Bromination at C-5 of pyrimidine and C-8 of purine nucleosides with 1,3-dibromo-5,5-dimethylhydantoin

Article abstract of DOI:10.1016/j.tetlet.2012.04.081

Treatment of the protected and unprotected nucleosides with 1,3-dibromo-5,5-dimethylhydantoin in aprotic solvents such as CH ₂Cl₂, CH₃CN, or DMF effected smooth bromination of uridine and cytidine derivatives at C-5 of pyrimidine rings as well as adenosine and guanosine derivatives at C-8 of purine rings. Addition of Lewis acids such as trimethylsilyl trifluoromethanesulfonate enhanced the efficiency of bromination.

Full text of DOI:10.1016/j.tetlet.2012.04.081

Tetrahedron Letters 53 (2012) 3333–3336
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Bromination at C-5 of pyrimidine and C-8 of purine nucleosides
with 1,3-dibromo-5,5-dimethylhydantoin
⇑
Ramanjaneyulu Rayala, Stanislaw F. Wnuk
Department of Chemistry & Biochemistry, Florida International University, Miami, FL 33199, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of the protected and unprotected nucleosides with 1,3-dibromo-5,5-dimethylhydantoin in
aprotic solvents such as CH2Cl2, CH3CN, or DMF effected smooth bromination of uridine and cytidine
derivatives at C-5 of pyrimidine rings as well as adenosine and guanosine derivatives at C-8 of purine
rings. Addition of Lewis acids such as trimethylsilyl trifluoromethanesulfonate enhanced the efficiency
of bromination.
Received 10 April 2012
Revised 16 April 2012
Accepted 17 April 2012
Available online 24 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Bromination
1,3-Dibromo-5,5-dimethylhydantoin
Lewis acids
Purines
Pyrimidines
Nucleosides
Halogen-substituted nucleosides and especially uracil deriva-
tives substituted at C-5 and adenine derivatives substituted at C-8
with bromine have been shown to possess interesting synthetic
and biological properties.1,2 The halogenated C-5 pyrimidine and
C-8 purine nucleosides are often used in the reactions involving
direct displacement with nucleophiles1,2 and in transition metal
catalyzed cross-coupling reactions3 resulting in the syntheses
of a variety of unnatural nucleosides of biological interest and
fluorescent probes.4 A number of 5-substituted uracil derivatives,
especially arabinofuranosyl- and 20-deoxyuridines, have been
investigated extensively for the clinical treatment of viral diseases.5
For instance, the high-yield coupling of 5-iodouracil derivatives
with terminal alkynes afforded 5-alkynyluracil nucleosides with
antiviral activity6,7 and such products can be transformed into
furanopyrimidine-2-one derivatives which possess potent and
selective inhibition of Varicella-Zoster virus.6,8 Radiolabeled 5-bro-
mo- and 5-iodouracil nucleosides are used in cellular biochemistry.9
Halogenated pyrimidine2 and purine1 nucleosides have been
prepared by direct reaction with halogens and other halogenating
agents but some of these methods required vigorous conditions.
The 5-bromination of uracil derivatives has been effected with
Br2/Ac2O/AcOH,2 Br2/H2O,10 N-bromosuccinimide (NBS) in DMF11
or ionic liquids,12 combination of 3-chloroperoxybenzoic acid/HBr
in aprotic solvents,13 ceric ammonium nitrate (CAN)/LiBr in protic
or aprotic solvents,14 or KBr/Oxone.15 Bromination of cytidine at
C-5 has been accomplished with Br2/CCl4/hm
16 or NBS in DMF11 or
ionic liquids.12 The 8-bromination of adenine or guanine nucleo-
sides has been typically achieved with Br2/AcOH/AcONa17 or NBS/
DMF.11
The 1,3-dibromo-5,5-dimethylhydantoin (DBDMH or DBH) is a
useful reagent for various organic transformations18–20 including
aromatic bromination.21–25 Enhanced reactivity of DBH toward
aromatic bromination in the presence of acids has been noted.22–24
Furthermore, Lewis acid-catalyzed benzylic bromination with
DBH26 and efficient oxidation of thiols to disulfides with DBH27,28
have been reported. The combination of DBH/TsOH was also used
for a
-bromination of aliphatic ketones.29 Herein, we report an effi-
cient bromination of pyrimidine (at C-5 position) and purine (at
C-8 position) nucleosides with 1,3-dibromo-5,5-dimethylhydan-
toin in aprotic solvents and the effect of Lewis acids.
