Efficient synthesis of pyrimidinecarbonitriles and their derivatives

Article abstract of DOI:10.3987/COM-07-11014

New approach to pyrimidinecarbonitriles was developed. Pyrimidine-4- and 6-carbonitriles were prepared by palladium-catalyzed cross-coupling reaction of iodopyrimidines with Zn(CN)₂ in very good yields. The cyano group was converted into the co

Full text of DOI:10.3987/COM-07-11014

HETEROCYCLES, Vol. 71, No. 5, 2007
1107
HETEROCYCLES, Vol. 71, No. 5, 2007, pp. 1107 - 1115. © The Japan Institute of Heterocyclic Chemistry
Received, 29th January, 2007, Accepted, 23rd March, 2007, Published online, 27th March, 2007. COM-07-11014
EFFICIENT SYNTHESIS OF PYRIMIDINECARBONITRILES AND
THEIR DERIVATIVES
Petra Doláková, Milena Masojídková, and Antonín Holý*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the
Czech Republic, 16610 Praha 6, Czech Republic, e-mail address:
dolakova@uochb.cas.cz
Abstract – New approach to pyrimidinecarbonitriles was developed.
Pyrimidine-4- and 6-carbonitriles were prepared by palladium-catalyzed
2
cross-coupling reaction of iodopyrimidines with Zn(CN) in very good yields. The
cyano group was converted into the corresponding acyl groups by the treatment
with Grignard reagents and transformed to amido and imido function as well.
INTRODUCTION
Pyrimidine derivatives bearing carbon substituents may lead to the potential biologically active nucleoside
1
2
3
4
analogues e.g. cytostatics, antivirals, adenosine receptor antagonists, cyclin dependent kinase inhibitors,
5
6
antibacterial agents or adenosine kinase inhibitors.
Pyrimidinecarbonitriles are versatile intermediates for the synthesis of many C-substituted pyrimidine
derivatives. Preparative methods of the pyrimidinecarbonitriles reported in the literature are nucleophilic
7
substitution of halopyrimidine derivatives with cyanide ion or reaction of pyrimidine N-oxides with
8
cyanide ion in the presence of acylating reagent (Reissert-Henze reaction). The first described method
involves cyanation of chloropyrimidines using NaCN in DMSO and affords pyrimidinecarbonitriles in the
yields about 30%. Pyrimidine N-oxides react with trimethylsilyl cyanide in the presence of base in
moderate to good yields depending upon the substitution of the pyrimidine ring to afford pyrimidine-2- and
6
-carbonitriles. 2-Amino-4-methylpyrimidine-6-carbonitrile and 2-aminopyrimidine-4,6-dicarbonitrile
were prepared by nitrosation of 2-amino-4,6-dimethylpyrimidine followed by dehydratation of iminoxy
9
3
derivative by POCl in the yields about 25%.
It is known from literature that the cross–coupling reaction of aryl halides with KCN in the presence of a
10
palladium complex was effective for preparation of aryl cyanides. Cross-coupling reaction employing
1
1
12
KCN and Pd(PPh
3 2 2 2 3 4
) Cl in DMF or Zn(CN) and Pd(PPh ) in NMP was also described for preparation
of purinecarbonitriles.

1108
HETEROCYCLES, Vol. 71, No. 5, 2007
RESULTS AND DISCUSSION
In this paper, we report on the synthesis of 2-aminopyrimidine-4,6-dicarbonitrile (2) and
,4-diaminopyrimidine-6-carbonitrile (4) by means of the palladium catalyzed cross-coupling reaction of
2
iodopyrimidines with Zn(CN)
2
. We were interested in introduction of cyano function onto the pyrimidine
1
ring to obtain analogues of alkynylpyrimidine derivatives that possess cytostatic activity. The
dichloropyrimidine 1a was unreactive towards copper(I) cyanide in DMF at 150 °C while reaction of
2 3 4
dichloropyrimidine 1a with Zn(CN) in NMP catalyzed by Pd(PPh ) gave desired dicarbonitrile 2 in a low
yield. This problem was solved by conversion of dichloropyrimidine 1a to 2-amino-4,6-diiodopyrimidine
1
,6
(
1b) by procedure using hydroiodic acid (57%) and sodium iodide. The diiodopyrimidine 1b reacted
smoothly with Zn(CN) in NMP under catalysis by Pd(PPh ) . NMP is a solvent of choice since the reaction
2
3 4
in DMF affords product 2 in a low yield. Reactions catalyzed by PdCl
Also 2,4-diaminopyrimidine-6-carbonitrile (4) was prepared from 2,4-diamino-6-iodopyrimidine (3b) by
the same procedure as dicarbonitrile in 84% yield. Commercially available
,4-diamino-6-chloropyrimidine (3a) was converted to iodo derivative 3b by treatment with 57%
2 3 2
(PPh ) failed (Scheme 1, Table 1).
