A simple one-pot synthesis of novel [1,2,4]triazolo[3,4-f]purines

Full text of DOI:10.1021/jo001626a

J . Org. Chem. 2001, 66, 4055-4057
4055
Sch em e 1a
A Sim p le On e-P ot Syn th esis of Novel
[1,2,4]Tr ia zolo[3,4-f]p u r in es
Ahmad S. Shawali,*,† Mosselhi A. N. Mosselhi, and
Nagla M. Tawfik
Department of Chemistry, Faculty of Science,
University of Cairo, Giza, Egypt
shawali@chem-sci.cairo.eun.eg
Received November 16, 2000
Our longstanding involvement in the use of hydra-
zonoyl halides 1 as starting materials to prepare new
heterocyclic systems1 led us to investigate their reactions
with some natural purine derivatives in an attempt to
develop a new synthetic approach for their respective
fused annelated derivatives. Here, we wish to report the
results of our study of the reaction of such halides with
8-chloro-, 8-nitro-, 8-methylthio-, and 8-mercaptotheo-
phylline derivatives 2-5, respectively. As outlined below,
the studied reactions proved useful for synthesis of
functionalized derivatives of the previously reported ring
system namely [1,2,4]triazolo[3,4-f]purines2 14 (Scheme
1). The only hitherto known [f]-fused purines include
pyrrolo[2,1-f]-,3 oxazolo[2,3-f]-,4,5 imidazo[2,1-f]-,6-8 py-
rido[2,1-f]-,3 pyrimido[2,1-f]-,3,9 oxazino[2,3-f]-,10 pyrazino-
[2,1-f]-,3 [1,2,4]triazino[3,2-f]-,11 and [1,2,4]triazepino [3,2-
f]-11 purines. Also, [1,2,4]triazolo[3,4-i]- and [1,2,4]tria-
zolo[5,1-i]purines were also reported.12,13 The interest in
synthesis of derivatives of the title ring system results
from the fact that certain fused xanthines, with theo-
phylline as the prototype, were reported to inhibit many
of the pharmacological and physiological effects of ad-
enosine, by acting as competitive antagonists at A1- and
A2-adenosine receptor subtypes.14 For this reason, con-
siderable efforts have been devoted in recent years to
synthesize functionalized xanthine congeners, as selective
a
R/Z: a, Ph/H; b, Ph/4-NO2; c, CH3/4-NO2; d, PhCHdCH/H; e,
CH3CO/H; f, PhCO/H; g, PhCO/4-Me; h, PhCO/4-NO2 i, 1-naph-
thoyl/H; j, 1-naphthoyl/4-Cl; k, 2-thenoyl/H; l, PhNHCO/H; m,
PhNHCO/4-Me; n, PhNHCO/4-Cl; o, EtOCO/H.
antagonists for one or the other type of adenosine
receptors.3,15,16
The hydrazonoyl halides 1a -i17 and 8-substituted
theophylline derivatives 2-5,18 prepared as reported in
the literature, were the key starting reagents for the
synthesis of the title compounds (Scheme 1). Reaction of
8-chlorotheophylline 2 with 1a -i in refluxing dioxane in
the presence of triethylamine as a base catalyst gave in
each case a single product as evidenced by TLC analysis
of the crude products. Likewise, refluxing of either 1a
with 8-nitrotheophylline 3 in dioxane in the presence of
triethylamine or with 8-methylthiotheophylline 4 or
8-mercaptotheophylline 5 in pyridine yielded in each case
one and the same product that proved identical in all
respects with that one obtained above from similar
reaction of 1a with 2.
† Fax: Internat. code 00202 567 556.
(1) For reviews see: Shawali, A. S. Chem. Rev. 1993, 93, 2731.
Shawali A. S. and Abdallah, M. A. Advances in Heterocyclic Chemistry;
Academic Press: New York, 1995; Vol. 63, p 277. Shawali, A. S.
Heterocycles 1983, 20, 2239. Shawali, A. S.; Parkanyi, C. J . Heterocycl.
Chem. 1980, 17, 833.
(2) El-Farargy, A. F.; Assay, M. G.; Hassanien, M. M. Pharmazie
1993, 48, 109.
