Cyanamides in cyclization reactions with anthranilates, 2-aminophenyl ketones, and methyl 2-(3-oxopiperazin-2-yl)acetate

Article abstract of DOI:10.1007/s11172-008-0025-8

Cyclization of aryl-, aroyl-, and (4,6-dimethylpyrimidin-2-yl)cyanamides with methyl anthranilates, 2-aminophenyl ketones, and methyl 2-(3-oxopiperazin-2-yl)acetate leads to 2-amino-3,4-dihydroquinazolin-4-one, 2-aminoquinazoline, and 6-amino-1,3,4,8,9,9a

Full text of DOI:10.1007/s11172-008-0025-8

Russian Chemical Bulletin, International Edition, Vol. 57, No. 1, pp. 170—176, January, 2008
170
Cyanamides in cyclization reactions with anthranilates,
2ꢀaminophenyl ketones, and methyl 2ꢀ(3ꢀoxopiperazinꢀ2ꢀyl)acetate
Kh. S. Shikhaliev,« A. S. Shestakov, S. M. Medvedeva, and N. V. Gusakova
Voronezh State University,
1 Universitetskaya pl., 394006 Voronezh, Russian Federation.
Fax: +7 (473) 255 6890. Еꢀmail: chocd261@chem.vsu.ru
Cyclization of arylꢀ, aroylꢀ, and (4,6ꢀdimethylpyrimidinꢀ2ꢀyl)cyanamides with methyl anꢀ
thranilates, 2ꢀaminophenyl ketones, and methyl 2ꢀ(3ꢀoxopiperazinꢀ2ꢀyl)acetate leads to
2ꢀaminoꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone, 2ꢀaminoquinazoline, and 6ꢀaminoꢀ1,3,4,8,9,9аꢀhexaꢀ
hydroꢀ2Hꢀpyrazino[1,2ꢀc]pyrimidineꢀ1,8ꢀdione derivatives, respectively.
Key words: cyanamides, anthranilic acid, 2ꢀaminophenyl ketones, methyl 2ꢀ(3ꢀoxopiperazinꢀ
2ꢀyl)acetate, 2ꢀaminoquinazoline, 2ꢀaminoꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone, 6ꢀaminoꢀ
1,3,4,8,9,9аꢀhexahydroꢀ2Hꢀpyrazino[1,2ꢀc]pyrimidineꢀ1,8ꢀdione, cyclization.
Achievements in preparative chemistry of cyanamides
usually used for this purpose. It turned out that they can
be successfully replaced by cyanamides.
We have obtained a number of cyanamides, which
were used in further work.
and possibility of their use in the synthesis of a number of
heterocycles caused an increased attention to these comꢀ
pounds.1,2 Unsaturation of the С≡N bond and its bipolar
character make it possible the participation of cyanamides
in cyclization reactions with various compounds, conꢀ
taining both electrophilic and nucleophilic reaction cenꢀ
ters.
The present work is aimed at investigation of potentiꢀ
alities in the synthesis of compounds containing pyrimiꢀ
dine fragment with the use of various organic cyanamides.
Condensation of the [2+4] type, in which the twoꢀ
atom fragment is represented by С(2) and N(3) atoms of
the forming heterocycle, is comparatively less spread
among methods for the synthesis of pyrimidine. Imino
esters,3 cyanates, isocyanates, amides, or thioamides4 are
Cyanamide 1 was obtained by the reaction of acetylꢀ
acetone with dicyanodiamide,5 2, by alkaline opening of
2ꢀiminoꢀ2,3ꢀdihydroꢀ4Hꢀ1,3ꢀbenzothiazinꢀ4ꢀone with
subsequent alkylation,6 3, by aсylation of calcium cyanaꢀ
mide,7 4, by desulfurization of the corresponding thiocarꢀ
bamides.8 Arylcyanamides 4 were used immediately after
preparation because of their instability.
Methyl anthranilates 5а—с, 2ꢀaminophenyl ketones
6a—d, 2ꢀaminobenzonitrile (7), and methyl 2ꢀ(3ꢀoxoꢀ
piperazinꢀ2ꢀyl)acetate (8) were used as the reagents with
5
R1
H
R2
H
6
R1
H
R2
H
R3
a
b
c
a
b
c
d
d
Me
Me
Ph
Ph
Ph
OMe OMe
Br
—OCH2O—
2: R = Me (a), Et (b);
3: R = H (a), 4ꢀMeO (b), 4ꢀCl (c), 4ꢀF (d);
4: R = 2ꢀMeO (a), 4ꢀMeO (b)
H
H
Cl
Cl
H
H
H
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 164—170, January, 2008.
1066ꢀ5285/08/5701ꢀ0170 © 2008 Springer Science+Business Media, Inc.

