Synthesis of bioactive heterocycles: Sigmatropic rearrangements of 1,3-dimethyl-6-[methyl(4-aryloxybut-2-ynyl)amino]pyrimidine-2,4(1H,3H)-diones

Article abstract of DOI:10.1055/s-2001-16097

A number of 1,3-dimethyl-6-[methyl (4-aryloxybut-2-ynyl)amino]pyrimidine-2,4(1H,3H)-diones 4a-i were synthesised in 69 to 80% yields by the reaction of 6-chloro-1,3-dimethyluracil (6-chloro-1,3-dimethylpyrimidine-2,4(1H, 3H)-diones) and 1-aryloxy-4-N-methylaminobut-2-yne in refluxing ethanol for 12 hours. The tertiary amines 4a-i were then heated in refluxing 1,2-dichlorobenzene for 17 hours to give 5-[(E)-aryloxymethylidene]-1,3,8-trimethyl-5,6,7,8-tetrahydropyrido[2,3-d] pyrimidine-2,4(1H,3H)- diones 5a-i in 55 to 75% yields.

Full text of DOI:10.1055/s-2001-16097

1568
PAPER
Synthesis of Bioactive Heterocycles: Sigmatropic Rearrangements of 1,3-
Dimethyl-6-[methyl(4-aryloxybut-2-ynyl)amino]pyrimidine-2,4(1H,3H)-
diones
S
ynthesis of Bioac
.
tive
H
eteroc
C
ycles . Majumdar,* T. Bhattacharyya
Department of Chemistry, University of Kalyani, Kalyani 741 235, W.B., India
Fax +91(033)5828282; E-mail: kcm@klyuniv.ernet.in
Received 13 March 2001; revised 20 April 2001
amino-Claisen rearrangement of 1,3-dimethyl-6-[meth-
yl(4-aryloxybut-2-ynyl)amino]pyrimidine-2,4(1H,3H)-
diones 4a–i.
Abstract: A number of 1,3-dimethyl-6-[methyl(4-aryloxybut-2-
ynyl)amino]pyrimidine-2,4(1H,3H)-diones 4a–i were synthesised
in 69 to 80% yields by the reaction of 6-chloro-1,3-dimethyluracil
(6-chloro-1,3-dimethylpyrimidine-2,4(1H,3H)-diones) and 1-ary-
loxy-4-N-methylaminobut-2-yne in refluxing ethanol for 12 hours.
The tertiary amines 4a–i were then heated in refluxing 1,2-dichlo-
robenzene for 17 hours to give 5-[(E)-aryloxymethylidene]-1,3,8-
trimethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-
diones 5a–i in 55 to 75% yields.
The starting materials 4a–i were prepared in 69–80%
yield by refluxing 6-chloro-1,3-dimethyluracil (3) with
the corresponding 4-aryloxy-1-N-methylaminobut-2-ynes
2a–i in ethanol for 9 to 12 hours (Scheme 1). The amines
2a–i in turn were prepared by dropwise addition of an al-
coholic solution of 1-aryloxy-4-chlorobut-2-ynes 1a–i to
excess aqueous methylamine (40%) and stirring the reac-
tion mixture at room temperature for 2 h. Excess methy-
lamine and alcohol were distilled off under reduced
pressure and the compounds 2a–i, isolated after usual
workup, were used without further purification in the next
step. Compounds 4a–i were characterised from their ele-
mental analyses and spectral data.
Key words: aza-Claisen rearrangement, cyclizations, heterocycles,
pyrido[2,3-d]pyrimidine-2,4-diones, sigmatropic rearrangement
The biological importance of pyrimidine and its deriva-
tives is well known.1,2 Numerous pyrimidine and uracil
(pyrimidine-2,4(1H,3H)-dione) based molecules have
found wide application in medicine and therapeutics.