(3) Gatta, F.; Del McGiudice, M. R.; Borioni, A.; Mustazza, C. J .
Heterocycl. Chem. 1994, 31, 81.
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317, 745.
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Chem. 1985, 22, 105.
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A.; Garmash, S. N.; Milonova, N. F. Khim. Farm. Zh. 1984, 18, 1456.
Chem. Abstr. 103, 22539e.
Both the mass spectral and elemental analysis data
of the isolated products are consistent with either [1,2,4]-
triazolo[3,4-f]theophylline or [1,2,4]triazolo[4,3-e]theo-
(8) Nosachenko, V. I.; Kochergin, P. M.; Steblyuk, P. N. Khim.
Geterotsikl. Soedin. 1976, 1132. Chem. Abstr. 1977, 86, 5414y.
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681.
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999.
(11) Ueda, T.; Adachi, T.; Nagai, S.; Sakakibura, J .; Murata, M. J .
Heterocycl. Chem. 1988, 25, 791.
(12) Balsiger, R. W.; Fikes, A. L.; J ohnston, T. P.; Montgomery, J .
A. J . Org. Chem. 1961, 26, 3446.
(15) Shamim, M. T.; Ukena, D.; Padgett, W. L.; Hong, O.; Daly, J .
W. J . Med. Chem. 1988, 31, 613.
(16) Shimada, J .; Suzuki, F.; Nonaka, H.; Ishii, A.; Ichikawa, S. J .
Med. Chem. 1992, 35, 2342.
(17) Favrel, G. Bull. Chim. Soc. Fr 1904, 31, 150. Dieckmann, W.;
Platz, L. Chem. Ber. 1905, 38, 2986. Shawali, A. S.; Abdelhamid, A.
O. Bull. Chem. Soc. J pn. 1976, 49, 321. Hassaneen, H. M.; Shawali,
A. S.; Elwan, N. M.; Abounada, N. M. Org. Prep. Proc. Int. 1992, 24,
171. Farag, A. M.; Algharib, M. S. Org. Prep. Proc. Int. 1988, 20, 521.
Curtius, T. J . Prakt. Chem. 1899, 51.
(13) Temple, C., J r.; Kussner, C. L.; Montgomery, J . A. J . Org. Chem.
1965, 30, 3601.
(14) J acobson, K. A.; van Galen, P. J . M.; Williams, M. J . Med. Chem.
1992, 35, 407 and references therein.
(18) (a) Mosselhi, M. A.; Pfleiderer, W. J . Heterocycl. Chem. 1993,
30, 1221. (b) Cacace, F.; Masironi, R. Ann. Chim. (Italy) 1957, 47, 366.
(c) Merz, K. W.; Stahl, P. H. Arznein Forschung 1965, 15, 10; Chem.
Abstr. 1965, 63, 4296b.
10.1021/jo001626a CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/04/2001

4056 J . Org. Chem., Vol. 66, No. 11, 2001
Notes
phylline derivatives 14 or 15, respecively (Scheme 1). The
latter structure was discarded, however, due to the steric
hindrance caused by the proximity of the N1-CH3 and
R groups as shown by molecular models. Assignment of
the structure 14 to the products isolated from the studied
reactions rather than the possible alternative structure
15 is also based on similar results in the literature
reports documenting that N-7 of the theophylline ring
system is the site of preference for nucleophilic additions5
as well as nucleophilic substitutions.3,19,20 In addition, the
Exp er im en ta l Section
Melting points were determined in open capillaries and are
uncorrected. 1H NMR specra were recorded at 200 MHz in CDCl3
or DMSO-d6 and referenced to TMS (1H). IR spectra were
recorded in KBr. Mass spectra were measured at 70 eV using a
GC-MS. Elemental analyses were provided by the Microana-
lytical Laboratory at Cairo University, Giza, Egypt. The starting
hydrazonoyl halides 1a -o17 and 8-substituted theophyllines
2-518 were prepared as previously described.
