Regioselective syntheses of 7-halogenated 7-deazapurine nucleosides related to 2-amino-7-deaza-2′-deoxyadenosine and 7-deaza-2′- deoxyisoguanosine

Article abstract of DOI:10.1055/s-2004-822382

The syntheses of 7-halogenated derivatives 3b-e of 2-amino-7-deaza- 2′-deoxyadenosine as well as 7-bromo and 7-chloro-7-deaza-2′- deoxyisoguanosines 4b-c are described. Nucleobase anion glycosylation was employed for the convergent nucleoside synthesis. T

Full text of DOI:10.1055/s-2004-822382

PAPER
1203
Regioselective Syntheses of 7-Halogenated 7-Deazapurine Nucleosides Related
to 2-Amino-7-deaza-2¢-deoxyadenosine and 7-Deaza-2¢-deoxyisoguanosine
R
egioselective
r
Synthes
a
e
s
of 7-H
a
n
keazapurine Nucle
S
s
eela,* Xiaohua Peng
Laboratorium für Organische und Bioorganische Chemie, Institut für Chemie, Universität Osnabrück, Barbarastr. 7, 49069 Osnabrück,
Germany and Center for Nanotechnology, Gievenbecker Weg 11, 48149 Münster, Germany
Fax +49(541)9692370; E-mail: Frank.Seela@uni-osnabrueck.de
Received 30 January 2004; revised 15 March 2004
osides, we report herein the synthesis and the conforma-
Abstract: The syntheses of 7-halogenated derivatives 3b–e of 2-
tional properties of the 7-halogenated 7-deazapurine
deoxynucleosides 3b–e and 4b,c. They are the key inter-
mediates for later studies on oligonucleotides.
amino-7-deaza-2¢-deoxyadenosine as well as 7-bromo and 7-chlo-
ro-7-deaza-2¢-deoxyisoguanosines 4b–c are described. Nucleobase
anion glycosylation was employed for the convergent nucleoside
synthesis. The regioselective 7-halogenation was performed either
on the nucleoside precursor 7 or on the nucleobase 12. Two bromo
substituents were introduced in the 7- and 8-position when the un-
protected 2-amino nucleoside 9 was used. Conformational analysis
of the sugar moiety of nucleosides 3a–e and 4a–c was performed on
the basis of vicinal 1H,1H NMR coupling constants.
NH2
O
R
R
N
HN
N
N
N
H2N
HO
N
O
O
Key words: glycosylations, nucleosides, pyrrolo[2,3-d]pyrim-
idines, halogenation, regioselectivity, sugar conformation
HO
HO
OH
HO
OH
1a: R = H
b: R = CN
c: R = CONH2
d: R = I
CH2NH
NH
2a: R =
b: R =
7-Deazapurine (pyrrolo[2,3-d]pyrimidine; purine num-
bering is used throughout the general section) nucleosides
have gained extensive attention since some of them, such
as tubercidin (1a), toyocamycin (1b), sangivamycin (1c),
queuosine (2a), or archaeosine (2b) exhibit a broad spec-
trum of biological activity.1–10 Moreover, 7-iodotuberci-
din (1d) is a potent inhibitor of adenosine kinase.11,12
Apart from the naturally occurring compounds, a number
of 7-deazapurine 2¢-deoxyribonucleosides have been syn-
thesized.13–21 Several have been incorporated into oligo-
nucleotides. Among these, the 7-halogeno substituents
have been found to enhance the DNA-duplex stability
compared to their unmodified counterparts.22–25 As oligo-
nucleotides containing 7-deaza-2¢-deoxyisoguanosine
(4a) form supramolecular assemblies, they can be used in
nanotechnology and material science. Compound 4a
(Figure 1), when incorporated in DNA, quenches the
ethidium bromide fluoroscence strongly.
OH
OH
C
NH2
NH2
R1
NH2
R
5
4
6
3
4a
5
7
1
N
2
HN
R2
6
8
7
N
N
4
7a
N
2
H2N
HO
N
3
9
O
1
O
O
HO
HO
3a: R1 = R2 = H
b: R1 = Cl, R2 = H
c: R1 = Br, R2 = H
d: R1 = I, R2 = H
e: R1 = R2 = Br
HO
4a: R = H
b: R = Cl
c: R = Br
purine numbering
systematic numbering
Figure 1
The first synthesis of 2-amino-7-deaza-2¢-deoxyadenos-
ine (3a) and 7-deaza-2¢-deoxyisoguanosine (4a) was re-
ported from our laboratory.16,17 Compound 4a has been
incorporated into oligonucleotides and found to be an ide-
al substitute of 2¢-deoxyisoguanosine.21 Recently, it was
reported that 3a can form a stable base pair not only with
thymine but also with cytosine without duplex destabili-
zation.24 Until now, the synthesis of 7-halogenated 7-dea-
za-2¢-deoxyisoguanosines or 7-bromo- or 7-chloro-2-
amino-7-deaza-2¢-deoxyadenosine has not been reported.
Continuing our studies on a series of 7-deazapurine nucle-
Two routes were employed for the synthesis of 7-haloge-
nated 7-deazapurine nucleosides: (i) conversion of a pre-
formed nucleoside precursor into a 7-halogenated
nucleoside; and (ii) the halogenation of the nucleobase
followed by glycosylation. In these two routes, the re-
gioselectivity of halogenation is of decisive importance.
During recent years, several detailed studies on the halo-
genations of 7-deazapurines have appeared.20,26–29 The
outcome of these experiments indicated that a direct halo-
genation of 2-amino-7-deazapurines to the corresponding
7-halo derivatives shows drawbacks as the 2-amino group
directs the electrophilic attack into the undesired 8-posi-
tion - a fact which was first recognized during the Man-
nich reaction of 7-deazaguanine and 7-deaza-2¢-
SYNTHESIS 2004, No. 8, pp 1203–1210
x
x
.
x
x
.2
0
0
4
Advanced online publication: 19.05.2004
DOI: 10.1055/s-2004-822382; Art ID: T01104SS
© Georg Thieme Verlag Stuttgart · New York

1204
F. Seela, X. Peng
PAPER
deoxyguanosine.30,31 However, a regioselective 7-haloge-
nation with N-halosuccinimide was accomplished by us-
ing the 2-amino-protected derivative 7-[2-deoxy-3,5-di-
O-(2-methylpropanoyl)-b-D-erythro-pentofuranosyl]-2-
(formylamino)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine
(systematic numbering) as the precursor.20 Compared to
the 6-methoxy nucleoside, 6-halogeno functionalized
derivatives can be more easily displaced by nucleophiles,
leading to nucleosides with various substituents at
C(6).32–35 Thus, in our present work, the 6-chloro com-
pounds 5 and 11 have been chosen as starting materials.
Compounds 5 and 11 were synthesized as described
earlier.17
Cl
N
Cl
N
Br
N
N
Br
N
N
H2N
H2N
CH2Cl2, NBS
66%
O
O
TolO
TolO
TolO
TolO
9
10
NH2
Br
N
Br
.