Treatment of 20,30,50-tri-O-acetyluridine 1a with DBH (1.1 equiv)
in CH2Cl2 at ambient temperature for 28 h gave protected 5-bromo-
uridine 2a in 95% yield (Scheme 1; Table 1, entry 1). Although the
DBH reagent can deliver two bromonium equivalents, reaction of
1a with 0.55 equiv of DBH was completed in only 60% yield even
after prolonged reaction time (48 h). We found, however, that addi-
tion of 0.55 equiv of a Lewis acid such as trimethylsilyl trifluoro-
methanesulfonate (TMSOTf) significantly enhanced the efficiency
of bromination yielding 2a in 94% yield after only 6 h. (entry 2).
Bromination of 1a at elevated temperature (40 °C) afforded 2a
quantitatively in only 2 h (entry 3), while bromination at lower tem-
perature was incomplete even after 8 h and required 1.1 equiv of
DBH for complete conversion (entry 4). Increasing the amount of
⇑
Corresponding author.
E-mail address: wnuk@fiu.edu (S.F. Wnuk).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.081

3334
R. Rayala, S. F. Wnuk / Tetrahedron Letters 53 (2012) 3333–3336
the bromination (entry 10). Bromination was much less efficient
in protic solvents (e.g., MeOH).
O
N
O
N
Br
HN
HN
The optimized procedure for the 5-bromination of the uracil ring
with DBH has general applicability. For example 1-(2,3,5-tri-O-acet-
O
O
O
DBH or
yl-b,D
-arabinofuranosyl)uracil 1b and 30,50-di-O-acetyl-20-deoxyur-
RO
RO
O
DBH/TMSOTf
idine 1c were efficiently transformed into 2b30 and 2c using this
approach (Scheme 1; Table 2, entries 2–6). Furthermore, bromina-
tion of the unprotected uridine 1d using DBH in DMF was completed
in only 20 min. producing 5-bromouridine 2d in 75% crystallized
Y
X
Y
X
0-40 oC/0.3-28 h
CH2Cl2 or CH3CN or DMF
RO
RO
2
1
yield (entry 7).31 DBH also effected efficient bromination of 1-(b,
D-
arabinofuranosyl)uracil 1e and the acid sensitive 20-deoxyuridine
1f (entries 8 and 9). The 5-bromination of cytidine 3a and 4-N-ben-
zoylcytidine 4a with DBH in DMF proceeded smoothly as well
providing 3b and 4b31 (Fig. 1; Table 3, entries 1 and 2).
Series: a X = OAc, Y = H, R = Ac
b
X = H, Y = OAc, R = Ac
c X = H, Y = H, R = Ac
d X = OH, Y = H, R = H
e
X = H, Y = OH, R = H
The DBH and DBH/TMSOTf combination also effected bromina-
tion of purine nucleosides at the 8 position, although reactions
usually required higher equivalency of DBH and longer reaction
time. Thus, adenosine 5a and 20-deoxyadenosine 6a afforded 8-
bromo products 5b and 6b, albeit in lower isolated yield when
compared to the 5-bromination of pyrimidine nucleosides (Table
3, entries 3 and 4). The 20,30,50-tri-O-acetylguanosine 7a and guano-
sine 8a were converted into 7b and 8b (entries 5–8). Both reactions
appear to be quantitative (TLC). However, protected product 7b
was isolated in 98% yield after aqueous workup, while 8-bromogu-
anosine 8b was obtained in approximately 50% yield after crystal-
lization of the crude reaction mixture from H2O. Treatment of
inosine with DBH or DBH/TMSOTf failed to afford 8-bromo
product.32
f X = H, Y = H, R = H
Scheme 1. Bromination of uracil-derived nucleosides
dimethylhydantoin (DBH). See Tables 1 and 2 for specific reaction parameters.
