼a: 1; b: 2; c: 3.

1032
A.P. Gorulya et al. / Tetrahedron 67 (2011) 1030e1035
organic layer was separated and thewater solutionwas washed with
ether (2ꢂ100 mL). The aqueous phase was neutralized with NaOH
and extracted with ether (3ꢂ100 mL). The extract was dried
(Na2SO4), the solvent was evaporated, and the residue was distilled
yielding the aldehyde 7c (13.69 g, 63%) as a yellowish liquid, bp
120e125 ꢀC/3 mmHg dH (CDCl3) 1.59 (8H, m, 4CH2), 2.63 (4H, m,
2NCH2), 3.91 (2H, s, CH2), 7.38 (2H, m, 3,4-H), 7.49 (1H, t, J¼7.0 Hz, 5-
H), 7.86(1H, d, J¼7.0 Hz, 6-H),10.47 (1H, s, CHO). dC (CDCl3)26.9, 28.4,
55.0, 59.8, 127.5, 128.7, 130.1, 132.9, 135.5, 142.8, 192.3. nmax(KBr)
2923, 1689, 1587, 1260, 1223, 1210, 1094, 1018, 767 cmꢁ1. Found: C,
77.31; H, 8.88; N, 6.41. C14H19NO requires C, 77.38; H, 8.81; N, 6.45.
3.3. Cinnamonitriles 8aec, 9aec and indanes 10aec, 11aec.
General procedure
3.3.1. Route A. An appropriate amine (0.021 mol) was added to the
ice-cooled and stirred solution of compounds 5,6 (0.01 mol) in
EtOH (25 mL) and resulting mixture was stirred at room temper-
ature overnight. Then it was poured into water (100 mL), the solid
formed was filtered and recrystallized from a suitable solvent to
give derivatives 8aec, 9aec (if the spectra were recorded in CDCl3)
or 10aec, 11aec (if the spectra were recorded in DMSO-d6). During
the recrystallization prolonged heating should be avoided.
Fig. 1. X-ray molecular structure of compound 15a with the atom numbering used in
the crystallographic analysis.
3.3.2. Route B. Malononitrile or ethyl cyanoacetate (0.01 mol) was
added to a solution of the aldehydes 7aec (0.01 mol) in EtOH
(20 mL) and the mixture obtained was left overnight at room
temperature. Then it was worked up as above yielding derivatives
8aec, 9aec or 10aec, 11aec dependent on the solvent where the
spectra were recorded.
CN
COOEt
CN
COOEt
H
H
N
( )n
N
( )n
3.3.3. [2-(Pyrrolidin-1-ylmethyl)benzylidene]-malononitrile
(8a). Yield 2.18 g, 92% via route A; 2.13 g, 90% via route B. Yellow
powder; mp 128e130 ꢀC (from i-PrOH). dH (CDCl3) 1.94 (4H, m,
2CH2), 2.82 (4H, m, 2NCH2), 3.96 (2H, s, NCH2), 7.30 (1H, d, J¼7.0 Hz,
3-H), 7.43 (2H, m, 4,5-H), 7.58 (1H, s, CH), 7.77 (1H, d, J¼7.0 Hz, 6-H).
dC (CDCl3) 23.2, 54.3, 59.7, 94.4, 116.4, 116.9, 128.0, 128.1, 128.2,
128.6, 131.8, 132.2, 144.8. nmax(KBr) 2176, 2133, 1459, 1440, 1367,
1331, 1274, 798, 755, 731, 670 cmꢁ1. Found: C, 76.14; H, 6.57; N,
17.71. C15H15N3 requires C, 75.92; H, 6.37; N, 17.71.
B
A
Fig. 2. The relative configuration of compounds 15aec.
assumption. Furthermore the reaction found has a practical aspect.
Thus, it enables the effortless preparation of hydrogenated fused 2-
benzazepines, the family of relatively rare heterocycles interesting
for medicinal chemistry.38e47 So, the further research on the scope
and synthetic applications of the homologous tert-amino effect is in
progress.
