Synthesis and special features of the structure of 6(7)-aminoperimidine derivatives

Article abstract of DOI:10.1007/s10593-010-0532-z

A method of synthesizing 6(7)-aminoperimidines has been developed based on the electrophilic amination of perimidines with sodium azide in PPA. The corresponding amides were synthesized by acylation and were also obtained by the Schmidt reaction from 6(7)

Full text of DOI:10.1007/s10593-010-0532-z

Chemistry of Heterocyclic Compounds, Vol. 46, No. 4, 2010
SYNTHESIS AND SPECIAL FEATURES OF THE
STRUCTURE OF 6(7)-AMINOPERIMIDINE
DERIVATIVES
A. V. Aksenov1*, A. S. Lyakhovnenko1, N. C. Karaivanov1, and I. I. Levina2
A method of synthesizing 6(7)-aminoperimidines has been developed based on the electrophilic amination of
perimidines with sodium azide in PPA. The corresponding amides were synthesized by acylation and were
also obtained by the Schmidt reaction from 6(7)-acetyl(or benzoyl)perimidines. A special feature of the
structure of the 2-substituted amines and amides is the presence of annular tautomerism slow in NMR time.
Keywords: sodium azide, 6(7)-aminoperimidines, perimidine, PPA (polyphosphoric acid), amination,
Schmidt reaction.
Aromatic amines serve as important synthetic building blocks. The standard method of synthesizing
them is sequential nitration and then reduction of the nitro compound formed at the first stage [1]. Direct one-
step amination is known, however it proceeds only in low yield [1, 2], since in many cases the initial aromatic
compound is used as solvent. Hydroxylamine [3, 4], alkylhydroxylamines [5], hydroxylamine O-sulfonic acid
[6], and hydrazoic acid [7] in the presence of a Lewis acids are used as aminating reagents. More recently Olah
has used hydrazoic acid [8] and trimethylsilyl azide [9] in the presence of a superacid for these purposes. The
latter system is the most efficient, the yield was ~90% calculated on azide, but as a result of using a large excess
of aromatic compound the degree of conversion of the latter does not exceed 10%.
In the present work we propose a method of aminating perimidines based on a new reactant system,
sodium azide – PPA (for preliminary communication see [10]).
We have proposed that the PPA azide 1 will be formed as a result of the reaction of sodium azide with
PPA, which may be protonated both at the nitrogen atom a and also b with the formation of two tautomeric
cations 2. As the result of azocoupling of the latter with perimidines 3a-c the intermediates 4a-c will be formed,
the hydrolysis of which leads to a mixture of tautomers of amines 5a-c and 6a-c.
_______
* To whom correspondence should be addressed, e-mail: biochem-org@stavsu.ru.
1Stavropol State University, Stavropol 355009, Russia.
2N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences, Moscow 119991, Russia;
e-mail: iilevina@rambler.ru.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 591-596, April, 2010. Original
article submitted June 11, 2009.
468
0009-3122/10/4604-0468©2010 Springer Science+Business Media, Inc.

O
O
P
O
a
N
b
N
+
N
+
N
+
N
PPA
PPA
...O
P
...O
R
N
N
...O
P
N
NH
NaN3
H
OH
OH
OH
2
1
N
NH
3a–c
PPA
...O
2
O
O
P
...O
P
N
N
N
N
N
N
N
N
H
H
R
R
OH
OH
N
H
N
H
4a–c
H+
H2O
HO
HO
N
R
+
N
HO
P
N
N
N
H
O
H
R
R
–H3PO4
–H+
N
NH
–N2
HN
N
NH2
5a–c
NH2
6a–c
3–6 a R = H, b R = Me, с R = Ph
In fact the reaction of perimidines 3a-c with a threefold excess of sodium azide in PPA* leads to a
mixture of the tautomeric amines 5a-c and 6a-c in 62-76% yield.
The special feature of the structure of 2-substituted amines is the presence of annular tautomerism slow
in NMR time. In the 1H NMR spectrum of a mixture of tautomers 5b and 6b of 6(7)-amino-2-methylperimidine
the signals of the protons in positions 4 and 6 have one broadened signal, which on heating to 100oC is
converted into two doublets. In the presence of the more bulky phenyl substituent the signals of both tautomers
1
5c and 6c (see Fig. 1) were observed in the H NMR spectrum at 50oC. On heating to 70oC the signals were
broadened, but at 100oC four averaged signals were observed. A similar phenomenon was observed previously
for 2-trifluoromethylperimidine-6(7)-carbaldehydes [12] and is linked with the presence of electron-withdrawing
substituents. In our opinion the presence of a bulky substituent in position 2, which prevents cleavage of proton
by the solvent, is most important. A donor or acceptor substituent in position 6(7) may either reduce the basicity
(increase the acidity) or increase the basicity (reduce the acidity) and hinder transfer of proton in this way.
_______
*PPA with a 86% content of P2O5 was used; obtained by the procedure of [11].
469

