A novel and efficient lewis acid catalysed preparation of pyrimidines: Microwave-promoted reaction of urea and β-formyl enamides

Article abstract of DOI:10.1055/s-2007-968018

A novel and efficient synthesis of pyrimidine from β-formyl enamide is described. The key step involves samarium chloride catalysed cyclisation of β-formyl enamides using urea as source of ammonia under microwave irradiation. Georg Thieme Verlag Stuttgart

Full text of DOI:10.1055/s-2007-968018

LETTER
223
A Novel and Efficient Lewis Acid Catalysed Preparation of Pyrimidines:
Microwave-Promoted Reaction of Urea and b-Formyl Enamides
Microwave-Promoted
a
d
Ure
a
and
b
-
a
F
ormyl En
n
Apurba Chetia, Romesh C. Boruah*
Medicinal Chemistry Division, Regional Research Laboratory, Jorhat 785006, India
Fax +91(376)2370011; E-mail: rc_boruah@yahoo.co.in
Received 16 October 2006
R'
R
NHAc
O
R'
R
N
Me
Abstract: A novel and efficient synthesis of pyrimidine from b-
formyl enamide is described. The key step involves samarium
chloride catalysed cyclisation of b-formyl enamides using urea as
source of ammonia under microwave irradiation.
SmCl3·6H2O
+
H2N NH2
N
CHO
2a–h
MW
4a–h
Key words: b-formyl enamide, urea, microwave, pyrimidine
OAc
OHC
Pyrimidines are a widespread heterocyclic motif found in
numerous natural products and synthetic pharmacophores
with antibacterial, antimicrobial, anticancer and anti-
mycotic activities. Pyrimidine derivatives are important
since compounds such as 1-[(2-hydroxyethoxy)methyl]-
2
a
AcHN
2b
AcHN
AcHN
2c
CHO
CHO
NHAc
CHO
NHAc
CHO
X
NHAc
NHAc
CHO
1
CHO
2g, X = Ph
h, X = p-ClC6H4
H
6
-(phenylthio)thymine (HEPT) and dihydroalkoxybenz-
AcO
2d
2e
2f
2
yloxopyrimidines (DABO) showed important anti-HIV-1
2
,3
activity and structurally related pyrimidines exhibited
4
Scheme 1
antirubella virus activity. The highly electron-deficient
nature of the pyrimidine ring renders nucleophilic aro-
matic substitution (S Ar) a general approach for synthesis
14
N
3,4-dihydropyrimidine-2(1H)-one, in contrast, we have
demonstrated urea as an efficient source of ammonia in
pyrimidine synthesis.
of a large number of pyrimidine derivatives from corre-
5
sponding halopyrimidines. However, adequate synthetic
methods to pyrimidines are limited and efforts are still
being made to accomplish more general and versatile
For example, irradiation of a finely ground mixture of 3-
acetamido-2-formyl-5a-cholest-2-ene (2a) with 3.0
equivalents of urea and 1.5 molar equivalents of samari-
um chloride hexahydrate in an open vessel in a Prolabo
Synthwave 402 microwave reactor for eight minutes at at-
mospheric pressure afforded 2¢-methyl-5a-cholest[2,3-
6
synthetic methods.
Enamides constitute the building blocks of many biologi-
7
cally active compounds and attract considerable attention
as prochiral substrates in asymmetric synthesis of b-ami-
8
no acids. In our earlier efforts we accomplished the syn-
15
e]pyrimidine (4a) in 82% yield (Scheme 1). The product
was identified from spectroscopic and analytical data.
thesis of b-formyl enamides from the Vilsmeier reaction
16
9
of enamides or conjugated oximes. Nevertheless, steroi-
1
The H NMR of 4a showed a singlet at d = 8.28 for the
dal b-formyl enamides have shown interesting diversity
1
3
1
0
aromatic proton of pyrimidine. The C NMR spectra ex-
hibited four characteristic signals for aromatic carbons at
d = 165.41, 165.35, 157.70 and 126.31. Similarly steroi-
dal, acyclic and aliphatic formyl enamides 2b–h reacted
with urea in the presence of samarium chloride to afford
annelated pyrimidines 4b–h in high yields (Table 1, en-
tries 2–8). However, when the same reaction was carried
out in refluxing xylene for 3–4 hours, it failed to afford
products 4a–h.
