Diversity-oriented synthesis of functionalized pyrrolo[3,2-d]pyrimidines with variation of the pyrimidine ring nitrogen substituents

Article abstract of DOI:10.1021/jo034684f

Nine 2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-carboxylic acid benzyl esters 12 were synthesized in four steps from 4-oxo-N-(PhF)proline benzyl ester 7 by a general method in which elements of molecular diversity were readily added onto the pyrimidine nitrogens. Conversion of 4-oxoproline 7 into the corresponding aminopyrrole 8 using benzyl-, allyl-, and isopropylamine followed by treatment with phenyl, allyl, and ethyl isocyanate gave nine different ureas 9.4-Ureido-1H-pyrrole-2-carboxylic acid benzyl esters 9 were then converted into the respective pyrrolo[3,2-d]pyrimidines 12 using trichloroacetyl chloride in acetonitrile followed by treatment with CS ₂CO₃. Crystallization from toluene gave the desired deazapurines in 37-55% overall yield from proline 7.

Full text of DOI:10.1021/jo034684f

Diver sity-Or ien ted Syn th esis of F u n ction a lized
P yr r olo[3,2-d ]p yr im id in es w ith Va r ia tion of th e P yr im id in e Rin g
Nitr ogen Su bstitu en ts
Fe´lix-Antoine Marcotte, Frederik J . R. Rombouts, and William D. Lubell*
De´partement de chimie, Universite´ de Montre´al, C.P. 6128, Succursale Centre Ville,
Montre´al, Que´bec, Canada H3C 3J 7
lubell@chimie.umontreal.ca
Received May 21, 2003
Nine 2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-carboxylic acid benzyl esters 12
were synthesized in four steps from 4-oxo-N-(PhF)proline benzyl ester 7 by a general method in
which elements of molecular diversity were readily added onto the pyrimidine nitrogens. Conversion
of 4-oxoproline 7 into the corresponding aminopyrrole 8 using benzyl-, allyl-, and isopropylamine
followed by treatment with phenyl, allyl, and ethyl isocyanate gave nine different ureas 9. 4-Ureido-
1H-pyrrole-2-carboxylic acid benzyl esters 9 were then converted into the respective pyrrolo-
[3,2-d]pyrimidines 12 using trichloroacetyl chloride in acetonitrile followed by treatment with
Cs2CO3. Crystallization from toluene gave the desired deazapurines in 37-55% overall yield from
proline 7.
In tr od u ction
Pyrrolo[3,2-d]pyrimidines form a class of deazapurine
analogues with interesting biological activity. For ex-
ample, phenyl-substituted deazaxanthines 1 (R1, R3
)
alkyl, R6 ) Ph, Figure 1) exhibit antagonistic activity,
but moderate selectivity for the A1- and A2-adenosine
receptors, in accordance with their structural resem-
blance to natural A1/A2 receptor antagonists such as the
xanthines caffeine and theophylline.1,2 Deazapurine-
based C-nucleosides, such as immucilin-H (2), as well as
the pyridinylmethyl deazapurine peldesine (3) are potent
purine nucleoside phosphorylase (PNP) inhibitors that
exhibit potential for the treatment of T-cell dependent
diseases, such as T-cell leukemia.3 C-Nucleosides con-
taining pyrazolo[3,2-d]pyrimidine and pyrazolo[4,3-d]-
pyrimidine moieties have also shown antibiotic and
antiviral activity.4 6-Piperidyl-8-phenyl-9-deazapurine (4)
was identified from a high throughput screen as a potent
neuropeptide Y5 receptor antagonist and lead compound
for the development of novel anti-obesity drugs.5 In
(1) (a) For a review on purine/pyrimidine receptors, see: Ralevic,
V.; Burnstock, G. Pharmacol. Rev. 1998, 50, 413-492. (b) For a review
on adenosine receptors, see: Fredholm, B. B.; Ijzerman, A. P.; J acobson,
K. A.; Koltz, K.-N.; Linden, J . Pharmacol. Rev. 2001, 53, 527-552.
(2) Grahner, B.; Winiwarter, S.; Lanzner, W.; Mu¨ller, C. E. J . Med.
Chem. 1994, 37, 1526-1534.
(3) (a) Evans, G. B.; Furneaux, R. H.; Gainsford, G. J .; Hanson, J .
C.; Kicska, G. A.; Sauve, A. A.; Schramm, V. L.; Tyler, P. C. J . Med.
Chem. 2003, 46, 155-160. (b) Basso, L. A.; Santos, D. S.; Shi, W.;
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Biochemistry 2001, 40, 8196-8203. (c) Pathak, V. P. Org. Process Res.