Cyclization of cyanamides with aminocarbonyls
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
171
Scheme 1
9: R1 = R2 = H; R4 = Z (a), 4ꢀMeOC6H4 (b), 2ꢀMeOC6H4 (c), 4ꢀClBz (d), 4ꢀMeOBz (e), 2ꢀMeSBz (f), 2ꢀEtSBz (g);
10: R1 = R2 = MeO; R4 = 4ꢀMeOC6H4 (a), Bz (b), 4ꢀClBz (c), 4ꢀMeOBz (d), 4ꢀFBz (e), 2ꢀEtSBz (f);
11: R1 = Br, R2 = H, R4 = 4ꢀFBz; 12: R1 = Cl, R2 = H, R3 = Ph; R4 = 2ꢀMeOC6H4 (a), Z (b);
13: R1, R2 = —OCH2O—, R3 = Me, R4 = Z (a), Bz (b), 4ꢀMeOBz (c), 2ꢀMeOBz (d), 4ꢀClBz (e), 4ꢀFBz (f), 2ꢀEtSBz (g);
14: R1 = R2 = H, R3 = Ph; R4 = 4ꢀMeOBz (a), 4ꢀClBz (b), 2ꢀMeSBz (c); 15: R1 = R2 = H, R3 = Me, R4 = 4ꢀMeOBz
electrophilic and nucleophilic reaction centers. 8 was obꢀ
tained by reaction of ethylenediamine with dimethyl maleꢀ
ate.9
amide carbon atom is significantly increased in these comꢀ
pounds, which allows them to enter the reaction with
aromatic amines 5—7.
The reactions of cyanamides with anthranilates 5 and
2ꢀaminophenyl ketones 6 are presented in Scheme 1. The
cyclization, apparently, proceeds in two steps, the first of
which includes formation of guanidine. The rate and diꢀ
rection of this process depend on the electrophilicity of
the carbon atom in the nitrile group of cyanamides 1—4.
If it is high enough (which is characteristic of compounds
2 and 3), the reaction proceeds in the absence of a cataꢀ
lyst. Thus, anthranilates 5 and aminophenyl ketones 6
react with aroylcyanamides 2 and 3 catalystꢀfree, whereas
the presence of equimolar amount of HCl is required for
their reaction with cyanamides 1 and 4.
In the presence of НCl, formation of guanidines takes
place most likely with participation of chloroformamidines
(intermediate А, see Scheme 1) and chloroformamidinium
chlorides, which are formed from cyanamides in hydroꢀ
chloric acid medium.1 The electrophilicity of the cyanꢀ
The cyclization with aminophenyl ketones proceeds
under the more drastic conditions and is slower than the
one with methyl anthranilates, since Н2О is the leaving
group in this case rather than methanol. The forming
2ꢀaminoquinoline derivatives with methyl or phenyl subꢀ
stituent in position 4 are compounds with high melting
points, which are difficult to crystallize.
Hydrochloric acid was added to the reaction mixture
as the 37% aqueous solution. Attempted synthesis of 2,4ꢀ
diaminoquinazoline derivative from compounds 1 and 7
by this method resulted in 2ꢀaminoꢀ3,4ꢀdihydroquinazoꢀ
linꢀ4ꢀone derivative 9a. This can be explained by the hyꢀ
drolysis of the nitrile group of the benzonitrile in the presꢀ
ence of Н2О in acidic medium.10 Therefore, the use of aq.
HCl is inadmissible in this case. The use of 2ꢀaminoꢀ
benzonitrile hydrochloride in anhydrous dioxane allowed
us to obtain hydrochloride 16 (Scheme 2).

172
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
Shikhaliev et al.
Table 2. 1NMR spectra of quinazolinones 9—11
Scheme 2
Compoꢀ
und:
δ(J/Hz)
9a
2.39 (s, 6 H, Me); 6.96 (s, 1 H, H(5), pyrimidine);
7.35 (t, 1 H, H arom., J = 7.3); 7.46 (d, 1 H, H arom.,
J = 7.5); 7.73 (t, 1 H, H arom., J = 7.1); 8.07 (d, 1 H,
H arom., J = 7.9); 11.03, 13.48 (both br.s, 1 H each,NH)
9b* 3.91 (s, 3 H, MeО); 7.12 (d, 2 H, H arom., J = 8.9);
7.46 (m, 3 H, H arom.); 7.50 (s, 1 H, NH); 7.58 (d, 1 H,
H arom., J = 7.2); 7.66 (s, 1 H, NH); 7.81 (t, 1 H,
H arom., J = 7.3); 8.06 (d, 1 H, H arom., J = 7.8);
8.32 (br.s, 1 H, HCl)
9c* 3.80 (s, 3 H, MeО); 7.19 (t, 1 H, H arom., J = 7.1);
7.31 (d, 1 H, H arom., J = 8.2); 7.40—7.68 (m, 4 H,
H arom.; 1 H, NH); 7.89 (t, 1 H, H arom., J = 7.5);
8.04 (d, 1 H, H arom., J = 7.9); 8.41 (br.s, 1 H, NH;
1 H, HCl)
The synthetic outcome for compounds 9—11 and their
1Н NMR spectral data are given in Tables 1 and 2, for
compounds 12—16, in Tables 3 and 4, respectively.