2
2
hydroiodic acid and NaI.
Table 1: Synthesis of 2-aminopyrimidine-4,6-dicarbonitrile 2
Compd
1a
X
Conditions
Yield of 2 (%)
X
N
CN
Cl
Cl
Cl
I
CuCN, DMF
n.r.
7
1
a
a
Zn(CN) , Pd(PPh ) , NMP
2 3 4
N
NH2
1
KCN, PdCl (PPh ) , DMF
n.r.
88
2
3 4
NH2
N
X
N
2
CN
1b
Zn(CN) , Pd(PPh ) , NMP
2 3 4
1b
1b
1b
I
Zn(CN) , Pd(PPh ) , DMF
26
2
3 4
1
a, 1b
I
Zn(CN) , PdCl (PPh ) , DMF
n.r.
n.r.
2
2
3 4
I
KCN, PdCl (PPh ) , DMF
2 3 4
NH2
NH2
Zn(CN) , Pd(PPh )
2
3 4
N
N
3
a, X = Cl
NMP
3b, X = I
H N
N
X
H N
2
N
4
CN
2
3
a, 3b
Scheme 1
We also tried to prepare pyrimidinecarbonitrile derivatives by treatment of halopyrimidine with
tetraethylammonium cyanide (TEACN) in the presence of base. This method was reported for the synthesis
13
of purine-6-carbonitrile derivatives. The amino group was protected by benzoylation. Reaction of
3
,14
2
-amino-4,6-dichloropyrimidine (1a) with benzoyl chloride gave protected pyrimidine in a low yield
15
and that’s why we used benzoyl cyanide in the presence of triethylamine. Because of the poor solubility of

HETEROCYCLES, Vol. 71, No. 5, 2007
1109
starting material the best yields were obtained using DMF as a solvent. Reaction of protected pyrimidine 5
with TEACN in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) afforded desired carbonitrile 6 in
a low yield (8%). This can be explained by formation of a stable quaternary ammonium salt of DABCO
with pyrimidine. This ammonium salt does not further react with TEACN (Scheme 2).
Cl
Cl
CN
BzCN, Et N
Et NCN, DABCO
4
3
N
N
N
DMF
MeCN
H N
N
Cl
BzHN
N
5
Cl
BzHN
N
6
CN
2
1
a
Scheme 2
We have further investigated the conversion of the cyano group into the acyl group by treatment with
1
1,16
Grignard reagent e.g. phenylmagnesium chloride or methylmagnesium iodide.
Treatment of 2 with
methylmagnesium iodide and phenylmagnesium chloride in THF at room temperature gave corresponding
carbonyl derivatives 7a and 7b by the addition of the Grignard reagents to the CN triple bond, selectively.
Reactions with allylmagnesium bromide or benzylmagnesium chloride afforded complex mixtures of
products. Although the reaction of 4 with phenylmagnesium chloride afforded desired product 8b in 32%
yield, the reaction of 4 with methylmagnesium iodide afforded inseparable mixture of the starting material
with product 8a (1:3) (Scheme 3).
CN
COR
N
RMgX
N
N
7
a, R = Me
b, R = Ph
7
H N
N
2
CN
H N
2
COR
COR
2
7a, 7b
NH2
NH2
RMgX
N
N
8
a, R = Me
b, R = Ph
8
H N
2
N
4
CN
H N
N
2
8a, 8b
Scheme 3
17
3
Pyrimidinecarbonitriles 2 and 4 were also treated with hydrogen peroxide in an aqueous Na
2
CO
to afford
corresponding carboxamide derivatives 9a and 10a in good yields. On treatment with a catalytic amount of
sodium methoxide in methanol compounds 2 and 4 formed imidate intermediates that were without

1110
HETEROCYCLES, Vol. 71, No. 5, 2007
isolation treated with ammonium chloride to afford amidines 9b and 10b which were isolated by
preparative HPLC using gradient of TEAB (Scheme 4).
