7-halogenated 7-deaza-2'-deoxyinosines

Article abstract of DOI:10.1002/(SICI)1522-2675(19990113)82:1<12::AID-HLCA12>3.0.CO;2-L

The synthesis of the 7-deaza-2'-deoxyinosine derivatives 3a-c with chloro, bromo, and iodo substituents at position 7 is described. Glycosylation of the 7-halogenated 6-chloro-7-deazapurines 4a-c or of the 7- halogenated 6-chloro-7-deaza-2-(methylthio)pur

Full text of DOI:10.1002/(SICI)1522-2675(19990113)82:1<12::AID-HLCA12>3.0.CO;2-L

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Helvetica Chimica Acta ± Vol. 82 (1999)
7-Halogenated 7-Deaza-2'-deoxyinosines
by Natalya Ramzaeva, Cathrin Mittelbach, and Frank Seela*
Laboratorium für Organische und Bioorganische Chemie, Institut für Chemie, Universität Osnabrück,
Barbarastrasse 7, D-49069 Osnabrück
The synthesis of the 7-deaza-2'-deoxyinosine derivatives 3a ± c with chloro, bromo, and iodo substituents at
position 7 is described. Glycosylation of the 7-halogenated 6-chloro-7-deazapurines 4a ± c or of the 7-
halogenated 6-chloro-7-deaza-2-(methylthio)purines 9a ± c with 2-deoxy-3,5-di-O-(4-toluoyl)-a-d-erythro-pen-
tofuranosyl chloride (5) furnished the intermediates 7a ± c and 11a ± c, respectively, which gave, upon
deprotection, the desired nucleosides 3a ± c.
Introduction. ± 2'-Deoxyinosine (1) is the classical universal nucleoside which
shows ambiguous base pairing with the four natural components of DNA [1]. It is used
for the synthesis of primers and probes in DNA technology [2± 5]. Recently, it was found
that 7-deaza-2'-deoxyinosine1) (2) is an efficient substitute of 2'-deoxyinosine [6].
The present investigation is part of a study involving 7-deazapurine 2'-deoxyribo-
nucleosides as substitutes of regular purine 2'-deoxynucleosides within DNA frag-
ments. Earlier, various substituents such as halogeno, alkyl, alkynyl, or alkenyl groups
were introduced at position 7 of 7-deaza-2'-deoxypurine nucleosides and incorporated
later into oligonucleotides [7 ± 11]. In the case of 7-deaza-2'-deoxyadenosine as well as
7-deaza-2'-deoxyguanosine, the 7-substitution led to a significant duplex stabilization
with retention of the particular DNA structure [7 ± 12]. Now, the synthesis of 7-chloro-
(3a), 7-bromo- (3b), and 7-iodo-7-deaza-2'-deoxyinosine (3c) derivatives is described,
which are the key intermediates for later studies on oligonucleotides.
Results and Discussion. ± As nucleobase precursors of compounds 3a ± c, the 7-
substituted 6-chloro-7-deazapurines1) 4a ± c [12][13] were chosen which have been
1
)
Purine numbering is used throughout the General Part; for systematic names, see Exper. Part.

Helvetica Chimica Acta ± Vol. 82 (1999)
13
used earlier in the synthesis of 7-substituted 7-deaza-2'-deoxyadenosine derivatives
[12]. Stereoselective nucleobase-anion glycosylation of these aglycones with 2-deoxy-
3,5-di-O-(4-toluoyl)-a-d-erythro-pentofuranosyl chloride (5) [14] was carried out as
described before [12], with the exception that the intermediates 6a ± c were not isolated
(Scheme 1). Now, a one-pot glycosylation of 4a ± c followed by simultaneous
detoluoylation and Cl/OMe exchange at position 6 with 0.5m NaOMe/MeOH was
performed, which yielded the corresponding 6-methoxy nucleosides 7a ± c directly and
improved the former procedure significantly. Besides the easier workup, the total yield
was increased by ca. 15% to 63 ± 70%. Subsequent nucleophilic displacement of the
MeO group by OH was performed with 2n aqueous NaOH giving the desired
nucleosides 3a ± c (75 ± 80% yield).