as organic synthons. Recently, we employed microwave
1
1
energy for the condensation of b-formyl enamides for
one-pot synthesis of pyridines via the Henry reaction.12
As a part of our continuing research on heterosteroids,13
herein we report an efficient one-pot synthesis of pyr-
imidines from b-formyl enamides employing urea and
samarium chloride under microwave irradiation. Al-
though Biginelli reaction represents an excellent example
of the utility of urea as amine component for synthesis of
SYNLETT 2007, No. 2, pp 0223–0226
0
1.
0
2.
2
0
0
7
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-968018; Art ID: D30106ST
©
Georg Thieme Verlag Stuttgart · New York

2
24
M. G. Barthakur et al.
LETTER
a
Table 1 Conversion of b-Formyl Enamides 2a–h to Pyrimidines 4a–h Using Urea and SmCl ·6H O under Microwave Irradiation
3
2
Entry
1
b-Formyl enamides
Reaction time (min)
8
Product
Yield (%)b
82
2a
N
Me
N
4
a
2
3
4
2b
2c
2d
10
10
9
84
80
86
N
Me
N
4
b
OAc
N
Me
N
4
c
Me
N
N
AcO
4
d
e
f
5
6
7
8
2e
2f
8
8
78
79
80
84
N
N
Me
4
4
N
N
Me
Me
2g
2h
10
10
N
Ph
N
4
g
N
Me
p-ClC6H4
N
4
h
a
The reactions were carried out in the solid phase.
Isolated yields.
b
In the absence of samarium chloride, the microwave-me- catalysed the reaction by activating the carbonyl group of
diated reaction of 2a with urea was found to be sluggish, amide intermediate A, thus facilitating imine cyclisation
and there was a considerable decrease in the yield of to B with subsequent loss of water to afford product 4a
product 4a. It was presumed that samarium chloride, (Scheme 2).
1
7
being a Lewis acid with coordinating properties, played
a key role as a catalyst in the pyrimidine formation.
To study the influence of Lewis acid on pyrimidine for-
mation, we carried out solid-phase cyclisation reactions of
A mechanism is proposed via amination of 2a followed by 2a, 2d and 2e with urea using BF ·OEt , anhydrous AlCl
3
2
3
cyclisation reaction. Under microwave heating, urea and TiCl . As shown in Table 2, the products 4a, 4d and
4
released ammonia1 which combined with 2a to afford 4e were obtained in good yields in each case.
8
imine intermediate A. Samarium chloride presumably
Synlett 2007, No. 2, 223–226 © Thieme Stuttgart · New York

LETTER
Microwave-Promoted Reaction of Urea and b-Formyl Enamides
225
References and Notes
H
O
(
1) (a) Brown, D. J. In Comprehensive Heterocyclic Chemistry,
R'
R
NHCOMe
CHO
CO(NH2)2
+ NH3)
R'
R
N
C
..
Me
Vol. 3; Katritzky, A. R.; Rees, C. W.; Scrieven, E. F. V.,
Eds.; Pergamon: Oxford, 1984, Chap 2.13, 142–155.
(
CH=NH
(
b) Callery, P.; Gannett, P. In Foye’s Principles of
2a
A
Medicinal Chemistry; Williams, D. A.; Lemke, T. L., Eds.;
Lippincott Williams and Wilkins: Philadelphia, 2002, 934–
935. (c) Jain, K. S.; Chitre, T. S.; Miniyar, P. B.; Kathiravan,
M. K.; Bendre, V. S.; Veer, V. S.; Shahane, S. R.; Shishoo,
C. J. Curr. Sci. 2006, 90, 793.
2) Botta, M.; Corelli, F.; Maga, G.; Manetti, F.; Renzulli, M.;
Spadari, S. Tetrahedron 2001, 57, 8357.