1,3-D i m e t h y l-2,4-d i o x o -6,8-d i s u b s t i t u t e d -1,2,3,4-
tetr ah ydr o[1,2,4]tr iazolo[3,4-f]pu r in es 14. Gen er al Meth od .
To a mixture of the appropriate hydrazonoyl halide 1 (0.01 mol)
and 8-chlorotheophylline 2 (0.01 mol) in dioxane (30 mL) was
added triethylamine (1.5 mL, 0.01 mol). The mixture was then
refluxed for 5.0-10.0 h according to the halide used. Then the
excess solvent was distilled under reduced pressure. The crude
product that precipitated upon cooling was collected by filtration,
washed with ethanol, dried, and finally crystallized from the
appropriate solvent to give the corresponding 14.
When the above procedure was repeated using 8-nitrotheo-
phylline 3 in place of 2, it yielded the respective 14 identical in
all respects with that one obtained above from 1 and 2.
Furthermore, when an equimolar mixture (0.01 mol each) of
1 and 8-methylthiotheophylline 4 (or 8-mercaptotheophylline 5)
in pyridine (20 mL) was refluxed till methanethiol (or hydrogen
sulfide) ceased to evolve (4.0-5.0 h), the respective 14 was also
obatined after workup.
1
structures of 14a -o were further evidenced by their H
NMR data. For example, the 1H NMR spectra of the
isolated products revealed the signal of the N1-CH3
protons at δ 3.50-3.70. This value is very close to that
of N3-CH3 of theophylline (δ 3.59). This similarity of δ
values is consistent with structure 14. This is because
had the products structure 15, it would be expected that
the N1-CH3 group will be shielded by the neighboring
group R, and thus its δ value will be less than 3.50 and
it will vary with the degree of shielding exerted by the R
group.
To account for the formation of the products 14 from
reactions of 1 with each of 2-4, the tentative mechanism
outlined in Scheme 1 is proposed. According to this
mechanism, it is suggested that the reaction of 1 with
each of 2-4 starts with 1,3-dipolar addition of N7-H of
2 to the nitrilium imide, generated in situ by the action
of triethylamine on 1, to give the respective amidrazone
intermediates 6-9, respectively. The latter then undergo
intramolecular addition to give the cycloadducts 10-13,
respectively. Alternatively, the latter cycloadducts 10-
13 can result directly via cycloaddition of the nitrilium
imide to the CdN bond in theophylline derivatives. The
resulting cycloadducts 10-13 in turn eliminate an HX
molecule to give 14 as the end products (Scheme 1). In
our hands, all attempts to isolate the amidrazone inter-
mediates 6-9 or the cycloadducts 10-13 failed.
With respect to reaction of 1 with 5 leading to 14, it
can be suggested that the reaction in this case can start
with the formation of the thiohydrazonate ester which
undergoes in situ Smiles type rearrangement to give the
respective thiohydrazide which in turn cyclizes intramo-
lecularly to give 14 as end product via elimination of
hydrogen sulfide. Similar rearrangements of the thiohy-
drazonate esters followed by elimination of hydrogen
sulfide have been reported previously.21 However, it is
not unreasonable to conclude, on the basis of our finding
that reactions of 1 with either 4 or 5 gave the same
product 14, that both reactions proceed via similar
intermediates, namely 12 and 13, respectively, as out-
lined in Scheme 1.
The physical constants of the products 14a -o are given below.
1,3-Dim eth yl-2,4-d ioxo-6,8-d ip h en yl-1,2,3,4-tetr a h yd r o-
[1,2,4]tr ia zolo[3,4-f]p u r in e (14a ): yield 82%, mp 286-288 °C
(dioxane); IR(KBr) 1712, 1674 cm-1; 1H NMR (CDCl3) δ 3.43 (s,
3H, N3-Me), 3.70 (s, 3H, N1-Me), 7.50-8.26 (m, 10H, ArH); MS
m/z 372(M+, 100%), 373(M+ +1, 92%). Anal. Calcd for C20H16N6O2:
C, 64.51; H, 4.33; N, 22.57. Found: C, 64.4; H, 4.5; N, 22.3.