Scheme 1
Alternatively, we also investigated the possibility to incorporate the halogeno
substituents at position 7 of the 6-chloro-7-deaza-2-(methylthio)purine 8. We selected
this substitution pattern because the nucleosides resulting after glycosylation can serve
as universal intermediates also for the synthesis of 7-substituted 7-deazaadenine and 7-
deazaguanine derivatives [15][16]. When compound 8 was treated with N-iodosuccin-
imide (NIS) in CH2Cl2 according to [13], a clean reaction was observed affording 7-
substituted 9c in 80% yield (Scheme 2). No formation of a 7,8-diiodo compound was
detected (TLC or NMR monitoring of the crude reaction mixture). On the other hand,
when compound 8 was brominated with N-bromosuccinimide (NBS) in the same

14
Helvetica Chimica Acta ± Vol. 82 (1999)
solvent, the formation of a mixture of three halogenated congeners took place (7-, 8-,
and 7,8-dibromo-7-deaza-2-(methylthio)purines). However, exchange of CH2Cl2 by
DMF overcame this problem and, therefore, DMF became the solvent of choice for this
particular reaction. In this way, compounds 9a ± c were synthesized in 85 ± 90% yield.
The fact that the halogeno substituent was incorporated at the 7 position was
established by 1H- (see Exper. Part) and 13C-NMR spectroscopy (see [17]).
Scheme 2
a) NXS ˆ N-chloro-, N-bromo, or N-iodosuccinimide
The subsequent glycosylation of the halogenated nucleobases 9a ± c was performed
as described above without isolation of the intermediates 10a ± c (Scheme 3). The
nucleosides 11a ± c were isolated in 60 ± 66% total yield. Finally, the nucleophilic OMe/
OH exchange reaction of 11a ± c was performed with 2n NaOH furnishing the
nucleosides 12a ± c (78 ± 82% yield). The latter were then desulfurized with Raney-Ni
to give the nucleosides 3a ± c.
Scheme 3

Helvetica Chimica Acta ± Vol. 82 (1999)
15
All compounds were characterized by 1H- and 13C-NMR spectroscopy as well as by
elemental analyses (Table 1 and Exper. Part). According to Table 1, the C(7) signal of
the 7-unsubstituted 7-deazapurine nucleoside 2 is shifted downfield upon chlorination
and upfield upon bromination and iodination (3a: Dd ˆ 3.8; 3b: Dd ˆ‡ 16.1; 3c:
Table 1. 13C-NMR Data of 7-Deaza-2'-deoxyinosinesa)
Dd ˆ‡ 50.9).
C(2)b) C(4)b) C(5)b) C(6)b) C(7)b) C(8)b) MeO MeS C(1') C(2') C(3') C(4') C(5')
C(2)c) C(7a)c) C(4a)c) C(4)c) C(5)c) C(6)c)
2
3a
b
143.7
144.9
145.3
144.6
147.4
146.2
146.8
147.2
150.1
150.7
150.9
150.8
151.3
152.1
108.4
104.8
105.9
108.0
102.7
104.1
106.5
99.3
158.2
156.9
157.7
157.7
162.3
162.3
162.1
164.0
163.8
163.4
102.5
106.3
90.2
55.4
102.7
86.6
51.1
102.9
86.9
120.7
117.8
120.1
125.6
121.6
124.1
129.0
119.9
122.4
127.6
116.6
119.1
123.9
83.2 40.2 71.0 87.4 62.0
d
82.9
83.0
83.2
)
)
)
70.7 87.5 61.7
70.7 87.5 61.7
70.9 87.6 61.8
d
d
c
7a [12] 151.6
53.9
53.9
53.6
83.1 40.6 70.9 87.6 61.6
d
b
c
151.5
151.2
161.4
161.4
161.6
83.2
83.6
)
)
)
)
)
)
)
)
70.9 87.6 61.6
70.7 87.4 61.6
70.7 87.4 61.6
70.7 87.4 61.6
70.8 87.4 61.7
70.7 87.4 61.6
70.7 87.4 61.6
70.7 87.3 61.6
d
d
d
d
d
d
d
11a
b
53.8 13.5 82.7
53.8 13.5 82.7
53.7 13.6 82.8
12.7 82.6
100.7
103.4
c
51.6
12a
b
156.7e) 146.3e) 101.2
156.4e) 146.7e) 102.3
156.6e) 146.5e) 104.3
157.3e) 106.3
157.4e) 90.4
157.7e) 55.3
12.7 82.6
12.7 82.7
c
a) Measured in (D6)DMSO. b) Purine numbering. c) Systematic numbering. c) Superimposed by (D6)DMSO.
e) Tentative.
