Synthesis and molecular structure of 2,3,4,5-tetrahydro-1H-3-benzazepine derivatives and dimethyl 4-cyano-2,3,6,7-tetrahydro-1H-3-benzazonine-5,6- dicarboxylate

Article abstract of DOI:10.1007/s10593-012-1141-9

A study was carried out on the direction of 1,2,3,4- tetrahydroisoquinolinium quaternary salt rearrangements by the action of base with or without dimethyl acetylenedicarboxylate. These quaternary salts containing a methylene group at the nitrogen atom, are converted in the presence of base through intermediate N-ylides into the Stevens rearrangement products, namely, tetrahydro-3-benzazepines. Upon the addition of dimethyl acetylenedicarboxylate as an electrophilic trap, this diester adds at the carbanion site of the ylide with subsequent recyclization of the piperidine fragment to give a 2-benzazonine derivative with an unusual 4,5-positioning of the olefin bond in the nine-membered heterocycle. An X-ray structural analysis established the molecular structures of 2-cyano-3-methyl-2,3,4,5-tetrahydro-1H- 3-benzazepine and dimethyl 4-cyano-2,3,6,7-tetrahydro-1H-3-benzazo-nine-5,6- dicarboxylate.

Full text of DOI:10.1007/s10593-012-1141-9

Chemistry of Heterocyclic Compounds, Vol. 48, No. 9, December, 2012 (Russian Original Vol. 48, No. 9, September, 2012)
SYNTHESIS AND MOLECULAR STRUCTURE OF
2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINE DERIVATIVES
AND DIMETHYL 4-CYANO-2,3,6,7-TETRAHYDRO-
1H-3-BENZAZONINE-5,6-DICARBOXYLATE
A. T. Soldatenkov1, S. A. Soldatova1*, J. A. Mamyrbekova-Bekro2,
G. S. Gimranova1, A. V. Malkova1, K. B. Polyanskii1,
N. M. Kolyadina1, and V. N. Khrustalev3
A study was carried out on the direction of 1,2,3,4-tetrahydroisoquinolinium quaternary salt
rearrangements by the action of base with or without dimethyl acetylenedicarboxylate. These
quaternary salts containing a methylene group at the nitrogen atom, are converted in the presence of
base through intermediate N-ylides into the Stevens rearrangement products, namely, tetrahydro-
3-benzazepines. Upon the addition of dimethyl acetylenedicarboxylate as an electrophilic trap, this
diester adds at the carbanion site of the ylide with subsequent recyclization of the piperidine fragment
to give a 2-benzazonine derivative with an unusual 4,5-positioning of the olefin bond in the nine-
membered heterocycle. An X-ray structural analysis established the molecular structures of 2-cyano-
3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and dimethyl 4-cyano-2,3,6,7-tetrahydro-1H-3-benzazo-
nine-5,6-dicarboxylate.
Keywords: tetrahydro-3-benzazepines, 2,3,6,7-tetrahydro-1H-3-benzazonine-5,6-dicarboxylate, quaternary
1,2,3,4-tetrahydroisoquinolinium salts, sigmatropic rearrangement.
Sigmatropic rearrangements proceeding through intermediate anhydro bases allow to obtain rare
azacyclic compounds with quite complicated structures [1-3], in particular, such synthetic compounds [2, 4, 5]
and natural products [6-9], which contain a tetrahydro-3-benzazepine fragment.
We should note that such rearrangements can occur with high regioselectivity and even complete
transfer of the stereochemical features of the starting compound to the product. However, there have been only a
few examples of such reactions in the presence of electrophilic traps for the anionic site of the intermediate
anhydro base [3, 10, 11].
_______
*To whom correspondence should be addressed, e-mail: sa.soldatova@gmail.com.
1Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russia.
2University of Abobo-Ajamé, 02 BP801, Abidjan, Republic of Côte d'Ivoire; e-mail: bekro2001@yahoo.fr.
3A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28 Vavilova St.,
Moscow 117813, Russia; e-mail: vkh@xrlab.ineos.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1430-1437, September, 2012.
Original article submitted February 23, 2012.