Derivatives of 2ꢀaminoꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone
9—11 and of 2ꢀaminoquinazoline 12—16, shown in
Schemes 1 and 2, are formed as a result of nucleophilic
attack of N(3) atom of guanidine at the carbonyl fragment
of the ester group. However, a version with participation
of N(2) atom to form regioisomeric 2ꢀaminoquinazoline
derivatives with substituent in position 3 can not be exꢀ
cluded either. The reactions of triazolylcyanamide with
9d
9e
9f
7.31 (d, 1 H, H arom., J = 7.4); 7.49 (m, 3 H, H arom.);
7.72 (t, 1 H, H arom., J = 7.3); 8.11 (d, 1 H, H arom.,
J = 7.4); 8.16 (d, 2 H, H arom., J = 8.4); 12.36 (br.s,
2 H, 2 NH)
3.86 (s, 3 H, Me); 7.35 (d, 1 H, H arom., J = 7.6);
7.51—7.83 (m, 4 H, H arom.); 8.05 (d, 1 H, H arom.,
J = 7.3); 8.13 (d, 2 H, H arom., J = 8.6); 12.27 (br.s,
2 H, 2 NH)
2.49 (s, 3 H, MeS); 7.22 (t, 1 H, H arom., J = 7.6);
7.30—7.45, 7.49—7.56 (both m, 2 H each, H arom.);
7.69 (t, 1 H, H arom., J = 7.4); 7.78 (d, 1 H, H arom.,
J = 7.5); 8.10 (d, 1 H, H arom., J = 8.1); 12.02 (br.s, 2
H, 2 NH)
Table 1. Characteristics of synthesized quinazolinones 9—11
Comꢀ Yield M.p.
Found
Calculated
Molecular
formula
(%)
pound (%)
/°С
C
H
N
9a
67
25
21
61
46
238
283
63.18 4.56 26.36 C14H13N5O
62.92 4.87 26.22
59.38 4.47 13.92 C15H14ClN3O2
9g
1.32 (t, 3 H, Me, J = 7.7); 2.98 (q, 2 H, SH2, J = 7.5);
7.21—7.57 (m, 5 H, H arom.); 7.70 (m, 2 H, H arom.);
8.11 (d, 1 H, H arom., J = 8.2); 11.97 (br.s, 2 H, 2 NH)
9b*
9c*
9d
(decomp.) 59.29 4.61 13.83
10a* 3.89, 3.95, 4.10 (all s, 3 H each, MeО); 7.02, 7.37 (both
s, 1 H each, H arom.); 7.22 (d, 2 H, H arom., J = 7.6);
7.35 (d, 2 H, H arom., J = 8.5); 7.90—8.20 (br.s, 2 H, 2
NH)
10b 3.89, 3.95 (both s, 3 H each, MeО); 6.98 (s, 1 H, H
arom.); 7.41—7.76 (m, 4 H, H arom.); 8.12 (d, 2 H,
H arom., J = 7.4); 12.02 (br.s, 2 H, 2 NH)
10c 3.89, 3.95 (both s, 3 H each, MeО); 6.98 (s, 1 H, H
arom.); 7.36—7.52 (m, 3 H, H arom.); 8.12 (m, 2 H,
H arom.); 12.11 (br.s, 2 H, 2 NH)
275
59.20 4.65 13.69 C15H14ClN3O2
(decomp.) 59.29 4.61 13.83
242
59.97 3.36 14.15 C15H10ClN3O2
60.06 3.34 14.01
65.10 4.43 14.18 C16H13N3O3
65.02 4.40 14.22
9e
225
9f
68 161—162 61.61 4.14 13.56 С16H13N3O2S
61.66 4.17 13.49
9g
52 173—174 58.94 4.29 12.13 C17H15N3O2S
58.89 4.33 12.12
10d 3.89, 3.96, 4.14 (all s, 3 H each, MeО); 7.01, 7.32 (both
s, 1 H each, H arom.); 7.12 (d, 2 H, H arom., J = 8.6);
7.38 (d, 2 H, H arom., J = 8.7); 7.95—8.23 (br.s, 2 H,
2 NH)
10e 3.90, 3.97 (both s, 3 H each, MeО); 7.01 (s, 1 H, H
arom.); 7.32—7.45 (m, 3 H, H arom.); 8.09 (m, 2 H,
H arom.); 12.21 (br.s, 2 H, 2 NH)
10f 1.30 (t, 3 H, Me, J = 7.9); 3.00 (q, 2 H, SH2, J = 7.7);
3.90, 3.95 (both s, 3 H each, MeО); 7.01 (s, 1 H,
H arom.); 7.21—7.52 (m, 4 H, H arom.); 7.62 (s, 1 H,
H arom.); 11.70—12.10 (br.s, 2 H, 2 NH)
10a*
10b
10c
10d
10e
10f
11
22
47
60
42
65
292
61.63 5.35 12.52 C17H18ClN3O2
(decomp.) 61.52 5.43 12.67
247
272
239
248
62.83 4.57 13.01 C17H15N3O4
62.77 4.62 12.92
56.72 3.89 11.64 C17H14ClN3O4
56.70 3.89 11.67
60.84 4.74 11.86 C18H17N3O5
60.78 4.78 11.82
59.55 4.02 12.19 C17H14FN3O4
59.42 4.08 12.23
67 244—245 62.63 5.47 10.92 C20H21N3O3S
62.58 5.48 10.95
55 295—299 49.63 2.41 11.48 C15H9BrFN3O2
49.70 2.48 11.60
11
6.95, 7.29 (both d, 1 H each, H arom., J = 8.2); 7.63 (d,
2H, H arom., J = 8.9); 7.81 (d, 2 H, H arom., J = 8.8);
8.11 (s, 1 H, H arom.); 12.17 (br.s, 2 H, 2 NH)
* Hydrochlorides.