Next, the sugar conformation of the nucleoside 2 as well as of 3a ± c in solution was
compared with that of the parent purine nucleoside 1. For this purpose, vicinal 3J(H,H)
couplings (Table 2) of 1, 2, and 3a ± c were taken from well-resolved 1H-NMR spectra
measured in D2O. The conformation in solution (N>S) was deduced from the
pseudorotational parameters P and Ym by application of the PSEUROT program2).
The data are listed in Table 2. The rotational equilibrium about the C(4') C(5') bond
1
was calculated according to Westhof et al. [19] using the vicinal H,1H couplings
between H C(4') and H C(5') as well as H' C(5'), respectively (Table 2). From
these data, a slight trend can be deduced: while ld (1) exhibits a gg‡ population of 52%,
this population is reduced to 44 ± 46% in the cases of the 7-deazapurine nucleosides 2
and 3a ± c. These findings are in line with those obtained for other 7-deazapurine 2'-
deoxynucleosides as compared to their corresponding purine counterparts [20].
Table 2. 3J(H,H) Coupling Constants of the Sugar Moieties and Conformer Populations of Nucleosides 1, 2, and
3a ± ca)
3J(H,H) [Hz]
Conformation
J(1',2') J(1',2'') J(2',3') J(2'',3') J(3',4') J(4',5')
%N %S %gg‡ %gt %gg
ld (1)
6.80
7.15
6.55
6.60
6.60
6.60
6.60
6.40
6.40
6.45
6.45
6.40
3.80
3.40
3.60
3.65
3.70
3.55
3.50
3.55
3.55
3.60
3.60, 4.75
3.90, 5.00
3.90, 5.10
3.95, 5.10
3.95, 5.10
35
31
33
33
34
65
69
67
67
66
52
46
45
44
44
30
33
34
34
34
18
21
21
22
22
c7ld (2)
Cl7c7ld (3a) 6.90
Br7c7ld (3b) 6.90
l7c7ld (3c)
6.90
a) Solvent, D2O; r.m.s. ꢀ0.18 Hz; j DJmax jꢀ 0.3 Hz; T 303 K.
2
)
Version 6.2; licensor: Prof. Dr. C. Altona, Gorlaeus Laboratories, Leiden, The Netherlands [18].

16
Helvetica Chimica Acta ± Vol. 82 (1999)
As it can be seen from Table 2, the N>S equilibrium of 7-deaza-2'-deoxyinosine
(2) is slightly biased towards the S-conformation. This effect is again compensated in
the cases of the 7-halogeno-substituted 7-deaza-2'-deoxyinosines 3a ± c which show
almost the same conformational parameters as 2'-deoxyinosine (1).
In conclusion, the halogenation reaction of 6-chloro-7-deaza-2-(methylthio)purine
(8) leads, in DMF, exclusively to the 7-halogenated products 9a ± c. These compounds
are useful precursors for the synthesis of 7-chloro- (3a), 7-bromo- (3b), and 7-iodo-7-
deaza-2'-deoxyinosine (3c) as well as for 7-halogenated 7-deazaadenosine or 7-
deazaguanosine derivatives. The importance of these 7-substituted 7-deazapurine
nucleosides for the synthesis of derivatives carrying a linker and a reporter group at this
favourable position is, meanwhile, well-established [15][17][21]. As the 2- and 8-
positions of the regular 2'-deoxyinosine are unfavourable for such purposes, compound
3c is an ideal precursor for the synthesis of 7-deaza-2'-deoxyinosine derivatives, which
carry a reporter group at the sterically unproblematic position 7, and which can act as
ambiguous primers and probes in DNA technology.
We thank Dr. Helmut Rosemeyer for the measurement of the NMR spectra and for helpful discussion.
