Studies on Pyrimidine-Annelated Heterocycles: Synthesis of Pyrrolo[3,2-d]pyrimidines by Amine Oxide Rearrangement

Article abstract of DOI:10.1021/jo9718861

A number of pyrrolo[3,2-d]pyrimidine derivatives (5a-f) were synthesized in 90-95% yields from the corresponding 5-[N-[4-(aryloxy)but-2-ynyl]-N-ethylamino]-1,3-dimethyluracils 4a-f by simple treatment with 1 equiv of m-chloroperoxybenzoic acid in dichloromethane at 0-5 °C for 12-15 h. The resulting benzoates (5a-f) were easily converted to methoxy derivatives 11a-f in 92-94% yields when refluxed in methanol for 20-22 h.

Full text of DOI:10.1021/jo9718861

3550
J . Org. Chem. 1998, 63, 3550-3553
Stu d ies on P yr im id in e-An n ela ted Heter ocycles: Syn th esis of
P yr r olo[3,2-d ]p yr im id in es by Am in e Oxid e Rea r r a n gem en t
K. C. Majumdar,* U. Das, and N. K. J ana
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
Received October 14, 1997 (Revised Manuscript Received March 17, 1998)
A number of pyrrolo[3,2-d]pyrimidine derivatives (5a -f) were synthesized in 90-95% yields from
the corresponding 5-[N-[4-(aryloxy)but-2-ynyl]-N-ethylamino]-1,3-dimethyluracils 4a -f by simple
treatment with 1 equiv of m-chloroperoxybenzoic acid in dichloromethane at 0-5 °C for 12-15 h.
The resulting benzoates (5a -f) were easily converted to methoxy derivatives 11a -f in 92-94%
yields when refluxed in methanol for 20-22 h.
Sch em e 1
In tr od u ction
The importance of pyrimidine and its derivatives is
well-known.1,2 Numerous pyrimidine and uracil-based
molecules,3 e.g., 3′-azido-3′-deoxythymidine (AZT), 2′,3′-
dideoxycytidine (DDC), (E)-5-[2-(bromovinyl)-2′-deoxyuri-
dine] (BVDU), active against cancer and AIDS viruses,4
have already been synthesized. Functionalization of
uracils at the C-5 and C-6 positions leads to biologically
interesting molecules but it is not a simple task; it
requires rather sophisticated and tedious reaction condi-
tions.5 6-Substituted uracils have been recently found
to be active against HIV and other viruses.6 [3,3]
Sigmatropic rearrangement is an excellent method for
C-C bond formation. We have recently reported facile
formation of furo[3,2-d]pyrimidines and pyrano[3,2-d]-
pyrimidines in excellent yields from the corresponding
5-(propargyloxy)uracils. Amine oxide rearrangement is
an excellent method7 for C-C bond formation as well as
the construction of the pyrrole ring in fused heterocycles.
This is a very mild and simple method affording fused
pyrroles in almost quantitative yields. This prompted
us to undertake a study on the synthesis of pyrrolo[3,2-
d]pyrimidine derivatives by the application of sigmatropic
rearrangements of suitably substituted amine oxides. We
now report the results of this investigation.
The starting materials for this study, 5-[N-[4-(aryloxy-
)but-2-ynyl]-N-ethylamino]-1,3-dimethyluracils were pre-
pared in 92-96% yields by the reaction of 1,3-dimethyl-
5-(N-ethylamino)uracil (2) with different 1-(aryloxy)-4-
chlorobut-2-ynes (3) in refluxing acetone in the presence
of anhydrous potassium carbonate for 20-22 h. 1,3-
Dimethyl-5-(N-ethylamino)uracil (2) in turn was pre-
pared in 80% yield from 5-bromo-1,3-dimethyluracil (1)
by heating with excess aqueous ethylamine (40%) on a
water bath for 1 h (Scheme 1).
(1) (a) Lunt, E. In Comprehensive Organic Chemistry; Barton, D.,
Ollis, W. D., Eds.; Pergamon Press: Oxford, 1974; Vol. 4, p 493. (b)
Brown, J . D. In Comprehensive Heterocyclic Chemistry; Katrizky, A.
