Benzoyl cyanide: A mild and efficient reagent for benzoylation of nucleosides

Article abstract of DOI:10.1081/SCC-200051693

Efficient benzoylation of various nucleosides has been accomplished in pyridine with a catalytic amount of DMAP and benzoyl cyanide under mild conditions.

Full text of DOI:10.1081/SCC-200051693

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Benzoyl Cyanide: A Mild and Efficient
Reagent for Benzoylation of Nucleosides
b
a
a
a
Ashok K. Prasad , Vineet Kumar , Jyotirmoy Maity , Zhiwei Wang
,
b
b c
a
Vasulinga T. Ravikumar , Yogesh S. Sanghvi
& Virinder S. Parmar
a
Bioorganic Laboratory, Department of Chemistry, University of Delhi,
Delhi, India
b
ISIS Pharmaceuticals Inc., Carlsbad, California, USA
c
Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, CA, 92024, USA
Published online: 21 Aug 2006.
To cite this article: Ashok K. Prasad , Vineet Kumar , Jyotirmoy Maity , Zhiwei Wang , Vasulinga T.
Ravikumar , Yogesh S. Sanghvi & Virinder S. Parmar (2005) Benzoyl Cyanide: A Mild and Efficient Reagent for
Benzoylation of Nucleosides, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:7, 935-945, DOI: 10.1081/SCC-200051693
To link to this article: http://dx.doi.org/10.1081/SCC-200051693
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Synthetic Communications , 35: 935–945, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200051693
Benzoyl Cyanide: A Mild and Efficient
Reagent for Benzoylation of Nucleosides
Ashok K. Prasad, Vineet Kumar, and Jyotirmoy Maity
Bioorganic Laboratory, Department of Chemistry, University of Delhi,
Delhi, India
#
#
Zhiwei Wang, Vasulinga T. Ravikumar, and Yogesh S. Sanghvi
ISIS Pharmaceuticals Inc., Carlsbad, California, USA
Virinder S. Parmar
Bioorganic Laboratory, Department of Chemistry, University of Delhi,
Delhi, India
Abstract: Efficient benzoylation of various nucleosides has been accomplished in
pyridine with a catalytic amount of DMAP and benzoyl cyanide under mild conditions.
Keywords: Benzoyl cyanide, nucleosides, DMAP, mild conditions
Protecting groups play a pivotal role in the synthesis of nucleic acids,
polypeptides, oligosaccharides, and natural products. One of the most frequently
used protecting groups for the blocking of hydroxyl and amino functionalities of
a compound is a benzoyl group. The classical method for benzoylation of
hydroxyl and amino groups is the treatment of the substrate with benzoyl
[1]
chloride/benzoic anhydride in the presence/absence of pyridine. A majority
of these benzoylation reactions requires extended time periods, elevated temp-
eratures or time-consuming work-up procedures. Further, acid chlorides and
Received in India November 18, 2004
#
Current address: Rasayan Inc., 2802 Crystal Ridge Road, Encinitas, CA 92024,
USA
Address correspondence to Ashok K. Prasad, Bioorganic Laboratory, Department
of Chemistry, University of Delhi, Delhi 110 007, India. Tel.: þ91-11-27666555;
Fax: þ91-11-27667206; E-mail: minuashok@now-india.net.in

9
36
A. K. Prasad et al.
acid anhydrides, because they are reactive species, often lead to the formation of
undesired products because of nonselective acylations.
During the course of the multistep synthetic protocol, particularly in
nucleic-acid chemistry, often selective manipulation of hydroxyl and amino
groups or different hydroxyl groups using mild protecting groups is
[
2–5]
required.
For example, protected nucleosides are required for the
synthesis of oligonucleotides. To synthesize these compounds, selective
manipulation of hydroxyl groups over amino groups of nucleobases and
vice versa are required under mild conditions. Among various mild benzoylat-
[
6]
[7–11]
ing agents, benzoyltetrazole and acyl cyanides
reagents of choice because of their chemoselectivity. Our ongoing interest
have emerged as
[
12,13]
in acylation reactions encouraged us to expand and thoroughly investi-
gate the applications of BzCN as a benzoylation reagent. Herein, we
0
describe our results on benzoylation of ribo- and 2 -deoxyribonucleosides
using BzCN as benzoylating agent.