* Hydrochlorides.

Cyclization of cyanamides with aminocarbonyls
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
173
Table 3. Characteristics of synthesized quinolines 12—16
Table 4. 1NMR spestra of quinolines 12—16
Comꢀ Yield M.p.
pound (%) /°С
Found
Calculated
Molecular
formula
Sompoꢀ
und:
δ (J/Hz)
(%)
C
H
N
12a
4.05 (s, 3 H, MeО); 7.01—7.12 (m, 3 H, H arom.);
7.63—7.91 (m, 8 H, H arom.); 8.13 (s, 1 H, H arom.);
8.86 (s, 1 H, NH)
12a
12b
13a
13b
13c
13d
13e
13f
55 152—153 69.75 4.40 11.58 C21H16ClN3O
69.69 4.42 11.62
12b
13a
2.41 (s, 6 H, Me); 6.80 (s, 1 H, H(5), pyrimidine);
7.48—7.92 (m, 8 H, H arom.); 9.88 (s, 1 H, NH)
2.43 (s, 6 H, Me); 2.82 (s, 3 H, Me); 6.18 (s, 2 H,
SH2); 6.80 (s, 1 H, H(5), pyrimidine); 7.09 (s, 1 H,
H arom.); 7.38 (s, 1 H, H arom.); 10.35 (s, 1 H, NH)
2.80 (s, 3 H, Me); 6.20 (s, 2 H, SH2); 7.11, 7.39 (both
s, 1 H each, H arom.); 7.45—7.60 (m, 3 H, H arom.);
7.98—8.08 (m, 2 H, H arom.); 10.29 (s, 1 H, NH)
2.79 (s, 3 H, Me); 3.82 (s, 3 H, MeО); 6.18 (s, 2 H,
SH2); 7.10, 7.41 (both s, 1 H each, H arom.); 7.64 (d,
2 H, H arom., J = 8.3); 7.95 (d, 2 H, H arom.,
J = 8.5); 10.34 (s, 1 H, NH)
2.80 (s, 3 H, Me); 3.85 (s, 3 H, MeО); 6.19 (s, 2 H,
SH2); 7.11, 7.40 (both s, 1 H each, H arom.); 7.45—7.76
(m, 3 H, H arom.); 8.04 (s, 1 H, H arom.);
10.38 (s, 1 H, NH)
2.81 (s, 3 H, Me); 6.20 (s, 2 H, SH2); 7.11, 7.39 (both s,
1 H each, H arom.); 7.47 (d, 2 H, H arom., J = 8.4); 8.02
(d, 2 H, H arom., J = 8.5); 10.48 (s, 1 H, NH)
2.80 (s, 3 H, Me); 6.21 (s, 2 H, SH2); 7.11, 7.40 (both s,
1 H each, H arom.); 7.19—8.10 (m, 4 H, H arom.);
10.43 (s, 1 H, NH)
1.27 (t, 3 H, Me, J = 7.7); 2.71 (s, 3 H, Me); 2.93
(q, 2 H, SH2, J = 7.5); 6.18 (s, 2 H, SH2); 6.93
(s, 1 H, H arom.); 7.20—7.52 (m, 5 H, H arom.);
10.02 (s, 1 H, NH)
3.88 (s, 3 H, MeО); 7.42—8.08 (m, 13 H, H arom.);
10.95 (s, 1 H, NH)
7.45—8.12 (m, 13 H, H arom.); 11.02 (s, 1 H, NH)
2.51 (s, 3 H, MeS); 7.19—8.09 (m, 13 H, H arom.);
10.90 (s, 1 H, NH)
2.95 (s, 3 H, Me); 3.90 (s, 3 H, MeО); 7.15—8.11
(m, 8 H, H arom.); 10.53 (s, 1 H, NH)
54
53
69
55
24
67
71
43
140
233
137
225
161
197
198
135
66.42 4.51 19.39 С20H16ClN5
66.37 4.42 19.36
62.13 4.76 22.68 C16H15N5O2
62.13 4.85 22.65
66.40 4.21 13.66 С17H13N3O3
66.38 4.23 13.67
64.13 4.52 12.45 С18H15N3O4
64.04 4.45 12.45
64.03 4.46 12.37 C18H15N3O4
64.04 4.45 12.45
59.76 3.57 12.34 C17H12ClN3O3
59.68 3.51 12.29
62.78 3.71 12.87 C17H12FN3O3
62.71 3.69 12.91
62.01 4.71 11.43 C19H17N3O3S
62.06 4.63 11.43
13b
13s
13d
13g
14a
14b
14c
15
13e
13f
65 156—158 74.36 4.76 11.82 C22H17N3O2
74.28 4.78 11.82
46 110—112 69.96 3.92 11.65 C21H14ClN3O
70.04 3.89 11.67
83 135—136 71.14 4.56 11.30 С22H17N3OS
71.06 4.58 11.31
27 205—207 69.64 5.12 14.31 C17H15N3O2
69.55 5.11 14.32
13g
16*
58
315
55.44 5.06 27.74 С14H15ClN6
(deomp.) 55.52 4.96 27.76
14a
* Hydrochloride.
