A new dimerization reaction producing 2-amino-9-oxopyrrolo-[2,1-b]quinazoline-1-carbonitriles and analogous pyrrolo-[1,2-a]thieno[3,2-d]pyrimidinecarbonitriles

Article abstract of DOI:10.1002/jhet.5570380217

A series of 2-alkylthio-4-oxo-3-quinazolineacetonitriles 4 and 2-alkylthio-4-oxothieno[3,2-d]pyrimidine-3-acetonitriles 8 was prepared. Upon treatment with sodium hydride, compounds 4 and 8 react to give 2-amino-4,9-dihydro-9-oxopyrrolo[2,1-b]quinazoline-1-carbonitriles 9 and 6-amino-4,9-dihydro-9-oxopyrrolo[1,2-a]thieno [3,2-d]pyrimidine-7-carbonitriles 10, respectively. The transformation of compounds 4 and 8 to the tricyclic aminonitriles 9 and 10 involves a dimerization step followed by a pyrrole cyclization. The tert-butyl ester derivatives 4d and 8d upon treatment with sodium hydride underwent a Thorpe-Ziegler cyclization to provide enaminoesters of fused 1,3-thiazines (16 and 17, respectively) as major products.

Full text of DOI:10.1002/jhet.5570380217

Mar-Apr 2001
A New Dimerization Reaction Producing 2-Amino-9-oxopyrrolo-
[2,1-b]quinazoline-1-carbonitriles and Analogous Pyrrolo-
[1,2-a]thieno[3,2-d]pyrimidinecarbonitriles
Michael Gütschow
419
Institute of Pharmacy, University of Leipzig, D-04103 Leipzig, Germany
James C. Powers*
School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA
Received August 8, 2000
A series of 2-alkylthio-4-oxo-3-quinazolineacetonitriles 4 and 2-alkylthio-4-oxothieno[3,2-d]pyrimidine-
3-acetonitriles 8 was prepared. Upon treatment with sodium hydride, compounds 4 and 8 react to give
2-amino-4,9-dihydro-9-oxopyrrolo[2,1-b]quinazoline-1-carbonitriles 9 and 6-amino-4,9-dihydro-9-
oxopyrrolo[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitriles 10, respectively. The transformation of compounds
4 and 8 to the tricyclic aminonitriles 9 and 10 involves a dimerization step followed by a pyrrole cyclization.
The tert-butyl ester derivatives 4d and 8d upon treatment with sodium hydride underwent a Thorpe-Ziegler
cyclization to provide enaminoesters of fused 1,3-thiazines (16 and 17, respectively) as major products.
J. Heterocyclic Chem., 38, 419 (2001).
Cysteine proteases, a group of proteolytic enzymes,
pyrimidine-3(4H)-acetonitriles 8a-d and their dimeriza-
tion to fused pyrrolopyrimidines upon treatment with
sodium hydride.
are important targets for the design of enzyme inhibitors,
because of their role in important biological processes
and their pathophysiological significance in several
disease states. Amino acid and dipeptide derived nitriles
are reported to inhibit several cysteine proteases [1]. We
have prepared a series of 2-alkylthio-4-oxo-3-quin-
azolineacetonitriles and isosteric thieno[3,2-d]pyrimi-
dine-3-acetonitriles. The reaction of these heterocyclic
acetonitriles with thiols under basic conditions was
investigated as a model reaction for the interaction of
these compounds with cysteine proteases [2]. In the
course of this mechanistic study [3], a dimerization
reaction of the fused 2-alkylthiopyrimidin-3-acetoni-
triles was observed. In this paper, we wish to report the
synthesis of 2-alkylthio-4-oxo-3(4H)-quinazolineace-
tonitriles 4a-d and 2-alkylthio-4-oxothieno[3,2-d]-
A three-step synthesis, starting from isatoic anhydride 1
was utilized for the preparation of the 2-alkylthio-3-quina-
zolineacetonitriles 4 (Scheme 1). The 2-Amino-N-
(cyanomethyl)benzamide 2 obtained by the reaction of 1
with aminoacetonitrile was reacted with thiophosgene to
form the 4-oxo-2-thioxo-3-quinazolineacetonitrile 3.