Thus FU (5-fluorouracil) and FUDR (5-fluoro-2’-deox-
yuridine) are used in chemotherapy for the treatment of
cancer.3 F3TDR (trifluorothymidine), BVDU [(E)-5-(2-
bromovinyl-2’-deoxyuridine)], AZT (3’-azido-3’-deox-
ythymidine)4–7 and 5-(2-chloroethyl-2’-deoxyuridine
(CEDU)8 are used against viral diseases. Both BVDU and
CEDU compounds effectively inhibit herpes simples type
1 virus (HSV-1) and Varicella zoster virus (VZV) replica-
tion in vitro4,8–11 and AZT12 is an anti AIDS drug. Func-
tionalisation of uracils at 5- and 6-positions lead to
biologically interesting molecules.13–15 Recently a 6-sub-
stituted uracil derivative, 1-[(2-hydroxyethoxy)methyl]-
6-phenylthiothymine (HEPT)16–18 has attained consider-
able significance as a specific HIV-1 inhibitor, a causative
against AIDS.19
Claisen rearrangement has been used for the synthesis of
a number of furo[3,2-d]pyrimidines, pyrano[3,2-d]pyrim-
idines and dihydrofuro[2,3-d]pyrimidine derivatives.20,21
Recently amine oxide rearrangement22 has been employed
for the synthesis of pyrrolo[3,2-d]pyrimidine derivatives
starting from 1,3-dimethyl-5-[ethyl(4-aryloxybut-2-
Scheme 1
The substrates 4a–i possess two potential sites for Claisen
rearrangement. The aryloxy propargyl ether part may un-
dergo oxygen-Claisen rearrangement while the vinyl pro-
pargyl amine part may undergo amino-Claisen
rearrangement. Hence the substrate provides an excellent
scope for competitive study of oxygen-Claisen rarrange-
ment versus amino-Claisen rearrangement in the same
molecule. It is well known that amino-Claisen rearrange-
ment requires higher activation energy24 than the oxygen-
ynyl)amino]pyrimidine-2,4(1H,3H)-diones.
Amino-
Claisen rearrangement of 5- and 6-substituted allyl and
propargyl amines of uracils was studied by Itoh and co-
workers.20,23 This prompted us to undertake a study of the
Synthesis 2001, No. 10, 30 07 2001. Article Identifier:
1437-210X,E;2001,0,10,1568,1572,ftx,en;Z03001SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
Cyclopenta[c]-Anellated Benzopyrans and Benzothiopyrans
1569
Claisen rearrangement. But the activation energy required
for the propargyl vinyl ether25 rearrangement is much less
than that of aryl propargyl ether rearrangement.26
The substrates 4a–i were refluxed in 1,2-dichlorobenzene
at 180 °C for 17 hours to give 5a–i in 55–75% yield
(Scheme 2). The compounds 5a–i were characterised on
the basis of their elemental analyses and spectral data.27
Scheme 4
Scheme 2
butadienyl derivative. An additional 1,3-prototropic shift
in 9 may also lead to product 5.
As in the case of amino-Claisen rearrangement of 1,3-
dimethyl-6-(N-methyl-N-propargyl)aminouracil,20 we ex-
pected dihydropyrido[2,3-d]pyrimidine derivative 9 via
“pathway a“ or pyrrolo[2,3-d]pyrimidine derivative 10
via “pathway b“ for this type of usual Claisen rearrange-
ment. Initially 4 may undergo a [3,3] sigmatropic rear-
rangement to the allene 6, followed by enamine 7
formation, which may then proceed via “pathway a“, viz.
[1,5] hydrogen shift, followed by electrocyclic ring clo-
sure to 9, or via “pathway b“, viz. cyclisation of the enam-
ine 7 to 10 (Scheme 3).
There are some reports on the formation of products sim-
ilar to 5 with exocyclic double bond from the Claisen re-
arrangement. Thus only in one case (4-cresoxyether), the
rearrangement of aryloxybutynyl ethers of 4-hydroxycou-
marin yielded exo-methylene pyranocoumarins along
with the normal Claisen rearrangement products.29 In the
case of 2-cresoxy ether also, a furocoumarin with an exo-
cyclic double bond was formed along with the normal
Claisen rearrangement product.29 In another instance, in
the case of alkylation30 of 4-hydroxy-1-methylquinolone
with 1-(2-chloroaryloxy)-4-chlorobut-2-ynes, a similar
kind of product was obtained. 4-(4-Aryloxybut-2-yny-
loxy)[1]benzopyran-2-thiones also gave exo-methylene
products along with normal endocyclic products.31
It is interesting to note that all the substrates studied so far
underwent [3,3] sigmatropic rearrangement at the propar-
gyl vinyl amine moiety in preference to the aryl propargyl
ether part of the substrates. However, it has been recently
reported32 that the thermal rearrangement of 1,3-dimeth-
yl-5-[methyl(4-aryloxybut-2-ynyl)amino]pyrimidine-
2,4(1H,3H)-diones furnished exclusively the correspond-
ing
5-[(2H-chromen-4-yl)(methyl)amino]-1,3-dimeth-
ylpyrimidine-2,4(1H,3H)-diones by the [3,3] sigmatropic
rearrangement at the aryloxypropynyl moiety. In the case
of uracil, the amino-Claisen rearrangement at the 6-posi-
tion is preferred over oxygen-Claisen rearrangement per-
haps due to the high reactivity of the 5-position of uracil.
