Synthesis of 3-hetaryl-1,2,4,5-tetrahydropyrrolo-[1,2-a]quinazoline-2,5-diones

Article abstract of DOI:10.1023/A:1015691421701

A convenient method has been developed for the synthesis of 3-hetary[-1,2,4,5-tetrahydropyrrolo- [1,2-a]quinazoline-2,5-diones by the interaction of 4-chloro-2-hetaryl-3-oxobutyronitriles with substituted anthranilic acids.

Full text of DOI:10.1023/A:1015691421701

Chemistry of Heterocyclic Compounds, Vol. 38, No. 3, 2002
SYNTHESIS OF 3-HETARYL-
1,2,4,5-TETRAHYDROPYRROLO-
a
[1,2- ]QUINAZOLINE-2,5-DIONES
Yu. M. Volovenko, E. V. Resnyanskaya, and A. V. Tverdokhlebov
A convenient method has been developed for the synthesis of 3-hetaryl-1,2,4,5-tetrahydropyrrolo-
[1,2-a]quinazoline-2,5-diones by the interaction of 4-chloro-2-hetaryl-3-oxobutyronitriles with
substituted anthranilic acids.
Keywords: anthranilic acids, 4-chloro-3-oxobutyronitriles, pyrrolo[1,2-a]quinazolines.
Derivatives of pyrrolo[1,2-a]quinazoline possess a broad spectrum of biological activity [1-3]. Among
them there are found compounds displaying analgesic [1], hypotensive [2], and anticonvulsant properties [3].
This stimulates the synthesis of new compounds of this type, among which pyrrolo[1,2-a]quinazoline-2,5-diones
are of particular interest since their biological and pharmacological properties have been the least investigated.
At the same time they are isomers of quinazoline alkaloids of the peganine series.
Two basic strategies for constructing the pyrrolo[1,2-a]quinazoline-2,5-diones skeleton are known. The
first consists of the preliminary construction of the quinazoline ring with subsequent annelation of the pyrrole
fragment along side a. This approach assumes the use as starting materials of anthranilic acid amides substituted
at the amino [4,5] and/or the amide [6] nitrogen atom. The second relies on the reverse sequence. The
quinazoline cycle is add to a pyrrole ring and the annelation of the latter occurs as a rule in situ in the process of
forming the pyrrole nucleus. Key intermediates in this approach are γ-arylamino nitriles which are generated
either by acylation of methylene-active nitriles with N-(2-carboxyphenyl)glycine or by amination of γ-halo
nitriles with an anthranilic acid ester [7-9].
The methods of synthesis described above use functional derivatives of anthranilic acid and do not
permit 6-, 7-, 8-, and 9-substituted pyrrolo[1,2-a]quinazoline-2,5-diones to be obtained. In view of the high
availability of anthranilic acids compared with their functional derivatives it seemed urgent to develop a method
of synthesis of pyrrolo[1,2-a]quinazoline-2,5-diones based on them. This work is devoted to obtaining 3-hetaryl-
substituted pyrrolo[1,2-a]quinazoline-2,5-diones from substituted 2-aminobenzoic acids (Scheme 1).
The interaction of 4-chloro-2-hetaryl-3-oxobutyronitriles 1a-g with anthranilic acid and substituted
anthranilic acids 2 in dioxane in the presence of equivalent amount of triethylamine led to 3-hetaryl-1,2,4,5-
tetrahydropyrrolo[1,2-a]quinazoline-2,5-diones 3a-z in 55-90% yield.
The first step of the reaction is probably nucleophilic substitution of halogen by the nitrogen of the
amino group with the formation of an alkylation product 4a-z, which is accompanied by an intramolecular
addition of the amino group to the nitrile leading to 1-aryl-2-amino-3-hetaryl-4(5H)-oxopyrroles 5a-z.
Subsequent intramolecular acylation at the amino group of compounds 5 leads to the final products 3a-z. Alkyl,
__________________________________________________________________________________________
Kiev Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail: atver@mail.univ.kiev.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 360-366, March, 2002. Original article
submitted June 23, 2000.