Compounds 4a-d were prepared in high yields by base
catalyzed treatment of 3 with the appropriate alkyl halide
in aqueous acetone at room temperature. The thieno-
pyrimidineacetonitriles 8 were synthesized from the
isothiocyanate 6 via the thioureidothiophene 7 (Scheme 2).
A one-pot reaction with the appropriate alkyl halide,
involving S-alkylation and cyclocondensation [4] afforded
the 2-alkylthio thienopyrimidineacetonitriles 8a-d.

420
M. Gütschow and J. C. Powers
Vol. 38
Table 1
2-(Alkylthio)-4-oxo-3(4H)-quinazolineacetonitriles 4 and 2-(Alkylthio)-4-oxothieno[3,2-d]pyrimidine-3(4H)-acetonitriles 8
1
Compound Yield
(%)
mp (°C)
(solvent)
Molecular
Formula
Analysis
Calcd./Found
H NMR [a]
EI-MS (70 eV)
δ (deuteriochloroform)
m/z (%)
C
H
N
+
4a
4b
92
88
180-180.5
(EtOH)
C
H N OS
57.13 3.92 18.17
56.92 3.83 18.03
2.75 (s, 3H, CH ), 5.10 (s, 2H, CH ),
7.42-7.47 (m, 1H), 7.59-7.63 (m, 1H),
7.73-7.77 (m, 1H), 8.22-8.25 (m, 1H)
231 (M , 100)
11
9
3
3
2
+
97-97.5
(cyclohexane)
C
C
H
N OS
60.21 5.05 16.20
60.37 5.10 16.13
1.11 (t, 3H, CH ), 1.86 (sextet, 2H,
259 (M , 22), 217
13 13
3
3
+
CH CH ), 3.36 (t, 2H, SCH ), 5.09
(M - C H , 100)
3
2
2
3 6
(s, 2H, CH ), 7.27-7.46 (m, 1H),
2
7.57-7.60 (m, 1H), 7.72-7.78 (m, 1H),
8.21-8.24 (m, 1H)
+
4c
92
79
129-130
(EtOH)
H
N OS
66.43 4.26 13.67
66.39 4.26 13.64
4.62 (s, 2H, SCH ), 5.05 (s, 2H, CH ),
307 (M , 78),
17 13
3
2
2
+
7.30-7.36 (m, 3H), 7.43-7.50
(m, 3H), 7.64-7.67 (m, 1H), 7.75-7.79
(m, 1H), 8.22-8.26 (m, 1H)
91 (C H , 100)
7
7
+
4d
140-141
(ethyl acetate/
cyclohexane)
C
H
N O S
57.99 5.17 12.68
57.97 5.17 12.65
1.49 (s, 9H, CH ), 4.03 (s, 2H,
331 (M , 21), 275
16 17
3
3
3
+
SCH ), 5.11 (s, 2H, CH ), 7.42-7.48
(M - C H , 44), 258
2
2
4 8
+
(m, 1H), 7.53-7.56 (m, 1H), 7.72-7.76
(m, 1H), 8.21-8.25 (m, 1H)
(M - C H O, 43),
4
9
+
57 (C H , 100)
4
9
+
8a
8b
89
91
189-190
(EtOH)
C H N OS
45.56 2.97 17.71
45.41 2.96 17.63
2.73 (s, 3H, CH ), 5.12 (s, 2H, CH ),
237 (M , 100)
9
7
3
2
3
2
7.26 (d, J = 5.3 Hz, 1H), 7.82
(d, J = 5.3 Hz, 1H)
+
103-104
(acetone/
water)
C
C
H
N OS
49.79 4.18 15.84
49.74 4.15 15.80
1.10 (t, 3H, CH ), 1.84 (sextet, 2H,
265 (M , 25), 223
11 11
3
2
3
+
CH CH ), 3.33 (t, 2H, SCH ), 5.12
(M - C H , 100)
3
2
2
3 6
(s, 2H, CH ), 7.23 (d, J = 5.2 Hz, 1H),
2
7.81 (d, J = 5.3 Hz, 1H)
+
8c
71
62
135-137
(acetone/
water)
150-151
(ethyl acetate/
diethyl ether)
H
N OS
57.49 3.54 13.41
57.34 3.63 13.33
4.59 (s, 2H, SCH ), 5.05 (s, 2H, CH ),
313 (M , 99),
15 11
3
2
2
2
+
7.27-7.49 (m, 6H), 7.83
(d, J = 5.3 Hz, 1H)
91 (C H , 100)
7
7
+
8d
C
H
N O S
49.84 4.48 12.45
49.63 4.48 12.45
1.49 (s, 9H, CH ), 4.01 (s, 2H, SCH ),
337 (M , 16),
14 15
3
3
2
3
2
+
5.13 (s, 2H, CH ), 7.23 (d, J = 5.3
281 (M - C H , 39),
2
4 8
+
Hz, 1H), 7.81 (d, J = 5.3 Hz, 1H)
264 (M - C H O, 34),
4 9
+
57 (C H , 100)
4
9
[a] Aromatic protons, unless otherwise assigned.
