Direct Chemoselective Synthesis of N-3-Substituted Pyrimidinones in a Microwave-Assisted Method

Article abstract of DOI:10.1080/00397911.2015.1017770

Synthesis of selectively N-3-substituted pyrimidine nucleobases or pyrimidinones has always been a challenge because of poor regioselectivity and chemoselectivity. In this article we demonstrate a single-step, de novo synthesis of selectively N-3-substitu

Full text of DOI:10.1080/00397911.2015.1017770

This article was downloaded by: [University of Saskatchewan Library]
On: 12 March 2015, At: 07:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Direct Chemoselective Synthesis of N-3 Substituted
Pyrimidinones in a Microwave-Assisted Method
Burgula Laxminarayanaa & Lal Mohan Kundua
a Department of Chemistry, Indian Institute of Technology Guwahati, Assam, India
Accepted author version posted online: 25 Feb 2015.
Click for updates
To cite this article: Burgula Laxminarayana & Lal Mohan Kundu (2015): Direct Chemoselective Synthesis of N-3 Substituted
Pyrimidinones in a Microwave-Assisted Method, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1017770
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1017770
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any

form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Direct chemoselective synthesis of N-3 substituted pyrimidinones in a microwave-
assisted method
Burgula Laxminarayana1, Lal Mohan Kundu1
1Department of Chemistry, Indian Institute of Technology Guwahati, Assam, India
Corresponding author E-mail: lmkundu@iitg.ernet.in
Abstract
Synthesis of selectively N-3 substituted pyrimidine nucleobases or pyrimidinones were
always a challenge, due to poor regioselectivity and chemoselectivity. In this article we
demonstrate a single-step, de novo synthesis of selectively N-3 substituted modified
pyrimidinones. We have developed a microwave-assisted methodology for direct,
chemoselective alkylation, benzylation and arylation of C-5 and C-6 substituted
pyrimidine nucleobases selectively at N-3 position. The reactions were found to proceed,
with high efficiency, without the requirement of solvent and were complete within 10-15
minutes of irradiation. The efficiency of the method was further improved by addition of
a Lewis acid which not only increases the yield significantly but also accelerates the
reaction rate.
1

KEYWORDS: Nucleobases, Pyrimidine, Lewis acid, Microwave and DNA damages
INTRODUCTION
Synthesized nucleobases and oligonucleotides have gained popularity for the
development of biomolecular probes,[1-6] therapeutic agents,[7-10] fluorescent nucleic
acids[11-13] and self-assembled DNA hybrid materials.[14-17] Pyrimidine analogs, especially
the C-5, C-6 and N-3 substituted pyrimidinones showed selective anticancer, antitumor,
antiviral, antitubercular and antifungal activity.[18-21] Followed by the success of 5-
fluorouracil as antitumor agent, several derivatives of uracil and thiouracil have been
synthesized to show antitumor proliferating activities.[22,23] Reports are available where
pyrimidine derivatives have also been applied for anti-HIV activities. For example, 6-
substituted uracil derivative HEPT and DABO’s showed a strong and selective activity
against HIV-1.[24] Apart from their pharmaceutical potentials, pyrimidinones in general,
have been widely studied for alternative non Watson-Crick base pairing properties for the
2

development of biomolecular probes.[3,25] Synthesis of modified nucleobases, especially
the family of uracils, thiouracil, thiocytosines and their N-1 or N-3 derivatives are very
interesting because of their wide natural occurrence and high bioactivity.[26-28] Biological
importance of such synthesized pyrimidinones is primarily attributed to their structural
similarities to that of the natural nucleobases and coenzymes. This enables the modified
pyrimidinones to act as inhibitors.
Conventional synthesis of N-1 or N-3 protected pyrimidinones is usually performed
through multistep protection and deprotection chemistry.[29] However, chemo- or regio-
selective substitution at either N-1 or N-3 position of nucleobases is difficult to achieve
because of poor reactivity difference between the two heteroatoms, particularly, where C-
5 and C-6 substitutions are present. As a result the reaction of the pyrimidinones with
alkyl or aryl halides often leads to a mixture of mono-substituted and di-substituted
derivatives.[30-32] Even the sugar-nucleobase coupling reactions also produce mixture of
isomers. Gambocotra et al. succeeded in the chemoselective alkylation of uracils by using
HSAB,[33] Weaver and co-workers have developed regioselective N-3 protection of
uracils.[34] Later on Willis et al. have reported palladium catalyzed regioselective
synthesis of N-alkylated uracil analogs.[35] However, most of the conventional methods
involve post-synthetic modifications of the pyrimidinones and are multistep processes
which required long reaction time, multiple reagents, catalysts and high temperature.[36,37]
Recently, Lee et al. have synthesized N-3 arylated derivatives using Blaise reaction
intermediate.[38] Synthetic procedures of selective N-substituted pyrimidinones from
readily available precursors are very limited.[39-41]
3