324
0009-3122/02/3803-0324$27.00©2002 Plenum Publishing Corporation

Scheme 1
R1
R3
CO2H
NH2
N
N
O
R2
S
4
R
R3
CO2H
CN Cl
R5
2
2
R
NC
4
R
S
H
N
Et3N
R1
R 5
H
1
N
R
O
O
R2
4a–z
S
CN Cl
1a–g
O
CO2H
NH2
6
R3
R3
5
1
2
1'
S
NH
R
– H2O
R2
R1
4
R
S
4
R
N
N
9
4'
3
R5
R5
N
R
N
1
O
O
5a–z
3a–z
1a R1+ R2 = CH=CHCH=CH, b R1 = CH3, c R1 = Ph, d R1 = 4-ClC6H4, e R1 = 4-BrC6H4,
f R1 = 1-Ad, g R1+ R2 = –(CH2)4–; b-f R2 = H; 3-5 a-f R1+ R2 = CH=CHCH=CH,
a R3 = R4 = H, b R3 = CH3, R4 = H, c R3 = Et, R4 =H, d R3 = Br, R4 =H, e R3 = H, R4 = Cl,
f R3 = F, R4 = H; g, h R1 = CH3, R2 = H, g R3 = R4 = H, h R3 = R4 = OCH3; i, j R1 = Ph, R2 = H,
i R3 = R4 = H, j R3 = R4 = OCH3; k-p R1 = 4-ClC6H4, R2 = H, k R3 = R4 = H, l R3 = CH3, R4 = H,
m R3 = R4 = H, n R3 = R4 = OCH3, o R3 = I, R4 = H, p R3 = H, R4 = CF3; q-u R1 = 4-BrC6H4,
R2 = H, q R3 = R4 = H, r R3 = CH3, R4 = H, s R3 = R4 = OCH3, t R3 = H, R4 = Cl,
u R3 = F, R4 = H; v, w R1 = 1-Ad, R2 = H, v R3 = R4 = H, w R3 = CH3, R4 = H;
x-z R1+ R2 = –(CH2)4–, x R3 = R4 = H, y R3 = CH3, R4 = H, z R3 = I, R4 = H;
3-5 a-l, h-z R5 = H, m R5 = CH3
alkoxy, and halogen substituted anthranilic acids 2 participate in the reaction described with the formation of
previously unknown 7-, 8-, and 9-substituted 1,2,4,5-tetrahydropyrrolo[1,2-a]quinazoline-2,5-diones 3b-f,h,j,l-
p,r-u,w,y,z. The yields of the substituted pyrrolo[1,2-a]quinazoline-2,5-diones correlate with the basicity of the
anthranilic acid amino group and vary from 70 (for the less basic) to 90% (for the more basic). When using
3-methylanthranilic acid with a sterically hindered amino group the yield of compound 3m was reduced to 55%.
The weakly basic anthranilic acids such as 5-nitro-, 5-chloro-3-methyl-, and 3,5-dichloroanthranilic acids did
not participate in this reaction.
The proposed reaction mechanism has been confirmed by model conversions of halo nitriles 1a-e on
their interaction with secondary [10,11] and primary [9,11,12] amines with the formation of products of types 4
1
and 5 respectively. The structures of products 3a-z were confirmed by data of IR and H NMR spectroscopy,
and also by the identity of compounds 3a,g with the samples obtained by another method [9].
1
In the H NMR spectra of compounds 3a,g,i,k,q,w,x recorded in DMSO-d6 a one-proton doublet was
observed for the 6-H proton at 8.4-8.5 ppm. The low-field shift of this signal compared with the signal for 6-H
in the initial anthranilic acid (at 7.8 ppm) is caused by the deshielding effect of the magnetically anisotropic
carbonyl group in position 5. The spectra of these compounds also show a two-proton singlet for the CH2 group
at 4.5-4.8 ppm, the presence of which confirms that under these conditions compounds 3a,g,i,k,q,w,x exist in
325

the ketonic tautomeric form. However in CF3COOD the signal of the methylene group is slowly reduced with
time (disappearing completely after 1-2 h). This indicates the deuteration of compounds 3a-z at position 1,
evidently proceeding through the enolic form.
