A facile synthesis of pyrrolo-[3,2-d]pyrimidines from 6-azidouracils and ylide phosphoranes

Article abstract of DOI:10.1002/hc.10048

A series of the title compounds, 9-deazaxanthines, was regioselectively prepared in reasonable yields as major products from the reactions of 6-azidouracils 1a,b with stabilized ester-2a,b or keto-2c ylide phosphoranes and a moderated phosphorus ylide 3, instead of the expected triazoles. Side products were also observed wherein pyrimido[5,4-g]pteridine-2,4,5,7-tetrone (15) and other fused ring systems or acyclic-substituted uracil derivatives were isolated. A comparative study on the reactivity of 1a in analogy to 1b toward phosphoranes is also described.

Full text of DOI:10.1002/hc.10048

Heteroatom Chemistry
Volume 13, Number 4, 2002
A Facile Synthesis of Pyrrolo-
[3,2-d]pyrimidines from 6-Azidouracils
and Ylide Phosphoranes
Wafaa M. Abdou,1 Amin F. M. Fahmy,2 and Azza A. Kamel1
1National Research Centre, Dokki, Cairo, Egypt
2Department of Chemistry, Faculty of Science, Ain-Shams University, Cairo, Egypt
Received 21 June 2001; revised 17 November 2001
Tuicamycin [4a]. In addition, many mono- and bi-
ABSTRACT: A series of the title compounds,
9-deazaxanthines, was regioselectively prepared in rea-
sonable yields as major products from the reactions
of 6-azidouracils 1a,b with stabilized ester-2a,b or
keto-2c ylide phosphoranes and a moderated phos-
phorus ylide 3, instead of the expected triazoles. Side
products were also observed wherein pyrimido[5,4-
g]pteridine-2,4,5,7-tetrone (15) and other fused ring
systems or acyclic-substituted uracil derivatives were
isolated. A comparative study on the reactivity of 1a
in analogy to 1b toward phosphoranes is also de-
cyclic uracils are used to protect plants, mostly
as herbicides [4b]. In a preceding communication,
therefore, we described the synthesis of a series
of phosphono-substituted uracils and some fused
pyrimidines [5] as antimicrobial compounds.
C
scribed. 2002 Wiley Periodicals, Inc. Heteroatom Chem
13:357–365, 2002; Published online in Wiley Interscience
(www.interscience.wiley.com). DOI 10.1002/hc.10048
In the course of investigations of the chem-
ical reactivity of alkylidenephosphoranes toward
carbon–nitrogen systems [6], we now report the
synthesis of the title compounds (also known as
9-deazaxanthines [7]) by reaction of stabilized ylides
2a–c and moderated phosphorus ylide 3 with
6-azidouracil (1a) and 6-azido-1,3-dimethyluracil
(1b). Some transformations of the products obtained
are also reported. These heterocyclic-fused uracils
might be useful for pharmaceutical purposes.
INTRODUCTION
Uracils have presented a class of compounds that
continually attracts organic chemists, medicinal
chemists, and photobiologists [1–3]. Several uracil
derivatives have been developed as drugs. Methyl-
thiouracil and propylthiouracil are thyroid in-
hibitors; Bucolome is an antiinflammatory; and
Uramustine (Uracil Mustard), Fluorouracil, and its
masked compounds are anticancer agents. Uracil
moieties were also detected in the antibiotic
Because of its strongly polar groups, uracil itself
shows only a weak solubility in organic solvents, and
it is almost insoluble in alcohol. It is soluble in hot
water and in aqueous alkali or ammonia, forming
*
)
ionized species derived from A
B. Thus, uracil
derivatives are, with a few exceptions, considered
not suited for chemical reactions. For this reason,
many research groups have chosen the 1,3-dimethyl
Correspondence to: Wafaa M. Abdou; e-mail; wabdou@intouch.
com.
2002 Wiley Periodicals, Inc.
c
357

358 Abdou, Fahmy, and Kamel
derivative as a versatile model compound. Therefore,
a comparative chemical study of the behavior of 1a
in analogy with 1b toward ylides 2 and 3 is herein
undertaken.
The reaction of phosphorus ylides with 1 might
be expected to follow Eq. (1), analogous to the re-
actions of phosphines [8], alkyl phosphites [9], and
carbanions [10] with 6-azidouracils. In these three
cases, nucleophilic attack occurs on the azide termi-
nus to give initially a triazo intermediate C, which
may be either stable or else it decomposes to other
products (Eq. (2)).
SCHEME 1
pyrimido[5,4-d]pyrrol-6-one (10a) in 24% yield
(Scheme 1). Triphenylphosphine oxide was not
isolated or identified (TLC) in the reaction mixture.