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A.; Robins, R. K.; Cottam, H. B. J . Med. Chem. 1990, 33, 2750-2755.
(5) Norman, M. H.; Chen, N.; Chen, Z.; Fotsch, C.; Hale, C.; Han,
N.; Hurt, R.; J enkins, T.; Kincaid, J .; Liu, L.; Lu, Y.; Moreno, O.;
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43, 4288-4312.
F IGUR E 1. Representative examples of biologically active
pyrrolo[3,2-d]pyrimidines.
search of potential antihypertensive drugs, several py-
rimido[5,4-b]indole-2,4-diones 5 have shown antagonist
activity at the R1-adrenoreceptors, some exhibiting se-
lectivity for the R1D-subtype.6 In addition, pyrrolopyrim-
idinone 6 inhibited phosphodiesterase with subnanomo-
lar activity.7
10.1021/jo034684f CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/13/2003
6984
J . Org. Chem. 2003, 68, 6984-6987

Synthesis of Functionalized Pyrrolo[3,2-d]pyrimidines
SCHEME 1. Syn th esis of P yr r olo[3,2-d ]p yr im id in es
F IGURE 2. Preparations of pyrrolo[3,2-d]pyrimidines from
3-aminopyrrole-2-carboxylates.
Among the reported syntheses of pyrrolo[3,2-d]pyrim-
idines, most start from pyrimidines possessing reactive
functional groups at positions 4 and 5.8 Although it may
be more advantageous to build the pyrrolo[3,2-d]pyrimi-
dine from an appropriately substituted pyrrole in order
to generate greater diversity at the pyrimidine core, few
syntheses of deazapurines have used this strategy.5,6,9-12
These strategies have all relied on the synthesis of an
appropriately substituted 3-aminopyrrole-2-carboxylate
intermediate which has been subsequently reacted with
nitrile,5 isothiocyanate,5,9,10 isocyanate,5,9 imidate,5,10 and
isothiourea11 reagents to form the pyrimidine (Figure 2).
Because of difficulties in synthesizing suitably N-alky-
lated 3-aminopyrrole-2-carboxylates, these approaches
generally fail to provide pyrrolo[3,2-d]pyrimidines with
N1-substituents.
Recently, we demonstrated that 4-aminopyrroles can
be effectively obtained by reacting 4-oxo-N-(PhF)prolinate
7 with primary and secondary amines and catalytic acid
in a polar solvent (PhF ) 9-(9-phenylfluorenyl), Scheme
1).13 This method has provided various 4-aminopyrrole-
2-carboxylates possessing diverse substituents at the
4-position. In light of the growing interest in deazapu-
rines as biologically active leads for drug development,
we have begun to explore the elaboration of 4-aminopyr-
role-2-carboxylates 8 into deazapurines by a general
approach for introducing diversity at various positions
around the heterocycle. This study has now led to an
effective means for preparing pyrrolo[3,2-d]pyrimidines
possessing various substituents at the pyrimidine nitro-
gens.
Resu lts a n d Discu ssion
Previously, we reported that treatment of a 50 °C
solution of 4-oxo-N-(PhF)prolinate 7 and 10 mol % of
TsOH with benzylamine in THF and allylamine in
acetonitrile, respectively, generated the corresponding
4-benzyl- and 4-allylaminopyrrole-2-carboxylates 8a and
8b in 84% and 75% respective yields.13 Isopropylamine
was found to react similarly with 7 in THF at 50 °C to
give 4-isopropylaminopyrrole-2-carboxylic acid benzyl
ester 8c in 70% yield after chromatographic purification
(Scheme 1). 4-Aminopyrroles 8 were then found to react
selectively on the exocyclic amine with isocyanates in
dichloromethane at room temperature to furnish a series
of 4-ureidopyrroles 9 in 88-99% yields (Table 1).
Trichloroacetyl chloride had been previously used to
acetylate the 2-position of pyrrole in order to generate
reactive ketone analogues14 that have been converted into
different amides15 and esters16 via haloform reactions
involving nucleophilic attack at the ketone carbonyl and
(6) Romeo, G.; Russo, F.; De Blasi, A. J . Heterocycl. Chem. 2001,
38, 391-395.
(7) Stamford, A. W. Ann. Rep. Med. Chem. 2002, 37, 53-64.
(8) Amarnath, V.; Madhav, R. Synthesis 1974, 837-859.
(9) Selic, L.; Stanovnik, B. Heterocycles 1999, 51, 1087-1092.
(10) Lim, Mu-I.; Ren, Wu-Y.; Otter, B. A.; Klein, R. S. J . Org. Chem.
