Formation of pyrimidin-2-ylcyanamide and 2-aminopyrimidine in the reaction of aniline derivatives with cyanamide and dimethylamino-1-pyridyl-2-propenone

Article abstract of DOI:10.1134/S1070428011080173

Substituted o- and p-nitroanilines and m-benzylaminoanilines in the reaction with cyanamide failed to yield the corresponding arylguanidines, and in the presence of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one formed 4-pyridyl-substituted pyrimidin-2-ylcyanamides and 2-amino-pyrimidines.

Full text of DOI:10.1134/S1070428011080173

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 8, pp. 1222−1226. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © E.V. Koroleva, Zh.V. Ignatovich, S.V. Ignatovich, K.N. Gusak, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 8,
pp. 1204−1208.
Formation of Pyrimidin-2-ylcyanamide
and 2-Aminopyrimidine in the Reaction
of Aniline Derivatives with Cyanamide
and Dimethylamino-1-pyridyl-2-propenone
E. V. Korolevaa, Zh. V. Ignatovicha, S. V. Ignatovichb, and K. N. Gusaka
aInstitute of Chemistry of New Materials, National Academy of Sciences of Belarus,
Skorini str., 36, 220141 Minsk, Republic of Belarus
bState Centre of Criminalistic Expertize of Ministry of Internal Affairs of Belarus, Belarus
Received June 28, 2010
Abstract—Substituted o- and p-nitroanilines and m-benzylaminoanilines in the reaction with cyanamide failed
to yield the corresponding arylguanidines, and in the presence of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one
formed 4-pyridyl-substituted pyrimidin-2-ylcyanamides and 2-amino-pyrimidines.
DOI: 10.1134/S1070428011080173
Guanidine condensation with β-dicarbonyl com-
pounds or with their latent forms, e.g., aminovinyl
ketones is a general procedure for the synthesis of 2-ami-
nopyrimidines [1]. A general method of synthesis was
developed underlain by the reaction of arylguanidines
with dimethylaminopropenones providing a wide range
of 2-arylaminopyrimidines [2–5]. Arylguanidine that as
a binucleophile formed the N1–C2–N3 fragment of the
pyrimidine ring was commonly obtained by the reaction
of aniline derivative with cyanamide.
reaction conditions formed a dimer, cyanoguanidine A,
and trimer, 2,4,6-triamino-1,3,5-triazine B, which were
detected by GC-MS analysis of the reaction mixture
(Scheme 1).
Obviously, anilines III–VI do not react with cyana-
mide due to the weak nucleophilicity of amines and/or
their salts. This result with derivatives III–VI having in
contrast to anilines I, II an electron-acceptor nitro group
in the ortho- or para-position with respect to the reaction
site is quite understandable in the case of the electronic
contral of this reaction. The reaction with cyanamide of
derivative VI unlike compound VII is probably impeded
by the ortho-methyl groups close to the reaction site.
However interestingly the steric factor of the methyl
substituent in 2-methyl-5-nitroaniline (I) does not hamper
the formation of guanidine VIII.
Aiming at the synthesis of a series of 2-arylami-
nopyrimidines we investigated in this transformations
sequence substituted anilines I–VII. For instance,
2-methyl-5-nitro-aniline (I) and 4-methyl-3-nitroaniline
(II) added the cyanamide in the presence of 65% nitric
acid to give in 90–93% yield arylguanidines VIII and IX
respectively. However we failed to obtain guanidines in
analogous conditions from substituted nitroanilines III–
V. The crystalline substances isolated in these reactions
proved to be the nitrates of the initial anilines. The same
result was obtained in the reaction of cyanamide with
benzylaminoaniline (VI), although its isomer aniline VII
afforded guanidine X in 75% yield. Cyanamide under the
We attempted to synthesize pyrimidines from anilines
III–VI, cyanamide, and 3-dimethylamino-1-(3-pyridyl)-
2-propen-1-one (XI) without isolation and purification of
intermediate reaction products. The filtered and washed
precipitate formed at heating the aniline derivative with
cyanamide was treated with dimethylaminopropenone XI
in 2-propanol in the presence of sodium hydroxide. Thus
1222

FORMATION OF PYRIMIDIN-2-YLCYANAMIDE
1223
Scheme 1.
