Reactions of N-(2-chloroacetyl)-α-amino acids with 3-cyanopyridine-2(1H)-thiones. New promising route to 3,4- dihydropyrido[3′,2′:4,5]thieno[3,2-e][1,4]diazepine-2(1H),5-diones

Article abstract of DOI:10.1023/B:RUCB.0000011878.52263.c4

The reactions of N-(2-chloroacetyl)-α-amino acids with 3-cyanopyridine-2(1H)-thiones afforded N-(3-ammothieno[2,3-b]pyridin-2- ylcarbonyl)-α-amino acids. Heating of the latter smoothly produced 3,4-dihydropyrido[3′,2′:4,5]thieno[3,2-e][1,4]diazepine-2(1H), 5-diones in high yields.

Full text of DOI:10.1023/B:RUCB.0000011878.52263.c4

Russian Chemical Bulletin, International Edition, Vol. 52, No. 10, pp. 2197—2202, October, 2003
2197
Reactions of Nꢀ(2ꢀchloroacetyl)ꢀαꢀamino acids
with 3ꢀcyanopyridineꢀ2(1H )ꢀthiones. New promising route
to 3,4ꢀdihydropyrido[3´,2´:4,5]thieno[3,2ꢀe][1,4]diazepineꢀ2(1H ),5ꢀdiones
A. E. Fedorov,ꢀ A. M. Shestopalov, and P. A. Belyakov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: aefed@ioc.ac.ru
The reactions of Nꢀ(2ꢀchloroacetyl)ꢀαꢀamino acids with 3ꢀcyanopyridineꢀ2(1H )ꢀthiones
afforded Nꢀ(3ꢀaminothieno[2,3ꢀb]pyridinꢀ2ꢀylcarbonyl)ꢀαꢀamino acids. Heating of the latter
smoothly produced 3,4ꢀdihydropyrido[3´,2´:4,5]thieno[3,2ꢀe][1,4]diazepineꢀ2(1H ),5ꢀdiones
in high yields.
Key words: Nꢀ(2ꢀchloroacetyl)ꢀαꢀamino acids, 3ꢀcyanopyridineꢀ2(1H )ꢀthiones,
Nꢀ(3ꢀaminothieno[2,3ꢀb]pyridinꢀ2ꢀylcarbonyl)ꢀαꢀamino
acids,
3,4ꢀdihydropyriꢀ
do[3´,2´:4,5]thieno[3,2ꢀe][1,4]diazepineꢀ2(1H ),5ꢀdiones, Thorpe—Ziegler cyclization.
3,4ꢀDihydrobenzo[1,4]diazepineꢀ2(1H ),5ꢀdiones are
no[2,3ꢀb]pyridinꢀ2ꢀylcarbonyl)ꢀαꢀamino acid without a
solvent (it should be noted that analogous thermal cyꢀ
clization has earlier been carried out for Nꢀ(2ꢀaminoꢀ
benzoyl)glycine35). We developed the new method based
on the studies of the reactions of 3ꢀcyanopyridineꢀ2(1H )ꢀ
thiones with chloroacetic acid amides.36,37
In the present study, we examined the reactions of
Nꢀ(2ꢀchloroacetyl)ꢀαꢀamino acids 1a—e with 3ꢀcyanoꢀ
pyridineꢀ2(1H )ꢀthiones 2a—g.
We used pyridinethiones 2a—g as the starting reagents.
The methods for the synthesis of these compound were
wellꢀdeveloped.36—40 NꢀChloroacetylꢀαꢀamino acids were
prepared from natural αꢀamino acids and chloroacetyl
chloride according to standard procedures (see the Exꢀ
perimental section).
The reactions of mercaptonitriles with electrophiles
were studied in sufficient detail.36—40 Based on the reꢀ
sults of these investigations, we assumed that the reactions
of Nꢀchloroacetylꢀαꢀamino acids 1a—e with 3ꢀcyanoꢀ
pyridineꢀ2(1H )ꢀthiones 2a—g proceed according to
Scheme 1.
The first step of the reaction involves the nucleophilic
displacement of the chlorine atom by the thiolate anion
to form Nꢀ[(3ꢀcyanopyridinꢀ2ꢀylthio)acetyl]ꢀαꢀamino
acids 3, which is confirmed by isolation of some of these
compounds in pure form. These reactions with the use of
amides of natural optically active amino acids afford optiꢀ
cally active products 3. The properties and results of analyꢀ
sis of acylated amino acids 3a—f are given in Table 1.