In the present work we have successfully developed a single-step, chemoselective
methodology for de novo synthesis of N-3 substituted pyrimidinones from their β-
carbonylester precursors, using substituted urea. Using microwave-assisted method, we
report here synthesis of alkyl, benzyl and aryl substituted pyrimidinone nucleobases
selectively at N-3 position. All reactions were carried out in solvent-free condition and
were completed in a very short period of time. The reaction yields were further improved
by using BF3.ether as Lewis acid.
RESULTS AND DISCUSSION
Alkylation or arylation of the pyrimidin-2,4-diones invariably yields mixture of N-1 and
N-3 substitution.[41] Although N-1 nitrogen is significantly more reactive compared to N-
3, the reactivity was found to be drastically reduced when C-6 substitution is present.
This is attributed to steric hindrance offered by the substituent at the C-6 position of the
pyrimidinones. As a result selective substitution at N-1 is difficult to achieve, especially
for C-6 modified pyrimidine nucleobases. On the other hand, selective substitution at N-3
position is extremely difficult without prior protection of the N-1 position.[42]
In the present methodology we have successfully synthesized selectively N-3 protected
uracil and thiouracil analogs with varying substitutions at C-5 and C-6. Instead of post-
pyrimidinone modification, we have utilized a chemoselective approach to synthesize the
N-3 protected pyrimidinones directly from their β-carbonylester precursors. Table 1
demonstrates a one-pot, microwave-directed approach for N-3 substitution of the
4

pyrimidines. This is a relatively greener protocol as no solvent was required and all
reactions were complete within minutes of irradiation, avoiding long hours of reflux. All
the reactions and experimental conditions are listed in Table 1. Reaction occurs when the
substrate β-carbonylester reacts with the urea derivative at elevated temperature in a
closed vessel CEM Discover LabMate microwave reactor for short period of irradiation.
As can be evident, a library of compounds (1-19) with varying substitution at C-5 and C-
6 of uracil and thiouracils were synthesized. A number of urea derivates have been used
to show diversity of the method. Although the reactions could proceed moderately well
without presence of additional reagents, use of BF3 in ether was found to enhance the
yields as well as the rate of the reactions, to a significant extent.
The substrate β-ketoesters were either purchased or were synthesized using published
protocols.[43,44] All the compounds (1-19) were characterized by 1H NMR, 13C NMR and
HRMS. We also have obtained three crystal structures of compound 3, 4 and 15, which
confirm that isolated compounds are indeed N-3 derivatized nucleobases (Figure 1). We
have performed a number of NOESY analyses (see supplementary information) to
authenticate that the selective alkylation and benzylation were taking place indeed at N-3
and not at N-1 of the pyrimidines (Figure 1). Compounds having C-6 substitution clearly
shows proton-proton coupling interaction with the free N-1 proton. For example, in
compound 1 and 7, a proton-proton coupling is observed (highlighted in Figure 1)
between the C-6 methyl group (~2 ppm) and N-1 proton (~11 ppm).
5

