Reactions of 3, 3-diaminoacrylic acid derivatives with o- haloarenecarbonitriles. synthesis of fused azines

Article abstract of DOI:10.1007/s10593-012-1011-5

The interaction of the ethyl ester or pyrrolidide of 3, 3-diaminoacrylic acid with aromatic and heteroaromatic nitriles containing a labile halogen atom in the ortho position, leads to the formation of products of its substitution by the α-carbon atom of the diaminoacrylic acid derivative. The compounds obtained are cyclized smoothly into fused diaminoazines.

Full text of DOI:10.1007/s10593-012-1011-5

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
REACTIONS OF 3,3-DIAMINOACRYLIC ACID
DERIVATIVES WITH o-HALOARENECARBONITRILES.
SYNTHESIS OF FUSED AZINES
E. M. Igumnova1, S. I. Selivanov1, D. V. Dar'in1, and P. S. Lobanov1*
The interaction of the ethyl ester or pyrrolidide of 3,3-diaminoacrylic acid with aromatic and
heteroaromatic nitriles containing a labile halogen atom in the ortho position, leads to the formation of
products of its substitution by the α-carbon atom of the diaminoacrylic acid derivative. The compounds
obtained are cyclized smoothly into fused diaminoazines.
Keywords: fused diaminoazines, 3,3-diaminoacrylic acid derivatives, o-haloarenecarbonitriles.
We have shown previously that α-acylacetamidines, existing in the form of enediamines, in reactions with
aromatic aldehydes, esters, and nitro compounds, containing a labile halogen atom in the ortho position, form fused
azines [1-4]. We also reported the sole successful example of the use of an aromatic nitrile in this reaction [5]. The
reaction of ortho halo-containing arenecarbonitriles with cyclic analogs of acylacetamidines has been described recently
[6-8]. Interest in the products of such reactions is caused by their potential biological activity [9, 10]. The present paper
is devoted to a systematic investigation of the reaction of ortho-haloarenecarbonitriles with enediamines.
The ethyl ester 1a and pyrrolidide 1b of 3,3-diaminoacrylic acid react with haloarenecarbonitriles 2-4
even at room temperature on simple mixing of reactants, forming products of substitution of the halogen atom by
the α-carbon atom of the 3,3-diaminoacrylic acid derivative under mild conditions. The conclusion that the
enamine reacts just like a C-nucleophile is confirmed by the disappearance of the proton signal in the vinyl
1
fragment and the retention of signals of the protons of the two NH2 groups in the H NMR spectra of the
intermediate products 5a, 7a,b, and 9a.
Compounds 5a, 7a,b, and 9a are stable at room temperature, their cyclization into fused azines occurs
on heating to 200-270oC. Unlike them, the derivatives 5b and 9b even at room temperature are converted into
fused azines 6b and 10b. Although we did not isolate the intermediate compounds 5b and 9b, it is possible with
sufficient confidence to propose that in reality they are formed in the course of the reaction. In the first stage of
the process, attack of the amino group at the C≡N bond seems improbable, at the same time the relative
readiness of this reaction in an intramolecular variant is quite explainable.
The best yields of azines 6b, 8b, and 10b, containing an amide group, were achieved on carrying out the
synthesis in the presence of base and without isolating the intermediate substitution products. All the reactions
were convenient in that no side products insoluble in water were formed and the products may be isolated in the
pure state after washing them with water.
_______
*To whom correspondence should be addressed, e-mail: pslob@mail.ru.
1St. Petersburg State University, 26 Universitetsky Ave., Saint Petersburg 198504, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 465-470, March, 2012. Original
article submitted March 8, 2011.
436
0009-3122/12/4803-0436©2012 Springer Science+Business Media, Inc.

NH2
CN
O2N
NH2
NH2
O2N
O2N
CN
F
NH2
NH2
8
5
1
2N
7
6
+
3
4
NH2
COR
1a,b
COR
COR
2
5a,b
6a,b
NH2
N
CN
CN
Cl
N
NH2
NH2
N
N
1a,b
+
MeS
N
MeS
N
MeS
N
NH2
COR
7a,b
3
COR
NH2
8a,b
CN
CN
N
N
NH2
NH2
5
4
N6
3N
2
1
Cl
1a,b
+
NH2
7
8
COR
10
9
COR
Me
Me
Me
4
9a,b
10a,b
a R = OEt, b R = N(CH2)4
For azines 6b and 10b, obtained in one stage, it was impossible to exclude the formation of the
alternative structures 11 and 12, respectively.