The recorded spectral data for pyrrole derivatives
8a and 10a were in agreement with the suggested
structures (cf. Experimental section). Treatment
of compound 8a with aromatic aldehydes (e.g.,
p-nitrobenzaldehyde) in refluxing toluene for
48 h afforded 7-(4-nitrobenzylidene)-6-oxo-2,4
(1H,3H,5H)-pyrrolo[3,2-d]pyrimidinedione (9a) in
20% yield. When the same reaction was carried
out in refluxing ethyl acetate for 18 h, compound
9a (one isomer, Z-form) was again obtained, but
in 72% yield. For similar reactions, pyrrolopyrimi-
dines have also been reported in the literature [12].
Notwithstanding, more evidence is necessary for
the configurational assignment of the product 9a.
The Z-configuration seems more favorable for the
compound in question because of reduced steric
hindrance.
(1)
(2)
In reality, the reaction of alkylidenephospho-
ranes with 1 is not as straightforward as implied in
Eq. (1). In fact, different routes leading to unexpected
products have been observed.
RESULTS AND DISCUSSION
A plausible mechanism for the formation of pyr-
rolidene phosphorane 8a is presented in Scheme 1.
Upon heating, denitrogenation occurs to form an in-
termediate nitrene 4, which cyclizes to give a bicyclic
azirine 5, and is then intercepted by the addition
reaction as discussed previously [13,14]. The addi-
tion of 2a to 5 affords an aziridine intermediate 6,
which is followed by ring cleavage and recyclization
to give the product 8a via elimination of an alco-
holic moiety (ROH). On the other hand, pyrrolone
10a might arise from the intermediate 7a via elimi-
nation of triphenylphosphine and an alcoholic moi-
ety. Another possibility involves usual nucleophilic
attack by 2 at the azide terminus to give an interme-
diate 12 (via 11), followed by intramolecular cycliza-
tion accompanied with the loss of ROH, nitrogen,
Reactions of 1a,b with Alkoxycarbonylmethyl-
enetriphenylphosphorane 2a,b
The reaction procedure for the preparation of the
title compounds, pyrrolo[3,2-d]pyrimidines, and the
course of the reactions are depicted in Schemes 1–6.
The required starting materials 6-azidouracil (1a)
and 6-azido-1,3-dimethyluracil (1b) were prepared
according to the literature in 75% yield by treat-
ing the parent chloride with sodium azide in
ethanol [11]. An ethyl acetate solution of the
azide 1a and the ester ylide 2a (1 mol equiv.) was
heated under reflux for 10 h. Separation of the pro-
duct mixture by column chromatography yielded
(7-triphenylphosphoranylidene)pyrimido[5,4-d]-
pyrrol-6-(5H)-one (8a) in 48% yield together with

Synthesis of Pyrrolo[3,2-d]pyrimidines From 6-Azidouracils and Ylide Phosphoranes 359
Yoneda et al. [14b]. The recorded mass spectrum,
the analytical data, and the infrared spectrum of
the yellow product 15, m.p. >300 C, are also con-
sistent with this assignment and exclude the ex-
pected structure 16 [18]. Furthermore, pteridine 15
has often been obtained as a by-product by the re-
action of 1b with a nucleophile [14a]. Neverthe-
less, the photochemical reaction of 1b in organic
solvents leads to 1,3,5,7-tetramethylpyrimido[4,5-g]
pteridine-2,4,6,8-tetrone (17) [19]. Repetition of the
reaction between 1b and 2a in dimethylformamide
(DMF) afforded again the cyclic ylide 8b as a ma-
jor product (32%) along with compounds 10b (15%)
and 15 (22%). When the cyclic ylide 8b was likewise
allowed to react with an aromatic aldehyde, the nor-
mal Wittig reaction took place and yielded the olefin
SCHEME 2
and triphenylphosphine, which also leads to the for-
mation of the constitution-isomer 14 (Scheme 2).
Nevertheless, formation of 14 via the intermediate
12, according to the literature [15–17], is quite unfa-
vorable; thus, it would rather lead to the formation
of 13 and/or to the corresponding iminophospho-
rane. The structure 10a has been, however, assigned
to the product in question on the basis of IR and
PMR spectral data in preference to 14. For example,
the data recorded for the methine proton (C-7-H)
at = 6.15 can readily eliminate from further con-
sideration the compound 14 (C-acylaldimine) which
would require a singlet between = 7.5 and 8.5 ppm
[N CH C(O)]. An attempt to convert 8 to 10 via de-
phosphorylation by heating in boiling ethyl acetate
or pyrolysis was unsuccessful. However, identifica-
tion of the structure 10 was established by an alter-
nate synthesis of 10a from the parent 5-aminouracil
(see Scheme 4 and Eq. (3)).