H2N
NH
NH
N
NH2
R1
R1
N
N
I, II, i
R1
ii
R3
HN
R3
R2
R2
R2
I_VII
VIII, IX
R3
XIV, XV
H2N
NH
N
NH
N
1. i
2. ii
N
N
R1
ii
H2N
NH2
i
R1
R3
III
ii
III_VI
.
HCl
N
N
HN
NH
R3
R2
NH2
XIII
R2
IV_VI
H2N
NH
iii
NH
NH2
H2N
N
NH
2
N
ii
i
H2N C
NH +
NH
+
N
N
N
N
HCO2C6H4CH2HN
HCO2C6H4CH2H
N
N
Me
Me
NH2
HN
CN
X
A
XII
B
VII
R1 = Me, R2 = H, R3 = NO2 ( I, VIII, XIV); R1 = H, R2 = Me, R3 = NO2 (II, IX, XV); R1 = NO2, R2 = R3 = H (III); R1 =
CH3, R2 = NO2, R3 = H (IV); R1 = CF3, R2 = NO2, R3 = H (V); R1 = Me, R2 = H, R3 = NHCH2C6H4CO2Me (VI). i = NH2CN,
HNO3, ∆; ii = 3-C5H4NC(O)HC=CHNMe2 (XI), i-PrOH, NaOH, Δ; iii = H2NNH2, Ni-Ra, MeOH, Δ.
we obtained N-[4-(3-pyridinyl)-pyrimidin-2-yl]cyana-
mide (XII) from compounds IV–VI and 4-(3-pyridyl)-2-
aminopyrimidine (XIII) from compound III. Pyrimidine
XII reduced with hydrazine hydrate was converted into
pyrimidine XIII,which by the TLC data and all physi-
cochemical parameters (IR, NMR, and mass spectra)
was identical to a sample of pyrimidine independently
synthesized from 3-dimethylamino-1-pyridyl-2-propen-
1-one and guanidine carbonate.
of the condensation m-nitroarylguanidines VIII, IX are
quite stable and are converted into the corresponding
nitroarylpyrimidines XIV, XV in preparative yields [6, 7].
Inasmuch as the nitrile moiety of the cyanamide may
be regarded as an equivalent of a carbonyl group the in-
activity of the primarily arising nitrates of nitroanilines
III–V and benzylaminoaniline VII in the reaction of the
nucleophilic addition in question is due to the low nucleo-
philicity of these substrates. Using hydrochloric instead
of nitric acid we succeeded to obtain in the reaction of
p-nitroaniline with cyanamide 4-nitrophenylguanidine
hydrochlorid in 25% yield. The ability of aniline deriva-
tives I–VII to add cyanamide is well consistent with the
data of the simplest calculations of the partial charges
on the nitrogen atom of the amino group (see the table).
Pyrimidine XII was also isolated in the reaction of
guanidine X with 3-dimethylamino-1-(3-pyridyl)-2-pro-
pen-1-one (XI). This fact may be due to the low activity
of arylguanidine X in the condensation reaction because
of the poor solubility. The low stability of proper guani-
dine X is hardly probable since under the used conditions
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011

KOROLEVA et al.
1224
Partial charge on nitrogen atom in aniline derivatives and
arylguanidine yields
Cyanamide under the reaction conditions reacts with acid
to give the intermediate salt form C that as a nucleophile
adds the second (and further the third) cyanamide mol-
ecule giving cyanoguanidine A and triaminotriazine B
(Scheme 2).