NH2
O
NH2
O
N
N
O2N
N
N
NH2
N
NH2
11
12
Me
Convincing proof of the fact that we have obtained exactly compounds 6b and 10b was served by their
NOESY spectra in which cross peaks between the signals of the pyrrolidine ring protons and the H-5
(compound 6b) and H-10 protons (compound 10b) were clearly seen. This indicates their relatively close
proximity, which is brought about in structures 6b and 10b, but not in structures 11 and 12.
3,3-Diaminoacrylic acid amide 1b reacts significantly faster than ester 1a both at the halogen
substitution stage and in the subsequent cyclization. This, in our opinion, is caused by the weaker electron-
withdrawing properties of the aminocarbonyl substituent in comparison with ethoxycarbonyl, which leads to an
increase in the nucleophilicity of both nucleophilic centers. Such a difference in the reactivity of these
compounds was observed by us previously [3]. Quinoline carbonitrile 4 reacts significantly slower than
benzonitrile 2 and pyrimidine carbonitrile 3.
NH2
NH2
Cl
EtOOC
EtOOC
KOH,
EtOH
NH2
N
CN
Cl
1a
N
+
CN
Cl
N
N
NH2
OEt
MeS
N
MeS
N
14
MeS
N
13
15
437

TABLE 1. Physicochemical Characteristics of Compounds 5-10, 14, 15
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
Mp, °C
C
H
N
C12H12N4O4
C12H12N4O4
C14H15N5O3
C11H13N5O2S
C13H16N6OS
C11H13N5O2S
C13H16N6OS
C16H16N4O2
C16H16N4O2
C18H19N5O
52.14
52.17
51.79
52.17
55.54
55.81
47.53
47.30
51.51
51.30
47.29
47.30
51.32
51.30
64.49
64.85
64.60
64.85
67.02
67.27
41.83
42.11
48.08
48.29
4.47
4.38
4.38
4.38
5.05
5.02
4.64
4.69
5.28
5.30
4.73
4.69
5.39
5.30
5.29
5.44
5.24
5.44
6.12
5.96
3.72
3.85
5.19
5.30
19.98
20.28
19.89
20.28
22.95
23.24
24.97
25.07
27.12
27.61
25.36
25.07
27.46
27.61
18.43
18.91
18.62
18.91
21.44
21.79
21.96
22.32
21.54
21.66
177-178
293-294
282-283
177-179
—*
71
5а
100
6а
28 (A), 92 (B)
6b
7а
93
53
7b
8а
285-286
303-305
257-258
283-285
261-263
195-198
173-175
100
80 (B)
8b
9а
90
100
10а
10b
14
50 (A), 68 (B)
C11H12ClN5O2S
C13H17N5O3S
93
84
15
_______
*Compound cyclizes at a temperature below the melting point.
