Efficient synthesis of 5-hydroxymethyl pyrimidines and their nucleosides using microwave irradiation

Article abstract of DOI:10.1055/s-2002-35592

Hydroxymethylation of uracil (1), cytosine (3), 5-hydroxymethyl-2′,3′-O-isopropylideneuridine (5), 5′-O-tert-butyldiphenylsilyl-2′,3′-O-isopropylideneuridine (7), 2′,3′-O-isopropylidenecytidine (9) and 2′,3′-O-isopropylidene-5′-O-tritylcytidine (11) was efficiently carried out with paraformaldehyde in alkaline medium under microwave irradiation in very high yield.

Full text of DOI:10.1055/s-2002-35592

LETTER
2043
Efficient Synthesis of 5-Hydroxymethyl Pyrimidines and their Nucleosides
Using Microwave Irradiation
E
A
fficient
S
ynthesis
d
of 5-Hydro
e
P
l
yrimidines an
A
d
their
N
ucleoside
.
s
-H. Abdel-Rahman, El Sayed H. El Ashry*b
a
a
Department of Chemistry, Faculty of Science, Menoufia University, Shebin El-Koam
b
Department of Chemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
Fax +20(3)4271360; E-mail: eelashry@link.net; E-mail: eelashry60@hotmail.com
Received 1 October 2002
This paper dedicated to Prof. H. S. El Khadem on the occasion of his 80 birthday.
th
Abstract: Hydroxymethylation of uracil (1), cytosine (3), 5-hy-
droxymethyl-2 ,3 -O-isopropylideneuridine (5), 5 -O-tert-butyl-
diphenylsilyl-2 ,3 -O-isopropylideneuridine (7), 2 ,3 -O-isopropyl-
idenecytidine (9) and 2 ,3 -O-isopropylidene-5 -O-tritylcytidine
(
11) was efficiently carried out with paraformaldehyde in alkaline
medium under microwave irradiation in very high yield.
Key words: microwave, uracil, cytosine, 5-hydroxymethyluracil,
uridine, cytidine, formaldehyde addition
There has been increasing interest in the application of
microwave irradiation to chemical reactions over recent
1
–3
years. Although reactions have been reported to pro-
ceed at equal rates under both microwave and convention-
4
–6
al heating at the same temperature, speculation about
the influence of microwaves on reaction rates have been
reported whereby the reaction could proceed faster than
that under conventional conditions at the same tempera-
7
–11
ture.
Addition products of formaldehyde with pyrimidines are
of considerable interest in connection with problems of
1
2,13
nucleic acid metabolism.
The 5-hydroxymethyl-2 -
deoxyuridine triphosphate has been found to be a sub-
strate for SP10c DNA replication and is present in SP10c
1
4
phage-infected Bacillus Subtilis. This has attracted the
attention towards the synthesis of its analogues. Conse-
15
quently, the 5-hydroxymethyl analogues of uracil, cy-
1
6
17
tosine, 2 ,3 -O-isopropylideneuridine, and 2 ,3 -O-
1
8
isopropylidenecytidine were prepared by treating of
uracil (1), cytosine (3), 2 ,3 -O-isopropylideneuridine
5), and 2 ,3 -O-isopropylidenecytidine
1
9
1
9
(
(9) with
paraformaldehyde in alkaline medium for one to three
days (Scheme 1).
We report here an efficient and easy method for the syn-
thesis of 5-hydroxymethyluracil (2), 5-hydroxymethyl-
cytosine (4), 5-hydroxymethyl-2 ,3 -O-isopropylidene-
uridine (6), 5 -O-tert-butyldiphenylsilyl-5-hydroxymeth-
yl-2 ,3 -O-isopropylideneuridine (8), 5-hydroxymethyl-
2
,3 -O-isopropylidenecytidine (10) and 5-hydroxy-
methyl-2 ,3 -O-isopropylidene-5 -O-tritylcytidine (12) in
3–99% yield by the hydroxymethylation of 1, 3, 5, 7, 9
9
Scheme 1
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2043,2044,ftx,en;D18102ST.pdf.
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