3.3.4. [2-(Piperidin-1-ylmethyl)benzylidene]-malononitrile
(8b). Yield 2.16 g, 86% via route A; 2.31 g, 92% via route B. Yellow
powder; mp 105e107 ꢀC; (from MeOH). dH (CDCl3) 1.51 (2H, m,
CH2), 1.59 (4H, m, 2CH2), 2.47 (4H, m, 2NCH2), 3.63 (2H, s, NCH2),
7.30 (1H, t, J¼7.5 Hz, 5-H), 7.42e7.49 (2H, m, 3,4-H), 7.90 (1H, d,
J¼7.5 Hz, 6-H), 8.29 (1H, s, CH). dC (CDCl3) 24.2, 25.8, 54.0, 62.3, 94.4,
116.4, 116.8, 128.0, 128.1, 128.2, 128.6, 131.7, 132.2, 144.8. nmax(KBr)
2979, 2157, 1636, 1452, 1392, 1375, 1270, 1249, 1093, 761, 740,
675 cmꢁ1. Found: C, 76.63; H, 6.82; N, 16.75. C16H17N3 requires C,
76.46; H, 6.82; N, 16.72.
3. Experimental
3.1. General
Cinnamonitriles 5,625 and aldehydes 7a,b26,27 were prepared
according to the described procedures. Other reagents were com-
mercially available. All melting points were determined in open
capillary tubes in a Thiele apparatus and are uncorrected. 1H and
13C NMR spectra were recorded on a Bruker Avance 500 spec-
trometer (500 MHz for 1H and 125 MHz for 13C) in DMSO-d6 or
CDCl3 solutions. Chemical shifts (d) are given in parts per million
3.3.5. [2-(Azepan-1-ylmethyl)benzylidene]-malononitrile (8c). Yield
2.07 g, 78% via route A; 2.01 g, 76% via route B. Yellow powder; mp
76 ꢀC; (from MeOH). dH (CDCl3) 1.64 (8H, m, 4CH2), 2.66 (4H, m,
2NCH2), 3.75 (2H, s, NCH2), 7.30 (1H, d, J¼7.5 Hz, 3-H), 7.43 (1H, t,
J¼7.5 Hz, 5-H), 7.48 (1H, t, J¼7.5 Hz, 4-H), 7.91, (1H, d, J¼7.5 Hz, 6-H),
8.38 (1H, s, CH). dC (CDCl3) 26.9, 28.0, 54.9, 61.2, 89.7, 113.5, 116.0,
128.2, 128.8, 129.7, 131.1, 132.6, 141.1, 159.3. nmax(KBr) 2918, 2849,
2176, 2139, 1736, 1593, 1538, 1471, 1452, 1355, 1279, 1219, 1177, 934,
796, 761, 729 cmꢁ1. Found: C, 76.75; H, 7.47; N, 15.74. C17H19N3
requires C, 76.95; H, 7.22; N, 15.84.
downfield from internal Me4Si. J values are in hertz. The purity of all
compounds obtained was checked by 1H NMR and LC/MS on an
Agilent 1100 instrument.
3.2. 2-(Azepan-1-ylmethyl)benzaldehyde (7c)
n-Butyllithium (125 mL, 1,6 M solution in hexane) was added
dropwise to a stirred solution of 1-benzylazepane (18.9 g, 0.1 mol) in
anhydrous ether (100 mL) under argon atmosphere at 0 ꢀC and
resulting mixture was stirred at rt for 2 days. Then it was cooled to
0
ꢀC and anhydrous DMF (13.1 mL) was added dropwise and the
3.3.6. Ethyl
2-cyano-3-[2-(pyrrolidin-1-ylmethyl)phenyl]acrylate
stirring was continued for 8 h. The mixturewas poured onto crushed
ice (200 g) and concd hydrochloric acid (25 mL) was added. The
(9a). Yield 2.75 g, 97% via route A; 2.41 g, 85% via route B. Yellow
powder; mp 102e104 ꢀC; (from i-PrOH). dH (CDCl3) 1.39 (3H, t,

A.P. Gorulya et al. / Tetrahedron 67 (2011) 1030e1035
1033
J¼7.0 Hz, CH3), 1.78 (4H, m, 2CH2), 2.60 (4H, m, 2NCH2), 3.79 (2H, s,
NCH2), 4.35 (2H, q, J¼7.0 Hz, OCH2), 7.33 (1H, d, J¼7.5 Hz, 3-H), 7.41
(2H, m, 4,5-H), 8.02 (1H, d, J¼7.5 Hz, 6-H), 8.67 (1H, s, CH). dC (CDCl3)
14.2, 23.6, 53.9, 58.8, 62.1, 98.9,116.3,127.9,128.6, 129.3, 131.7,131.8,
140.6,151.0,163.4. nmax(KBr) 2973, 2895, 2161,1734,1634,1441,1376,
1343, 1267, 1248, 1084, 801, 759, 745, 657 cmꢁ1. Found: C, 71.74; H,
7.05; N, 9.80. C17H20N2O2 requires C, 71.81; H, 7.09; N, 9.85.
