Enamine-induced Ring Transformations of 6-Substituted 5-Formyl-1,3-dimethyluracils

Article abstract of DOI:10.1039/a708683k

5-Formyl-1,3,6-trimethyluracil 1 undergoes facile ring transformation with enamines under acidic conditions to provide 1-heteroaroyl-1,3-dimethylurea derivatives.

Full text of DOI:10.1039/a708683k

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3
52 J. CHEM. RESEARCH (S), 1998
J. Chem. Research (S),
Enamine-induced Ring Transformations of
-Substituted 5-Formyl-1,3-dimethyluracils$
Harjit Singh,* Dolly, Swapandeep Singh Chimni and Subodh Kumar*
1998, 352±353$
6
Department of Chemistry, Guru Nanak Dev University, Amritsar-143 005, India
5
1
-Formyl-1,3,6-trimethyluracil 1 undergoes facile ring transformation with enamines under acidic conditions to provide
-heteroaroyl-1,3-dimethylurea derivatives.
Uracil derivatisation at each of its reactive sites has attained
paramount signi®cance in potential medicinal target com-
1
pounds. The nucleophile-induced modi®cations of uracil
and its derivatives emanating from their reactions at C(5)
and/or C(6) or at an electrophilic appendage at C(5) make
use of relatively strong nucleophiles, viz. amines, hydrazines,
cyanide ion, etc. or of strongly basic reaction conditions
2
±6
(
NaOH, NaOEt, BuLi, etc.).
The steric bulk of a methyl
group at C(6) of uracil, in general, slows down or com-
pletely restricts nucleophilic addition at C(6) and causes
4
b,7
alternative reactions due to generation of an anion
8
at
CCH . Recently, we have reported that 5-formyl-1,3-
3
dimethyluracil reacts with enamines, even under acidic con-
ditions, to provide unique annulation products. We envi-
saged that in the reactions of enamines with 5-formyl-1,3,6-
9
trimethyluracil under acidic conditions the probability of
generation of an anion at the 6-CH carbon would be low
3
and annulation might constitute the major mode of reaction.
Hence, the reactions of 5-formyl-1,3,6-trimethyluracil 1 with
enamines have been studied.
5-Formyl-1,3,6-trimethyluracil 1 on reaction with 3-amino-
,5-dimethylcyclohex-2-enone 2 in re¯uxing acetonitrile±
5
TFA solution gives a product (50%), mp 92 8C. The parent
ion peak at m/z 303 (M ) in its mass spectrum shows it
‡
1
to be a condensation product of 1 and 2. In its H NMR
spectrum the appearance of one Me signal as a doublet
Scheme 1
‡
(d 2.99, J 4.8 Hz) and other Me units as singlets points
mp 180 8C, M at m/z 259 and corresponding ring-
transformed products are not formed (Scheme 2).
The formation of compounds 3, 5 and 7 could be
rationalised through the initial nucleophilic attack of
enamine at CHO to give intermediate 12 which subsequently
towards the N(1)0C(6) ring opening of the uracil moiety
and a 1 H singlet at d 8.07 shows the presence of the
aromatic ring. From these spectral data and the elemental
analysis the structure 3 is proposed for this compound.
Therefore, 1 undergoes ring transformation with enamines
and the 6-Me of 1 does not participate in the reaction
through intramolecular attack of NH
provides ring-transformed products
2
at C(6) of uracil
3, 5, 7. The well
6,8
11
(
Scheme 1).
Similarly, compound 1 reacts with 6-amino-1,3-dimethyl-
documented reversibility of nucleophilic attack of amines,
thiols, alcohols etc. at C(6) of uracil and higher reactivity of
formyl than C(6) carbon rule out the possibility of alter-
native initial attack of amine nitrogen at C(6) of 1. Also, as
uracil
4
and 3-aminobut-2-enenitrile
6
acetonitrile±TFA solution to give ring transformation
in re¯uxing
‡
products 5 (80%), mp 180±182 8C, M at m/z 319 and 7
‡
(
8%), mp 120±125 8C, M at m/z 246, respectively.
Therefore, despite the presence of a methyl group, com-
pound 1 reacts with enamines through attack at CHO with
subsquent annulation at C(6) but the area unit is eliminated
and after annulation the uracil ring is opened. We argued
that if uracil is substituted at C(6) with Cl, a leaving group,
the formation of annulation products with intact uracil
units could be facilitated.
The reaction of compound
acetonitrile±TFA solution gives annulation product 9, mp
8 with 4 in re¯uxing
‡
3
00±310 8C, M at m/z 303. However, ethyl b-amino/anilino
crotonates 10 with 8 provide respective 6-anilino-5-formyl-
10
uracils 11a (70%), mp 222 8C (lit., 225 8C) and 11b (45%),
*To receive any correspondence.
$This is a Short Paper as de®ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).
Scheme 2