1
with 1,3-dibromo-5,5-
TMSOTf to 1.1 equiv had no effect on the rate of reaction (entry 5).
Bromination with DBH or the DBH/TMSOTf combination was also
effective in polar aprotic solvents such as CH3CN and DMF (entries
6–9) providing 2a in shorter reaction times. However, it is notewor-
thy that bromination in CH2Cl2 provides pure 2a after aqueous
workup only and does not require prior evaporation of the solvent
from the crude reaction mixture.30 Moreover, other organic acids
such as p-toluenesulfonic acid (TsOH) also efficiently catalyzed
Table 1
Effect of various reaction parameters on 5-bromination of 20,30,50-tri-O-acetyluridine 1a with DBHa
Entry
Solvent
Temp (°C)
DBH (equiv)
TMSOTf (equiv)
Time (h)
Yieldb,c 2a (%)
1
2
3
4
5
6
7
8
9
10
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
DMF
25
25
40
0
25
25
25
25
25
25
1.1
—
28
6
2
3
6
11
2.5
0.6
0.3
8
95
94
98
98
91
86f
90
95
98
94
0.55
0.55
1.1e
0.55
0.55
0.55
0.55
0.55
0.75
0.55d
0.55
0.55
1.10
—
0.55
—
DMF
CH2Cl2
0.55
0.75g
a
b
c
d
e
f
Bromination was performed on 0.1 mmol scale of 1a.
Isolated yield after aqueous work-up.
Purity of the product 2a was determined by TLC and 1H NMR and was higher than 97% unless otherwise noted.
Reaction without TMSOTf showed 60% conversion to 2a (TLC) after 48 h and complete conversion after 68 h with purity over 90% (1H NMR).
Reaction with 0.55 equiv of DBH was complete in 65% after 8 h.
With purity over 90%.
TsOH was used instead of TMSOTf.
g
Table 2
5-Bromination of the uracil-derived nucleosides 1a–fa
Entry
Substrate
Product
Solvent
Temp (°C)
DBH (equiv)
TMSOTf (equiv)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
1a
1b
1b
1c
1c
1c
1d
1e
1f
2a
2b
2b
2c
2c
2c
2d
2e
2f
CH2Cl2
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
DMF
25
25
25
25
25
40
25
25
25
0.55
0.55
0.55
1.10
0.55
0.55
0.55
0.55
0.55
0.55
0.55
0.55
—
0.55
0.55
—
6
10
2
18
2.5
0.5
0.33
1
94c
91c
98c
72d
90c
93c
75e
65d
80d
DMF
DMF
—
—
0.75
a
b
c
Bromination was performed on 0.25–2.0 mmol scale.
Isolated yield.
After aqueous work-up with purity higher than 97% (1H NMR).
After column chromatography.
d
e
After crystallization.

R. Rayala, S. F. Wnuk / Tetrahedron Letters 53 (2012) 3333–3336
3335
O
O
N
NHR
N
NH2
X
X
N
HN
HN
N
N
N
N
X
X
N
O
O
H2N
N
O
O
O
N
SiO
RO
HO
HO
O
O
O
RO
HO
OR
Y
HO OH
3a
X = H, R = H
X = Br, R = H
5a X = H, Y = OH
7a
7b
X = H, R = Ac
X = Br, R = Ac
9a
X = H
3b
5b
6a
X = Br, Y = OH
X = H, Y = H
9b X = Br
4a X = H, R = Bz
8a X = H, R = H
6b X = Br, Y = H
4b
X = Br, R = Bz
8b
X = Br, R = H
Figure 1. Selected nucleoside precursors (series a) and their brominated products (series b).