9b in 69% yield.
Treatment of the azide 1a with an equimolar
amount of ethoxycarbonymethylenetriphenylphos-
phorane (2b) in refluxing ethyl acetate for 10 h af-
forded ethyl 5-amino-2,4-(1H,3H)-pyrimidinedione-
6-car-boxylate (18) (36%) and compound 10a (26%)
(Scheme 4). Compound 8a was not isolated from
this reaction mixture. The structure of compound
18 was confirmed by its analytical and spectral data.
When the reaction between 1a and 2b was repeated
in refluxing DMF, besides 10a (25%), compounds
18 (25%) and 8a (16%) were obtained. We consider
that compound 18 arose through the previously sug-
gested intermediate 7c, which could be treated with
water to give the pyrimidine 18 and triphenylphos-
phine oxide. The isolation of the cyclic product 8a
together with 18 from the reaction in DMF can be
attributed to the higher temperature applied. When
compound 18 was heated for 30 h in boiling toluene
(or DMF), 18 was recovered unchanged. The pyrimi-
dine 18, however, when heated in a mixture of acetic
anhydride and pyridine, underwent cyclization,
furnishing the pyrrole 19.
When 6-azido-1,3-dimethyluracil (1b) was trea-
ted with an equimolar amount of 2a under the
same experimental conditions, products 8b (28%),
10b (13%), and the known [14] 1,3,6,8-tetramethyl-
pyrimido[5,4-g]pteridine-2,4,5,7-tetrone (15) (17%)
were obtained (Scheme 3). The structure 15 was eas-
ily established from its spectral data, reported by
SCHEME 3
SCHEME 4

360 Abdou, Fahmy, and Kamel
Treatment of 19 with 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) provided a second synthe-
sis of 10a, which was found to be identical with the
product described above. Furthermore, compounds
18, 19, and 10a were independently synthesized and
characterized (Eq. (3)). Thus, the ester 18, prepared
by treating 5-aminouracil with ethyl bromoacetate,
was cyclized to 19 by refluxing in a mixture of acetic
anhydride and pyridine. Conversion of 19 to 10a
could be accomplished by dehydrogenation with
DDQ in chloroform solution.
the known pyrrole 22a in 55% yield, m.p. >300 C,
previously reported by Senda et al. [20a]. Further-
more, compound 22a (37%) and the pteridine 15
(18%) were obtained by treatment of 1b with ylide
2c in a way analogous to the one described for 1a
(Scheme 5).
It is worth mentionning here that the meth-
ods previously described for the preparation of
pyrrolo-fused pyrimidines are lengthy and indirect
[1,12,20,21]. For example, compound 22b was syn-
thesized by the condensation of 1,3,6-trimethyl-
5-nitrouracil with benzaldehyde in ethanol. The
6-styryluracil produced was cyclized to 22b on re-
duction or by treatment with triethyl phosphite, fol-
lowed by irradiation in benzene [20b]. In the present
context, compounds 21 and 22a could be available
by a one-step synthesis from the reaction of the
proper 6-azidouracil with the keto ylide 2c.
(3)
6-Azido-1,3-dimethyluracil (1b), on the other
hand, reacted with 2b in either ethyl acetate or DMF
(better yields in DMF) to give compounds 8b (33%)
and 10b (19%) along with the pteridine 15 (13%)
(Eq. (4)).
Reaction of 6-Azidouracils 1a,b with Allyl
Phosphorane 3
Treatment of 1a with allyltriphenylphosphorane
(3), prepared in situ from its bromide salt 23, in
the presence of lithium hydride in ethyl methyl
ketone yielded 6-aminouracil (28) [22] (26%) along
with a white substance (43%), m.p. >300 C, and
typical in all aspects with the known [23] 2,4-dioxo-
1,2,3,4-tetrahydropyrrolo[3,2-d]pyrimidine (25a).
In a systemic study, compound 1b was treated
with the phosphonium bromide 23 under phase-
transfer catalysis conditions, as described for 1a,
and afforded 25b [7] (52%) and 1,3-dimethyl-
2,4-dioxo-6-[(triphenylphosphoranylidene)amino]-
1,2,3,4-tetrahydropyrimidine (27b) [24] (14%). A
mechanism for the formation of the pyrrolo-fused
pyrimidine 25 can be rationalized as occurring
through the attack of the ylide 3B on the initially
formed azirine 5, to generate the intermediate
24 (Scheme 6, A). Extrusion of methylidenephos-
phorane afforded compounds 25. The reaction
at the central carbon of the allyl group in 3 and
further elimination of the phosphorane moiety is a
documented process [25]. Furthermore, the ready
elimination of the phosphonium species from 24 in
the second step occurs through a carbanion mech-
anism, driven by the resulting gain in aromaticity.