Y
N
NH2
CN
H O Na CO or NH Cl
2
2,
2
3
4
N
9
a, Y = O
9
b, Y = NH
Y
H N
2
N
2
CN
H N
2
N
NH2
9a, 9b
NH2
NH2
H O Na CO or NH Cl
2
2,
2
3
4
N
N
1
0a, Y = O
1
0b, Y = NH
Y
H N
N
4
CN
H N
N
2
2
NH2
10a, 10b
Scheme 4
Our attempts to reduce cyano function to formyl or aminomethyl group failed. The hydrogenation of the
1
8
compound 2 in methanol over palladium on charcoal in acidic conditions
afforded
1
9
2
-aminopyrimidine-4-carbonitrile (11) in a yield of 23%. The reduction using DIBAL in THF did not
proceed at all and the starting material was recovered.
Compounds 2, 4 and 7a, 7b, 8b, 9a, 9b, 10a, 10b and 11 were tested for their cytostatic and/or antiviral
activity. None of these compounds exhibited any significant cytostatic or cytotoxic activity.
In conclusion, we developed an efficient synthesis of pyrimidine carbonitriles by Pd mediated
2
cross-coupling reaction with Zn(CN) . 2-Aminopyrimidine-4,6-dicarbonitrile and 2,4-diamino-
pyrimidine-6-carbonitrile were further transformed to acyl, amide and amidine derivatives. None of these
compounds possess significant cytostatic and/or antiviral activity.
ACKNOWLEDGEMENTS
This work is a part of the research project Z4 055 0506. It was supported by the "Centre for New
Antivirals and Antineoplastics" (1M0508), by the Programme of Targeted Projects of Academy of Sciences
of the Czech Republic (1QS400550501) and by Gilead Sciences, Inc. (Foster City, CA, U. S. A.). In vitro
antiviral effects were examined at the Rega Institute for Medical Research (Prof. E. De Clercq, Head),
Catholic University Leuven (Belgium); in vitro cytostatic activity was tested by Dr. I. Votruba (this
Institute). The authors’ thanks are also due to the staff of the mass spectrometry and analytical departments
of the Institute of Organic Chemistry and Biochemistry.

HETEROCYCLES, Vol. 71, No. 5, 2007
1111
EXPERIMENTAL
Unless otherwise stated, solvents were evaporated at 40 °C/2 kPa and compounds were dried overnight at 2
kPa over P . Melting points were determined on a Büchi Melting Point B-545 aparatus and are
uncorrected. TLC was performed on plates of Kieselgel 60 F254 (Merck). NMR spectra were measured on
2
O
5
1
13
an FT NMR spectrometer Varian UNITY 500 ( H at 500 MHz and C at 125.7 MHz) in dimethyl
sulfoxide-d . Chemical shifts (δ ppm) and coupling constants (J, Hz) were obtained by the first-order
6
analysis of the spectra. Mass spectra were measured on a ZAB-EQ (VG Analytical) spectrometer using
FAB (ionization by Xe, accelerating voltage 8 kV, glycerol matrix).
Preparative HPLC purification was performed on a column packed with 10 µm C18 reversed phase (Luna),
2
50 x 21 mm; in ca 300 mg portions of mixtures using linear gradient H O – MeOH (20 – 100% of MeOH
2
in 60 min) or in 0.1 M triethylammonium hydrogen carbonate (TEAB) in water and in 50% MeOH (linear
gradient of TEAB in 50% MeOH, 0 – 100%).
2
-Amino-4,6-diiodopyrimidine (1b): 2-Amino-4,6-dichloropyrimidine (3 g, 18 mmol), NaI (13.5 g, 89
mmol) and 57% HI (17 mL) in acetone (90 mL) was stirred overnight at rt. The precipitate was filtered,
washed with ice cold water and acetone, yield 4.65 g (73%), mp 222 – 224 °C (decomp). MS (FAB) m/z:
+
1
13
3
47.8 [MH ] (100). H NMR (DMSO-d
6 2 6
): 7.45 (s, 1H, H-5); 7.35 (br s, 2H, NH ). C NMR (DMSO-d ):
1
61.62 (C-2); 130.71 (2C, C-4 and C-6); 128.52 (C-5).