R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol. 3, p 57. (c)
Sasaki, T.; Minamoto, K.; Suzuki, T.; Yamashita, S. Tetrahedron 1980,
36, 865 and references therein. (d) Bradshow, T. K.; Hutchison, D. W.
Chem. Soc. Rev., 1977, 6, 43.
(2) (a) Marumoto, R.; Furukawa, Y. Chem. Pharm. Bull. 1977, 25,
2974. (b) Cheng, C. C.; Roth, B. Prog. Med. Chem. 1971, 8, 61. (c) J ones,
A. S.; Swgers, J . R.; Walker, R. T.; Clercq, E. D. J . Med. Chem., 1988,
31, 268. (d) Griengl, H.; Wanck, E.; Schwarz, W.; Streicher, W.;
Rosenwirth, B.; Clercq, E. D. J . Med. Chem. 1987, 30, 1199. (e) Clercq,
E. D.; Bernaerts, R. J . Boil. Chem. 1987, 262, 14905.
(3) (a) Macilwain, C. Nature 1993, 365, 378. (b) Balzarini, J .;
Pauwels, R.; Hardewijn, P.; Clercq, E. De.; Cooney, D. A.; Kanj, G. J .;
Dalai, M.; J ohns, D. G.; Broder, S. Biochem. Biophys. Res. Commun.,
1986, 140, 735. (c) J ones, A. S.; Sugers, J . R.; Walker, R. T.; Clercq, E.
De. J . Med. Chem. 1988, 31, 268.
(4) (a) Miyasaka, T.; Tanaka, H.; Baba, M.; Hayasaka, H.; Walker,
R. T.; Balzarini, J .; Clercq, E. De. J . Med. Chem. 1989, 32, 2507. (b)
Baba, M.; Panwels, R.; Herdwig, P.; Clercq, E. De.; Desmyster, J .;
Vandepulfe, M. Biochem. Biophy. Res. Commun., 1987, 142, 128. (c)
Clercq, E. De. J . Med. Chem. 1986, 29, 1561. Clercq, E. De. Anticancer.
Res. 1986, 6, 549.
(5) (a) Kundu, N. G.; Das, P. J . Chem. Soc., Chem. Commun. 1995,
99. (b) Botta, M.; Saladino, R.; Lamba, D.; Nicolelli, R. Tetrahedron
1993, 49, 6053. (c) Kundu, N. G.; Dasgupta, S. K. J . Chem. Soc., Perkin
Trans. 1 1993, 2657.
(6) (a) Baba, M.; Tanaka, H.; Clercq, E. De.; Pauwels, R.; Balzarini,
J .; Schols, D.; Nakashima, H.; Perno, C. F.; Walker, R. T.; Miyasaka,
T. Biochem. Biophys. Res. Commun. 1989, 165, 1375. (b) Clercq, E.
De. Med. Res. Rev. 1993, 13, 229. (c) Gallo, R. C. Sci. Am. 1986, 255,
78; 1987, 256, 46. (d) Schroeder, A. C.; Bloch, A.; Perlman, J . L.; Bobek,
M. J . Med. Chem. 1982, 25, 1255.
Resu lts a n d Discu ssion
Substrates 4a -f contain a propargylamine moiety. As
our aim was to use sigmatropic rearrangement for the
formation of the C-C single bond at the C-6 position of
(7) (a) Thyagarajan, B. S.; Hillard, J . B.; Reddy, K. V.; Majumdar,
K. C. Tetrahedron Lett. 1974, 1999. (b) Hillard, J .; Reddy, K. V.;
Majumdar, K. C.; Thyagarajan, B. S. J . Heterocycl. Chem. 1974, 11,
369. (c) Thyagarajan, B. S.; Majumdar, K. C. J . Heterocyl. Chem. 1975,
12, 43. (d) Majumdar, K. C.; Chattopadhyay, S. K. J . Chem. Soc., Chem.
Commun. 1987, 524. (e) Majumdar, K. C.; Chattopadhyay, S. K.; Khan,
A. T. J . Chem. Soc., Perkin Trans. 1 1989, 1285. (f) Majumdar, K. C.;
Ghosh, S. K. J . Chem. Soc., Perkin Trans 1. 1994, 2889.