powder; mp 102e104 ꢀC; (from i-PrOH). dH (DMSO-d6) 1.18 (3H, t,
J¼7.0 Hz, CH3), 2.02 (4H, m, 2CH2), 3.25 (4H, m, 2NCH2), 4.01 (2H, q,
J¼7.0 Hz, OCH2), 4.55 (2H, s, 3-CH2), 6.47 (1H, s, 1-H), 7.30e7.41 (4H,
m, 4,5,6,7-H). dC (DMSO-d6) 15.4, 22.2, 40.6, 56.5, 58.6, 62.3, 98.2,
124.3, 124.8, 125.6, 128.7, 129.5, 135.8, 136.5, 169.5. nmax(KBr) 2973,
2895, 2161, 1734, 1634, 1441, 1376, 1343, 1267, 1248, 1084, 801, 759,
745, 657 cmꢁ1. Found: C, 71.74; H, 7.05; N, 9.80. C17H20N2O2 requires
C, 71.81; H, 7.09; N, 9.85.
3.3.7. Ethyl 2-cyano-3-[2-(piperidin-1-ylmethyl)phenyl]acrylate (9b).
Yield 2.86 g, 96% via route A; 2.83 g, 95% via route B. Pale yellow
powder; mp 55 ꢀC; (from MeOH). dH (CDCl3) 1.43 (5H, m, CH3, CH2),
1.52 (4H, m, 2CH2), 2.41 (4H, m, 2NCH2), 3.57 (2H, s, NCH2), 4.40 (2H,
q, J¼7.0 Hz, OCH2), 7.31 (1H, d, J¼7.0 Hz, 3-H), 7.42 (2H, m, 4,5-H),
8.07 (1H, d, J¼7.0 Hz, 6-H), 8.89 (1H, s, CH). dC (CDCl3) 14.2, 24.2, 25.8,
54.0, 62.0, 62.3, 101.0, 116.0, 127.9, 128.9, 130.1, 131.6, 131.8, 140.4,
154.6, 163.0. nmax(KBr) 2965, 2176, 2133,1736, 1480, 1459,1371, 1309,
1288,1249,1029, 777, 752, 717, 689 cmꢁ1. Found: C, 72.59; H, 7.50; N,
9.27. C18H22N2O2 requires C, 72.46; H, 7.43; N, 9.39.
3.3.13. Ethyl
2-cyano-1-(piperidin-1-yl)indane-2-carboxylate
(11b). Yield 2.86 g, 96% via route A; 2.83 g, 95% via route B. Pale
yellow powder; mp 55 ꢀC; (from MeOH). dH (DMSO-d6) 1.25 (3H, t,
J¼7.5 Hz, CH3), 1.45 (2H, m, CH2), 1.60 (4H, m, 2CH2), 2.69 (4H, m,
2NCH2), 4.13 (2H, s, 3-CH2), 4.16 (2H, q, J¼7.5 Hz, OCH2), 7.37, (1H, d,
J¼6.5 Hz, 4-H), 7.44 (2H, m, 5,6-H), 7.53 (1H, s, 1-H), 7.57 (1H, d,
J¼6.5 Hz, 7-H). dC (DMSO-d6) 15.0, 23.1, 23.8, 40.7, 53.9, 60.3, 60.6,
89.8, 120.4, 127.4, 127.8, 128.4, 130.8, 133.8, 138.3, 166.1. nmax(KBr)
2965, 2176, 2133,1736,1480,1459,1371,1309,1288,1249,1029, 777,
752, 717, 689 cmꢁ1. Found: C, 72.59; H, 7.50; N, 9.27. C18H22N2O2
requires C, 72.46; H, 7.43; N, 9.39.