Experimental Part
General. See [9]. TLC: Aluminium sheets coated with a 0.2-mm layer of silica gel 60 F254 (Merck,
Germany). Flash chromatography (FC): at 0.5 bar; silica gel 60 H (Merck, Germany). Solvent systems for TLC
and FC: CH2Cl2/MeOH 9 :1 (A), CH2Cl2/MeOH 8 :2 (B). UV Spectra: Hitachi-150-20 spectrometer (Hitachi,
Japan). NMR Spectra: Bruker-Avance-DPX-250 and -AMX-500 spectrometers; d values in ppm rel. to Me4Si as
internal standard (1H and 13C). Elemental analyses were performed by Mikroanalytisches Laboratorium Beller,
Göttingen, Germany.
5-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (7a). To a soln. of
4a [12] (1 g, 5.3 mmol) in MeCN (40 ml), KOH (0.75 g, 13.4 mmol) and TDA-1 (ˆtris[2-(2-methoxyethoxy)-
ethyl]amine; 125 ml, 0.4 mmol) were added. After stirring at r.t. for 15 min, 2-deoxy-3,5-di-O-(4-toluoyl)-a-d-
erythro-pentofuranosyl chloride [14] (5; 3.0 g, 7.7 mmol) was added, and stirring was continued for another
15 min. Insoluble material was filtered off and the filtrate evaporated and suspended in 0.5m NaOMe (20 ml).
The suspension was stirred overnight and then evaporated and the residue applied to FC (column 20 Â 5 cm, A):
7a (1.0 g, 63%). Colourless solid. TLC (silica gel, A): Rf 0.53. All anal. data were identical to those described [12].
5-Bromo-7-(2-deoxy-b-d-erythro-pentofuranosyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (7b). As de-
scribed for 7a with 4b [12] (1.4 g, 6.0 mmol), MeCN (40 ml), KOH (0.95 g, 17 mmol), TDA-1 (200 ml,
0.6 mmol), 5 (2.5 g, 6.4 mmol), and 0.5m NaOMe (20 ml): 7b (1.4 g, 68%). Colourless solid. TLC (silica gel, A):
Rf 0.56. UV (MeOH): 265(9100), 281(9700). 1H-NMR ((D6)DMSO): 8.44 (s, H C(2)); 7.84 (s, H C(6)); 6.59
(t, J ˆ 6.8, H C(1')); 5.27 (d, J ˆ 3.9, OH C(3')); 4.96 (t, J ˆ 5.3, OH C(5')); 4.34 (m, H C(3')); 4.04
(s, MeO); 3.82 (d, H C(4')); 3.51 (m, 2 H C(5')); 2.23 (m, H C(2')). Anal. calc. for C12H14BrN3O4 (344.17):
C 41.88, H 4.10, N 12.21; found: C 41.81, H 4.08, N 12.13.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (7c). As descri-
bed for 7a, with 4c [12] (1.7 g, 6.0 mmol), MeCN (40 ml), KOH (0.95 g, 17 mmol), TDA-1 (200 ml, 0.6 mmol), 5
(2.5 g, 6.4 mmol), and 0.5m NaOMe (20 ml): 7c (1.65 g, 70%). Colourless solid. TLC (silica gel, A): Rf 0.60. UV
(MeOH): 260(9400), 282(10800). 1H-NMR ((D6)DMSO): 8.43 (s, H C(2)); 7.84 (s, H C(6)); 6.58 (t, J ˆ 6.9,
H
C(1')); 5.26 (d, J ˆ 4.0, OH C(3')); 4.96 (t, J ˆ 5.3, OH C(5')); 4.35 (m, H C(3')); 4.05 (s, MeO); 3.83
(d, H C(4')); 3.56 (m, 2 H C(5')); 2.24 (m, H C(2')). Anal. calc. for C12H14IN3O4 (391.16): C 36.85, H 3.61,
N 10.74; found: C 36.70, H 3.80, N 10.60.