S0022-3263(97)01886-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 05/13/1998

Studies on Pyrimidine-Annelated Heterocycles
J . Org. Chem., Vol. 63, No. 11, 1998 3551
Sch em e 2
the uracils 4a -f, we considered the well-known amine
oxide rearrangement methodology for the construction
of fused pyrrole rings. This was shown to be an excellent
one-step process, and the fused pyrroles were obtained
in almost quantitive yields simply by stirring a solution
of the arylpropargylamine in dichloromethane at room
temparature with 1 equiv of m-chloroperoxybenzoic acid
(m-CPBA). We therefore decided to find whether the five-
membered pyrrole ring with a 5,6-double bond in the
uracil moiety could be constructed via the aforesaid
amine oxide rearrangement. Consequently, the tertiary
amine 4a was treated with 1 equiv of m-chloroperoxy-
benzoic acid in dichloromethane at ambient temperature
to provide pyrrolopyrimidine derivative 5a as a sole
isolable compound (95%, mp 150 °C). Thus, all the
remaining substrates 4b-f have also been similarly
treated to furnish the corresponding pyrrolopyrimidine
derivatives 5b-f (Scheme 2).
The formation of the pyrrolopyrimidine derivatives 5
from 4 is easily explicable8 by the formation of the
N-oxide 6 followed by a [2,3]-sigmatropic rearrangement9
to give the intermediate 7, which subsequently undergoes
a [3,3]-sigmatropic rearrangement10 and ketolization to
give ketol 9. Presumably, intermediate 9 first loses water
in acid-catalyzed elimination to give iminium ion 10,
which is then added to benzoic acid (a poor nucleophile)
(Scheme 2).
Sch em e 3
In conclusion, this is an extremely facile and mild
synthesis of pyrrolo[3,2-d]pyrimidine derivatives. The
generality of the method has been demonstrated by the
successful conversion of six substrates 4a -f into pyrrol-
opyrimidine derivatives 5a -f in excellent yields. These
materials have the potential to be useful as drugs. The
methodology described here seems to be the simplest one
for the synthesis of these compounds.
Exp er im en ta l Section
Melting points are uncorrected. UV absorption spectra were
recorded in EtOH. IR spectra were run for KBr disks. 1H
NMR spectra were determined for solutions in CDCl3 with
TMS as internal standard. Elemental analyses and recording
of mass spectra [J EOL D-300 (EI)] were carried out at RSIC
(CDRI), Lucknow. Silica gel (60-120 mesh) was used for
chromatographic separation. Petroleum ether refers to the
fraction boiling between 60 and 80 °C.
P r ep a r a tion of 1,3-Dim eth yl-5-(eth yla m in o)u r a cil (2).
A mixture of 5-bromo-1,3-dimethyluracil (11.0 g, 50 mmol) and
40% aqueous EtNH2 (50 mL) was refluxed on a water bath
for 1 h. The reaction mixture was evaporated to dryness, and
the residue was extracted with CHCl3 (3 × 25 mL). The CHCl3
extract was washed with water and dried (Na2SO4). The
solvent was removed to give a solid that was recrystallized
from CHCl3-petroleum ether.
The m-chlorobenzoate group of the pyrrolopyrimidine
derivatives 5a -f is easily replaced by a methoxy group
by refluxing compounds 5a -f in absolute methanol for
20-22 h to give a series of methoxy derivatives 11a -f
(Scheme 3). This can be achieved in 1 h if catalytic
amount of hydrochloric acid is added to the reaction
mixture.
(8) Majumdar, K. C.; Biowas, P.; J ana, G. H. J . Chem. Res., Synop.
1997, 310; J . Chem. Res., Miniprint 1997, 2068.
(9) Majumdar, K. C.; J ana, G. H. J . Org. Chem. 1997, 62, 1506.
(10) Majumdar, K. C.; Thyagarajan, B. S. J . Chem. Soc., Chem.
Commun. 1972, 83.
1,3-Dim eth yl-5-(eth yla m in o)u r a cil (2): yield 80%; mp
102 °C; λmax (log ꢀ) 240 (2.90), 312 (2.83) nm; IR (KBr) νmax
3350, 1690, 1660, 1630 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.28 (t, J ) 10.5 Hz, 3H), 2.91 (q, J ) 10.5 Hz, 2H), 3.37 (s,

3552 J . Org. Chem., Vol. 63, No. 11, 1998
Majumdar et al.