1983, 48, 780-788.
(14) Bailey, D. M.; J ohnson, R. E.; Albertson, N. F. Org. Synth. 1971,
51, 100-102.
(15) (a) Lindel, T.; Hochgu¨rtel, M. J . Org. Chem. 2000, 65, 2806-
2809. (b) Donohoe, T. J .; Guyo, P. M.; Beddoes, R. L.; Helliwell, M. J .
Chem. Soc., Perkin Trans. 1 1998, 667-676. (c) Little, T. L.; Webber,
S. E. J . Org. Chem. 1994, 59, 7299-7305. (d) Dumas, D. J . J . Org.
Chem. 1988, 53, 4650-4653.
(11) Elliott, A. J .; Montgomery, J . A.; Walsh, D. A. Tetrahedron Lett.
1996, 37, 4339-4340.
(12) Garcia-Lo`pez, M. T.; de las Heras, F. G.; Stud, M. J . Chem.
Soc., Perkin Trans. 1 1978, 483-487.
(13) Marcotte, F.-A.; Lubell, W. D. Org. Lett. 2002, 4, 2601-2603.
(16) Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J . Am. Chem.
Soc. 2000, 122, 10708-10709.
J . Org. Chem, Vol. 68, No. 18, 2003 6985

Marcotte et al.
TABLE 1. Isola ted Yield s of Ur eid op yr r oles a n d
hydroxide, as well as with saturated aqueous NaHCO3
overnight, caused deacetylation and urea 9a was recov-
ered. A more expedient procedure (B) was later developed
in which acylurea 11 was not isolated; instead, it was
treated directly with Cs2CO3. Product from this two-step
one-pot process could not be usually crystallized and a
chromatography on silica gel was necessary for isolating
pure deazapurine 12f-i. Cyclization of 3-phenylureas
11c,f,i proceeded significantly faster than their 3-alkyl
counterparts. Reactions of the former were usually
complete after 1 h; on the other hand, those of the latter
form required stirring overnight.
P yr r olo[3,2-d ]p yr im id in es
yield (%)
entry
R1
R2
9
12
a
b
c
d
e
f
g
h
i
CH2C6H5
CH2C6H5
CH2C6H5
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH2CHdCH2
CH2CHdCH2
CH2CHdCH2
CH2CH3
CH2CHdCH2
C6H5
CH2CH3
CH2CHdCH2
C6H5
CH2CH3
CH2CHdCH2
C6H5
88
92
94
93
94
99
88
91
92
75a
70a
59a
67a
66a
53b
79c
76c
69c
a
b
Procedure A. Procedure B. c Procedure B without crystal-
Con clu sion s
lization.
In summary, we have developed a novel method for
synthesizing pyrimidine-functionalized deazapurines. 2,4-
Dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-6-
carboxylic acid benzyl esters 12 were prepared in four
steps in 37-55% isolated overall yields from 4-oxo-N-
(PhF)proline benzyl ester 7. In light of the potential to
further modify the pyrrole core of deazapurine 12 by
transformations of the carboxylate as well as nitrogen
alkylation, our route should serve as a general method
for preparing libraries of structurally diverse pyrrolo[3,2-
d]pyrimidines that may exhibit interesting biological
activity.
expulsion of chloroform anion as leaving group. However,
to the best of our knowledge, no corresponding intramo-
lecular cyclization of a ureidopyrrole to deazapurine has
been reported. The analogous acylation of 4-ureidopyr-
role-2-carboxylates 9 was thus considered as a means for
preparing a similarly reactive intermediate 10 (Scheme
1), which could be converted to the desired pyrimidine
by an intramolecular haloform reaction. Intramolecular
cyclizations with trichloroacetyl chloride have previously
been used to make cyclic carbamates, cyclic ureas, hy-
droxypyrrazoles, and isoxazolones.17 Acylation of 4-ure-
idopyrrole 9 was effectively performed using 1000 mol
% of trichloroacetyl chloride in acetonitrile at reflux for
3 h. Acylation at the pyrrole 5-position was not observed;
instead, the proton NMR spectra of the product from
treatment of 9 with trichloroacetyl chloride indicated a
disappearance of the urea proton, which was either a
triplet between 4.36 and 4.79 ppm or a singlet between
6.38 and 6.64 ppm for the N-alkyl- and N-arylureidopyr-
roles 9, respectively. Additional proof that ketone 10 was
not produced, and N-acylurea 11 was formed instead,18
came from heterocorrelation NMR experiments. In the
HMQC NMR spectra of ureas 11a -e, a correlation was
seen respectively between the signals of the pyrrole
hydrogens (6.43-6.84 ppm) and their adjacent carbons
(112.6-121.5 ppm). Although, intermolecular acylation
had taken place at the urea nitrogen instead of at the
pyrrole 5-position, ring closure with displacement of
chloroform anion could still be effected by intramolecular
pyrrole acylation.
