Synthesis of 2-R-2-(1-aryl-7,8-dimethoxy-5H-2,3-benzodiazepin-4-yl)acetic acid esters in the Eschenmoser reaction

Article abstract of DOI:10.1007/s10593-013-1384-0

A method for the synthesis of 2-R-2-(1-aryl-7,8-dimethoxy-5H-2,3- benzodiazepin-4-yl)acetic acid esters from 2-R-2-(1-aryl-7,8-dimethoxy-5H-2,3- benzodiazepin-4-ylsulfanyl)acetic acid esters through Eschenmoser reaction has been developed.

Full text of DOI:10.1007/s10593-013-1384-0

Chemistry of Heterocyclic Compounds, Vol. 49, No. 9, December, 2013 (Russian Original Vol. 49, No. 9, September, 2013)
SYNTHESIS OF 2-R-2-(1-ARYL-7,8-DIMETHOXY-
5H-2,3-BENZODIAZEPIN-4-YL)ACETIC ACID
ESTERS IN THE ESCHENMOSER REACTION
E. S. Sizonenko1*, I. K. Kobrakov2, V. Yu. Popov1, S. Yu. Suikov1, and S. L. Bogza1
A method for the synthesis of 2-R-2-(1-aryl-7,8-dimethoxy-5H-2,3-benzodiazepin-4-yl)acetic acid esters
from 2-R-2-(1-aryl-7,8-dimethoxy-5H-2,3-benzodiazepin-4-ylsulfanyl)acetic acid esters through
Eschenmoser reaction has been developed.
Keywords: 5H-2,3-benzodiazepine, triethyl phosphite, Eschenmoser reaction, functionalization, sulfide
contraction.
5H-Benzodiazepine derivatives were first obtained about 50 years ago and its core practically never
found in nature, however occupied the position of a promising subject in medicinal chemistry for the
construction of a new generation anxiolytic and nootropic agents [1]. However, the ability of these compounds
to contract the seven-membered ring in the presence of acids [2, 3] significantly limits the range of synthetic
applications. Progress in the chemistry of 5H-2,3-benzodiazepines in recent years is based on conversions of
their 4- and 1-thioxo derivatives, for annelation of heterocyclic nuclei to the diazepine ring [4, 5]. Up until now
the chemistry of 5H-2,3-benzodiazepines has led to the formation of carbon–heteroatom bonds, which markedly
depletes the spectrum of products available and, correspondingly, the spectrum of possible types of biological
activity. The formation of carbon–carbon bonds should be the challenge of organic chemistry in the synthesis
and modifications of 5H-2,3-benzodiazepines.
In our opinion, one of the most interesting of the current methods for forming carbon–carbon bonds is
the Eschenmoser reaction, known also as "sulfide contraction", described for the first time by Knott [6]. The
Eschenmoser reaction involves formation of β-enaminocarbonyl derivatives 3 from C-(2-oxoalkyl)-substituted
thioamides and thiolactams 1 by the elimination of the sulfur atom from episulfide intermediate 2 by thiaphilic
reagents – strong bases and/or trivalent phosphorus derivatives [7-11].
This reaction was used effectively for the first time in the synthesis of vitamin B12 [7, 8]. Eschenmoser
showed the scope of this conversion in the example of the condensation of pyrrolidine-2-thione with
_______
*To whom correspondence should be addressed, e-mail: esizonenko@i.ua.
1L. M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, National Academy of Sciences
of Ukraine, 70 R. Luxemburg St., Donetsk 83114, Ukraine.
2I. M. Gubkin Russian State University of Oil and Gas, 65 Leninsky Ave., Moscow 119991, Russia; e-mail:
ikobrakov@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1451-1456, September, 2013.
Original article submitted May 15, 2013; revision submitted July 8, 2013.
1352
0009-3122/13/4909-1352©2013 Springer Science+Business Media New York