Fig. 1. Fragments of the 1H NMR spectra of mixtures of tautomers of 6-amino- (5c)
and 7-amino-2-phenylperimidine (6c) obtained at a – 50, b – 70, and c – 100oC.
We further synthesized the acetyl derivatives 7 by reacting amines 5(6) with acetic anhydride in acetic
acid, and also from 6(7)-acetylperimidines 8a-c by the Schmidt reaction.
R
R
R
R
HN
N
NH
N
N
NH
HN
N
NaN3
PPA
Ac2O
6a–с
5a–с
AcOH
Me
NH
Me
NH
O
Me
O
8a–с
7a–с
Me
O
O
a R = H, b R = Me, с R = Ph
1
Broadening of the signals of protons in positions 4 and 9 was observed in the H NMR spectra of
13
compounds 7b,c at room temperature. In the C NMR spectrum of amide 7b the signals of the C-4 and C-9
atoms were absent. On heating to 100oC the broadened signal was converted into two doublets and signals of the
corresponding carbon atoms appeared.
470

In the presence of an acetamide group, which is less donating than an amino group, the tautomerism is
therefore slowed to a lesser extent.
EXPERIMENTAL
The NMR spectra were recorded on Bruker instruments, WP 200 (200 MHz) for compounds 5(6)a-c and
JNM-ECX 400 (1H and 13C, 400 and 100 MHz respectively) for compounds 7a-c in DMSO-d6, internal standard
was TMS. A check on the progress of reactions and the homogeneity of the synthesized compounds was carried
out on Silufol UV-254 plates in the system ethyl acetate–alcohol, 3:1.
Amination of Perimidines (General Method). A mixture of perimidine 3a-c (1 mmol) and sodium
azide (0.13 g, 2 mmol) in PPA (2-3 g) was heated for 2 h at 70-80oC with vigorous stirring. If all the starting
material had not reacted (check by TLC) then further sodium azide (0.65 g, 1 mmol) was added and the mixture
heated for 2 h more. The mixture was then poured into water (50 ml), neutralized with ammonia solution, the
precipitated solid was filtered off, dried, and purified by recrystallization from ethyl acetate.
6(7)-Aminoperimidine (5(6)a). Yield 0.114 g (62%); mp 261-262oC (ethyl acetate). 1H NMR spectrum,
δ, ppm (J, Hz): 3.30 (2H, br. s, NH2); 6.35 (1H, d, J = 7.9, H-4(9)); 6.40 (1H, d, J = 7.3, H-9(4)); 7.07 (1H, dd, J
= 8.6, J = 7.3, H-8(5)); 7.27 (1H, s, H-2); 7.32 (1H, d, J = 7.9, H-5(8)); 7.96 (1H, d, J = 8.6, H-7(6)); 10.44 (1H,
br. s, NH). Found, %: C 72.68; H 4.37; N 22.95. C11H9N3. Calculated, %: C 72.51; H 4.43; N 23.06.
6(7)-Amino-2-methylperimidine (5(6)b). Yield 0.136 g (69%); mp 274-275oC (ethyl acetate).
Dihydrochloride: mp >310oC [13]). 1H NMR spectrum, δ, ppm (J, Hz): 2.01 (3H, s, CH3); 3.40 (2H, br. s, NH2);
6.35 (2H, br. m, H-4(9), 9(4)); 7.05 (1H, dd, J = 8.8, J = 7.3, H-8(5)); 7.31(1H, d, J = 7.6, H-5(8)); 7.91 (1H, d,
J = 8.8, H-7(6)); 10.43 (1H, br. s, NH). Found, %: C 73.22; H 5.58; N 21.20. C12H11N3. Calculated, %: C 73.07;
H 5.62; N 21.31.
6(7)-Amino-2-phenylperimidine (5(6)c). Yield 0.197 g (76%); mp 288-289oC (ethyl acetate). Found,
%: C 78.92; H 4.98; N 16.10. C17H13N3. Calculated, %: C 78.74; H 5.05; N 16.21.
6-Amino-2-phenylperimidine (6c). 1H NMR spectrum, δ, ppm (J, Hz); 3.40 (2H, br. s, NH2); 6.57 (1H,
d, J = 7.7, H-9); 6.64 (1H, d, J = 8.0, H-4); 7.12 (1H, dd, J = 8.8, J = 7.7, H-8); 7.42 (1H, d, J = 8.0, H-5); 7.54
(3H, m, 3,4,5-C6H5); 8.03 (3H, m, 2,6-C6H5, H-7); 10.47 (1H, br. s, NH).
7-Amino-2-phenylperimidine (6c). 1H NMR spectrum, δ, ppm (J, Hz): 3.40 (2H, br. s, NH2); 6.50 (1H,
d, J = 7.7, H-4); 6.71 (1H, d, J = 7.8, H-9); 7.18 (1H, dd, J = 8.8, J = 7.7, H-5); 7.35 (1H, d, J = 7.8, H-8); 7.54
(3H, m, 3,4,5-C6H5); 8.03 (3H, m, 2,6-C6H5, H-7); 10.43 (1H, br. s, NH).
Synthesis of Amides 7a-c (General Method). A. Acetic anhydride (0.153 g, 1.5 mmol) in acetic acid
(3 ml) was added to a solution of amine 5(6) (1mmol) in acetic acid (5 ml). The mixture was left for 1 h at room
temperature, after which it was poured into water (50 ml), neutralized with ammonia solution, and extracted
with butyl alcohol (3×30 ml). The solvent was evaporated, and the residue purified by recrystallization.
B. A mixture of acetylperimidine 8a-c (1 mmol) and sodium azide (0.13 g, 2 mmol) in PPA (2-3 g) was
heated at 50-60oC with vigorous stirring for 1 h, poured into water (50 ml), neutralized with ammonia solution,
and extracted with butyl alcohol (3×30 ml). The solvent was evaporated, and the residue purified by
recrystallization.
1
6(7)-Acetylaminoperimidine (7a). Yield 94% (A), 86% (B); mp 225-226oC (ethyl acetate). H NMR
spectrum, δ, ppm (J, Hz): 2.08 (3H, s, COCH3); 6.43 (2H, m, H-4(9), 9(4)); 7.03 (1H, d, J = 8.5, H-7(6)); 7.15
(1H, dd, J = 8.5, J = 7.3, H-8(5)); 7.24 (1H, d, J = 8.1, H-7(6)); 7.32 (1H, s, H-2); 9.21 (1H, br. s, NHCO); 10.61
(1H, br. s, NH). Found,%: C 69.45; H 4.86; N 18.61. C13H11N3O. Calculated, %: C 69.32; H 4.92; N 18.65.
6(7)-Acetylamino-2-methylperimidine (7b). Yield 95% (A), 88% (B); mp 247-248oC (ethyl acetate).
1H NMR spectrum, δ, ppm (J, Hz): 2.04 (3H, s, CH3); 2.07 (3H, s, COCH3); 6.43 (2H, br. m, H-4(9),
471