N
NH3 H2O/dioxane
120 °C, 24 h
H2N
HO
N
O
In the first route, the nucleoside 5 was converted into the
key intermediate 7 in which both of the hydroxyl groups
as well as the base moiety were protected (Scheme 1).
Then, compound 7 was treated with N-halosuccinimide
(NXS, X = Cl, Br, I) in DMF or CH2Cl2. A clean reaction
was observed, affording the 7-substituted derivatives
8a–c in 60–90% yield. No formation of 7,8-dihalo com-
pound was detected by TLC inspection. For bromination,
the reaction was carried out either in DMF or CH2Cl2,
which gave a complete conversion at room temperature.
The chloro and iodo analogues 8a and 8c were prepared
only in DMF between 50 and 60 °C. Compounds 3b–d
were obtained by treatment of 8a–c, respectively, with
25% aqueous ammonia in a sealed stainless steel vessel at
120 °C (Scheme 1).
65%
HO
3e
Tol = p-methylbenzoyl
Scheme 2
When the 2-amino compound 917 was used as the precur-
sor for bromination with N-bromosuccinimide, the 7,8-di-
bromonucleoside 10 was formed but no 7-halogenated
compound was detected (Scheme 2). Nucleoside 10 was
treated with 25% aqueous ammonia in a steel bomb to
give 2-amino-7-deaza-7,8-dibromo-2¢-deoxyadenosine
(3e).
The most likely explanation for the regioselective forma-
tion of 7-halogenated nucleoside is the mesomeric stabili-
zation of the d-complex formed during electrophilic
attack at the 7-position which is stabilized by the structure
shown in formula A (Figure 2).20
Cl
N
Cl
N
N
N
Me2NCH(OMe)2,
MeOH, r.t., 36 h
N
N
H2N
HO
Me2N C N
H
O
O
91%
HO
Cl
E
HO
HO
H
6
5
N
O
Cl
N
RC
N
N
R1
N
H
N
(i) (i-Bu)2O, Et3N, MeCN,
r.t., 24 h
(ii) MeOH, H2O, r.t., 48 h
O
N
HC
N
A
NXS, DMF
H
O
76%
a: 76%
b: 84%
c: 62%
Figure 2 Structure of A
i-BuO
i-BuO
7
Compounds 3b–d were also prepared by nucleobase-an-
ion glycosylation.15,36 As in the case of nucleosides, direct
halogenation of 2-amino-6-chloro-7-deazapurine (11)
was unsuccessful, but selective 7-halogenation was
achieved by using 2-amino-protected derivatives. A piv-
aloyl group as well as (dimethylamino)methylidene was
used as the NH2 protecting group. It was observed that the
yield of halogenation is strongly affected by the protecting
group. 6-Chloro-2-[(dimethylamino)methylidene]amino-
7-deazapurine resulted in a rather low yield (ca. 40%),
whereas a much better yield (ca. 85%) was obtained when
the pivaloyl derivative 12 was used (Scheme 3). Both de-
rivatives gave the 7-halogenated products selectively.
Cl
R
NH2
R
N
O
N
.
NH3 H2O/dioxane
120 °C, 24 h
N
N
HC
N
N
H2N
HO
N
H
O
O
b: 87%
c: 87%
d: 84%
i-BuO
i-BuO
HO
3b: R = Cl
c: R = Br
d: R = I
8a: R = Cl
b: R = Br
c: R = I
i-Bu = Me2CHC(O)
Scheme 1
Synthesis 2004, No. 8, 1203–1210 © Thieme Stuttgart · New York

PAPER
Regioselective Syntheses of 7-Halogenated 7-Deazapurine Nucleosides
1205
Thus, 12 was selected as the precursor for halogenation, Selective deamination of compounds 3b and 3c with sodi-
and 7-chloro (13a), 7-bromo (13b), and 7-iodo (13c) de- um nitrite in HOAc–H2O (1:5) furnished the nucleosides
rivatives of 12 were prepared by the action of N-chloro-, 7-chloro-7-deaza-2¢-deoxyisoguanosine (4b) and 7-bro-
N-bromo- and N-iodosuccinimide, respectively, on 12 in mo-7-deaza-2¢-deoxyisoguanosine (4c) in 60–70% yield,
DMF or CH2Cl2.
respectively. Unfortunately, 7-deaza-7-iodo-2¢-deoxy-
isoguanosine could not be obtained by this method be-
cause of the insolubility of precursor 3d under the reaction
conditions.
Subsequent nucleobase-anion glycosylation15,36 of 13a–c
with 2-deoxy-3,5-di-O-(p-toluoyl)-a-D-erythro-pentofur-
anosyl chloride (14) afforded the toluoyl-protected b-D-
nucleosides 15a–c in 60–70% yields (Scheme 3). In all The compounds were characterized by 1H and 13C NMR
cases, the reaction was stereoselective and gave the b-D spectroscopy as well as by elemental analysis. To confirm
anomer exclusively. All compounds were isolated in crys- the position of halogenation of all halogenated nucleo-
1
talline form. Removal of the toluoyl protecting groups and sides and intermediates, H-NOE difference spectra of
displacement of the 6-chloro group of 15a–c were effect- compounds 3c and 4c were measured as representative ex-
ed by treatment with 25% aqueous ammonia in a steel amples. Irradiation of the corresponding H-8 signals re-
bomb without affecting the 7-halogeno substituents, sulted in NOE effects at H-1¢ (6.0% for 3c and 6.8% for
thereby furnishing compounds 3b–d. The second route is 4c). This proves both the halogenation site at C-7 as well
superior to the first one because of its higher total yield as a preferred syn-conformation at the N-glycosylic bond
(30–35% for route 1 and 40–45% for route 2). Also, route which is 55% syn for 3c and 59% for 4c.37 Characteristic
2 requires fewer reaction steps.
