Synthesis of structurally related purines: Benzimidazo[1,2-a]pyridines, benzimidazo-[1,2-c]pyrimidines, and pyrazolo-[1,5-a]pyrimidines

Article abstract of DOI:10.1007/s007060050025

Reactions of sodium salts of 3-hydroxymethylene-2-alkanones with 2-cyanomethylbenzimidazole afforded benzimidazo[1,2-a]pyridines. Analogues reactions with 2-aminobenzimidazole and 5-aminopyrazoles afforded benzimidazo[1,2-c]pyrimidines and pyrazolo[1-5-a]pyrimidines.

Full text of DOI:10.1007/s007060050025

Monatshefte fuÈr Chemie 131, 779±785 (2000)
Synthesis of Structurally Related Purines:
Benzimidazo[1,2-a]pyridines, Benzimidazo-
[1,2-c]pyrimidines, and Pyrazolo-
[1,5-a]pyrimidines
Galal H. Elgemeie1;Ã and Nadia H. Metwally2
1
Department of Chemistry, Faculty of Science, Helwan University, Helwan, Cairo, Egypt
2
Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Summary. Reactions of sodium salts of 3-hydroxymethylene-2-alkanones with 2-cyanomethylben-
zimidazole afforded benzimidazo[1,2-a]pyridines. Analogues reactions with 2-aminobenzimidazole
and 5-aminopyrazoles afforded benzimidazo[1,2-c]pyrimidines and pyrazolo[1,5-a]pyrimidines.
Keywords. 3-Hydroxymethylene-2-alkanone salts; Benzimidazole derivatives; 5-Aminopyrazoles;
Benzimidazo pyridines; Pyrazolo pyrimidines.
Introduction
Synthetic analogs of purines are widely used in the medical sciences and in clinical
medicine. Typically, most applications exploit the role of their nucleotides as
components of the nucleic acids essential for cellular growth and division. For a cell
todivide, itsDNA must be replicated, andthereforeallitsprecursors must be available.
Thepharmacologicapproachusesananaloginwhichtheheterocyclicringstructurehas
beenalteredinawaytoinducetoxiceffectswhentheanalogisincorporatedintospeci®c
cellularconstituents.Asapartofourprogramdirectedtothedevelopmentofnewsimple
and ef®cient procedures for the synthesis of antimetabolites [1±3], we have recently
reported different successful approaches for the synthesis of purine, pyrimidine
nucleoside, and 5-deazafolic analogues [4, 5]. Derivatives of these ring system are
interesting because they have useful properties as antimetabolites in biochemical
reactions. We now report a one-step synthesis of interesting purine analogues by
reactionsofsubstitutedmethyldiazolesandaminodiazolederivativeswithsodiumsalts
of 3-hydroxymethylene-2-alkanones.
Results and Discussion
It was found that 2-cyanomethylbenzimidazole (1) reacts with sodium salts of 3-
hydroxymethylene-2-alkanones (2) to yield a 1:1 adduct. Two isomeric structures
Ã
Corresponding author

780
G. H. Elgemeie and N. H. Metwally
Scheme 1
are possible in principle (3 and 4, Scheme 1). The spectroscopic data were of little
help in discriminating between these structures. In order to establish unambigu-
ously the structure of the products, their crystal structure was determined. The X-
ray analysis con®rmed the exclusive presence of 4 in the solid state (Fig. 1). This
implies that the active methylene group of 1 will initially attack the unhindered
formyl group of 2 to yield the substituted imidazo[1,2-a]pyridine-4-carbonitriles 4
rather than attacking the hindered and electronically disfavoured keto group
leading to 3. The X-ray analysis for compound 4b revealed that molecules of type 4
Ê
are planar (mean deviation of non-H atoms from least-squares plane: 0.030 A). The
bond lengths and angles are closely similar to those of a benzimidazo[1,2-
a]pyridine derivative with a further annelated seven-membered ring [6]. In
Fig. 1. Crystal structure of 4b; ellipsoids represent 50% probability levels; H atom radii are arbitrary