The structures of 4a-d and 8a-d were confirmed based on
elemental analyses, mass spectra, and H nmr data (Table 1).
course of 4d and 8d is discussed below. The structures of
9a-d and 10a-d were confirmed based on elemental
analyses, mass spectra, ir spectra, and H nmr values
1
1
Compounds 4 and 8 are the first examples of bicyclic 4(3H)-
pyrimidinones fused at C-5 and C-6, which have a
cyanomethyl and an alkylthio moiety at positions 3 and 2.
Compounds 4 and 8 are heterocyclic substituted
acetonitriles containing an activated methylene group,
which should be deprotonated under strong basic condi-
tions. The acidity of this methylene group is supported by
the downfield shifted methylene signals of 4a-d and 8a-d
which appear in the range of 5.05-5.13 ppm (Table 1).
However, the resulting carbanion is not situated at a favor-
able distance from any electrophilic site in the molecule.
Therefore, under basic conditions an intermolecular reaction
might be expected. When 4a-c and 8a-c were treated with
sodium hydride in dimethylformamide at 0° for one hour the
products 9a-c and 10a-c (Scheme 3) were conveniently
obtained in good yields (Table 2). Treatment of the tert-
butyl ester derivatives 4d and 8d with sodium hydride
provided 9d and 10d only as by-products; the reaction
(Table 2). The analytical and spectroscopic data indicated
that the reaction products are dimers of the starting hetero-
1
cycles and that one alkylthio group is lost. The H nmr spec-
tra of 9a-d and 10a-d showed two signals exchangeable
with deuterium oxide: a singlet arising from one proton at
12.17-12.92 ppm, and a singlet integrating for two protons
in the range of 6.43-6.46 ppm (for 9a-d) or 6.26-6.30 ppm
(for 10a-d). The latter signal clearly indicated the presence
of a NH moiety in the reaction products. From these data,
2
the pyrroloquinazoline and pyrrolothienopyrimidine struc-
tures 9 and 10 could be unambiguously deduced.
The reaction of the heterocyclic substituted acetoni-
triles 4 and 8 can be envisioned to occur by the mecha-
nism shown for the quinazoline series in Scheme 4. The
initial step might be a Thorpe reaction involving an
intermolecular attack of the carbanion adjacent to the
cyano group at the cyano group of another molecule.