1332
0009-3122/12/4807-1332©2012 Springer Science+Business Media New York

In a continuation of our work on the reactivity of quaternary pyridinium salts and their derivatives
[12-18], we investigated the directions of the transformations of tetrahydroisoquinolinium salts 1 by the action
of bases with or without dimethyl acetylenedicarboxylate (DMAD). In the first case (without DMAD), we
propose the formation of 2-substituted tetrahydrobenzazepine derivatives 2 due to a [1,2]-sigmatropic shift of
the endocyclic benzyl fragment to the exocyclic anionic site of the intermediate N-ylide A [15, 16]. The
formation of α-R-methyl derivatives of tetrahydroisoquinoline is also likely due to a [1,2]-shift of the R-methyl
group to the endocyclic anionic site of the other possible intermediate zwitterion, namely, a cyclic ammonium
ylide [18]. In the second case, due to the presence of DMAD (an electrophilic trap for the exo- or endocyclic
anionic sites of the intermediate N-ylides) in the initial mixture, a [1,4]-rearrangement giving azonine
derivatives may occur instead of the Stevens [1,2]-shift indicated above [3, 16]. This is a fundamentally new
direction of the reaction, which we recently discovered for partially reduced indeno- and indolopyridinium salts
[10, 11, 17]. In the present work, we initially studied the transformations of quaternary salts 1a-e upon refluxing
their suspensions with NaH in 1,4-dioxane for 7-12 h without DMAD. After suitable treatment of the reaction
mixtures and chromatographic separation on silica gel columns, we obtained tetrahydro-3-benzazepines 2a-e in
30-95% yield.
5
6
4
5a
7
8
N Me
3
9a
9
2
2a–e 1
X–
R
NaH
Dioxane

N+
CHR
N+
Me
+
Me
CH2
CH2R
1a–e
A
–
N
CN
Me
3 (from 1а)
a R = CN, b R = CH=CH2, c R = С≡СН, d R = COC6H4Me-p, e R = COC6H4Br-p; а X = Cl, b-e X = Br
N-Ylides A are formed in the first step of the transformations of quaternary salts 1a-e by the action of
base. These ylides then undergo a [1,2]-sigmatropic rearrangement and are converted mainly to
tetrahydrobenzazepines 2a-e. The nature of the substituents at the nitrogen atom in starting quaternary salts 1a-e
affects the selectivity of tetrahydrobenzazepine formation; the selectivity is higher in the case of electron-
withdrawing substituents in the starting quaternary salts 1d,e. Styrene 3 was formed as a side product in 10%
yield in addition to the tetrahydrobenzazepine 2a, which was formed in 60% yield from the quaternary salt 1a.
This parallel reaction proceeds due to intramolecular β-elimination of a proton, which is transferred to the
carbanionic site of the −CH-−CN group with concurrent dissociation of the N(2)−C(3) bond (Hofmann
elimination).
Analogous experiments were carried out with quaternary salts 4a,b of the alkaloid laudanosine.
Benzazepines 5a,b were isolated in 50 and 40% yield, respectively, from the reaction mixtures. These products
have structural similarity with the alkaloids bulgaramine and isopavine [6].
X–
MeO
MeO
N Me
R
N+
CH2R
NaH
MeO
MeO
Me
Dioxane
OMe
OMe

OMe
4a,b
5a,b
OMe
a R = CN, X = Cl; b R = COC6H4Br-p, X = Br
1333

Fig. 1. General view of the salt 2a·HCl with atoms represented by thermal ellipsoids of 50% probability. The
hydrogen bond is shown by the dashed line.
The tetrahydro-3-benzazepine hydrochloride 2a·HCl was obtained to unequivocally confirm this
direction of the reaction and the structures of tetrahydrobenzazepines 2a-e and 5a,b, which were mainly isolated
as oils. The molecular structure of this salt was studied by X-ray structural analysis (Fig. 1), which showed that
the seven-membered heterocycle is present in the crystal in a "chair" conformation. The cyano group occupies
an axial position and is in gauche configuration to the equatorial N-methyl group, which is fixed by
quaternization of the nitrogen atom. The cation [2aH]+ is chiral with two asymmetric centers at carbon C(2) and
nitrogen N(3) atoms. The crystal is a racemate with relative configuration of the chiral atoms rac-2S*,3S*.
COOMe
Me
COOMe
COOMe
COOMe
+N
CN
8
6
7a
7
1
9
5
NaOH
·
·
1a
+
CN
H
4
CH2Cl2
room temp.