NOEs were also observed for Hb2¢ (4.2% for 3c and 3.2%
Table 1 13C NMR Chemical Shifts (d) of 7-Deazapurine 2¢-Deoxynucleosidesa
Productb,c C(2)d
C(2)
C(4)d
C(6)
C(4a)
C(5)
C(5)
C(7)
C(6)
C(8)
C(7a)d
C(4)
C(1¢)
C(2¢)
C(3¢)
C(4¢)
C(5¢)
e
3a17
3b
159.3
160.4
157.5
157.2
96.3
93.3
99.7
103.3
117.5
114.5
152.2
151.9
82.7
82.0
–
–
71.0
71.0
86.8
86.9
62.1
62.0
e
e
3c
3d
3e
4a21
4b
4c
7
160.1
159.7
159.5
153.9
153.2
153.6
152.0
152.6
152.3
151.9
159.1
151.9
151.9
152.5
152.2
152.5
152.5
157.2
157.5
156.5
156.3
156.2
156.0
151.3
150.9
151.2
151.8
153.0
149.7
150.0
150.6
151.8
151.7
152.4
94.3
96.4
87.4
52.3
117.0
122.4
95.4
152.1
152.6
151.9
152.6
81.9
82.0
85.2
83.4
82.6
82.5
83.4
83.3
83.2
83.2
85.7
–
–
70.9
70.9
71.2
71.2
70.9
70.8
73.7
73.9
73.8
73.8
75.0
–
86.9
86.9
87.5
87.2
87.2
87.2
81.2
81.4
81.3
81.3
81.4
–
61.9
61.9
62.3
62.0
61.9
61.8
63.4
63.5
63.4
63.4
64.3
–
e
–
104.7
92.6
91.7
37.3
e
100.8
103.7
87.4
118.9
116.2
118.8
126.9
124.1
126.5
131.7
113.0
124.8
127.3
132.7
122.7
125.4
133.4
–
f
e
90.2
–
–
f
e
91.0
–
–
114.0
110.3
111.1
113.7
107.2
101.6
110.1
112.3
110.9
112.0
113.9
100.5
103.8
88.2
151.8
151.0
151.1
151.6
150.7
151.5
151.7
151.4
150.9
151.3
152.1
35.6
35.7
35.7
35.7
35.0
–
8a
8b
8c
54.5
10
92.4
13a
13b
13c
109.1
85.8
–
–
–
–
–
51.7
–
–
–
–
–
15ag
15bg
15c
106.1
89.8
84.4
84.5
84.8
40.3
40.3
74.8
74.8
75.9
82.6
82.6
82.4
63.9
63.9
64.9
e
54.9
-
a Measured in DMSO-d6.
b Systematic numbering.
c Purine numbering.
d Tentative.
e Superimposed by DMSO.
f Not detected.
g Measured in CDCl3.
Synthesis 2004, No. 8, 1203–1210 © Thieme Stuttgart · New York

1206
F. Seela, X. Peng
PAPER
O
TolO
Cl
Cl
N
Cl
N
Cl
R
14
TolO
N
NXS, CH2Cl2
N
MeCN, KOH, TDA-1
N
Pyridine, t-BuCOCl
84%
O
C
O
C
a: 81%
b: 80%
c: 85%
a: 62%
b: 68%
c: 58%
N
N
N
t-Bu
N
t-Bu
N
H2N
N
H
H
H
H
H
11
12
13a: R = Cl
b: R = Br
c: R = I
Cl
NH2
R
R
N
HN
O
C
.
AcOH, NaNO2,
r.t., 0.5 h
NH3 H2O/dioxane
120 °C, 24 h
N
N
N
O
t-Bu
N
N
3b: R = Cl
c: R = Br
d: R = I
H
O
O
b: 85%
c: 88%
d: 89%
b: 61%
c: 65%
TolO
HO
TolO
15a: R = Cl
b: R = Br
c: R = I
HO
4b: R = Cl
c: R = Br
TDA-1 = tris[2-(2-methoxyethoxy)ethyl]amine
Scheme 3
for 4c), establishing b-D configuration. The position of the expressed by the root-mean-square (rms) difference. This
halogenation was also confirmed by 13C NMR spectrosco- procedure presupposes the existence of a two state N/S
py (Table 1). Compared to the nonhalogenated com- equilibrium (Figure 3).39 The input contained the follow-
pound, the C-7 signal is shifted about 15 ppm upfield ing coupling constants: J(H1¢,H2¢), J(H1¢,H2¢¢),
upon bromination (3c, 4c, 8b, 13b, 15b), about 50 ppm J(H2¢,H3¢), J(H2¢¢,H3¢), J(H3¢,H4¢). During the iterations
upfield upon iodination (3d, 8c, 13c, 15c), and about 3 either the puckering parameters (P, ymax) of the minor
ppm downfield upon chlorination. For the dibromo nucle- conformer (N) or the puckering amplitudes of both con-
osides 10 and 3e, the bromo substituent shifts the signals formers were constrained. The coupling constants
for both C-7 and C-8 upfield (about 8 ppm for C-7 and 12 J(H1¢,H2¢), J(H1¢,H2¢¢), J(H2¢,H3¢), J(H2¢¢,H3¢),
ppm for C-8).
J(H3¢,H4¢) and the pseudorotational parameters are
shown in Table 2.
Next, a conformational analysis of the sugar moiety of nu-
cleosides 3a–e and 4a–c was performed with the aid of the From the data given in Table 2, it is apparent that all nu-
PSEUROT program (version 6.3).38 In this program, a cleosides are in the N'S equilibrium in solution showing
minimization of the differences between the experimental a preferred S conformer population. The value of the non-
and calculated couplings is accomplished by a nonlinear halogenated nucleosides 3a and 4a show a population of
Newton–Raphson minimization; the quality of the fit is around 74% S; while the conformations of the nucleosides
3
Table 2 JH, H Coupling Constant of the Sugar Moiety and Conformer Population of Nucleosides 3a–e and 4a–ca
Product
3JH,H (Hz)
1¢,2¢
Pseudorotational Parametersb
1¢,2¢¢
2¢,3¢
2¢¢,3¢
3¢,4¢
%N
% S
PS (deg)
yS (deg)
rms (Hz) |DJm|
3a
3b
3c
3d
3e
4a
4b
4c
7.64
6.43
6.57
6.46
6.62
6.61
6.21
6.50
5.80
6.16
6.54
6.52
6.52
5.84
6.40
6.00
6.16
2.89
3.13
3.18
3.18
2.02
2.88
2.98
2.88
3.34
3.52
3.54
3.49
2.68
3.38
3.24
3.68
26
28
29
28
17
27
28
31
74
72
71
72
83
73
72
69
152.7
153.3
153.5
154.7
159.6
154.6
163.2
153.9
31.0
27.6
28.1
27.6
30.6
28.9
30.5
30.6
0.14
0.20
0.25
0.17
0.22
0.36
0.22
0.61
0.19
0.33
0.42
0.30
0.28
0.58
0.27
0.90
6.99
6.92
6.99
8.34
6.99
7.20
6.54
a Measured in D2O.
b PN (deg) = 18 and yN (deg) = 38 were fixed during the final minimization.
Synthesis 2004, No. 8, 1203–1210 © Thieme Stuttgart · New York

PAPER
Regioselective Syntheses of 7-Halogenated 7-Deazapurine Nucleosides
1207
obtained. To this solution, MeOH (10.0 mL) and H2O (5.0 mL)
were added, and the mixture was stirred at r.t. for 48 h. The solvent
was evaporated, and the residue was subjected to FC (silica gel, col-
umn 5 × 15 cm, A → B). After evaporation, the main zone gave a
colorless semisolid material. Crystallization from CH2Cl2–petro-
leum ether (2:1) yielded colorless needles (1.83 g, 76%); mp 130
°C; TLC (silica gel, B): Rf = 0.38.