Concurrent with formation of the intermediate
24, the triazole intermediate 26 is also produced.
Collapse of 26 led directly to the phosphinimines
27a,b. Further hydrolysis of 27a gave 28. The
absence of compound 15 and the appearance of
the intermediate 26 were, however, attributed to
the short time of heating in the latter reaction
(1b + 3).
DMF
1b + 2b → 8b + 10b + 15
(4)
Reaction of 6-Azidouracils 1a,b with Keto
Ylide 2c
Next, the reactions of azides 1a,b with benzoyl-
methylenetriphenylphosphorane (2c) were studied
(Scheme 5). A DMF suspension of the azide 1a and
an equimolar amount of ylide 2c was heated under
reflux for 12 h and furnished 6-phenylpyrrolo[3,2-d]-
pyrimidine (21) (63%) (along with other unidentified
products of high melting points) according to the
mechanism proposed in Scheme 5. Triphenylphos-
phine oxide was also isolated and identified. In order
to provide additional support to the mechanism, pyr-
role 21 was alkylated by the usual method to give
SCHEME 5

Synthesis of Pyrrolo[3,2-d]pyrimidines From 6-Azidouracils and Ylide Phosphoranes 361
SCHEME 6
Turning now to the scope of the above three reac-
MHz) instrument, using TMS as an internal refe-
rence. The 31P NMR spectra were recorded relative to
external H3PO4 (85%) with a Varian CFT-80 instru-
ment. The mass spectra were performed at 70 eV on
an MS-50 Kratos (A.E.I.) spectrometer provided with
a data system. The appropriate precautions in han-
dling moisture-sensitive compounds were observed.
tions of 1a and 1b with ester-2a,b, keto-2c, and mod-
erated allyl-3 ylides, some concluding remarks can
be made: (1) the results clearly showed a marked re-
semblance between the substrates 1a and 1b in their
chemical behavior toward triphenylmethylenephos-
phoranes; (2) the azirine intermediate 5, generated
from the parent azide via denitrogenation, is a key
intermediate for subsequent transformations; (3) the
construction of different hetero products depends
upon the electronic characteristic of the ylide used
and the experimental conditions.
Finally, the present work describes an efficient
and simple approach to the synthesis of a vari-
ety of 9-deazaxanthine derivatives (cf. compounds
8a,b, 9a,b, 10a,b, 21, 22a, and 25a,b) in reasonable
yields. This general method consists of suitable ap-
plications of the appropriate ylide phosphorane with
6-azidopyrimidines. Data on the pharmaceutical po-
tency of the new compounds 8a,b, 10a,b, 9a,b, and
18 will be published elsewhere.
Reaction of 6-Azido-2,4(1H,3H)-
pyrimidinedione (1a) with Methoxycarbonyl-
methylene(triphenyl)phosphorane (2a):
Preparation of Compounds 8a and 10a
(A) A stirred suspension of 6-azidouracil (1a) (0.8 g,
5.2 mmol) and the ylide 2a (1.83 g, 5.5 mmol)
in dry ethyl acetate (20 ml) was boiled under re-
flux for 10 h. After removal of the solvent the
residue was chromatographed on silica gel. Elution
with dichloromethane–ethyl acetate (CH2Cl2–AcOEt;
3:7 → 0:10 v/v) and further with pure methyl alcohol
afforded two fractions. The first fraction gave col-
orless crystals of 2,4-(1H,3H,6H)-6-oxo-pyrrolo[3,2-
d]pyrimidinedione (10a) (210 mg, 24%), m.p. 315–
317 C (from AcOEt) (Found: C, 43.73; H, 1.77; N,
25.31. C6H3N3O3 (165.11) requires: C, 43.64; H, 1.83;
EXPERIMENTAL
All melting points are uncorrected. IR spectra
were recorded on a Perkin-Elmer spectrophotometer
1
N, 25.45%); max(KBr)/cm 3330W (NH), 1735 (C-6-
model 297 (Grating) using KBr discs. The 1H and 13
C
(O)], 1685, 1635 [C-4-(O), C-2-(O)], 1622 (C CH);
NMR spectra were run on a Varian Gemini 200 (200
(d6-DMSO) 6.15 (s, 1H, C-7-H), 9.95, 11.43 (2 s,
H

362 Abdou, Fahmy, and Kamel
2
1H, N-3-H, N-1-H, deuterium exchangeable);
(2 N-CH3), 98.4 (C-9), 131.4 (C-7-H), 148.8 (C-8),
151.8, 163.4 [C-2-(O), C-4-(O)], 170.3 [C-6-(O)]; m/z
(%) 193 (30) [M+].
