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I. Devi, P. J. Bhuyan / Tetrahedron Letters 45 (2004) 7727–7728
Table 1. Intramolecular hetero Diels–Alder reactions of 1-oxa-1,3-
butadienes 4a–4c
Biol. Chem. 1987, 262, 14905; (d) Jones, A. S.; Sayers, J.
R.; Walker, R. T.; De Clercq, E. J. Med. Chem. 1988, 31,
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1990, 249, 1533; (f) Pontikis, R.; Monneret, C. Tetrahe-
dron Lett. 1994, 35, 4351.
Entry
Product
R1
R2
Reaction
time (h)
Mp
(°C)
Yield
(%)
1
2
3
4
5
6
5a
6a
5b
6b
5c
6c
CH3
CH3
H
CH3
CH3
CH3
CH3
H
12
12
16
16
18
18
189
146
198
181
251
226
75
5
4. (a) Bradshaw, T. K.; Hutchison, D. W. Chem. Soc. Rev.
1977, 6, 43; (b) Lunt, E. In Comprehensive Organic
Chemistry; Barton, D.H.R., Ollis, W. D., Eds.; Pergamon:
Oxford, 1979; Vol. 4, p 493; (c) Brown, D. J. In Katritzky,
A. R., Rees, C., Eds.; Comprehensive Heterocyclic
Chemistry; Pergamon: Oxford, 1984; Vol. 3, p 57; (d)
Sasaki, T.; Minamoto, K.; Suzuki, T.; Yamashita, S.
Tetrahedron 1980, 36, 865; (e) Prajapati, D.; Bhuyan, P. J.;
Sandhu, J. S. J. Chem. Soc., Perkin Trans. 1 1988, 607; (f)
Bhuyan, P. J.; Borah, H. N.; Sandhu, J. S. J. Chem. Soc.,
Perkin. Trans. 1 1999, 3083.
5. (a) Wamhoff, H.; Winfried, S. J. Org. Chem. 1986, 51,
2787; (b) Hirota, K.; Benno, K.; Yumuda, Y.; Senda, S. J.
Chem. Soc., Perkin. Trans. 1 1985, 1137; (c) Walsh, E. B.;
Wamhoff, H. Chem. Ber. 1989, 122, 1673; (d) Thakur, A.
J.; Saikia, P.; Prajapati, D.; Sandhu, J. S. Synlett 2001,
1299.
6. (a) Bhuyan, P. J.; Borah, H. N.; Sandhu, J. S. Tetrahedron
Lett. 2002, 43, 895; (b) Bhuyan, P. J.; Borah, H. N.;
Boruah, R. C. Tetrahedron Lett. 2003, 44, 1847; (c) Devi,
I.; Kumar, B. S. D.; Bhuyan, P. J. Tetrahedron Lett. 2003,
44, 8307; (d) Devi, I.; Bhuyan, P. J. Synlett 2004, 283.
7. Devi, I.; Borah, H. N.; Bhuyan, P. J. Tetrahedron Lett.
2004, 45, 2405.
8. Oppolzer, W. Tetrahedron Lett. 1970, 35, 3091.
9. To a stirred solution of N,N-dimethyl barbituric acid 3a
(280mg, 0.18mmol) in aqueous HCl (23mL, 13%), was
added allylated aldehyde 2 (300mg) dropwise at room
temperature. After stirring for 1.5h the precipitated light
yellow solid was filtered and washed with hot water and
ethanol. The resulting material was obtained in 90% yield
(488mg) after drying and was confirmed as 4a from
spectroscopic data. Mp 145–146°C. 1H NMR 90MHz
(CDCl3): d 3.15 (s, 3H), 3.25 (s, 3H), 4.45 (d, J = 9.0, 2H),
5.25 (m, 2H), 5.75–6.20 (m, 2H), 6.50–7.20 (m, 4H). mmax
(KBr): 1675, 1700, 1745cmÀ1. (M+H)+ 301. Similarly
compounds 4b and 4c were synthesised by reaction of 3b
and 3c with 2. Compound 4b mp 135°C (yield 87%); 4c mp
189°C (85%).