O
H
H
O
N
S
N
R
N
S
R
X
+
R
O
1
3
– S
O
OH
H
S
N
N
S
R
R
2
bromomethyl ketones and 2-halocarboxylic acid esters, with the formation of the corresponding vinylogs of
amides and urethanes. The Eschenmoser reaction has a series of advantages as an alternative route for the
formation of a carbon–carbon bond; the reaction conditions are fairly mild, reagents are inexpensive, and the
process is highly selective. In addition, sulfur contraction does not affect the majority of functional groups and
retains the configuration of the other fragments of the molecule. The area of application of the reaction was
broadened significantly with the use of universal thiaphilic reagents, the trialkyl phosphites [9]. It has been
applied widely in the synthesis of 2-oxoalkyl derivatives of nitrogen heterocycles with a various ring size. The
Eschenmoser reaction was employed in the total syntheses of natural compounds, alkaloids, such as
pumiliotoxin S, gephyrotoxin [10], allosedamine [11], and many others.
In a previous publication [12], we investigated the conversion of 4-phenacylsulfanyl derivatives of
5H-2,3-benzodiazepine 4 under Eschenmoser reaction conditions using triethyl phosphite as thiaphilic reagent.
Sulfides 4 upon heating with triethyl phosphite are converted into ketones 5 in good yields. In the
overwhelming majority of cases of Eschenmoser reaction the formed C=C bond is exocyclic. However in our
case, it was established that the products of the conversion of keto sulfides 4 under the conditions of the
Eschenmoser reaction are 2-(1-aryl-7,8-dimethoxy-3H-2,3-benzodiazepin-4-yl)-1-phenylethanones 5, that was
confirmed with the help of heteronuclear two-dimensional HCQC and HMBC experiments.
O
Ar1
S
5
6
9
Ar1
MeO
MeO
MeO
MeO
7
4
(EtO)3P
N
O
NH
8
N
N
2
1
Ar
Ar
4
5
The introduction of readily modifiable groups, such as carboxyl, carbonyl, or amino, into the molecule
significantly increases its biological potential. Consequently, the aim of the present work was the development
of a method for the synthesis of carboxylic acids with a 2,3-benzodiazepine fragment as a general scheme,
analogous to that described in study [12]. It was established that the alkylation of 1-aryl-7,8-dimethoxy-3,5-di-
hydro-2,3-benzodiazepine-4-thiones 6a,b with the methyl esters of chloroacetic or 2-bromopropionic acids in
methanol in the presence of alkali proceeds with the formation of the methyl esters of 2-R-2-(7,8-dimethoxy-
1-phenyl-5H-2,3-benzodiazepin-4-ylsulfanyl)acetic acids 7a-c in 65-75% yield, the structures of which were
confirmed by IR and 1H NMR spectroscopy and by data of elemental analysis (Table 1).
Sulfides 7a-c were converted upon heating with triethyl phosphite over 6 h into desired products which,
according to data of elemental analysis, did not contain sulfur. The spectral characteristics of the final
compounds 8a-c confirmed their structure as the methyl esters of 2-R-2-(1-aryl-7,8-dimethoxy-5H-2,3-benzo-
diazepin-4-yl)acetic acids. When a chiral center was present in the exocyclic substituent (compounds
1353

O
R
OMe
O
OMe
Hal
O
S
S
MeO
MeO
MeO
MeO
MeO
MeO
R
(EtO)3P
150°C, 6 h
R
OMe
N
NH
N
NaOH, MeOH
H2O, , 30 min
N
N
N
Ar
8a–c
Ar
Ar
6a,b
7a–c
6 a Ar = Ph, b Ar = 4-MeC6H4; 7, 8 а Ar = Ph, R = Н; b Ar = 4-MeC6H4, R = Me;
c Ar = 4-MeC6H4, R = Н; Hal = Br, Cl
7b and 8b), both proton and carbon spectra were complicated by the doubling of sets of signals. The spectra
were fairly complex due to the overlap of several signals and the presence of dynamic effects (the mobility of
the diazepine ring was within the NMR time scale). A complete assignment of the signals in the spectrum was
carried out using heteronuclear HCQC and HMBC correlations (Figs. 1 and 2).
Fig. 1. Assignment of signals in the spectrum of compound 8b using the HCQC procedure.
1
The downfield quartet signal in the H NMR spectrum of compound 8b is masked completely by the
more intense signals of the methyl groups, and the identification of its position without using the two-
dimensional procedures was impossible. An analogous selective splitting of signals was observed in the
13C NMR spectrum. It should be mentioned that according to the HMBC data all these multiplexes are in the
same structure and seemingly belong to optical isomers displayed in the spectrum as a result of the mutual
influence of the overall chiral seven-membered ring and the asymmetric exocyclic tertiary carbon. The
assignment of signals carried out enables unequivocal establishment of the position of the double bond, between
atoms N(3) and C(4) of the diazepine ring.
1354

Fig. 2. Assignment of exocyclic and endocyclic methylene groups in the spectrum of compound 8c using the
HMBC procedure.
The successful employment of the Eschenmoser reaction in a series of 1-aryl-2,3-benzodiazepines has
therefore enabled significant expansion of the synthetic potential of this class of heterocyclic compounds.
EXPERIMENTAL
The IR spectra were recorded on an IR-75 instrument in KBr pellets. The 1H and 13C NMR spectra were
recorded on a Bruker Avance II instrument (400 and 100 MHz, respectively) in DMSO-d6, internal standard was
TMS. Elemental analysis was carried out on an Elementar Vario EL Cube Elemental Analyzer (C,H,N,S).
TABLE 1. Physicochemical Characteristics of the Obtained Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Mp, °С
Yield, %
С
H
N
C20H20N2O4S
C22H24N2O4S
C21H22N2O4S
C20H20N2O4
C22H24N2O4
C21H22N2O4
62.37
62.48
63.95
64.06
63.19
63.30
68.26
68.17
69.56
69.46
68.95
68.84
5.13
5.24
5.75
5.86
5.44
5.56
5.62
5.72
6.26
6.36
5.97
6.05
7.41
7.29
6.91
6.79
7.16
7.03
8.04
7.95
7.51
7.36
7.76
7.65
151-152
107-108
131-132
171-172
129-130
152-153
70
75
65
66
51
56
7a
7b
7c
8a
8b
8c
1355