C
99.2 (C-9), 133.6 (C-7-H), 149.5 (C-8), 152.2, 164.8
(C-2-(O), C-4-(O)], 171.3 [C-6-(O)]; m/z (%) 165 (100)
[M+], 122 (66) [M+ 43, HNCO].
The second fraction gave colorless crystals of
6-oxo-7-(triphenylphosphoranylidene)-2,4(1H, 3H,
5H)pyrrolo[3,2-d]pyrimidinedione (8a) (1.1 g, 48%),
m.p. 328–330 C (from ethyl alcohol) (Found: C,
67.56; H, 4.19; N, 9.71; P, 7.22. C24H18N3O3P (427.41)
requires: C, 67.44; H, 4.24; N, 9.83; P, 7.25%);
The second fraction yielded colorless crystals of
1,3-dimethyl-6-oxo-7(triphenylphosphoranylidene)-
2,4(1H,3H,5H)pyrrolo[3,2-d]pyrimidinedione (8b)
(563 mg, 28%), m.p. 308–310 C (from methyl al-
cohol) (Found: C, 68.71; H, 4.81; N, 9.14; P, 6.83.
C26H22N3O3P (455.45) requires: C, 68.56; H, 4.87;
1
N, 9.23; P, 6.8%); max(KBr)/cm 3245, 3340 (NH),
1
max(KBr)/cm 3230, 3342 (NH), 1687, 1645 [C-4-
1680, 1635 [C-4-(O), C-2-(O)], 1620 [C-6-(O)], 1485
(O), C-2-(O)], 1610 [C-5-(O)], 1483 (=PPh3), 980
(=PPh3), 980 (P-C, Ph-H); (d6-DMSO) 15.66 ppm;
P
(P-C, Ph-H);
(d6-DMSO) 14.88;
7.44–7.86 (m,
2.40 (d, 3H, N-1-CH3), 3.12 (S, 3H, N-3-CH3),
P
H
H
15H, Ar-H), [8.54 (s, 1H, N-5-H), 9.95 (s, 1H, N-3-H),
7.23–7.85 (m, 15H, Ph-H), 8.83 (s, 1H, N-5-H,
11.33 (d, JHP = 9.5 Hz, N-1-H, deuterium exchange-
deuterium exchangeable); 29.2, 29.4 (2 N-CH3),
C
2
2
able);
89.3 (d, JCP = 103.5 Hz, C P), 110.8 (C-
87.4 (d, JCP = 107.4 Hz, C P), 105.3 (C-9), 143.6
C
9), 141.2 (d, JCP = 15.7 Hz, C-8), 152.5, 163.4 [2d,
C-2-(O), C-5-(O)], 155.3 [d, JCP = 18.5 Hz, C-6-(O)];
m/z (%) 427 (11) [M+], 384 (32) [M+ 43, HNCO],
341 (20) [(M+ 43) 43, HNCO], 262 (9) (Ph3P), 165
(100) [M+ 262, Ph3P].
(B) A sample of 8a (0.1 g) was refluxed in DMF
(or toluene) (5 ml) for 20 h. After evaporation of
the solvent in vacuo, the yellow solid that remained
was collected (>90%) with a small amount of chlo-
roform and shown to be identical with 8a (TLC and
comparative IR and mass spectra).
(d, JCP = 15.5 Hz,C-8), 151.8, 162.6 [2d, C-2-(O),
C-4-(O)], 154.4 [d, JCP = 18.2 Hz, C-6-(O)]; m/z (%)
455 (15) [M+], 193 (100) [M+ 262, Ph3P].
(B) The reaction between equimolar amounts
of compounds 1b and 2a in dry DMF under the
conditions described above, afforded compounds 8b
(670 mg, 32%), 10b (128 mg, 15%), and 15 (147 mg,
22%), which were identical with the products ob-
tained previously.
Wittig Reaction of Ylides 8a,b with p-Nitro-
benzaldehyde: Preparation of Compounds 9a,b
(C) Pyrolysis of 0.1 g of 8a at 250 C (0.01 mm)
for 2 h gave a dark lavender mass which afforded
unidentified products on chromatography.