3H), 3.38 (s, 3H), 6.06 (s, 1H), 6.80 (s, 1H); MS m/z 183 (M+).
Anal. Calcd for C8H13N3O2: C, 52.45; H, 7.10; N, 22.95.
Found: C, 52.55; H, 7.17; N, 23.02.
7-[[(3′-Ch lor ob en zoyl)oxy]m et h yl]-6-[(2′-ch lor op h e-
n oxy)m eth yl]-1,3-d im eth yl-5-eth ylp yr r olo[3,2-d ]p yr im i-
d in e-2,4-d ion e (5a ): yield 95%; mp 150 °C; λmax (log ꢀ) 224
(3.16), 273 (2.72) nm; IR (KBr) νmax 1715, 1690, 1650 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.45 (t, J ) 7.5 Hz, 3H), 3.44 (s,
3H), 3.81 (s, 3H), 4.49 (q, J ) 7.5 Hz, 2H), 5.30 (s, 2H), 5.50
(s, 2H), 7.36-7.46 (m, 6H), 7.86-7.92 (m, 2H); MS m/z 520,
516 (M+). Anal. Calcd for C25H23Cl2N3O5: C, 58.13; H, 4.45;
N, 8.13. Found: C, 58.19; H, 4.55; N, 8.33.
7-[[(3′-Ch lor ob en zoyl)oxy]m et h yl]-6-[(4′-ch lor op h e-
n oxy)m eth yl]-1,3-d im eth yl-5-eth ylp yr r olo[3,2-d ]p yr im i-
d in e-2,4-d ion e (5b): yield 90%; mp 160 °C; λmax (log ꢀ) 228
(3.62), 273 (3.19) nm; IR (KBr) νmax 1710, 1690, 1640 cm-1; 1H
NMR (300 MHz, CDCl3) δ 1.43 (t, J ) 7.5 Hz, 3H), 3.44 (s,
3H), 3.81 (s, 3H), 4.49 (q, J ) 7.5 Hz, 2H), 5.21 (s, 2H), 5.48
(s, 2H), 6.95 (dt, J ) 8.5, 1.5 Hz, 2H), 7.36 (q, J ) 7.5 Hz, 4H),
7.54 (d, J ) 7.8 Hz, 1H), 7.86 (d, J ) 7.8 Hz, 1H); MS m/z 520,
516 (M+). Anal. Calcd for C25H23Cl2N3O5: C, 58.13; H, 4.45;
N, 8.13. Found: C, 58.23; H, 4.56; N, 8.27.
7-[[(3′-Ch lor oben zoyl)oxy]m eth yl]-1,3-dim eth yl-5-eth yl-
6-(p h en oxym et h yl)p yr r olo[3,2-d ]p yr im id in e-2,4-d ion e
(5c): yield 91%; mp 145 °C; λmax (log ꢀ) 225 (3.60), 272 (3.20)
nm; IR (KBr) νmax 1710, 1685, 1645 cm-1; 1H NMR (300 MHz,
CDCl3) δ 1.45 (t, J ) 7.5 Hz, 3H), 3.45 (s, 3H) 3.80 (s, 3H),
4.51 (q, J ) 7.5 Hz, 2H), 5.23 (s, 2H), 5.49 (s, 2H), 7.03 (t, J )
7.5 Hz, 3H), 7.36 (q, J ) 7.5 Hz, 4H) 7.54 (d, J ) 7.8 Hz, 1H),
7.86 (d, J ) 7.8 Hz, 1H); MS m/z 483, 481 (M+). Anal. Calcd
for C25H24ClN3O5: C, 62.30; H, 4.98; N, 8.72. Found: C, 62.44;
H, 5.10; N, 8.83.