General procedure for cross-coupling of dihalopyrimidines (1a or 1b) with Zn(CN)
dihalopyrimidine (1mmol), Zn(CN) (1.2 mmol) and the catalyst (see Table 1) (0.1 mmol) in NMP or DMF
6 mL) was heated at 100 °C under Ar atmosphere for 4 - 16 h. The reaction mixture was cooled and 2M aq.
ammonia was added. The mixture was extracted with EtOAc (3 x 50 mL), the combined organic extracts
were washed with brine (1 x 50 mL), dried with MgSO and evaporated. The crude product was purified by
flash chromatography in a gradient of MeOH (0 – 5%) in CHCl and crystallized from water.
-Amino-4,6-dicarbonitrile (2): White crystalline product, yield 88%, mp 201 °C (decomp). MS (EI) m/z:
2
: A mixture of a
2
(
4
3
2
1
7
1
2
2
+
1
45.2 [M ] (100). HRMS (EI): found 145.0386, calculated for C H N : 145.0388. H NMR (DMSO-d ):
6
3
5
6
1
3
.94 (br s, 2H, NH ); 7.72 (s, 1H, H-5). C NMR (DMSO-d ): 163.50 (C-2); 143.55 (2C, C-4 and C-6);
2
6
15.38 (2C, CN); 115.27 (C-5). Anal. Calcd for C
6
H
3
N
5
: C, 49.66; H, 2.08; N, 48.26. Found.: C, 49.41; H,
.04; N, 48.11.
,4-Diamino-6-iodopyrimidine (3b): To the suspension of 2,4-diamino-6-chloropyrimidine (5 g, 35
mmol) and NaI (15 g, 99 mmol) in 57% HI (50 mL) acetone (20 mL) was added and the resulting mixture
was heated at 50 °C for 30 min and then stirred at rt overnight. The precipitate was collected by suction,
taken to ethyl acetate and washed with aqueous NaHCO
3
and brine and dried with MgSO
4
. The crude
+
product was used without further purification, yield 6.7 g (82%), mp 188 °C. MS (EI) m/z: 236 [M ] (76).

1112
HETEROCYCLES, Vol. 71, No. 5, 2007
1
13
H NMR (DMSO-d
6
): 6.42 (br s, 2H) and 6.25 (br s, 2H, NH
63.54 (C-4); 162.08 (C-2); 128.20 (C-6); 104.09 (C-5).
,4-Diaminopyrimidine-6-carbonitrile (4): A mixture of 2,4-diamino-6-iodopyrimidine 3b (1 g, 4.2
(300 mg, 2.5 mmol) and Pd(PPh (529 mg, 0.42 mmol) in NMP (20 mL) was heated at
00°C under Ar atmosphere for 2 h. The reaction mixture was cooled and 2M aq. ammonia was added. The
mixture was extracted with EtOAc (3 x 100 mL), the combined organic extracts were washed with brine (1
x 100 mL), dried with MgSO and evaporated. The crude product was purified by flash chromatography in
a gradient of MeOH (0 – 10%) in CHCl , crystallization from EtOH afforded 2,4-
diaminopyrimidine-6-carbonitrile 4 as white crystals (0.48g, 84%), mp 244 °C (decomp). MS (EI) m/z:
2 6
); 6.13 (s, 1H, H-5). C NMR (DMSO-d ):
1
2
mmol), Zn(CN)
2
3 4
)
1
4
3
+
1
13
1
35 [M ] (100). H NMR (DMSO-d
DMSO-d ): 164.36 (C-4); 163.80 (C-2); 138.93 (C-6); 117.42 (CN); 99.95 (C-5). Anal. Calcd for C
C, 44.44; H, 3.73; N, 51.83. Found: C, 44.23; H, 3.53; N, 51.88.