In the case of 5-substituted uracil the low reactivity of the
6-position pushes the reaction towards the more favour-
able oxygen-Claisen rearrangement pathway. This work
derives additional interest from the fact that pyrido[2,3-
d]pyrimidines are shown to be biologically highly active
compounds possessing antitumour, antibacterial and anti-
convulsive activities.33
Scheme 3
The formation of product 5 from 4 may be explained by
an initial [3,3] sigmatropic shift to give the intermediate
allene 6, which can then proceed via “pathway c“ viz. 1,3-
H+ shift to give butadienyl intermediate 11, enamine for-
mation and 6-endo cyclisation to give the product 5. An-
other “pathway d“ has been considered as an alternative to
1,3-H+ shift. This may involve [1,5] H shift of enamine H
to the central allene carbon in 13, followed by another
[1,5] H shift (or tautomerism) to give 12 which then un-
dergoes 6-endo cyclisation (Scheme 4). There is a litera-
ture report28 for the 1,3-H+ shift in an allene to give
Melting points are uncorrected. UV absorption spectra were record-
ed in absolute EtOH on a Hitachi 200-20 Spectrophotometer. IR
spectra were run on KBr discs on a Perkin-Elmer 1330 apparatus.
Synthesis 2001, No. 10, 1568–1572 ISSN 0039-7881 © Thieme Stuttgart · New York

1570
K. C. Majumdar, T. Bhattacharyya
PAPER
1H NMR spectra were recorded for solutions in CDCl3 with SiMe4
as an internal standard on Jeol Fx-100 at IICB, Calcutta, Bruker
(300 MHz) spectrometer at IICB, Calcutta and Bruker (500 MHz)
spectrometer at Bose Institute, Calcutta. Elemental analyses and re-
cording of mass spectra (EI) were carried out by RSIC (CDRI), Luc-
know. Silica gel (60–120 mesh) was used for chromatograpic
separation.
4d
Yield 80%; mp 84 °C.
UV (EtOH): max (log ) = 210 (2.83), 276 nm (2.67).
IR (KBr): = 2920, 1680, 1630, 1290 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.28 (s, 6 H), 2.73 (s, 3 H),
3.31 (s, 3 H), 3.36 (s, 3 H), 3.76 (s, 2 H), 4.68 (s, 2 H), 5.34 (s, 1 H),
6.57 (s, 2 H), 6.64 (s, 1 H).
4-Aryloxy-1-N-methylaminobut-2-ynes 2a–i; General
Procedure
MS: m/z = 341 (M+).
Anal.Calcd for C19H23N3O3: C, 66.86; H, 6.74; N, 12.31. Found: C,
67.92; H, 6.62; N, 12.30.
To an aqueous methylamine solution (40%, 10 mL, excess) was
added dropwise a solution of 1a–i (6 mmol) in EtOH (20 mL) and
stirred at r.t. for 2 h. The excess methylamine and EtOH were dis-
tilled off under reduced pressure. The residue was then extracted
with CHCl3 (3 20 mL). The CHCl3 extract was washed with water
(3 20 mL) and dried (Na2SO4). The solvent was evaporated and
the residual liquid obtained was used in the next step without further
purification.
4e
Yield 76%; viscous liquid.
UV (EtOH): max (log ) = 214 (3.39), 276 nm (3.30).
IR (KBr): = 2935, 1690, 1640, 1220 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.19 (s, 3 H), 2.26 (s, 3 H),
2.71 (s, 3 H), 3.32 (s, 3 H), 3.36 (s, 3 H), 3.75 (s, 2 H), 4.70 (s, 2 H),
5.34 (s, 1 H), 6.77–6.79 (m, 1 H), 6.93–6.96 (m, 2 H).