7-[[(3′-Ch lor oben zoyl)oxy]m eth yl]-1,3-dim eth yl-5-eth yl-
6-[(4′-m eth oxyph en oxy)m eth yl]pyr r olo[3,2-d]pyr im idin e-
2,4-d ion e (5d ): yield 94%; mp 174 °C; λmax (log ꢀ) 226 (3.48),
267 (2.98) nm; IR (KBr) νmax 1705, 1680, 1640 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.44 (t, J ) 7.5 Hz, 3H), 3.44 (s, 3H), 3.76
(s, 3H), 3.79 (s, 3H), 4.51 (q, J ) 7.5 Hz, 2H), 5.16 (s, 2H),
5.46 (s, 2H), 6.86-6.92 (m, 4H), 7.36 (t, J ) 7.5 Hz, 1H), 7.48-
7.56 (m, 1H), 7.87 (d, J ) 1.5 Hz, 1H), 7.94 (t, J ) 1.5 Hz,
1H); MS m/z 513, 511 (M+). Anal. Calcd for C26H26ClN3O6:
C, 60.99; H, 5.08; N, 8.21. Found: C, 61.05; H, 5.19; N, 8.33.
7-[[(3′-Ch lor oben zoyl)oxy]m eth yl]-1,3-dim eth yl-5-eth yl-
6-[(4′-m eth ylp h en oxy)m eth yl]p yr r olo[3,2-d ]p yr im id in e-
2,4-d ion e (5e): yield 94%; mp 151 °C; λmax (log ꢀ) 224 (3.65),
274 (3.26) nm; IR (KBr) νmax 1710, 1690, 1640 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.45 (t, J ) 10.5 Hz, 3H), 2.29 (s, 3H),
3.42 (s, 3H), 3.71 (s, 3H), 4.49 (q, J ) 10.5 Hz, 2H), 5.17 (s,
2H), 5.45 (s, 2H), 6.80-6.86 (m, 2H), 6.96-7.20 (m, 2 H), 7.26-
7.38 (m, 1H), 7.48-7.54 (m, 1H), 7.84-7.90 (m, 1H); MS m/z
497, 495 (M+). Anal. Calcd for C26H26ClN3O5: C, 62.96; H,
5.24; N, 8.47. Found: C, 62.77; H, 5.31; N, 8.33.
P r ep a r a tion of 1-(Ar yloxy)-4-ch lor obu t-2-yn e. These
compounds were prepared according to published procedures.7a,e,f
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
4a -f. A mixture of 1-(aryloxy)-4-chlorobut-2-yne (4 mmol),
1,3-dimethyl-5-(ethylamino)uracil (0.732 g, 4 mmol), anhyd K2-
CO3 (3 g), and NaI (0.05 g) was refluxed in dry Me2CO (75
mL) for 18-22 h. The solvent was removed, and the residual
solid was subjected to column chromatography over silica gel.
The products 4a -f were obtained as viscous liquids when the
column was eluted with benzene-ethyl acetate (3:1).
5-[N-[4-(2′-Ch lor op h en oxy)bu t-2-yn yl]-N-eth yla m in o]-
1,3-d im eth ylu r a cil (4a ): yield 96%; liquid; λmax (log ꢀ) 223
(3.34), 275 (2.95) nm; IR (KBr) νmax 1690, 1640 cm-1; 1H NMR
(100 MHz, CDCl3) δ 1.08 (t, J ) 7.5 Hz, 3H), 2.94 (q, J ) 7.5
Hz, 2H), 3.28 (s, 3H), 3.34 (s, 3H), 3.96 (t, J ) 1.5 Hz, 2H), 4.8
(t, J ) 1.5 Hz, 2H), 6.68 (s, 1H), 6.88-7.44 (m, 4H); MS m/z
363, 361 (M+). Anal. Calcd for C18H20ClN3O3: C, 59.75; H,
5.53; N, 11.61. Found: C, 59.83; H, 5.65; N, 11.71.
5-[N-[4-(4′-Ch lor op h en oxy)bu t-2-yn yl]-N-eth yla m in o]-
1,3-d im eth ylu r a cil (4b): yield 92%; liquid; λmax (log ꢀ) 226
(3.36), 275 (2.80) nm; IR (KBr) νmax 1695, 1640 cm-1; 1H NMR
(100 MHz, CDCl3) δ 1.08 (t, J ) 7.5 Hz, 3H), 2.94 (q, J ) 7.5
Hz, 2H), 3.28 (s, 3H), 3.34 (s, 3H), 3.96 (t, J ) 1.5 Hz, 2H),
4.68 (t, J ) 1.5 Hz, 2H), 6.66 (s, 1H), 6.82-6.98 (dt, J ) 8.5,
1.5 Hz, 2H), 7.18-7.32 (dt, J ) 8.5, 1.5 Hz, 2H); MS m/z 363,
361 (M+). Anal. Calcd for C18H20ClN3O3: C, 59.75; H, 5.53;
N, 11.61. Found: C, 59.87; H, 5.55; N, 11.77.