20 h
10
–
3N
11a
2
COOMe
11
Me
COOMe
6
B
When the analogous reaction of salt 1a was carried out in the presence of DMAD, benzazonine
derivative 6 was isolated in 27% yield from the reaction mixture. The structure of product 6 was established
unequivocally by NMR spectroscopy and an X-ray structural analysis. These results indicate that, in the
presence of DMAD as an electrophilic trap, the initially generated N-ylide rapidly adds this electrophile at the
carbanionic site and is transformed into 1,4-zwitterion B, which then rearranges with expansion of the
tetrahydropyridine ring to tetrahydrobenzazonine structure 6. We should have expected that the second double
bond in the nine-membered heterocycle arising upon the introduction of the DMAD residue should be located at
1
the C(5)−C(6) atoms of compound 6. However, the X-ray structural analysis data (Fig. 2) and H NMR
spectroscopy showed that this second double bond is unexpectedly located at the C(4)−C(5) atoms due to a
prototropic shift. This behavior apparently should be attributed to the additional π,n-conjugation of the ethylene
bond in the cyanoenamine fragment.
The X-ray structural analysis of benzazonine 6 indicates that the conformation of the nine-membered
ring can be described as a "distorted chair", in which the N(3), C(4), C(7), and C(7a) atoms form a central plane,
while the C(5) and C(6) atoms deviate significantly to one side, and the C(1), C(2), and C(11a) atoms deviate to
the opposite side. The molecule has E-configuration of the substituents at the C(4)-C(5) double bond. The
1334

benzazonine 6 is a chiral compound, which contains an asymmetric carbon atom, C(6). The crystal is a
racemate.
Fig. 2. General view of the benzazonine 6 with atoms represented by thermal ellipsoids of 50% probability.
Thus, we have found that the action of base on quaternary tetrahydroisoquinolinium salts in the absence
of DMAD leads to tetrahydro-3-benzazepine derivatives through the Stevens reaction. We also established the
feasibility of switching the reaction from a [1,2]-sigmatropic shift to a [1,4]-rearrangement by using DMAD as
an electrophilic trap, which leads to the formation of tetrahydro-3-benzazonine with an unusual position of the
ethylenic bond introduced with the DMAD residue in the nine-membered ring.
EXPERIMENTAL
1
The IR spectra were recorded on an Infralum FT-801 spectrometer for KBr pellets. The H NMR
spectra were recorded on a Bruker WP-400 spectrometer at 400 MHz in DMSO-d6 (for compounds 1a-e, 4a,b)
and CDCl3 (for compounds 2a-e, 3, 5a,b, 6). The residual protons of the deuterated solvents served as internal
standard (δ 2.51 for DMSO-d6 and δ 7.27 ppm for CDCl3). Reaction mixture analysis and checking the purity of
products 2a-e, 3, 5a,b, 6 were carried out on an Agilent 1100 liquid chromatograph with DAD and ELSD Sedex
75 detectors, which was connected to an Agilent LC/MSD VL mass spectrometer using electrospray ionization.
The elemental analyses were carried out on a Vario MACRO cube automatic analyzer. The melting points were
determined on a Stuart SMP10 instrument.
The starting N-methyl-1,2,3,4-tetrahydroisoquinoline was obtained by N-methylation of a commercial
sample of 1,2,3,4-tetrahydroisoquinoline obtained from Aldrich using methyl iodide in the presence of
potassium hydroxide. The alkaloid laudanosine was obtained according to Tietze [19] from a commercial
sample of papaverine obtained from Aldrich.
N-Methyl-N-R-methyl-1,2,3,4-tetrahydroisoquinolinium Halides 1a-e, 4a,b (General Method). A
solution of a mixture of 2-methyl-1,2,3,4-tetrahydroisoquinoline (1.47 g, 10 mmol) (for compounds 1a-e) or
laudanosine (3.57 g, 10 mmol) (for compounds 4a,b) and the corresponding R-methyl halide (10 mmol) in THF
(20 ml) was heated at reflux for 2 h under a nitrogen atmosphere. The precipitate of the formed desired
quaternary salt was filtered off, washed with ether, and dried in air.
1335

N-Cyanomethyl-N-methyl-1,2,3,4-tetrahydroisoquinolinium Chloride (1a). Yield 2.1 g (95%).
Colorless crystals, mp 175-176°С (EtOH) (mp 174-176°С (EtOH) [17]).
N-Methyl-N-(3-propenyl)-1,2,3,4-tetrahydroisoquinolinium Bromide (1b). Yield 2.60 g (97%).