We have performed a number of NOESY analyses (see supplementary information) to
authenticate that the selective alkylation and benzylation were taking place indeed at N-3
and not at N-1 of the pyrimidines (Figure 1). Compounds having C-6 substitution clearly
shows proton-proton coupling interaction with the free N-1 proton. For example, in
compound 1 and 7, a proton-proton coupling is observed (highlighted in Figure 1)
between the C-6 methyl group (~2 ppm) and N-1 proton (~11 ppm).
A proposed mechanism of this chemoselective reaction is shown in Figure 2. Our earlier
report had established that the activated β-carbonyl carbon first reacts with urea followed
by dehydration, forming the first intermediate.[45] This intermediate was trapped and
characterized. In the present case, where unsymmetrical urea is used, preferentially the
free –NH2 group of the urea reacts with the β-carbonyl carbon, compared to that of the
secondary amine. This is presumably to avoid a large amount of steric strain that would
be created from reaction of the substituted nitrogen (-NHR) of urea and R1 of the β-
carbonylester, making the intermediate highly unfavorable. A similar mechanism had
been reported by Kappe for a 3-component Biginelli reaction.[46]
In conclusion, we have successfully demonstrated a robust chemoselective method for
direct synthesis of N-3 alkylated and arylated pyrimidinones with varying substitution at
C-5 and C-6 position. The method involves short microwave irradiation of the β-
carbonylester precursor and urea derivative in a solvent-free reaction. Such selective N-3
derivatization otherwise require multistep reactions in harsh condition. Addition of Lewis
acid was found to accelerate the reactions significantly.
6

EXPERIMENTAL SECTION
1) General Information
All chemicals were purchased from reputed pharmaceuticals and were used without
further purification. All microwave-directed reactions were carried out in a closed vessel
CEM Discover LabMate microwave reactor at about 145°C for variable durations. The
temperature of the reaction mixtures were all measured by an internal built-in IR sensor.
1H-NMR (400 MHz) and 13C-NMR (100 MHz) were all recorded from a DRX-400
Varian spectrometer using CDCl3 and DMSO-D6 as solvents. Chemical shifts are
reported in parts per million (ppm). Melting points were determined using Büchi B-545
apparatus and are uncorrected. High resolution mass spectrometry was analyzed from
Agilent Q-TOF 6500 LC/MS system and Micromass Q-TOF ESI-MS instrument (model
HAB 273). X-Ray data were collected from a Bruker SMART APEX equipped with a
CCD area detector using Mo. The structures were solved by direct method using
SHELLX-97 (Göttingen, Germany). The melting points, characterization and relevant
literature of the reported compounds are given.
2) Representative Procedure For Synthesis Of Compound 4
Ethyl 3-oxo-3-phenylpropanoate (4a, 2 mmol), taken in a reactor vessel, was mixed
thoroughly for 1 min with Methyl urea (2.6 mmol). The vessel was closed immediately
and was subjected to microwave irradiation for 12 min at about 145°C. The completion
of reaction was monitored by checking TLC at regular time interval. Compound (4) was
7

further purified by column chromatography (Silica gel 60-120 mesh, 60% ethyl acetate in
hexane).
Representative Procedure For Synthesis Of Compound 4 With Lewis Acid
Ethyl 3-oxo-3-phenylpropanoate (4a, 2 mmol), taken in a reactor vessel with BF3. Et2O
(339 mg, 2.4 mmol) was mixed thoroughly for 1 min with urea (2.6 mmol). The vessel
was closed immediately and was subjected to microwave irradiation at 145°C for about 8
min. Reaction was complete within 8 min irradiation, which was verified by TLC.
Compound (4) was further purified by column chromatography (Silica gel 60-120 mesh,
60% ethyl acetate in hexane).
3) Characterization Data
3-Methyl-6-Phenylpyrimidine-2,4(1H,3H)-Dione (4):
Yield: 90%, white solid, m.p: 230-232°C, 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s,
1H), 7.74 (d, 2H, J= 6.8 Hz), 7.56-7.49 (m, 3H), 5.96 (s, 1H), 3.17 (s, 3H). 13C NMR
(100 MHz, DMSO-d6) δ 164.3, 152.6, 151.7, 132.0, 129.6, 128.4, 127.5, 97.5, 27.3.
HRMS (ESI) m/z [M+H]+ calculated (C11H10N2O2): 203.0815; observed: 203.0817.
Crystal data: CCDC# 991093; C11 H10 N2 O2; M = 202.21, m.p. = 230-232°C,
monoclinic; P21/n, a = 5.8924(19)Å; b = 21.161(6)Å, c = 8.054(3)Å, α = 90°, β =
103.67(2)°, γ = 90°, V = 975.8(5)Å, Z = 4, μ = 0.097 mm-1, ρ = 1.376 g.cm-3, Mo-Kα
radiation, R1 = 0.0621, wR2 = 0.1032, S = 0.968. The crystallographic data for the
complexes has been deposited with the Cambridge Crystallographic Data Centre. Copies
of this information may be obtained free of charge from the Director, CCDC, 12, Union
8