The second step involves Thorpe—Ziegler cyclizaꢀ
tion under the action of a base to produce Nꢀ(thieꢀ
no[2,3ꢀb]pyridinꢀ2ꢀylcarbonyl)ꢀαꢀamino acids 4. We
studied the reactions of compounds 2a—g with Nꢀchloroꢀ
known as potential antitumor,1,2, anesthetic,3—5 hypotenꢀ
sive,3—5 and antiamebic6 drugs, bactericides,7 neuroꢀ
leptics,8 and herbicides.9 Diazepinones are also used as
the starting compounds in the synthesis of biologically
active diazepines.2,5,10—13 3,4ꢀDihydro[1,4]diazepineꢀ
2(1H ),5ꢀdiones fused with a heterocycle can also be of
practical interest. 3,4ꢀDihydro[1,4]diazepineꢀ2(1H ),5ꢀ
diones fused with imidazole,14—22 indole,23 pyridine24,
thiophene,24,25 isothiazole,26 isoselenoazole,26 and
quinoline27 are known, whereas 3,4ꢀdihydropyriꢀ
do[3´,2´:4,5]thieno[3,2ꢀe][1,4]diazepineꢀ2(1H ),5ꢀdiones
were not described in the literature.
Many procedures were developed for the synthesis
of systems containing the 3,4ꢀdihydro[1,4]ꢀdiazepineꢀ
2(1H ),5ꢀdione fragment.2—35
Among the drawbacks of the available methods is the
necessity of introducing the corresponding functional
groups at a specified position of the molecule followed by
activation of these groups, for example, by transforming
into 1,3ꢀoxazineꢀ2,6ꢀdione derivatives. It is apparent that
in the case of the starting substrates containing other funcꢀ
tional groups, which are labile under reaction conditions,
these methods have very limited application due to the
possibility of competitive reactions.
We developed a new procedure for the synthesis of
3,4ꢀdihydropyrido[3´,2´:4,5]thieno[3,2ꢀe][1,4]diazepineꢀ
2(1H ),5ꢀdiones, which differs from the known methods
in that a fragment, which is ready to undergo cyclization
and does not require additional activation, is generated as
a result of successive (domino) reactions proceeding
regioselectively under rather mild conditions in high
yield, and cyclization occurs upon heating of Nꢀ(thieꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2081—2086, October, 2003.
1066ꢀ5285/03/5210ꢀ2197 $25.00 © 2003 Plenum Publishing Corporation

2198
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Fedorov et al.
Scheme 1
1
R4
R5
2
R1
R2
R3
3
R1
R2
R3
R4
R5
4
R1
R2
R3
R4
R5
a
b
c
d
e
(Gly)
(LꢀAla)
(LꢀVal)
(LꢀPhe) Bn
(LꢀPro)
H
Me
Pri
H
H
H
H
a
b
c
d
e
f
Me
H
H
H
H
Me
4ꢀpyridyl
Me
a
b
c
d
e
f
Me
Me
Me
Me
Me
Ph
H
H
H
H
H
H
Me
Me
Me
Me
CF3
2ꢀthienyl
H
Me
Bn
—(CH2)3—
H
H
H
H
H
a
b
c
d
e
f
g
h
i
Me
H
H
H
H
Me
4ꢀpyridyl
Me
H
H
H
H
H
H
H
Me
Pri
Bn
H
H
H
H
H
H
H
H
H
H
Ac
CN NH2
H
H
H
Ac
CN NH2
H
H
—(CH2)3—
CF3
Ph
Me
Ph
2ꢀthienyl
CF3
H
H
CF3
Ph
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
Ph
2ꢀthienyl
CF3
Me
Me
Me
g
j
k
Me
—(CH2)3—
a. KOH; b. 1) KOH, 2) HCl.
acetylglycine (1a). It was found that pyridinethiones conꢀ
taining Ar and Het substituents at positions 4 and 6 are
much more difficult to subject to Thorpe—Ziegler cyclizaꢀ
tion, and a much longer reaction time and higher temꢀ
perature are required for completion of the reaction comꢀ
pared to the reactions with alkylꢀsubstitueted pyridineꢀ
thiones. This fact should be taken into account when
planning the synthesis because the use of more drastic
reaction conditions increases the probability of decomꢀ
position of both the starting Nꢀchloroacetyl derivative of
amino acid and intermediate 3. We also carried out the
reactions of 3ꢀcyanoꢀ4,6ꢀdimethylpyridineꢀ2(1H )ꢀthione
(2a) with Nꢀchloroacyl derivatives of optically active
amino acids, such as Lꢀalanine, Lꢀphenylalanine, Lꢀvaꢀ
line, and Lꢀproline. However, we failed to evaluate
the optical activity of the resulting compounds 4a—k
due to strong absorption by solutions of 3ꢀaminothieꢀ
no[2,3ꢀb]pyridines in the spectral region used in a polaꢀ
rimeter (sodium D line). The properties of compounds 4
are given in Table 2.