Mar-Apr 2001
Producing 2-Amino-9-oxopyrrolo[2,1-b]quinazoline-1-carbonitriles
421
at the adjacent electrophilic C(2) or C(2') carbon of
intermediate 11 would lead to the formation of the fused
imidazoles 12 or 13, respectively. However, neither
structure 12 or 13, nor tautomers that might be formed
1
from 12 or 13, are in agreement with the H nmr data for
the reaction products that we obtained. The same is the
case for another isomeric structure, the pyrrolo-
quinazoline 14, that might be formed by the attack of
the (deprotonated) methine moiety at the C(2') carbon
of 11. An attack of the activated methylene group at the
C(2) carbon of 11, followed by displacement of the
alkylthio group and subsequent tautomeric rearrange-
ment would form the final products 9. The structures of
the 2-aminopyrrolo[2,1-b]quinazoline-1-carbonitriles 9
(and the analogous pyrrolothienopyrimidines 10) are
completely in agreement with the spectral data for the
reaction products that we obtained. The reaction
products 9 could also be formed by an intermolecular
attack of the activated methylene group initially at the
1
C(2) carbon to form the dinitrile 15 [5]. The H nmr
data of the reaction products are not consistent with 15,
an isomer of 9. However, a subsequent Thorpe-Ziegler
cyclization [6] of the intermediate 15 and a tautomeric
rearrangement could easily provide 9. Thus, the
The initially formed dimer 11 could subsequently react
to displace one alkylthio group. Four different cycliza-
tions leading to a fused five-membered ring are
conceivable. Nucleophilic attack of the imino nitrogen
transformation of 4 and 8 to the heteroaromatic aminon-
itriles 9 and 10 occurs via a dimerization step followed
by a pyrrole cyclization. However, we can not distin-
guish between the two possible mechanisms.

422
M. Gütschow and J. C. Powers
Vol. 38
Table 2
9-Oxopyrrolo[2,1-b]quinazoline-1-carbonitriles 9 and 9-Oxopyrrolo[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitriles 10
1
Compound Yield
(%)
mp
(°C)
Molecular
Formula
Analysis
Calcd./Found
IR [a]
(cm )
H NMR (dimethyl-d sulfoxide) [b]
FAB-MS
MH
6
-1
+
δ
C
H
N
9a
9b
79
73
>320
(dec.) [c]
C
C
H
N O S
60.86 3.40 20.28 2190 (CN),
60.54 3.49 19.99 1696, 1644
(C=O)
2.46 (s, 3H, CH ), 6.46 (s, 2H [f], NH ),
415
443
21 14
6
2
3
2
7.22-7.32 (m, 2H), 7.43-7.50 (m, 1H),
7.61-7.65 (m, 1H), 7.68-7.75 (m, 1H),
7.80-7.86 (m, 1H), 8.08-8.12 (m, 2H),
12.18 (s, 1H [f], NH)
>310
(dec.) [c]
H
N O S
62.43 4.10 18.99 2188 (CN),
62.11 4.15 18.75 1696, 1640
(C=O)
0.95 (t, 3H, CH ), 1.67 (sextet, 2H,
23 18
6
2
3
CH CH ), 3.00-3.15 (m, 2H, SCH ),
3 2 2
6.43 (s, 2H, [f], NH ), 7.21-7.31 (m, 2H),
2
7.43-7.49 (m, 1H), 7.59-7.63 (m, 1H),
7.68-7.74 (m, 1H), 7.79-7.86 (m, 1H), 8.06-8.13
(m, 2H), 12.17 (s, 1H [f], NH)
9c
66 318- 320
[c]
C
H
N O S
66.11 3.70 17.13 2190 (CN),
65.82 3.71 17.14 1696, 1644
(C=O)
4.36 (d, J = 13.5 Hz, 1H, CH ), 4.41
491
515
27 18
6
2
2
(d, J = 13.5 Hz, 1H, CH ), 6.43 (s, 2H [f],
2
NH ), 7.20-7.31 (m, 5H), 7.42-7.52 (m, 3H),
2
7.66-7.74 (m, 2H), 7.81-7.88 (m, 1H),
8.06-8.12 (m, 2H), 12.19 (s, 1H [f], NH)
9d
10
58
>250
(dec.) [e]
C
H