(3) Garg, R.; Gupta, S. P.; Gao, H.; Babu, M. S.; Debnath, A. K.;
Hansch, C. Chem. Rev. 1999, 99, 3525.
H
R'
N
Me
OH
Me
–
H2O
R'
N
(
N
R
N
R
4
a
B
Scheme 2
(4) Botta, M.; Occhionero, F.; Nicoletti, R.; Mastromarino, P.;
Conti, C.; Magrini, M.; Saladino, R. Bioorg. Med. Chem.
1999, 7, 1925.
(
5) (a) Hurst, D. In An Introduction to Chemistry &
Biochemistry of Pyrimidines, Purines & Pteridines; Wiley:
Chichester, 1988. (b) Brown, D. J. In The Pyrimidines;
Interscience Publishers: New York, 1994.
6) (a) Zanatta, N.; Flores, D. C.; Madruga, C. C.; Flores, A. F.
C.; Bonacorso, H. G.; Martins, M. A. P. Tetrahedron Lett.
Table 2 Effect of Lewis Acids on Cyclisation Reaction of b-Formyl
Enamides with Pyrimidines under Microwave Irradiation
Entry b-Formyl enamides Lewis acid
Product
4a
Yield (%)
(
1
2
3
4
5
6
7
8
9
2a
2a
2a
2d
2d
2d
2e
2e
2e
BF ·OEt
72
70
68
70
66
65
75
70
71
3
2
2
2
2
006, 47, 573. (b) Jeong, J. U.; Chen, X.; Rahman, A.;
Yamashita, D. S.; Luengo, J. I. Org. Lett. 2004, 6, 1013.
c) Mabry, J.; Ganem, B. Tetrahedron Lett. 2006, 47, 55.
(d) Peng, Z.; Journet, M.; Humphrey, G. Org. Lett. 2006, 8,
95. (e) Cernuchova, P.; Vo-Thanh, G.; Milata, V.; Loupy,
AlCl3
TiCl4
4a
(
4a
3
BF ·OEt
4d
A.; Jantova, S.; Theiszova, M. Tetrahedron 2005, 61, 5379.
7) (a) Lin, S.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2002,
3
(
AlCl3
TiCl4
4d
41, 512. (b) Musso, D. L.; Cochran, F. R.; Kelley, J. L.;
McLean, E. W.; Selph, J. L.; Rigdon, G. C.; Orr, G. F.;
Davis, R. G.; Cooper, B. R.; Styles, V. L.; Thompson, J. B.;
Hall, W. R. J. Med. Chem. 2003, 46, 399. (c) Petersen, A.
B.; Petersen, M. A.; Henriksen, U.; Hammerum, S.; Dahl, O.
Org. Biomol. Chem. 2003, 1, 3293.
4d
BF ·OEt
4e
3
AlCl3
4e
(
8) (a) You, J.; Drexler, H. J.; Zhang, S.; Fischer, C.; Heller, D.
Angew. Chem. Int. Ed. 2003, 42, 913. (b) Yan, Y.; Zhang,
X. Tetrahedron Lett. 2006, 47, 1567. (c) Zhang, Y. J.; Park,
J. H.; Lee, S. Tetrahedron: Asymmetry 2004, 15, 2209.
9) (a) Ahmed, S.; Boruah, R. C. Tetrahedron Lett. 1996, 37,
TiCl4
4e
In conclusion, we have developed a novel strategy for the
preparation of annelated pyrimidines from the one-pot
reaction of b-formyl enamide with urea under microwave
irradiation. The cyclisation reaction was found to be catal-
ysed by Lewis acids such as trivalent samarium chloride.
In contrast to the role of urea as amine component in Big-
(
8231. (b) Boruah, R. C.; Ahmed, S.; Sharma, U.; Sandhu, J.
S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.
1999, 38, 274.
(10) (a) Sharma, U.; Ahmed, S.; Boruah, R. C. Tetrahedron Lett.