Colorless crystals, mp 185-186°С (EtOH). IR spectrum, ν, cm-1: 1623 (CH=CH2). 1Н NMR spectrum, δ, ppm (J,
Hz): 2.89-2.92 (2Н, m, 4-CH2); 3.22 (3Н, s, NСН3); 3.88-3.91 (2Н, m, 3-CH2); 4.03 (2H, s, 1-CH2); 4.07 (2H,
2
3
dd, J = 10.9, J = 1.0, NCH2CH=СН2); 4.97 (1Н, d, J = 10.2, СН=CН2-cis); 5.10 (1Н, d, J = 17.5, СН=СН2-
trans); 5.17-5.19 (1H, m, СН=СН2); 7.21-7.26 (4Н, m, H Аr). Found, %: C 58.30; Н 6.68; Br 29.71; N 5.22.
C13H18BrN. Calculated, %: C 58.22; H 6.76; Br 29.79; N 5.22.
N-Methyl-N-(3-propynyl)-1,2,3,4-tetrahydroisoquinolinium Bromide (1c). Yield 2.50 g (95%).
Colorless crystals, mp 187-188°С (EtOH). IR spectrum, ν, cm-1: 2120 (C≡CH). 1Н NMR spectrum, δ, ppm: 2.02
(1Н, s, С≡СН); 3.11-3.15 (2Н, m, 4-CH2); 3.53 (3Н, s, NСН3); 3.95-4.03 (2Н, m, 3-CH2); 4.01 (2H, s, 1-CH2);
4.32 (2H, s, NCH2C≡С); 7.20-7.26 (4Н, m, Н Аr). Found, %: C 58.47; H 6.10; Br 30.13; N 5.24. C13H16BrN.
Calculated, %: C 58.66; H 6.06; Br 30.02; N 5.26.
N-Methyl-N-(4-methylbenzoylmethyl)-1,2,3,4-tetrahydroisoquinolinium Bromide (1d). Yield 3.50 g
1
(98%). Colorless crystals, mp 197-198°С (EtOH). IR spectrum, ν, cm-1: 1685 (C=О). Н NMR spectrum, δ, ppm
(J, Hz): 2.15 (2Н, t, J = 10.2, 4-CH2); 2.42 (3Н, s, ArСН3); 3.33 (3Н, s, NСН3); 4.15 (1Н, d, J = 10.2) and 4.32
(1Н, d, J = 10.2, 3-CH2); 4.61 (1H, d, J = 10.7) and 5.03 (1H, d, J = 10.7, 1-CH2); 5.22 (1Н, d, J = 9.8) and 5.41
(1Н, d, J = 9.8, NСН2СО); 7.21-8.00 (8Н, m, H Аr). Found, %: С 63.57; Н 6.12; Br 22.16; N 3.98.
C19H22BrNO. Calculated, %: C 63.34; H 6.15; Br 22.18; N 3.89.
N-(4-Bromobenzoylmethyl)-N-methyl-1,2,3,4-tetrahydroisoquinolinium Bromide (1e). Yield 4.16 g
1
(98%). Colorless crystals, mp 204-205°С (EtOH). IR spectrum, ν, cm-1: 1685 (C=О). Н NMR spectrum, δ, ppm
2
(J, Hz): 2.13 (2Н, t, J = 11.0, 4-СН2); 3.28 (3Н, s, NСН3); 4.09-4.12 (1H, m) and 4.19-4.21 (1H, m, 3-СН2);
2
2
2
2
4.80 (1H, d, J = 10.8) and 5.00 (1H, d, J = 10.8, 1-СН2); 5.32 (1H, d, J = 9.5) and 5.63 (1H, d, J = 9.5,
NСН2СО); 7.21-8.05 (8Н, m, H Аr). Found, %: С 50.97; Н 4.41; Br 37.56; N 3.34. C18H19Br2NO. Calculated, %:
C 50.85; H 4.50; Br 37.59; N 3.29.