Synthesis of Purine Derivatives
781
Scheme 2
particular, wide angles are observed exocyclic to the ®ve-membered ring (e.g. C1-
N1-C9: 132.41(18), C8-C9-N1: 134.2(2)ꢀ).
We became interested to see if these reactions can be extended to aminodiazoles.
Thus,thebehaviourof2-aminobenzimidazole(5)towardssalts2wasalsoinvestigated.
Products resulting from condensation at the active sites of benzimidazole were
obtained. Accordingly, substituted imidazo[1,2-a]pyrimidines 6 were obtained
(Scheme 2). The structure of compounds 6 could be established and con®rmed on the
basis of their elemental analyses and spectroscopic data (IR, 1H NMR, 13C NMR, and
MS; see Experimental).
Similarly, 5-aminopyrazoles (7) reacted with 2 under the same conditions to
yield the pyrazolo[1,5-a]pyrimidines 8. The structure of compounds 8 was
established on the basis of their elemental analyses and spectroscopic data (IR, 1H
NMR, 13C NMR, and MS; see Experimental).
In conclusion, we have developed an excellent route for the synthesis of several
otherwise dif®cult accessible purine analogues by the reaction of sodium salts of 3-
hydroxymethylene-2-alkanones with substituted methylazoyl and aminodiazole
derivatives. The obtained products are promising for biological evaluation studies.
Experimental
Melting points were determined on an electrothermal apparatus and are uncorrected. IR spectra
(KBr): Pye Unicam; 1H NMR and 13C NMR spectra (DMSO-d6): Wilmad 270 MHz, TMS as internal
standard, chemical shift in ꢀ (ppm); mass spectra: Shimadzu GCMS-QP 100 EX (70 eV);
microanalytical data: Microanalytical Data Center at Cairo University.
1,2-Disubstituted Benzo[4,5]imidazo[1,2-a]pyridine-4-carbonitriles (4a±d; general method)
A solution of 2-cyanomethylbenzimidazole (1, 0.01 mol), sodium salt of 3-hydroxymethylene-2-
alkanones 2 (0.01 mol), and 1 cm3 piperidine acetate in 50 cm3 H2O and 30 cm3 EtOH was re¯uxed

782
G. H. Elgemeie and N. H. Metwally
for 10 min. 1.5 cm3 acetic acid were added to the hot solution. The precipitated solid was collected
by ®ltration and crystallized from the appropriate solvent.
1-Methyl-benzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (4a; C13H9N3)
Yield: 1.2 g (60%); m.p.: 210ꢀC (EtOH); IR (KBr): 2229 (CN) cm 1; 1H NMR (270 MHz, ꢀ, DMSO-