1,3-Dimethyl-6-[methyl(4-aryloxybut-2-ynyl)amino]pyrim-
idine-2,4(1H,3H)-diones 4a–i; General Procedure
A mixture of an ethanolic solution (100 mL) of 3 (0.872 g, 5 mmol)
and 2a–i (12 mmol) was refluxed for 9 to12 h on a water bath. The
alcohol was then removed under reduced pressure and the residue
was extracted with CHCl3 (3 20 mL). The extract was washed
with water (2 20 mL) and dried (Na2SO4). After removal of
CHCl3, the crude mass was chromatographed over silica gel and
elution of the column with EtOAc–benzene (1:3) gave products 4a–
i.
MS: m/z = 341 (M+).
Anal. Calcd for C19H23N3O3: C, 66.86; H, 6.74; N, 12.31. Found: C,
66.98; H, 6.64; N, 12.28.
4f
Yield: 70%; viscous liquid.
UV (EtOH): max (log ) = 218 (2.54), 275 nm (2.47).
IR (KBr): = 2900, 1680, 1635, 1260 cm–1.
1H NMR (CDCl3/TMS, 100 MHz): = 2.68 (s, 3 H), 3.30 (s, 3 H),
3.33 (s, 3 H), 3.77 (s, 2 H), 4.83 (s, 2 H), 5.35 (s, 1 H), 6.88–7.48
(m, 4 H).
4a
Yield: 72%; viscous liquid.
UV (EtOH): max (log ) = 216 (2.95), 276 nm (2.89).
IR (KBr): = 2980, 2860, 1710, 1640, 1250 cm–1.
1 H NMR (CDCl3/TMS, 300 MHz): = 2.71 (s, 3 H), 3.32 (s, 3 H),
3.35 (s, 3 H), 3.76 (s, 2 H), 4.72 (s, 2 H), 5.34 (s, 1 H), 6.93–7.02
(m, 3 H), 7.28–7.33 (m, 2 H).
MS: m/z = 349 and 347 (M+).
Anal. Calcd for C17H18ClN3O3: C, 58.78; H, 5.18; N, 12.10. Found:
C, 58.90; H, 5.08; N, 12.18.
MS: m/z = 313 (M+).
4g
Yield: 72%; viscous liquid.
Anal. Calcd for C17H19N3O3: C, 65.17; H, 6.07; N, 13.41. Found: C,
65.25; H, 5.98; N, 13.35.
UV (EtOH): max (log ) = 218 (2.76), 276 nm (2.39).
IR (KBr): = 2940, 1690, 1630, 1215 cm–1.
4b
1H NMR (CDCl3/TMS, 500 MHz): = 2.64 (s, 3 H), 3.24 (s, 3 H),
3.28 (s, 3 H), 3.69 (s, 2 H), 4.62 (s, 2 H), 5.27 (s, 1 H), 6.80 (d, J =
9 Hz, 2 H), 7.18 (d, J = 9 Hz, 2 H).
Yield: 75%; mp 64 °C.
UV (EtOH): max (log ) = 215 (2.48), 276 nm (2.49).
IR (KBr): = 2960, 1700, 1640, 1230 cm–1.
1 H NMR (CDCl3/TMS, 300 MHz): = 2.23 (s, 3 H), 2.71 (s, 3 H),
3.32 (s, 3 H), 3.36 (s, 3 H), 3.76 (s, 2 H), 4.74 (s, 2 H), 5.34 (s, 1 H),
6.88–6.92 (m, 2 H), 7.13–7.16 (m, 2 H).
MS: m/z = 349 and 347 (M+).
Anal. Calcd for C17H18ClN3O3: C, 58.78; H, 5.18; N, 12.10. Found:
C, 58.76; H, 5.29; N, 12.02.
MS: m/z = 327 (M+).
4h
Yield: 69%; viscous liquid.
Anal. Calcd for C18H21N3O3: C, 66.05; H, 6.42; N, 12.84. Found: C,
66.14; H, 6.51; N, 12.81.
UV (EtOH): max (log ) = 222 (2.12), 280 (2.96), 329 nm (2.19).