Because unprotected nucleosides are soluble in pyridine at high concen-
trations, pyridine was chosen as the solvent of choice. Furthermore, we
decided to use DMAP as a catalyst because of its known beneficial
[
14]
[15–17]
effects.
pyridine and DMAP followed by usual workup to give white crystalline 3 ,5 -
Thymidine (1a) was treated with BzCN
in the presence of
0
0
di-O-benzoylthymidine (2a) in 94% yield (Scheme 1 and Table 1). The
0
benzoylation of 2 -deoxyadenosine (1b) under similar conditions afforded
0
0
0
3 ,5 -di-O-benzoyl-2 -deoxyadenosine (2b) in 93% yield. Interestingly, BzCN
showed chemoselectivity toward the hydroxyl groups of sugar moiety over
6
the C amino group in 1b. However, benzoylation of 2 -deoxycytidine (1c)
0
under similar conditions with 2.2 equivalents of BzCN led to the formation
3
0
0
0
0
0
4
5
0
of 3 ,5 -di-O-benzoyl-2 -deoxycytidine (2c) and N ,O , O -tribenzoyl-2 -deox-
ycytidine (2d) in 79.3 and 17.2% yields, respectively. Use of excess of BzCN
(
yield (Scheme 1); benzoylation of 1c carried out with 2.3 to 7.9 equivalents
8.0 equivalents) led to the formation of perbenzoylated product 2d in 96.5%
0
of BzCN led to the formation of inseparable mixtures. Benzoylation of 2 -deox-
yguanosine (1d) under similar conditions led to the formation of multiple
products with a major amount of starting material. The slow reaction of 1d
could be attributed to its poor solubility in pyridine at 408C. The perbenzoyla-
tion of 1d was accomplished with 6.0 equivalents of BzCN at 1158C, furnishing
0
0
2
3
5
0
N ,O ,O -tribenzoyl-2 -deoxyguanosine (2e) in 89% yield.
Next, we extended the benzoylation study with ribonucleosides
(
the expected 2 ,3 ,5 -tri-O-benzoyl-5-methyluridine (4a; 89%). On the other
Scheme 2 and Table 2). Benzoylation of 5-methyluridine (3a) furnished
0
0
0
0
0
0
hand, benzoylation of adenosine (3b) led to the formation of 2 ,3 ,5 -tri-O-ben-
0
0
0
5
6
2
3
zoyladenosine (4b) as a major product and N ,O ,O ,O -tetrabenzoyladeno-
sine (4c) as a minor product (Scheme 2). Treatment of cytidine (3c) and
guanosine (3d) with excess of BzCN furnished the anticipated perbenzoy-
0
0
0
0
0
3
4
2
3
5
2
2
lated N ,O ,O , O -tetrabenzoylcytidine (4d; 92.0%) and N ,O ,O ,

Benzoyl Cyanide
937

9
38
A. K. Prasad et al.
Table 1.
Reaction
time/temperature
Starting
compd.
BzCN
(equiv.)
Product (s)
Yield (%)
1
1
1
a
b
c
2.5
2.1
2.2
5 h/408C
6 h/408C
2 h/408C
2a
2b
2c
94.0
93.0
ꢀ
ꢀ
ꢀ
79.3
17.2
2
d
1
1
c
8.0
6.0
2 h/408C
4 h/1158C
2d
2e
96.5
89.0
d
ꢀ
The yields reported are on the basis of LC-MS analysis data.
0
5
O -tetrabenzoylguanosine (4e; 88.5%). The high chemoselectivity observed
in 1b when treated with 2.1 equivalent of BzCN encouraged us to treat
various nucleosides (1c, 1d, 3b–d) under similar conditions. Contrary to
our expectations, all attempts to accomplish O-benzoylation with restricted
amounts (ꢀ2–3 equivalents) of BzCN resulted in the formation of complex
mixtures of O- and N-benzoylated products.