N-(4,6-Dichloropyrimidin-2-yl)benzamide (5): 2-Amino-4,6-dichloropyrimidine 1a (4 g, 24.4 mmol),
benzoyl cyanide (3.6 mL, 30 mmol) and Et N (1 mL) in DMF (60 mL) was stirred under Ar atmosphere for
2 h. The reaction mixture was evaporated in vacuo and crystallization from EtOAc – light petroleum
6 2
): 6.91 (br s, 2H) and 6.46 (br s, 2H, NH ); 6.13 (s, 1H, H-5). C NMR
(
6
5 5 5
H N :
3
7
+
mixture afforded white crystalline product (4.7 g, 72%), mp 186 °C. MS (FAB) m/z: 268 [MH ] (100).
1
HRMS (FAB): found 268.0035, calculated for C11
H
8
N
3
OCl
2
: 268.0044. H NMR (DMSO-d
6
): 11.56 (br s,
): 165.51
C=O); 161.50 (2C, C-4 and C-6); 157.94 (C-2); 133.61, 128.78 (2C), 128.43 (2C) and 127.94 (arom.);
16.32 (C-5).
N-(4,6-Dicyanopyrimidin-2-yl)benzamide (6): To stirred solution of the protected dichloropyrimidine 5
1.08 g, 4 mmol) and TEACN (2.48 g, 16 mmol) in dry acetonitrile (80 mL) at -20°C DABCO (1.8 g, 16
13
1
H, NH); 7.96 (d, 2H), 7.62 (t, 1H) and 7.52 (t, 2H, arom.); 7.69 (s, 1H, H-5). C NMR (DMSO-d
6
(
1
(
mmol) was added and the resulting solution was allowed to stand overnight at rt. The solvent was
evaporated (the reaction mixture turned dark brown during evaporation) and the residue was purified by
column chromatography in CHCl
3
, the crude product was crystallized from EtOAc – light petroleum
mixture to give protected 4,6-dicyanopyrimidine 6 (83 mg, 8%) as yellow crystals, mp 174 °C (decomp).
+
1
MS (EI) m/z: 249 [M ] (79). H NMR (DMSO-d
6
): 11.88 (br s, 1H, NH); 8.5 (s, 1H, H-5); 7.98 (m, 1H)
): 165.66 (C=O); 159.08 (C-2); 158.33 (C-4); 143.60 (C-6);
33.41, 133.08 and 128.75 (arom.); 123.12 (C-5); 115.10 (CN).
General procedure for reaction with Grignard reagents: To the solution of pyrimidinedicarbonitrile 2
1 mmol) or pyrimidinecarbonitrile 4 (1 mmol) in dry THF (10 mL) was added dropwise solution of
phenylmagnesium chloride (2M solution in THF, 4 mmol) or methylmagnesium iodide (solution in Et O,
mmol), the reaction mixture was stirred under Ar atmosphere at rt overnight; 15 mL of water and 15 mL
of 3M HCl was added and the reaction mixture was extracted with ethyl acetate (3 x 50 mL), combined
1
3
and 7.61 (m, 4H, arom.). C NMR (DMSO-d
6
1
(
2
4

HETEROCYCLES, Vol. 71, No. 5, 2007
1113
organic extracts were washed with brine (2 x 50 mL) and dried with MgSO
4
. The crude product was
purified by flash chromatography in a gradient of MeOH in CHCl
3
.
1
,1'-(2-Aminopyrimidine-4,6-diyl)diethanone (7a): Crystallized from water, yellow crystals, yield 17%,
+
1
mp 146 °C. MS (EI) m/z: 179.1 [M ] (100). H NMR (DMSO-d
6
): 7.36 (br s, 1H) and 7.27 (br s, 1H, NH
): 199.49 (2C, C=O); 164.46 (C-2); 162.26, (2C, C-4 and C-6);
). Anal. Calcd for C : C, 53.63; H, 5.06; N, 23.45; O, 17.86. Found:
2
);
1
3
2.55 (s, 6H, CH
3 6
). C NMR (DMSO-d
1
00.82 (C-5); 25.67 (2C, CH
3
6 7 5 2
H N O
C, 53.44; H, 5.26; N, 23.59.