1,3-Dim eth yl-5-[N-(4-p h en oxybu t-2-yn yl)-N-eth yla m i-
n o]u r a cil (4c): yield 93%; liquid; λmax (log ꢀ) 223 (3.40), 297
(2.97) nm; IR (KBr) νmax 1685, 1635, 1210 cm-1; 1H NMR (100
MHz, CDCl3) δ 1.08 (t, J ) 7.5 Hz, 3H), 2.94 (q, J ) 7.5 Hz,
2H), 3.2 (s, 3H), 3.32 (s, 3H), 3.96 (t, J ) 1.5 Hz, 2H), 4.7 (t, J
) 1.5 Hz, 2H), 6.64 (s, 1H), 6.92-7.40 (m, 5H); MS m/z 327
(M+). Anal. Calcd for C18H21N3O3: C, 66.05; H, 6.42; N, 12.84.
Found: C, 66.15; H, 6.53; N, 12.92.
1,3-Dim eth yl-5-[N-[4-(4′-m eth oxyp h en oxy)bu t-2-yn yl]-
N-eth yla m in o]u r a cil (4d ): yield 93%; liquid; λmax (log ꢀ) 226
(3.40), 290 (3.06) nm; IR (KBr) νmax 1685, 1630 cm-1; 1H NMR
(100 MHz, CDCl3) δ 1.08 (t, J ) 7.5 Hz, 3H), 2.94 (q, J ) 7.5
Hz, 2H), 3.24 (s, 3H), 3.32 (s, 3H), 3.78 (s, 3H), 3.96 (t, J ) 1.5
Hz, 2H), 4.65 (t, J ) 1.5 Hz, 2H), 6.68 (s, 1H), 6.84-6.88 (m,
4H); MS m/z 357 (M+). Anal. Calcd for C19H23N3O4: C, 63.86;
H, 6.44; N, 11.76. Found: C, 63.92; H, 6.55; N, 11.79.
1,3-Dim eth yl-5-[N-[4-(4′-m eth ylp h en oxy)bu t-2-yn yl]-N-
eth yla m in o]u r a cil (4e): yield 94%; liquid; λmax (log ꢀ) 223
(3.24), 297 (2.76) nm; IR (KBr) νmax 1685, 1635 cm-1; 1H NMR
(100 MHz, CDCl3) δ 1.08 (t, J ) 7.5 Hz, 3H), 2.28 (s, 3H), 2.94
(q, J ) 7.5 Hz, 2H), 3.2 (s, 3H), 3.34 (s, 3H), 3.96 (t, J ) 1.5
Hz, 2H), 4.72 (t, J ) 1.5 Hz, 2H), 6.64 (s, 1H), 6.8-7.4 (m,
4H); MS m/z 341 (M+). Anal. Calcd for C19H23N3O3: C, 66.86;
H, 6.74; N, 12.31. Found: C, 66.95; H, 6.77; N, 12.44.
1,3-Dim eth yl-5-[N-[4-(2′-m eth ylp h en oxy)bu t-2-yn yl]-N-
eth yla m in o]u r a cil (4f): yield 95%; liquid; λmax (log ꢀ) 223
(3.07), 297 (2.67) nm; IR (KBr) νmax 1690, 1640, cm-1; 1H NMR
(100 MHz, CDCl3) δ 1.08 (t, J ) 7.5 Hz, 3H), 2.22 (s, 3H), 2.94
(q, J ) 7.5 Hz, 2H), 3.2 (s, 3H), 3.34 (s, 3H), 3.96 (t, J ) 1.5
Hz, 2H), 4.72 (t, J ) 1.5 Hz, 2H), 6.64 (s, 1H), 6.82-7.4 (m,
4H); MS m/z 341 (M+). Anal. Calcd for C19H23N3O3: C, 66.86;
H, 6.74; N, 12.31. Found: C, 66.99; H, 6.69; N, 12.42.