d6): 2.32 (s, 3H, CH3), 6.50 (d, 1H, H-5), 7.81±8.10 (m, 4H, C6H4), 8.20 (d, 1H, H-4) ppm; MS:
‡
m/z ˆ 207(M , 72.6%).
1,2-Dimethyl-benzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (4b; C14H11N3)
Yield: 1.1 g (50%); m.p.: 254ꢀC (EtOH/dioxane); IR (KBr): 2229 (CN) cm 1; 1H NMR (270 MHz, ꢀ,
DMSO-d6): 2.40 (s, 3H, CH3), 3.04 (s, 3H, CH3), 7.90±8.42 (m, 4H, C6H4), 8.18 (s, 1H, H-4) ppm;
‡
MS: m/z ˆ 221 (M , 85.3%).
1-Phenyl-benzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (4c; C18H11N3)
1
Yield: 1.7 g (67%); m.p.: > 300ꢀC (AcOH); IR (KBr): 2229 (CN) cm 1; H NMR (270 MHz, ꢀ,
DMSO-d6): 6.51 (d, 1H, H-5), 6.90±8.0 (m, 4H, C6H4), 7.18±7.70 (m, 5H, C6H5), 8.32 (s, 1H, H-4)
‡
ppm; MS: m/z ˆ 269 (M , 78.3%).
1-(4-Methoxyphenyl)-benzo[4,5]imidazo[1,2-a]pyridine-4-carbonitrile (4d; C19H13N3O)
Yield: 2 g (67%); m.p:. >300ꢀC (AcOH); IR (KBr): 2228 (CN) cm 1; 1H NMR (270 MHz, ꢀ, DMSO-
d6): 6.61 (d, 1H, H-5), 6.90±7.80 (m, 4H, C6H4), 7.21±8.20 (m, 4H, C6H4), 8.35 (d, 1H, H-4) ppm;
‡
MS: m/z ˆ 299 (M , 80.0%).
3,4-Disubstituted Benzo[4,5]imidazo[1,2-a]pyrimidines (6a±c; general method)
A solution of 2-aminobenzimidazole (5, 0.01 mol), sodium salt of 3-hydroxymethylene-2-alkanones
2 (0.01 mol), and 1 cm3 piperidine acetate in 50 cm3 H2O and 30 cm3 EtOH was re¯uxed for 10 min.
1.5 cm3 acetic acid were added to the hot solution. The precipitated solid was collected by ®ltration
and crystallized from the appropriate solvent.
4-Methyl-benzo[4,5]imidazo[1,2-a]pyrimidine (6a; C11H9N3)
‡
Yield: 0.8 g (45%); m.p.: 225ꢀC (EtOH); MS: m/z ˆ 183 (M , 82.3%).
3,4-Dimethyl-benzo[4,5]imidazo[1,2-a]pyrimidine (6b: C12H11N3)
Yield: 0.7 g (40%); m.p.: 267ꢀC (EtOH); 1H NMR (270 MHz, ꢀ, DMSO-d6): 2.31 (s, 3H, CH3), 2.49
‡
(s, 3H, CH3), 7.32±7.50 (m, 4H, C6H4), 8.20 (s, 1H, H-4) ppm; MS: m/z ˆ 197 (M , 78.5%).
4-Methyl-3-phenyl-benzo[4,5]imidazo[1,2-a]pyrimidine (6c; C16H11N3)
‡
Yield: 1.4 g (60%); m.p.: 285ꢀC (EtOH); MS: m/z ˆ 245 (M , 84.3%).
6,7-Disubstituted Pyrazolo[1,5-a]pyrimidines (8a±h; general method)
A solution of 5-aminopyrazoles (7, 0.01 mol), sodium salt of 3-hydroxymethylene-2-alkanones 2
(0.01 mol), and 1 cm3 piperidine acetate in 50 cm3 H2O and 30 cm3 EtOH was re¯uxed for 10 min.