The structures of benzoylated nucleosides, i.e., compounds 2a–e and
a–e, were unambiguously established on the basis of their spectral analysis
4
1
IR, H and C NMR and LC-MS) and comparison of their melting points
13
(
and/or spectral data with those reported in the literature;
[
18–25]
melting
points/physical states of known compounds 2c, 2d, and 4e were not
[
20,21,25]
mentioned in their earlier reports.
not in good agreement with mp reported in the literature; however, their
The observed mp of 4a and 4d are
1
13
spectral data ( H and C NMR spectral data) match well with the reported
[
23]
data.
different authors
Further, different mp of compounds 4b and 4c have been reported by
[
23–25]
(see Experimental); our observed mp is in agreement
13
1
with one of them in each case. We report herein the H and C NMR
spectral data of all the benzoylated nucleosides.
In summary, we have demonstrated that BzCN is an efficient and mild
benzoylating agent for a variety of compounds. Compared to the traditional
benzoylation reagents such as benzoyl chloride or benzoic anhydride, use of
BzCN has certain advantages. Most important, the by-product formed
[17]
during benzoylation with BzCN is hydrogen cyanide,
which, being
volatile, is easily removed, thus simplifying the reaction workup. For
example, benzoylated nucleosides were isolated in a pure state by pouring
the reaction mixtures into water and filtering the precipitated products.
This protocol eliminates the tedious and expensive silica-gel column-
chromatographic step for the isolation of the final products. We believe that
the generality and simplicity of this reaction would encourage the use of
BzCN as a reagent of choice for benzoylation in nucleic acid chemistry
under mild conditions.

Benzoyl Cyanide
939

9
40
A. K. Prasad et al.
Table 2.
Reaction
time/temperature
Starting
compd.
BzCN
(equiv.)
Product (s)
Yield (%)
89.0
3
3
a
5.0
6.0
3 h/408C
5 h/408C
4a
4b
ꢀ
b
71.5
11.0
ꢀ
4
c
3
c
6.8
7.0
7 h/408C
7 h/1158C
4d
4e
92.0
88.5
ꢀ
3
d
ꢀ
The yields reported are on the basis of LC-MS analysis data.
EXPERIMENTAL
Melting points were determined on a Mettler FP 62 instrument or in a sulfuric-
acid bath. The IR spectra were recorded on a Perkin-Elmer model 2000 FT-IR
spectrometer by making KBr disc for solid samples and thin films for oils. The
1
13
H and C NMR spectra were recorded on a Bruker AC-300 Avance spec-
trometer at 300 and 75 MHz, respectively, using TMS as internal standard.
The chemical shift values are on d scale and the coupling constants (J) are
in Hz. The LC-MS analysis was carried out on Agilent Ion Trap instrument.
All nucleosides were coevaporated twice with pyridine and dried in vacuum
desiccators prior to benzoylation. Analytical TLCs were performed on
precoated Merck silica-gel 60F254 plates; the spots were detected either
under UV light or by charring with 4% alcoholic H SO .
2
4
General Experimental Procedure for Benzoylation of Nucleosides
with BzCN
The anhydrous compound (1 mmol) was dissolved in dry pyridine (5 ml, 20 ml
in case of dG and G) followed by the addition of DMAP (10 mg) and BzCN
(
2.1–8.0 equivalents). The reaction mixture was allowed to stir at 408C
1158C in the cases of dG and G) and the progress of the reaction followed
(
by TLC. Upon completion, the reaction was poured over crushed ice under
vigorous stirring and the precipitate filtered under vacuum, washed with
water and petroleum ether, and dried to afford the corresponding benzoylated
1
13
compounds. The melting points and H and C NMR data of benzoylated
nucleosides are given below.