TABLE 2. 1H NMR Spectra of Compounds 5-10, 14, 15
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
1.05 (3H, t, J = 7.1, CH3); 3.92 (2H, q, J = 7.1, CH2); 6.70 (4H, br. s, 2NH2);
7.57 (1H, d, J = 8.8, H-6); 8.32 (1H, dd, J = 8.8, J = 2.6, H-5); 8.58 (1H, d, J = 2.6, H-3)
5а
6а
6b
1.35 (3H, t, J = 7.1, CH3); 4.32 (2H, q, J = 7.1, CH2); 7.84 (4H, br. s, 2NH2);
8.18 (1H, dd, J = 9.6, J = 2.2, H-6); 8.56 (1H, d, J = 9.6, H-5); 9.04 (1H, d, J = 2.2, H-8)
1.68-1.94 (4H, m, CH2CH2); 2.95-3.27 (2H, m, NCH2); 3.43-3.65 (2H, m, NCH2);
6.27 (2H, br. s, NH2); 7.20 (1H, d, J = 9.4, H-5); 7.41 (2H, br. s, NH2);
8.06 (1H, dd, J = 9.4, J = 2.0, H-6); 9.06 (1H, d, J = 2.0, H-8)
1.15 (3H, t, J = 7.1, CH2CH3); 2.50 (3H, s, SCH3); 4.04 (2H, q, J = 7.1, CH2);
7.57 (4H, br. s, 2NH2); 8.63 (1H, s, H Ar)
7а
7b
8а
8b
9а
1.65-1.95 (4H, m, CH2CH2); 2.44 (3H, s, SCH3); 3.00-3.50 (4H, m, 2NCH2);
7.61 (4H, br. s, 2NH2); 8.22 (1H, s, H Ar)
1.30 (3H, t, J = 7.1, CH2CH3); 2.57 (3H, s, SCH3); 4.25 (2H, q, J = 7.1, CH2);
7.70 (4H, br. s, 2NH2); 9.03 (1H, s, H Ar)
1.65-2.00 (4H, m, CH2CH2); 2.43 (3H, s, SCH3); 2.97-3.12 (2H, m, NCH2);
3.35-3.62 (2H, m, NCH2); 6.45 (2H, br. s, NH2); 7.40 (2H, br. s, NH2); 8.99 (1H, s, H Ar)
0.91 (3H, t, J = 7.0, CH2CH3); 2.49 (3H, s, CH3 Ar); 3.85 (2H, q, J = 7.0, CH2);
5.73 (2H, br. s, NH2); 7.49 (2H, br. s, NH2); 7.68 (1H, s, H-5); 7.69 (1H, d, J = 8.2, H-7);
7.96 (1H, d, J = 8.2, H-8); 8.95 (1H, s, H-2)
1.08 (3H, t, J = 7.1, CH2CH3); 2.44 (3H, s, 6-CH3); 4.20 (2H, q, J = 7.1, CH2);
6.84 (2H, br. s, NH2); 7.51 (2H, br. s, NH2); 7.51 (1H, s, H-10); 7.54 (1H, d, J = 8.7, H-8);
7.80 (1H, d, J = 8.7, H-7); 9.22 (1H, s, H-5)
10а
1.48-2.00 (4H, m, CH2CH2); 2.41 (3H, s, CH3); 2.65-3.13 (2H, m, NCH2);
3.40-3.74 (2H, m, NCH2); 6.05 (2H, br. s, NH2); 7.11 (2H, br. s, NH2);
10b
7.51 (1H, d, J = 8.3, H-8); 7.77 (1H, d, J = 8.3, H-7); 7.81 (1H, s, H-10); 9.17 (1H, s, H-5)
14
15
1.16 (3H, t, J = 7.1, CH2CH3); 2.52 (3H, s, SCH3); 4.05 (2H, q, J = 7.1, CH2);
7.60 (4H, br. s, 2NH2)
1.28 (3H, t, J = 7.3, CH2CH3); 1.38 (3H, t, J = 7.3, CH2CH3); 2.54 (3H, s, SCH3);
4.31 (2H, q, J = 7.3, CH2); 4.41 (2H, q, J = 7.3, CH2); 7.32 (4H, br. s, 2NH2)
438

TABLE 3. 13C NMR Spectra of Compounds 5-10, 14, 15
Com-
pound
Chemical shifts, δ, ppm
5а
15.4 (CH3); 58.5 (CH2); 76.2 (ССО2Et); 117.6, 118.4, 127.8, 128.7, 135.9, 145.4,
150.5 (C Ar, CN); 161.7 (C(NH2)2); 167.5 (CO)
6а
15.2 (CH3); 60.7 (CH2); 87.7, 112.6, 122.6, 125.4, 125.6, 140.9, 143.7, 161.2,
162.5 (С Ar); 168.5 (CO)
6b
7а
25.0 (CH2); 26.3 (CH2); 46.2 (NCH2); 47.7 (NCH2); 98.1, 109.7, 123.0, 123.8, 124.9,
139.9, 140.7, 156.3, 160.2 (С Ar); 167.0 (CO)
14.6 (SCH3); 14.9 (CCH3); 59.4 (CH2); 79.3 (ССО2Et); 118.1 (CN); 103.3, 160.6,
162.3, 173.4 (C Ar); 167.1 (C(NH2)2); 168.8 (CO)
7b
8а
14.5 (SCH3); 25.0 (CH2); 26.2 (CH2); 45.6 (NCH2); 48.1 (NCH2); 87.1 (ССО2Et);