2-Aminopyrimidine-4,6-diyl)bis(phenylmethanone) (7b): Crystallized from EtOH, white crystals,
(
+
1
yield 43%, mp 185 °C. MS (FAB) m/z: 304.2 [MH ] (100). H NMR (DMSO-d
6
): 7.39 (br s, 2H, NH
2
);
1
3
7
.22 (s, 1H, H-5); 8.00 (d, 4H), 7.72 (t, 2H), 7.58 (t, 4H) (arom). C NMR (DMSO-d ): 193.00 (2C,
6
C=O); 164.80 (2C, C-4 and C-6); 162.64 (C-2); 134.91 (2C), 134.12 (2C), 130.66 (4C) and 128.80 (4C,
arom); 106.08 (C-5). Anal. Calcd for C18 : C, 71.28; H, 4.32; N, 13.85; O, 10.55. Found: C,
13 3 2
H N O
7
1.16; H, 4.35; N, 13.59.
1-(2,4-Diaminopyrimidin-6-yl)ethanone (8a): To the reaction mixture was added additional
methylmagnesuim iodide (4 mmol) and the reaction mixture was heated at 45 °C for 8 h. Purified by
preparative HPLC using linear gradient of MeOH, isolated as an inseparable mixture of product with
+
1
6
starting material (3:1, 105 mg). MS (FAB) m/z: 153.1 [MH ] (100). H NMR (DMSO-d ): 6.75 and 6.28
2 3
(2 x br s, 2 x 2H, NH ); 6.23 (s, 1H, H-5); 2.43 (s, 1H, CH ).
(
2
2,4-Diaminopyrimidin-6-yl)(phenyl)methanone (8b): Crystallized from EtOH – Et O mixture, yellow
+
crystals, yield 32%, mp 177 °C (decomp). MS (FAB) m/z: 215 [MH ] (100). HRMS (FAB): found 215.0927,
1
calculated for C11
H
10
N
4
O: 215.0932. H NMR (DMSO-d
6
): 7.93 (d, 2H), 7.64 (7, 1H) and 7.52 (t, 2H,
13
arom); 6.65 (br s, 2H) and 6.19 (br s, 2H, NH
2
); 6.06 (s, 1H, H-5). C NMR (DMSO-d
6
): 194.43 (C=O);
1
2
1
65.18 (C-4); 163.21 (C-2); 161.75 (C-6); 135.92, 133.40, 130.35 (2C) and 128.53 (2C, arom); 94.28 (C-5).
-Aminopyrimidine-4,6-dicarboxamide (9a): Acetone (5 mL) was added to a mixture of 2 (200 mg,
.38 mmol) in 10% aqueous Na CO until uniform solution was obtained, 10% H O (5 mL) was added
2
3
2
2
dropwise and the resulting mixture was allowed to stir at rt for 6 h. The reaction mixture was evaporated
in vacuo, the crude product was crystallized from H O – EtOH mixture to give white crystalline product
2
+
1
(
191 mg, 77%), mp 320 °C (decomp). MS (EI) m/z: 181.1 [M ] (100). H NMR (DMSO-d
6
): 7.84 (br
): 165.23 (2C,
: C, 39.78; H,
1
3
2 6
s, 2H), 7.80 (br s, 2H), 7.05 (br s, 2H) (NH ); 7.53 (s, 1H, H-5). C NMR (DMSO-d
C=O); 163.07 (C-2); 160.74 (2C, C-4 and C-6); 103.66 (C-5). Anal. Calcd for C
6
H
7
N
5
O
2
3
.89; N, 38.66; O, 17.66. Found: C, 39.61; H, 3.78; N, 38.56.
-Aminopyrimidine-4,6-dicarboxamidine (9b): To the solution of 2 (200 mg, 1.38 mmol) in MeOH
2
(160 mL) was added 1M solution of MeONa in MeOH (0.276 mL, 0.276 mmol) and the resulting mixture
was stirred for 2 days at rt. Then NH Cl (300 mg, 5.52 mmol) was added and the reaction mixture was
4

1114
HETEROCYCLES, Vol. 71, No. 5, 2007
refluxed for 3h and evaporated in vacuo. The crude product was purified by preparative HPLC using
+
gradient of TEAB. Yellowish powder (55 mg, 22%), mp 305 – 308 °C (decomp). MS (EI) m/z: 179 [M ]
1
(
15). HRMS (EI): found 179.0911, calculated for C
6
H
9
N
7
: 179.0919. H NMR (DMSO-d
6
): 7.86 (br s,
):
1
3
2
1
2
H), 7.80 (br s, 2H), 7.78 (br s, 2H) and 7.05 (br s, 2H, NH); 7.53 (s, 1H, H-5). C NMR (DMSO-d
65.21 (2C, C-4, C-6); 163.05 (C-2); 160.75 (2C, CN); 103.64 (C-5).