5-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (3a). a)
A soln. of 7a (1.0 g, 3.3 mmol) in 2m NaOH (20 ml) was heated under reflux for 5 h. After cooling to r.t., the
soln. was neutralized with 1m AcOH to pH 7 yielding a solid which was filtered and washed with H2O: 3a
(710 mg, 75%). Colourless solid. TLC (silica gel, B): Rf 0.52. UV (MeOH): 263(9000), 282 (sh, 7600). 1H-NMR
((D6)DMSO): 12.10 (s, NH); 7.92 (s, H C(2)); 7.49 (s, H C(6)); 6.45 (t, J ˆ 6.3, H C(1')); 5.27 (br. s,
OH C(3')); 4.96 (br. s, OH C(5')); 4.30 (m, H C(3')); 3.79 (d, H C(4')); 3.50 (m, 2 H C(5')); 2.39

Helvetica Chimica Acta ± Vol. 82 (1999)
17
(m, Hb C(2')); 2.20 (m, Ha C(2')). Anal. calc. for C11 H12ClN3O4 (285.69): C 46.25, H 4.23, N 14.71; found:
C 46.36, H 4.24, N 14.62.
b) To a soln. of 12a (1.65 g, 5 mmol) in N,N-dimethylacetamide (40 ml), Raney-Ni suspension (20 ml) was
added. After heating under reflux for 1.5 h, the soln. was filtered through a 1-cm layer of silica gel and washed
with hot N,N-dimethylacetamide (3 Â 50 ml). The combined filtrates were evaporated: 3a (970 mg, 68%).
Anal. data: identical to those described above.
5-Bromo-7-(2-deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (3b). a)
As described for 3a (in a)), with 7b (1.1 g, 3.3 mmol): 3b (860 mg, 79%). Colourless solid. TLC (silica gel, B):
1
Rf 0.64. UV (MeOH): 264(10900), 287(8700). H-NMR ((D6)DMSO): 12.10 (s, NH); 7.94 (s, H C(2)); 7.50
(s, H C(6)); 6.44 (t, J ˆ 6.3, H C(1')); 5.27 (br. s, OH C(3')); 4.96 (br. s, OH C(5')); 4.32 (d, H C(3')); 3.81
(d, H C(4')); 3.52 (m, 2 H C(5')); 2.37 (m, Hb C(2')); 2.20 (m, Ha C(2')). Anal. calc. for C11H12BrN3O4
(330.14): C 40.02, H 3.66, N 12.73; found: C 40.01, H 3.75, N 12.65.
b) As described for 3a (in b)), with 12b (1.88 g, 5 mmol) in N,N-dimethylacetamide (40 ml) and Raney-Ni
suspension (20 ml): 3b (1.1 g, 67%). Anal. data: identical to those described above.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-5-iodo-4H-pyrrolo[2,3-d]pyrimidin-4-one (3c). a) As
described for 3a (in a)), with 7c (1.2 g, 3.3 mmol): 3c (995 mg, 80%) after crystallization from MeCN. Colourless
solid. TLC (silica gel, B): Rf 0.69. UV (MeOH): 265(13100), 282(12000). 1H-NMR ((D6)DMSO): 12.01
(s, NH); 7.92 (s, H C(2)); 7.53 (s, H C(6)); 6.42 (t, J ˆ 6.3, H C(1')); 5.26 (d, J ˆ 4.0, OH C(3')); 4.94 (t, J ˆ
6.6, OH C(5')); 4.31 (br. s, H C(3')); 3.80 (d, H C(4')); 3.43 (m, 2 H C(5')); 2.38 (m, Hb C(2')); 2.20
(m, Ha C(2')). Anal. calc. for C11H12IN3O4 (377.13): C 35.03, H 3.21, N 11.14; found: C 35.09, H 3.43, N 10.93.
b) As described for 3a (in b), with 12c (2.1 g, 5 mmol) in N,N-dimethylacetamide (40 ml) and Raney-Ni
suspension (20 ml): 3c (1.3 g, 69%). Anal. data: identical to those described above.
4,5-Dichloro-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (9a). To a soln. of 8 (1.0 g, 5 mmol) in DMF
(20 ml), N-chlorosuccinimide (1.0 g, 7.2 mmol) was added. After stirring for 18 h at r.t., the solvent was
evaporated. The residue was crystallized from MeOH: 9a (1.0 g, 85%). Colorless solid. M.p. 220 ± 2218. TLC
(silica gel, A): Rf 0.81. UV (MeOH): 224 (29000), 255(28200), 282(8800). 1H-NMR ((D6)DMSO): 12.66 (br. s,
NH); 7.68 (d, H C(6)); 2.54 (s, Me). Anal. calc. for C7H5Cl2N3S (234.10): C 35.91, H 2.15, N 17.95; found:
C 36.00, H 2.13, N 17.89.