3.3.8. Ethyl 3-[2-(azepan-1-ylmethyl)phenyl]-2-cyanoacrylate (9c).
Compound 9c was separated as oil after the aqueous work up. It was
taken up in ethyl acetate (20 mL), washed with water (2ꢂ10 mL),
dried (Na2SO4), and evaporated in vacuo. The residue was purified by
column chromatography on silica gel with ethyl acetateehexane
(1:4, v/v; Rf 0.76) mixture as eluent yielding compound 9c. Yield
2.31 g, 74% via route A; 1.68 g, 54% via route B. Yellow oil. dH (CDCl3)
1.42 (3H, t, J¼7.0 Hz, CH3), 1.56 (8H, m, 4CH2), 2.61 (4H, m, 2NCH2),
3.72 (2H, s, NCH2), 4.40 (2H, q, J¼7.0 Hz, OCH2), 7.30 (1H d, J¼7.0 Hz,
3-H), 7.43 (2H, m, 4,5-H), 8.06 (1H, d, J¼7.0 Hz, 6-H), 8.92 (1H, s, CH).
dC (CDCl3) 14.3, 26.9, 28.4, 54.8, 61.5, 62.3, 101.4, 115.9, 127.9, 129.0,
130.0, 131.6, 131.9, 141.5, 155.6, 163.0. nmax(KBr) 2922, 2858, 2242,
2192, 1739, 1732, 1642, 1454, 1360, 1236, 1163, 1128, 1076, 1050, 955,
893, 857, 757 cmꢁ1. Found: C, 72.97; H, 7.80; N, 8.90. C19H24N2O2
requires C, 73.05; H, 7.74; N, 8.97.
3.3.14. Ethyl 1-(azepan-1-yl)-2-cyanoindane-2-carboxylate (11c).
Compound 11c was separated as oil after the aqueous work up. It
was taken up in ethyl acetate (20 mL), washed with water
(2ꢂ10 mL), dried (Na2SO4), and evaporated in vacuo. The residue
was purified by column chromatography on silica gel with ethyl
acetateehexane (1:4, v/v; Rf 0.76) mixture as eluent yielding
compound 11c. Yield 2.31 g, 74% via route A; 1.68 g, 54% via route B.
Yellow oil. dH (DMSO-d6) 1.25 (3H, t, J¼7.0 Hz, CH3), 1.65 (4H, m,
2CH2), 1.84 (4H, m, 2CH2), 3.21 (4H, m, 2NCH2), 4.12e4.18 (4H, m, 3-
CH2, OCH2), 6.44 (1H, s, 1-H), 7.40 (2H, m, 4,7-H), 7.43 (2H, m, 5,6-
H). dC (DMSO-d6) 15.0, 24.2, 27.4, 40.7, 53.9, 60.3, 60.6, 89.8, 120.4,
127.4, 127.8, 128.4, 130.8, 133.8, 138.3, 166.1. nmax(KBr) 2922, 2858,
2242, 2192, 1739, 1732, 1642, 1454, 1360, 1236, 1163, 1128, 1076,
1050, 955, 893, 857, 757 cmꢁ1. Found: C, 72.97; H, 7.80; N, 8.90.
C19H24N2O2 requires C, 73.05; H, 7.74; N, 8.97.
3.3.9. 1-(Pyrrolidin-1-yl)indane-2,2-dicarbonitrile (10a). Yield 2.18 g,
92% via route A; 2.13 g, 90% via route B. Yellowish powder; mp
128e130 ꢀC; (from i-PrOH). dH (DMSO-d6) 2.12 (4H, m, 2CH2), 3.35
(4H, m, 2NCH2), 4.59 (2H, s, 3-CH2), 5.94 (1H, s,1-H), 7.35 (2H, m, 5,6-
H), 7.42 (2H, m, 4,7-H). dC (DMSO-d6) 21.9, 40.6, 56.9, 62.7, 90.3,
124.0, 125.2, 126.0, 126.1, 129.0, 129.5, 134.6, 136.2. nmax(KBr) 2176,
2133,1459,1440,1367,1331,1274, 798, 755, 731, 670 cmꢁ1. Found: C,
76.14; H, 6.57; N, 17.71. C15H15N3 requires C, 75.92; H, 6.37; N, 17.71.
3.4. Pyrrolo[1,2-b][2]benzazepines 14a,15a. General procedure
A solution of appropriate indane 10a,11a (5 mmol) in DMSO
(15 mL) was heated at 140e150 ꢀC for 2 h. Upon cooling the solvent
was evaporated in vacuo, the residue was triturated with water, fil-
tered, and recrystallized from i-PrOH yielding compounds 14a,15a.