IR (KBr): = 2980, 1680, 1640, 1230 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.75 (s, 3 H), 3.35 (s, 3 H),
3.39 (s, 3 H), 3.81 (s, 2 H), 4.92 (s, 2 H), 5.36 (s, 1 H), 7.12–7.31
(m, 2 H), 7.58–7.64 (m, 1 H), 7.87–7.91 (m, 1 H).
4c
Yield 73%; viscous liquid.
UV (EtOH): max (log ) = 219 (2.62), 276 nm (2.56).
IR (KBr): = 2960, 1690, 1640, 1220 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.29 (s, 3 H), 2.72 (s, 3 H),
3.32 (s, 3 H), 3.36 (s, 3 H), 3.79 (s, 2 H), 4.69 (s, 2 H), 5.35 (s, 1 H)
6.84 (d, J = 9 Hz, 2 H), 7.10 (d, J = 9 Hz, 2 H).
MS: m/z = 358 (M+).
Anal. Calcd for C17H18N4O5: C, 56.98; H, 5.02; N, 15.64. Found: C,
57.15; H, 5.11; N, 15.58.
MS: m/z = 327 (M+).
4i
Yield: 70%; mp 74 °C.
Anal. Calcd for C18H21N3O3: C, 66.05; H, 6.42; N, 12.84. Found: C,
66.13; H, 6.44; N, 12.92.
Synthesis 2001, No. 10, 1568–1572 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Cyclopenta[c]-Anellated Benzopyrans and Benzothiopyrans
1571
UV (EtOH): max (log e) = 222 (3.50), 277 nm (3.45).
IR (KBr): = 2980, 2900, 1700, 1640, 1250 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 1.61 (s, 3 H), 2.72 (s, 3 H),
3.32 (s, 3 H), 3.36 (s, 3 H), 3.78 (s, 2 H), 4.67 (s, 2 H), 5.35 (s, 1 H),
6.83–6.91 (m, 4 H).
IR (KBr): = 2900, 1680, 1620, 1280 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.32 (s, 6 H), 2.74 (t, J = 6
Hz, 2 H), 2.80 (s, 3 H), 3.15 (t, J = 6 Hz, 2 H), 3.41 (s, 3 H), 3.48 (s,
3 H), 6.62–6.73 (m, 3 H), 8.25 (s, 1 H).
MS: m/z = 341 (M+).
MS: m/z = 343 (M+).
Anal. Calcd for C19H23N3O3 : C, 66.86; H, 6.74; N, 12.31. Found:
C, 66.93; H, 6.66; N, 12.25.
Anal. Calcd for C18H21N3O4: C, 62.97; H, 6.12; N, 12.24. Found: C,
63.03; H, 5.82; N, 12.13.
5e
Yield: 73%; mp 162 °C.
5-[(E)–Aryloxymethylidene]-1,3,8-trimethyl-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones 5a–i;
General Procedure
Compounds 4a–i (4 mmol) were refluxed in 1,2-dichlorobenzene
for 17 h. The reaction mixture was cooled and chromatographed
over silica gel. 1,2-Dichlorobenzene was eluted out with petroleum
ether (bp 60–80 °C) and the rearranged products 5a–i were obtained
by eluting the column with EtOAc–benzene (1:9).
UV (EtOH): max (log ) = 209 (3.06), 267 (2.98), 317 nm (2.92).
IR (KBr): = 2960, 1700, 1620, 1220 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.24 (s, 3 H), 2.30 (s, 3 H),
2.68–2.75 (m, 2 H), 2.77 (s, 3 H), 3.11–3.15 (m, 2 H), 3.37 (s, 3 H),
3.45 (s, 3 H), 6.94–6.96 (m, 3 H), 8.20 (s, 1 H).
MS: m/z = 341 (M+).
Anal. Calcd for C19H23N3O3: C, 66.86; H, 6.74; N, 12.31. Found: C,
66.75; H, 6.60; N, 12.42.
5a
Yield 70%, viscous liquid.
UV (EtOH): max (log ) = 267 (2.88), 314 nm (2.83).
IR (KBr): = 2920, 1660, 1610, 1200 cm–1.
5f
Yield: 68%; viscous liquid.