0
0
3
,5 -Di-O-benzoylthymidine (2a) (18): White solid (423 mg; 94%); mp
1
[
18]
1
80–1828C (lit.
mp 192–1938C). H NMR (300 MHz, CDCl ): d 1.63
3
0
(
3 H, s, C5-CH ), 2.34 (1 H, p, J ¼ 5.4 Hz C-2 H ), 2.72 (1 H, dd,
3
a
0
0
J ¼ 5.4 Hz and 14.8Hz, C-2 H ), 4.54 (1 H, d, J ¼ 2.1 Hz, C-4 H), 4.70 (1 H,
b
0
dd, J ¼ 3.0 Hz and 15.9Hz, C-5 H ), 4.79 (1 H, dd, J ¼ 3.0 Hz and 15.9Hz,
a

Benzoyl Cyanide
941
0
0
C-5 H ), 5.66 (1 H, d, J ¼ 6.3 Hz, C-3 H), 6.47 (1 H, dd, J ¼ 2.9 Hz and
b
0
0
0
0
0
0
5.4 Hz, C-1 H), 7.26 (1 H, s, C-6H), 7.46–7.51 (4 H, m, C-3 H, C-3 H,
C-5 H, and C-5 H), 7.60–7.64 (2 H, m, C-4 H and C-4 H), 8.03–8.08
00
000
00
000
00 000 00 000
13
4 H, m, C-2 H, C-2 H, C-6 H, and C-6 H) and 8.76 (1 H, s, NH); C
(
NMR (75 MHz, CDCl ): d 12.50 (CH ), 38.38 (C-2 ), 64.68 (C-5 ), 75.37
0
0
3
3
0 0 0
(
C-3 ), 83.04 (C-4 ), 85.31 (C-1 ), 112.10 (C-5), 128.97, 129.15, 129.39,
00 000 00 000 00 000 00
29.71, 129.87, and 130.18 (C-1 , C-1 , C-2 , C-2 , C-3 , C-3 , C-5 ,
1
C-5 , C-6 , and C-6 ), 134.07 and 134.09 (C-4 and C-4 ), 134.74 (C-4),
000
00
000
00
000
1
50.64 (C-2), 163.74 (C-6), 166.35 and 166.41 (2 ꢁ ester CO); HRMS
þ
[M þ H] calcd. for C H N O 451,1505; found 451,1521.
2
4 22 2 7
0
0
0
3
,5 -Di-O-benzoyl-2 -deoxyadenosine (2b) (19): White solid (427 mg;
[
19]
1
9
3%); mp 116–1208C (lit.
mp 105–1078C). H NMR (300 MHz,
0
CDCl ): d 2.84 (1 H, dd, J ¼ 5.1 Hz and 13.8 Hz, C-2 H ), 3.17 (1 H, p,
3
a
0
0
0
J ¼ 7.2 Hz, C-2 H ), 4.67–4.81 (3 H, m, C-4 H and C-5 H), 5.79 (2 H, br s,
b
0
0
-
NH ), 5.84 (1 H, br d, J ¼ 5.9 Hz, C-3 H), 6.54 (1 H, t, J ¼ 6.9 Hz, C-1 H),
2
00 000 00 000
7
C-4 H, and C-4 H), 7.98–8.10 (5 H, m, C-8H, C-2 H, C-2 H, C-6 H, and
13
C-6 H), 8.32 (1 H, s, C-2H); C NMR (75 MHz, CDCl ): d 38.34 (C-2 ),
.41–7.51 (4 H, m, C-3 H, C-3 H, C-5 H, and C-5 H), 7.55–7.65 (2 H, m,
0
000
00
000
00
0
00
0
3
0 0 0 0
6
1
4.73 (C-5 ), 75.85 (C-3 ), 83.44 (C-4 ), 85.38 (C-1 ), 129.09, 129.12,
000
00
000
00
000
00
00
30.20 and 130.34 (C-5, C-2 , C-2 , C-3 , C-3 , C-5 , C-5 , C-6 , and
000
000
00
00
000
C-6 ), 133.89 and 134.19 (C-4 and C-4 ), 139.21 (C-1 and C-1 );
1
51.03 (C-6); 153.70 (C-2 and C-8), 156.09 (C-4), 166.45 and 166.68 (2 x
þ
ester CO); HRMS [M þ H] calcd. for C H N O 460,1621; found
2
4 21 5 5
4
60,1636.