2
044
A. A.-H. Abdel-Rahman, El S. H. El Ashry
LETTER
and 11 with paraformaldehyde in 0.5 N potassium hy-
droxide solution under microwave irradiation for 3 min-
utes followed by acidification by dilute hydrochloric acid.
Each of the H NMR spectra of 2, 4, 6, 8, 10 and 12
showed a singlet at = 4.11, 3.51, 4.12, 4.15, 3.49 or
(15) Cline, R. E.; Fink, R. M.; Fink, K. J. Am. Chem. Soc. 1959,
81, 2521.
(
(
(
16) Alegria, A. H. Biochim. Biophys. Acta. 1967, 149, 317.
17) Scheit, K. H. Chem. Ber. 1966, 3884.
18) Fourrey, J.-L.; Henry, G.; Jouin, P. J. Chem. Res., Synop.
1
20
1979, 226.
3
.50 ppm corresponding to the CH group, indicated the
2
(19) Fromageot, H. P. M.; Grieffin, B. E.; Reese, C. B.; Sulston,
successful hydroxymethylation.
J. E. Tetrahedron 1967, 23, 2315.
20) Selected Physical Data: 2: White powder; mp >300 °C
(
In conclusion, a succesful hydroxymethylation of pyrimi-
dines and their nucleosides using microwave irradiation
has been achieved. Moreover, various protecting groups
in the nucleosides have not been affected under such con-
ditions, which could allow further chemical modifications
on them. Furthermore, the method saves time, the prod-
ucts were easily isolated, giving high yield, economic and
it is friendly to the environment.
1
(
(
H O); TLC (CHCl –MeOH, 8.5:1.5 v/v): R 0.59. H NMR
2
3
f
DMSO-d , 300 MHz): = 4.11 (s, 2 H, CH ), 7.24 (s, 1 H,
6
2
13
H-6), 10.71 (br s, 1 H, NH), 11.05 (br s, 1 H, NH). C NMR
(DMSO-d , 75.04 MHz): = 55.7 (CH ), 112.6 (C-5), 138.1
6
2
(C-6), 151.3 (C-2), 163.7 (C-4). 4: White powder; mp
300 °C (H O); TLC (CHCl –MeOH, 8:2 v/v): R 0.35. H
1
>
2
3
f
NMR (DMSO-d , 300 MHz): = 3.51 (s, 2 H, CH ), 7.12 (br
6
2
s, 2 H, NH ), 8.15 (s, 1 H, H-6), 11.18 (br s, 1 H, NH). 6:
2
White powder; mp 170–172 °C (H O); TLC (CHCl –
2
3
1
MeOH, 8.5:1.5 v/v): R 0.50. H NMR (DMSO-d , 300
f
6
MHz): = 1.36 (s, 3 H, CH ), 1.57 (s, 3 H, CH ), 3.85 (d, 1
3
3
H, Jgem = 12.1 Hz, H-5 ), 3.97 (d, 1 H, J = 12.1 Hz, H-
General Procedure
a
gem
5 b), 4.12 (s, 1 H, CH ), 4.80 (dd, 1 H, J = 3.0 Hz,
To 2 mL of 0.5 N KOH was added 1 mmol of 1, 3, 5, 7, 9 or 11 and
paraformaldehyde (0.04 g, 1.2 mmol) and each mixture was taken
in a round-bottom flask and irradiated in MW oven (Master KOG
2
3 ,4
J4 ,5 = 2.4 Hz, H-4 ), 4.95 (dd, 1 H, J3 ,4 = 3.0 Hz, J2 ,3 = 6.2
Hz, H-3 ), 4.98 (brs, 1 H, OH), 5.01 (dd, 1 H, J2 ,3 = 6.2 Hz,
J1 ,2 = 2.5 Hz, H-2 ), 5.67 (d, 1 H, J1 ,2 = 2.5 Hz, H-1 ), 7.57
8
40-P, output 1500 W) for 3 min. The reaction mixture was acidi-
(
s, 1 H, H-6), 9.01 (br s, 1 H, NH). 7: White foam; TLC
fied by diluted HCl (pH ~ 6.5) and then reprecipitated from acetone
and water (2:1) to afford pure products of 2, 4, 6, 8, 10 and 12 in
1
(CHCl –MeOH, 9.5:0.5 v/v): R 0.61. H NMR (CHCl , 300
3
f
3
MHz): = 1.08 (s, 9 H, 3 CH ), 1.34 (s, 3 H, CH ), 1.57 (s,
9
3–99% yields.
3
3
3
H, CH ), 3.94 (d, 1 H, J = 12.4 Hz, H-5 ), 3.96 (d, 1 H,