When studying the properties of Nꢀ(3ꢀaminoꢀ4,6ꢀ
dimethylthieno[2,3ꢀb]pyridinꢀ2ꢀylcarbonyl)glycine (4a),
Table 1. Spectroscopic characteristics of compounds 3a—f
Comꢀ
pound
IR, ν/cm–1
1H NMR (DMSOꢀd6, δ, J/Hz)
3a
3b
3304 (NH), 2216 (CN), 1716 (COOH), 2.52, 2.75 (both s, 3 H each, Me); 3.75 (d, 2 H, CH2 J = 3.7);
1628, 1584 (CO) 4.05 (s, 2 H, SCH2); 7.10 (s, 1 H, CH of pyridine); 8.41 (br.m, 1 H, NH)
3304 (NH), 2216 (CN), 1720 (COOH), 1.27 (d, 3 H, Me, J = 7.3); 2.35, 2.45 (both s, 3 H each, Me);
1624, 1584 (CO)
4.02 (s, 2 H, SCH2); 4.25 (dq, 1 H, CH, J = 7.3, J = 7.5);
7.12 (s, 1 H, CH of pyridine); 8.43 (d, 1 H, NH, J = 7.5)
3c
3d
3280 (NH), 2220 (CN), 1736 (COOH), 2.30, 2.40 (both s, 3 H each, Me); 3.02 (m, 2 H, CH2); 3.89 (s, 2 H, SCH2);
1624, 1548 (CO)
4.25 (m, 1 H, CH); 7.05 (s, 1 H, CH of pyridine); 7.15 (m, 5 H, Ar);
8.25 (br.m, 1 H, NH)
2224 (CN), 1728 (COOH), 1620 (CO)
1.90 (m, 2 H, CH2); 2.21 (m, 1 H, CH2); 2.35, 2.45 (both s, 3 H each, Me);
3.41 (m, 1 H, CH2); 3.75 (m, 2 Н CH2); 4.15 (s, 2 H, SCH2);
4.22 (m, 1 H, CH); 7.14 (s, 1 H, CH of pyridine)
3e
3f
3312 (NH), 2228 (CN), 1736 (COOH), 2.61 (s, 3 H, Me); 3.70 (br.s, 2 H, CH2); 4.10 (s, 2 H, SCH2);
1636, 1556 (CO) 7.63 (s, 1 H, CH of pyridine); 8.28 (br.s, 1 H, NH)
3292 (NH), 2212 (CN), 1720 (COOH), 3.75 (d, 2 H, CH2, J = 4.8); 4.15 (s, 2 H, SCH2); 7.23 (t, 1 H, CH of thiophene,
1640, 1564 (CO)
J = 3.5); 7.55 (m, 3 H, Ar); 7.70 (m, 3 H, CHAr + CH of pyridine);
8.09 (br.m, 1 H, NH); 8.62 (m, CH of thiophene)
Note. c/g•100 cm–3: 8.5 (3b), 2.8 (3c), 5.03 (3d); [α]D20 (K salt in water): –47.2 (3b), –36 (3c), –36.1 (3d).

Pyrido[3',2':4,5]thieno[3,2ꢀe][1,4]diazepine
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2199
Table 2. Spectroscopic characteristics of compounds 4a—k
Comꢀ
pound
IR, ν/cm–1
1H NMR (DMSOꢀd6, δ, J/Hz)
4a
4b
3380, 3320 (NH2, NH), 1700 (COOH), 2.52, 2.72 (both s, 3 H each, Me); 3.70 (d, 2 H, CH2, J = 5.9);
1604, 1548 (CO)
7.10 (s, 1 H, CH of pyridine); 7.91 (t, 1 H, NH, J = 5.9)
3336, 3316 (NH2, NH), 1700 (COOH),
1604, 1524 (CO)
3.79 (d, 2 H, CH2, J = 5.5); 7.25 (br.s, 2 H, NH2); 8.02 (t, 1 H, NH, J = 5.5);
8.13 (d, 2 H, CH of pyridine, J = 3.9); 8.20 (d, 1 H, CH of pyridine, J = 8.5);
8.63 (d, 1 H, CH of pyridine, J = 8.5); 8.75 (d, 2 H, CH of pyridine, J = 3.9)
4c
4d
4e
4f
3448, 3324 (NH, NH2), 1696 (COOH), 2.62 (s, 3 H, Me); 2.75 (s, 3 H, Ac); 3.80 (d, 2 H, CH2, J = 6.1); 7.32 (br.s,
1676, 1616, 1588 (CO) 2 H, NH2); 8.05 (t, 1 H, NH, J = 6.1); 9.13 (s, 1 H, CH of pyridine)
3428, 3320, 3216 (NH, NH2), 2224 (CN), 3.75 (d, 2 Н, CH2, J = 4.9); 7.12, 7.30 (both br.s, 2 H each, NH2);
1700 (COOH), 1640, 1520, (СО) 7.71 (t, 1 H, NH, J = 4.9); 8.52 (s, 1 H, CH of pyridine)
3516, 3324 (NH, NH2), 1720 (COOH), 3.85 (d, 2 H, CH2, J = 4.9); 6.75 (br.s, 2 H, NH2); 7.55 (m, 3 H, CHAr
+
1604, 1540 (CO)