14b
14s
glycine methyl ester hydrochloride11 and of 2ꢀaminoꢀ3ꢀ
thienylcyanide with phenylcyanamides10 are thought to
follow such a pathway. Nevertheless, the results of alterꢀ
native synthesis of 9a with participation of disubstituted
guanidines and isatoic anhydride12 indicate the formation
of 3,4ꢀdihydroquinazolinꢀ4ꢀone with substituent in the
position 2. Similar results were obtained in the synthesis
of 2ꢀphenylaminoadenosine13 and thienopyrimidinꢀ
4(3H)ꢀones14 with the use of phenylcyanamide.
15
16*
2.47 (s, 6 H, Me); 7.14 (s, 1 H, H(5), pyrimidine);
7.59 (t, 1 H, H arom., J = 7.1); 7.88 (d, 1 H, H arom.,
J = 7.6); 7.96 (t, 1 H, H arom., J = 7.2); 8.46 (d, 1 H,
H arom., J = 7.7); 9.22, 9.51 (both s, 1 H each, NH2);
11.98 (s, 1 H, NH); 14.33 (s, 1 H, HSl)
* Hydroshloride.
Quinazolinones, unsubstituted at the NH group, are
known to exist in various tautomeric forms: 1,4ꢀdihydroꢀ
quinazolinꢀ4ꢀones (A), 3,4ꢀdihydroquinazolinꢀ4ꢀones (B),
and quinazolinꢀ4ꢀols (C).
According to modern conception, heterocycles of this
type exist preferably in the oxoꢀform.15 In this way, the
choice should be made between forms A and B. The
quantumꢀchemical calculations give preferences to
3,4ꢀdihydroꢀ4ꢀquinazolinone tautomer B,16 which is in
accordance with the earlier data concerning this quesꢀ
tion.17 Recent structural investigations of quinazolones
by IR spectroscopy,18 13С NMR (HSQC), and Xꢀray
crystallography19 undoubtedly confirm their existence in
the form of 3,4ꢀdihydroquinazolinꢀ4ꢀone (B).

174
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
Shikhaliev et al.
Scheme 3
2ꢀ(3ꢀOxopiperazinꢀ2ꢀyl)acetate 8 is a convenient and
available bꢀamino ester for the construction of tetraꢀ
hydropyrimidine ring. Its catalystꢀfree cyclization with
cyanamides 1—3 proceeds smoothly upon heating in diꢀ
oxane (Scheme 3).
Cyanamides 1—3 show pronounced acidic properties,
while the imino group in piperazinone 8 is a strong enough
organic base, therefore, in the first step they form ionic
compound B (see Scheme 3), which upon heating underꢀ
goes the Woehler rearrangement with the formation of
guanidine С.20
Table 6. 1H NMR spectra of compounds 17
Compoꢀ
und:
δ (J/Hz)
17a 2.48 (s, 6 H, Me); 2.67—2.98 (м, 2 H, CОCH2CH);
3.21—3.52 (м, 3 H, NCH2CH2NH, CH); 4.31 (d.d,
1 H, NCH2CH2NH, J = 14.3, J = 6.2); 4.75 (d.d, 1 H,
NCH2CH2NH, J = 14.9, J = 3.8); 6.73 (s, 1 H, H(5),
pyrimidine); 8.19 (s, 1 H, CОNH); 12.89 (s, 1 H, NH)
17b 2.81—3.01 (м, 2 H, CОCH2CH); 3.33—3.61 (м, 3 H,
NCH2CH2NH, CH); 4.52 (d.d, 1 H, NCH2CH2NH,
J = 14.2, J = 6.8); 4.52 (d.d, 1 H, NCH2CH2NH,
J = 14.2, J = 3.6); 7.46—7.53 (м, 3 H, H arom.); 8.18
(d, 2 H, H arom., J = 7.4); 8.72 (s, 1 H, CОNH);
12.37 (s, 1 H, NH)
17c 2.79—3.03 (м, 2 H, CОCH2CH); 3.29—3.50 (м, 3 H,
NCH2CH2NH, CH); 3.82 (s, 3 H, MeО); 4.48 (d.d,
1 H, NCH2CH2NH, J = 14.3, J = 6.5); 4.62 (d.d, 1 H,
NCH2CH2NH, J = 14.3, J = 3.6); 7.12, 7.35 (both d,
2 H each, H arom., J = 8.5); 8.42 (s, 1 H, CОNH);
12.44 (s, 1 H, NH)
17d 2.77—3.00 (м, 2 H, CОCH2CH); 3.28—3.49 (м, 3 H,
NCH2CH2NH, CH); 3.83 (s, 3 H, MeО); 4.47 (d.d,
1 H, NCH2CH2NH, J = 14.2, J = 6.4); 4.60 (d.d, 1 H,
NCH2CH2NH, J = 14.3, J = 3.5); 6.86—7.00 (м, 2 H,
H arom.); 7.45 (t, 1 H, H arom., J = 8.4); 7.69 (d, 1 H,
H arom., J = 8.5); 8.29 (s, 1 H, CОNH); 12.24 (s, 1 H,