,4-Diaminopyrimidine-6-carboxamide (10a): Prepared according the procedure described for
6
compound 9a. Crystallized from water, white crystals (124 mg, 55%), mp 284 °C (decomp). MS (EI)
+
1
m/z: 153.1 [M ] (35). HRMS (EI): found 153.0647, calculated for C
DMSO-d ): 7.54 (br s, 1H), 7.52 (br s, 1H), 6.61 (br s, 2H) and 6.33 (s, 2H, NH
NMR (DMSO-d ): 166.30 (C=O); 165.70 (C-4); 163.19 (C-2); 156.72 (C-6); 93.06 (C-5). Anal. Calcd for
5 7 5
H N O: 153.0650. H NMR
1
3
(
6
2
); 6.33 (s, 1H, H-5). C
6
C
5
H
7
N
5
O: C, 39.21; H, 4.61; N, 45.73; O, 10.45. Found: C, 38.98; H, 4.41; N, 45.74.
,4-Diaminopyrimidine-6-carboxamidine (10b): Prepared according to the procedure described for
compound 9b. Crystallized from hot water, white crystals (130 mg, 58%), mp 210 °C (decomp). MS (ESI)
2
+
1
m/z: 153 [MH ] (100). H NMR (DMSO-d
6
): 8.00 (br s, 5H), 6.93 (br s, 1H) and 6.29 (br s, 1H, NH); 6.315
): 165.20 (C-4); 163.66 and 163.43 (C-2 and C=N); 152.00 (C-6);
: C, 39.47; H, 5.30; N, 55.23. Found: C, 39.41; H, 5.40; N, 55.05.
-Aminopyrimidine-4-carbonitrile (11): 2-Aminopyrimidine-4,6-dicarbonitrile (2, 400 mg, 1.38 mmol)
1
3
(
s, 1H, H-5). C NMR (DMSO-d
6
9
5 8 6
4.55 (C-5). Anal. Calcd for C H N
2
was hydrogenated in MeOH (40 mL) and hydrochloric acid (0.2 mL) over 5% palladium on charcoal (0.16
g) under stirring for 18 h at rt. The mixture was filtered through a pad of Celite and the catalyst was washed
with MeOH. The filtrate was neutralized with methanolic ammonia and evaporated (during evaporation the
reaction mixture turned violet). The crude product was purified by column chromatography on silica gel
3
(elution with 0 – 3% MeOH in CHCl ) to give 98 mg (23%) of 2-aminopyrimidine-4-carbonitrile 11, mp
+
1
2
22 °C (decomp). MS (EI) m/z: 120.0 [M ] (100). H NMR (DMSO-d ): 8.51 (br s, 1H, H-6); 7.07 (br s, 1H,
6
13
H-5); 7.32 (br s, 2H, NH
2
). C NMR (DMSO-d
6
): 163.71 (C-2); 161.19 (C-6); 140.88 (C-4); 116.49 (CN);
1
5 4 4
12.97 (C-5). Anal. Calcd for C H N : C, 50.00; H, 3.36; N, 46.65. Found: C, 49.89; H, 3.28; N, 46.55.
REFERENCES
1
2
. D. Hocková, A. Holý, M. Masojídková, and I. Votruba, Tetrahedron, 2004, 60, 4983.
. D. W. Ludovici, M. J. Kukla, P. G. Groups, S. Krishnan, K. Andries, M. P. de Bethune, H. Azijn, R.
Pauwels, E. De Clercq, E. Arnold, and P. A. J. Janssen, Bioorg. Med. Chem. Lett., 2001, 11, 2225.
. L. C. W. Chang, R. F. Spanjersberg, J. K. von Frijtag Drabbe Künzel, T. Mulder-Krieger, G. van den
Hout, M. W. Beukers, J. Brussee, and A. P. Ijzerman, J. Med. Chem., 2004, 49, 6529.