3 gem a
Jgem = 12.4 Hz, H-5 ), 4.26 (dd, 1 H, J = 3.3 Hz,
b
3 ,4
References
J
5
4 ,5 = 2.6 Hz, H-4 ), 4.75 (m, 1 H, H-3 ), 4.82 (m, 1 H, H-2 ),
.44 (d, 1 H, J1 ,2 = 3.1 Hz, H-1 ), 5.97 (d, 1 H, J5,6 = 5.0 Hz,
(
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H-5), 7.34–7.41 (m, 5 H, Ar-H), 7.44–7.65 (m, 6 H, Ar-H,
H-6), 9.51 (br s, 1 H, NH). C NMR (CHCl , 75.04 MHz):
1
13
3
(
=
19.3 (Me C), 25.3 (CH ), 26.9 (Me C), 27.2 (CH ), 63.9
3 3 3 3
1.
(
C-5 ), 80.1 (C-3 ), 84.9 (C-2 ), 86.4 (C-4 ), 91.5 (C-1 ),
(
(
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1
1
02.4 (Me C), 114.3 (C-5), 127.8, 127.9, 129.9, 130.0,
2
32.2, 132.7, 135.3, 135.5 (Ar-Carbons), 140.6 (C-6), 150.1
(
C-2), 163.3 (C-4). 8: White foam; TLC (CHCl –MeOH, 9:1
3
(
5) Pollington, S. D.; Bond, G.; Moyes, R. B.; Whan, D. A.;
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1
v/v): R 0.58. H NMR (CHCl , 300 MHz): = 1.10 (s, 9 H,
3
Jgem = 12.2 Hz, H-5 ), 3.94 (d, 1 H, J = 12.2 Hz, H-5 b),
4
f
3
CH ), 1.35 (s, 3 H, CH ), 1.60 (s, 3 H, CH ), 3.90 (d, 1 H,
3 3 3
(
(
a
gem
.15 (s, 2 H, CH ), 4.15 (dd, 1 H, J = 3.0 Hz, J4 ,5 = 2.7
2 3 ,4
Hz, H-4 ), 4.77 (dd, 1 H, J3 ,4 = 3.0 Hz, J2 ,3 = 6.3 Hz, H-3 ),
.80 (dd, 1 H, J2 ,3 = 6.3 Hz, J1 ,2 = 3.2 Hz, H-2 ), 5.50 (d, 1
H, J1 ,2 = 3.2 Hz, H-1 ), 7.35–7.44 (m, 5 H, Ar-H), 7.50–7.60
m, 5 H, Ar-H), 8.01 (s, 1 H, H-6), 10.32 (br s, 1 H, NH). 10:
(8) (a) Lewis, D. A.; Ward, T. C.; Summers, J. S.; McGrath, J.
E. Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.)
4
1
988, 29, 174. (b) Lewis, D. A.; Summers, J. D.; Ward, T.
C.; McGrath, J. E. J. Polym. Sci. Part A: Polym. Chem. 1992,
0, 1647.
(
Pale yellow foam; TLC (CHCl –MeOH, 9:1 v/v): R 0.45.
3
f
3
1
H NMR (DMSO-d , 300 MHz): = 1.36 (s, 3 H, CH ), 1.63
6
3
(9) Bose, A. K.; Manhas, M. S.; Ghosh, M.; Raju, V. S.; Tabei,
(
(
(
s, 3 H, CH ), 3.49 (s, 2 H, CH ), 4.01 (m, 2 H, H-5 ), 4.31
m, 1 H, H-4 ), 4.39 (m, 1 H, H-3 ), 4.78 (m, 1 H, H-2 ), 5.51
d, 1 H, J1 ,2 = 2.8 Hz, H-1 ), 7.21 (br s, 2 H, NH ), 8.01 (s,
3
2
K.; Urbanczyk-Lipkowska, Z. Heterocycles 1990, 30, 741.
(
10) Berlan, J.; Giboreau, P.; Lefeuvre, S.; Marchand, C.
Tetrahedron Lett. 1991, 32, 2363.
2
1
H, H-6). 12: Yellow foam; TLC (CHCl –MeOH, 9:1 v/v):
3
(11) Adamek, F.; Hajek, M. Tetrahedron Lett. 1992, 33, 2039.
(12) Wyatt, G. R.; Cohen, S. S. Biochem. J. 1953, 55, 774.
(13) Flaks, J. G.; Cohen, S. S. Biochim Biophys. Acta 1957, 25,
1
R 0.65. H NMR (CDCl , 300 MHz): = 1.37 (s, 3 H, CH3),
f
3
1
4
5
.63 (s, 3 H, CH ), 3.50 (s, 2 H, CH ), 3.79 (m, 2 H, H-5 ),
3
2
.33 (m, 1 H, H-4 ), 4.95 (m, 1 H, H-3 ), 5.09 (m, 1 H, H-2 ),
.60 (d, 1 H, J1 ,2 = 2.9 Hz, H-1 ), 7.09–7.25 (m, 8 H, NH2,
667.
(14) Dosmar, M.; Witmer, H. Curr. Microbiol. 1979, 2, 361.
Ar-H), 7.29–7.38 (m, 9 H, Ar-H), 8.06 (s, 1 H, H-6).
Synlett 2002, No. 12, 2043–2044 ISSN 0936-5214 © Thieme Stuttgart · New York