Mild and efficient synthesis of aryliodonium ylides of 2,6- dimethylpyrimidin-4-ol

Article abstract of DOI:10.1002/hc.20608

Mild and efficient synthesis of new synthetically useful aryliodonium ylides of 2,6-dimethylpyrimidin-4-ol (3a-d) using (dichloroiodo)arenes in aqueous medium is reported. Antibacterial activity of these ylides 3a-d against Escherichia coli and Bacillus L

Full text of DOI:10.1002/hc.20608

Heteroatom Chemistry
Volume 21, Number 5, 2010
Mild and Efficient Synthesis of Aryliodonium
Ylides of 2,6-Dimethylpyrimidin-4-ol
Ravi Kumar,1,2 Reshmi R. Nair,1 and Om Prakash1
1Department of Chemistry, Kurukshetra University, Kurukshetra-136 119, India
2Department of Chemistry, Dyal Singh College, Karnal-132 001, India
Received 21 February 2010; revised 6 April 2010
As a privileged scaffold, pyrimidine is a ubiq-
ABSTRACT: Mild and efficient synthesis of new syn-
thetically useful aryliodonium ylides of 2,6-dimethyl-
pyrimidin-4-ol (3a–d) using (dichloroiodo)arenes
in aqueous medium is reported. Antibacterial ac-
tivity of these ylides 3a–d against Escherichia
coli and Bacillus Licheniformis is also described.
2010 Wiley Periodicals, Inc. Heteroatom Chem 21:339–
342, 2010; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20608
uitous subunit in many natural products with re-
markable biological activities and unique physical
properties. Pyrimidine derivatives have proved to be
of great importance in exhibiting therapeutic appli-
cations [3]. A large number of pyrimidine nucleo-
sides are clinically useful for the control of retrovi-
ral infections [4–7]. One of the important class of
antiherpetic nucleosides is a series of 5-substituted
uracil nucleosides such as (E)-5-(2-bromovinyl)-2ꢁ-
deoxyuridine [8] showed specific antivaricella zoster
virus activity. In view of effect of 5-substitution on
the activity of thiouracil, synthesis and antithyroid
activity of several 5-substituted pyrimidine deriva-
tives have been reported [9]. In addition, 5-alkyl or
5-aryl-substituted pyrimidine derivatives are useful
intermediates in the synthesis of nucleosides [10].
Also, many 5-substituted pyrimidines have shown
inhibitory activity against Streptococcus faecalis R
growth [11] and some are evaluated as inhibitors of
enzymes involved in the pyrimidine catabolism like
dihydrouracil dehydrogenase and uridine phospho-
rylase [12]. Further, 5-iodo substituted pyrimidine
analogues are known for their antimicrobial [13] and
antiviral activity [14,15].
In view of the synthetic utility of iodonium
ylides and biological properties associated with
pyrimidine derivatives, in particular 5-substituted
pyrimidines, we wish to synthesize pyrimidine ana-
logues substituted at C-5 position. Thus, as a gen-
eral approach for the synthesis of subsequent ana-
logues, our attention was focused on the report
of Habib and Kappe regarding the synthesis of
iodonium ylides [16a]. In the present communica-
tion, we report herein mild and efficient synthesis
ꢀ
C
INTRODUCTION
In recent years, considerable attention has been
devoted to the use of hypervalent iodine reagents
in organic synthesis for various synthetically use-
ful transformations due to their low toxicity, ready
availability, and ease of handling [1]. As an impor-
tant class of this family, zwitterionic iodonium com-
pound (iodonium ylide) represents a molecule with
a positive charge at iodine compensated by an in-
ternal negative charge that is localized formally at
an α-carbon atom or nitrogen atom (1,2-dipole) or,
in some instances, delocalized to a neighboring oxy-
gen or nitrogen (1,4-zwitterionic structure) [2]. Iodo-
nium ylides can be used for the synthesis of new
reagents and in fine organic synthesis due to consid-
erable synthetic potential [1].
Correspondence to: Ravi Kumar; e-mail: ravi.dhamija@
rediffmail.com.
Contract grant sponsor: Department of Science and Technol-
ogy, New Delhi, India.
Contract grant number: SR/FTP/CS-125/2006.
2010 Wiley Periodicals, Inc.
c
ꢀ
339