1H NMR (CDCl3/TMS, 300 MHz): = 2.73 (t, J = 6 Hz, 2 H), 2.77
(s, 3 H), 3.13 (t, J = 6 Hz, 2 H), 3.38 (s, 3 H), 3.45 (s, 3 H), 7.03–
7.10 (m, 3 H), 7.27–7.31 (m, 2 H), 8.27 (s, 1 H).
13C NMR (CDCl3/TMS): d = 18.32 (C-6), 27.94 (CH3), 33.09
(CH3), 40.95 (N8-CH3), 49.28 (C-7), 95.97 (C-4a), 111.57 (C-5),
116.20 (C-12), 122.40 (C-14), 129.60 (C-13), 138.34 (C-9), 153.44
(C-2), 157.63 (C-8a, 11), 161.58 (C-4).
UV (EtOH): max (log ) = 211 (3.14), 312 nm (2.84).
IR (KBr): = 2900, 1690, 1630, 1250 cm–1.
1H NMR (CDCl3/TMS, 100 MHz): = 2.64–2.72 (m, 2 H), 2.77 (s,
3 H), 3.05–3.24 (m, 2 H), 3.36 (s, 3 H), 3.44 (s, 3 H), 6.84–7.46 (m,
4 H), 8.28 (s, 1 H).
MS: m/z = 349 and 347 (M+).
Anal. Calcd for C17H18ClN3O3: C, 58.78; H, 5.18; N, 12.10. Found:
C, 58.80; H, 5.09; N, 12.12.
MS: m/z = 313 (M+).
Anal. Calcd for C17H19N3O3: C, 65.17; H, 6.07; N, 13.41. Found: C,
65.26; H, 6.15; N, 13.37.
5g
Yield: 66%; viscous liquid.
5b
UV (EtOH): max (log ) = 209 (3.05), 306 nm (2.60).
IR (KBr): = 2960, 1680, 1630, 1240 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.71 (t, J = 6 Hz, 2 H), 2.78
(s, 3 H), 3.13 (t, J = 6 Hz, 2 H), 3.35 (s, 3 H), 3.45 (s, 3 H), 6.99–
7.02 (m, 2 H), 7.22–7.27 (m, 2 H), 8.21 (s, 1 H).
Yield: 74%; mp 142 °C.
UV (EtOH): max (log ) = 267 (2.41), 317 nm (2.44).
IR (KBr): = 2960, 1700, 1620, 1250 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.27 (s, 3 H), 2.73–2.75 (m,
2 H), 2.77 (s, 3 H), 3.11–3.14 (m, 2 H), 3.36 (s, 3 H), 3.42 (s, 3 H),
6.92–7.15 (m, 4 H), 8.23 (s, 1 H).
MS: m/z = 349 and 347 (M+).
Anal.Calcd for C17H18ClN3O3: C, 58.78; H, 5.18; N, 12.10. Found:
C, 58.85; H, 5.29; N, 12.14.
MS: m/z = 327 (M+).
Anal. Calcd for C18H21N3O3: C, 66.05; H, 6.42; N, 12.84. Found: C,
66.19; H, 6.31; N, 12.72.
5h
Yield: 55%; mp 142 °C.
5c
UV (EtOH): max (log ) = 312 nm (3.15).
IR (KBr): = 2940, 1690, 1630, 1250 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.70–2.75 (m, 2 H), 2.78 (s,
3 H), 3.12–3.16 (m, 2 H), 3.35 (s, 3 H), 3.43 (s, 3 H), 7.05–7.10 (m,
1 H), 7.31–7.34 (m, 1 H), 7.48–7.54 (m,1 H), 7.85–7.88 (m, 1 H),
8.30 (s, 1 H).
Yield: 72%; viscous liquid.
UV (EtOH): max (log ) = 224 (2.81), 282 (2.97), 317 nm (3.01).
IR (KBr): = 2920, 1690, 1640, 1240 cm–1.
1H NMR (CDCl3/TMS, 300 MHz): = 2.27 (s, 3 H), 2.70 (t, J = 6
Hz, 2 H), 2.75 (s, 3 H), 3.10 (t, J = 6 Hz, 2 H), 3.35 (s, 3 H), 3.43 (s,
3 H), 6.93–6.99 (m, 2 H), 7.05–7.08 (m, 2 H), 8.20 (s, 1 H).
MS: m/z = 358 (M+).