Table 3
Bromination of selected purine and pyrimidine nucleosides at ambient temperature (see Fig. 1 for structures)a
Entry
Substrate
Product
Solvent
DBH (equiv)
TMSOTf (equiv)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
3a
4a
5a
6a
7a
7a
8a
8a
9a
3b
4b
5b
6b
7b
7b
8b
8b
9b
DMF
DMF
DMF
DMF
DMF
CH3CN
DMF
DMF
DMF
0.55
0.55
1.75
1.50
0.55
0.55
0.75g
0.60
0.55
—
—
—
—
—
—
—
0.55
—
0.5
0.5
5
3.5
2.5
4
2.5
0.5
0.5
72c
74c,d
48c,e
68c,e
83c
98f
51h
48h
98f
a
b
c
Bromination was performed on 0.5–1 mmol scale.
Isolated yield.
After column chromatography.
Direct crystallization of the crude reaction mixture from MeOH gave 4b in 46% yield.
Reaction showed formation of the product in approximately 80% yield (TLC).
Isolated yield after aqueous work-up.
d
e
f
g
h
Reaction with 0.55 equiv of DBH was completed in 24 h.
After crystallization from water. Bromination was quantitative as judged by TLC.
8. McGuigan, C.; Yarnold, C. J.; Jones, G.; Velázquez, S.; Barucki, H.; Brancale, A.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem. 1999, 42, 4479.
9. Mercer, J. R.; Xu, L. H.; Knaus, E. E.; Wiebe, L. I. J. Med. Chem. 1989, 32, 1289.
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11. Srivastava, P. C.; Nagpal, K. L. Experientia 1970, 26, 220.
12. Kumar, V.; Yap, J.; Muroyama, A.; Malhotra, S. V. Synthesis 2009, 3957.
13. Ryu, E. K.; MacCoss, M. J. J. Org. Chem. 1981, 46, 2819.
The bromination with DBH is also compatible with common
protecting groups used in nucleoside chemistry. Thus, treatment
of 50-O-(tert-butyldimethylsilyl)-20,30-O-isopropylideneuridine 9a
with 0.55 equiv of DBH in DMF afforded the corresponding 5-bro-
mo product 9b in quantitative yield (entry 9).
In summary, we have developed an efficient procedure for the
bromination of all RNA nucleobases with 1,3-dibromo-5,5-dimeth-
ylhydantoin in polar aprotic solvents at ambient temperature with
or without the presence of Lewis acids. The method offers a general
and convenient procedure for the synthesis of C-5 pyrimidine and
C-8 purine brominated nucleosides and 20-deoxynucleosides. The
protocol is also compatible with common protecting groups used
in nucleoside chemistry.
14. Asakura, J.; Robins, M. J. J. Org. Chem. 1990, 55, 4928.
15. Ross, S. A.; Burrows, C. J. Tetrahedron Lett. 1997, 38, 2805.
16. Fukuhara, T. K.; Visser, D. W. J. Am. Chem. Soc. 1955, 77, 2393.
17. Holmes, R. E.; Robins, R. K. J. Am. Chem. Soc. 1964, 86, 1242.
18. Markish, I.; Arrad, O. Ind. Eng. Chem. Res. 1995, 34, 2125.
19. Virgil, S. C. Encyclopedia of Reagents for Organic Synthesis 2001. http://
dx.doi.org/10.1002/047084289X.rd038.
20. Alam, A. Synlett 2005, 2403.
21. Auerbach, J.; Weissman, S. A.; Blacklock, T. J.; Angeles, M. R.; Hoogsteen, K.
Tetrahedron Lett. 1993, 34, 931.