TABLE 1. Characteristics of the Synthesized Compounds 3a-z
Found, %
——————
Calculated, %
Com-
Empirical
formula
Yield, %
pound*
N
S
C18H11N3O2S
12.54
12.60
9.43
9.62
82
80
83
72
77
73
85
69
83
65
90
76
55
81
80
65
81
66
86
63
69
79
82
77
81
75
3a
3b
3c
3d
3e
3f
C19H13N3O2S
12.32
9.46
12.10
9.23
C20H15N3O2S
11.78
11.63
8.74
8.87
C18H10BrN3O2S
C18H10ClN3O2S
C18H10FN3O2S
C15H11N3O2S
10.21
7.76
10.19
7.78
11.30
11.42
8.63
8.72
12.09
8.98
11.96
9.13
14.01
14.13
10.89
10.78
3g
3h
3i
C17H15N3O4S
11.88
9.09
11.76
8.97
C20H13N3O2S
11.61
11.69
9.07
8.92
C22H17N3O4S
10.21
7.79
3j
10.02
7.64
C20H12ClN3O2S
C21H14ClN3O2S
C21H14ClN3O2S
C22H16ClN3O4S
C20H11ClIN3O2S
C21H11ClF3N3O2S
C20H12BrN3O2S
C21H14BrN3O2S
C22H16BrN3O4S
C20H11BrClN3O2S
C20H11BrFN3O2S
C18H15N3O2S
10.53
10.67
8.33
8.14
3k
3l
10.55
8.08
10.30
7.86
10.44
10.30
8.01
7.86
3m
3n
3o
3p
3q
3r
3s
9.76
7.66
9.91
7.57
8.24
8.08
6.28
6.17
8.93
7.06
9.10
6.94
9.84
9.59
7.49
7.32
9.24
7.00
9.29
7.09
8.67
8.43
6.68
6.43
9.10
6.62
3t
8.89
6.78
9.33
9.21
6.85
7.03
3u
3v
3w
3x
3y
3z
12.53
9.39
12.45
9.50
C19H17N3O2S
11.88
11.96
8.99
9.12
C18H14IN3O2S
C24H23N3O2S
9.12
7.13
9.07
6.92
9.91
7.74
7.68
10.02
C25H25N3O2S
9.83
7.35
9.74
7.43
_______
* Compounds 3a-z melt above 300°C.
326

TABLE 2. Data of IR and 1H NMR Spectra of Compounds 3a-z
Com-
pound
1
IR spectrum, ν, сm-1
1H NMR spectrum (CF3COOD), δ, ppm,
coupling constant J (Hz)
CO
2
others*
3
4
1660, 1720
1660, 1710
1650,1710
955
5.16 (2Н, s, СН2); 7.60 (1Н, d, J = 8.0, 9-Н);
3a
(CSC) 7.70-8.00 (3Н, m, 2НR1+R2, 7-Н); 8.18 (3Н, m, 2НR1+R2, 8-Н);
8.52 (1Н, d, J = 8.0, 6-Н)
960
2.62 (3Н, s, СН3); 5.15 (2Н, s, СН2);
3b
3c
(CSC) 7.53 (1Н, d, J = 8.0, 9-Н); 7.74 (2H, m, HR1+R2);
8.00-8.19 (3H, m, 2HR1+R2, 8-H); 8.32 (1Н, s, 6-Н)
1.41 (3Н, t, J = 10.0, СН3); 2.94 (2Н, q, J = 10.0, СН2СН3);
960
(CSC) 5.16 (2Н, s, СН2); 7.55 (1Н, d, J = 8.0, 9-Н);
7.68-8.00 (2Н, m, НR1+R2); 8.10 (3H, m, 2HR1+R2, 8-Н);
8.35 (1Н, s, 6-Н)
1670, 1700
955
5.14 (2Н, s, СН2); 7.53 (1Н, d, J = 8.0, 9-Н);
3d