(A) To a stirred suspension of ylide 8a (0.3 g,
0.7 mmol) in toluene (10 ml) p-nitrobenzaldehyde
(113 mg, 0.75 mmol) was added and the reaction
mixture was heated under reflux for 48 h. After the
evaporation of the solvent the residue was triturated
with chloroform to give 7(4-nitrobenzylidene)-
6-oxo-2,4(1H,3H,5H)pyrrolo[3,2-d]pyrimidinedione
(9a) (42 mg, 20%), m.p. 316–318 C (from ethyl alco-
hol) (Found: C, 52.08; H, 2.62; N, 18.48. C13H8N4O5
Reaction of 6-Azido-1,3-dimethyl-2,4-(1H,3H)-
pyrimidinedione (1b) with 2a: Preparation
of Compounds 8b, 10b and 15
(A) A stirred solution of the azide 1b (0.8 g,
4.42 mmol) and the ylide 2a (1.56 g, 4.5 mmol) in
dry ethyl acetate (20 ml) was heated at reflux for 8 h.
After cooling to room temperature, the precipitated
crystals were collected, recrystallized from DMF,
and identified as 1,3,6,8-tetramethylpyrimido[5,
4-g]pteridine-2,4,5,7-(1H,3H,6H,8H)-tetrone (15)
(115 mg, 17%), m.p. >300 C (Lit. [14b], m.p.
>300 C); m/z (%) 304 (66) [M+].
(300.24) requires: C, 52.00; H, 2.68; N, 18.66%);
1
max(KBr)/cm
3230, 3340w (NH), 1695, 1640
[C-4-(O), C-2-(O)], 1615 [C-6-(O)], 1598 (C CH);
(d6-DMSO) 7.24–7.44 (m, 4H, Ph-H), 7.82 (d,
H
1H, J = 4.2 Hz, CH), 8.58 (s, 1H, N-5-H), 9.72 (d,
diffused, 1H, N-1-H), 10.02 (s, 1H, N-3-H, deuterium
exchangeable); m/z (%) 300 (33) [M+].
The filtrate was separated by column chro-
matography on silica gel, CH2Cl2 AcOEt as eluent
(3:7 → 0:10 v/v) afforded two fractions. The first
fraction furnished colorless crystals of 1,3-dime-
thyl-2,4(1H,3H,6H)-6-oxo-pyrrolo[3,2-d]pyrimidi-
nedione (10b) (110 mg, 13%), m.p. 253–255 C
(from CHCl3) (Found: C, 49.67; H, 3.52; N, 21.67.
C8H7N3O3 (193.17) requires: C, 49.74; H, 3.65; N,
When the same reaction (8a + p-nitrobenzal-
dehyde) was repeated in boiling ethyl acetate for 18 h
(TLC), compound 9a (150 mg, 72%) was obtained.
(B) A solution of the ylide 8b (0.3 g, 0.66 mmol)
and p-nitrobenzaldehyde (100 mg, 0.68 mmol) in
ethyl acetate (10 ml) was heated under reflux for
14 h. After evaporation of the solvent the residue
was triturated with dichloromethane to yield yellow
leaflets of 1,3-dimethyl-7(4-nitrobenzylidene)-6-oxo-
2,4(1H,3H,5H)pyrrolo[3,2-d]pyrimidinedione (9b)
1
21.75%); max(KBr)/cm 1735 [C-6-(O)], 1674, 1624
[C-4-(O), C-2-(O)], 1618 (C CH);
(d6-DMSO) 3.25
H
(br.s, 6H, 2 N-CH3), 5.88 (s, 1H, C CH);
27.8
C

Synthesis of Pyrrolo[3,2-d]pyrimidines From 6-Azidouracils and Ylide Phosphoranes 363
(149 mg, 69%), m.p. 286–288 C (from ethyl alco-
hol) (Found: C, 54.94; H, 3.62; N, 16.90. C15H12N4O5
(328.29) requires: C, 54.88; H, 3.68; N, 17.07%);
1615 [3 C(O)];
(d6-DMSO) 4.72 (br.s, 2H, CH2),
H
8.83 (s, 1H, N-5-H), 9.95 (s, 1H, N-3-H), 10.72 (dd,
J = 4.5, 1.0 Hz, N-1-H, deuterium exchangeable); m/z
(%) 167 (100) [M+].
1
max(KBr)/cm 3225 (NH), 1680, 1635 [C-4-(O), C-
2-(O)], 1612 [C-6-(O)], 1605 (C CH);
2.54 (d,
(B) A sample of compound 18 (0.1 g) was re-
fluxed in DMF (or toluene) (5 ml) for 30 h. After evap-
oration of the solvent in vacuo, the residual yellow
solid was taken up (>90%) with a small amount of
chloroform and shown to be identical with 18 (TLC
and comparative IR and mass spectra).