+ CH of pyridine); 8.25 (m, 3 H, Ar); 8.35 (t, 1 H, NH, J = 4.9)
3.81 (d, 2 H, CH2, J = 5.5); 5.80 (br.s, 2 H, NH2); 7.15 (dd, 1 H,
CH of thiophene, J = 3.6, J = 4.9); 7.64 (m, 5 H, Ar); 7.72 (m, 2 H,
3488, 3388, 3448 (NH, NH2),
1732 (COOH), 1608, 1536 (CO)
CH of pyridine + CH of thiophene); 8.03 (d, 1 H, CH of thiophene, J = 3.6);
8.10 (t, 1 H, NH, J = 5.5)
4g
4h
3452, 3331 (NH, NH2), 1743 (COOH), 2.93 (s, 3 H, Me); 3.91 (d, 2 H, CH2, J = 5.5); 6.94 (br.s, 2 H, NH2);
1491, 1579 (CO)
7.65 (s, 1 H, CH of pyridine); 8.25 (t, 1 H, NH, J = 5.5)
1.35 (d, 3 H, Me, J = 7.3); 2.45, 2.70 (both s, 3 H each, Me);
4.35 (dq, 1 H, CH, J = 6.7, J = 7.3); 6.82 (br.s, 2 H, NH2);
7.12 (s, 1 H, CH of pyridine); 7.92 (d, 1 H, NH, J = 6.7, J = 7.3)
0.95 (t, 6 H, CHMe2, J = 7.3); 2.15 (m, 1 H, CHMe2); 2.45, 2.70 (both s,
3 H each, Me); 4.35 (m, 1 H, CH); 6.75 (br.s, 2 H, NH2); 7.03 (s, 1 H,
CH of pyridine); 7.35 (d, 1 H, NH, J = 6.7)
3448,3388, 3324 (NH, NH2),
1700 (COOH), 1604, 1552 (CO)
4i
3472, 3396, 3336 (NH, NH2),
1704 (COOH), 1604, 1556 (CO)
4j
3484, 3324 (NH, NH2), 1724 (COOH), 2.45, 2.70 (both s, 3 H each, Me); 3.15 (m, 2 H, CH2); 4.61 (dt, 1 H,
1612, 1552 (CO)
CH, J = 7.3, J = 6.1); 7.03 (s, 1 H, CH of pyridine); 7.25 (m, 5 H, Ar);
7.75 (d, 1 H, NH, J = 6.1)
4k
3344 (NH2), 1728 (COOH),
1600, 1548 (CO)
2.15 (m, 4 H, CH2CH2); 2.45, 2.70 (both s, 3 H each, Me); 3.78 (m, 2 Н, CH2N);
4.51 (m, 1 H, CH); 6.84 (br.s, 2 H, NH2); 7.05 (s, 1 H, CH of pyridine)
we found that in the course of heating to the melting
point, compound 4a first melted, then solidified, and again
melted at higher temperature. Analysis of the resulting
product by 1H NMR spectroscopy revealed that the specꢀ
trum has a singlet at δ 10.2 characteristic of the amide
KOH solution, which is evidence for the presence of eiꢀ
ther the primary or secondary amide group.
Based on the results of the present study, we assumed
that the resulting compound is a new polyheterocyclic sysꢀ
tem, viz., 8,10ꢀdimethylꢀ3,4ꢀdihydropyrido[3´,2´:4,5]thieꢀ
no[3,2ꢀe][1,4]diazepineꢀ2(1H ),5ꢀdione (5a).
1
group (it should be noted that the H NMR spectrum of
compound 4a does not show a signal of the amino group
due to deuterium exchange). The IR spectrum of the
product has a narrow band at 3412 cm–1 characteristic of
secondary amide instead of a broad absorption band at
3380 cm–1 characteristic of the amino group. Besides, the
IR spectrum shows two bands at 1690 and 1584 cm–1
characteristic of the carbonyl fragment of the CONH
group instead of the absorption band of the carboxy group
at 1700 cm–1. The mass spectrum has a molecular ion
peak at m/z 261 (18 units lower than that of the starting
compound), which indicates that the reaction was acꢀ
companied by elimination of a water molecule. In adꢀ
dition, this spectrum contains ion peaks at m/z 232
[M – NHCH2], 205 [M – NHCH2CO], 190, and 176.