5-Bromo-4-chloro-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (9b). As described for 9a, with 8 (1 g,
5 mmol) and N-bromosuccinimide (1 g, 5.5 mmol): 9b (1.25 g, 90%). Colourless solid. TLC (silica gel, A):
Rf 0.86. UV (MeOH): 228(16600), 255(25200), 284(5300). 1H-NMR ((D6)DMSO): 12.72 (br. s, NH); 7.72
(d, H C(6)); 22.53 (s, Me). Anal. calc. for C7H5BrClN3S (278.55): C 30.18, H 1.81, N 15.08; found: C 30.14,
H 1.92, N 14.97.
4-Chloro-5-iodo-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (9c). As described for 9a, with 8 (1.0 g,
5 mmol) and N-iodosuccinimide (1.2 g, 5.2 mmol): 9c (1.46 g, 90%). Colourless solid. TLC (silica gel, A):
Rf 0.84. UV (MeOH): 225(17300), 261(27100), 285(7800). 1H-NMR ((D6)DMSO): 12.70 (br. s, NH); 7.72
(s, H C(6)); 2.54 (s, Me). Anal. calc. for C7H5ClIN3S (325.55): C 25.83, H 1.55, N 12.91; found: C 25.98, H 1.59,
N 12.77.
5-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-4-methoxy-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine
(11a). To a soln. of 9a (234mg, 1 mmol) in MeCN (30 ml), KOH (0.38 g, 6.8 mmol) and TDA-1 (30 ml,
0.1 mmol) were added. After stirring at r.t. for 15 min, 2-deoxy-3,5-di-O-(4-toluoyl)-a-d-erythro-pentofuranosyl
chloride [14] (5; 0.6 g, 1.5 mmol) was added and stirring continued for another 15 min. Insoluble material was
filtered off and the filtrate evaporated and suspended in 0.5m NaOMe (20 ml). The suspension was stirred for
24 h and then evaporated and the residue applied to FC (column 20 Â 5 cm, A): 11a (207 mg, 60%). Colourless
solid. TLC (silica gel, A): Rf 0.49. UV (MeOH): 244 (19900), 285 (11500). 1H-NMR ((D6)DMSO): 7.63
(s, H C(6)); 6.54 (t, J ˆ 6.5, H C(1')); 5.28 (d, J ˆ 4.0, OH C(3')); 4.91 (t, J ˆ 5.2, OH C(5')); 4.34 (br. s,
H
C(3')); 4.03 (s, MeO); 3.82 (d, H C(4')); 3.56 (m, 2 H C(5')); 2.56 (s, MeS); 2.23 (m, H C(2')). Anal.
calc. for C13H16ClN3O4S (345.80): C 45.15, H 4.66, N 12.15; found: C 45.29, H 4.75, N 12.05.
5-Bromo-7-(2-deoxy-b-d-erythro-pentofuranosyl)-4-methoxy-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine
(11b). As described for 11a with 9b (280 mg, 1.0 mmol), MeCN (30 ml), KOH (0.38 g, 6.8 mmol), TDA-1
(30 ml, 0.1 mmol), 5 (0.6 g, 1.5mmol), and 0.5m NaOMe (20 ml): 11b (234 mg, 60%). Colourless solid. TLC
(silica gel, A): Rf 0.50. UV (MeOH): 245 (24200), 287 (13300). 1H-NMR ((D6)DMSO): 7.63 (s, H C(6)); 6.54
(t, J ˆ 6.2, H C(1')); 5.31 (d, J ˆ 3.7, OH C(3')); 4.94 (t, J ˆ 4.6, OH C(5')); 4.33 (br. s, H C(3')); 4.03
(s, MeO); 3.81 (d, H C(4')); 3.50 (m, 2 H C(5')); 2.56 (s, MeS); 2.23 (m, H C(2')). Anal. calc. for
C13H16BrN3O4S (390.26): C 40.01, H 4.13, N 10.77; found: C 40.31, H 4.40, N 10.78.

