Benzhydryl as an efficient selective nitrogen protecting group for uracils

Article abstract of DOI:10.1021/jo0485076

Regioselective N-substitution of the less active nitrogen within uracil analogues has been achieved following preliminary N-protection at the more active N-position with a benzhydryl protecting group. This protecting group is stable to concentrated HCl (a

Full text of DOI:10.1021/jo0485076

ethyl group is expensive and requires harsh deprotection
conditions (40% of HF at 70 °C for 1.5 h).4a Alternatively,
amine or amide nitrogens can be protected using a
benzhydryl group. A literature search indicates that only
two papers have employed the use of a benzhydryl group
for protection of uracil analogues. Martinez et al.8 at-
tempted to use the benzhydryl group to protect both the
N1 and N3 positions of 5-nitrouracil but failed because
of unsuccessful deprotection. Odijk et al.9 employed the
benzhydryl group to selectively protect the N1 position
of 5-fluorouracil. The benzhydryl group was introduced
in a low yield (40%) by converting 5-flurouracil into its
anion (NaH/HMPT) and then reacting with benzhydryl
chloride. The removal of the benzhydryl group was
performed with palladium-catalyzed hydrogenation (3-4
atm) but proved to be inefficient and highly sensitive to
the hydrogenation procedure. Herein, we report our
studies on the use of the benzhydryl group as an efficient
protecting group for uracil and uracil analogues and
illustrate its application by the preparation of uracil
analogues monobenzylated at the less active nitrogen.
Direct introduction of the benzhydryl group using the
sodium salt of uracil or uracil analogues and benzhydryl
bromide gave the monoprotected products in low yield,
along with disubstituted uracils and the starting materi-
als. However, monobenzhydrylated uracil analogues could
be conveniently and regioselectivity prepared in excellent
yield by the reaction of a uracil analogue with bis-
(trimethylsilyl)actamide (BSA) in acetonitrile, followed
by treatment with benzhydryl bromide in the presence
Benzhydryl as an Efficient Selective
Nitrogen Protecting Group for Uracils
Fan Wu,†,‡ Musole G. Buhendwa,† and
Donald F. Weaver*,†,‡,§
Departments of Chemistry and Medicine (Neurology) and
School of Biomedical Engineering, Dalhousie University,
Halifax, Nova Scotia, Canada B4H 4J3
donald.weaver@dal.ca
Received August 25, 2004
Abstract: Regioselective N-substitution of the less active
nitrogen within uracil analogues has been achieved following
preliminary N-protection at the more active N-position with
a benzhydryl protecting group. This protecting group is
stable to concentrated HCl (aqueous) at reflux temperature,
TFA at room temperature, and Pd-C-catalyzed normal
pressure hydrogenation at room temperature; the benzhy-
dryl group can be removed quantitatively and selectively
with a 10% triflic acid solution in TFA at 0 °C.
Direct substitution at the nitrogen positions of uracil
analogues may yield the disubstituted product, the
product monosubstituted at the more active N-position,
or a complex mixture of mono- and disubstituted prod-
ucts. Selective protection/deprotection of the more active
nitrogen is critical for the synthesis of uracil analogues
monosubstituted at the less active nitrogen. A number
of protecting groups have been proposed and used for the
protection of endocyclic nitrogen atoms within uracils:
acyl,1 benzyl,2 p-methoxylbenzyl (PMB),3 alkoxymethyl,4
alkoxycarbonyl,5 and benzyloxycarbonyloxymethyl.6 How-
ever, these protecting groups suffer significant limita-
tions. For example, acyl-protected uracil analogues are
susceptible to the ongoing reaction conditions, the benzyl
group requires demanding reaction conditions for re-
moval,7 tert-butoxylcarbonyl (BOC)-protected uracil ana-
logues are very labile (and the introduction of BOC to
5-nitrouracil failed),5 and the bis(trimethylsiloxy)ethoxym-
of a catalytic amount of I2
or tetrabutylammonium iodide
(Scheme 1).10 The results are summarized in Table 1. The
position of benzhydrylation was dependent on the steric
properties at the uracil C6 position. If C6 is hydrogen,
the benzhydryl group was introduced at the less sterically
hindered N1 position; otherwise, the benzhydryl group
was introduced at the N3 position. The regiochemistry
of these derivatives was assessed by NOE experiments.