N-Cyanomethyl-6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-N-methyl-1,2,3,4-tetrahydroisoquinolinium
Chloride (4a). Yield 2.15 g (50%). Colorless crystals, mp 213-214°С (EtOH). IR spectrum, ν, cm-1: 2253
(C≡N). 1Н NMR spectrum, δ, ppm (J, Hz): 2.92 (2Н, t, J = 10.4, 4-СН2); 3.12 (2H, d, J = 7.5, CHCH2Ar); 3.21
(3Н, s, NСН3); 3.71 (3Н, s), 3.73 (3Н, s), 3.74 (3Н, s) and 3.76 (3Н, s, 4OСН3); 4.28 (2Н, t, J = 10.4, 3-СН2);
5.03 (2H, s, NCH2CN); 5.82 (1Н, t, J = 7.5, 1-СH); 6.52-6.81 (5Н, m, H Аr). Found, %: С 63.54; Н 6.82;
Cl 8.21; N 6.35. C23H29ClN2O4. Calculated, %: C 63.81; H 6.75; Cl 8.19; N 6.47.
N-(4-Bromobenzoylmethyl)-6,7-dimethoxy-1-(3,4-dimethoxybenzyl)-N-methyl-1,2,3,4-tetrahydro-
isoquinolinium Bromide (4b). Yield 2.40 g (37%). Colorless crystals, mp 224-225°С (EtOH). IR spectrum, ν,
1
cm-1: 1685 (C=О). Н NMR spectrum, δ, ppm (J, Hz): 2.93 (2Н, t, J = 10.5, 4-СH2); 3.12 (2H, d, J = 7.8,
CHСН2Ar); 3.21 (3Н, s, NСН3); 3.69 (3Н, s), 3.72 (3Н, s), 3.75 (3Н, s), and 3.76 (3Н, s, 4-OСН3); 4.65-4.71
(2Н, m, 3-СН2); 5.10 (2H, s, NCH2CO); 5.85 (1Н, t, J = 7.8, 1-СН); 6.85-7.61 (9Н, m, H Аr). Found, %:
С 54.78; Н 5.11; Br 25.24; N 2.10. C29H33Br2NO5. Calculated, %: C 54.82; H 5.23; Br 25.15; N 2.20.
Benzazepines 2a-e, 5a,b and Aminomethylstyrene 3 (General Method). NaH (0.3 g, 12.5 mmol) was
added to a suspension of salt 1a-e, 4a,b (10.0 mmol) in absolute dioxane (50 ml). The mixture was heated at
reflux under an inert atmosphere for 7-12 h and then cooled. The excess NaH was neutralized by adding ethanol.
The solvent was distilled off in vacuum. The residue was treated with water and extracted with methylene chloride.
The extract was dried and evaporated. The residue was separated on a silica gel column. Aminomethyl- styrene 3
was eluted with 9:1 hexane−EtOAc, while benzazepines 2a-e were eluted with 3:1 hexane−EtOAc.
2-Cyano-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2a). Yield 1.1 g (60%). Thick oil. IR
1
spectrum, ν, cm-1: 2253 (CN). Н NMR spectrum, δ, ppm (J, Hz): 2.52 (3Н, s, NCH3); 2.70-3.32 (6Н, m,
1,4,5-СН2); 4.05 (1Н, t, 2J = 6.3, 2-СH); 7.21-7.60 (4H, m, Н Аr). Mass spectrum, m/z: 187 [M+H]+. Found, %:
C 77.34; Н 7.47; N 14.85. C12H14N2. Calculated, %: C 77.38; Н 7.58; N 15.04. Compound 2а hydrochloride: mp
172-174°С (EtOH).
1336

2-Ethenyl-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2b). Yield 0.5 g (27%). Thick brown oil.
1
IR spectrum, ν, cm-1: 1650 (С=С). Н NMR spectrum, δ, ppm (J, Hz): 2.41 (3Н, s, NСН3); 2.60-3.39 (6Н, m,
2
3
2
1,4,5-СН2); 3.48-3.51 (1Н, m, 2-СН); 4.81 (1Н, dd, J = 1.0, J = 12.1, СН=СН2-cis); 5.03 (1Н, dd, J = 1.0,
3J = 15.0, СН=СН2-trans); 5.77-5.79 (1Н, m, СН=СН2); 7.03-7.53 (4Н, m, Н Ar). Mass spectrum, m/z: 188
[M+H]+. Found, %: С 83.35; Н 9.12; N 7.65. C13H17N. Calculated, %: С 83.37; Н 9.15; N 7.48.