118.2 (CN); 92.8, 159.2, 161.0, 172.4 (С Ar); 161.7 (C(NH2)2); 167.2 (CO)
14.4 (SCH3); 15.4 (CH3); 60.4 (CH2); 87.7, 103.2, 155.6, 157.3, 160.6, 164.7,
173.0 (С Ar); 169.1 (CO)
8b
9а
14.1 (SCH3); 25.1 (CH2); 26.4 (CH2); 46.3 (NCH2); 47.7 (NCH2); 95.4, 101.0, 153.7,
155.7, 159.7, 160.9, 172.2 (С Ar); 166.8 (CO)
15.5(CH2CH3); 22.2 (9-CH3); 58.2 (CH2); 71.6 (ССО2Et); 119.0 (CN); 111.6, 126.4,
129.0, 130.1, 134.6, 137.7, 148.3, 150.5, 151.4 (С Ar); 161.5 (C(NH2)2); 167.7 (CO)
10а
10b
14
14.6 (CH2CH3); 22.1 (9-CH3); 61.0 (CH2); 89.5, 105.2, 122.3, 127.8, 129.5, 132.4,
134.4, 141.7, 146.6, 147.3, 160.2, 160.6 (С Ar); 170.5 (CO)
21.8 (CH3); 24.5 (CH2); 25.6 (CH2); 46.0 (NCH2); 46.9 (NCH2); 97.5, 102.4, 121.8,
124.6, 129.2, 131.5, 134.9, 136.8, 145.2, 147.9, 156.5, 159.0 (С Ar); 168.7 (CO)
14.1 (SCH3); 14.1 (CCH3); 58.9 (CH2); 79.7 (ССО2Et); 115.7 (CN); 100.8, 160.4,
161.6, 172.6 (С Ar); 167.9 (C(NH2)2); 168.1 (CO)
15
14.3 (SCH3); 15.0 (CCH3); 15.3 (CCH3); 60.3 (CH2); 64.2 (CH2); 89.6, 91.0, 159.1,
159.9, 163.1, 166.2, 169.1, 171.5 (C Ar, CO)
Nitrile 13, having two equivalent chlorine atoms in the ring, also reacts readily with 3,3-diaminoacrylic
acid ethyl ester (1a), forming the product of substitution of one chlorine atom 14. Further attempts of thermal
cyclization of compound 14 did not lead to the formation of a cyclic product. On heating, it resinified
completely. The same resinification of a compound containing a second reactive chlorine atom, was observed
by us previously [5]. We suggested that cyclization could be carried out successfully after replacing the chlorine
atom by another substituent such as an ethoxy group. On treating compound 14 with an alcoholic solution of
potassium hydroxide, pyridopyrimidine 15 was obtained as a result of replacing the chlorine atom and
subsequent cyclization. The reasons for unsuccessful cyclization attempts of compound 14 and the previously
described analog with two chlorine atoms in the molecule remain unclear.
Thus, the ortho-haloarenecarbonitriles studied by us react with enediamines giving fused diaminoazines.
Initially products are formed by substitution of the aromatic halogen by the α-carbon atom of the enediamine.
Cyclization of these intermediate products, proceeding by addition of the amino group to the nitrile group,
occurs fairly readily.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on a Bruker DPX-300 instrument (at 300 and 75 MHz) in
DMSO-d6, the residual signals of the solvent (2.50 and 39.7 ppm, respectively) were used as internal standard.
Elemental analysis was carried out on a HP-165B CHN analyzer. A check on the progress of reactions was
effected by TLC (Silufol UV-254, eluent hexane–ethyl acetate, 5:1).
Physicochemical and spectral properties of the synthesized compounds are given in Tables 1-3.