N O S•H O 58.64 4.54 15.78 2190 (CN),
1.40 (s, 9H, CH ), 3.83 (s, 2H, CH ), 6.45
26 22
6
4
2
3 2
58.37 4.57 15.68 1696, 1644
(C=O)
(s, 2H [f], NH ), 7.23-7.33 (m, 2H),
2
7.44-7.55 (m, 2H), 7.69-7.76 (m, 1H),
7.80-7.87 (m, 1H), 8.07-8.13 (m, 2H), 12.23
(s, 1H [f], NH)
10a
10b
>330
C
H
N O S •H O 45.94 2.72 18.91 2190 (CN),
2.42 (s, 3H, CH ), 6.27 (s, 2H [f], NH ), 7.03
427
455
17 10
6
2
3
2
3
2
(dec.) [d]
46.39 2.92 18.89 1684, 1630
(C=O)
50.21 3.10 18.49 2192 (CN),
49.83 3.44 18.01 1684, 1630
(C=O)
(d, 1H), 7.41 (d, 1H), 8.16 (d, 1H),
8.21 (d, 1H), 12.88 (s, 1H [f], NH)
51 312-314
[c]
C
H
N O S
0.93 (t, 3H, CH ), 1.65 (sextet, 2H, CH CH ),
19 14
6
2
3
3 3 2
2.95-3.09 (m, 2H, SCH ), 6.26 (s, 2H [f], NH ),
2
2
7.03 (d, 1H), 7.39 (d, 1H), 8.15 (d, 1H),
8.20 (d, 1H), 12.85 (s, 1H [f], NH)
10c
10d
76 300-302 C
[d]
H
N O S •H O 53.06 3.10 16.14 2192 (CN),
4.31 (d, J = 13.5 Hz, 1H, CH ), 4.37
503
527
23 14
6
2
3
2
2
53.42 3.01 16.11 1686, 1632
(C=O)
(d, J = 13.5 Hz, 1H, CH ), 6.28 (s, 2H [f], NH ),
2
2
7.03 (d, 1H), 7.21-7.30 (m, 3H), 7.40-7.46
(m, 3H), 8.15 (d, 1H), 8.22 (d, 1H),
12.88 (s, 1H [f], NH)
5
>325
C
H
N O S •H O 48.52 3.70 15.43 2192 (CN),
1.41 (s, 9H, CH ), 3.80 (s, 2H, CH ), 6.30
22 18
6
4
3
2
3 2
(dec.) [e]
48.51 3.64 15.20 1686, 1632
(C=O)
(s, 2H [f], NH ), 7.05 (d, 1H), 7.30 (d, 1H),
2
8.17 (d, 1H), 8.20 (d, 1H), 12.92 (s, 1H [f], NH)
[a] In potassium bromide pellets. [b] Aromatic protons, unless otherwise assigned. [c] Recrystallization from ethyl acetate/cyclohexane. [d] Recrystallization
from 2-methoxyethanol/water. [e] See Experimental. [f] Exchangeable with deuterium oxide.
Reaction of the tert-butyl ester derivatives 4d and 8d
with sodium hydride provided the tricyclic enamino-
esters 16 and 17 as the major products (Scheme 5). The
reaction involves an intramolecular nucleophilic attack
of the deprotonated thiomethylene moiety at the nitrile
group followed by the tautomeric rearrangement of the
imine to the more stable enamine [7,8]. Similar Thorpe-
Ziegler cyclizations have found broad application for the
synthesis of five-membered heterocycles [6,8]; the
examples presented here involve the less common
formation of fused thiazines. Additionally, the dimeriza-
tion reaction occurred to form 9d and 10d, respectively,
which could be separated from the major products
(16 and 17) by fractional crystallization. The Dieckmann
condensation products 18 and 19 were not formed in this
reaction probably due to the lower reactivity of the
tert-butyl ester carbonyl.
In conclusion, we discovered a convenient preparation
of heteroaromatic aminonitriles of the pyrrolo[2,1-b]-
quinazoline ring system and of the isosteric pyrrolo[1,2-a]-
thieno[3,2-d]pyrimidine ring system by a new dimeriza-
tion reaction. Despite several reports dealing with the
chemistry and biological activity of pyrrolo[2,1-b]-
quinazolines [9], 2-aminosubstituted pyrrolo[2,1-b]quina-
zolin-9-ones are still unknown. Only one pyrrolo[2,1-b]-
quinazolin-9-one containing an aromatic pyrrole ring
(2-phenylpyrrolo[2,1-b]quinazolin-9(4H)-one) has been
described in the literature so far [10].