2-Ethynyl-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2c). Yield 0.6 g (32%). Thick oil. IR
1
spectrum, ν, cm-1: 2100 (С≡С). Н NMR spectrum, δ, ppm (J, Hz): 2.02 (1Н, s, С≡СН); 2.45 (3Н, s, NСН3);
2
2.50-2.89 (6Н, m, 1,4,5-СН2); 3.39 (1Н, t, J = 8.3, 2-СН); 7.25-7.57 (4Н, m, Н Ar). Mass spectrum, m/z: 186
[M+H]+. Found, %: С 84.26; Н 8.22; N 7.42. C13H15N. Calculated, %: С 84.28; Н 8.16; N 7.56.
3-Methyl-2-(4-methylbenzoyl)- 2,3,4,5-tetrahydro-1H-3-benzazepine (2d). Yield 2.5 g (89%). Thick
1
oil. IR spectrum, ν, cm-1: 1683 (С=О). Н NMR spectrum, δ, ppm (J, Hz): 2.12 (3Н, s, ArСН3); 2.33 (3Н, s,
NСН3); 2.61-3.25 (6Н, m, 1,4,5-СН2); 4.07 (1Н, t, J1,2 = 10.2, 2-CН); 7.20-8.02 (8Н, m, Н Ar). Mass spectrum,
m/z: 280 [M+H]+. Found, %: С 81.54; Н 7.33; N 4.98. C19H21NO. Calculated, %: С 81.68; Н 7.58; N 5.01.
2-(4-Bromobenzoyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2e). Yield 3.27 g (95%). Thick
1
oil. IR spectrum, ν, cm-1: 1680 (С=О). Н NMR spectrum, δ, ppm (J, Hz): 2.22 (3Н, s, NСН3); 2.45-3.17 (6Н,
m, 1,4,5-СН2); 4.13 (1Н, t, 2J = 9.8, 2-CН); 7.18-8.08 (8Н, m, Н Ar). Mass spectrum, m/z: 345 [M+H]+. Found,
%: С 62.65; Н 5.18; N 3.97. C18H18BrNO. Calculated, %: С 62.80; Н 5.27; N 4.07.
[(2-Ethenylbenzyl)(methyl)amino]acetonitrile (3). Yield 1.8 g (10%). Thick yellowish oil. IR
1
spectrum, ν, cm-1: 2253 (CN). Н NMR spectrum, δ, ppm (J, Hz): 2.50 (3Н, s, NCH3); 3.30 (2Н, s, ArСН2N);
2
3
2
3
3.60 (2Н, s, NСН2CN); 5.28 (1Н, dd, J = 1.0, J = 10.9, CH=CH2-cis); 5.72 (1Н, dd, J = 1.0, J = 14.8,
CH=CH2-trans); 7.21-7.50 (5Н, m, CH=CH2, Н Ar). Mass spectrum, m/z: 187 [M+H]+. Found, %: C 77.36;
Н 7.46; N 15.30. C12H14N2. Calculated, %: C 77.38; Н 7.58; N 15.04.
2-Cyano-7,8-dimethoxy-1-(3,4-dimethoxybenzyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine
(5a). Yield 1.98 g (50%). Colorless crystals, mp 181-182°С (EtOH). IR spectrum, ν, cm-1: 2252 (С≡N).
1Н NMR spectrum, δ, ppm (J, Hz): 2.13 (3Н, s, NСН3); 2.81-3.35 (5Н, m, 1-СН, 4,5-СН2); 3.81 (6Н, s,
2
2ОСН3); 4.05 (6Н, s, 2ОСН3); 4.15 (1Н, d, J = 10.0, 2-СH); 4.22 (2Н, d, J = 7.9, СН2Аr); 6.42-7.19 (5Н, m,
Н Ar). Mass spectrum, m/z: 397 [M+H]+. Found, %: С 69.55; Н 7.18; N 7.21. C23H28N2O4. Calculated, %:
С 69.68; Н 7.12; N 7.07.
2-(4-Bromobenzoyl)-7,8-dimethoxy-1-(3,4-dimethoxybenzyl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benz-
azepine (5b). Yield 2.2 g (40%). Colorless crystals, mp 186-187°С (EtOH). IR spectrum, ν, cm-1: 1684 (С=О).