000, 41, 3493. (b) Boruah, R. C.; Ahmed, S.; Sharma, U.;
2
1
4
Sandhu, J. S. J. Org. Chem. 2000, 65, 922. (c) Ahmed, S.;
Boruah, R. C. Tetrahedron Lett. 1997, 38, 1845.
inelli reaction, we successfully demonstrated the utility
of urea as an environmentally benign and safe source of
ammonia in pyrimidine synthesis. The method reported
herein represents a new application of b-formyl enamides
and is expected to be a general route for facile and com-
binatorial synthesis of a wide range of annelated
pyrimidines. Further synthetic application of the newly
developed b-formyl enamide system is in progress.
(
d) Longchar, M.; Chetia, A.; Ahmed, S.; Boruah, R. C.;
Sandhu, J. S. Synth. Commun. 2001, 31, 3281.
(11) (a) Varma, R. S. In Microwaves: Theory and Application in
Material Processing IV; Clark, D. E.; Sutton, W. H.; Lewis,
D. A., Eds.; American Ceramic Society: Westerville / OH,
1
1
997, 357–365. (b) Varma, R. S.; Dahiya, R. Tetrahedron
998, 54, 6293. (c) Bora, U.; Saikia, A.; Boruah, R. C. Org.
Lett. 2003, 5, 435.
(
(
12) Chetia, A.; Longchar, M.; Lekhok, K. C.; Boruah, R. C.
Synlett 2004, 1309.
13) (a) Saikia, A.; Barthakur, M. G.; Borthakur, M.; Saikia, C. J.;
Bora, U.; Boruah, R. C. Tetrahedron Lett. 2006, 47, 43.
(b) Barhtakur, M. G.; Chetia, A.; Boruah, R. C. Tetrahedron
Lett. 2006, 47, 4925.
Acknowledgment
We thank the Department of Science & Technology, New Delhi
for financial support and CSIR, New Delhi for the award of a
fellowship to one of us (M.B.). We also thank Dr P. G. Rao,
Director of this Institute for his keen interest.
(14) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org.
Chem. 2004, 4957.
Synlett 2007, No. 2, 223–226 © Thieme Stuttgart · New York

2
26
M. G. Barthakur et al.
LETTER
3 H), 0.94 (s, 3 H), 0.88 (s, 3 H), 1.00–2.82 (m, 35 H). 13
(
15) Representative Procedure for the Synthesis of 2¢-Methyl-
C
5
3
1
a-cholest[2,3-e]pyrimidine (4a):
NMR (75 MHz, CDCl ): d = 166.6, 161.9, 160.0, 154.4,
3
-Acetamido-2-formyl-5a-cholest-2-ene (2a; 0.46 g,
126.3, 122.5, 56.6, 56.3, 54.2, 42.8, 40.1, 39.9 (2 × C), 39.5,
mmol), urea (0.18 g, 3.0 mmol) and samarium chloride
38.5, 36.5, 36.4, 36.2, 32.5, 31.6, 28.6, 28.4, 26.1, 24.7, 24.2,
+
hexahydrate (0.55 g, 1.5 mmol) were mixed intimately in a
mortar and irradiated in an open reaction vessel of a
Synthwave 402 Prolabo focused microwave reactor
manufactured by M/s Prolabo, 54 rue Roger Salengro,
Cedex, France) after setting the reaction temperature at 140
C and the power at 80% (maximum output 300 Watts). On
23.2, 23.0, 19.1, 18.0, 12.3. MS (ESI): m/z = 435 [M + 1].
Compound 4d: mp 165–67 °C; R = 0.3 (EtOAc–CHCl ,
f
3
10:90). IR (KBr): 2943, 1735, 1668, 1594, 1555, 1420, 1245,
–
1 1
(
1033, 755 cm . H NMR (300 MHz, CDCl ): d = 8.31 (br s,
3
1 H), 5.35 (br s, 1 H), 4.52 (m, 1 H), 2.62 (s, 3 H), 1.97 (s, 3
H), 1.03 (s, 3 H), 0.92 (s, 3 H), 1.06–2.66 (m, 17 H). C
1
3
°
completion of reaction (vide TLC), the reaction mixture was
NMR (75 MHz, CDCl ): d = 181.9, 170.7, 166.5, 152.0,
3
treated with H O (50 mL) and extracted with CH Cl (3 × 30
140.7, 130.8, 122.1, 74.1, 56.2, 51.0, 46.3, 38.5, 37.3, 33.2,
31.7, 31.2, 29.1, 28.3, 28.1, 26.2, 21.6, 20.8, 19.7, 17.2. MS
2
2
2
mL). The organic portion was washed with H O, dried over
2
+
anhyd Na SO and the solvent was removed to obtain a crude
(ESI): m/z = 381 [M + 1]. Anal. Calcd for C H N O : C,
2
4
24 32
2
2
product. Column chromatography separation using EtOAc–
hexane (1:9) as eluent over silica gel afforded 4a in 82%
yield. This procedure was followed for the synthesis of all
products listed in Table 1.