The substance under consideration is insoluble in 10%
aqueous KHCO3 and 5% aqueous HCl, which is, preꢀ
sumably, indicative of the absence of both the carboxy
and amino groups. The substance is soluble in a 20%
Since this reaction was first found for Nꢀ(thieꢀ
no[2,3ꢀb]pyridinꢀ2ꢀylcarbonyl)ꢀαꢀamino acids, we decided
to study the field of its application. All compounds 4 synꢀ
thesized were subjected to thermal treatment (Scheme 2).
Our investigation demonstrated that virtually all Nꢀacylꢀ
αꢀamino acids 4 were transformed into the corresponding
3,4ꢀdihydropyrido[3´,2´:4,5]thieno[3,2ꢀe][1,4]diazepineꢀ
2(1H ),5ꢀdiones 5. It was found that the substituents in the
pyridine ring have only a slight effect on the course of the
reaction. The reaction rate substantially decreases as the
size of the substituent in the amino acid fragment increases
in the series of glycine, alanine, valine, phenylalanine, and
proline. For this reaction, we empirically found that it is
optimum to keep the starting amino acids 4 at 220 °C for 1 h.
It should be noted that 4ꢀdihydropyrido[3´,2´:4,5]thieꢀ
no[3,2ꢀe][1,4]diazepineꢀ2(1H ),5ꢀdiones 5h—k prepared
from optically active amino acids also exhibit optical acꢀ
tivity.

2200
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Fedorov et al.
Scheme 2
4,5
R1
R2
R3
R4
R5
4,5
R1
R2
R3
R4
R5
a
b
c
d
e
f
Me
H
H
H
CF3
Ph
H
H
Ac
CN
H
Me
4ꢀpyridyl
Me
NH2
Ph
H
H
H
H
H
H
H
H
H
H
H
H
g
h
i
j
k
Me
Me
Me
Me
Me
H
H
H
H
H
CF3
Me
Me
Me
Me
H
H
H
H
H
Me
Pri
Bn
—(CH2)3—
H
2ꢀthienyl
polarimeter using a 100ꢀmm path length cell at λ = 589 nm
(sodium D line). Pyridinethiones 2a—g were prepared accordꢀ
ing to procedures described earlier.36—40
NꢀChloroacetylꢀαꢀamino acids 1a—e (general procedure).
Freshly distilled chloroacetyl chloride (0.1 mol) was added
dropwise to a suspension of amino acid (0.2 mol) in dry
Experimental
The IR spectra were recorded on a Specord Mꢀ80 instruꢀ
1
ment (KBr pellets). The H NMR spectra were measured on a
Bruker AMꢀ300 spectrometer (300.13 MHz) in DMSOꢀd6 and
CDCl3. The optical rotation was measured on a CMꢀ2 circle
Table 3. Spectroscopic characteristics of compounds 5a—k
Comꢀ
pound
IR, ν/cm–1
1H NMR (DMSOꢀd6, δ, J/Hz)
5a
5b
3412, 3320 (NH), 1690, 1584,
1604, 1548 (CO)
3184, 3052 (NH), 1676, 1648,
1572, 1552 (CO)
2.52, 2.72 (both s, 3 H each, Me); 3.71 (d, 2 H, CH2, J = 5.5);
7.15 (s, 1 H, CH of pyridine); 7.89 (t, 1 H, NH J = 5.5); 10.20 (s, 1 H, NH)
3.85 (d, 2 H, CH2, J = 4.4); 8.05 (d, 2 H, CH of pyridine, J = 5.2); 8.11 (d, 2 H,
CH of pyridine, J = 3.9); 8.33 (d, 1 H, CH of pyridine, J = 8.5); 8.60 (m, 2 H,
CH of pyridine + NH); 8.75 (d, 2 H, CH of pyridine, J = 5.2); 11.32 (br.s, 1 H, NH)
2.72 (s, 3 H, Me); 2.81 (s, 3 H, Ac); 3.92 (d, 2 H, CH2, J = 4.4); 8.58 (t, 1 H,
NH, J = 4.4); 9.11 (s, 1 H, CH of pyridine); 11.33 (s, 1 H, NH)
5c
5d
3212, 3068 (NH), 1688, 1656,
1592, 11564, 1520 (CO)