Road, Cambridge, CB2 1EZ, UK (Fax: +44 1223336033; e-mail:
deposit@ccdc.cam.ac.uk or http://www.ccdc.cam. ac.uk).
3-Benzyl-6-Methylpyrimidine-2,4(1H,3H)-Dione (7):
Yield: 72%, white solid, m.p: 194-198°C, 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s,
1H), 7.40 (d, 2H, J= 6.8 Hz), 7.27-7.22 (m, 3H), 5.50 (s, 1H), 5.03 (s, 3H), 2.04 (s, 3H).
13C NMR (100 MHz, DMSO-d6) δ 163.5, 158.6, 152.0, 137.0, 128.2, 128.1, 127.1, 99.1,
42.9, 18.4. HRMS (ESI) m/z [M+H]+ calculated (C12H12N2O2): 217.0972; observed:
217.0973.
3-Ethyl-6-Phenylpyrimidine-2,4(1H,3H)-Dione (12):
Yield: 64%, white solid, m.p: 220-223°C 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H),
7.62-7.45 (m, 5H), 5.84 (s, 1H), 3.24 (q, 2H, J= 6.0 Hz), 1.15 (t, 3H, J= 7.2 Hz). 13C
NMR (100 MHz, CDCl3) δ 163.5, 152.8, 150.5, 136.2, 131.4, 126.5, 125.6, 98.7, 35.6,
14.5. HRMS (ESI) m/z [M+H]+ calculated (C12H13N2O2): 217.0972; observed: 217.0971.
3-Ethyl-2,3-Dihydro-6-Phenyl-2-Thioxopyrimidin-4(1H)-One (18):
Yield: 62%, white solid, m.p: 206-208°C, 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H),
7.82 (d, 2H, J= 7.4 Hz), 7.58 (t, 2H, J= 7.6 Hz), 5.97 (s, 1H), 3.35 (q, 2H, J= 6.8 Hz),
1.21 (t, 3H, J= 7.2 Hz). 13C NMR (100 MHz, DMSO-d6) δ 174.2, 161.5, 149.5, 139.4,
128.0, 127.6, 126.9, 113.8, 43.0, 16.0. HRMS (ESI) m/z [M+H]+ calculated
(C12H13N2OS): 233.0743; observed: 233.0749.
9

SUPPLEMENTARY INFORMATION
General experimental methods, full characterization of compounds, ORTEP
presentations, details crystallographic data, copies of 1H NMR, 13C NMR and HRMS
spectra for this article can be accessed on the publisher’s website.
ACKNOWLEDGMENTS
We would like to acknowledge DST-SERB (Grant No. SR/FT/SC-27/2011), New Delhi,
India, for providing laboratory equipment and financial assistance. The Central
Instrumental Facility (CIF), IIT Guwahati, is hereby acknowledged for recording NMR.
REFERENCES
1.
Schroder, A. S.; Steinbacher, J.; Steigenberger, B.; Gnerlich, F. A.; Schiesser, S.;
Pfaffeneder, T.; Carell, T. Angew. Chem. Int. Ed. 2014, 53, 315-318.
2.
3.
Lee, A. H. F.; Kool, E. T. J. Am. Chem. Soc. 2005, 127, 3332-3338.
Liu, H. B.; Gao, J. M.; Maynard, L.; Saito, Y. D.; Kool, E. T. J. Am. Chem. Soc.
2004, 126, 1102-1109.
4.
Nielsen, P. E.; Egholm, M.; Berg, R. H.; Buchardt, O. Science 1991, 254, 1497-
1500.
5.
Singh, S. K.; Nielsen, P.; Koshkin, A. A.; Wengel, J. Chem. Commun. 1998, 455-
456.
6.
Cahova, H.; Havran, L.; Brazdilova, P.; Pivonkova, H.; Pohl, R.; Fojta, M.;
Hocek, M. Angew. Chem. Int. Ed. 2008, 47, 2059-2062.
10