1Н NMR spectrum, δ, ppm (J, Hz): 2.99 (3Н, s, NСН3); 3.77 (3Н, s, ОСН3); 3.88 (6Н, s, 2ОСН3); 3.97 (3Н, s,
ОСН3); 3.42-4.08 (8Н, m, 1,2-СН, 4,5-СН2, ArСН2); 6.59 (1Н, s, Н-6); 6.62 (1Н, s, Н-9); 6.64 (1H, s, Н Ar); 6.82
(1Н, d, J = 7.5, Н Ar); 6.90 (1Н, d, J = 7.5, Н Ar); 7.39 (2H, d, J = 7.6, Н Ar); 7.55 (2H, d, J = 7.6, Н Ar). Mass
spectrum, m/z: 555 [M+H]+. Found, %: C 62.95; H 5.69; Br 14.20; N 2.34. C29H32BrNO5. Calculated, %:
C 62.82; H 5.82; Br 14.41; N 2.53.
Dimethyl 4-Cyano-3-methyl-2,3,6,7-tetrahydro-1H-3-benzazonine-5,6-dicarboxylate (6).
A
suspension of salt 1a (2.2 g, 10 mmol) in methylene chloride (20 ml), DMAD (1.42 g, 10 mmol), and 20%
aqueous sodium hydroxide (2 ml) was stirred for 20 h at 20°C, and then water (30 ml) was added. The mixture
was extracted with CH2Cl2 (3×20 ml). The extract was dried, and the solvent was distilled off. The residue was
subjected to chromatography on a silica gel column using 2:1 hexane−EtOAc as the eluent, the compound 6 was
isolated. Yield 0.8 g (27%). Colorless crystals, mp 116-117°С (Et2O) (mp 116-117°С (Et2O) [17]). IR spectrum,
ν, cm-1: 2360 and 2341 sh. (CN), 1741 (С=О). 1Н NMR spectrum, δ, ppm (J, Hz): 2.50 (3Н, s, NCH3); 2.65-2.67
2
3
(2Н, m, 1-СН2); 3.03-3.07 (3Н, m, 2-СH2, 7-СНA), 3.58 (1Н, dd, J = 11.7, J = 4.8, 7-СНB); 3.71 (3Н, s,
COОСН3); 3.83 (3Н, s, COОСН3); 4.39 (1Н, t, 3J = 4.8, 6-CН); 7.14-7.48 (4Н, m, Н Ar). Mass spectrum, m/z:
329 [M+H]+. Found, %: C 65.90; Н 6.21; N 8.24. C18H20N2O4. Calculated, %: C 65.84; Н 6.14; N 8.53.
X-ray Structural Analysis of Compound 2a·HCl. Crystals of salt 2a·HCl (C12H15N2Cl, M 222.71) are
monoclinic with space group P21/n. The unit cell parameters at 100 K were as follows: a 7.1934(8), b 7.3625(8), c
22.433(3) Å, β 96.527(2)°, V 1180.4(2) Å3, Z 4, dcalc 1.253 g/cm3, F(000) 472, μ 0.293 mm-1, R1 0.053 for 2523
1337

independent reflections with I > 2σ(I), wR2 = 0.135 for all data, GOOF = 0.985. The data set (10374 reflections, of
which 2820 were independent reflections, Rint = 0.032) was measured on a Bruker APEX II CCD diffractometer
using MoKα radiation, graphite monochromator, φ- and ω-scanning, 2θmax = 56°.
X-ray Structural Analysis of Diester 6. Crystals of diester 6 (C18H20N2O4, M 328.36) are
orthorhombic with space group Fdd2. The unit cell parameters at 100 K were as follows: a 17.5783(12),
b 43.776 (3), c 8.5960(6) Å, V 6614.7(8) Å3, Z 16, dcalc 1.319 g/cm3, F(000) 2784, μ 0.094 mm-1, R1 0.038 for
2184 independent reflections with I > 2σ(I), wR2 0.093 for all the data, GOOF 1.000. The data set (a total of
17991 reflections, of which 2336 were independent reflections, Rint = 0.029) was measured on a Bruker APEX
II CCD diffractometer using MoKα radiation, graphite monochromator, φ- and ω-scanning, 2θmax = 58°.
The structures of both compounds were determined by direct methods and refined by the full-matrix
least-squares method for F2 in anisotropic approximation for the non-hydrogen atoms. The hydrogen atom of
the NH group in salt 2a·HCl was localized objectively from the Fourier synthesis difference map and refined
isotropically. The positions of the other hydrogen atoms in both compounds were calculated geometrically and
refined anisotropically with fixed positional parameters using the "rider" model. All the calculations were
carried out using the SHELXTL software package [20].
The complete crystallographic data sets for the salt 2a·HCl (CCDC 759264) and diester 6 (CCDC
759263) were deposited at the Cambridge Crystallographic Data Center.
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