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Helvetica Chimica Acta ± Vol. 82 (1999)
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-5-iodo-4-methoxy-2-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine
(11c). As described for 11a, with 9c (325 mg, 1.0 mmol), MeCN (30 ml), KOH (0.38 g, 6.8 mmol), TDA-1
(30 ml, 0.1 mmol), 5 (0.6 g, 1.5 mmol), and 0.5m NaOMe (20 ml): 11c (288 mg, 66%). Yellow solid. TLC (silica
gel, A): Rf 0.52. UV (MeOH): 248 (28500), 287 (12500). 1H-NMR ((D6)DMSO): 7.67 (s, H C(6)); 6.51 (t, J ˆ
6.0, H C(1')); 5.27 (d, J ˆ 4.2, OH C(3')); 4.89 (t, J ˆ 5.4, OH C(5')); 4.33 (m, H C(3')); 4.03 (s, MeO); 3.81
(d, H C(4')); 3.54 (m, 2 H C(5')); 2.56 (s, MeS); 2.22 (m, H C(2')). Anal. calc. for C13H16IN3O4S (437.26):
C 35.71, H 3.69, N 9.61; found: C 35.88, H 3.51, N 9.78.
5-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-2-(methylthio)-4H-pyrrolo[2,3-d]pyrimidin-
4-one (12a). A soln. of 11a (1.7 g, 5 mmol) in 2m NaOH (25 ml) was heated under reflux for 3 h. After cooling to
r.t., the soln. was neutralized with 1m AcOH to pH 7 yielding a solid which was filtered off and washed with
H2O: 12a (1.3 g, 78%). Colourless solid. TLC (silica gel, B): Rf 0.70. UV (MeOH): 275 (10000). 1H-NMR
((D6)DMSO): 12.39 (s, NH); 7.37 (s, H C(6)); 6.43 (t, J ˆ 6.6, H C(1')); 5.30 (br. s, OH C(3')); 4.94 (br. s,
OH C(5')); 4.32 (br. s, H C(3')); 3.80 (d, H C(4')); 3.51 (m, 2 H C(5')); 2.53 (s, MeS); 2.41 (m, Hb C(2'));
2.20 (m, Ha C(2')). Anal. calc. for C12H14ClN3O4S (331.77): C 43.44, H 4.25, N 12.67; found: C 43.25, H 4.27,
N 12.49.
5-Bromo-7-(2-deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-2-(methylthio)-4H-pyrrolo[2,3-d]pyrimidin-4-
one (12b). As described for 12a, with 11b (1.9 g, 5 mmol) and 2m NaOH (20 ml): 12b (1.55 g, 82%). Colourless
solid. TLC (silica gel, B): Rf 0.71. UV (MeOH): 276 (16100). 1H-NMR ((D6)DMSO): 12.34 (s, NH); 7.41
(s, H C(6)); 6.45 (t, J ˆ 6.2, H C(1')); 5.30 (br. s, OH C(3')); 4.95 (br. s, OH C(5')); 4.32 (br. s, H C(3'));
3.80 (d, H C(4')); 3.51 (m, 2 H C(5')); 2.53 (s, MeS); 2.40 (m, Hb C(2')); 2.20 (m, Ha C(2')). Anal. calc. for
C12H14BrN3O4S (376.22): C 38.31, H 3.75, N 11.17; found: C 38.62, H 3.92, N 10.92.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-5-iodo-2-(methylthio)-4H-pyrrolo[2,3-d]pyrimidin-4-
one (12c). As described for 12a, with 11c (2.2 g, 5 mmol) and 2m NaOH (20 ml): 12c (1.7 g, 80%). Colourless
solid. TLC (silica gel, B): Rf 0.75. UV (MeOH): 276(16100). 1H-NMR ((D6)DMSO): 12.34 (s, NH); 7.37
(s, H C(6)); 6.42 (t, J ˆ 6.5, H C(1')); 5.26 (br. s, OH C(3')); 4.93 (br. s, OH C(5')); 4.31 (br. s, H C(3'));
3.79 (d, H C(4')); 3.52 (m, 2 H C(5')); 2.51 (s, MeS); 2.17 (m, H C(2')). Anal. calc. for C12H14IN3O4S
(423.22): C 34.06, H 3.33, N 9.93; found: C 34.35, H 3.38, N 9.75.
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Received September 28, 1998