22. Eguchi, H.; Kawaguchi, H.; Yoshinaga, S.; Nishida, A.; Nishiguchi, T.; Fujisaki, S.
Bull. Chem. Soc. Jpn. 1994, 67, 1918.
Acknowledgments
23. Herault, X.; Bovonsombat, P.; McNelis, E. Org. Prep. Proced. Int. 1995, 27, 652.
24. Chassaing, C.; Haudrechy, A.; Langlois, Y. Tetrahedron Lett. 1997, 38, 4415.
25. Alam, A.; Takaguchi, Y.; Ito, H.; Yushida, T.; Tsuboi, S. Tetrahedron 2005, 61, 1909.
26. Shibatomi, K.; Zhang, Y.; Yamamoto, H. Chem. Asian J. 2008, 3, 1581.
27. Alam, A.; Takaguchi, Y.; Stuboi, S. Synth. Commun. 2005, 35, 1329.
28. Khazaei, A.; Zolfigol, M. A.; Rostami, A. Synthesis 2004, 2959.
29. Chen, Z.-Z.; Guan, X.-X.; Zheng, Z.-B.; Zou, X.-Z. J. East China Normal Univ.;
Natural Science 2010, 7, 125.
This investigation was supported by an award from NIGMS/NCI
(SC1CA138176). We thank Ms. Patricia Theard for her assistance
during the project.
References and notes
30. Typical procedure for the bromination of protected nucleosides: DBH (161 mg,
0.56 mmol) and TMSOTf (0.1 mL, 125 mg, 0.56 mmol) were added to a stirred
solution of 1a (380 mg, 1.03 mmol) in CH2Cl2 (15 mL). The resulting brownish-
orange mixture was stirred at room temperature for 6 h or until TLC showed
the absence of starting material and formation of less polar product. The
reaction mixture was diluted with CHCl3 (35 mL) and was washed with
saturated NaHCO3/H2O (2 ꢀ 100 mL) and brine (100 mL). The organic layer was
dried (MgSO4) and concentrated in vacuo to yield 2a (433 mg, 94%) as a
colorless foam with purity over 98% (1H NMR) with data as reported.14
Compound 2b had: 1H NMR (400 MHz, CDCl3) d 1.98 (s, 3, Ac), 2.07 (s, 3, Ac),
2.09 (s, 3, Ac), 4.12–4.16 (m, 1, H40), 4.32 (dd, J = 3.9, 12.1 Hz, 1, H500), 4.38 (dd,
J = 5.8, 12.1 Hz, 1, H50), 5.04 (‘q’, J = 1.9 Hz, 1, H30), 5.35 (dd, J = 3.7, 4.1 Hz, 1,
H20), 6.22 (d, J = 4.1 Hz, 1, H10), 7.77 (s, 1, H6), 9.33 (br s, 1, NH); 13C NMR
1. Srivastava, P. C.; Robins, R. K.; Meyer, R. B. In Chemistry of Nucleosides and
Nucleotides; Townsend, L. B., Ed.; Plenum Press: New York, 1988; pp 113–281.
Vol. 1.
2. Ueda, T. In Chemistry of Nucleosides and Nucleotides; Townsend, L. B., Ed.;
Plenum Press: New York, 1988; pp 1–112. Vol. 1.
3. Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003, 103, 1875.
4. Clima, L.; Bannwarth, W. Helv. Chim. Acta 2008, 91, 165.
5. Machida, H.; Sakata, S. In Nucleosides and Nucleotides as Antitumor and Antiviral
Agents; Chu, C. K., Baker, D. C., Eds.; Plenum Press: New York, 1993; pp 245–264.
6. Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854.
7. De Clercq, E.; Descamps, J.; Balzarini, J.; Giziewicz, J.; Barr, P. J.; Robins, M. J. J.
Med. Chem. 1983, 26, 661.