Synthesis of Purine Derivatives
783
1.5 cm3 acetic acid were added to the hot solution. The precipitated solid was collected by ®ltration
and cystallized from the appropriate solvent.
7-Methyl-2-phenyl-pyrazolo[1,5-a]pyrimidine (8a; C13H11N3)
Yield: 0.4 g (78%); m.p.: 200ꢀC (EtOH); 1H NMR (270 MHz, ꢀ, DMSO-d6): 2.40 (s, 3H, CH3), 6.92
(d, 1H, H-6), 7.07 (s, 1H, H-3), 7.46±8.04 (m, 5H, C6H5), 8.97 (d, 1H, H-5) ppm; MS: m/z ˆ 209
‡
(M , 76.5%).
7-Methyl-2-(4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (8b; C14H13N3)
Yield: 1.3 g (60%); m.p.: 220ꢀC (EtOH); 1H NMR (270 MHz, ꢀ, DMSO-d6): 2.35 (s, 3H, CH3), 2.45
(s, 3H, CH3), 6.90 (d, 1H, H-6), 7.10 (s, 1H, H-3), 7.50±8.20 (m, 4H, C6H4), 8.95 (d, 1H, H-5) ppm;
‡
MS: m/z ˆ 223 (M , 76.5%).
6,7-Dimethyl-2-phenyl-pyrazolo[1,5-a]pyrimidine (8c; C14H13N3)
Yield: 1.7 g (78%); m.p.: 165ꢀC (EtOH); 1H NMR (270 MHz, ꢀ, DMSO-d6): 2.24 (s, 3H, CH3), 2.46
(s, 3H, CH3), 6.98 (s, 1H, H-3), 7.46±8.0 (m, 5H, C6H5), 8.81 (s, 1H, H-5) ppm; MS: m/z ˆ 223.
6,7-Dimethyl-2-(4-methylphenyl)-pyrazolo[1,5-a]pyrimidine (8d; C15H15N3
1
Yield: 2 g (84%); m.p.: 215ꢀC (AcOH); H NMR (270 MHz, ꢀ, DMSO-d6): 2.24 (s, 3H, CH3), 2.34
(s, 3H, CH3), 2.46 (s, 3H, CH3), 6.92 (s, 1H, H-3), 7.27±7.85 (m, 4H, C6H4), 8.79 (s, 1H, H-5) ppm;
13C NMR (67.5 MHz, ꢀ, DMSO-d6): 15.4 (CH3), 20.8 (CH3), 22.7 (CH3), 91.0 (C-3), 117.4 (C-7),
125.8±132.4 (aromatic carbons), 138.0 (C-6), 147.7 (C-5), 154.0 (C-2) and 159.6 (C-3a) ppm; MS:
‡
m/z ˆ 237 (M , 81.4%).
2,7-Diphenyl-pyrazolo[1,5-a]pyrimidine (8e; C18H13N3)
1
Yield: 2 g (82%); m.p.: 200ꢀC (EtOH); H NMR (270 MHz, ꢀ, DMSO-d6): 6.90 (d, 1H, H-6), 7.12
(s, 1H, H-3), 7.36±8.10 (m, 10H, 2C6H5), 8.92 (d, 1H, H-5) ppm; MS: m/z ˆ 271.
2-(4-Methylphenyl)-7-phenyl-pyrazolo[1,5-a]pyrimidine (8f; C19H15N3)
Yield: 2.1 g (75%); m.p.: 230ꢀC (EtOH); 1H NMR (270 MHz, ꢀ, DMSO-d6): 2.34 (s, 3H, CH3), 6.90
(d, 1H, H-6), 7.06 (d, 1H, H-3), 7.24±8.0 (m, 4H, C6H4), 7.46±7.74 (m, 5H, C6H5), 8.97 (d, 1H, H-5)
‡
ppm; MS: m/z ˆ 285 (M , 78.5%).
2-Phenyl-7-(4-methoxyphenyl)-pyrazolo[1,5-a]pyrimidine (8g; C19H15N3O)
1
Yield: 2.3 g (75%); m.p.: 140ꢀC (EtOH); H NMR (270 MHz, ꢀ, DMSO-d6): 7.19 (d, 1H, H-6),
7.23±8.0 (m, 5H, C6H5), 7.30 (s, 1H, H-3), 7.47±8.38 (m, 4H, C6H4), 8.55 (d, 1H, H-5) ppm; MS:
‡
m/z ˆ 301 (M , 84.2%).
2-(4-Methylphenyl)-7-(4-methoxyphenyl)-pyrazolo[1,5-a]pyrimidine (8h; C20H17N3O)
Yield: 2 g (65%); m.p.: 166ꢀC (EtOH); 1H NMR (270 MHz, ꢀ, DMSO-d6): 2.26 (s, 3H, CH3), 3.80 (s,
3H, OCH3), 7.10 (d, 1H, H-6), 7.20 (s, 1H, H-3), 7.30±8.34 (m, 8H, 2C6H4), 8.53 (d, 1H, H-5) ppm;
MS: m/z ˆ 315.