(CSC) 7.77-7.95 (2Н, m, НR1+R2); 8.13 (2H, m, HR1+R2);
8.24 (1Н, dd, 3J = 8.0, 4J = 2.0, 8-Н);
8.60 (1Н, d, J = 2.0, 6-Н)
1710, 1670
1670, 1700
1650, 1720
970
(CSC) 8.08-8.25 (2H, m, HR1+R2); 8.45 (1Н, d, J = 8.0, 6-Н)
965 5.18 (2Н, s, СН2); 7.60-7.95 (4Н, m, 2НR1+R2, 8-, 9-Н);
(CSC) 8.07-8.20 (3H, m, 2HR4, 6-H)
5.13 (2Н, s, СН2); 7.58-8.02 (4Н, m, 2НR1+R2, 7-, 9-Н);
3e
3f
2.70 (3Н, s, 4'-CH3); 5.12 (2Н, s, СН2); 7.30 (1Н, s, 5'-H);
3g
7.50-7.80 (2Н, d and t, J = 8.0, J = 8.0, 9-Н, 7-Н);
8.10 (1Н, t, J = 8.0, 8-Н); 8.49 (1Н, d, J = 8.0, 6-Н)
1660, 1680
1260
2.69 (3Н, s, 4'-CH3); 4.17 (3Н, s, ОСН3);
3h
(COC) 4.20 (3Н, s, ОСН3); 5.12 (2Н, s, СН2); 7.05 (1Н, s, 9-Н);
7.26 (1Н, s, 5'-H); 7.86 (1Н, s, 6-Н)
1660, 1700
1650, 1690
5.17 (2Н, s, СН2); 7.55-7.85 (8Н, m, 4'-Ph, 5'-,7-, 9-H);
3i
3j
8.12 (1Н, t, J = 8.0, 8-Н); 8.50 (1Н, d, J = 8.0, 6-Н)
1260
4.17 (3Н, s, ОСН3); 4.22 (3Н, s, ОСН3); 5.21 (2Н, s, СН2);
(COC) 7.09 (1Н, s, 9-Н); 7.60-7.80 (6Н, m, 4'-Ph, 5'-H);
7.87 (1Н, s, 6-Н)
1660, 1700
1650, 1700
5.18 (2H, s, CH2); 7.54-7.83 (7Н, m, 4'-Ar, 5'-, 7-, 9-H);
8.12 (1Н, t, J = 8.0, 8-Н); 8.51 (1Н, d, J = 8.0, 6-Н)
3k
3l
2.60 (3Н, s, СН3); 5.21 (2Н, s, СН2);
7.50 (1Н, d, J = 8.0, 9-H); 7.58-7.78 (5Н, m, 4'-Ar, 5'-H);
7.95 (1Н, d, J = 8.0, 8-Н); 8.28 (1Н, s,6-H)
1640, 1690
1650, 1700
1660, 1720
2.92 (3Н, s, СН3); 5.20 (2Н, s, СН2);
3m
3n
3o
7.58-7.80 (6Н, m, 4'-Ar, 5'-, 9-H);
7.95 (1Н, d, J = 8.0, 8-Н); 8.40 (1Н, d, J = 8.0, 6-H)
1260
4.17 (3Н, s, ОСН3); 4.21 (3Н, s, ОСН3); 5.20 (2Н, s, СН2);
(COC) 7.08 (1Н, s, 9-H); 7.66 (5Н, m, 4'-Ar, 5'-H);
7.87 (1Н, s, 6-H)
5.20 (2Н, s, СН2); 7.35 (1Н, d, J = 8.0, 9-H);
7.60-7.80 (5Н, m, 4'-Ar, 5'-H);
8.38 (1Н, dd, 3J = 8.0, 4J = 2.0, 8-Н);
8.80 (1Н, d, J = 2.0, 6-H)
1660, 1700
1670, 1690
1650, 1710
5.23 (2Н, s, СН2); 7.66 (7Н, m, 4'-Ar, 5'-, 7-, 9-H);
3p
3q
3r
8.56 (1Н, d, J = 8.0, 6-H)
5.17 (2H, s, CH2); 7.55-7.86 (7Н, m, 4'-Ar, 5'-, 7-, 9-H);
8.12 (1Н, t, J = 8.0, 8-Н); 8.50 (1Н, d, J = 8.0, 6-Н)
2.61 (3Н, s, СН3); 5.16 (2H, s, CH2);
7.52 (1Н, d, J = 8.0, 9-H); 7.60-8.00 (6Н, m, 4'-Ar, 5'-, 8-H);