3
4
. V. Mesguiche, R. J. Parsons, Ch. E. Arris, J. Bentley, F. T. Boyle, M. J. Curtin, T. G. Davies, J. A.
Endicott, A. E. Gibson, B. T. Golding, R. J. Griffin, P. Jewsbury, L. N. Johnson, D. R. Newell, M. E. M.

HETEROCYCLES, Vol. 71, No. 5, 2007
1115
Noble, L. Z. Wang, and I. R. Hardcastle, Bioorg. Med. Chem. Lett., 2003, 13, 217.
5
6
7
8
. A. Ali, S. D. Aster, D. W. Graham, G. F. Patel, G. E. Taylor, R. L. Tolman, R. E. Painter, L. L. Silver,
K. Young, K. Ellsworth, W. Geissler, and G. S. Harris, Bioorg. Med. Chem. Lett., 2001, 11, 2185.
. A. Gomtsyan, S. Didomenico, Ch. Lee, M. A. Matulenko, K. Kim, E. A. Kowaluk, C. T. Wismer, J.
Mikusa, H. Yu, K. Kohlhaas, M. F. Jarvis, and S. S. Bhagwat, J. Med. Chem., 2002, 45, 3639.
. J. C. Martin, J. Heterocycl. Chem., 1980, 17, 1111; L. S. German, S. A. Postovoi, E. M. Kagramanova,
and Yu. Zeifman, Izv. Akad. Nauk Ser. Khim., RU, 1997, 11, 2024.
. T. Sakamoto, H. Yoshizawa, S. Kaneda, and H. Yamanaka, Heterocycles, 1984, 21, 560; H.
Yamanaka, T. Sakamoto, S. Nishimura, and M. Sagi, Chem. Pharm. Bull., 1987, 35, 3119.
. O. P. Shkurko and V. P. Mamaev, Khim. Geterotsikl. Soedin., 1977, 13, 821.
0. A. Sekiya and N. Ishikawa, Chem. Lett., 1975, 4, 277; K. Takagi, T. Okamoto, Y. Sasakibara, A.
Ohno, S. Oka, and N. Hayama, Bull. Chem. Soc. Jpn., 1975, 48, 3298; M. Sundermeier, A. Zapf, and
M. Beller, Angew. Chem. Int. Ed., 2003, 42,1661.
9
1
1
1
1
1. K. Tanji and T. Higashino, Heterocycles, 1990, 30, 435.
2. L. Gundersen, Acta Chem. Scand., 1996, 50, 58.
3. P. Herdewijn, A. Vanaerschot, and W. Pfleiderer, Synthesis, 1989, 12, 961; M. Hocek and A Holý,
Collect. Czech. Chem. Commun., 1995, 60, 1386.
1
4. G. Giovanninetti, L. Garuti, V. Cavrini, P. Roveri, A. Manninipalenzona, P. Sinibaldi, and P. A. Fusco,
Farmaco Ed. Sci., 1980, 35, 879.
1
1
5. A. Holý, Collect. Czech. Chem. Commun., 1973, 38, 3912.
6. G. Manikumar, R. M. Wadkins, D. Bearss, D. D. Von Hoff, M. C. Wani, and M. E. Wall, Bioorg.
Med. Chem. Lett., 2004, 14, 5377; R. I. Fryer, Z. Gu, and Ch. Wang, J. Heterocycl. Chem., 1991, 28,
1
661; W. Zhang, K. F. Koehler, B. Harris, P. Skolnick, and J. M. Cook, J. Med. Chem., 1994, 37, 745.
7. A. Miyashita, S. Sato, N. Taido, K. Tanji, E. Oishi, and T. Higashino, Chem. Pharm. Bull., 1990, 38,
30.
1
1
1
2
8. D. Hocková, A. Holý, M. Masojídková, G. Andrei, R. Snoeck, E. De Clercq, and J. Balzarini, Bioorg.
Med. Chem., 2004, 12, 3197.
9. N. Robert, Ch. Hoarau, S.Célanire, P. Ribéreau, A. Godard, G. Quéguiner, and F. Marsais, Tetrahedron,
2
005, 61, 4569.