784
G. H. Elgemeie and N. H. Metwally
Table 1. Fractional atomic coordinates and equivalent isotropic displacement parameters; Ueq
ꢁ1=3† ÆiÆjUijꢂiꢂjaiaj
ˆ
x
y
z
Ueq
N1
0.2307(2)
0.1953(2)
0.2334(3)
0.3030(3)
0.3375(3)
0.2983(2)
0.1294(2)
0.1821(3)
0.1854(3)
0.1233(3)
0.0592(3)
0.0568(3)
0.1195(3)
0.1920(3)
0.4099(3)
0.3195(3)
0.1578(3)
0.4811(2)
0.3651(3)
0.4113(3)
0.5640(3)
0.6783(3)
0.6374(3)
0.2243(2)
0.4030(3)
0.4491(3)
0.3372(3)
0.1819(3)
0.1342(3)
0.2468(3)
0.2956(3)
0.8459(3)
0.7521(3)
0.2015(3)
0.52358(9)
0.46758(11)
0.39549(11)
0.38293(11)
0.44046(12)
0.51024(11)
0.49023(9)
0.58794(11)
0.66176(11)
0.71037(12)
0.68801(12)
0.61540(12)
0.56517(11)
0.33753(12)
0.42232(14)
0.57402(12)
0.29170(12)
0.0266(4)
0.0263(5)
0.0315(5)
0.0324(5)
0.0315(5)
0.0288(5)
0.0296(4)
0.0281(5)
0.0369(6)
0.0432(6)
0.0411(6)
0.0340(5)
0.0287(5)
0.0387(6)
0.0441(6)
0.0387(6)
0.0593(7)
C2
C3
C4
C5
C6
N2
C7
C8
C9
C10
C11
C12
C13
C14
C15
N3
X-Ray analysis
The X-ray structure analysis for 4b was performed at the Institute of Organic Chemistry at
Braunschweig, Germany. H atoms: methyl groups were held rigid, allowed to rotate, however not to
tip; starting positions from difference synthesis, others riding. Data collection: Stoe DIF4 [7]. Cell
re®nement: Stoe DIF4. Data reduction: Stoe REDU4 [8]. Program used to solve structure:
SHELXS86 [9]. Program used to re®ne structure: SHELXL97 [10]. Molecular graphics: Siemens XP
[11]. Software used to prepare material for publication: SHELX-97.
The molecule of 4b (Fig. 1) is planar (mean deviation of non-H atoms from least-squares plane:
Ê
0.030A). Crystal data of 4b: C14H11N3; Mr ˆ 221.26; monoclinic; P21/n; a ˆ 7.469(2), b ˆ 8.106(2),
ꢀ
c ˆ 18.238(4) A; ꢁ ˆ 93.78 (3) ; V ˆ 1101.8 (5) A ; Z ˆ 4; Dx ˆ 1.334 Mg Á m 3; Dm not measured;
Ê
Ê 3
MoKꢂ radiation; ꢃ ˆ 0.71073 A. Cell parameters from 46 re¯ections; ꢄ ˆ 10.0±11.5ꢀ;
Ê
ꢅ ˆ 0.082 mm 1; T ˆ 143(2) K; crystal: 0.80Â0.25Â0.10 mm, pale yellow. Data collection: Stoe
Stadi-4 diffractiometer; w=ꢄ scans; absorption correction: none; 2722 measured re¯ections; 1935
independent re¯ections; 1448 re¯ections with I > 2ꢆ(I) Rint ˆ 0.0284; ꢄmax ˆ 25:03ꢀ; h ˆ 0!8;
k ˆ 9!3; l ˆ 12!21; 3 standard re¯ections; frequency: 60 min 1; intensity decay: none;
re®nement on F2; R(F2 > 2ꢆ(F2)) ˆ 0.0490; wR (F2) ˆ 0.1316; S ˆ 1.043; 1935 re¯ections; 156
parameters; mixed; w ˆ 1/(ꢆ2 (Fo2) ‡(0.0631 P)2 ‡0.2377 P) where P ˆ ꢁFo2 ‡ 2Fo2†=3;
3
ꢀ
ꢀ
ꢁÁ=ꢆ†
< 0:001; Áꢇmax ˆ 0:159 e Á A 3; Áꢇmin
ˆ
0:18 e Á A
;
extinction correction: none
max
scattering factors: see Ref. [12].
References
[1] Elgemeie GH, Attia AM, Farag DI, Sherif SM (1994) J Chem Soc Perkin Trans 1, 1285
[2] Elgemeie GH, El-Ezbawy SE, Ali HA, Mansour AK (1994) Bull Chem Soc Jpn 76: 738
[3] Elgemeie GH, Fathy NM (1995) Tetrahedron 51: 3345
[4] Elgemeie GH, Hussain BA (1994) Tetrahedron 50: 199

Synthesis of Purine Derivatives
785
[5] Elgemeie GH, Attia AM, Hussain BA (1998) Nucleosides and Nucleotides 17: 855
[6] Elgemeie GH, Fathy NM, Hopf H, Dix I, Jones PG (1998) Acta Cryst C 54: 1107
[7] Stoe & Cie (1992a) DIF4, Diffractometer Control Program. Stoe & Cie, Darmstadt, Germany
[8] Stoe & Cie (1992b) REDU4, Data Reduction Program. Stoe & Cie, Darmstadt, Germany
[9] Sheldrick GM (1990) Acta Cryst A 46: 467±473
[10] Sheldrick GM (1997) SHELXL-97. Program for Re®nement of Crystal Structures. University of
È
Gottingen, Germany
[11] Siemens (1994) XP. Molecular Graphics Program, Version 5.03. Siemens Analytical X-ray
Instruments Inc, Madison, Wisconsin, USA
[12] International Tables for Crystallography, vol C
Received December 12, 1999. Accepted (revised) February 12, 2000