Exp er im en ta l Section
4-Isop r op yla m in o-1H-p yr r ole-2-ca r boxylic Acid Ben -
zyl Ester (8c). A stirred solution of benzyl N-PhF-4-oxopro-
linate (7, 1.50 g, 3.26 mmol) in 30 mL of THF was treated with
isopropylamine (1.11 mL, 13.04 mmol) followed by TsOH (62
mg, 0.33 mmol), heated to 50 °C, stirred for 8 h, and treated
with 100 mL of a solution of saturated aqueous NH4Cl followed
by 100 mL of EtOAc. The layers were separated, and the
aqueous layer was extracted with EtOAc (50 mL × 2). The
organic layers were combined, washed with brine, dried
(MgSO4), and concentrated to a residue that was purified by
column chromatography on silica gel using 30% ethyl acetate
in hexanes as eluant. Evaporation of the collected fractions
yielded pyrrole 8c (593 mg, 2.28 mmol, 70%) as a green oil.
1H NMR (400 MHz, CDCl3): δ 9.20 (s, 1H), 7.32-7.43 (m, 5H),
6.52 (s, 1H), 6.43 (s, 1H), 5.29 (s, 2H), 3.29 (m, 1H), 3.06 (s,
1H), 1.16 (d, J ) 6.3 Hz, 6H). 13C NMR (100 MHz, CDCl3): δ
161.4, 136.7, 136.2, 129.0, 128.6, 128.5, 120.9, 110.6, 106.3,
66.3, 48.5, 23.5. HRMS: calcd for C15H18N2O2 258.1368, found
258.1368.
Typ ica l P r oced u r e for Ur ea Syn th esis: 4-(1-Ben zyl-3-
eth ylu r eid o)-1H-p yr r ole-2-ca r boxylic Acid Ben zyl Ester
(9a ). A stirred solution of pyrrole 8 (8a , 317 mg, 1.04 mmol,
prepared as described in ref 13) in 20 mL of dry CH2Cl2, was
treated with ethyl isocyanate (90 µL, 1.10 mmol) and stirred
for 2 h at room temperature. Solvent was removed under
reduced pressure. The residue was purified on a short column
of silica gel using 20% ethyl acetate in hexanes as eluant.
Evaporation of the collected fractions yielded urea 9a (345 mg,
0.915 mmol, 88%) as a white powder. Mp: 165.3-166.0 °C. 1H
NMR (400 MHz, CDCl3): δ 9.98 (s, 1H), 7.28-7.41 (m, 5H),
7.21-7.26 (m, 5H), 6.70 (d, J ) 1.8 Hz, 1H), 6.59 (d, J ) 1.8
Hz, 1H), 5.27 (s, 2H), 4.75 (s, 2H), 4.64 (t, J ) 5.5 Hz, 1H),
3.22 (q, J ) 7.1 Hz, 2H), 1.06 (t, J ) 7.3 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 160.9, 158.1, 139.3, 136.2, 129.0, 128.9,
128.7, 128.6, 128.5, 127.5, 127.3, 122.3, 121.4, 114.0, 66.7, 53.5,
36.1, 15.9. HRMS: calcd for [M + H+] C22H24N3O3 378.1818,
found 378.1800.
The cyclization of 11 to the corresponding pyrrolo[3,2-
d]pyrimidines was initially performed using 1000 mol %
of cesium carbonate in acetonitrile at room temperature.
The corresponding pyrimidines 12a -e were isolated in
59-75% overall yields (Table 1) after this two-step
procedure (A) and recrystallization. Excess of trichloro-
acetyl chloride was destroyed in procedure A by a brief
washing of the reaction mixture with saturated aqueous
NaHCO3. Treatments of acylurea 11a with ammonium
(17) (a) Ogawa, H.; Tamada, S.; Fujioka, T.; Teramoto, S.; Kondo,
K.; Yamashita, S.; Yabuuchi, Y.; Tominaga, M.; Nakagawa, K. Chem.
Pharm. Bull. 1988, 36, 2401-2409. (b) Yamamoto, M.; Yamamoto, H.
Chem. Pharm. Bull. 1981, 29, 2135-2156. (c) Flores, A. F. C.; Zanatta,
N.; Rosa, A.; Brondani, S.; Martins, M. A. P. Tetrahedron Lett. 2002,
43, 5005-5008. (d) Friesen, R. W.; Kolaczewska, A. E. J . Org. Chem.