8.29 (1Н, s, 6-H)
1640, 1680
1660, 1700
1265
4.17 (3Н, s, ОСН3); 4.22 (3Н, s, ОСН3); 5.20 (2H, c, CH2);
3s
3t
(COC) 7.09 (1Н, s, 9-H); 7.61 (2Н, d, J = 8.0, 4'-Ar);
7.70 (1Н, s, 5'-H); 7.80 (2Н, d, J = 8.0, 4'-Ar);
7.90 (1Н, s, 6-H)
5.20 (2H, s, CH2); 7.56-7.77 (7Н, m, 4'-Ar, 5'-, 7-, 9-H);
8.42 (1Н, d, J = 8.0, 6-H)
327

TABLE 2 (continued)
1
2
3
4
1670, 1700
5.16 (2H, s, CH2); 7.56-7.76 (7Н, m, 4'-Ar, 5'-, 8-, 9-H);
8.15 (1Н, dd, 3J = 8.0, 4J = 4.0, 6-H)
1.94 (6Н, m, 3CН2 in Ad); 2.12 (6Н, m, 3CH2 in Ad);
2.23 (3H, CHAd); 5.15 (2Н, s, СН2); 7.29 (1H, s, 5'-H);
7.55 (1H, d, J = 8.0, 9-H); 7.76 (1H, t, J = 8.0, 7-H);
8.10 (1Н, t, J = 8.0, 8-Н); 8.45 (1Н, d, J = 8.0, 6-Н)
1.94 (6Н, m, 3CН2 in Ad); 2.12 (6Н, m, 3CH2 in Ad);
2.23 (3H, CHAd); 2.59 (3Н, s, СН3); 5.12 (2Н, s, СН2);
7.37 (1Н, s, 5'-H); 7.48 (1Н, d, J = 8.0, 9-Н);
7.92 (1Н, d, J = 8.0, 8-Н); 8.29 (1Н, s, 6-Н)
3u
1660, 1700
2820,
2850
(СH)
3v
1660,1700
2820,
2850
(СH)
3w
1640, 1700
1660, 1720
1650, 1710
2850
2.09 (4Н, s, HR1+R2); 2.95 (4Н, s, HR1+R2); 5.07 (2Н, s, СН2);
7.50 (1H, d, J = 8.0, 9-H); 7.71 (1H, t, J = 8.0, 7-H);
8.1 (1Н, t, J = 8.0, 8-Н); 8.45 (1Н, d, J = 8.0, 6-Н)
3x
3y
3z
(СН)
2850
2.09 (4Н, s, HR1+R2); 2.59 (3Н, s, СН3); 2.93 (4Н, s, HR1+R2);
(СН)
5.04 (2Н, s, СН2); 7.42 (1Н, d, J = 8.0, 9-Н);
7.90 (1Н, d, J = 8.0, 8-Н); 8.27 (1Н, s, 6-Н)
2.07 (4Н, s, HR1+R2); 2.93 (4Н, s, HR1+R2); 5.47 (2Н, s, СН2);
7.28 (1Н, d, J = 8.0, 9-Н);
8.35 (1Н, dd, 3J = 8.0, 4J = 2.0, 8-Н);
8.75 (1Н, d, J = 2.0, 6-H)
_______
*In the IR spectra of the benzothiazolyl derivatives 3a-f a strong CSC
absorption band was observed, probably caused by the asymmetric
stretching vibrations of CSC (in the IR spectra of the remaining compounds
this band was weak and when among others was not separated). For
compounds 3h,j,n,s the strong COC absorption band is caused by the
asymmetric COC stretching vibrations (the band for the symmetric COC
vibrations has low intensity and when among others the band is not
separated).