3436, 3312, 3184 (NH, NH2),
2216 (CN), 1692, 1628, 1596,
1520, 1504 (СО)
3.82 (d, 2 H, CH2, J = 4.4); 7.40 (br.s, 2 H, NH2); 8.40 (t, 1 H, NH, J = 4.4);
8.55 (s, 1 H, CH of pyridine); 11.00 (s, 1 H, NH)
5e
5f
3440, 3180 (NH), 1716, 1664,
1592, 1544 (CO)
3368, 3164 (NH), 1696, 1660,
1576, 1536 (CO)
3.85 (d, 2 H, CH2, J = 4.9); 7.55 (m, 3 H, Ar); 8.25 (m, 2 H, Ar); 8.32 (s, 1 H,
CH of pyridine); 9.10 (t, 1 H, NH, J = 4.9); 9.21 (br.s, 1 H, NH)
3.85 (d, 2 H, CH2, J = 5.5); 7.15 (m, 1 H, CH of thiophene); 7.56 (m, 5 H, Ar);
7.68 (m, 2 H, CH of thiophene); 7.90 (s, 1 H, CH of pyridine);
8.02 (m, 1 H, CH of thiophene);
8.51 (s, 1 H, NH); 8.74 (t, 1 H, NH, J = 5.5)
5g
5h
3404, 3331 (NH) 1796, 1660),
1588, 1528 (CO)
3420, 3164 (NH), 1696, 1636,
1584, 1556 (CO)
2.92 (s, 3 H, Me); 3.89 (d, 2 H, CH2, J = 4.1); 7.65 (s, 1 H, CH of pyridine);
8.93 (t, 1 H, NH, J = 4.5); 10.41 (s, 1 H, NH)
1.35 (d, 3 H, Me, J = 6.6); 2.72, 3.40 (both s, 3 H each, Me); 4.15 (dq, 1 H,
CH, J = 6.6, J = 4.3); 7.10 (s, 1 H, CH of pyridine); 8.62 (d, 1 H, NH, J = 6.6);
10.35 (s, 1 H, NH)
5i
3156, 3040 (NH), 1696, 1644,
1584, 1552 (CO)
0.95 (m, 6 H, CHMe2); 2.15 (m, 1 H, CHMe2); 2.53, 2.70 (both s, 3 H each, Me);
3.48 (m, 1 H, CH); 7.02 (s, 1 H, CH of pyridine); 7.35 (d, 1 H, NH, J = 6.1);
10.25 (br.s, 1 H, NH)
5j
3484, 3324 (NH, NH2),
1724 (COOH), 1612,
1552 (CO)
2.45, 2.70 (both s, 3 H each, Me); 3.15 (m, 2 H, CH2); 4.33 (m, 1 H, CH);
7.03 (s, 1 H, CH of pyridine); 7.25 (m, 5 H, Ar); 7.75 (d, 1 H, NH, J = 4.4);
10.31 (br.s, 1 H, NH)
5k
3400 (NH), 1700, 1684,
1632, 1552 (CO)
2.01 (m, 4 H, CH2CH2); 2.55, 2.75 (both s, 3 H each, Me); 3.83 (m, 2 H, CH2N);
4.41 (m, 1 H, CH); 6.79 (br.s, 2 H, NH2); 7.01 (s, 1 H, CH of pyridine)
Note. c/g•100 cm–3: 2.6 (5h), 2.8 (5i), 1.7 (5j), 2.6 (5k); [α]D20 (DMSO): +11.3 (5h), +10.7 (5i), +18.3 (5j), +10.9 (5k).

Pyrido[3',2':4,5]thieno[3,2ꢀe][1,4]diazepine
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2201
MeCN (200 mL) with cooling to ∼20 °C. The resulting susꢀ
pension was stirred at ∼20 °C for 48 h. The precipitate of
amino acid hydrochloride was filtered off and the filtrate
was concentrated to dryness under reduced pressure. The
residue was used in subsequent transformation without purifiꢀ
cation.
2 H, ClCH2); 4.59 (m, 1 H, CHNH); 7.15 (d, 1 H, NH, J =
8.1 Hz); 8.50 (br.s, 1 H, COOH). IR, ν/cm–1: 3344 (NH), 1718
(COOH), 1636, 1582 (CO).
NꢀChloroacetylꢀLꢀphenylalanine (1d). The yield was 93%,
m.p. 119 °C (cf. lit. data42: 125 °C), [α]D20 +28.5 (c 8.4, K salt,
H2O). Found (%): C, 54.59; H, 6.05; N, 6.35. C11H12ClNO3.
Calculated (%): C, 54.67; H, 5.00; N, 5.80. 1H NMR (CDCl3),
δ: 3.20 (m, 2 H, CH2); 4.10 (s, 2 H, ClCH2); 4.85 (m, 1 H, CH);
7.05 (br.m, 1 H, NH); 7.25 (m, 2 H, Ar); 7.35 (m, 3 H, Ar); 8.70
(br.s, 1 H, COOH). IR, ν/cm–1: 3356 (NH), 1722 (COOH),
1676, 1552 (CO).
NꢀChloroacetylꢀLꢀproline (1e). The yield was 93%, m.p.