1991, 56, 4888-4895.
(18) An alternative approach for synthesizing N-tricholoroacetyl
ureas is reported in: Knapp, S.; Shieh, W.-C.; J aramillo, C.; Trilles,
R. V.; Nandan, S. R. J . Org. Chem. 1994, 59, 946-948 and ref 30
therein.
Syn th esis of 1H-P yr r olo[3,2-d ]p yr im id in es 12. P r oce-
d u r e A. A solution of 100 mg of urea 9 (100 mol %) in 10 mL
6986 J . Org. Chem., Vol. 68, No. 18, 2003

Synthesis of Functionalized Pyrrolo[3,2-d]pyrimidines
of dry acetonitrile was treated with 1000 mol % of distilled
trichloroacetyl chloride, stirred with heating at reflux for 3 h,
cooled to room temperature, and quenched with 25 mL of a
saturated aqueous solution of NaHCO3. Extraction of the
aqueous phase with ethyl acetate (3 × 20 mL) followed by
washing of the combined organic layers with brine, drying on
anhydrous MgSO4, and removal of the solvent yielded the
crude acetylated compound 11. Peak listings for the proton
NMR data of 11a -e have been reported in the Supporting
Information. This residue was dissolved in 10 mL of dry
acetonitrile, treated with 1000 mol % of Cs2CO3, and stirred
for 1 h in the case of 3-phenylureas or overnight in the case of
3-alkylureas. The reaction was quenched with 25 mL of a
saturated aqueous solution of NH4Cl, and the aqueous phase
was extracted with 3 × 20 mL of ethyl acetate. Washing of
the combined organic layers with brine followed by drying on
anhydrous MgSO4 and removal of the solvent yielded the crude
deazapurine, which was crystallized from toluene; an ad-
ditional crop may be obtained on addition of hexanes. P r oce-
d u r e B. A solution of 100 mg of urea 9 (100 mol %) in 10 mL
of dry acetonitrile was treated with 1000 mol % of distilled
trichloroacetyl chloride, stirred at reflux for 3 h, cooled to room
temperature, treated with 1000 mol % of Cs2CO3, stirred for
12 h, and quenched with 25 mL of a saturated solution of NH4-
Cl. The aqueous phase was separated and extracted with 3 ×
20 mL of ethyl acetate. Washing of the combined organic layers
with brine, drying on anhydrous MgSO4, and removal of the
solvent yielded the crude deazapurine, which was purified by
flash column chromatography on silica gel using a gradient of
20-50% EtOAc in hexanes. Evaporation of the collected
fractions gave a residue that was crystallized from toluene
with added hexanes.
1-Ben zyl-3-et h yl-2,4-d ioxo-2,3,4,5-t et r a h yd r o-1H -p yr -
r olo[3,2-d ]p yr im id in e-6-ca r b oxylic Acid Ben zyl E st er
(12a ). P r oced u r e A. Yield: 75% as a crystalline white solid.
Mp: 190.8-191.8 °C. IR (KBr, cm-1): 3214.3 (NH), 1725.3,
1
1696.2, 1648.2 (CdO). H NMR (400 MHz, CDCl3): δ 9.98 (s,
1H), 7.42-7.31 (m, 10H), 6.58 (d, J ) 2 Hz, 1H), 5.34 (s, 2H),
5.14 (s, 2H), 4.15 (q, J ) 7 Hz, 2H), 1.29 (t, J ) 7 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 159.7, 155.3, 151.1, 135.6, 135.0,
133.8, 128.8, 128.7, 128.6, 127.9, 127.8, 127.3, 113.8, 99.9, 67.3,
48.9, 37.0, 13.3. HRMS: calcd for C23H21N3O4 403.1532, found
403.1513. Anal. Calcd for C23H21N3O4: C, 68.47; H, 5.25; N,
10.42. Found: C, 68.07; H, 5.45; N, 10.19.
Ack n ow led gm en t. This research was supported in
part by the NSERC of Canada, the Ministe`re de l’EÄ du-
cation du Que´bec (FQRNT), and Valorisation-Recherche
Que´bec. F.-A.M. thanks NSERC for a postgraduate
scholarship.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal information, characterization data for 9b-i, 11a -e, and
12b-i, 1H and 13C spectra for compound 8c, 9a -i, 11a -e, and
12a -i, and HMQC NMR spectra of ureas 11a -e. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
J O034684F
J . Org. Chem, Vol. 68, No. 18, 2003 6987