Reaction of benzhydryl-protected uracils 2a-h with
benzyl bromide in DMF in the presence of potassium
carbonate gave benzylated derivatives 3a-h in excellent
yield,11 as shown in Table 1.
† Department of Chemistry.
Reports on removal of the benzhydryl group from an
‡ Department of Medicine (Neurology).
amide nitrogen are limited. Martinez8 failed in the
§ School of Biomedical Engineering.
(1) Cruickshank, K. A.; Jiricny, J.; Reese, C. B. Tetrahedron Lett.
1984, 25, 681.
(2) Kundu, N. G.; Hertzberg, R. P.; Hannon, S. J. Tetrahedron Lett.
1980, 21, 1109.
(8) Martinez, A. P.; Lee, W. W.; Goodman, L. J. Med. Chem. 1968,
11 (2), 384.
(9) Odijk W. M.; Wanner, M. J.; Kooman, G. J.; Pandit, U. K.
Heterocycles 1978, 9 (10), 1403.
(3) Takaku, H.; Kamaike, K.; Tsuchiya, J. J. Org. Chem. 1984, 49,
51.
(4) (a) Arias, L.; Guzma´n, A.; Jaime-Figueroa, S.; Lopez, F. J.;
Morgans, D. J., Jr.; Padilla, F.; Pe´rez-Medrano, A.; Quintero, C.;
Romero, M.; Sandoval, L. Synlett 1997, 1233. (b) Kundu, N. G.; Khatri,
S. G. Synthesis 1985, 323. (c) Ito, T.; Ueda, S.; Takaku, H. J. Org.
Chem. 1986, 51, 931. (d) Kishi, Y.; Nakatsuka, S.; Fukuyama, T.;
Mavel, M. J. Am. Chem. Soc. 1973, 95, 6493. (e) Fukuyama, T.;
Nakatsuka, S.; Kishi, Y. Tetrahedron 1981, 37, 2045. (f) Nakatsuka,
S.; Miyszaki, H.; Goto, T. Tetrahedron Lett. 1980, 21, 2817.
(5) Jaime-Figueroa, S.; Zamilpa, A.; Guzma´n, A.; Morgans, D. J.,
Jr. Synth. Commun. 2001, 31, 3739.
(10) Representative Procedure. To a suspension of thymine 1b
(1.26 g, 10.0 mmol) in acetonitrile (30 mL) was added bis(trimethyl-
silyl)actamide (6.2 mL, 25 mmol) under argon. After the reaction
mixture became a clear solution (in several minutes), benzhydryl
bromide (3.71 g, 15.0 mmol) and a catalytic amount of I2 were added.
The reaction solution was heated at reflux until all starting material
was consumed. After cooling to room temperature, the mixture was
concentrated on a rotary evaporator, diluted with 100 mL of ethyl
acetate, and washed with 50 mL of H2O. The organic phase was dried
over Na2SO4 and evaporated to dryness. The residue was purified by
flash chromatography (hexane/ethyl acetate ) 3:2) to give 1-benzhy-
(6) Nagase, T.; Seike, K.; Shiraishi, K.; Yamada, Y.; Ozaki, S. Chem.
Lett. 1988, 8, 1381.
drylthymine 2b (2.78 g, 95%) as a white powder: mp 226-227 °C; 1
H
(7) (a) Mueller, C. E.; Thorand, M.; Qurishi, R.; Diekmann, M.;
Jacobson, K. A.; Padgett, W. L.; Daly, J. W. J. Med. Chem. 2002, 45
(16), 3440. (b) Philips, K. D.; Horwitz, J. P. J. Org. Chem. 1975, 40,
1856. (c) Philips K. D.; Horwitz, J. P. J. Org. Chem. 1975, 40, 1856.
NMR (500 MHz, DMSO) δ 1.71 (d, J ) 0.69 Hz, 3H), 6.94 (s, 1H), 7.16-
7.43 (m, 11H), 11.43 (s, 1H); 13C NMR (125 MHz, DMSO) δ 12.1, 61.0,
109.3, 127.9, 128.3, 128.8, 137.9, 138.2, 151.0, 163.6; HRMS calcd for
C18H16N2O2 292.1212, found 292.1211.