7.
Peacock, H.; Fucini, R. V.; Jayalath, P.; Ibarra-Soza, J. M.; Haringsma, H. J.;
Flanagan, W. M.; Willingham, A.; Beal, P. A. J. Am. Chem. Soc. 2011, 133, 9200-9203.
8.
Mackman, R. L.; Cihlar, T. Annu. Rep. Med. Chem. 2004, 39, 305-321.
Kole, R.; Krainer, A. R.; Altman, S. Nat. Rev. Drug. Discov. 2012, 11, 125-140.
Seo, Y. J.; Hwang, G. T.; Ordoukhanian, P.; Romesberg, F. E. J. Am. Chem. Soc.
9.
10.
2009, 131, 3246-3252.
11.
12.
13.
14.
15.
Saito, Y.; Motegi, K.; Bag, S. S.; Saito, I. Bioorg. Med. Chem. 2008, 16, 107-113.
Okamoto, A.; Tanaka, K.; Fukuta, T.; Saito, I. Chembiochem 2004, 5, 958-963.
Wilson, J. N.; Kool, E. T. Org. Biomol. Chem. 2006, 4, 4265-4274.
Clever, G. H.; Kaul, C.; Carell, T. Angew. Chem. Int. Ed. 2007, 46, 6226-6236.
Cafferty, B. J.; Gallego, I.; Chen, M. C.; Farley, K. I.; Eritja, R.; Hud, N. V. J.
Am. Chem. Soc. 2013, 135, 2447-2450.
16. Arnal-Herault, C.; Barboiu, M.; Pasc, A.; Michau, M.; Perriat, P.; van der Lee, A.
Chem. Eur. J. 2007, 13, 6792-6800.
17.
18.
Rajendran, A.; Endo, M.; Sugiyama, H. Angew. Chem. Int. Ed. 2012, 51, 874-890.
Kumar, K.; Sagar, S.; Esau, L.; Kaur, M.; Kumar, V. Eur. J. Med. Chem. 2012,
58, 153-159.
19.
20.
21.
Parker, W. B. Chem. Rev. 2009, 109, 2880-2893.
Pathak, T. Chem. Rev. 2002, 102, 1623-1667.
Novikov, M. S.; Ivanova, O. N.; Ivanov, A. V.; Ozerov, A. A.; Valuev-Elliston,
V. T.; Temburnikar, K.; Gurskaya, G. V.; Kochetkov, S. N.; Pannecouque, C.; Balzarini,
J.; Seley-Radtke, K. L. Bioorg. Med. Chem. 2011, 19, 5794-5802.
11

22.
Cancer Res. 1995, 55, 6227-6230.
23. Baccanari, D. P.; Davis, S. T.; Knick, V. C.; Spector, T. Proc. Natl. Acad. Sci.
USA 1993, 90, 11064-11068.
Cao, S.; Baccanari, D. P.; Joyner, S. S.; Davis, S. T.; Rustum, Y. M.; Spector, T.
24.
Gu, S. X.; Yang, S. Q.; He, Q. Q.; Ma, X. D.; Chen, F. E.; Dai, H. F.; De Clercq,
E.; Balzarini, J.; Pannecouque, C. Bioorg. Med. Chem. 2011, 19, 7093-7099.
25.
26.
27.
Radhakrishnan, K.; Burgula, L. N.; Kundu, L. M. Rsc Adv. 2013, 3, 7282-7284.
Cernova, M.; Cerna, I.; Pohl, R.; Hocek, M. J. Org. Chem. 2011, 76, 5309-5319.
Chen, C.; Wu, D. P.; Guo, Z. Q.; Xie, Q.; Reinhart, G. J.; Madan, A.; Wen, J.;
Chen, T. K.; Huang, C. Q.; Chen, M.; Chen, Y. S.; Tucci, F. C.; Rowbottom, M.;
Pontillo, J.; Zhu, Y. F.; Wade, W.; Saunders, J.; Bozigian, H.; Struthers, R. S. J. Med.
Chem. 2008, 51, 7478-7485.
28.
Medda, F.; Russell, R. J. M.; Higgins, M.; McCarthy, A. R.; Campbell, J.; Slawin,
A. M. Z.; Lane, D. P.; Lain, S.; Westwood, N. J. J. Med. Chem. 2009, 52, 2673-2682.
29.
30.
Keen, S. P.; Weinreb, S. M. Tetrahedron Lett. 2000, 41, 4307-4310.
Skulnick, H. I.; Ludens, J. H.; Wendling, M. G.; Glenn, E. M.; Rohloff, N. A.;
Smith, R. J.; Wierenga, W. J. Med. Chem. 1986, 29, 1499-1504.
31. Atwal, K. S.; Rovnyak, G. C.; Oreilly, B. C.; Schwartz, J. J. Org. Chem. 1989, 54,
5898-5907.
32.
Jacobsen, S. A.; Rodbotten, S.; Benneche, T. J. Chem. Soc. Perkin Trans. 1 1999,
3265-3268.
33.
34.
Gambacorta, A.; Farah, M. E.; Tofani, D. Tetrahedron 1999, 55, 12615-12628.
Fan, W.; Buhendwa, M. G.; Weaver, D. F. J. Org. Chem. 2004, 69, 9307-9309.
12