N
S
C5'
C5'
N
N
O
O
C2'-exo-C3'-endo
C2'-endo-C3'-exo
1H NMR (DMSO-d6): d = 1.05 (d, 6 H, J = 6.7 Hz, 2 CH3), 1.13 (d,
6 H, J = 6.8 Hz, 2 CH3), 2.49–2.52 (m, 3 H, 2 CH, H- 2¢); 2.96–2.98
(m, 1 H, H-2¢), 4.20–4.23 (m, 3 H, H-4, 2 H-5¢), 5.37–5.39 (m, 1 H,
H-3¢), 6.50–6.52 (m, 1 H, H-1¢), 6.68 (d, 1 H, J = 3.7 Hz, H-5), 7.72
(d, 1 H, J = 3.7 Hz, H-6), 9.38 (d, 1 H, J = 9.0 Hz, NH), 11.10 (d, 1
H, J = 9.0 Hz, HCO).
Figure 3 N and S conformations of nucleosides
3b–d and 4b,c with 7-halogeno substituents are shifted a
little towards the N-population (around 70% S). In the
case of the 7,8-dibromo-substituted derivative 3e, the S-
conformer population increases to 83%, which is 12%
higher than that of the 7-bromo nucleoside 3c (71% S). As
bulky 8-substituent can shift the equilibrium around the
N-glycosylic bond more to the syn population which can
change the N'S equilibrium of 3e towards S. These find-
ings demonstrate that electron-withdrawing substituents
in position-7 of 7-deazapurine shift the sugar conforma-
tion towards N, while bulky substituents in position 8
drive the N'S equilibrium towards the S population.40,41
UV (MeOH): lmax (e) = 244 (33400), 279 nm (8900).
Anal. Calcd for C20H25ClN4O6 (452.9): C, 53.04; H, 5.56; N,12.37.
Found: C, 53.15; H, 5.38; N, 12.26.
4,5-Dichloro-7-[2-deoxy-3,5-bis-O-(2-methylpropanoyl)-b-D-
erythro-pentofuranosyl]-2-(formylamino)-7H-pyrrolo[2,3-d]py-
rimidine (8a); Typical Procedure
To a solution of compound 7 (1.1 g, 2.43 mmol) in DMF (30 mL)
was added N-chlorosuccinimide (390 mg, 2.92 mmol). After stir-
ring for 24 h at 50 °C, the reaction mixture was evaporated to dry-
ness, redissolved in CH2Cl2 and chromatographed (silica gel,
column 4 × 12 cm, A → B). From the main zone, a colorless foam
was obtained. Crystallization from CH2Cl2–petroleum ether (2:1)
gave colorless crystals (900 mg, 76%); mp 127 °C; TLC (silica gel,
B): Rf = 0.42.
1H NMR (DMSO-d6): d = 1.06 (d, 6 H, J = 6.9 Hz, 2 CH3), 1.13 (d,
6 H, J = 6.9 Hz, 2 CH3), 2.50–2.64 (m, 3 H, 2 CH, H-2¢), 2.86–2.94
(m, 1 H, H-2¢), 4.18–4.28 (m, 3 H, H-4¢, 2 H-5¢), 5.35–5.37 (m,
H-3¢), 6.52 (t, 1 H, J = 6.8, 6.8 Hz, H-1¢), 7.93 (s, 1 H, H-6), 9.37
(d, 1 H, J = 9.5 Hz, NH), 11.21 (d, 1 H, J = 9.5 Hz, HCO).
All chemicals were purchased from Sigma-Aldrich. Solvents were
of laboratory grade. Petroleum ether used had bp 40–60 °C. TLC:
aluminum sheets, silica gel 60 F254 (0.2 mm, VWR International).
Column flash chromatography (FC): silica gel 60 (VWR Interna-
tional) at 0.4 bar. Solvent systems of FC and TLC: CH2Cl2–MeOH,
99:1 (A), CH2Cl2–MeOH, 98:2 (B), CH2Cl2–MeOH, 9:1 (C),
CH2Cl2–MeOH, 4:1 (D), NH3 (25%)–i-PrOH–H2O (1:7:2) (E). UV
Spectra: U-3200 UV-Vis spectrometer (Hitachi, Japan). NMR spec-
tra: Avance-250 or AMX-500 spectrometers (Bruker); d values in
ppm relative to Me4Si as internal standard, J values are in Hz. Melt-
ing points were determined by a Linström apparatus and are not cor-
rected. Elemental analyses were performed by the
Mikroanalytisches Laboratorium Beller, Göttingen, Germany.
UV (MeOH): lmax (e) = 248 nm (38100).
Anal. Calcd for C20H24Cl2N4O6 (487.3): C, 49.29; H, 4.96; N, 11.50.
Found: C, 49.29; H, 4.90; N, 11.33.
5-Bromo-4-chloro-7-[2-deoxy-3,5-bis-O-(2-methylpropanoyl)-
b-D-erythro-pentofuranosyl]-2-(formylamino)-7H-pyrrolo[2,3-
d]pyrimidine (8b)
As described for 8a, the reaction was carried out with 7 (1.1 g, 2.43
mmol) and N-bromosuccinimide (516 mg, 2.90 mmol, 5 h) in DMF
or CH2Cl2 (30 mL). FC resulted in a colorless foam of 8b. Crystal-
lization from CH2Cl2–petroleum ether (2:1) yielded colorless crys-
tals (1.08 g, 84%); mp 121 °C; TLC (silica gel, B): Rf = 0.42.
1H NMR (DMSO-d6): d = 1.06 (d, 6 H, J = 6.9 Hz, 2 CH3), 1.13 (d,
6 H, J = 6.9 Hz, 2 CH3), 2.53–2.67 (m, 3 H, 2 CH, H-2¢), 2.87–2.99
(m, 1 H, H-2¢), 4.19–4.27 (m, 3 H, H-4¢, 2 H-5¢), 5.34–5.37 (m, 1 H,
H-3¢), 6.53 (t, 1 H, J = 6.8 Hz, H-1¢), 7.98 (s, 1 H, H-6), 9.38 (d, 1
H, J = 9.5 Hz, NH), 11.21 (d, 1 H, J = 9.5 Hz, HCO).
4-Chloro-7-(2-deoxy-b-D-erythro-pentofuranosyl)-N2-[(dimeth-
ylamino)methylidene]-7H-pyrrolo[2,3-d]pyrimidine (6)
A solution of 2-amino-4-chloro-7-(2-deoxy-b-D-erythro-pentofura-
nosyl)-7H-pyrrolo[2,3-d]pyrimidine17 (5; 1.70 g, 5.97 mmol) in
MeOH (50 mL ) was stirred with dimethylformamide dimethyl ac-
etal (5.0 mL, 37.3 mmol) for 36 h at r.t. After evaporation, the resi-
due was subjected to FC (silica gel, column 5 × 15 cm, B → C),
yielding a colorless foam (1.85 g, 91%); TLC (silica gel, C): Rf =
0.50.
1H NMR (DMSO-d6): d = 2.20–2.24 (m, 1 H, H-2¢), 2.44–2.50 (m,
1 H, H-2¢), 3.03 (s, 3 H, CH3), 3.15 (s, 3 H, CH3), 3.47–3.55 (m, 2
H, H-5¢), 3.80–3.83 (m, 1 H, H-4¢), 4.34–4.36 (m, 1 H, H-3¢), 4.99
(t, 1 H, J = 5.6 Hz, 5¢-OH), 5.32 (d, 1 H, J = 4.1 Hz, 3¢-OH), 6.49
(d, 1 H, J = 3.8 Hz, H-5), 6.55 (t, 1 H, J = 6.0 Hz, H-1¢), 7.59 (d, 1
H, J = 3.8 Hz, H-6), 8.61 (s, 1 H, CH=N).