1,3-Dim eth yl-2,4-dioxo-6-ph en yl-8-(p-n itr oph en yl)-1,2,3,4-
tetr a h yd r o[1,2,4]tr ia zolo[3,4-f]p u r in e (14b): yield 80%, mp
> 340 °C (DMF), IR(KBr) 1716, 1682 cm-1 1H NMR (DMSO-
;
d6) δ 3.26 (s, 3H, N3-Me), 3.59 (s, 3H, N1-Me), 7.60-8.60 (m,
9H, ArH); MS m/z 417(M+, 100%), 418(M+ +1, 30%). Anal. Calcd
for C20H15N7O4: C, 57.55; H, 3.62; N, 23.49. Found: C,57.5; H,
3.7; N, 23.7.
1,3-Dim eth yl-2,4-dioxo-6-m eth yl-8-(p-n itr oph en yl)-1,2,3,4-
tetr a h yd r o[1,2,4]tr ia zolo[3,4-f]p u r in e (14c): yield 80%, mp
278-280 °C (dioxane /EtOH), IR(KBr) 1711, 1680 cm-1; 1H NMR
(CDCl3) δ 2.96 (s, 3H, CH3), 3.46 (s, 3H, N3-Me), 3.59 (s, 3H,
N1-Me), 7.80-8.70 (m, 4H, ArH); MS m/z 355 (M+, 26%), 356-
(M+ +1, 17%). Anal. Calcd for C15H13N7O4: C, 50.71; H, 3.69; N,
27.59. Found: C,50.4; H, 3.4; N, 27.3.
1,3-Dim et h yl-2,4-d ioxo-6-(2-p h en ylet h en yl)-8-p h en yl-
1,2,3,4-t et r a h yd r o[1,2,4]t r ia zolo[3,4-f]p u r in e (14d ): yield
78%, mp 296-298 °C (dioxane), IR(KBr) 1707, 1665 cm-1 1H
,
NMR (DMSO-d6) δ 3.31 (s, 3H, N3-Me), 3.51 (s, 3H, N1-Me),
7.10-8.15 (m, 12H, ArH, CHdCH); MS m/z 398 (M+, 78%), 399-
(M+ +1, 77.8%). Anal. Calcd for C22H18N6O2: C, 66.32; H, 4.55;
N, 21.09. Found: C,66.6; H, 4.3; N, 21.3.
1,3-D i m e t h y l-2,4-d i o x o -6-a c e t y l-8-p h e n y l-1,2,3,4-
tetr a h yd r o[1,2,4]tr ia zolo[3,4-f]p u r in e (14e): yield 75%, mp
300-302 °C (dioxane), IR(KBr) 1717, 1697, 1662 cm-1, 1H NMR
(CDCl3) δ 2.75 (s, 3H, CH3), 3.39 (s, 3H, N3-Me), 3.68 (s, 3H,
N1-Me), 7.20-8.20 (m, 5H, ArH); MS m/z 338 (M+, 85.9%), 339
(M+ +1, 78.5%). Anal. Calcd for C16H14N6O3: C, 56.80; H, 4.17;
N, 24.84. Found: C, 56.8; H, 4.0; N, 24.6.
Compounds 14a -o represent important extensions in
the chemistry ring-fused purines. The availability of
various functional groups for further reactions offers the
potential for novel biologically active materials. Further
studies to shed light on the affinity of the compounds
prepared above for A1- and A2-adenosine receptors and
their inhibitory effects on phosphodiesterase are still in
progress.
1,3-D im e t h y l-2,4-d io x o -6-b e n zo y l-8-p h e n y l-1,2,3,4-
tetr a h yd r o[1,2,4]tr ia zolo[3,4-f]p u r in e (14f): yield 80%, mp
298-300 °C (dioxane), IR(KBr) 1712, 1670 cm-1 1H NMR
,
(DMSO-d6) δ 3.38 (s, 3H, N3-Me), 3.58 (s, 3H, N1-Me), 7.35-
8.30 (m, 10H, ArH); MS m/z 400 (M+, 66.1%), 401 (M+ +1,
44.6%). Anal. Calcd for C21H16N6O3: C, 63.00; H, 4.03; N, 20.99.
Found: C, 63.0; H, 4.1; N, 21.1.