H
JHH = 3.5 Hz, 3H, N-1-CH3), 3.23 (s, 3H, N-3-CH3),
7.43–7.84 (m, 4H, Ph-H), 7.85 (q, JHH = 3.5 Hz, =CH),
8.74 (s, 1H, N-5-H, deuterium exchangeable); m/z
(%) 328 (40) [M+].
Reaction of 6-Azidouracil (1a) with Ethoxy-
carbonylmethylene(triphenyl)phosphorane (2b):
Preparation of Compounds 8a, 10a and 18
Conversion of 19 into 10a
To a stirred solution of 0.14 g (0.4 mmol) of 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in
50 ml of chloroform was added 0.05 g (0.3 mmol)
of 19, and the mixture was heated under reflux for
1 h, and then concentrated to dryness under reduced
pressure. The residual solid was extracted with 5 ml
of warm ethanol to remove the formed hydroquinone
(TLC). Recrystallization of the residual solid from
ethyl acetate gave 31 mg (63%) of 10a, m.p. 315–
317 C, identical with the material prepared as de-
scribed above by using 2a.
(A) The reaction between the azide 1a (0.8 g,
5.2 mmol) and the ylide 2b (1.8 g, 5.25 mmol) in
boiling ethyl acetate (20 ml) for 8 h was carried
out and the reaction mixture was worked up ac-
cording to the above described procedure for ylide
2a. Ethyl 5-amino-2,4-dioxo(1H, 3H)pyrimidine-6-
carboxylate (18) was eluted first (410 mg, 36%),
m.p. 322–323 C (from dioxan) (Found: C, 45.18; H,
5.12; N, 19.58. C8H11N3O4 (213.2) requires: C, 45.07;
1
H, 5.20; N, 19.71%); max(KBr)/cm 3325w (NH),
3410 (NH2), 1727 [C(O), ester], 1690, 1642 [2 C(O),
amides];
(d6-DMSO) 1.05 (t, JHH = 7.3 Hz, 3H,
H
Preparation of Compounds 18, 19 and 10a
CH2 CH3), 3.15 (s, 2H, CH2), 3.85 (s, 2H, NH2,
deuterium exchangeable), 3.96 (q, JHH = 7.3 Hz,
CH2 CH3), 10.04, 11.52 (2 s, 2 1H, N-3-H, N-
The procedure reported by Ogura et al. [26] for
the alkylation of 6-amino-1,3-dimethyluracil at the
5-position was modified as follows: A mixture of
2.5 g (0.02 mol) of 5-aminouracil (available from
Aldrich) and 4.2 g (0.025 mol) of ethyl bromoacetate
in 100 ml of acetonitrile was heated under reflux
for 4 h. After removal of the solvent the residue was
chromatographed on silica gel. Elution with CH2Cl2–
AcOEt (3:7 → 0:10 v/v) gave colorless crystals of 18
(0.92 g, 22%), m.p. 323–325 C (from dioxan) and
other unidentified products. Compound 18 was con-
verted to 19 by heating in a mixture of acetic anhy-
dride and pyridine. Dehydrogenation of 19 by DDQ
afforded 10a. The prepared compounds 18, 19, and
10a are identical in all aspects with the materials
previously obtained.
1-H, deuterium exchangeable);
13.9 (CH2CH3),
C
48.6 [CH2 C(O)], 61.6 (CH2CH3), 117.3 (C-6), 148.9
(C-5), 152.4 (C-4), 161.8 (C-2), 169.3 (C-8); m/z (%)
213 (100) [M+].
The second fraction afforded compound 10a
(223 mg, 26%).
(B) The reaction between the azide 1a (0.4 g,
2.6 mmol) and the ylide 2b (0.9 g, 2.62 mmol) in
boiling DMF (15 ml) for 8 h was carried out and the
product mixture was worked up as above to give first
compound 18 (142 mg, 25%). The next fraction af-
forded compound 10a (107 mg, 25%). The third frac-
tion gave ylide 8a (178 mg, 16%).
Conversion of 18 into 19
Reaction of 6-Azido-1,3-dimethyluracil (1b)
with Ylide 2b: Preparation of Compounds 8b,
10b and 15
The pyrimidine 18 (0.1 g) in a mixture of acetic
anhydride (1.0 ml) and pyridine (2 ml) was heated
on a steam bath for 30 min. The reaction mix-
ture was kept overnight and the solid that separated
was filtered off, washed well with a small amount
of water, and finally crystallized from ethanol to
give compound 19 as white flakes (47 mg, 60%),
m.p. 318–320 C (Found: C, 43.22; H, 2.94; N, 25.05.