10. Compound 4a (200mg) was allowed to reflux in toluene
(8mL) at 110°C for 12h. After completion of the reaction
(monitored by TLC) the solvent was removed under
reduced pressure. The residue was purified by preparative
TLC using: hexane ethyl acetate (3:2) as eluent, to give 5a
(150mg, 75% yield) and 6a (10mg, 5% yield). Compound
5a: Mp 189°C. 1H NMR 300MHz (CDCl3): d 2.35 (m,
1H), 3.32 (s, 3H), 3.44 (s, 3H), 4.33 (m, 4H), 4.65 (d, 1H,
J = 3.0 Hz), 6.75–7.46 (m, 4H). 13C NMR 75MHz
(CDCl3): d 164.1 (C-12a), 156.1 (C-2), 151.8 (C-4), 150.8,
130.5, 128.0, 123.0, 121.7, 116.7 (Ph), 90.3 (C-4a), 67.8 (C-
10), 65.5 (C-11), 30.5 (N–CH3), 29.5 (C-10a), 28.8 (N–
CH3), 28.3 (C-4b). mmax (KBr): 1575, 1705cmÀ1. (M+H)+
301. CHN analysis (calcd %) C, 64.00; H, 5.37; N, 9.33;
(C16H16N2O4) (found %) C, 64.23; H, 5.30; N, 9.39.
Compound 6a: Mp 146°C. 1H NMR 300MHz (CDCl3): d
2.35 (m, 1H), 3.30 (s, 3H), 3.42 (s, 3H), 4.31 (m, 4H), 4.65
(d, 1H, J = 9.0 Hz), 6.74–7.45 (m, 4H). 13C NMR 75MHz
(CDCl3): d 163.1 (C-12a), 156.1 (C-2), 152.8 (C-4), 147.8,
130.5, 129.0, 123.0, 120.7, 116.7 (Ph), 90.3 (C-4a), 66.8 (C-
10), 65.5 (C-11), 31.5 (N–CH3), 29.5 (C-10a), 28.7 (N–
CH3), 28.3 (C-4b). mmax (KBr): 1575, 1705cmÀ1. (M+H)+
301. CHN analysis (calcd %) C, 64.00; H, 5.37; N, 9.33;
(C16H16N2O4) (found %) C, 64.12; H, 5.32; N, 9.37.
70
5
H
H
65
4
H
H
Allylation of salicylaldehyde8 was accomplished using
the phase transfer catalyst TBAB (tetrabutylammonium
bromide) in a two-phase system of dichloromethane and
20% aqueous sodium hydroxide. The acid catalysed
(HCl) condensation of the aldehyde 2 and barbituric
acid 3a in aqueous medium afforded compound 4a9 in
quantitative yield. The structure of 4a was confirmed
from spectroscopic data. Heating10 4a in refluxing tolu-
ene for 12h, afforded a mixture of the cis hetero Diels–
Alder adduct 5a (75%) and its trans fused stereoisomer
6a (5%) in overall high yields. The structures of the
adducts were confirmed from spectroscopic data and
elemental analyses. The stereochemistries were deter-
mined from the coupling constants of the protons H-
4b and H-10a (for the cis-isomer J = 3.0 Hz and for the
trans-isomer J = 9.0 Hz). Both stereoisomers 5a and 6a
exhibited strong molecular ion peaks at (M+H)+ 301
(employing the positive ionisation technique).
Similarly, compounds 4b and 4c were synthesised by uti-
lising 2 and barbituric acids 3b and 3c under acidic con-
ditions. On refluxing in toluene, 4b and 4c afforded the
two isomeric series of the compounds 5b and 5c and
6b and 6c as reported in Table 1. The structures of the
cycloadducts were confirmed from spectroscopic data
and elemental analyses.
In conclusion, the results delineated here demonstrate a
novel intramolecular hetero Diels–Alder reaction of 1-
oxa-1,3-butadienes and the synthesis of complex annu-
lated uracils in a stereoselective manner and in overall
high yields.
References and notes
1. (a) For leading references, see: Daly, J. W.; Spande, T. F.
In Alkaloids: Chemical and Biological Perspectives; Pelle-
tier, S. W., Ed.; Wiley: New York, 1986; Vol. 4, p 1; (b)
Foder, G. B.; Colasanti, B. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, 1985; Vol. 3, p 1; (c) Boger, D.; Weinreb, S. M.
Hetero Diels–Alder Methodology in Organic Synthesis;
Academic: San Diego, 1987; Chapter 2,
p 34; (d)
Buomora, P.; Olsen, J. C.; Oh, T. Tetrahedron 2001, 57,
6099.
2. Demising, G.; Tacconi, G. Chem. Rev. 1975, 75, 651.
3. (a) Marumoto, R.; Furukawa, Y. Chem. Pharm. Bull.
1977, 25, 29734; (b) Griengl, R.; Wack, E.; Schwarz, W.;
Streicher, W.; Rosenwirth, B.; De Clercq, E. J. Med.
Chem. 1987, 30, 1199; (c) De Clercq, E.; Bernaerts, R. J.