UV (MeOH): lmax (e) = 250 nm (39400).
Anal. Calcd for C20H24BrClN4O6 (531.8): C, 45.17; H, 4.55; N,
10.54. Found: C, 45.57; H, 4.62; N, 10.33.
UV (MeOH): lmax (e) = 264 (19000), 299 nm (16800).
4-Chloro-7-[2-deoxy-3,5-bis-O-(2-methylpropanoyl)-b-D-eryth-
ro-pentofuranosyl]-2-(formylamino)-5-iodo-7H-pyrrolo[2,3-
d]pyrimidine (8c)
Anal. Calcd for C14H18ClN5O3 (339.8): C, 49.49; H, 5.34; N, 20.61.
Found: C, 49.48; H, 5.39; N, 20.39.
As described for 8a, the reaction was carried out with 7 (1.10 g, 2.43
mmol) and N-iodosuccinimide (655 mg, 2.91 mmol, 25 h) in DMF
(30 mL). Compound 8c (867 mg, 62%) was obtained as colorless
crystals from CH2Cl2–petroleum ether (2:1); mp 126 °C; TLC (sili-
ca gel, B): Rf = 0.42.
4-Chloro-7-[2-deoxy-3,5-bis-O-(2-methylpropanoyl)-b-D-eryth-
ro-pentofuranosyl]-2-(formylamino)-7H-pyrrolo[2,3-d]pyrimi-
dine (7)
A suspension of compound 6 (1.80 g, 5.30 mmol) in MeCN (30 mL)
was treated with isobutyric anhydride (9.0 mL, 54.3 mmol) in the
presence of Et3N (4.0 mL) at r.t. for 24 h. Then, a clear solution was
Synthesis 2004, No. 8, 1203–1210 © Thieme Stuttgart · New York

1208
F. Seela, X. Peng
PAPER
2-Amino-5,6-dibromo-4-chloro-7-[2-deoxy-3,5-di-O-(4-tolu-
oyl)-b-D-erythro- pentofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine
(10)
A solution of compound 9 (600 mg, 1.15 mmol) and N-bromosuc-
cinimide (499 mg, 2.80 mmol) in CH2Cl2 (20 mL ) was stirred for
1.5 h at r.t. After evaporation, the residue was redissolved in CH2Cl2
(5 mL) and submitted to FC (silica gel, column 4 × 10 cm, A → B).
The main zone was collected and evaporated to give a colorless
foam. Crystallization from CH2Cl2–petroleum ether (2:1) yielded
10 as colorless crystals (518 mg, 66%); mp 180 °C; TLC (silica gel,
A): Rf = 0.50.
1H NMR (DMSO-d6): d = 2.35 (s, 3 H, CH3), 2.39 (s, 3 H, CH3),
2.62–2.69 (m, 1 H, H-2¢), 3.54–3.64 (m, 1 H, H-2¢), 4.48–4.54 (m,
2 H, 2 H-5¢), 4.66–4.75 (m, 1 H, H-4¢), 5.88–5.92 (m, 1 H, H-3¢),
6.48 (t, 1 H, J = 6.8 Hz, H-1¢), 7.09 (br s, 2 H, NH2), 7.27, 7.35,
7.79, 7.92 (4 d, 8 H, J = 8.1 Hz, 2 C6H4).
1H NMR (DMSO-d6): d = 1.02 (d, 6 H, J = 6.9 Hz, 2 CH3), 1.12 (d,
6 H, J = 6.9 Hz, 2 CH3), 2.53–2.66 (m, 3 H, 2 CH, H-2¢), 2.85–2.97
(m, 1 H, H-2¢), 4.19–4.29 (m, 3 H, H-4¢, 2 H-5¢), 5.34–5.36 (m, 1
H, H-3¢), 6.50 (t, 1 H, J = 6.6 Hz, H-1¢), 7.95 (s, 1 H, H-6), 9.36 (d,
1 H, J = 9.2 Hz, NH), 11.21 (d, 1 H, J = 9.2 Hz, HCO).
UV (MeOH): lmax (e) = 252 nm (38500).
Anal. Calcd for C20H24ClIN4O6 (578.8): C, 41.50; H, 4.18; N, 9.68.
Found: C, 41.49; H, 4.20; N, 9.70.
5-Chloro-7-(2-deoxy-b-D-erythro-pentofuranosyl)-7H-pyrro-
lo[2,3-d]pyrimidine-2,4-diamine (3b); Typical Procedure
A suspension of compound 8a (1.12 g, 2.30 mmol) in dioxane (20
mL) and 25% NH3/H2O (60 mL) was introduced into an autoclave
and stirred at 120 °C for 24 h. The clear solution was evaporated,
and the residue was submitted to flash chromatography (silica gel,
column 4 × 16 cm, B → C). After evaporation, the main zone gave
crude 3b. Crystallization from MeOH yielded colorless crystals
(596 mg, 87%); mp 210 °C (dec.); TLC (silica gel, C): Rf = 0.33.
1H NMR (DMSO-d6): d = 2.00–2.07 (m, 1 H, H-2¢), 2.28–2.38 (m,
1 H, H-2¢), 3.48–3.50 (m, 2 H, 2 H-5¢), 3.74–3.76 (m, 1 H, H-4¢),
4.26–4.28 (m, 1 H, H-3¢), 5.00 (t, 1 H, J = 5.3 Hz, 5¢-OH), 5.21 (d,
J = 3.5 Hz, 3¢-OH), 5.86 (br s, 2 H, NH2), 6.32–6.38 (m, 3 H, H-1¢,
NH2), 7.09 (s, 1 H, H-6).
UV (MeOH): lmax (e) = 243 (55700), 328 (6200), 341 nm (5300).
Anal. Calcd for C27H23Br2ClN4O5 (678.8): C, 47.78; H, 3.42; N,
8.25. Found: C, 47.82; H, 3.31; N, 8.20.
5,6-Dibromo-7-(2-deoxy-b-D-erythro-pentofuranosyl)-7H-pyr-
rolo[2,3-d]pyrimidine-2,4-diamine (3e)
As described for 3b, the reaction was carried out with 10 (400 mg,
0.59 mmol) and 25% NH3/H2O (50 mL) in dioxane (15 mL). FC
(solvent CH2Cl2–MeOH 95:5) gave crude 3e as colorless solid
which was crystallized from MeOH to yield colorless crystals (161
mg, 65%); mp 137 °C; TLC (silica gel, C): Rf = 0.54.
UV (MeOH): lmax (e) = 228 (26800), 268 (9900), 287 nm (shoul-
der, 7700).
Anal. Calcd for C11H14ClN5O3 (299.7): C, 44.08; H, 4.71; N, 23.37.
Found: C, 44.15; H, 4.81; N, 23.36.