0
0 0
,5 -Di-O-benzoyl-2 -deoxycytidine (2c) (20): White solid (345 mg;
3
1
79.3%); mp 202–2058C. H NMR (300 MHz, CDCl ): d 2.04 (2 H, brs,
NH ), 2.16–2.28 (1 H, m, C-2 H ), 2.89–2.93 (1 H, m, C-2 H ), 4.56 (1 H,
3
0
0
2
a
b
0
0
d, J ¼ 2.1 Hz, C-4 H), 4.68–4.69 (2 H, brs, C-5 H), 5.59 (1 H, d,
0
J ¼ 6.0 Hz, C-5H), 5.65 (1 H, d, J ¼ 6.0 Hz, C-3 H), 6.40 (1 H, t,
0
00
000
00
J ¼ 6.5 Hz, C-1 H), 7.42–7.49 (4 H, m, C-3 H, C-3 H, C-5 H, and
000
00
000
C-5 H), 7.56–7.65 (3 H, m, C-6H, C-4 H, and C-4 H), and 7.99 and 8.05
0
0
000
00
000
(
4 H, 2d, 2 H each, J ¼ 7.5 Hz each, C-2 H, C-2 H, C-6 H, and C-6 H);
0 0 0
3
1
3
C NMR (75 MHz, CDCl ): d 39.20 (C-2 ), 64.80 (C-5 ), 75.53 (C-3 ),
0
0
8
1
3.12 (C-4 ), 87.19 (C-1 ), 95.29 (C-5), 128.92, 129.00, 129.54, 129.76,
000
00
000
00
000
00
00
29.92, and 130.16 (C-2 , C-2 , C-3 H, C-3 H, C-5 H, C-5 H, C-6 H and
00
000
000
00
000
C-6 H), 133.86 and 133.96 (C-1 , C-1 , C-4 and C-4 ), 140.50 (C-6),
56.02 (C-4), 166.10, 166.41 and 166.50 (C-2 and 2 ꢁ ester CO); HRMS
1
þ
3
[M þ H] calcd. for C H N O 436,1509; found 436,1511.
2
3 21 3 6
0
0
N ,O ,O -Tribenzoyl-2 -deoxycytidine (2d) (21): White solid (520 mg;
0
4
5
1
9
6.5%); mp 198–2008C. H NMR (300 MHz, CDCl ): d 2.26–2.36 (1 H,
3
0
0
m, C-2 H ), 3.10 (1 H, dd, J ¼ 4.4 Hz and 14.2 Hz, C-2 H ), 4.67–4.80
a
b
0
0
0
(
3 H, m, C-4 H, and C-5 H), 5.64 (1 H, br d, J ¼ 5.7 Hz, C-3 H), 6.40 (1 H,
0 00 000 0000
t, J ¼ 6.5 Hz, C-1 H), 7.43–7.53 (7 H, m, C-5H, C-3 H, C-3 H, C-3 H,
00
000
0000
00
000
C-5 H, C-5 H, and C-5 H), 7.56–7.63 (3 H, m, C-4 H, C-4 H, and

9
42
A. K. Prasad et al.
0
000
C-4 H), 7.88, 7.99, and 8.07 (6 H, 3d, 2H each, J ¼ 7.3 Hz, 7.6 Hz, and
00 00 000 000 0000 0000
7
8
.9 Hz, respectively, C-2 H, C-6 H, C-2 H, C-6 H, C-2 H, and C-6 H),
1
.12 (1 H, s, C-6H) and 8.71 (1 H, brs, NH); C NMR (75 MHz, CDCl3):
3
0
0
0
0
0
d 40.77 (C-2 ), 65.55 (C-5 ), 76.39 (C-3 ), 85.00 (C-4 ), 88.99 (C-1 ), 98.16
00
(
C-2 , C-2 , C-3 H, C-3 H, C-3 H, C-5 H, C-5 H, C-5 H, C-6 H,
C-5), 128.91, 129.95, 130.08, 130.44, 130.63, 130.90 and 131.20 (C-2 ,
000
0
00
0000
00
000
0000
00
0000
00
0000
000
0000
00
000
C-6 H, and C-6 H), 134.60, 134.99 and 135.05 (C-6, C-1 , C-1 , C-1 ,
0000
00
000
C-4 , C-4 and C-4 ), 144.84 (C-4), 163.68 (C-2), and 167.38 and 167.44
þ
(
2 ꢁ ester CO and amidic CO); HRMS [M þ H] calcd. for C H N O
3
0 25 3 7
5
40,1771; found 540,1794.