Melting points were determined on a Boetius hot stage apparatus and are not corrected. 1-Aryl-7,8-dimethoxy-
3,5-dihydro-2,3-benzodiazepine-4-thiones 6a,b were obtained by the described procedure [13].
Synthesis of Esters 7a-c (General Method). A solution of NaOH (0.6 g, 0.015 mol) in H2O (5 ml) was
added to a solution of thione 6a,b (0.010 mol) in MeOH (50 ml) and stirred until dissolution. Chloroacetic acid
methyl ester (0.120 mol) or 2-bromopropionic acid methyl ester (0.120 mol) was added to the obtained solution,
and the mixture was refluxed for 30 min. The solution was cooled, diluted with water (two volumes), the solid
was filtered off, dried, and recrystallized from 2-PrOH.
Methyl (7,8-Dimethoxy-1-phenyl-5H-2,3-benzodiazepin-4-ylsulfanyl)acetate (7a). IR spectrum, ,
1
cm-1: 1200 (С–С), 1620 (C=N), 1740 (O=C–O). H NMR spectrum, δ, ppm (J, Hz): 3.22 (1H, d, J = 12.0) and
3.40 (1H, d, J = 12.0, 5-CH2); 3.68 (3H, s) and 3.69 (3H, s, OCH3, СОOCH3); 3.71 (1H, d, J = 14.4) and 3.80
(1H, d, J = 14.4, SCH2); 3.91 (3H, s, OCH3); 6.67 (1H, s, H-6); 6.91 (1H, s, H-9); 7.36-7.46 (3H, m, H Ph); 7.61
(2H, d, J = 7.4, H Ph). 13C NMR spectrum, δ, ppm: 31.9; 38.0; 51.8; 55.2; 55.3; 109.4; 112.0; 121.6; 127.6;
129.0; 129.2; 132.3; 138.4; 147.7; 150.3; 151.9; 157.8; 167.8.
Methyl
2-[7,8-Dimethoxy-1-(4-methylphenyl)-5H-2,3-benzodiazepin-4-ylsulphanyl]propionate
(7b). IR spectrum, , cm-1: 1190 (С–С), 1600 (C=N), 1740 (O=C–O). H NMR spectrum, δ, ppm (J, Hz): 1.31
(1.5H, d, J = 8.0) and 1.50 (1.5H, d, J = 8.0, СНCH3); 2.36 (3H, s, ArCH3); 3.21 (1H, d, J = 8.0) and 3.45 (1H,
d, J = 8.0, 5-CH2); 3.49 (1.5H, s) and 3.66 (1.5H, s, COOCH3); 3.62 (3H, s, OCH3); 3.86 (3H, s, OCH3); 4.23
(0.5H, q, J = 8.0) and 4.29 (0.5H, q, J = 8.0, CHMе); 6.70 (1H, s, H-6); 7.06 (0.5H, s) and 7.07 (0.5H, s, H-9);
7.26 (2H, d, J = 7.6, H Ar); 7.48 (2H, d, J = 7.6, H Ar). 13C NMR spectrum , δ, ppm: 17.5; 20.9; 38.0; 38.1; 41.1
(2С); 52.3; 52.5; 55.6; 55.8; 109.8; 109.9; 112.1; 121.8 (2С); 128.9; 129.1; 132.7; 135.7; 139.6; 147.6; 150.9;
151.2; 151.9; 158.3; 171.6; 171.9.
1
Methyl [7,8-Dimethoxy-1-(4-methylphenyl)-5H-2,3-benzodiazepin-4-ylsulfanyl]acetate (7c). IR
1
spectrum, , cm-1: 1200 (С–С), 1620 (C=N), 1740 (O=C–O). H NMR spectrum, δ, ppm (J, Hz): 2.39 (3H, s,
ArCH3); 3.22 (1H, d, J = 12.8) and 3.50 (1H, d, J = 12.8, 5-CH2); 3.63 (3H, s) and 3.64 (3H, s, OCH3,
СООСН3); 3.74-3.78 (2H, m, SCH2); 3.88 (3H, s, OCH3); 6.69 (1H, s, H-6); 7.08 (1H, s, H-9); 7.26 (2H, d,
J = 8.1, H Ar); 7.48 (2H, d, J = 8.1, H Ar). 13C NMR spectrum, δ, ppm: 20.9; 32.1; 37.9; 52.3; 55.6; 55.8;