Mar-Apr 2001
Producing 2-Amino-9-oxopyrrolo[2,1-b]quinazoline-1-carbonitriles
423
recrystallized from water to obtain 8.0 g of compound 2. An addi-
tional portion of the product (6.1 g) was isolated after cooling the
1
filtrate overnight. Colorless crystals; yield 64%; mp 94-95°; H
nmr (dimethyl-d sulfoxide): δ 4.22 (d, 2H, CH ), 6.49-6.55
6
2
(m, 3H), 6.70-6.73 (m, 1H), 7.15-7.20 (m, 1H), 7.45-7.48
(m, 1H), 8.85 (t, broad, 1H, NH); ms (70 eV): m/z 175
+
(M , 53%), 119 (100%).
Anal. Calcd. for C H N O•0.5 H O: C, 58.69; H, 5.47; N,
9
9
3
2
22.81. Found: C, 58.97; H, 5.25; N, 22.71.
1,4-Dihydro-4-oxo-2-thioxo-3(2H)-quinazolineacetonitrile (3).
A solution of 2 (3.68 g, 20 mmoles) in dichloromethane
(350 ml) was added over a period of 5 minutes to a mixture of
thiophosgene (2.75 g, 24 mmoles), dichloromethane (100 ml),
ice-water (160 ml), and potassium carbonate (5.5 g,
40 mmoles). The mixture was stirred for 2 hours at 0° and the
precipitate that formed was removed by filtration and washed
with water to give 3.6 g (83%) of 3 as a slightly yellow solid;
1
mp 264-266° (ethyl acetate/cyclohexane);
H nmr
(dimethyl-d sulfoxide): δ 5.28 (s, 2H, CH ), 7.36-7.43
6
2
(m, 2H, aromatic), 7.77-7.83 (m, 1H, aromatic), 7.99-8.02
+
(m, 1H, aromatic); ms (70 eV): m/z 217 (M , 100%).
Anal. Calcd. for C H N OS: C, 55.29; H, 3.25; N, 19.34.
10
7 3
Found: C, 55.42; H, 3.56; N, 19.00.
2-(Alkylthio)-4-oxo-3(4H)-quinazolineacetonitriles 4a-d.
General Procedure.
A solution of sodium hydroxide in water (1 M, 4.4 ml) was
added to a mixture of 3 (870 mg, 4 mmoles), the appropriate alkyl
halide (iodomethane, 1-bromopropane, benzyl chloride,
tert-butyl chloroacetate, respectively, each 5 mmoles), and
acetone (10 ml). The resulting mixture was stirred at room
temperature for 24 hours, diluted with water and cooled. The
precipitate was collected by filtration, dried, and recrystallized as
indicated (Table 1).
Methyl 3-[3-(Cyanomethyl)thioureido]thiophene-2-carboxy-
late (7).
EXPERIMENTAL
Compound 6 (2.99 g, 15 mmoles) was added to a stirred
mixture of aminoacetonitrile bisulfate (2.77 g, 18 mmoles)
and triethylamine (1.82 g, 18 mmoles) in dimethylformamide
(75 ml). After stirring at room temperature for 2 hours, the
reaction mixture was cooled at -10° for 1 hour, diluted with
Thin-layer chromatography was performed using aluminum
sheets coated with 0.2 mm silica gel 60 F (Merck). Melting
254
points were obtained on a Büchi capillary apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin Elmer
1
16PC FTIR. H nmr spectra were determined on a Varian
water, and cooled at 0° for 2 hours to produce 3.2 g (84%) of 7
Gemini 300 instrument. Mass spectra were recorded on a
Varian MAT 1125 spectrometer. Elemental analyses were
performed by Atlanta Microlab Inc., Norcross, GA. Isatoic
anhydride (1), methyl 3-amino-2-thiophenecarboxylate (5),
aminoacetonitrile bisulfate, thiophosgene, and the alkyl halides
were purchased from Aldrich Co., Milwaukee, WI. Methyl
3-isothiocyanatothiophene-2-carboxylate (6) was prepared
from 5 and thiophosgene according to a reported procedure
[11], mp 56-58°, ref [12] 54-56°.