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J. CHEM. RESEARCH (S), 1998 353
�
1
1
700 cm (C1O). (Found: C, 63.5; H, 6.6; N, 13.8. C16
H N O
21 3 3
requires C, 63.37; H, 6.93; N, 13.86%).
‡
Compound 5.ÐYield 80%, mp 180±182 8C (EtOH), M at m/z
1
3
3
19; H NMR (CDCl
.30 (s, 3 H, CH ), 3.47 (s, 3 H, NCH
), 8.25 (s, 1 H, 1CH); C NMR (CDCl
DEPT-135) ꢀ 25.10 (‡ve, CH ), 28.43 (‡ve, NCH ), 29.49 (‡ve,
NCH ), 134.93 (‡ve, CH),
), 39.36 (‡ve, NCH
06.43 (absent), 107.95 (absent), 127.28 (absent), 134.97 (absent),
54.97 (absent), 160.17 (absent), 164.6 (absent), 171.17 (absent);
3
) ꢀ 2.56 (s, 3 H, CH
3 3
), 3.10 (s, 3 H, CH ),
3
3
), 3.71 (d, J ˆ 4.63 Hz, 3 H,
13
NHCH
3
3
) (Normal/
3
3
3
), 34.38 (‡ve, NCH
3
3
1
1
�
1
IR (KBr) ꢁ~max 1610 (C1O), 1700 cm (C1O) (Found: C, 51.9;
H, 5.24; N, 21.3.
N, 21.94%).
C
14
H
17
N
5
O
4
requires C, 52.66; H, 5.37;
‡
Compound 7.ÐYield 8%, mp 120±125 8C (EtOH), M at m/z
1
46; H NMR (CDCl
2
2
1
3
) ꢀ 2.58 (s, 3 H, CH
), 3.09 (s, 3 H, NCH
) (Normal/DEPT-135) ꢀ 22.76 (‡ve,
),
3
), 2.79 (s, 3 H, CH
3
),
.96 (d, J ˆ 4.8 Hz, 3 H, NHCH
3
3
), 7.72 (s,
13
H, 1CH); C NMR (CDCl
3
CH
3
), 23.58 (‡ve, CH
3
), 27.12 (‡ve, NCH
3
), 34.07 (‡ve, NCH
3
1
1
06.74 (absent), 115.99 (absent), 129.59 (absent), 136.67 (‡ve, CH),
54.66 (absent), 157.41 (absent), 162.19 (absent), 171.02 (absent);
�
1
IR (KBr) ꢁ~max 1661 (C1O), 1690 (C1O), 2240 cm (C2N).
Compound 9.ÐYield 80%, mp 300±310 8C (CHCl ±hexane), M
), 3.75 (s,
‡
Scheme 3
3
1
at m/z 303; H NMR (CDCl
3
) ꢀ 3.49 (s, 6 H, 2Â NCH
3
13
1
the electron-withdrawing ability of the substituent (R ) at
6 H, 2 ÂNCH
3
), 9.18 (s, 1 H, CH); C NMR (CDCl
3
q NCH ), 30.15 (q, NCH
3
) ꢀ 28.71
(
3
), 96.20 (s, >C<), 106.52 (s, >C<),
the b position of the enamine increases, the nucleophilicity
1
39.73 (d, CH), 172.6 (s, C1O), 193 (s, C1O); IR (KBr) ꢁ~max 1660
�
1
of enamine NH
2
and consequently the yield of the ring-
(C1O), 1600 cm (C1C) (Found: C, 50.74; H, 4.02; N, 24.68%.
requires C, 51.48; H, 4.29; N, 23.10%).
transformation product [CON (80%), CO (50%), CN (8%)]
decreases. Further in the case of reactions of 5-formyl-1,3-
dimethyluracil with these enamines, the formation of
13 13 5 4
C H N O
We thank the University Grants Commission (India) for
nancial assistance.
8
®
dihydropyridines through intermediate 14 occurs but when
Me is present at C(6), the intermediate 13 does not
form dihydropyridine derivatives. It has been found that
Received, 2nd December 1997; Accepted, 9th March 1998
Paper E/7/08683K
5
-vinyluracil and 6-methyl-5-vinyluracils have cis- and trans-
diene con®gurations, respectively, which the intermediates
3 and 14 would respectively acquire. In intermediate 13 the
1
References
steric bulk of the Me group probably restricts the attack of
enamine and respective dihydropyridine derivatives are not
formed (Scheme 3).
1
H. Wamho€, J. Dzenis and K. Hirota, in Adv. Heterocycl.
Chem., 1992, 55, 129; D. J. Brown, in Comprehensive
Heterocyclic ChemistryÐThe Structure, Reactions, Synthesis and
Uses Of Heterocyclic Compounds, ed. A. R. Katritzky and C. W.
Rees, Pergamon Press, Oxford, 1984, vol. 3, pp. 57±155.
Thus, 5-formyl-1,3,6-trimethyluracil 1 undergoes facile
ring tranformations with enamines under acidic conditions