The IR spectra of pyrrolo[1,2-a]quinazolinediones 3a-z show two strong bands for the stretching
vibrations of the carbonyl groups at 1680-1720 (5-CO) and 1640-1660 cm-1 (2-CO)*. The stretching vibrations
of the N–H group are observed as weak bands at 3150-3200 cm-1.
We have therefore developed a method for the synthesis of 3-hetaryl-1,2,4,5-tetrahydropyrrolo[1,2-a]-
quinazoline-2,5-diones, which may be of interest as biologically active compounds.
EXPERIMENTAL
A check on the progress of reactions and the purity of substances obtained was effected by TLC on
Silufol UV 254 plates in chloroform–methanol, 9:1, and benzene–ethanol, 9:1. The IR spectra were recorded on
1
a Pye Unicam SP 3-300 in KBr tablets. The H NMR spectra were recorded in DMSO-d6 or CF3COOD on a
Bruker WP 100 SY (100 MHz) instrument.
_______
* The reverse assignment of the absorption bands of the carbonyl groups was mistakenly made in [7-9].
Analysis of the IR spectra of substituted synthesized compounds 3 showed that the introduction of a substituent
into positions 7, 8, and 9 proved to have a significant influence only on the position of the shorter wave
absorption band. This enables its assignment as the vibration of the 5-CO group.
328

The analytical characteristics of the 3-hetaryl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinazoline-2,5-diones
are given in Table 1, and the spectral characteristics in Table 2.
4-Chloro-2-hetaryl-3-oxobutyronitriles 1a-e [10,12] and the substituted 2-aminobenzoic acids 2 [13,14]
were obtained by known methods.
2-[4-(1-Adamantyl)-2-thiazolyl]-4-chloro-3-oxobutyronitrile (1f). A. 1-(α-Bromoacetyl)adamantane
[15] (24 g, 0.093 mol) was added to a solution of thiocyanoacetamide (9.3 g, 0.093 mol) in ethanol (50 ml). The
mixture became heated and the bromo ketone dissolved. After 10 min yellow crystals of 4-(1-adamantyl)-2-
cyanomethylthiazole hydrobromide precipitated. The mixture was cooled, the solid hydrobromide was filtered
off, and washed with ethanol. The crystals obtained were treated with 25% ammonia solution (about 50 ml),
which converted them into an oil, and the oil was removed with a separating funnel. The aqueous ammonia
layer was extracted with benzene (2 × 30 ml), the extract combined with the obtained oil, washed with water
(2 × 50 ml), and dried over MgSO4. The benzene was distilled off in the vacuum of a water-jet pump, the
residue was distilled in vacuum, collecting the fraction with bp 176-181°C (0.07 mm Hg), which crystallized in
1
the receiver. 4-(1-Adamantyl)-2-cyanomethylthiazole (17 g, 71%) was obtained; mp 47°C. H NMR spectrum
(DMSO-d6), δ, ppm: 7.20 (1H, s, 5-H); 4.50 (2H, s, CH2); 2.02 (3H, m, 3CH in Ad); 1.92 (6H, m, 3CH2 in Ad);
1.73 (6H, m, 3CH2 in Ad). Found, %: N 9.92; S 11.01. C15H18N2S. Calculated, %: N 9.71; S 11.12.
B. Chloroacetyl chloride (1.6 ml, 0.021 mol) was added to a solution of 4-(1-adamantyl)-2-
cyanomethylthiazole (5.1 g, 0.02 mol) and pyridine (1.7 ml, 0.021 mol) in dry dioxane (8 ml). The mixture
became heated and a yellow solid was precipitated. The obtained mixture was heated on a water bath for 1 h.