0
0
N ,O ,O -Tribenzoyl-2 -deoxyguanosine (2e) (22): White solid (516 mg;
2
3
5
0
[
22]
1
8
9%); mp 210–2158C (lit
d 2.65–2.75 (1 H, m, C-2 H ), 3.26–3.35 (1 H, m, C-2 H ), 4.72 (2 H, d,
a
mp 2148C). H NMR (300 MHz, CDCl ):
3
0
0
b
0
0
0
J ¼ 6.9 Hz, C-5 H), 5.12 (1 H, q, J ¼ 7.3 Hz, C-4 H), 6.02 (1 H, s,C-3 H),
0
6
.32 (1 H, t, J ¼ 6.4 Hz, C-1 H), 7.37–8.16 (16 H, m, aromatic protons, and
1
C-8H), 9.55 (1 H, s, N -H) and 12.01 (1 H, s, C-2NH); C NMR (75 MHz,
13
0
0
0
0
CDCl ): d 36.70 (C-2 ), 63.65 (C-5 ), 75.21 (C-3 ), 82.64 (C-4 ), 86.20
3
0
(
(
C-1 ), 123.27 (C-5), 128.45, 128.95, 128.99, 129.38, 129.96 and 130.11
0000
00
000
0000
00
000
00
000
0000
0000
00
000
C-2 , C-2 , C-2 , C-3 , C-3 , C-3 , C-5 , C-5 , C-5 , C-6 , C-6 , and
00
0000
00
000
000
C-6 ), 134.02 and 134.09 (C-4 , C-4 , and C-4 ), 138.95 (C-1 , C-1 ,
and C-1 ), 147.73 and 147.91 (C-4 and C-8), 155.83 (C-2), 166.36 (C-6),
0000
þ
and 167.32 and 168.28 (2 ꢁ ester CO and amidic CO); HRMS [M þ H]
calcd. for C H N O 580,1832; found 580,1886.
3
1 25 5 7
0
0
0
2
,3 ,5 -Tri-O-benzoyl-5-methyluridine (4a) (23): White solid (507 mg;
1
[
23]
8
9%); mp 155–1608C (lit mp 98.0–99.58C). H NMR (300 MHz,
CDCl ): d 1.61 (3 H, s, CH ), 4.64–4.68 (2 H, m, C-5 H), 4.89 (1 H, d,
0
3
3
0
0
J ¼ 10.8 Hz, C-4 H), 5.75 (1 H, t, J ¼ 6.0 Hz, C-3 H), 5.90 (1 H, d,
0
0
J ¼ 3.6 Hz, C-2 H), 6.42 (1 H, d, J ¼ 6.3 Hz, C-1 H), 7.16 (1 H, s, C-6H),
1
3
7
.36–8.15 (15 H, m, aromatic protons) and 8.48 (1 H, s, NH); C NMR
0 0 0
75 MHz, CDCl ): d 13.43 (CH ), 65.27 (C-5 ), 72.82 (C-3 ), 74.74 (C-4 ),
3 3
(
0
0
8
1
2.01 (C-2 ), 88.35 (C-1 ), 113.56 (C-6), 129.92, 130.23, 130.63, 131.02,
00
0
0
00
000
000
0000
0000
00
000
0000
0000
31.21, 131.30, 135.13, 136.18 (C-1 , C-1 , C-1 ,C-2 , C-2 , C-2 , C-3 ,
000
000
0000
00
000
0000
00
C-3 , C-3 , C-4 , C-4 , C-4 , C-5 , C-5 , C-5 , C-6 , C-6 , C-6 , and
C-5), 151.55 (C-2), 164.42 (C-4), 166.69, 166.77 and 167.35 (3 ꢁ ester
þ
CO); HRMS [M þ H] calcd. for C H N O 571,1717; found 571,1736.