UV (MeOH): lmax (e) = 227 (27200), 267 (10900), 289 nm (shoul-
der, 8000).
5-Bromo-7-(2-deoxy-b-D-erythro-pentofuranosyl)-7H-pyrro-
lo[2,3-d]pyrimidine-2,4-diamine (3c)
1H NMR (DMSO-d6): d = 1.97–2.04 (m, 1 H, H-2¢), 3.02–3.13 (m,
1 H, H-2¢), 3.46–3.56 (m, 1 H, H-5¢), 3.60–3.69 (m, 1 H, H-5¢),
3.78–3.81 (m, 1 H, H-4¢), 4.36–4.38 (m, 1 H, H-3¢), 5.24 (d, J = 4.0
Hz, 3¢-OH), 5.35 (dd, J = 4.5 Hz, 5¢-OH), 5.84 (br s, 2 H, NH2), 6.33
(dd, 1 H, J = 6.6, 8.3 Hz, H-1¢), 6.47 (br, s, 2 H, NH2).
As described for 3b, the reaction was carried out with 8b (1.17 g,
2.20 mmol) and 25% NH3/H2O (60 mL) in dioxane (20 mL). FC re-
sulted in crude 3c as a colorless solid. Crystallization from MeOH
afforded colorless crystals (660 mg, 87%); mp 208 °C (dec.); TLC
(silica gel, C): Rf = 0.33.
1H NMR (DMSO-d6): d = 2.00–2.06 (m, 1 H, H-2¢), 2.29–2.40 (m,
1 H, H-2¢), 3.48–3.52 (m, 2 H, 2 H-5¢), 3.74–3.78 (m, 1 H, H-4¢),
4.25–4.29 (m, 1 H, H-3¢), 4.99 (t, 1 H, J = 5.4 Hz, 5¢-OH), 5.21 (d,
1 H, J = 3.6 Hz, 3¢-OH), 5.86 (br s, 2 H, NH2), 6.28 (br s, 2 H, NH2),
6.34 (dd, 1 H, J = 6.5, 6.9 Hz, H-1¢), 7.15 (s, 1 H, H-6).
Anal. Clacd for C11H13Br2N5O3 (423.1): C, 31.23; H, 3.10; N, 16.55.
Found: C, 31.41; H, 3.16; N, 16.39.
4-Chloro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimidine (12)
To a solution of 2-amino-4-chloropyrrolo[2,3-d]pyrimidine17 (11;
8.70 g, 51.6 mmol) in pyridine (40 mL), was added dropwise piv-
aloyl chloride (8.04 mL, 65.3 mmol) over 15 min, and the mixture
was stirred for 5 h at r.t. The solution was evaporated to an amber
solid, which was coevaporated with H2O (2 × 10 mL). The resulting
solid was filtered, washed with cold H2O and then dried in vacuo
over KOH to yield 12 as a reddish solid (10.9 g, 84%); mp 226 °C.
UV (MeOH): lmax (e) = 228 (27800), 268 (9300), 288 nm (shoul-
der, 7500).
Anal. Calcd C11H14BrN5O3 (344.2): C, 38.39; H, 4.10; N 20.35.
Found: C, 38.22; H, 4.08; N, 20.25.
1H NMR (DMSO-d6): d = 1.24 (s, 9 H, 3 CH3), 6.53 (m, 1 H, H-5),
7.63 (m, 1 H, H-6), 10.06 (s, 1 H, CONH), 12.34 (s, 1 H, NH). These
data are identical to those published earlier.23
7-(2-Deoxy-b-D-erythro-pentofuranosyl)-5-iodo-7H-pyrro-
lo[2,3-d]pyrimidine-2,4-diamine (3d)
As described for 3b, the reaction was carried out with 8c (1.24 g,
2.14 mmol) and 25% NH3/H2O (60 mL) in dioxane (20 mL). FC re-
sulted in crude 3d as white solid, which was crystallized from
MeOH to give colorless crystals (700 mg, 84%); mp 204 °C (dec.);
TLC (silica gel, C): Rf = 0.33.
1H NMR (DMSO-d6): d = 2.00–2.08 (m, 1 H, H-2¢), 2.29–2.37 (m,
1 H, H-2¢), 3.46–3.52 (m, 2 H, 2 H-5¢), 3.73–3.76 (m, 1 H, H-4¢),
4.26–4.28 (m, 1 H, H-3¢), 4.99 (t, 1 H, J = 5.5 Hz, 5¢-OH), 5.20 (d,
1 H, J = 3.7 Hz, 3¢-OH), 5.82 (br s, 2 H, NH2), 6.18 (br s, 2 H, NH2),
6.33 (dd, J = 6.6, 7.0 Hz, H-1¢), 7.19 (s, 1 H, H-6).
4,5-Dichloro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimidine
(13a); Typical Procedure
A solution of compound 12 (5.7 g, 22.6 mmol) and N-chlorosuccin-
imide (3.62 g, 27.1 mmol) in CH2Cl2 (100 mL) was stirred at 40 °C
for 5 h. The yellow solution was evaporated to an amber residue
which was crystallized from MeOH to give yellowish crystals (5.26
g, 81%); mp 238 °C.
1H NMR (DMSO-d6): d = 1.23 (s, 9 H, 3 CH3), 7.74 (s, 1 H, H-6),
10.18 (s, 1 H, CONH), 12.65 (s, 1 H, NH).
UV (MeOH): lmax (e) = 230 (28100), 269 (9500), 289 nm (shoul-
der, 8000).
Anal. Calcd for C11H12Cl2N4O (287.2): C, 46.01; H, 4.21; N, 19.51.
Found: C, 46.22, H, 4.30; N, 19.35.
Anal. Calcd for C11H14IN5O3 (391.2): C, 33.78; H, 3.61; N, 17.90.
Found: C, 33.70; H, 3.68; N, 17.81.
Synthesis 2004, No. 8, 1203–1210 © Thieme Stuttgart · New York

PAPER
Regioselective Syntheses of 7-Halogenated 7-Deazapurine Nucleosides
1209
5-Bromo-4-chloro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimi-
dine (13b)
8.03, 8.10 (4 d, 8 H, J = 8.1 Hz, 2 C6H4), 8.28 (s, 1 H, H-6), 10.29
(s, 1 H, NH).
As described for 13a, the reaction was carried out with 12 (5.70 g,
22.6 mmol) and N-bromosuccinimide (4.82 g, 27.1 mmol) in
CH2Cl2 (100 mL). The yellow solution was evaporated to an amber
residue which was crystallized from MeOH to give pink crystals
(6.0 g, 80%); mp 204 °C (dec.).
1H NMR (DMSO-d6): d = 1.23 (s, 9 H, 3 CH3), 7.78 (s, 1 H, H-6),
10.16 (s, 1 H, CONH), 12.72 (s, 1 H, NH).
UV (MeOH): lmax (e) = 245 nm (55300).