1
as light brown crystals; mp 142-143°; H nmr (dimethyl-d
6
sulfoxide): δ 3.82 (s, 3H, CH ), 4.56 (d, 2H, CH ), 7.85 (d, J =
3
2
5.5 Hz, 1H), 8.21 (d, J = 5.5 Hz, 1H), 9.47 (t, 1H, NH), 10.23
+
(s, 1H, NH); ms (70 ev): m/z 255 (M , 94%), 223
+
(M - CH OH, 100%).
3
Anal. Calcd. for C H N O S : C, 42.34; H, 3.55; N, 16.46.
9
9 3 2 2
Found: C, 42.15; H, 3.56; N, 16.33.
2-(Alkylthio)-4-oxothieno[3,2-d]pyrimidine-3(4H)-acetonitriles
8a-d.
2-Amino-N-(cyanomethyl)benzamide (2).
General Procedure.
Aminoacetonitrile bisulfate (38.5 g, 250 mmoles) and isatoic
anhydride 1 (19.6 g, 120 mmoles) were added to a mixture of
sodium hydroxide (9.6 g, 240 mmoles) and water (250 ml). The
mixture was stirred on a boiling water-bath for 45 minutes and a
portion of the product was collected by filtration and
Following the general procedure to prepare 4a-d the
appropriate alkyl halide was reacted with compound 7 (1.05 g,
4 mmoles). The crude products were recrystallized as indicated
(Table 1).

424
M. Gütschow and J. C. Powers
Vol. 38
2-Amino-4,9-dihydro-9-oxopyrrolo[2,1-b]quinazoline-1-
carbonitriles 9a-c and 6-Amino-4,9-dihydro-9-oxopyrrolo-
[1,2-a]thieno[3,2-d]pyrimidine-7-carbonitriles 10a-c.
terium oxide), 8.20 (d, 1H), 8.12-8.28 (s, broad, 1H, NH,
exchangeable with deuterium oxide); ms (70 eV): m/z 337
+
+
+
(M , 19%), 281 (M - C H , 100%), 237 (M - C H - CO , 74%).
4
8
4
8
2
Anal. Calcd. for C
Found: C, 49.81; H, 4.59; N, 12.54.
H N O S : C, 49.84; H, 4.48; N, 12.45.
14 15 3 3 2
General Procedure.
The methanol filtrate was evaporated, the resulting solid was
recrystallized first from acetone/n-hexane and afterwards from
methanol/water with silica gel to obtain 25 mg (5%) of
compound 10d (Table 2).
Compound 4 or 8 (each 2 mmoles) was added at 0° to a
mixture of sodium hydride (48 mg, 2 mmoles) and dimethyl-
formamide (7.5 ml). The reaction mixture was stirred at 0° for
1 hour, diluted with brine (300 ml) and extracted with ethyl
acetate (3 × 120 ml). The combined organic layers were washed
with water (300 ml) and dried (sodium sulfate). The solution was
evaporated under reduced pressure and the residue was washed
with a small amount of cold methanol. The products are shown in
Table 2.
Acknowledgement.
We thank BASF Biotechnology Corp., for financial support.
REFERENCES AND NOTES
Treatment of tert-Butyl [[3-(Cyanomethyl)-3,4-dihydro-4-oxo-2-
quinazolinyl]thio]acetate (4d) with Sodium Hydride.
[*] Corresponding Author: James C. Powers, School of
Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta,
GA 30332-0400, Tel: (404) 894-4038, Fax: (404) 894-7452.
[1] For a review, see: H.-H. Otto and T. Schirmeister, Chem. Rev.,
97, 133 (1997).
[2] Compounds 4 and 8 react with thiols under basic conditions
via thioimidates generated by the attack of the thiolate at the nitrile
function. The subsequent ring closure provides alkylthio derivatives of
imidazo[2,1-b]quinazolinones and imidazo[1,2-a]thieno[3,2-d]pyrim-
idinones, respectively. This "trapped thioimidate" cyclization might be
useful for the design of new types of cysteine protease inhibitors [3].
[3] M. Gütschow and J. C. Powers, manuscript in preparation.
[4] S. Leistner, M. Gütschow and G. Wagner, Arch. Pharm.