101 °C (cf. lit. data42: 125 °C), [α]D20 –21.7 (c 9.2, K salt, H2O).
Found (%): C, 43.96; H, 5.34; N, 7.75. C7H10ClNO3. Calcuꢀ
lated (%): C, 43.88; H, 5.26; N, 7.31. 1H NMR (acetoneꢀd6), δ:
1.90, 2.25, and 3.75 (all m, 2 H each, CH2); 4.25 (s, 2 H,
ClCH2); 4.40 (m, 1 H, CH). IR, ν/cm–1: 1712 (COOH), 1668,
1576 (CO).
Nꢀ[(3ꢀCyanopyridinꢀ2ꢀylthio)acetyl]ꢀαꢀamino acids (3a,f)
(general procedure). A 10% aqueous KOH solution (12 mL) and
solid Nꢀchloroacetylꢀαꢀamino acid 1 (10 mmol) were added to a
solution of pyridinethione 2 (10 mmol) in DMF (10 mL) at
20 °C. The reaction mixture was stirred at ∼20 °C for 40 min and
acidified with 10% HCl to Congo red. Then water (25 mL) was
added. The precipitate that formed was filtered off and purified
NꢀChloroacetylglycine (1a). The yield was 95%, m.p. 96 °C
(cf. lit. data41: 98—100 °C). Found (%): C, 31.59; H, 4.06;
N, 9.03. C4H6ClNO3. Calculated (%): C, 31.70; H, 3.99;
N, 9.24. 1H NMR (DMSOꢀd6), δ: 3.75 (d, 2 H, CH2, J =
3.7 Hz); 4.15 (s, 2 H, ClCH2); 8.50 (br.m, 1 H, NH). IR,
ν/cm–1: 3318 (NH), 1722 (COOH), 1631, 1574 (CO).
NꢀChloroacetylꢀLꢀalanine (1b). The yield was 90%, m.p.
20
72 °C (cf. lit. data42: 93 °C), [α]D –10.2 (c 11, K salt, H2O).
Found (%): C, 36.19; H, 5.01; N, 9.11. C5H8ClNO3. Calcuꢀ
lated (%): C, 36.27; H, 4.87; N, 8.46. 1H NMR (CDCl3), δ: 1.53
(d, 3 H, Me, J = 6.6 Hz); 4.10 (s, 2 H, ClCH2); 4.51 (dq, 1 H,
CH, J = 6.6 Hz, J = 7.4 Hz); 7.20 (d, 1 H, NH, J = 7.4 Hz); 8.50
(br.s, 1 H, COOH). IR, ν/cm–1: 3328 (NH), 1731 (COOH),
1624, 1566 (CO).
NꢀChloroacetylꢀLꢀvaline (1c). The yield was 98%, m.p. 112 °C
20
(cf. lit. data42: 114 °C), [α]D –13.9 (c 7.9, K salt, H2O).
Found (%): C, 43.39; H, 6.36; N, 6.93. C7H12ClNO3. Calcuꢀ
lated (%): C, 43.42; H, 6.25; N, 7.23. 1H NMR (CDCl3), δ: 0.95
(t, 6 H, CHMe2, J = 5.9 Hz); 2.15 (m, 1 H, CHMe2); 4.10 (s,
Table 4. Melting points, yields, and elemental analysis data for compounds 3—5
Comꢀ M.p. Yield
pound /°C (%)
Found
Calculated
Molecular
formula
Comꢀ M.p. Yield
pound /°C (%)
Found
Calculated
Molecular
formula
(%)
N
(%)
N
C
H
C
H
3a
3b
3c
3d
3e
3f
104
230
192
83
87
83
81
69
73
79
91
94
88
81
83
80
68
87
51.53 4.80 14.72 C12H13N3O3S
51.60 4.69 15.04
53.11 5.27 15.12 C13H15N3O3S
53.23 5.15 14.32
61.65 5.25 10.92 C19H19N3O3S
61.77 5.18 11.37
56.37 5.49 12.53 C15H17N3O3S
56.41 5.37 13.16
43.37 3.08 11.95 C12H10F3N3O3S
43.24 3.02 12.61
58.60 3.74 10.51 C20H15N3O3S2
58.66 3.69 10.20
51.58 4.73 14.74 C12H13N3O3S
51.60 4.69 15.04
54.95 3.53 16.56 C15H12N4O3S
54.87 3.68 17.06
50.80 4.19 13.14 C13H13N3O4S
50.81 4.26 13.67
45.37 3.09 24.33 C11H9N5O3S
45.36 3.11 24.04
51.55 2.97 11.01 C17H12F3N3O3S
51.64 3.06 10.63
58.67 3.73 10.03 C20H15N3O3S2
58.66 3.69 10.26
43.35 3.07 12.87 C12H10F3N3O3S
43.24 3.02 12.61
53.28 5.13 14.81 C13H15N3O3S
53.23 5.15 14.32
4i
225
144
138
337
>360
330
>360
277
343
282
298
315
268
148
82
85
69
—
—
—
—
—
—
—
—
—
—
—
56.16 5.88 12.73 C15H19N3O3S
56.06 5.96 13.07
61.86 5.25 12.06 C19H19N3O3S
61.77 5.18 11.37
56.41 5.37 13.16 C15H17N3O3S
56.41 5.37 13.16