1,3-Dim et h yl-2,4-d ioxo-6-b en zoyl-8-(p -m et h ylp h en yl)-
1,2,3,4-tetr a h yd r o[1,2,4]tr ia zolo[3,4-f]p u r in e (14g): yield
80%, mp 236-238 °C (AcOH/H2O), IR(KBr) 1713,1666 cm-1, 1H
NMR (CDCl3) δ 2.44 (s, 3H, CH3), 3.46 (s, 3H, N3-CH3), 3.71 (s,
3H, N1-CH3), 7.20-8.40 (m, 9H, ArH); MS m/z 413 (M+-1,
0.4%), 415 (M+ + 2, 34%). Anal. Calcd for C22H18N6O3: C, 63.76;
H, 4.38; N, 20.28. Found: C, 64.0; H, 4.1; N, 20.1.
(19) Ueda, T.; Oh, R.; Nagai, S.; Sakakibora, J . J . Heterocycl. Chem.
1998, 35, 135.
(20) DaSettimo, A.; Primofiore, G.; Cristina, B. M.; DaSettimo, F.;
Marini, A. M. J . Heterocycl. Chem. 1995, 32, 941.
(21) Shawali, A. S.; Gomha, S. M. J . Prakt. Chem. 2000, 342, 599
and the references therein.

Notes
J . Org. Chem., Vol. 66, No. 11, 2001 4057
1,3-Dim eth yl-2,4-dioxo-6-ben zoyl-8-(p-n itr oph en yl)-1,2,3,4-
tetr a h yd r o[1,2,4]tr ia zolo[3,4-f]p u r in e (14h ): yield 78%, mp
280-282 °C (AcOH/H2O), IR(KBr) 1705, 1659 cm-1 1H NMR
(CDCl3) δ 3.46 (s, 3H, N3-CH3), 3.74 (s, 3H, N1-CH3), 7.20-
8.50 (m, 9H, ArH); MS m/z 445 (M+, 25%), 446 (M+ + 1, 27%).
Anal. Calcd for C21H15N7O5: C, 56.63; H, 3.39; N, 22.01. Found:
C, 56.3; H, 3.1; N, 22.0.
NMR(DMSO-d6) δ 3.40 (s, 3H, N3-CH3), 3.55 (s, 3H, N1-CH3),
7.40-8.20 (m, 10H, ArH), 12.6 (s,1H, NH); MS m/z 415(M+,
100%), 416 (M+ + 1, 28.2%). Anal. Calcd for C21H17N7O3: C,
60.72; H, 4.12; N, 23.60. Found: C, 60.7; H, 4.4; N, 23.7.
;
1,3-Dim et h yl-2,4-d ioxo-6-p h en ylca r b a m oyl-8-(p -m et h -
ylp h en yl)-1,2,3,4-t et r a h yd r o[1,2,4]t r ia zolo[3,4-f]p u r in e
(14m ): yield 85%; mp 320-322 °C (DMF/EtOH); IR(KBr) 1705,
1666 cm-1; 1H NMR(DMSO-d6) δ 2.40 (s, 3H, CH3), 3.32 (s, 3H,
N3-CH3), 3.60 (s, 3H, N1-CH3), 7.30-8.20 (m, 9H, ArH), 12.6
(s,1H, NH); MS m/z 428 (M+, 4.9%), 430 (M+ + 1, 99.3%), 431
(M+ + 2, 31.1%). Anal. Calcd for C22H19N7O3: C, 61.53; H, 4.46;
N, 22.83. Found: C, 61.2; H, 4.5; N, 22.6.
1,3-Dim eth yl-2,4-d ioxo-6-(1-n a p h th oyl)-8-p h en yl-1,2,3,4-
tetr a h yd r o[1,2,4]tr ia zolo[3,4-f]p u r in e (14i): yield 83%; mp
288-290 °C (AcOH/H2O); IR(KBr) 1711, 1672 cm-1 1H NMR-
;
(DMSO-d6) δ 3.47 (s, 3H, N3-CH3), 3.54 (s, 3H, N1-CH3), 7.30-
8.50 (m, 12H, ArH); MS m/z 450 (M+, 58.5%), 451 (M+ + 1,
53.9%). Anal. Calcd for C25H18N6O3: C, 66.66; H, 4.03; N, 18.66.