NH)
17e 2.81—3.04 (м, 2 H, CОCH2CH); 3.35—3.62 (м, 3 H,
NCH2CH2NH, CH); 4.50 (d.d, 1 H, NCH2CH2NH,
J = 14.3, J = 6.6); 4.72 (d.d, 1 H, NCH2CH2NH,
J = 14.2, J = 3.7); 7.49, 8.13 (both d, 2 H each, H arom.,
J = 8.5); 8.36 (s, 1 H, CОNH); 12.32 (s, 1 H, NH)
17f 2.80—3.01 (м, 2 H, CОCH2CH); 3.32—3.59 (м, 3 H,
NCH2CH2NH, CH); 4.46 (d.d, 1 H, NCH2CH2NH,
J = 14.4, J = 6.5); 4.70 (d.d, 1 H, NCH2CH2NH,
J = 14.3, J = 3.6); 7.22, 8.26 (both br.s, 2 H each,
H arom.); 8.34 (s, 1 H, CОNH); 12.16 (s, 1 H, NH)
17g 1.23 (t, 3 H, SCH2CH3, J = 7.5); 2.74—3.01 (м, 4 H,
CОCH2CH, SCH2CH3); 3.26—3.52 (м, 3 H, CH,
NCH2CH2NH); 4.58 (d.d, 1 H, NCH2CH2NH, J =
14.4, J = 6.5); 4.67 (d.d, 1 H, NCH2CH2NH, J = 14.3,
J = 3.6); 7.14 (t, 1 H, H arom., J = 7.3); 7.32 (d, 1 H,
H arom., J = 7.5); 7.41 (t, 1 H, H arom., J = 7.3); 8.08
(d, 1 H, H arom., J = 7.6); 8.39 (s, 1 H, CОNH);
12.19 (s, 1 H, NH)
17: R4 =
(a), Bz (b), 4ꢀMeOBz (c), 2ꢀMeOBz (d),
4ꢀClBz (e), 4ꢀFBz (f), 2ꢀEtSBz (g)
Table 5. Characteristics of synthesized 1,3,4,8,9,9аꢀhexahydroꢀ
2Hꢀpyrazino[1,2ꢀc]pyrimidines 17
Comꢀ Yield M.p.
pound (%) /°С
Found
Calculated
Molecular
formula
(%)
C
H
N
17а
17b
17c
17d
17e
17f
29 335—336 54.23 5.48 29.18 C13H16N6O2
54.11 5.55 29.14
62
252
58.56 4.92 19.64 C14H14N4O3
58.68 4.89 19.56
82 277—278 57.02 4.98 17.79 С15H16N4O4
56.91 5.06 17.70
40 251—252 56.83 5.05 17.72 С15H16N4O4
56.91 5.06 17.70
61
276
52.49 4.05 17.42 С14H13ClN4O3
52.39 4.05 17.46
70
255
55.23 4.18 18.36 C14H13FN4O3
55.21 4.27 18.40
17g
38 230—232 55.43 5.13 16.28 С16H18N4O3S
55.43 5.20 16.17

Cyclization of cyanamides with aminocarbonyls
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
175
1
with water until neutral pH and recrystallized from propanꢀ2ꢀol—
dioxane (1 : 1) to obtain compound 12a (2.0 g, 55%).
6ꢀChloroꢀ2ꢀ(4,6ꢀdimethylpyrimidinꢀ2ꢀyl)aminoꢀ4ꢀphenylꢀ
quinazoline (12b) was obtained similarly.
8ꢀMethylꢀ6ꢀ(4,6ꢀdimethylpyrimidinꢀ2ꢀyl)amino[1,3]dioxoꢀ
lo[4,5ꢀg]quinazoline (13a). Concentrated HCl (0.92 mL) was
added to a mixture of 6b (1.79 g, 0.01 mol) and cyanamide 1
(1.48 g, 0.01 mol) in methanol (25 mL), and the reaction mixture
was refluxed for 3 h. Then it was poured in cold deionized water
(200 mL) and, by addition of conc. NH4OH, рН value was raised
to 9. A precipitate formed was filtered off and recrystallized from
dioxane to obtain compound 13a (1.65 g, 53%).
According to H NMR spectroscopy data, the reacꢀ
tion product has the structure 17. The downfield singlets
at 8.3 and 12—13 ppm represent signals of the protons of
the amide and guanidine groups. In the region 4.30—4.80
ppm, two doublets of doublets are observed, the distance
between which (50—140 Hz) depends on the substituent
R, which allows us to assign these signals to the protons of
the —СН2— group in position 4 of the heterocyclic sysꢀ
tem 17. The synthetic outcome for compounds 17 and
their 1Н NMR spectral data are given in Tables 5 and 6.
8ꢀMethylꢀ6ꢀphenylcarboxamido[1,3]dioxolo[4,5ꢀ
g]quinazoline (13b). A mixture of 6b (1.34 g, 7.5 mmol) and
benzoylcyanamide 3a (1.1 g, 7.5 mmol) was heated in dioxane
(20 mL) at 80 °С for 4 h. The reaction mixture was poured in cold
deionized water (200 mL), a precipitate formed was filtered off and
recrystallized from dioxane to obtain compound 13b (1.59 g, 69%).