(Weinheim), 322, 227 (1989).
[5] It was found that compounds 4 react with water or thiols under
basic aqueous conditions exclusively at the nitrile function [3]. Under
stronger basic conditions, deprotonation of the cyanomethylene moiety
might shift the nucleophilic attack to the C(2) carbon.
[6] E. C. Taylor and A. McKillop, The Chemistry of Cyclic
Enaminonitriles and o-Aminonitriles in Advances in Organic Chemistry,
Vol 7, E. C. Taylor, ed, Wiley Interscience, New York, 1970, pp 1-390.
[7] H. Wamhoff, in Advances in Heterocyclic Chemistry, Vol 38,
A. R. Katritzky, ed, Academic Press, Orlando, 1985, pp 299-368.
[8] V. P. Litvinov, Yu. A. Sharanin and F. S. Babichev, Sulfur
Reports, 6, 97 (1986).
Compound 4d (662 mg, 2 mmoles) was treated with sodium
hydride according to the procedure described above. The crude
product was recrystallized from ethanol to obtain 245 mg (37%)
of tert-butyl 3-amino-4,6-dihydro-6-oxo[1,3]thiazino-
[2,3-b]quinazoline-2-carboxylate 16, mp 225-226°; ir (potassium
-1
1
bromide): ν 1670 cm (C=O); H nmr (dimethyl-d sulfoxide): δ
6
1.46 (s, 9H, CH ), 4.91 (s, 2H, CH ), 7.43-7.56 (m, 2H,
3
2
aromatic), 7.77-7.83 (m, 1H, aromatic), 7.84-7.94 (s, broad, 1H,
NH, exchangeable with deuterium oxide), 8.07-8.13 (m, 1H,
aromatic), 8.12-8.22 (s, broad, 1H, NH, exchangeable with
+
deuterium oxide); ms (70 eV) m/z 331 (M , 27%), 275
+
+
(M - C H , 97%), 231 (M - C H - CO , 100).
4
8
4
8
2
Anal. Calcd for C
H N O S: C, 57.99; H, 5.17; N, 12.68.
16 17 3 3
Found: C, 58.19; H, 5.24; N, 12.81.
The ethanol filtrate was concentrated to a small volume, the
resulting solid was collected and recrystallized from acetone/n-
hexane to afford 55 mg (10%) of compound 9d (Table 2).
Treatment of tert-Butyl [[3-(Cyanomethyl)-3,4-dihydro-4-oxo-
thieno[3,2-d]pyrimidin-2-yl]thio]acetate (8d) with Sodium
Hydride.
Compound 8d (674 mg, 2 mmoles) was treated with sodium
hydride according to the procedure described above. The crude
product was washed with methanol (15 ml) to obtain 280 mg
(42%) of tert-butyl 7-amino-8,10-dihydro-10-oxothieno-
[3',2':4,5]pyrimido[2,1-b][1,3]thiazine-6-carboxylate 17. An
analytical sample was obtained by recrystallization from ethanol,
[9] For a review, see: M. A. E. Shaban, M. A. M. Taha and E. M.
Sharshira, in Advances in Heterocyclic Chemistry, Vol 52, A. R.
Katritzky, ed, Academic Press, San Diego, 1991, pp 7-15.
[10] D. Ranganathan, F. Farooqui, D. Bhattacharyya, S. Mehrotra
and K. Kesavan, Tetrahedron, 42, 4481 (1986).
[11] F. Kienzle, G. Kaiser and R. E. Minder, Helv. Chim. Acta, 66,
148 (1983).
[12] M. Sugiyama, T. Sakamoto, K. Tabaka, K. Endo, K. Ito, M.
Kobayashi and H. Fukumi, Chem. Pharm. Bull., 37, 2122 (1989).
-1
1
mp 217-218°; ir (potassium bromide): ν 1670 cm (C=O); H nmr
(dimethyl-d sulfoxide): δ 1.45 (s, 9H, CH ), 4.91 (s, 2H, CH ),
7.29 (d, 1H), 7.80-7.92 (s, broad, 1H, NH, exchangeable with deu-
6
3
2