to provide carbamoylpyridine derivatives, and the methyl
2 E. G. Sander, in Bioorganic Chemistry, ed. E. E. Van Tamelen,
Academic Press, New York, 1977, vol. 2, pp. 273±297 and refs.
therein; T. K. Bradshaw and D. W. Hutchinson, Chem. Soc.
Rev., 1977, 6, 43.
�
at C(6) does not contribute 6-CH2 induced annulation
reactions and rather restricts the usual Hantszch-type
dihydropyridine formation reactions of the 5-formyl group.
3
H. C. van der Plas, Ring Transformations of Heterocycles,
Academic Press, New York, 1975, vol. 1±2; Tetrahedron, 1985,
Experimental
41, 237.
Melting points were determined in capillaries and are uncorrected.
H and C NMR spectra were run on a Bruker AC200 MHz
4 K. Hirota, Y. Kitade and S. Senda, (a) J. Chem. Soc., Perkin
Trans. 1, 1984, 1859 and refs. therein; (b) J. Org. Chem., 1981,
46, 3949.
5 S. Kumar, S. S. Chimni, D. Cannoo and J. Singh, Bioorg. Med.
Chem., 1995, 3, 891 and refs. therein.
1
13
instrument using TMS as an internal standard. Mass, infrared
and UV spectra were recorded on Shimadzu GCMS-QP-2000,
Philips Scienti®c SP3-300 and Shimadzu UV-240 spectrometers,
respectively. Elemental analyses of solid samples were performed
at the microanalytical laboratory of the Regional Sophisticated
Instrumentation Centre, Chandigarh.
Reactions of 5-Formyluracils 1, 8 with Enamines: General Procedure.
ÐA solution of compound 1 or 8 (1.00 g, 5.95 mmol), enamine
3
2 equivalent, 12 mmol) in CH CN (10 ml) containing TFA (0.1 ml)
6 H. Singh, P. Singh, S. S. Chimni and S. Kumar, J. Chem. Soc.,
Perkin Trans. 1, 1995, 2363.
7 K. Hirota, K. A. Watanabe and J. J. Fox, J. Org. Chem., 1978,
43, 1193; K. Hirota, T. Asao, I. Sugiyama and S. Senda,
Heterocycles, 1987, 15, 289; M. Noguchi, K. Sakamoto,
S. Nagata and S. Kajigaeshi, J. Heterocycl. Chem., 1988, 25,
205; N. Yasue, S. Ishikawa and M. Noguchi, Bull. Chem. Soc.
Jpn., 1992, 65, 2845; K. Hirota, Y. Kitade, K. Shimada and
Y. Maki, J. Org. Chem., 1985, 50, 1512.
8 H. Singh, Dolly, S. S. Chimni and S. Kumar, Tetrahedron, 1995,
51, 12775.
9 Under neutral conditions, enamines fail to react with aldehydes.
See also K. Hirota, K. Kubo, H. Sajaki, Y. Kitade, M. Sako
and Y. Maki, J. Org. Chem., 1997, 62, 2999.
10 A. Sivaprasad, J. S. Sandhu and J. N. Baruah, Indian J. Chem.,
Sect. B, 1985, 24, 305.
11 I. H. Pitman, M. J. Cho and G. S. Pork, J. Am. Chem. Soc.,
1974, 96, 1840; B. A. Otter, E. A. Falco and J. J. Fox, J. Org.
Chem., 1968, 33, 3593.
(
was re¯uxed. The progress of the reaction was monitored by TLC
and after completion (5±6 h) the solvent was distilled o€. The
residue was chromatographed on a silica gel column using hexane±
ethyl acetate mixtures as eluents.
+
Compound 3.ÐYield 50%, mp 92 8C, M at m/z 303 (EtOH);
1
H NMR (CDCl
3
) ꢀ 1.14 (s, 6 H, 2Â CH
.99 (d, J ˆ 4.8 Hz, 3 H, NHCH ), 3.02 (s, 3 H, CH
H, CH ), 8.07 (s, 1 H, C1CH), 9.03 (br, 1 H, NH); C NMR
) (Normal/DEPT-135) ꢀ 22.72 (‡ve, CH ), 27.04 (‡ve,
), 26.23 (‡ve, CH ), 34.15 (‡ve, CH ), 46.22 (�ve, CH ), 51.75
3
), 2.58 (s, 4 H, 2Â CH
2
),
2
3
3
3
), 3.09 (s,
13
3
(
CDCl
3
3
CH
3
3
3
2
(
�ve, CH
2
), 131.52 (‡ve, CH), 124.60 (absent), 131.53 (absent),
1
1
54.60 (absent), 156.42 (absent), 162.55 (absent), 172.15 (absent),
96.36 (absent); IR (KBr) ꢁ~max 1660 (C1O), 1600 (C1O),