Anal. Calcd for C32H32BrClN4O6 (684.0): C, 56.19; H, 4.72; N,
8.19. Found: C, 56.12; H, 4.79; N, 8.33.
4-Chloro-7-[2-deoxy-3,5-di-O-(p-toluoyl)-b-D-erythro-pento-
furanosyl]-5-iodo-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimi-
dine (15c)
Anal. Calcd for C11H12BrClN4O (331.6): C, 39.84; H, 3.65; N,
16.90. Found: C, 39.87; H, 3.63; N, 16.90.
As described for 15a, the reaction was carried out with 13c (1.9 g,
5.0 mmol) and 14 (2.53 g, 6.51 mmol) in the presence KOH (1.15
g, 85%, 17.4 mmol) and TDA-1 (0.2 mL, 0.63 mmol) MeCN (60
mL). FC (silica gel, column 6 × 12 cm, CH2Cl2) resulted in 15c as
a foam. Crystallization from CH2Cl2–petroleum ether (2:1) yielded
colorless needles (2.12 g, 58%); mp 220 °C; TLC (silica gel, A):
Rf = 0.53.
1H NMR (DMSO-d6): d = 1.21 (s, 9 H, 3 CH3), 2.37, 2.39 (2 s, 6 H,
2 CH3), 2.69–2.75 (m, 1 H, H-2¢), 3.19–3.25 (m, 1 H, H-2¢), 4.47–
4.53 (m, 2 H, 2 H-5¢), 4.61–4.67 (m, 1 H, H-4¢), 5.77–5.79 (m, 1 H,
H-3¢), 6.63 (t, 1 H, J = 6.8 Hz, H-1¢), 7.31, 7.37, 7.84, 7.94 (4 d, 8
H, J = 8.1 Hz, 2 C6H4), 7.99 (s, 1 H, H-6), 10.29 (s, 1 H, NH).
4-Chloro-5-iodo-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimi-
dine (13c)
As described for 13a, the reaction was carried out with 12 (5.7 g,
22.6 mmol) and N-iodosuccinimide (6.12 g, 27.2 mmol) in CH2Cl2
(100 mL). The yellow solution was evaporated to an amber residue
which was crystallized from MeOH to furnish colorless crystals
(7.3 g, 85%); mp 240 °C.
1H NMR (DMSO-d6): d = 1.22 (s, 9 H, 3 CH3), 7.77 (s, 1 H, H-6),
10.13 (s, 1 H, CONH), 12.71 (s, 1 H, NH). These data are identical
to those published.23
UV (MeOH): lmax (e) = 247 nm (54500).
Anal. Calcd for C11H12ClIN4O (378.6): C, 34.60; H, 3.19; N, 14.80.
Found: C, 34.90; H, 3.20; N, 14.95.
Anal. Calcd for C32H32ClIN4O6 (731.0): C, 52.58; H, 4.41; N, 7.66.
Found: C, 52.81; H, 4.43; N, 7.63.
4,5-Dichloro-7-[2-deoxy-3,5-di-O-(p-toluoyl)-b-D-erythro-
pentofuranosyl]-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimi-
dine (15a); Typical Procedure
5-Chloro-7-(2-deoxy-b-D-erythro-pentofuranosyl)-7H-pyrrolo-
[2,3-d]pyrimidine-2,4-diamine (3b); Typical Procedure
A suspension of compound 15a (1.5 g, 2.35 mmol) in dioxane (30
mL) and 25% NH3/H2O (80 mL) was introduced into an autoclave
and stirred at 120 °C for 24 h. The clear solution was evaporated and
the residue was subjected to flash chromatography (silica gel, col-
umn 4 × 16 cm, B → C). The main zone was collected and con-
densed to a colorless solid, which was crystallized from MeOH to
yield colorless crystals of 3b (596 mg, 85%). NMR data were iden-
tical to those obtained for the compound by synthetic route 1.
To a suspension of powdered KOH (1.15 g, 85%, 17.4 mmol) and
TDA-1 (0.2 mL, 0.63 mmol) in MeCN (60 mL), was added com-
pound 13a (1.44 g, 5.00 mmol). After stirring the mixture for 5 min,
2-deoxy-3,5-di-O-(p-toluoyl)-a-D-erythro-pentofuranosyl chlor-
ide42 (14; 2.53 g, 6.51 mmol) was added over 15 min, and the stir-
ring was continued for 1 h. Insoluble material was filtered off, the
precipitate was washed with MeCN, and the filtrate was evaporated
to dryness. The residue was subjected to FC (silica gel, column
6 × 12 cm), eluting with CH2Cl2. The combined fractions containing
product were evaporated to give a foam. Crystallization from
CH2Cl2–petroleum ether (2:1) yielded colorless needles (1.98 g,
62%); mp 234 °C; TLC (silica gel, A): Rf = 0.53.
1H NMR (CDCl3): d = 1.35–1.37 (m, 9 H, 3 CH3), 2.42 (s, 3 H,
CH3), 2.45 (s, 3 H, CH3), 2.78–2.82 (m, 1 H, H-2¢), 2.91–2.97 (m, 1
H, H-2¢), 4.55–4.58, 4.63–4.66, 4.73–4.76 (3 m, 3 H, H-4¢, 2 H-5¢),
5.77–4.78 (m, 1 H, H-3¢), 6.74 (t, 1 H, J = 6.8 Hz, H-1¢), 7.25, 7.28,
7.90, 7.98 (4 d, 8 H, J = 8.1 Hz, 2 C6H4), 8.16 (s, 1 H, H-6), 10.29
(s, 1 H, NH).
5-Bromo-7-(2-deoxy-b-D-erythro-pentofuranosyl)-7H-pyrrolo-
[2,3-d]pyrimidine-2,4-diamine (3c)
As described for 3b, the reaction was carried out with 15b (1.5 g,
2.19 mmol) and 25% NH3/H2O (80 mL) in dioxane (30 mL). FC re-
sulted in a colorless solid, which was crystallized from MeOH to
give colorless crystals of 3c (667 mg, 88%). NMR data were iden-
tical to those obtained for the compound by synthetic route 1.
7-(2-Deoxy-b-D-erythro-pentofuranosyl)-5-iodo-7H-pyrrolo-
[2,3-d]pyrimidine-2,4-diamine (3d)
As described for 3b, the reaction was carried out with 15c (1.5 g,
2.05 mmol) and 25% NH3/H2O (80 mL) in dioxane (30 mL). FC re-
sulted in a colorless solid, which was crystallized from MeOH to
yield colorless crystals of 3d (717 mg, 89%). NMR data are identi-
cal to those obtained for the compound by synthetic route 1.
UV (MeOH): lmax (e) = 246 nm (54400).
Anal. Calcd for C32H32Cl2N4O6 (639.5): C, 60.10; H, 5.04; N, 8.76.
Found: C, 59.99; H, 4.91; N, 8.80.