MS: m/z = 327 (M+).
Anal. Calcd for C17H18N4O5: C, 56.98; H, 5.02; N, 15.64. Found: C,
57.05; H, 5.11; N, 15.71.
Anal. Calcd for C18H21N3O3: C, 66.05; H, 6.42; N, 12.84. Found: C,
66.29; H, 6.35; N, 12.70.
5i
5d
Yield: 58%; viscous liquid.
Yield: 75%; mp 134 °C.
UV (EtOH): max (log e) = 226 (2.99), 273 nm (2.85).
IR (KBr): = 2960, 1700, 1635, 1230 cm–1.
UV (EtOH): max (log ) = 209 (2.94) 266 (2.72), 316 nm (2.69).
Synthesis 2001, No. 10, 1568–1572 ISSN 0039-7881 © Thieme Stuttgart · New York

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K. C. Majumdar, T. Bhattacharyya
PAPER
(11) Rosenwirth, B.; Griengl, H.; Wanek, E.; Clercq, E. D.
1H NMR (CDCl3/TMS, 300 MHz): = 2.70–2.74 (m, 2 H), 2.77 (s,
3 H), 3.11–3.14 (m, 2 H), 3.37 (s, 3 H), 3.45 (s, 3 H), 3.77 (s, 3 H),
6.77–7.02 (m, 4 H), 8.18 (s, 1 H).
Antiviral Res. 1985, Suppl.1, 21.
(12) Macilwain, C. Nature 1993, 365, 378.
(13) Kundu, N. G.; Dasgupta, S. K. J. Chem. Soc., Perkin Trans.
1 1993, 2657.
(14) Otter, B. A.; Saluja, S. S.; Fox, J. J. J. Org. Chem. 1972, 37,
2858.
MS: m/z 343 (M+).
Anal. Calcd for C18H21N3O4: C, 62.97; H, 6.12; N, 12.24. Found: C,
63.09; H, 6.05; N, 12.17.
(15) Chauhan, S. M. S.; Kholi, T. S.; Rao, K. V.; Gulati, A. Ind.
J. Chem. 1990, 29B, 539.
(16) Miyasaka, T.; Tanaka, H.; Baba, M.; Hayakawa, H.; Walker,
R. T.; Balzarini, J.; Clercq, E. D. J. Med. Chem. 1989, 32,
2507.
(17) Baba, M.; Tanaka, H.; Clercq, E. D.; Pauwels, R.; Balzarini,
J.; Schols, D.; Nakashima, H.; Perno, C. F.; Walker, R. T.;
Miyasaka, T. Biochem. Biophys. Res. Commun. 1989, 165,
1375.
(18) Clercq, E. D. Medicinal Res. Rev. 1993, 13, 229.
(19) (a) Gallo, R. C. Sci. Am. 1986, 255, 78. (b) Gallo, R. C. Sci.
Am. 1987, 256, 46.
(20) Kawahara, N.; Nakajima, T.; Itoh, T.; Ogura, H. Chem.
Pharm. Bull. 1985, 33, 4740.
(21) (a) Majumdar, K. C.; Das, U. J. Chem. Res., Synop. 1997,
309. (b) Majumdar, K. C.; Das, U. J. Chem. Res., Miniprint
1997, 2062. (c) Majumdar, K. C.; Das, U. Synth. Commun.
1997, 27, 4013.
(22) Majumdar, K. C.; Das, U.; Jana, N. K. J. Org. Chem. 1998,
63, 3550.
(23) Itoh, T.; Imini, T.; Ogura, H.; Kawahara, N.; Nakajima, T.;
Watanabe, K. A. Chem. Pharm. Bull. 1985, 33, 1379.
(24) Marcinkiewcz, S.; Green, J.; Mamalis, P. Tetrahedron 1961,
14, 208.
References
(1) (a) Lunt, E. Comprehensive Organic Chemistry, Vol. 4;
Barton, D. H. R.; Ollis, W. D., Eds.; Pergamon Press:
Oxford, 1974, 493. (b) Brown, J. D. Comprehensive
Heterocyclic Chemistry, Vol. 3; Katritzky, A. R.; Rees, C.