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
5a -f. A solution of m-chloroperbenzoic acid (0.35 g, 1 mmol)
in CH2Cl2 (20 mL) was added dropwise to a well-stirred
solution of 4a -f (1 mmol) in CH2Cl2 (20 mL) at 0-5 °C during
15 min. The mixture was stirred for an additional 12-15 h
at room temperature. The reaction mixture was then succes-
sively washed with 10% aqueous Na2CO3 (3 × 50 mL) and
water (3 × 50 mL) and dried (Na2SO4). The solvent was
evaporated to give a crude residue that was purified by
chromatography over silica gel, eluted with benzene-ethyl
acetate (9:1). All the products 5a -f were recrystallized from
CHCl3-petroleum ether.
7-[[(3′-Ch lor oben zoyl)oxy]m eth yl]-1,3-dim eth yl-5-eth yl-
6-[(2′-m eth ylp h en oxy)m eth yl]p yr r olo[3,2-d ]p yr im id in e-
2,4-d ion e (5f): yield 94%; mp 138 °C; λmax (log ꢀ) 225 (3.51),
273 (3.19) nm; IR (KBr) νmax 1710, 1685, 1640 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.44 (t, J ) 10.5 Hz, 3H), 2.13 (s, 3H),
3.42 (s, 3H), 3.80 (s, 3H), 4.53 (q, J ) 10.5 Hz, 2H), 5.20 (s,
2H), 5.45 (s, 2H), 6.90-6.96 (m, 2H), 7.48-7.52 (m, 1 H), 7.84-
7.88 (m, 2H); MS m/z 497, 495 (M+). Anal. Calcd for
C
26H26ClN3O5: C, 62.96; H, 5.24; N, 8.47. Found: C, 62.99;
H, 5.35; N, 8.45.
Gen er a l P r oced u r e for t h e Syn t h esis of Com p ou n d
11a -f. The benzoates 5a -f (0.5 mmol) in dry methanol (25
mL) were refluxed on a water bath for 20-22 h. Methanol
was removed, and the residual mass was extracted with
CHCl3. The CHCl3 solution was then washed with 5% aqueous
Na2CO3 (3 × 25 mL) and water (3 × 10 mL) and dried over
Na2SO4. The solvent was removed to give a crude residue that
was purified by chromatography over silica gel. Compounds
11a -f were obtained when the column was eluted with
benzene-ethyl acetate (3:1). All the products 11a -f were
recrystallized from CHCl3-petroleum ether. This was achieved
in 1 h when one drop of HCl was added to the compound 5
(0.1 mmol) in MeOH (5 mL).
6-[(2′-Ch lor op h en oxy)m eth yl]-1,3-d im eth yl-5-eth yl-7-
(m e t h oxym e t h yl)p yr r olo[3,2-d ]p yr im id in e -2,4-d ion e
(11a ): yield 94%; mp 188 °C; λmax (log ꢀ) 224 (3.01), 273 (2.69)

Studies on Pyrimidine-Annelated Heterocycles
J . Org. Chem., Vol. 63, No. 11, 1998 3553
nm; IR (KBr) νmax 1680, 1645 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.45 (t, J ) 7.5 Hz, 3H), 3.38 (s, 3H), 3.44 (s, 3H), 3.76 (s,
3H), 4.49 (q, J ) 7.5 Hz, 4H), 5.1 (s, 2H), 7.10-7.24 (m, 2H),
7.42-7.46 (m, 2H); MS m/z 393, 391 (M+). Anal. Calcd for
C19H22ClN3O4: C, 58.23; H, 5.61; N, 10.72. Found: C, 58.29;
H, 5.77; N, 10.77.
δ 1.40 (t, J ) 7.5 Hz, 3H), 3.37 (s, 3H), 3.43 (s, 3H), 3.73 (s,
3H), 3.79 (s, 3H), 4.47 (q, J ) 7.5 Hz, 4H), 4.98 (s, 2H), 6.88-
6.92 (m, 4H); MS m/z 387 (M+). Anal. Calcd for C20H25N3O5:
C, 62.01; H, 6.45; N, 10.85. Found: C, 62.11; H, 6.55; N, 10.93.