5-Bromo-4-chloro-7-[2-deoxy-3,5-di-O-(p-toluoyl)-b-D-erythro-
pentofuranosyl]-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimi-
dine (15b)
As described for 15a, the reaction was carried out with 13b (1.66 g,
5.0 mmol) and 14(2.53 g, 6.51 mmol) in the presence of KOH (1.15
g, 85%, 17.4 mmol) and TDA-1 (0.2 mL, 0.63 mmol) in MeCN (60
mL). FC (silica gel, column 6 × 12 cm, CH2Cl2) resulted in crude
15b as colorless foam. Crystallization from CH2Cl2–petroleum
ether (2:1) gave colorless needles (2.32 g, 68%); mp 229–230 °C;
TLC (silica gel, A): Rf = 0.53.
1H NMR (CDCl3): d = 1.38–1.47 (m, 9 H, 3 CH3), 2.55 (s, 3 H,
CH3), 2.57 (s, 3 H, CH3), 2.91–2.93 (m, 1 H, H-2¢), 3.04–3.08 (m, 1
H, H-2¢), 4.69–4.70, 4.76–4.78, 4.85–4.87 (3 m, 3 H, H-4¢, 2H-5¢),
5.88–5.91 (m, 1 H, H-3¢), 6.84 (t, 1 H, J = 6.7 Hz, H-1¢), 7.37, 7.43,
4-Amino-5-chloro-7-(2-deoxy-b-D-erythro-pentofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine-2-one (4b); Typical Procedure
To a stirred solution of compound 3b (500 mg, 1.67 mL) in AcOH–
H2O (1:5; 40.0 mL), was added dropwise a solution of NaNO2 (250
mg, 3.62 mmol) in H2O (8.0 mL) at r.t. The stirring was continued
for 30 min, and the pH of the dark solution was adjusted to 6.0 with
25% aq NH3. The solution was applied to a Serdolit AD-4 column
(4 × 20 cm, resin 0.1–0.2 mm; Serva, Germany), the column was
washed with H2O (200 mL), and the product was eluted with H2O–
i-PrOH (95:5, 500 mL). Compound 4b was crystallized from the
solvent as yellowish needles (306 mg, 61%); mp 223 °C (dec.); TLC
(silica gel, E): Rf = 0.9.
Synthesis 2004, No. 8, 1203–1210 © Thieme Stuttgart · New York

1210
F. Seela, X. Peng
PAPER
1H NMR (DMSO-d6): d = 2.03–2.10 (m, 1 H, H-2¢), 2.25–2.36 (m,
1 H, H-2¢), 3.44–3.51 (m, 2 H, 2 H-5¢), 3.75–3.77 (m, 1 H, H-4¢),
4.26–4.28 (m, 1 H, H-3¢), 5.06–5.09 (m, 1 H, 5¢-OH), 5.23 (d, 1 H,
J = 3.9 Hz, 3¢-OH), 6.25 (dd, 1 H, J = 6.5, 7.2 Hz, H-1¢), 7.15 (br s,
3 H, H-6, NH2), 10.77 (br s, 1 H, NH).
(9) Ramasamy, K.; Robins, R. K.; Revankar, G. R. Tetrahedron
1986, 42, 5869.
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A.; Di Pasquale, G.; Carson, D. A. J. Med. Chem. 1993, 36,
3424.
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3, 401.
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Chan, M. C.; Lau, K. F. Cancer Chemother. Rep. 1972, 3,
71.
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Trans. 2 1986, 525.
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Chem. 1987, 15.
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1999, 82, 12.
UV (MeOH): lmax (e) = 231 (27100), 263 (6500), 310 nm (6600).
Anal. Calcd for C11H13ClN4O4 (300.7): C, 43.94; H, 4.36; N, 18.63.
Found: C, 43.75; H, 4.23; N, 18.39.
4-Amino-5-bromo-7-(2-deoxy-b-D-erythro-pentofuranosyl)-7H-
pyrrolo[2,3-d]pyrimidine-2-one (4c)
As described for 4b, the reaction was carried out in a mixture of 3c
(500 mg, 1.45 mmol) in AcOH–H2O (1:5, 40.0 mL) and NaNO2
(250 mg, 3.62 mmol) in H2O (8.0 mL). The solution was applied to
a Serdolit AD-4 column (4 × 20 cm, resin 0.1–0.2 mm; Serva, Ger-
many). The column was washed with H2O (150 mL), and the prod-
uct was eluted with H2O–i-PrOH (95:5, 500 mL). Compound 4c
was crystallized from the solvent as yellowish needles (325 mg,
65%); mp 220 °C (dec.); TLC (silica gel, E): Rf = 0.9.
1H NMR (DMSO-d6): d = 2.00–2.08 (m, 1 H, H-2¢), 2.25–2.33 (m,
1 H, H-2¢), 3.50–3.51 (m, 2 H, 2 H-5¢), 3.74–3.77 (m, 1 H, H-4¢),
4.25–4.28 (m, 1 H, H-3¢), 5.04–5.06 (m, 1 H, 5¢-OH), 5.23 (d, 1 H,
J = 3.9 Hz, 3¢-OH), 6.25 (dd, 1 H, J = 5.8, 6.5 Hz, H-1¢), 6.85 (br s,
2 H, NH2), 7.21 (s, 1 H, H-6), 10.77 (br s, 1 H, NH).
(20) Ramzaeva, N.; Seela, F. Helv. Chim. Acta 1995, 78, 1083.
(21) Seela, F.; Wei, C. Helv. Chim. Acta 1999, 82, 726.
(22) Seela, F.; Zulauf, M. Chem. Eur. J. 1998, 4, 1781.
(23) Balow, G.; Mohan, V.; Lesnik, E. A.; Johnston, J. F.; Monia,
B. P.; Acevedo, O. L. Nucleic Acids Res. 1998, 26, 3350.
(24) Okamoto, A.; Tanaka, K.; Saito, I. Bioorg. Med. Chem. Lett.
2002, 12, 97.
(25) Seela, F.; Thomas, H. Helv. Chim. Acta 1995, 78, 94.
(26) Taylor, E. C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindey,
G. B.; Barredo, J.; Jannatipour, M.; Moran, R. G. J. Med.
Chem. 1992, 35, 4450.
(27) Barnett, C. J.; Kobierski, M. E. J. Heterocycl. Chem. 1994,
31, 1181.
(28) Seela, F.; Mittelbach, C. unpublished work.
(29) Revankar, G. R.; Rao, T. S.; Ramasamy, K.; Smee, D. F.
Nucleosides Nucleotides 1995, 14, 671.
UV (MeOH): lmax (e) = 232 (26800), 262 (5900), 310 nm (5800).
Anal. Calcd for C11H13BrN4O4 (345.2): C, 38.28; H, 3.80; N, 16.23.
Found: C, 38.54; H, 3.72; N, 16.45.
Acknowledgment
We thank Dr. Helmut Rosemeyer and Dr. Yang He for the measu-
rement of NMR spectra, and Dr. Hong Li for the calculation of
pseudorotational parameters. We thank Mrs. Dubiel and Miss Fei-
ling for their kind help. Financial support by the European Commu-
nity (Grant No.: QLRT-2001-00506, ‘Flavitherapeutics’) is
gratefully acknowledged.
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Trans. 1 1988, 697.
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Synthesis 2004, No. 8, 1203–1210 © Thieme Stuttgart · New York