55.13 4.19 15.73 C12H11N3O2S
55.16 4.24 16.08
57.93 3.17 17.37 C15H10N4O2S
58.05 3.25 18.05
53.89 3.71 14.06 C13H11N3O3S
53.97 3.83 14.52
48.29 2.63 25.77 C11H7N5O2S
48.35 2.58 25.63
54.03 2.75 10.85 C17H10F3N3O2S
54.11 2.67 11.14
61.45 3.26 11.04 C20H13N3O2S2
61.36 3.35 10.73
45.59 2.39 12.79 C12H8F3N3O2S
45.72 2.56 13.33
56.69 4.79 15.57 C13H13N3O2S
56.71 4.76 15.26
59.27 5.60 14.19 C15H17N3O2S
59.38 5.65 13.85
65.02 4.77 11.69 C19H17N3O2S
64.94 4.88 11.96
59.82 4.98 14.23 C15H15N3O2S
59.78 5.02 13.94
4j
4k
5a
5b
5c
5d
5e
5f
228
212
260
183
220
290
178
226
147
240
4a
4b
4c
4d
4e
4f
5g
5h
5i
4g
4h
5j
5k

2202
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Fedorov et al.
by either precipitation or recrystallization from 95% EtOH if
necessary.
18. O. Mahdi, J.ꢀP. Lavergne, P. Viallefont, M. Akssira, and
A. Sedqui, Bull. Soc. Chim. Fr., 1995, 12, 675.
19. E. I. Ivanov, Khim. Geterotsikl. Soedin., 1998, 828 [Chem.
Heterocycl. Compd., 1998, 34, 723 (Engl. Transl.)].
20. E. I. Ivanov, G. D. Kalayanov, and I. M. Yaroshenko, Khim.
Geterotsikl. Soedin., 1990, 997 [Chem. Heterocycl. Compd.,
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Nꢀ(Thieno[2,3ꢀb]pyridinꢀ2ꢀylcarbonyl)ꢀαꢀamino
acids
(4a—k) (general procedure). A. A 10% aqueous KOH solution
(16 mL) and Nꢀchloroacetylꢀαꢀamino acid 1 (10 mmol) were
added to a solution of pyridinethione 2 (10 mmol) in DMF
(10 mL) at 20 °C. The reaction mixture was stirred at 50 °C for 8
and 12 h in the case of alkylꢀsubstituted pyridinethiones and
pyridinethiones containing aromatic and heteroaromatic subꢀ
stituents, respectively. The reaction mixture was cooled and
acidified with 10% HCl to Congo red. Then water (25 mL) was
added. The precipitate that formed was filtered off and purified
by either precipitation or recrystallization from 95% EtOH if
necessary.
22. D. V. Nilov, A. V. Kadushkin, I. F. Kerbnikova, I. S.
Nikolaeva, V. V. Peters, T. A. Gus´kova, R. A. Dubinskii,
and V. G. Granik, Khim.ꢀfarm. Zh., 1995, 27 [Pharm. Chem.
J., 1995, 29, 106 (Engl. Transl.)].
B. A 10% aqueous KOH solution (5 mL) was added to a
solution of Nꢀacylꢀαꢀamino acid 3 (10 mmol) in DMF (10 mL)
at 20 °C and stirred at 50 °C for 7 and 12 h in the case of alkylꢀ
substituted compounds and compounds containing aromatic and
heteroaromatic substituents, respectively. Then the reaction mixꢀ
ture was treated as described in the method A.
3,4ꢀDihydropyrido[3´,2´:4,5]thieno[3,2ꢀe][1,4]diazepineꢀ
2(1H ),5ꢀdiones (5a—k). NꢀAcylꢀαꢀamino acids 4 (1 mmol) were
heated to 220 °C without a solvent and kept at this temperature
for 1 h. Analytically pure products were prepared in virtually
quantitative yields (96—98%). The optical activity was meaꢀ
sured for the samples recrystallized from aqueous DMSO.
The spectroscopic characteristics of diazepineꢀ2,5ꢀdiones 5
are given in Table 3. The results of elemental analysis are preꢀ
sented in Table 4.
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Received July 9, 2003;
in revised form August 28, 2003