W., Eds.; Pergamon Press: Oxford, 1984, 57. (c) Sasaki, T.;
Minamoto, K.; Suzuki, T.; Yamashita, S. Tetrahedron 1980,
36, 865 and references cited therein. (d) Bradshow, T. K.;
Hutchison, D. W. Chem. Soc. Rev. 1977, 6, 43.
(2) (a) Marumato, R.; Farukawa, Y. Chem. Pharm. Bull. 1977,
25, 2974. (b) Cheng, C. C.; Roth, B. Progr. Med. Chem.
1971, 8, 61. (c) Jones, A. S.; Swgers, J. R.; Walker, R. T.;
Clercq, E. D. J. Med. Chem. 1988, 31, 268. (d) Griengl, H.
H.; Wanck, E.; Schwarz, W.; Streicher, W.; Rosenwirth, B.;
Clercq, E. D. J. Med. Chem. 1987, 30, 1199. (e) Clercq, E.
D.; Benaerts, R. J. Biol. Chem. 1987, 262, 14905.
(3) Heidelberger, C. Pyrimidine and Pyrimidine
Antimetabolites in Cancer Medicine; Holland J. F., Frei E.
Lea Febiger: Philadelphia, 1984, 801.
(4) Clercq, E. D.; Descamps, J.; Somer, P. D.; Barr, P. J.; Jones,
A. S.; Walker, R. T. Proc. Natl. Acad. Sci. USA 1979, 76,
2947.
(25) Claisen, L. Ber. Dtsch. Chem. Ges. 1912, 45, 3157.
(26) (a) Zsindely, J.; Schmidt, H. Helv. Chim. Acta. 1968, 51,
1510. (b) Majumdar, K. C.; Thyagarajan, B. S.;
Balasubramanian, K. K. J. Heterocycl. Chem. 1973, 10, 159.
(27) Majumdar, K. C.; Das, U. J. Org. Chem. 1998, 63, 9997.
(28) Ramakanth, S.; Narayanan, K.; Balasubramanian, K. K.
Tetrahedron Lett. 1984, 25, 103.
(29) Majumdar, K. C.; Das, D. P.; Jana, G. H.; Khan, A. T. Ind.
J. Chem. 1994, 33B, 120.
(30) Majumdar, K. C.; Choudhury, P. K. Synth. Commun. 1994,
23, 1087.
(31) Majumdar, K. C.; Jana, G. H. Synthesis 2001, 924.
(32) Majumdar, K. C.; Jana, N. K. Synth. Commun. 2000, 30,
2613.
(33) (a) Suzuki, N. Chem. Pharm. Bull. 1980, 28, 761.
(b) Grivsky, E. M.; Lee, S.; Siegel, C. W.; Duck, D. S.;
Nichol, C. A. J. Med. Chem. 1980, 23, 327.
(c) Kretzschmer, E. Pharmazie 1980, 35, 253.
(5) Heidelberger, C.; King, D. H. Antiviral Agents in
Pharmacology and Theraupeutics; Shugar, D., Ed.;
Pergamon Press: Oxford, 1979, 6, 427.
(6) Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; Clair, M. H.;
Lehrman, S. N.; Gallo, R. C.; Bolognesi, D.; Barry, D. W.;
Broder, S. Proc. Natl. Acad. Sci. USA 1985, 82, 7096.
(7) Fischl, M. A.; Richman, D. D.; Grieco, M. H.; Gottlieb, M.
S.; Volberdin, P. A.; Laskin, O. L.; Leedom, J. M.;
Groopman, J. E.; Mildvan, D.; Schooley, R. T.; Jackson, G.
G.; Durack, D. T.; King, D. N. Eng. J. Med. 1987, 317, 185.
(8) Griengl, H.; Bodenteich, M.; Hayden, W.; Wanek, E.;
Streicher, W.; Stutz, P.; Bachmayer, H.; Ghazzouli, I.;
Rosenwirth, B. J. Med. Chem. 1985, 28, 1679.
(9) Clercq, E. D.; Descamps, J.; Ogata, M.; Shigeta, S.
Antimicrob. Agents Chemother. 1982, 21, 33.
(10) Clercq, E. D.; Rosenwirth, B. Antimicrob. Agents
Chemother. 1985, 28, 246.
Synthesis 2001, No. 10, 1568–1572 ISSN 0039-7881 © Thieme Stuttgart · New York