340 Kumar et al.
SCHEME 1 Synthesis of aryliodonium ylides 3a–d.
of new synthetically useful aryliodonium ylides
(3a–d) of 2,6-dimethylpyrimidin-4-ol (1) using
(dichloroiodo)arenes in aqueous medium. Reaction
provides easy accessibility of the aryliodonium ylides
3a–d in excellent yields under mild conditions.
RESULTS AND DISCUSSION
Accordingly, 2,6-dimethylpyrimidin-4-ol (1) was
treated with (dichloroiodo)benzene (2a) in water at
room temperature, followed by addition of sodium
carbonate. The reaction afforded phenyliodonium
ylide 3a in 76% yield. Encouraged by this observa-
tion, 4-hydroxypyrimidine 1 was treated with other
(dichloroiodo)arenes (2b–d) (Scheme 1). The reac-
tion afforded corresponding iodsonium ylides 3b–d
in good yields thereby establishing the generality
of the method. The structures of compounds 3a–d
were confirmed by their spectral as well as elemental
analysis. These results were highly promising, as the
presence of the iodo substituent at C-5 in compounds
3 opens up a broad range of opportunities to intro-
duce diverse substituents at C-5. The probable mech-
anism for the formation of iodonium ylides might
involve the attack of iodosoarene, generated in situ
from (dichloroiodo)arene, on C-5 of compound 1
leading to the formation of intermediate which sub-
sequently rearrange to give ylide 3 [16a].
SCHEME 3 Probable mechanism for the formation of com-
pound 4.
It is worthwhile to mention that reaction of nucleic
bases under similar conditions has been reported to
yield C-5 chlorinated product [16b]. The probable
mechanism for the formation of 4 might involve the
electrophilic attack of (dichloroiodo)benzene (2a)
at C-5 position of compound 1, followed by nu-
cleophilic attack of “Cl− (chloride ion)” leading to
reductive elimination of iodobenzene to give in-
termediate 5 which subsequently rearrange to give
compound 4 (Scheme 3).
The compounds 3a–d and 4 were also screened
for their antibacterial activity against Escherichia
coli and Bacillus licheniformis. Results of the an-
tibacterial testing are summarized in Table 1. Re-
sults revealed that ylide 3c is comparable or even
more potent than the commercial antibiotic, strepto-
mycin, against E. coli whereas compound 3d showed
promising results against B. licheniformis. How-
ever, the parent compound 1 neither shows activ-
ity against E. coli nor against B. licheniformis. These
observations led to the conclusion that the presence
of iodine atom at C-5 position might have a positive
impact on the antibacterial activity.
In another experiment, we attempted the
reaction of 2,6-dimethylpyrimidin-4-ol (1) with
(dichloroiodo)benzene (2a) in acetic acid. The reac-
tion led to the nuclear chlorination with the forma-
tion of 5-chloro-2,6-dimethyl-4-hydroxypyrimidine
(4) in 73% yield (Scheme 2). Structure of compound
4 was confirmed by the spectral and elemental data.
CONCLUSION
A mild and efficient synthesis of new synthet-
ically useful aryliodonium ylides (3a–d) using
SCHEME 2 Reaction of compound 1 with (dichloroiodo)-
benzene in acetic acid.
Heteroatom Chemistry DOI 10.1002/hc