3
1 26 2 9
0
0
0
2
,3 ,5 -Tri-O-benzoyladenosine (4b) (23,24): White solid (414 mg;
[
23]
[24]
1
7
1.5%); mp 92–968C (lit mp 90–948C, lit
300 MHz, CDCl ): d 4.69–4.91 (3 H, m, C-4 H, and C-5 H), 5.87 (2 H, s,
mp 246–2478C). H NMR
0
0
(
3
0
0
NH ), 6.29 (1 H, d, J ¼ 4.5 Hz, C-3 H), 6.39–6.42 (2 H, m, C-1 H, and
2
0
00
00
000
000
0000
00
000
C-2 H), 7.33–7.46 (6 H, m, C-3 H, C-3 H, C-3 H, C-5 H, C-5 H, and
C-5 H), 7.51–7.57 (3 H, m, C-4 H, C-4 H, and C-4 H), 7.93–8.10 (7 H,
0000
0000
00
000
0000
00
000
0000
m, C-8H, C-2 H, C-2 H, C-2 H, C-6 H, C-6 H and C-6 H) and
0
.28 (1 H, s, C-2H); C NMR (75 MHz, CDCl ): d 64.00 (C-5 ), 71.90
3
C-3 ), 74.42 (C-4 ), 81.08 (C-2 ), 87.33 (C-1 ), 120.58 (C-5), 128.88,
1
3
8
0 0 0 0
(

Benzoyl Cyanide
943
1
1
28.92, 129.18, 129.81, 130.14, 130.20, 130.23, 133.75, 134.03, 134.11 and
0000
00
000
0000
00
000
0000
00
000
00
39.52 (C-1 , C-1 , C-1 ,C-2 , C-2 , C-2 , C-3 , C-3 , C-3 , C-4 ,
0000
000
0000
00
000
0000
00
000
C-4 , C-4 , C-5 , C-5 , C-5 , C-6 , C-6 , and C-6 ), 150.24 (C-6),
1
53.78 (C-4 and C-8), 155.93 (C-2), and 165.51, 165.68, and 166.54
þ
(
3 ꢁ ester CO); HRMS [M þ Na] calcd. for C H N O 602,1652; found
3
1 25 5 7
6
02,1731.
0
N ,O ,O ,O -Tetrabenzoyladenosine (4c) (23,25): White solid (75 mg;
0
0
6
2
3
5
[
23]
[25]
1
1
1%); mp 116–1208C (lit
mp 88–928C, lit
mp 128.5–129.28C). H
0
NMR (300 MHz, CDCl ): d 4.72 (1 H, dd, J ¼ 3.9 Hz and 12.1 Hz, C-5 H ),
3
a
0
4
.84 (1 H, q, J ¼ 4.1 Hz, C-4 H), 4.91 (1 H, dd, J ¼ 4.0 Hz and 12.0 Hz,
0
0
0
C-5 H ), 6.26 (1 H, t, J ¼ 5.3 Hz, C-3 H), 6.37 (1 H, t, J ¼ 5.4 Hz, C-2 H),
b
0
6
C-2H, and C-8H), and 9.66 (1 H, brs, NH); C NMR (75 MHz, CDCl ):
.45 (1 H, d, J ¼ 4.8 Hz, C-1 H), 7.38–8.25 (22 H, m, aromatic protons,
1
3
3
0
0
0
0
0
d 63.91 (C-5 ), 71.89 (C-3 ), 74.58 (C-4 ), 81.22 (C-2 ), 87.53 (C-1 ), 119.80
(C-5), 128.72, 128.93, 128.97, 130.12, 130.23, 130.25, 130.34, 131.01,
00 000 0000 00000 00 000
1
C-2 , C-2 , C-3 , C-3 , C-3 , C-3 ,C-4 , C-4 , C-4 , C-4 ,C-5 ,
33.42, 133.83, 134.10 and 134.19 (C-1 , C-1 , C-1 , C-1 , C-2 , C-2 ,
0000
0000
00000
00
000
00000
00
000
0000
00000
00
000
0000
00000
00
000
0000
00000
C-5 , C-5 , C-5 , C-6 , C-6 , C-6 , and C-6 ), 142.33 (C-6), 149.80
(
(
C-4), 152.95 (C-8), 156.20 (C-2), and 165.57, 165.97, 166.58, and 171.03
3 ꢁ ester CO and amidic CO).