9(4)); 7.02 (1H, d, J = 8.2, H-7(6)); 7.15 (1H, dd, J = 8.2, J = 7.3, H-8(5)); 7.24 (1H, d, J = 8.3, H-7(6)); 9.14
13
(1H, br. s, NHCO); 10.5 (1H, br. s, NH). C NMR spectrum, δ, ppm: 21.34, 23.41, 107.59, 107.63, 114.41,
114.64, 121.92, 125.14, 126.29, 128.75, 141.55, 154.58, 162.79, 169.22. Found, %: C 70.43; H 4.42; N 17.52.
C14H13N3O. Calculated, %: C 70.28; H 5.48; N 17.56.
6(7)-Acetylamino-2-phenylperimidine (7c). Yield 93% (A), 84% (B); mp 302-303oC (ethyl acetate).
1H NMR spectrum, δ, ppm, (J, Hz): 2.09 (3H, s, COCH3); 6.67 (2H, br. m, H-4(9), 9(4)); 7.11 (1H, d, J = 8.4,
H-7(6)); 7.21 (1H, dd, J = 8.4, J = 7.3, H-8(5)); 7.34 (1H, d, J = 8.0, H-7(6)); 7.54 (3H, m, 3,4,5-C6H5); 8.03
(2H, d, J = 7.7, 2,6-C6H5); 9.19 (1H, br. s, NHCO); 10.5 (1H, br. s, NH). Found, %: C 75.91; H 4.98; N 13.89.
C19H15N3O. Calculated, %: C 75.73; H 5.02; N 13.94.
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