Mild and Efficient Synthesis of Aryliodonium Ylides of 2,6-Dimethylpyrimidin-4-ol 341
TABLE 1 Antibacterial Activity of Aryliodonium Ylides 3a–d
was prepared from ethyl acetoacetate and acetami-
dine hydrochlride by following the literature proce-
dure [17]. (Dichloroiodo)arenes 2a-d, needed for the
present study, were prepared according to the pro-
cedures reported in the literature [18,19]. The an-
tibacterial activities of the newly synthesized com-
pounds were evaluated by Agar Well Diffusion Assay
technique [20].
and 5-Chloro-4-Hydroxy-2,6-Dimethylpyrimidine (4)
Diameter of Zone Inhibition
Conc.
(μg/mL)
Escherichia
coli
Bacillus
Licheniformis
Compound
1
50
100
250
500
50
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Nil
Synthesis of Aryliodonium Ylides (3a–d)
3a
100
250
500
50
100
250
500
50
100
250
500
50
Nil
Nil
Nil
Nil
Nil
Nil
Nil
4 mm
6 mm
8 mm
12 mm
Nil
Nil
Nil
1 mm
Nil
Nil
Nil
1 mm
Nil
2 mm
4 mm
6 mm
Nil
General Procedure. To a solution of 2,6-dimethyl-
pyrimidin-4-ol (1, 10 mmol) in water, was added
(dichloroiodo)arenes (2a–d, 11 mmol), followed by
sodium carbonate (10 mmol). The resulting mixture
was stirred for 6–7 h. Solid was filtered and washed
with water and dried to give pure ylide (3a–d).
3b
3c
Characterization Data of the Ylides (3a–d)
3d
1
3a: mp 224◦C; yield 76%; H NMR (DMSO, δ): 2.58
100
250
500
50
100
250
500
50
Nil
Nil
Nil
Nil
Nil
Nil
Nil
4 mm
6 mm
8 mm
10 mm
2 mm
4 mm
9 mm
Nil
Nil
Nil
(s, 3H, CH3), 2.59 (s, 3H, CH3), 7.32–7.42 (m,
2H), 7.42–7.51 (m, 1H), 7.58–7.63 (m, 2H); Elemen-
tal analysis: C12H11N2OI Found (C, 44.15; H, 3.35; N,
8.53%); Requires (C, 44.19; H, 3.40; N, 8.59%); Mass,
m/z: 326 (M+).
4
Nil
1
3b: mp 225◦C; yield 78%; H NMR (DMSO, δ):
Streptomycin
3 mm
6 mm
8 mm
10 mm
2.57 (s, 3H, CH3), 2.61 (s, 3H, CH3), 7.34–7.37
(d, 2H, J = 8.4 Hz), 7.82–7.85 (d, 2H, J = 8.4 Hz);
Elemental analysis: C12H10N2OBrI Found (C, 35.52;
H, 2.45; N, 6.89%); Requires (C, 35.58; H, 2.49; N,
6.92%); Mass, m/z: 405 (M+).
100
250
500
1
3c: mp 234◦C; yield 79%; H NMR (DMSO, δ):
(dichloro)iodo arenes in aqueous medium is de-
scribed. Aryliodonium ylides (3a–d), obtained from
the present study, can be utilized in organic synthe-
sis as useful synthetic precursors to synthesize vari-
ety of pyrimidine derivatives, such as, o-iodoaryloxy
ethers, 5-aryl/hetryl pyrimidines, and so forth. Fur-
thermore, ylides 3c and 3d showed significant an-
tibacterial activity as compared to the commercial
antibiotic, streptomycin.
2.55 (s, 3H, CH3), 2.58 (s, 3H, CH3), 7.24–7.26
(d, 2H, J = 8.2 Hz), 7.73–7.75 (d, 2H, J = 8.2 Hz);
Elemental analysis: C12H10N2OClI Found (C, 39.95;
H, 2.85; N, 7.77%); Requires (C, 39.97; H, 2.80; N,
7.77%); Mass, m/z: 360 (M+).
1
3d: mp 230◦C; yield 70%; H NMR (DMSO, δ):
2.58 (s, 3H, CH3), 2.64 (s, 3H, CH3), 3.88 (s,
3H, OCH3), 7.45–7.53 (m, 1H), 7.77–7.88 (m, 2H),
7.87–7.99 (m, 1H); Elemental analysis: C14H13N2O3I
Found (C, 43.75; H, 3.39; N, 7.28%); Requires (C,
43.77; H, 3.41; N, 7.29%); m/z: 384 (M+).
EXPERIMENTAL
Melting points were taken in open capillaries and
are uncorrected. Infrared (IR) spectra were recorded
on Perkin-Elmer IR spectrophotometer. The 1H
NMR spectra were recorded on BRUKER 400 MHz
instrument. The chemical shifts are expressed in
ppm units (δ) downfield from an internal TMS
standard. Elemental analyses were performed on
Perkin-Elmer 2400 instrument and mass spectra
were recorded on Kratos MS-50 mass spectrome-
ter. 2,6-Dimethylpyrimidin-4-ol (1) needed for study
Synthesis of 5-Chloro-2,6-dimethylpyrimidin-
4-ol (4)
(Dichloroiodo) benzene (2a, 3 mmol) was added to a
stirred solution of of 4-hydroxy-2,6-dimethyl pyrim-
idine (1, 2.5 mmol) in acetic acid (15 mL) at 80◦C.
Stirring was continued at 80◦C for 1 h. The result-
ing mixture was evaporated in vacuo. Repeated ad-
dition and evaporation of methanol-water and then
with methanol, resulted solid product. This solid was
Heteroatom Chemistry DOI 10.1002/hc