Partial charge
on nitrogen
atoma
Guanidine
yield, %
Initial compound
Cyanamide
–0.115 (NH2)
–0.561 (CN)
Cyanoguanidine A and triaminotriazine B generated
from cyanamide apparently precipitated with the nitrtes of
the derivatives and were present in the precipitate brought
further into the condensation with compound XI. In the
second stage of the transformations cyanamide dimer A
was involved as a competeing binucleophile into the cy-
clocondensation with 3-dimethylamino-1-pyridyl-2-pro-
pen-1-one (XI) instead of derivatives III–VII affording
pyrimidine XII. As the source of pyrimidine XIII served
likely the guanidine in situ generated by triaminotriazine
B labile under the reaction conditions since the labile
behavior under these conditions both of pyrimidine XII
and cyanoguanidine A was hardly probable.
Aniline
0.108
–
2-Methylaniline
0.092
–
2-Methyl-5-nitroaniline (I)
0.100 (NH2)
1.231 (NO2)
92
4-Methyl-3-nitroaniline (II)
2-Nitroaniline (III)
0.090 (NH2)
1.234 (NO2)
93
0.117 (NH2)
1.211 (NO2)
Does not
form
2-Methyl-4-nitroaniline (IV)
3-Nitroaniline
0.155 (NH2)
1.213 (NO2)
0.108 (NH2)
1.240 (NO2)
0.166 (NH2)
1.215 (NO2)
Does not
form
90
EXPERIMENTAL
4-Nitroaniline
25
IR spectra were recorded on a Fourier spectropho-
tometers Nicolet Protege-460 and Specord 75IR from
2-Trifluoromethyl-4-nitroaniline 0.050 (NH2)
(V) 1.214 (NO2)
2-Methyl-5-(4-carboxybenzyl- 0.084 (NH2)
amino)aniline (VI) 0.151 ( NH)
4-Methyl-3-(4-carboxybenzyl- 0.088 (NH2)
Does not
form
1
pellets with KBr in the range 400–4000 cm–1. H and
Does not
form
13C NMR spectra were registered on a spectrometer
BrukerAvance-500 at operating frequencies 500 (1H) and
125 MHz (13C), internal reference TMS. Chromatograph-
ic analysis and recording of mass spectra were performed
on instruments Hewlett Packard 6850/5973 and Thermo
Scientific Trace GC Ultra/DSQ II in the electron impact
mode at the energy 70 eV. The reaction progress was
monitored by TLC on Merk DC-Plasticfolien Kieselgel
60 F254 plates, eluent chloroform– methanol, 95 : 5.
67
amino)aniline (VII)
0.153 (NH)
2-Methyl-4-(4-
carboxybenzylamino)-aniline
0.020 (NH2)
0.091 (NH)
–
a The data were obtained by the extended semiempirical Hueckel
method by the calculation program ChemOffice (Chem.3D.Ultra
9.0) using the standard set of initial parameters.
Scheme 2.
H2N
N
NH2
H
H
CN
N
N
N
H
H
CN
NH2
B
N
NH2
N
C
NH
+
_
H2N
N HX
NH2CN + HX
NH
_
XI, OH
A
C
N
N
N
HN
CN
XII
HX = HNO3, HCl.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011

FORMATION OF PYRIMIDIN-2-YLCYANAMIDE
1225
Arylguanidines VIII–X. General procedure [4,
5, 7]. To a solution of 0.01 mol of nitroaniline I, II, VII
in 15 ml of anhydrous ethanol at cooling to 0°C was
added dropwise 0.45 ml (0.01 mol) of 65% nitric acid;
yellow dispersion formed. At the end of self-heating
1 ml (0.012 mol) of 50% water solution of cyanamide
was added, and the reaction mixture was boiled for 12 h.
Then again 1 ml (0.012 mol) of 50% water solution of
cyanamide and 0.45 ml (0.01 mol) of 65% nitric acid were
added (pH of the reaction mixture ~3), and the heating
was continued for 6–18 h. The separated precipitate of the
guanidine nitrate was filtered off, washed with the mixture
ethanol–ethyl ether, 1 : 1, and recrystallized from ethanol.
slightly colored crystals, mp 280–282°C. IR spectrum, ν,
cm–1: 3400, 3160, 2950, 1680, 1630, 1580, 1520, 1350.