3,3-Diamino-2-(2-cyano-4-nitrophenyl)acrylic Acid Ethyl Ester (5a). A solution of nitrile 2 (0.50 g,
3.0 mmol) and 3,3-diaminoacrylic acid ester 1a (0.47 g, 3.6 mmol) in abs. dimethylacetamide (DMA)
439

(5 ml) was stirred at room temperature for 4 h. The reaction mixture was poured into water, the precipitated
orange solid was filtered off and air-dried.
3,3-Diamino-2-(5-cyano-2-methylsulfanylpyrimidin-4-yl)acrylic acid ethyl ester (7a), 3,3-di-
amino-2-(5-cyano-2-methylsulfanylpyrimidin-4-yl)acrylic acid pyrrolidide (7b), 3,3-diamino-2-(3-cyano-
6-methyl-quinolin-4-yl)acrylic acid ethyl ester (9a) were obtained analogously to compound 5a. The
formation of compound 7a was complete after 4 h (4.5 mmol ester 1a was used). The synthesis of compound 7b
was finished after 1 h, and of compound 9a after 21 days.
1,3-Diamino-7-nitroisoquinoline-4-carboxylic Acid Ethyl Ester (6a). Compound 5a (100 mg) was
melted and heated to 200oC. After several minutes, the melt hardened.
5,7-Diamino-2-methylsulfanylpyrido[4,3-d]pyrimidine-8-carboxylic acid ethyl ester (8a) and 2,4-di-
amino-9-methylbenzo[c][2,7]naphthyridine-1-carboxylic acid ethyl ester (10a) were obtained analogously
to compound 6a from compounds 7a (on heating to 200oC) and 9a (on heating to 270oC), respectively.
1,3-Diamino-7-nitroisoquinoline-4-carboxylic Acid Pyrrolidide (6b). A. A solution of nitrile 2 (0.20 g,
1.2 mmol) and amide 1b (0.23 g, 1.45 mmol) in abs. DMA (2 ml) was maintained at room temperature for 1 h,
the reaction mixture was then poured into water, the precipitated orange solid was filtered off and air-dried.
B. A solution of nitrile 2 (0.30 g, 1.8 mmol), amide 1b (0.34 g, 2.2 mmol), and (iPr)2NEt (0.46 g,
3.6 mmol) and abs. DMA (3 ml) was maintained at room temperature for 4 h, after which the reaction mixture
was poured into water, the precipitated orange solid was filtered off and air-dried.
5,7-Diamino-2-methylsulfanylpyrido[4,3-d]pyrimidine-8-carboxylic acid pyrrolidide (8b) was
obtained analogously from compound 6b by method B.
2,4-Diamino-9-methylbenzo[c][2,7]naphthyridine-1-carboxylic Acid Pyrrolidide (10b). A. A
solution of nitrile 4 (0.20 g, 1 mmol) and amide 1b (0.34 g, 2.2 mmol) in abs. DMA (2 ml) was maintained at
room temperatre for 7 days. The reaction mixture was then poured into water, the precipitated gray solid was
filtered off and air-dried.
B. A solution of nitrile 4 (0.51 g, 2.5 mmol), amide 1b (0.47 g, 3 mmol), and (i-Pr)2NEt (0.65 g,
5 mmol) in abs. DMA (5 ml) was maintained at room temperature for 7 days. The reaction mixture was then
poured into water, the precipitated gray solid was filtered off and air-dried.
3,3-Diamino-2-(6-chloro-5-cyano-2-methylsulfanylpyrimidin-4-yl)acrylic Acid Ethyl Ester (14). A
solution of nitrile 13 (0.51 g, 2.3 mmol) and ester 1a (0.65 g, 5 mmol) in abs. DMA (5 ml) was maintained at
room temperature for 2 h, after which the reaction mixture was poured into water, the precipitated solid was
filtered off and air-dried.
5,7-Diamino-4-ethoxy-2-methylsulfanylpyrido[4,3-d]pyrimidine-8-carboxylic Acid Ethyl Ester
(15). Compound 14 (0.23 g, 0.73 mmol) was added with stirring to a solution of KOH (0.06 g, 1.1 mmol) in abs.
EtOH (4 ml), and the mixture was maintained at room temperature for 2 h. The solvent was evaporated in
vacuum, and the residue was washed thoroughly with water. The solid was filtered off and air-dried.
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