109.9; 112.2; 121.8; 128.9; 129.1; 132.8; 135.8; 139.5; 147.6; 151.6; 151.8; 158.3; 168.8.
Synthesis of Esters 8a-c (General Method). A mixture of compound 7a-c (2.6 mmol) and triethyl
phosphite (3 ml) was heated under reflux in a flask at 150°C for 6 h. The reaction mixture was evaporated in the
vacuum of a water-jet pump to minimum volume, cooled, and t-BuOMe (10 ml) was added. After 12 h, the solid
was filtered off, washed with t-BuOMe, and dried.
Methyl (7,8-Dimethoxy-1-phenyl-5H-2,3-benzodiazepin-4-yl)acetate (8a). IR spectrum, , cm-1:
1620 (C=N), 1740 (O=C–O). 1H NMR spectrum, δ, ppm (J, Hz): 3.24 (1H, d, J = 13.4) and 3.51 (1H, d, J = 13.4,
5-CH2); 3.60 (3H, s) and 3.61 (3H, s, ОCH3, СООСН3); 3.83 (2H, br. s, CH2СО); 3.87 (3H, s, ОCH3); 6.68 (1H, s,
13
H-6); 7.10 (1H, s, H-9); 7.42-7.52 (3H, m, H Ph); 7.58 (2H, d, J = 7.2, H Ph). C NMR spectrum, δ, ppm: 32.9;
38.8; 53.1; 56.5; 56.6; 110.7; 113.0; 122.6; 129.1; 130.0; 130.7; 133.8; 139.3; 148.5; 152.6; 152.7; 159.3; 169.4.
Methyl 2-[(7,8-Dimethoxy)-1-(4-methylphenyl)-5H-2,3-benzodiazepin-4-yl]propionate (8b). IR
1
spectrum, , cm-1: 1630 (C=N), 1740 (O=C–O), 2800 (CH). H NMR spectrum, δ, ppm (J, Hz): 1.42 (1.5H, d,
J = 7.2) and 1.62 (1.5H, d, J = 7.2, СНCH3); 2.37 (3H, s, ArCH3); 2.80 (1H, d, J = 12.7), 3.57 (0.5H, d,
J = 12.7) and 3.62 (0.5H, d, J = 12.7, 5-CH2); 3.59 (3H, s) and 3.62 (3H, s, OCH3, СООСН3); 3.60 (0.5H, q,
J = 7.1) and 3.66 (0.5H, q, J = 7.1, CHMе); 3.85 (3H, s, OCH3); 6.71 (1H, s, H-6); 7.03 (0.5H, s) and 7.09
(0.5H, s, H-9); 7.26 (2H, d, J = 8.0, H Ar); 7.47 (1H, d, J = 8.0) and 7.50 (1H, d, J = 8.0, H Ar). 13C NMR
spectrum, δ, ppm: 14.3; 14.8; 20.9; 34.6; 35.4; 45.7; 46.5; 51.9; 55.5; 55.6; 55.7; 55.8; 109.7; 109.9; 112.0;
121.5 (2С); 128.9; 129.1; 133.3; 133.7; 135.8 (2С); 139.5; 147.4 (2С); 151.6; 155.0; 155.4; 157.1; 157.2; 172.0;
172.1.
Methyl [(7,8-Dimethoxy)-1-(4-methylphenyl)-5H-2,3-benzodiazepin-4-yl]acetate (8c). IR spectrum,
1
ν, сm-1: 1620 (C=N), 1740 (O=C–O), 2900, 2950 (CH2). H NMR spectrum, δ, ppm (J, Hz): 2.36 (3H, s,
ArCH3); 3.22 (1H, d, J = 12.0) and 3.49 (1H, d, J = 12.0, 5-CH2); 3.60 (3H, s) and 3.62 (3H, s, OCH3,
1356

СООСН3); 3.81-3.85 (2H, m, CH2СО); 3.86 (3H, s, OCH3); 6.68 (1H, s, H-6); 7.09 (1H, s, H-9); 7.26 (2H, d,
J = 8.0, H Ar); 7.48 (2H, d, J = 8.0, H Ar). 13C NMR spectrum, δ, ppm: 20.9; 32.1; 37.9; 52.3; 55.6; 55.8;
109.9; 112.2; 121.8; 128.9; 129.1; 132.8; 135.7; 139.5; 147.6; 151.6; 151.8; 158.3; 168.8.
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