0
0
0
5
4
2
3
N ,O ,O ,O -Tetrabenzoylcytidine (4d) (23): White solid (606 mg;
[
23]
1
9
2%); mp 170–1758C (lit
mp 206.5–208.08C). H NMR (300 MHz,
0
0
CDCl þ DMSO-d ): d 4.70–4.88 (3 H, m, C-4 H, and C-5 H), 5.84 (1 H, t,
3
6
0
0
J ¼ 5.2 Hz, C-3 H), 5.92 (1 H, t, J ¼ 5.5 Hz, C-2 H), 6.46 (1 H, d,
0
J ¼ 4.5 Hz, C-1 H), 7.35–8.12 (22 H, m, aromatic protons, and C-5H,
1
3
C-6H), and 8.95 (1 H, brs, NH); C NMR (75 MHz, CDCl þ DMSO-d ):
3
6
0
0
0
0
0
d 64.42 (C-5 ), 71.53 (C-3 ), 74.76 (C-4 ), 79.18 (C-2 ), 92.74 (C-1 ), 97.71
(C-5), 129.08, 129.29, 130.12 and 130.19 (C-2 , C-2 , C-2 , C-2 , C-3 ,
C-3 , C-3 , C-3 , C-5 , C-5 , C-5 , C-5 , C-6 , C-6 , C-6 , and
00 000 0000 00000 00
0
00
0000
00000
00
000
0000
00000
00
000
0000
00000
00
000
0000
00000
C-6 ), 133.41, 134.10, 134.39 and 134.49 (C-6, C-1 , C-1 , C-1 , C-1 ,
0000
00
000
0000
C-4 , C-4 , C-4 , and C-4 ), 147.75 (C-4), 164.50 (C-2), and 165.40,
þ
1
66.01, and 166.25 (3 ꢁ ester CO and amidic CO); HRMS [M þ Na]
calcd. for C H N O , 682,1801; found 682,1901.
3
7 29 3 9
0
0
0
5
2
2
3
N ,O ,O ,O -Tetrabenzoylguanosine (4e) (25): White solid (619 mg;
1
8
m, C-4 H, and C-5 H), 6.17 (1 H, brs, C-3 H), 6.45 (1 H, brs, C-2 H), 6.93
8.5%); mp 130–1358C. H NMR (300 MHz, CDCl ): d 4.76–4.85 (3 H,
3
0
0
0
0
0
(
1 H, brs, C-1 H), 7.26–8.17 (21 H, m, aromatic protons, and C-8H), 9.50
1
1 H, s, N -H), and 11.93 (1 H, s, C-2NH); C NMR (75 Mz, CDCl ): d
13
(
3
0 0 0 0 0
1.93 (C-5 ), 71.18 (C-3 ), 74.69 (C-4 ), 79.74 (C-2 ), 88.46 (C-1 ), 122.86
C-5), 128.42, 128.84, 128.97, 129.03, 129.40, 129.65, 130.17 and 130.22
6
(
(
0
0
000
00
0000
000
00000
0000
00
000
0000
00000
00
000
0000
C-2 , C-2 , C-2 , C-2 , C-3 , C-3 , C-3 , C-3 , C-5 , C-5 , C-5 ,
00000
0
0000
C-5 , C-6 , C-6 , C-6 , and C-6 ), 131.76, 134.04, 134.21, 134.29, and
0000
00
000
0000
00000
00
000
00000
1
39.37 (C-2, C-1 , C-1 , C-1 , C-1 , C-4 , C-4 , C-4 , and C-4 ),
47.38 and 147.89 (C-4 and C-8), 155.69 (C-6), 165.55, 166.43, 166.72,
1

9
44
A. K. Prasad et al.
þ
and 167.72 (3 ꢁ ester CO and amidic CO); HRMS [M þ Na] calcd. for
C H N O 722,1863, found 722,1981.
38 29 5 9
ACKNOWLEDGMENT
This project was funded by ISIS pharmaceuticals Inc., California, U.S.A.
V. K. and J. M. thank the Council of Scientific and Industrial Research
(
New Delhi, India) for the award of Junior Research Fellowships.
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