35.
Willis, M. C.; Snell, R. H.; Fletcher, A. J.; Woodward, R. L. Org. Lett. 2006, 8,
5089-5091.
36.
Dolman, N. P.; More, J. C. A.; Alt, A.; Knauss, J. L.; Pentikainen, O. T.; Glasser,
C. R.; Bleakman, D.; Mayer, M. L.; Collingridge, G. L.; Jane, D. E. J. Med. Chem. 2007,
50, 1558-1570.
37.
Frija, L. M. T.; Khmelinskii, I. V.; Cristiano, M. L. S. Tetrahedron Lett. 2005, 46,
6757-6760.
38.
39.
Chun, Y. S.; Xuan, Z.; Kim, J. H.; Lee, S. G. Org. Lett. 2013, 15, 3162-3165.
Fustero, S.; Piera, J.; Sanz-Cervera, J. F.; Catalan, S.; de Arellano, C. R. Org.
Lett. 2004, 6, 1417-1420.
40.
41.
Sweet, F.; Fissekis, J. D. J. Am. Chem. Soc. 1973, 95, 8741-8749.
Dhuguru, J.; Gheewala, C.; Kumar, N. S. S.; Wilson, J. N. Org. Lett. 2011, 13,
4188-4191.
42.
Jacobsen, M. F.; Knudsen, M. M.; Gothelf, K. V. J. Org. Chem. 2006, 71, 9183-
9190.
43.
Davies, S. J.; Ayscough, A. P.; Beckett, R. P.; Clements, J. M.; Doel, S.; Pratt, L.
M.; Spavold, Z. M.; Thomas, S. W.; Whittaker, M. Bioorg. Med. Chem. Lett. 2003, 13,
2715-2718.
44.
45.
Puterova, Z.; Andicsova, A.; Vegh, D. Tetrahedron 2008, 64, 11262-11269.
Burgula, L. N.; Radhakrishnan, K.; Kundu, L. M. Tetrahedron Lett. 2012, 53,
2639-2642.
46. Kappe, C. O. J. Org. Chem. 1997, 62, 7201-7204.
13

Table 1 Chemoselective synthesis of N-3 substituted pyrimidine derivatives (1-19). All
irradiations were performed at 145°C in a closed vessel. Variation of irradiation time
refers to completion of a reaction. X= O or
S.
S. Substrate
Urea
Mocrowave
%
Product 1-10
% Yield
with
N
o
irradiation( Yiel
min)
12
d
BF3.Et2O(
min)
1
2
3
4
76
85(8)
12
12
12
68
67
78
80(8
78(8)
90(8)
5
12
66
75(8)
14

6
7
8
9
12
12
12
12
65
61
60
56
73(8
72(8)
70(8)
65(8)
1
0
15
58
70(8)
1
1
15
15
32
55
40(10)
64(10)
1
2
1
3
15
12
25
72
40(10)
85(8)
1
4
15

1
5
12
65
78(8)
1
6
12
15
64
38
75(8)
1
7
59(10)
1
8
15
15
48
62(10)
1
9
No reaction
16

Figure 1 Top: representative NOESY spectra of compound 1 and 7, respectively.
Bottom: ORTEP diagram of compound 3, 4 and 15, respectively.
17

Figure 2 Proposed mechanism of formation of selective N-3 protected nucleobases, using
Lewis acid.
18