75.75; H, 8.48; N, 7.36. Found: C, 75.90; H, 8.64; N, 7.17.
Compound 4e: oil; R = 0.3 (EtOAc–CHCl , 20:80). IR
f
3
–
1 1
(KBr): 2925, 1641, 1583, 1553, 1438 cm . H NMR (300
MHz, CDCl ): d = 8.29 (s 1 H), 2.83 (t, J = 5.96 Hz, 2 H),
3
(
16) Spectral and analytical data of selected compounds:
2.70 (t, J = 6.05 Hz, 2 H), 2.65 (s, 3 H), 1.80–1.93 (m, 4 H).
1
3
Compound 4a: mp 90–92 °C; R = 0.3 (EtOAc–hexane,
C NMR (75 MHz, CDCl ): d = 166.1, 165.2, 157.2, 127.0,
3
+
f
–
1
1
2
0:80). IR (KBr): 2925, 1641, 1582, 1559, 1442 cm . H
32.1, 25.8, 25.5, 22.6, 22.5. MS (ESI): m/z = 149 [M + 1].
Compound 4h: mp 91–93 °C; R = 0.5 (EtOAc–CHCl ,
NMR (300 MHz. CDCl ): d = 8.28 (br s, 1 H), 2.65 (s, 3 H),
3
f
3
1
3
0
. 96 (s, 3 H), 0.74 (s, 3 H), 0.91–2.78 (m, 38 H). C NMR
10:90). IR (KBr): 2924, 1655, 1578, 1545, 1435, 825, 773
–
1 1
(
75 MHz, CDCl ): d = 165.4, 165.4, 157.7, 126.3, 56.8, 54.1,
cm . H NMR (300 MHz, CDCl ): d = 8.68 (d, J = 5.34 Hz,
3
3
4
3
1
2.9 (3 × C), 39.9 (2 × C), 36.6, 36.4, 36.1 (2 × C), 35.4, 31.9,
1 H), 8.03 (d, J = 8.55 Hz, 2 H), 7.46–7.49 (m, 3 H), 2.80 (s,
1
3
0.0, 28.9, 28.5, 28.3, 25.8, 24.6, 24.2, 23.1, 22.9, 21.7, 19.1,
3 H). C NMR (75 MHz, CDCl ): d = 168.9, 163.2, 158.1,
3
+
2.4, 11.9. MS (ESI): m/z = 437 [M + 1]. Anal. Calcd for
137.5, 135.7, 129.6 (2 × C), 128.9 (2 × C), 114.1, 26.7. MS
+
C H N : C, 82.51; H, 11.08; N, 6.41. Found: C, 82.28; H,
(ESI): m/z = 205 [M + 1]. Anal. Calcd for C H N Cl: C,
30
48
2
11
9
2
1
0.95; N, 6.59.
64.55; H, 4.43; N, 13.68. Found: C, 64.41; H, 4.33; N, 13.40.
(17) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573.
(18) Cooper, H. B. H.; Spencer, H. W. III US Patent 6077491,
2000.
Compound 4b: gum; R = 0.3 (EtOAc–hexane, 30:70). IR
f
–
1 1
(
KBr): 2925, 1631, 1578, 1552, 1440 cm . H NMR (300
MHz, CDCl ): d = 8.24 (br s, 1 H), 6.19 (br s, 1 H), 2.64 (s,
3
Synlett 2007, No. 2, 223–226 © Thieme Stuttgart · New York

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