3.3.10. 1-(Piperidin-1-yl)indane-2,2-dicarbonitrile
(10b). Yield
3.4.1. 1,2,3,5,10,11a-hexahydro-11H-pyrrolo[1,2-b][2]benzazepine-
11,11-dicarbonitrile (14a). Yield 0.95 g, 80%. White powder; mp
99 ꢀC dH (CDCl3) 1.92 (1H, m, 1-H), 2.03e2.17 (2H, m, 1,2-H), 2.40
(1H, m, 2-H), 2.73 (1H, m, 11a-H), 3.16 (1H, m, 3-H), 3.33 (1H, m, 3-
H), 3.48 (1H, d, J¼14.5 Hz, 10-H), 3.58 (1H, d, J¼14.5 Hz, 10-H), 3.84
(1H, d, J¼14.5 Hz, 5-H), 4.10 (1H, d, J¼14.5 Hz, 5-H), 7.22 (1H, d,
J¼6.5 Hz, 6-H), 7.29e7.33 (3H, m, 7,8,9-H). dC (CDCl3) 22.0, 30.8,
40.8, 42.3, 56.0, 58.7, 71.5, 113.6, 115.5, 128.1, 128.8, 129.0, 131.4,
132.0, 138.9. nmax(KBr) 2960, 2844, 1457, 1443, 1397, 1272, 1263,
2.16 g, 86% via route A; 2.31 g, 92% via route B. Yellowish powder;
mp 105e107 ꢀC; (from MeOH). dH (DMSO-d6) 1.61 (2H, m, CH2), 1.82
(4H, m, 2CH2), 3.04 (4H, m, 2NCH2), 4.57 (2H, s, 3-CH2), 6.06 (1H, s,
1-H), 7.38 (2H, m, 5,6-H), 7.44 (2H, m, 4,7-H). dC (DMSO-d6) 21.5,
22.1, 39.6, 40.5, 53.5, 58.6, 116.2, 117.3, 124.8, 125.8, 128.0, 129.9,
134.7, 135.1. nmax(KBr) 2979, 2157, 1636, 1452, 1392, 1375, 1270,
1249, 1093, 761, 740, 675 cmꢁ1. Found: C, 76.63; H, 6.82; N, 16.75.
C16H17N3 requires C, 76.46; H, 6.82; N, 16.72.
1221, 1191, 1142, 1101, 1086, 1036, 1022, 793, 777, 761, 729 cmꢁ1
.
3.3.11. 1-(Azepan-1-yl)indane-2,2-dicarbonitrile (10c). Yield 2.07 g,
78% via route A; 2.01 g, 76% via route B. Yellowish powder; mp
76 ꢀC; (from MeOH). dH (DMSO-d6) 1.65 (4H, m, 2CH2), 1.84 (4H, m,
2CH2), 3.20 (4H, m, 2NCH2), 4.43 (2H, s, 3-CH2), 6.44 (1H, s, 1-H),
7.38 (2H, m, 5,6-H), 7.43 (2H, m, 4,7-H). dC (DMSO-d6) 24.2, 27.3,
27.4, 40.6, 57.0, 61.6, 125.5, 126.3, 127.8, 128.4, 128.8, 130.3, 134.9,
136.3. nmax(KBr) 2918, 2849, 2176, 2139, 1736, 1593, 1538, 1471,
1452, 1355, 1279, 1219, 1177, 934, 796, 761, 729 cmꢁ1. Found: C,
76.75; H, 7.47; N, 15.74. C17H19N3 requires C, 76.95; H, 7.22; N, 15.84.
Found: C, 75.74; H, 6.28; N, 17.77. C15H15N3 requires C, 75.92; H,
6.37; N, 17.71.