1,3-Dim et h yl-5-et h yl-7-(m et h oxym et h yl)-6-[(4′-m et h -
ylp h en oxy)m et h yl]p yr r olo[3,2-d ]p yr im id in e-2,4-d ion e
(11e): yield 95%; mp 140 °C; λmax (log ꢀ) 225 (3.05), 275 (2.76)
nm; IR (KBr) νmax 1685, 1645 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.41 (t, J ) 10.5 Hz, 3H), 2.33 (s, 3H), 3.35 (s, 3H),3.42 (s,
3H), 3.73 (s, 3H), 4.47 (q, J ) 7.5 Hz, 4H), 4.98 (s, 2H), 6.84
(d, J ) 2.5 Hz, 2H), 7.11 (d, J ) 12 Hz, 2H); MS m/z 371 (M+).
Anal. Calcd for C20H25N3O4: C, 64.69; H, 6.73; N, 11.32.
Found: C, 64.82; H, 6.81; N, 11.38.
6-[(4′-Ch lor op h en oxy)m eth yl]-1,3-d im eth yl-5-eth yl-7-
(m e t h oxym e t h yl)p yr r olo[3,2-d ]p yr im id in e -2,4-d ion e
(11b): yield 92%; mp 182 °C; λmax (log ꢀ) 228 (3.50), 272 (3.18)
nm; IR (KBr) νmax 1685, 1640 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.40 (t, J ) 7.5 Hz, 3H), 3.38 (s, 3H), 3.43 (s, 3H), 3.73 (s,
3H), 4.46 (q, J ) 7.5 Hz, 4H), 5.01 (s, 2H), 6.90-6.96 (m, 2H),
7.26-7.30 (m, 2H); MS m/z 393, 391 (M+). Anal. Calcd for
C
19H22ClN3O4: C, 58.23; H, 5.61; N, 10.72. Found: C, 58.33;
1,3-Dim et h yl-5-et h yl-7-(m et h oxym et h yl)-6-[(2′-m et h -
ylp h en oxy)m et h yl]p yr r olo[3,2-d ]p yr im id in e-2,4-d ion e
(11f): yield 95%; mp 148 °C; λmax (log ꢀ) 224 (3.50), 272 (3.20)
nm; IR (KBr) νmax; 1685, 1640 cm-1; 1H NMR (300 MHz, CDCl3)
δ 1.41 (t, J ) 10.5 Hz, 3H), 2.16 (s, 3H), 3.34 (s, 3H), 3.42 (s,
3H), 3.73 (s, 3H), 4.49 (q, J ) 10.5 Hz, 4H), 5.01 (s, 2H), 6.94
(d, J ) 9 Hz, 2H), 7.16 (d, J ) 12 Hz, 2H); MS m/z 371 (M+).
Anal. Calcd for C20H25N3O4: C, 64.69; H, 6.73; N, 11.32.
Found: C, 64.71; H, 6.77; N, 11.45.
H, 5.66; N, 10.88.
1,3-Dim et h yl-5-et h yl-7-(m et h oxym et h yl)-6-(p h en oxy-
m eth yl)p yr r olo[3,2-d ]p yr im id in e-2,4-d ion e (11c): yield
93%; mp 138 °C; λmax (log ꢀ) 224 (2.97), 270 (2.70) nm; IR (KBr)
νmax 1680, 1640 cm-1; H NMR (300 MHz, CDCl3) δ 1.41 (t, J
1
) 7.5 Hz, 3H), 3.38 (s, 3H), 3.44 (s, 3H), 3.75 (s, 3H), 4.48 (q,
J ) 7.5 Hz, 4H), 5.04 (s, 2H), 7.04 (dd, J ) 7.5 Hz, J ) 1.5 Hz,
3H), 7.36 (t, J ) 7.5 Hz, 2H); MS m/z 557 (M+). Anal. Calcd
for C19H23N3O4: C, 63.86; H, 6.44; N, 11.76. Found: C, 63.90;
H, 6.55; N, 11.66.
1,3-Dim eth yl-5-eth yl-7-(m eth oxym eth yl)-6-[(4′-m eth ox-
yp h en oxy)m et h yl]p yr r olo[3,2-d ]p yr im id in e-2,4-d ion e
(11d ): yield 93%; mp 168 °C; λmax (log ꢀ) 224 (3.11), 272 (2.79)
nm; IR (KBr) νmax 1680, 1640 cm-1; 1H NMR (300 MHz, CDCl3)
Ack n ow led gm en t. We thank the CSIR (New Delhi)
for financial assistance.
J O9718861