6ꢀ(4ꢀMethoxyphenylcarboxamido)ꢀ8ꢀmethyl[1,3]dioxoloꢀ
[4,5ꢀg]quinazoline (13c), 6ꢀ(2ꢀmethoxyphenylcarboxamido)ꢀ8ꢀ
methyl[1,3]dioxolo[4,5ꢀg]quinazoline (13d), 6ꢀ(4ꢀchlorophenylꢀ
carboxamido)ꢀ8ꢀmethyl[1,3]dioxolo[4,5ꢀg]quinazoline (13e), 6ꢀ
(4ꢀfluorophenylcarboxamido)ꢀ8ꢀmethyl[1,3]dioxolo[4,5ꢀg]quinꢀ
azoline (13f), and 6ꢀ(2ꢀethylsulfanylphenylcarboxamido)ꢀ8ꢀmethꢀ
yl[1,3]dioxolo[4,5ꢀg]quinazoline (13g) were obtained by similar
procedure.
2ꢀ(4ꢀMethoxyphenylcarboxamido)ꢀ4ꢀphenylquinazoline (14a).
A mixture of 2ꢀaminobenzophenone 6с (1.97 g, 0.01 mol) and
4ꢀmethoxybenzoylcyanamide 3b (1.76 g, 0.01 mol) was refluxed in
anhydrous dioxane (25 mL) for 10 h. The reaction mixture was
poured in cold deionized water (200 mL), acidified with diluted
HCl to рН 2—3. An oily precipitate formed was washed with
water and dissolved in minimum propanꢀ2ꢀol. A precipitate was
formed after few days, which was filtered off and dried in vacuo at
40 °С to obtain compound 14a (2.3 g, 65%).
Experimental
Monitoring of the course of the reaction and purity of comꢀ
pounds synthesized was performed by TLC on Merck UVꢀ254
plates (eluent: chloroform—methanol, 20 : 1). 1Н NMR spectra
were recorded on a Bruker ACꢀ300 spectrometer (300 MHz) at
20 °С in DMSOꢀd6, Me4Si was used as the internal standard.
2ꢀ(4,6ꢀDimethylpyrimidinꢀ2ꢀylamino)ꢀ3,4ꢀdihydroquinazolinꢀ
4ꢀone (9a) was obtained as described earlier.20
2ꢀ(4ꢀMethoxyanilino)ꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone (9b).
Concentrated HCl (1.37 mL) was added to a solution of methyl
anthranilate 5a (2.27 g, 0.015 mol) and 4ꢀmethoxyphenylꢀ
cyanamide 4a (2.22 g, 0.015 mol) in propanꢀ2ꢀol (30 mL), and
the mixture was refluxed for 2 h. A precipitate of hydrochloride
9b formed was filtered off, recrystallized from propanꢀ2ꢀol—
DMF (1 : 2), washed with propanꢀ2ꢀol, and dried at 40 °С in
vacuo to obtain hydrochloride 9b (1.14 g, 25%).
2ꢀ(2ꢀMethoxyanilino)ꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone (9c) and
6,7ꢀdimethoxyꢀ2ꢀ(4ꢀmethoxyanilino)ꢀ3,4ꢀdihydroquinazolinꢀ4ꢀ
one (10a) were obtained similarly.
2ꢀ(4ꢀChlorophenylcarboxamido)ꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone
(9d). A solution of methyl anthranilate 5a (1.13 g, 7.5 mmol) and
4ꢀchlorobenzoylcyanamide 3c (1.35 g, 7.5 mmol) in dioxane
(25 mL) was heated at 80 °С for 1—2 h. A precipitate was formed
toward the end of heating. After cooling, the reaction mixture
was poured in cold deionized water (200 mL). The precipitate
was filtered off and recrystallized from propanꢀ2ꢀol—dioxane
(1 : 2), washed with propanꢀ2ꢀol, and dried at 40 °С in vacuo to
obtain compound 9d (1.38 g, 61%).
2ꢀ(4ꢀMethoxyphenylcarboxamido)ꢀ3,4ꢀdihydroquinazolinꢀ4ꢀ
one (9e), 2ꢀ(2ꢀmethylsulfanylphenylcarboxamido)ꢀ3,4ꢀdihydroꢀ
quinazolinꢀ4ꢀone (9f), 2ꢀ(2ꢀethylsulfanylphenylcarboxamido)ꢀ3,4ꢀ
dihydroquinazolinꢀ4ꢀone (9g), 6,7ꢀdimethoxyꢀ2ꢀphenylcarboxꢀ
amidoꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone (10b), 2ꢀ(4ꢀchlorophenylꢀ
carboxamido)ꢀ6,7ꢀdimethoxyꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone (10c),
6,7ꢀdimethoxyꢀ2ꢀ(4ꢀmethoxyphenylcarboxamido)ꢀ3,4ꢀdihydroꢀ
quinazolinꢀ4ꢀone (10d), 2ꢀ(4ꢀfluorophenylcarboxamido)ꢀ6,7ꢀ
dimethoxyꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone (10e), 2ꢀ(2ꢀethylsulfanylꢀ
phenylcarboxamido)ꢀ6,7ꢀdimethoxyꢀ3,4ꢀdihydroquinazolinꢀ4ꢀone
(10f), and 6ꢀbromoꢀ2ꢀ(4ꢀfluorophenylcarboxamido)ꢀ3,4ꢀdihydroꢀ
quinazolinꢀ4ꢀone (11) were obtained similarly.