342 Kumar et al.
[7] Balzarini, J.; Pannecouque, C.; De Clercq, E.; Aquaro,
S.; Perno, C. F.; Egberink, H. Antimicrob Agents
Chemother 2002, 46, 2185–2193.
[8] De Clerecq, E.; Descamps, J.; De Somer, P.; Barr,
P. J.; Jones, A. S.; Walker, R. T. Proc Nat Acad Sci
USA 1979, 76, 2947–2951.
dissolved in minimum volume of hot chloroform
and then methanol was added and the mixture was
cooled. Solid separated out was filtered and dried to
give pure 4.
1
4: mp 201◦C; yield 73%; H NMR (DMSO, δ):
[9] Barrett, H. W.; Goodman, I.; Dittmer, K. J Am Chem
Soc 1948, 70, 1753–1756.
[10] Schinazi, R. F.; Arbiser, J.; Lee, J.; Kalman, T.;
Prusoff, W. J Med Chem 1986, 29, 1293–1295.
[11] Puleston, H. S.; Charles, F. P.; Norman, F. W. J Biol
Chem 1955, 212, 319–323.
2.67 (s, 3H, CH3), 2.69 (s, 3H, CH3); Elemental
analysis: C6H7N2OCl Found (C, 45.42; H, 4.41; N,
17.63%); Requires (C, 45.44; H, 4.45; N, 17.66%);
m/z: 158 [M+]
[12] Goudgaon, N. M.; Naguib, F. N. M.; El-Kouni, M. H.;
Schinazi, R. F. J Med Chem 1993, 36, 4250–4254.
[13] Melvin, D. T.; Anthony, B. N.; Kyoichi, A. W.; Jack,
J. F. Invest Opthlmol Vis Sci 1981, 21, 826–832.
[14] Kaufman, H. E.; Martola, E. L.; Dolman, H. Arch
Opthalmol 1962, 68, 235–238.
REFERENCES
[1] (a) Varvoglis, A. The Organic Chemistry of Polycoor-
dinated Iodine; VCH: New York, 1992; (b) Varvoglis,
A. Hypervalent Iodine in Organic Synthesis; Aca-
demic: London, 1997; (c) Zhdankin, V. V.; Stang, P.
J. Chem Rev 2002, 102, 2523–2584; (d) Wirth, T. Top-
ics in Current Chemistry, Springer-Verlag: Berlin,
2003, Vol. 224; (e) Kitamura, T.; Fujiwara, Y. Org
Prep Proced Int 1997, 29(4), 409–458; (f) Zhdankin,
V. V.; Stang, P. J. Chem Rev 2008, 108, 5299–5358;
(g) Zhdankin, V. V. ARKIVOC 2009(i), 1–62.
[2] Margolis, A. Hypervalent Iodine In Organic Synthe-
sis; Academic Press: San Diego, CA: 1997.
[3] Jain, K. S.; Chitre, T. S.; Maniyar, P. B.; Kathiravan,
M. K.; Bindre, V. S.; Veer, V. S. Curr Sci 2006, 90,
793–803.
[4] Mitsuya, H.; Weinhold, K. J.; Furman, P. A.; St. Clair,
M. H.; Nusinoff-Lehman, S.; Gallo, R. C. Proc Natl
Acad Sci USA 1985, 82, 7096–7100.
[15] Kuafman, H. E.; Nesburn, A. B.; Maloney, E. D. Arch
Opthalmol 1962, 67, 583–588.
[16] (a) Habib, N. S.; Kappe, T. J Hetroatom Chem,
1984, 21(2), 385–388; (b) Robins, M. J.; Barr, P. J.;
Giziewicz, J. Can J Chem 1984, 60, 554–557.
[17] (a) Synder, H. R.; Foster, H. A. J Am Chem Soc 1954,
76, 118–123; (b) Murray, T. P.; Hay, J. V.; Portlock,
D. E.; Wolfe, J. F. J Org Chem, 1974, 39, 595–600.
[18] Obeid, N.; Skulski, L. Molecules 2001, 6, 869–874.
[19] Kazmierczak, P.; Skulski, L.; Obeid, N. J Chem Res,
1999, 64–65.
[20] (a) Method for Dilution Antimicrobial Susceptibil-
ity Test for Bacteria That Grow Aerobically Ap-
proved Standard, 5th ed.; National Committee for
Clinical Laboratory Standards: Villanova, PA, 2000;
(b) McFarland, J. J Am Med Assoc 1907, 49,
1176–1178; (c) Greenwood, D.; Slack, R.; Peutherer,
J. Medical Microbiology: A Guide to Microbial Infec-
tions: Pathogenesis, Immunity, Laboratory Diagnosis
and Control, 1997, 15th ed.; Churchill Livingstone,
Oxford.
[5] Lin, T. S.; Guo, J. Y.; Schinazi, R. F.; Chu, C. K.;
Xiang, J. N.; Prusoff, W. H. J Med Chem 1988, 31,
336–340.
[6] Choo, H.; Chong, Y.; Choi, Y.; Mathew, J.; Schinazi,
R. F.; Chu, C. K. J Med Chem 2003, 46, 389–398.
Heteroatom Chemistry DOI 10.1002/hc