3.4.2. Ethyl 11-cyano-2,3,5,10,11,11a-hexahydro-1H-pyrrolo[1,2-b][2]
benzazepine-11-carboxylate (15a). Yield 0.92 g, 65%. White crystals;
mp 87 ꢀC dH (CDCl3) 1.37 (3H, t, J¼7.0 Hz, CH3), 1.77 (1H, m, 1-H),
1.92 (2H, m, 1,2-H), 2.01 (1H, m, 2-H), 2.61 (1H, m, 11a-H), 3.02 (1H,
m, 3-H), 3.14 (1H, d, J¼14.5 Hz, 10-H), 3.30 (1H, m, 3-H), 3.50 (1H, d,
J¼14.5 Hz, 10-H), 3.73, (1H, d, J¼14.5 Hz, 5-H), 3.92 (1H, d,
J¼14.5 Hz, 5-H), 4.32 (2H, m, OCH2), 7.21e7.27 (4H, m, 6,7,8,9-H). dC
(CDCl3) 14.1, 21.3, 29.8, 41.7, 53.0, 56.4, 59.3, 62.8, 72.5, 116.7, 127.7,
128.0, 129.1, 131.0, 134.6, 139.1, 168.1. nmax(KBr) 2939, 2833, 2793,
3.3.12. Ethyl
2-cyano-1-(pyrrolidin-1-yl)indane-2-carboxylate
(11a). Yield 2.75 g, 97% via route A; 2.41 g, 85% via route B. Yellow

1034
A.P. Gorulya et al. / Tetrahedron 67 (2011) 1030e1035
1737, 1460, 1444, 1246, 1151, 1095, 1038, 1010, 771 cmꢁ1. Found: C,
71.80; H, 7.10; N, 9.83. C17H20N2O2 requires C, 71.81; H, 7.09; N, 9.85.
2
K
q
a
scan mode, 2qmax¼60ꢀ, and using graphite monochromated Mo
ꢀ
radiation (
l
¼0.71073 A). Crystal data: C17H20N2O2, Mr¼284.35,
3
ꢀ
ꢀ
ꢀ
ꢀ
orthorhomibc, a¼13.552 A, b¼9.678 A, c¼11.630 A, V¼1525.4 A ,
3.5. Pyrido[1,2-b][2]benzazepines 14b, 15b and Azepino[1,2-b]
[2]benzazepines 14c, 15c. General procedure
T¼293 K, space group Pna21, Z¼4,
m
(Mo K
a
)¼0.082 mmꢁ1. The
structure was solved by direct method with the SHELXTL program
package.52 Positions of hydrogen atoms were located from electron
difference density maps and refined isotropically. Full-matrix least-
squares refinement against F2 in anisotropic approximation for
non-hydrogen atoms using 4186 reflections was converged to
A solution of appropriate indane 10b,c, 11b,c (5 mmol) in DMSO
(15 mL) was heated at 140e150 ꢀC for 2 h. After cooling the solvent
was evaporated in vacuo, the residue was treated with hot heptane
and insoluble materials were removed by filtration. The heptane
filtrate was concentrated in vacuo and the residue was subjected to
column chromatography on silica gel using ethyl acetateehexane
(1:4, v/v) mixture as eluent yielding compounds 14b,c, 15b,c.
wR2¼0.076, R1¼0.036 [for 2830 reflections with F>4 (F)], S¼0.865.
s
Full crystallographic data (excluding structure factors) for the
structure in this paper have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication number
CCDC 781983. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
þ44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
3.5.1. 1,3,4,6,11,12a-Hexahydropyrido[1,2-b][2]benzazepine-12,12
(2H)-dicarbonitrile (14b). Yield 0.15 g, 12%. White solid; mp 112 ꢀC.
Rf (25% EtOAc/hexane) 0.64. dH (CDCl3) 1.59 (1H, m, 2-H), 1.68 (2H,
m, 1,2-H), 2.02 (2H, m, 1,3-H), 2.24 (1H, m, 3-H), 2.48 (1H, m, 4-H),
3.01 (1H, m, 4-H), 3.11 (1H, m, 12a-H), 3.47 (1H, d, J¼14.0 Hz, 11-H),
3.75 (2H, m, 6,11-H), 3.97 (1H, d, J¼14.0 Hz, 6-H), 7.24 (1H, m, 10-H),
7.33 (3H, m, 7,8,9-H). dC (CDCl3) 21.1, 25.1, 28.6, 30.6, 39.8, 43.3, 52.8,
62.1, 114.3, 116.2, 128.3, 128.8, 129.4, 130.5, 133.1, 138.7. nmax(KBr)
2951, 2812, 2779, 2232, 1731, 1591, 1457, 1286, 1247, 1223, 1080,
1057, 766, 731 cmꢁ1. Found: C, 76.50; H, 6.76; N, 16.81. C16H17N3
requires C, 76.46; H, 6.82; N, 16.72.