2ꢀ(4ꢀChlorophenylcarboxamido)ꢀ4ꢀphenylquinazoline (14b)
and 2ꢀ(2ꢀmethylsulfanylphenylcarboxamido)ꢀ4ꢀphenylquinazoline
(14c) were obtained similarly.
2ꢀ(4ꢀMethoxyphenylcarboxamido)ꢀ4ꢀmethylquinazoline (15).
A mixture of 2ꢀaminoacetophenone 6a (1.35 g, 10 mmol) and
4ꢀmethoxybenzoylcyanamide 4a (1.32 g, 7.5 mmol) in anhyꢀ
drous dioxane (20 mL) was kept at 80 °С for 10 h followed by
pouring of the mixture in deionized water (200 mL), acidified
with diluted HCl to рН 2—3. An oily precipitate formed was
washed with water, recrystallized from acetonitrile, and dried in
vacuo at 40 °С to obtain compound 15 (0.59 g, 27%).
4ꢀAminoꢀ2ꢀ(4,6ꢀdimethylpyrimidinꢀ2ꢀyl)aminoquinazoline hyꢀ
drochloride (16). A mixture of cyanamide 1 (1.48 g, 0.01 mol) and
hydrochloride 7 (1.55 g, 0.01 mol) in anhydrous dioxane (30 mL)
was refluxed for 4 h. A precipitate formed was filtered off, washed
with hot propanꢀ2ꢀol, and recrystallized from DMF to obtain
hydrochloride of compound 16 (1.75 g, 58%).
6ꢀPhenylcarboxamidoꢀ1,3,4,8,9,9аꢀhexahydroꢀ2Hꢀpyraziꢀ
no[1,2ꢀс]pyrimidineꢀ1,8ꢀdione (17b). A mixture of benzoylcyanꢀ
amide 3a (1.46 g, 0.01 mol) and 8 (1.72 g, 0.01 mol) in dioxane
(20 mL) was heated at 80 °С for 3 h. A precipitate formed was
filtered off and recrystallized from propanꢀ2ꢀol—dimethylꢀ
acetamide (2 : 1) to obtain compound 17b (1.76 g, 62%).
6ꢀ(4,6ꢀDimethylꢀ2ꢀpyrimidinylamino)ꢀ1,3,4,8,9,9аꢀhexaꢀ
hydroꢀ2Hꢀpyrazino[1,2ꢀс]pyrimidineꢀ1,8ꢀdione (17a), 6ꢀ(4ꢀ
methoxyphenylcarboxamido)ꢀ1,3,4,8,9,9аꢀhexahydroꢀ2Hꢀ
6ꢀChloroꢀ2ꢀ(2ꢀmethoxyphenyl)aminoꢀ4ꢀphenylquinazoline
(12a). Concentrated HCl (0.91 mL) was added to a solution of
2ꢀaminoꢀ5ꢀchlorobenzophenone 6d (2.32 g, 0.01 mol) and 2ꢀmethꢀ
oxyphenylcyanamide 4a (1.48 g, 0.01 mol) in propanꢀ2ꢀol
(30 mL), and the mixture was refluxed for 2 h. The cooled dark red
reaction mixture was poured in solution of NaOH (0.5 g) in
deionized water (200 mL). A tarꢀlike precipitate formed was washed

176
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 1, January, 2008
Shikhaliev et al.
11. V. V. Dovlatyan, E. N. Ambartsumyan, G. S. Amazaspyan,
Khim. Geterotsikl. Soedin., 1996, 84 [Chem. Heterocycl. Compd.,
1996, 32 (Engl. Transl.)].
12. Kh. S. Shikhaliev, D. V. Krylґskii, A. S. Shestakov, A. V.
Falaleev, Zh. Obshch. Khim., 2003, 73, 1216 [Russ. J. Gen.
Chem., 2003, 73 (Engl. Transl.)].
pyrazino[1,2ꢀс]pyrimidineꢀ1,8ꢀdione (17c), 6ꢀ(2ꢀmethoxyphenylꢀ
carboxamidoꢀ1,3,4,8,9,9аꢀhexahydroꢀ2Hꢀpyrazino[1,2ꢀс]pyrimiꢀ
dineꢀ1,8ꢀdione (17d), 6ꢀ(4ꢀchlorophenylcarboxamido)ꢀ1,3,4,8,9,9аꢀ
hexahydroꢀ2Hꢀpyrazino[1,2ꢀс]pyrimidineꢀ1,8ꢀdione (17e), 6ꢀ(4ꢀ
fluorophenylcarboxamido)ꢀ1,3,4,8,9,9аꢀhexahydroꢀ2Hꢀpyraziꢀ
no[1,2ꢀс]pyrimidineꢀ1,8ꢀdione (17f), and 6ꢀ(2ꢀethylsulfanylꢀ
phenylcarboxamido)ꢀ1,3,4,8,9,9аꢀhexahydroꢀ2Hꢀpyrazino[1,2ꢀ
с]pyrimidineꢀ1,8ꢀdione (17g) were obtained similarly.
13. K. Omura, R. Marumoto, Y. Furukawa, Chem. Pharm. Bull.,
1981, 29, 1870.
14. K. N. Rajasekharan, L. Thomas, Ind. J. Chem., 1983, 22, 76.
15. J. A. Joule, K. Mills, Heterocyclic Chemistry, Blackwell Sciꢀ
ence, Oxford, 2000.
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