Mass spectrum, m/z (Irel, %): [M]+ 179.98 (100), [M –
NH2CNH]+ 137.97, 107.96 (34), 91.96 (21), [NH2CNH]+
42.95 (39). Found, %: N 25.44. C7H9ClN4O2. Calculated,
%: N 25.87.
Reaction of derivatives III–VII with cyanamide
and 3-dimethylamino-1-(pyridin-3-yl)-2-propenone
(XI). From the reaction mixture obtained by the above
procedure from anilines III–VII with cyanamide in the
presence of nitric acid the precipitate was filtered off and
added to the solution of 1 equiv of 3-dimethylamino-1-
(3-pyridyl)-2-propen-1-one (XI) in 2-propanol. Into the
mixture a hot solution of 1.2 equiv of NaOH in 2-propanol
was added, and the mixture was boiled for 18–24 h. The
precipitate was filtered off, washed with 2-propanol and
ethyl ether (3 × 50 ml).
N1-Amino(imino)methyl-2-methyl-5-nitroaniline
nitrate (VIII). Yield 92%, slightly colored crystals,
mp 220–224°C (mp 219–226°C from 2-propanol [6]).
IR spectrum, ν, cm–1: 3490, 3360, 3150, 1680, 1580,
1
1515, 1475, 1310. H NMR spectrum (DMSO-d6), δ,
From compounds IV–VI N-[4-(pyridin-3-yl)pyrim-
idin-2-yl]cyanamide (XII) was obtained. Yield 75%,
ppm: 1.30 s (3H, CH3), 3.34 s (1H, NH), 6.57 br.s (3H,
3
NH2, NH), 6.78 d (1H, Harom, J 8.5 Hz), 7.24 d (1H,
slightly colored crystals, mp 232–234°C. IR spectrum,
H
arom, 4J 2.5 Hz), 7.30 d.d (1H, Harom, 3J 8.5, 4J 2.5 Hz).
1
ν, cm–1
: 3380 (NH), 2160 (C≡N), 1445, 1567. H NMR
13C NMR spectrum, δ, ppm: 17.40, 122.30, 122.57,
132.00, 134.30, 143.50, 146.16, 155.87. Mass spectrum,
m/z (Irel, %): [M]+ 194 (100), [M – Me]+ 179 (78), [M –
NO2]+ 147 (43), [M + 1]+ 195 (10), 106, 94, 77. Found,
%: N 27.54. C8H11N5O5. Calculated, %: N 27.24.
spectrum (D2O), δ, ppm: 7.09 d (1H, Harom, 4J 5.3 Hz),
7.47 d.d (1H, Harom, 3J 7.9, 4J 5.0 Hz), 8.25 t (1H, Harom
4J 1.8 Hz), 8.26 d (1H, Harom, 3J 5.3 Hz), 8.53 d.d (1H,
arom, 3J 4.9, 4J 1.5 Hz), 8.93 d (1H, Harom, 4J 1.7 Hz).
,
H
13C NMR spectrum (D2O), δ, ppm: 108.30, 124.35,
125.68, 132.64, 135.96, 147.32, 150.37, 159.32, 163.39,
167.52. Mass spectrum: [M]+ 197. Found, %: N 36.01.
C10H7N5. Calculated, %: N 35.51. M 197.20.
N1-Amino(imino)methyl-4-methyl-3-nitroaniline
nitrate (IX). Yield 91%, slightly colored crystals,
mp 218°C. IR spectrum, ν, cm–1: 3380, 1690–1580,
1
1550, 1345. H NMR spectrum (CDCl3), δ, ppm: 2.50 s
From compound III 4-(pyridin-3-yl)-pyrimidin-2-
ylamine (XIII) was obtained. Yield 70%, slightly colored
crystals, mp 180–182°C. IR spectrum, ν, cm–1: 3540, 3380
(3H, Me), 5.07 br.s (4H, NH, NH2), 7.03 d.d (1H, Harom
,
3J 8.2, 4J 2.2 Hz), 7.19 d (1H, Harom, 3J 8.2 Hz), 7.39 d
(1H, Harom, 4J 2.2 Hz). 13C NMR spectrum, δ, ppm: 19.09,
117.95, 123.03, 128.07, 132.25, 149.07, 149.83, 153.15.