10.1021/jo0485076 CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/17/2004
J. Org. Chem. 2004, 69, 9307-9309
9307

SCHEME 1
TABLE 1. Preparation of Benzhydryl Uracils 2 and
Their Benzylation to 3
SCHEME 2
product 2
product 3
sub-
strate 1 R5
yield
(%)
mp
(°C)
yield
(%)
mp
(°C)
R6
1a
1b
1c
1d
1e
1f
H
2a 80 212-213 3a
2b 95 226-227 3b
94 167-168
96 148-150
99 194-196
Me
Br
NO2
F
2c
81 214-216 3c
2d 72 262-263 3d 100 162-164
2e 88 175-176a 3e
i-Pr 2f 92 180-181 3f
n-Bu 2g 55 135-136 3g
Bn
95 159-160
95 146-147
93 100-102
1g
1h
2h 90 211-213 3h 100 169-171
a Lit.9 mp 169-170 °C.
deprotection of the benzhydryl group from 5-aminouracil.
Kita12 achieved the deprotection of benzhydryl protected
azetidine-2-one under Birch reduction conditions, but
these conditions are not compatible with a N-benzyl
group or with other reducible groups such as a bromo or
nitro group. Wipf13 effected the cleavage of the benzhydryl
group in a quinone with TFA (at 50 °C overnight).
Effenberger14 used TFA for the deprotection of the
benzhydryl group of oxoproline (at 70 °C for 40 h). We
found that the benzhydryl group on uracils was stable
to TFA at room temperature or concentrated HCl (aque-
ous) at reflux temperature and was only partially cleaved
by TFA at refluxing temperature even after an extended
reaction time. Effenberger14 also effected the cleavage of
the benzhydryl group from the oxoproline nitrogen by
means of catalytic hydrogenation with Pd(OH)2/C in
acetic acid at 40 °C for 85 h. Odijk et al.9 used palladium-
TABLE 2. Deprotection of Benzhydryl-Protected
Uracils 3
mp (°C)
sub-
strate 3 R5
product yield
R6
4
(%)
observed
literature
3a
3b
3c
3d
3e
3f
H
4a
4b
4c
4d
4e
4f
100 181-182
177-1784a
Me
Br
NO2
F
100 208-210 (dec) 200-2024a
100 196-198 (dec) 160-1614a
100 234-236 (dec) 222-2244a
100 157-159
100 177-178
100 121-122
100 208-210 (dec)
156-15716
i-Pr
n-Bu
Bn
3g
3h
4g
4h
catalyzed hydrogenation (3-4 atm) for removal of the
benzhydryl group in 5-fluorouracil, but this proved to be
highly sensitive to the hydrogenation procedure. We
found that the benzhydryl group on a uracil was only
partially cleaved by Pd-C (or Pd(OH)2/C)-catalyzed
hydrogenation at 60 psi and room temperature or by
hydrogenation at normal pressure in methanol, THF, or
acetic acid at refluxing temperature. Therefore, the
deprotection of benzhydyl-protected uracil analogues was
further investigated. We found that the benzhydyl group
was deprotected quantitatively and selectively in less
than 30 min with a 10% triflic acid solution in TFA at 0
°C, without any affect on the benzyl group or other
functional groups on the uracil analogues (Scheme 2 and
Table 2).15
(11) Representative Procedure. To a suspension of 1-benzhy-
drylthymine 2b (1.46 g, 5.0 mmol) and potassium carbonate (0.83 g,
6.0 mmol) in DMF (8 mL) under argon was added benzyl bromide (0.90
mL, 7.5 mmol) at room temperature. The mixture was stirred overnight
at room temperature, diluted with ether (50 mL), washed with water
(2 × 30 mL), dried over Na2SO4, and evaporated to dryness. The crude
product was purified by flash chromatography (hexane/ethyl acetate
) 5:1) to give 1-benzhydryl-3-benzylthymine 3b (1.83 g, 96%) as a white
powder: mp 148-150 °C; 1H NMR (500 MHz, DMSO) δ 1.78 (d, J )
0.67 Hz, 3H), 5.03 (s, 2H), 7.01 (s, 1H), 7.21-7.43 (m, 16H); 13C NMR
(125 MHz, DMSO) δ 12.7, 44.0, 62.4, 108.6, 127.0, 127.4, 128.0, 128.2,
128.3, 128.8, 136.9, 137.0, 138.0, 151.2, 162.5; HRMS calcd for
C
25H22N2O2 382.1681, found 382.1673.