Found: C, 66.8; H, 4.2; N,18.5.
1,3-Dim et h yl-2,4-d ioxo-6-p h en ylca r b a m oyl-8-(p -ch lo-
r op h en yl)-1,2,3,4-t et r a h yd r o[1,2,4]t r ia zolo[3,4-f]p u r in e
(14n ): yield 85%; mp 336-338 °C (dioxane/EtOH); IR(KBr)
1,3-Dim eth yl-2,4-d ioxo-6-(1-n a p h th oyl)-8-(p-ch lor op h e-
n yl)-1,2,3,4-tetr ah ydr o[1,2,4]tr iazolo[3,4-f]pu r in e (14j): yield
1705, 1666 cm-1 1H NMR(DMSO-d6) δ 3.34 (s, 3H, N3-CH3),
;
82%; mp 296-298 °C (AcOH/H2O); IR(KBr) 1705, 1659 cm-1
;
1H NMR(CDCl3) δ 3.54 (s, 3H, N3-CH3), 3.68 (s, 3H, N1-CH3),
7.20-8.90 (m, 11H, ArH); MS m/z 485 (M+ + 1, 33.6%), 486 (M+
+ 2, 9.1%), 487 (M+ + 3, 11.8%). Anal. Calcd for C25H17ClN6O3:
C, 61.93; H, 3.53; N, 17.33. Found: C, 61.7; H, 3.2; N, 17.1.
1,3-Dim et h yl-2,4-d ioxo-6-(2-t h en oyl)-8-p h en yl-1,2,3,4-
tetr a h yd r o[1,2,4]tr ia zolo[3,4-f]p u r in e (14k ): yield 82%; mp
324-326 °C (dioxane/H2O); IR(KBr) 1713, 1672 cm-1; 1H NMR-
(DMSO-d6) δ 3.45 (s, 3H, N3-CH3), 3.60 (s, 3H, N1-CH3), 7.40-
8.50 (m, 8H, ArH); MS m/z 406 (M+, 46.3%), 407 (M+ + 1, 10.6%);
3.56 (s, 3H, N1-CH3), 7.20-8.20 (m, 9H, ArH), 12.5 (s,1H, NH);
MS m/z 450 (M+, 95.5%), 451 (M+ + 1, 29.0%), 452 (M+ + 2,
31.7%). Anal. Calcd for C21H16ClN7O3: C, 56.07; H, 3.59; N, 21.79.
Found: C, 56.0; H, 3.2; N, 21.7.
1,3-Dim eth yl-2,4-dioxo-6-eth oxycar bon yl-8-ph en yl-1,2,3,4-
tetr a h yd r o[1,2,4]tr ia zolo[3,4-f]p u r in e (14o): yield 76%; mp
244-246 °C (AcOH); IR(KBr) 1741, 1705, 1670 cm-1; 1H NMR-
(CDCl3) δ 1.50 (t, J ) 7 Hz, 3H,CH3), 3.46 (s, 3H, N3-CH3), 3.69
(s, 3H, N1-CH3), 4.60 (q, J ) 7 Hz, 2H, CH2), 7.50-8.24 (m,
5H, ArH); MS m/z 368 (M+, 100%), 369 (M+ + 1, 92.7%). Anal.
Calcd for C17H16N6O4: C, 55.43; H, 4.38; N, 22.82. Found: C,
55.4; H, 4.7; N, 22.8.
Anal. Calcd. for
C19H14N6O3S: C, 56.15; H, 3.47; N, 20.68.
Found: C, 56.1; H, 3.2; N, 20.6.
1,3-Dim e t h yl-2,4-d ioxo-6-p h e n ylca r b a m oyl-8-p h e n yl-
1,2,3,4-t et r a h yd r o[1,2,4]t r ia zolo[3,4-f]p u r in e (14l): yield
80%; mp 352-354 °C (dioxane); IR(KBr) 1697, 1651 cm-1
;
1H
J O001626A