3336
R. Rayala, S. F. Wnuk / Tetrahedron Letters 53 (2012) 3333–3336
(100 MHz, CDCl3): d 20.4, 20.6, 20.8 (3ꢀAc), 62.5 (C50), 74.4 (C20), 76.1 (C30),
5.10 (d, J = 5.9 Hz, 1, 30OH), 5.41(t, J = 4.6 Hz , 1, 50OH), 5.57 (d, J = 3.9 Hz, 1,
20OH), 5.7 (d, J = 3.6 Hz, 1, H10), 7.53 (t, J = 7.6 Hz, 2H, Bz), 7.62 (t, J = 7.3 Hz, 1H,
Bz), 8.10–8.24 (br s, 2H, Bz), 8.79 (s, 1, H6), 12.81 (br s, 1, NH); 13C NMR
(100 MHz, DMSO-d6) d 59.5 (C50), 68.6 (C30), 74.2 (C20), 84.5 (C40), 89.7 (C10),
95.0 (C5), 128.4, 129.4, 132.8, 136.1 (Bz), 142.1 (C6), 147.2 (C4), 154.5 (C2),
177.8 (Bz); MS (ESI) m/z 426 (100, [79Br], MH+), 428 (98, [81Br], MH+). Anal.
Calcd for C16H16BrN3O6ꢂ0.5 MeOH (442.24): C, 44.81; H, 4.10; N, 9.50. Found: C,
44.62; H, 3.71; N, 9.13. The products 2e,33 2f,14 3b,12 5b,34 6b,4 and 8b36 had
physical and spectroscopic properties as reported.
80.7 (C40), 84.4 (C10), 96.3 (C5), 139.8 (C6), 149.2 (C2), 158.6 (C4), 168.6, 169.6,
170.5 (3ꢀAc); MS (ESI) m/z 447 (100, [79Br], MHꢁ), 449 (98, [81Br], MHꢁ). The
products 2c,14 7b,35 and 9b37 had physical and spectroscopic properties as
reported.
31. Typical procedure for the bromination of unprotected nucleosides: DBH
(323 mg, 1.13 mmol) was added to
a stirred solution of 1d (500 mg,
2.05 mmol) in DMF (5 mL). The resulting pale-yellow solution was stirred at
room temperature for 20 minutes or until TLC showed absence of starting
material and formation of less polar product. Volatiles were evaporated and
the residue was coevaporated with MeCN. The resulting pale solid was
crystallized from hot acetone to give 2d (500 mg, 75%) as colorless crystals
with data as reported.14 Compound 4b had: mp 193–195 °C; UV (MeOH) kmax
32. Unsuccessful attempt of bromination of inosine with NBS in DMF has been
reported.11
33. Kumar, R.; Wiebe, L. I.; Knaus, E. E. Can. J. Chem. 1994, 72, 2005.
34. Lin, T. S.; Cheng, J. C.; Ishiguro, K.; Sartorelli, A. C. J. Med. Chem. 1985, 28, 1481.
35. Niles, J. C.; Wishnok, J. S.; Tannenbaum, S. R. Chem. Res. Toxicol. 2000, 13, 390.
36. Lin, T. S.; Cheng, J. C.; Ishiguro, K.; Sartorelli, A. C. J. Med. Chem. 1985, 28, 1194.
37. Kotra, L.; Pai, E. F.; Paige, C. J.; Bello, A. M. WO 2008/083465 A1, 2008.
252, 335 nm (
e 8900, 13 900), kmin 228, 292 nm (e
7300, 4200); 1H NMR
(400 MHz, DMSO-d6) d 3.63 (ddd, J = 2.1, 4.4, 12.2 Hz, 1, H500), 3.74–3.82 (m, 1,
H50), 3.90–3.96 (m, 1, H40), 4.04 (‘q’, J = 5.9 Hz, 1, H30), 4.07–4.13 (m, 1, H20),