C6H5N3O3 (167.13) requires: C, 43.12; H, 3.01; N,
To a stirred solution of the azide 1b (0.8 g,
4.42 mmol) and the ylide 2b (1.53 g, 4.42 mmol) in
ethyl acetate (or DMF, best yields in DMF) (20 ml)
was heated under reflux for 8 h. The hot product mix-
ture was then filtered to give crystals of compound
15 (87 mg, 13%). The filtrate was evaporated to dry-
ness. Chromatography with CH2Cl2–AcOEt (3:7 v/v)
1
25.14%); max(KBr)/cm 3330w (NH), 1687, 1635,

364 Abdou, Fahmy, and Kamel
as eluent afforded compound 10b (160 mg, 19%) and
then elution with pure ethyl acetate gave compound
8b (0.69 g, 33%).
evolution had ceased ( 1 h), and the azide 1a or 1b
(5.2 mmol) was introduced all at once. The reaction
mixture was allowed to remain at room temperature
for a further 2 h and then refluxed for 2 h. The pro-
duct mixture was concentrated to 10 ml, diluted with
30 ml distilled H2O, acidified with conc. HCl and
then extracted with two 100 ml portions of ethyl ace-
tate. The ethyl acetate extracts were combined, back
washed with 100 ml of H2O, dried over anhydrous
MgSO4, and evaporated to dryness. The residue was
chromatographed on silica gel with CH2Cl2–AcOEt
(2:8 v/v) and further with methanol as eluents to give
two fractions.
Reaction of 1a with Benzoylmethylenetriphenyl-
phosphorane (2c): Preparation of Compound 21
A stirred suspension of the azide 1a (0.8 g, 5.2 mmol)
and the ylide 2c (2.1 g, 5.5 mmol) in ethyl ac-
etate (20 ml) was heated under reflux for 12 h
and then evaporated to dryness. Chromatography
on silica gel with pure ethanol afforded 6-phenyl-
2,4(1H,3H,5H)-pyrrolo[3,2-d]pyrimidinedione (21)
(744 mg, 63%), m.p. >300 C (from ethyl alcohol)
(Found: C, 63.55; H; 3.87, N; 18.36. C12H9N3O2
(227.23) requires: C, 63.43; H, 3.99; N, 18.49%);
max(KBr)/cm 1 3340W (NH), 1687, 1638, [C-4-(O), C-
With 1a. The first fraction afforded color-
less crystals of 2,4-dioxo(1H,3H,5H)-pyrrolo[3,2-
d]pyrimidine (25a) (280 mg, 36%), m.p. 311–312 C
(from methanol, Lit. [23], m.p. >300 C); m/z (%) 151
(100) [M+]. The second fraction afforded colorless
crystals of 6-aminouracil (28) (153 mg, 26%), m.p.
>330 C (from ethyl alcohol, Lit. [22], 312–315 C);
m/z(%) 127 (100) [M+].
2-(O)];
(d6-DMSO) 6.55 (s, 1H, C-7-H), 7.45-7.76
H
(m, 5H, Ph-H), 8.55 (s, 1H, N-5-H), 9.94, 11.32 (2 s,
2
1H, N-3-H, N-1-H, deuterium exchangeable); m/z
(%) 227 (100) [M+].
Preparation of 1,3-Dimethyl-6-phenyl-2,4-
(1H,3H,5H)pyrrolo[3,2-d] pyrimidinedione(22a)
With 1b. The reaction afforded 9-deazaxant
hine 25b (52%), m.p. 212–214 C (from CHCl3, Lit.
[7], 210 C); m/z (%) 179 (100) [M+], and 1,3-dimethyl-
2,4-dioxo-6[(triphenylphosphoranylidene)-amino]-
1,2,3,4-tetrahydropyrimidine (27b) [24] (14%).
To a stirred solution of 21 (0.2 g, 0.88 mmol) in NaOH
(5 ml, aqueous, 40%), dimethyl sulfate (252 mg,
2 mmol) was added dropwise ( 0.5 h) at room tem-
perature. The reaction mixture was heated to boil-
ing, cooled, then extracted thrice with 30 ml each of
chloroform and dried over anhydrous MgSO4. After
evaporation of the solvent, the residue was triturated
with CH2Cl2 to give compound 22a (100 mg, 45%),
m.p. >300 C (from DMF) (Lit. [20a], m.p. >300 C);
m/z (%) 255 (100) [M+].
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