Mass spectrum, m/z (Irel, %): [M]+ 194 (100), [M – Me]
1
(NH). H NMR spectrum (CDCl3), δ, ppm: 5.22 br.s (2H,
NH2), 7.07 d (1H, Harom, 3J 5.4 Hz), 7.41 d.d (1H, Harom
,
3J 7.8, 4J 4.8 Hz), 8.31 d ( 1H, Harom, 3J 7.8 Hz), 8.40 d
+
179 (67), [M – NO2] + 147 (33). Found, %: N 27.64.
3
4
(1H, Harom, J 5.4 Hz), 8.71 d (1H, Harom, J 4.7 Hz),
9.20 s (1H, Harom). 13C NMR spectrum, δ, ppm: 107.61,
123.56, 132.76, 134.41, 148.49, 151.38, 159.20, 162.94,
163.31. Mass spectrum: [M]+ 173.
C8H11N5O5. Calculated, %: N 27.24.
N1-Amino(imino)methyl-4-methyl-3-(4-carboxy-
benzylamino)aniline nitrate (X). Yield 67%, red-violet
light crystals, mp 136–138°C. IR spectrum, ν, cm–1: 3480,
3360, 3150, 1680, 1580, 1475, 1310.Mass spectrum, m/z
(Irel, %): [C6H5CO2]+ 121 (100), [M]+ 298 (90), 135 (60),
107 (25), 89 (25), 77. Found, %: N 18.90. C16H19N5O5.
Calculated, %: N 19.38.
N1-Amino(imino)methyl-4-nitroaniline hydro-
chloride was similarly prepared from 4-nitroaniline us-
ing hydrochloric acid instead of nitric acid. Yield 25%,
By GC-MS analysis of the reaction mixture cyanogua-
nidine A [mass spectrum, m/z (Irel, %): [M]+ 84 (100), 68
(54), 43 (100), C2H4N4] and 2,4,6-triamino-1,3,5-triazine
B [mass spectrum, m/z (Irel, %): [M]+ 126, 85 (20), 68
(12), 43 (50), C3H6N6] were detected.
Comound XIII was also obtained by reduction of
compound XII with hydrazine hydrate in the presence
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011

KOROLEVA et al.
1226
of Raney nickel by procedure [6]. Into a solution of
0.01 mol of pyrimidine XII in 30 ml of methanol con-
taining 0.006 mol of Raney nickel was added dropwise
at stirring 0.04 mol of 80% solution of hydrazine hydrate
in 1 ml of methanol. The reaction mixture was stirred for
15 min at 50–60°C and 1 h at room temperature, filtered
through a celite bed, the filtrate was evaporated, the
reaction product was recrystallized. Yield 68%, physico-
chemical characteristics were identical to the properties
of above described compound XIII, and of that obtained
by the condensation of propenone XI with guanidine
hydrochloride.
Physicochemical parameters of compound XIV were
published in [7].
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To a solution of 5.3 g (0.03 mol) of compound XI
in 2-propanol was added 2.8 g (0.03 mol) of guanidine
hydrochloride, then a hot solution of 1.4 g (0.035 mol)
of NaOH in 2-propanol. The reaction mixture was boiled
for 12 h, the precipitate was filtered off, washed with
2-propanol (3 × 50) ml, and purified by precipitation with
hexane from the solution in dichloromethane. Yield 3.8 g
(75%), slightly colored crystals, mp 180–182°C.
,
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Kovalev, V.V., Izv. Belarussian Akad. Nauk, Ser. Khim.
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 8 2011