(12) Kita, Y.; Shibata, N.; Kawano, N.; Tohjo, T.; Fujimori, C.;
Matsumoto, K.; Fujita, S. J. Chem. Soc., Perkin Trans. 1 1995, 2405.
(13) Wipf, P.; Hopkins, C. R. J. Org. Chem. 1999, 64, 6881.
(14) Effenberger, F.; Muller, W.; Keller, R.; Wild, W.; Ziegler, T. J.
Org. Chem. 1990, 55, 3064.
To further study the compatibility of the deprotection
conditions with other function groups, several N3-
9308 J. Org. Chem., Vol. 69, No. 26, 2004

SCHEME 3
TABLE 3. Preparation of N3-Substituted
Acknowledgment. D.F.W. acknowledges salary sup-
port from a Canadian Research Chair. The authors
thank the Atlantic Region Magnetic Resonance Centre
(ARMRC) for NOE experiments. This work was sup-
ported by the Natural Sciences and Engineering Re-
search Council of Canada.
1-Benzhydrylthymines 3 and Their Deprotection
product 3
product 4
yield
(%)
mp
(°C)
yield
(%)
mp
(°C)
R3
EtOCOCH2-
p-CN-C6H4CH2-
o-CF3-C6H4CH2-
m-MeO-C6H4CH2- 3l
p-Br-C6H4COCH2- 3m 90 193-195 4m 100 210-212
3i
3j
92 119-120 4i
95 148-149 4j
90 192-194 4k
96 120-121 4l
100 156-158
100 244-246
100 143-144
100a 150-152
3k
Supporting Information Available: 1H and 13C NMR
spectra of all compounds and 1D NOE spectra of compounds
2a-h. This material is available free of charge via the Internet
at http://pubs.acs.org.
a Five equivalents of anisole was added to trap the benzhydryl
cation formed in the deprotection and prevent benzhydrylation of
the methoxybenzene ring in the product.
JO0485076
substituted 1-benzhydrylthymine derivatives were pre-
pared and their deprotections were studied (Scheme 3
and Table 3). It was found that the benzhydryl groups
were selectively cleaved and that the ester, ketone, ether,
trifluoromethyl, and cyano groups were stable to those
deprotection conditions.
In conclusion, as a protecting group for uracils, the
benzhydryl group offers an alternative to other protecting
groups by its easy introduction, stability to ongoing
reaction conditions, and selective deprotection under mild
condition.
(15) Representative Procedure. To an ice-cooled solution of triflic
acid (0.5 mL) in TFA (5 mL) was added 1-benzhydryl-3-benzylthymine
3b (764 mg, 2.0 mmol). The mixture was stirred at 0 °C for 30 min.
TLC showed that all starting material was consumed. The reaction
mixture was slowly poured onto 50 g of ice water. After warming to
room temperature, the white precipitate was collected by filtration.
The crude product was purified by flash chromatography (ethyl acetate/
hexane ) 2:1) to give 3-benzylthymine 4b (432 mg, 100%) as a white
powder: mp 208-210 °C; 1H NMR (500 MHz, DMSO) δ 1.79 (d, J )
0.86 Hz, 3H), 4.96 (s, 2H), 7.22-7.31 (m, 5H), 7.35 (d, J ) 4.34 Hz,
1H), 10.99 (s, 1H); 13C NMR (125 MHz, DMSO) δ 12.3, 42.7, 107.2,
126.9, 127.5, 128.2, 136.4, 137.4, 151.3, 163.7; HRMS calcd for
C12H12N2O2 216.0899, found 216.0895.
(16) Shionogi and Co. Ltd. Jpn. Kokai Tokkyo Koho JP 57-32270,
1982.
J. Org. Chem, Vol. 69, No. 26, 2004 9309