After cooling, the precipitated solid was filtered off, washed with dioxane, and then with water. Compound 1f
(6.1 g, 91%) was obtained; mp 178°C (dioxane). 1H NMR spectrum (DMSO-d6), δ, ppm: 13.20 (1H, br. s, NH);
7.25 (1H, s, 5-H); 4.40 (2H, s, CH2); 2.02 (3H, m, 3CH in Ad); 1.92 (6H, m, 3CH2 in Ad); 1.76 (6H, m, 3CH2 in
Ad). Found, %: Cl 10.52; N 7.79; S 8.93. C17H19ClN2OS. Calculated, %: Cl 10.59; N 7.68; S 8.79.
4-Chloro-3-oxo-2-(4,5,6,7-tetrahydro-2-benzothiazolyl)butyronitrile (1g). A. 2-Bromocyclohexanone
(70.8 g, 0.4 mol) was added to a hot solution of thiocyanoacetamide (40 g, 0.4 mol) in isopropanol (250 ml) and
the mixture was refluxed for 1.5 h. The solvent was evaporated in vacuum, and the oil obtained was treated with
25% ammonia solution (150 ml). The aqueous ammonia layer was extracted with benzene (3 × 50 ml), the
combined extract washed with water (2 × 50 ml), and dried over MgSO4. The benzene was distilled off in the
vacuum of a water-jet pump, the residue was distilled in vacuum collecting the fraction with bp 123-128°C
1
(0.06 mm Hg). 2-Cyanomethyl-4,5,6,7-tetrahydrobenzothiazole (58 g, 81%) was obtained. H NMR spectrum
(DMSO-d6), δ, ppm: 4.50 (2H, s, CH2); 2.02 (4H, m, 4,4,7,7-H); 1.92 (4H, m, 5,5,6,6-H). Found, %: N 15.82;
S 18.11. C9H10N2S. Calculated, %: N 15.73; S 17.97.
B. Chloroacetyl chloride (1.6 ml, 0.021 mol) was added to a solution of 2-cyanomethyl-4,5,6,7-
tetrahydrobenzothiazole (3.2 ml, 0.02 mol) and pyridine (1.7 ml, 0.021 mol) in dry dioxane (10 ml). Heating of
the mixture occurred and a yellow solid was precipitated. The mixture obtained was heated on a water bath for 1
h. After cooling, the precipitated solid was filtered off, washed with dioxane, and then with water. Compound
1
1g (4.0 g, 80%) was obtained; mp 205°C (dioxane). H NMR spectrum (DMSO-d6), δ, ppm: 13.20 (1H, br. s,
NH); 4.40 (2H, s, CH2); 2.50 (4H, m, HR1+R2); 1.76 (4H, m, HR1+R2). Found, %: Cl 13.96; N 10.02; S 11.13.
C11H11ClN2OS. Calculated, %: Cl 13.92; N 11.00; S 11.26.
a
3-(2-Benzothiazolyl)-1,2,4,5-tetrahydropyrrolo[1,2- ]quinazoline-2,5-dione (3a) {General
1
2
a
Procedure for Synthesizing 3-(4-R -5-R -2-thiazolyl)-1,2,4,5-tetrahydropyrrolo[1,2- ]quinazoline-2,5-
diones 3a-z}. Triethylamine (0.48 ml, 0.0035 mol) was added to a suspension of 2-(2-benzothiazolyl)-4-chloro-
3-oxobutyronitrile 1a (0.75 g, 0.003 mol) and anthranilic acid 2 (0.45 g, 0.0035 mol) in dioxane (5 ml) and the
mixture was refluxed for 6 h until disappearance of the initial nitrile 1a from the reaction mixture (TLC). The
mixture was cooled, the precipitated solid filtered off, washed with dioxane, and then with water. The solid was
dried, and recrystallized from DMF. Compound 3a (0.80 g) was obtained.
329

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