Supplementary data
1H and 13C NMR spectra of all compounds obtained are available
in pdf file format as the Supplementary data. Supplementary data
related to this article can be found online version, at doi:10.1016/
j.tet.2010.11.101. These data include MOL files and InChIKeys of the
most important compounds described in this article.
References and notes
3.5.2. 5,7,8,9,10,11,11a,13-octahydro-12H-azepino[1,2-b][2]benzaze-
pine-12,12-dicarbonitrile (14c). Yield 0.25 g, 19%. White solid; mp
137 ꢀC. Rf (25% EtOAc/hexane) 0.79. dH (CDCl3) 1.33 (1H, m, 9-H),
1.44e1.58 (3H, m, 9,10,10-H), 1.89e2.01 (3H, m, 8,8,11-H), 2.44 (1H,
m,11-H), 2.76 (1H, m, 7-H), 3.19 (1H, m,11a-H), 3.48 (2H, m, 7,13-H),
3.65 (1H, d, J¼14.0 Hz, 13-H), 4.08 (1H, d, J¼15.0 Hz, 5-H), 4.23 (1H,
d, J¼15.0 Hz, 5-H), 7.19 (1H, m, 1H), 7.30 (3H, m, 2,3,4-H). dC (CDCl3)
26.2, 28.3, 29.8, 32.0, 39.7, 42.4, 47.7, 59.2, 70.3, 115.0, 115.9, 127.9,
128.3, 128.6, 131.4, 132.2, 139.6. nmax(KBr) 2946, 2918, 2839, 2237,
1736, 1445, 1399, 1367, 1237, 1161, 1124, 955, 939, 886, 761, 746,
699 cmꢁ1. Found: C, 77.04; H, 6.99; N, 15.61. C17H19N3 requires C,
76.95; H, 7.22; N, 15.84.
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12-cyano-1,2,3,4,6,11,12,12a-octahydro-pyrido[1,2-b][2]
benzazepine-12-carboxylate (15b). Yield 0.16 g,11%. Pale yellow oil. Rf
(25% EtOAc/hexane) 0.70.dH (CDCl3) 1.40 (4H, m, 2-H, CH3), 1.68 (4H,
m, 1,2,3,3-H), 1.90 (1H, m, 1-H), 2.45 (1H, m, 4-H), 3.03e3.12 (3H, m,
4,11,12a-H), 3.69(2H, m, 6,11-H), 3.97 (1H, d, J¼15.0 Hz, 6-H), 4.35 (2H,
m, OCH2), 7.23e7.29 (4H, m, 7,8,9,10-H). dC (CDCl3) 14.1, 21.8, 25.5,
30.3, 42.2, 52.6, 54.3, 62.7, 62.9, 69.1, 117.8, 128.0, 128.1, 129.3, 130.1,
135.4,138.7,168.8. nmax(KBr) 2946, 2932, 2849, 2176, 2135,1460,1441,
1318,1283,1146,1105,1078, 990, 752, 704, 652 cmꢁ1. Found: C, 72.27;
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b][2]benzazepine-12-carboxylate (15c). Yield 0.19 g, 12%. White solid;
mp 91 ꢀC. Rf (25% EtOAc/hexane) 0.68. dH (CDCl3) 1.25 (1H, m, 9-H),
1.38 (4H, m, 9-H, CH3), 1.53 (2H, m, 10-CH2), 1.85 (4H, m, 8,11-CH2),
2.58 (1H, m, 7-H), 3.13 (2H, m, 11a,13-H), 3.61e3.69 (2H, m, 7,13-H),
3.94 (1H, d, J¼15.0 Hz, 5-H), 4.20 (1H, d, J¼15.0 Hz, 5-H), 4.31 (2H, m,
OCH2), 7.17 (1H, m, 2-H), 7.26 (3H, m, 1,3,4-H). dC (CDCl3) 14.1, 21.2,
29.7, 29.8, 41.7, 53.0, 56.4, 59.3, 62.9, 72.5,72.6,116.7,127.8,128.1,129.1,
131.0, 134.6, 139.0, 168.1. nmax(KBr) 2937, 2834, 2793,1735,1459,1443,
1244, 1149, 1094, 1057, 1036, 1008, 860, 770, 708 cmꢁ1. Found: C,
73.25; H, 7.62; N, 9.14. C19H24N2O2 requires C, 73.05; H, 7.74; N, 8.97.
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