7-Halogenated 7-deazapurine 2′-deoxyribonucleosides related to 2′-deoxyadenosine, 2′-deoxyxanthosine, and 2′- deoxyisoguanosine: Syntheses and properties

Article abstract of DOI:10.1002/hlca.200890117

A series of 7-fluorinated 7-deazapurine 2′-deoxyribonucleosides related to 2′-deoxyadenosine, 2′-deoxyxanthosine, and 2′-deoxyisoguanosine as well as intermediates 4b - 7b, 8, 9b, 10b, and 17b were synthesized. The 7-fluoro substituent was introduced in 2,6-dichloro-7-deaza-9H-purine (11a) with Selectfluor (Scheme 1). Apart from 2,6-dichloro-7-fluoro-7-deaza-9H-purine (11b), the 7-chloro compound 11c was formed as by-product. The mixture 11b/11c was used for the glycosylation reaction; the separation of the 7-fluoro from the 7-chloro compound was performed on the level of the unprotected nucleosides. Other halogen substituents were introduced with N-halogenosuccinimides (11a→11c - 11e). Nucleobase-anion glycosylation afforded the nucleoside intermediates 13a - 13e (Scheme 2). The 7-fluoro- and the 7-chloro-7-deaza-2′-deoxyxanthosines, 5b and 5c, respectively, were obtained from the corresponding MeO compounds 17b and 17c, or 18 (Scheme 6). The 2′-deoxyisoguanosine derivative 4b was prepared from 2-chloro-7-fluoro-7-deaza-2′-deoxyadenosine 6b via a photochemically induced nucleophilic displacement reaction (Scheme 5). The pK_a values of the halogenated nucleosides were determined (Table 3). ¹³C-NMR Chemical-shift dependencies of C(7), C(5), and C(8) were related to the electronegativity of the 7-halogen substituents (Fig. 3). In aqueous solution, 7-halogenated 2′-deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).

Full text of DOI:10.1002/hlca.200890117

Helvetica Chimica Acta – Vol. 91 (2008)
1083
7-Halogenated 7-Deazapurine 2’-Deoxyribonucleosides Related to
2’-Deoxyadenosine, 2’-Deoxyxanthosine, and 2’-Deoxyisoguanosine:
Syntheses and Properties
by Frank Seela* and Kuiying Xu
Laboratory of Bioorganic Chemistry and Chemical Biology, Center for Nanotechnology,
Heisenbergstrasse 11, D-48149 Münster, and Laboratorium für Organische und Bioorganische Chemie,
Institut für Chemie, Universität Osnabrück, Barbarastrasse 7, D-49069 Osnabrück
(phone: þ 49(0)25153406500; mobile; þ 40(0)1737250297; fax: þ 49(0)25153406857;
e-mail: Frank.Seela@uni-osnabrueck.de, Seela@uni-muenster.de; www.seela.net)
A series of 7-fluorinated 7-deazapurine 2’-deoxyribonucleosides related to 2’-deoxyadenosine, 2’-
deoxyxanthosine, and 2’-deoxyisoguanosine as well as intermediates 4b – 7b, 8, 9b, 10b, and 17b were
synthesized. The 7-fluoro substituent was introduced in 2,6-dichloro-7-deaza-9H-purine (11a) with
Selectfluor (Scheme 1). Apart from 2,6-dichloro-7-fluoro-7-deaza-9H-purine (11b), the 7-chloro com-
pound 11c was formed as by-product. The mixture 11b/11c was used for the glycosylation reaction; the
separation of the 7-fluoro from the 7-chloro compound was performed on the level of the unprotected
nucleosides. Other halogen substituents were introduced with N-halogenosuccinimides (11a ! 11c –
11e). Nucleobase-anion glycosylation afforded the nucleoside intermediates 13a – 13e (Scheme 2). The
7-fluoro- and the 7-chloro-7-deaza-2’-deoxyxanthosines, 5b and 5c, respectively, were obtained from the
corresponding MeO compounds 17b and 17c, or 18 (Scheme 6). The 2’-deoxyisoguanosine derivative 4b
was prepared from 2-chloro-7-fluoro-7-deaza-2’-deoxyadenosine 6b via a photochemically induced
nucleophilic displacement reaction (Scheme 5). The pKa values of the halogenated nucleosides were
determined (Table 3). 13C-NMR Chemical-shift dependencies of C(7), C(5), and C(8) were related to
the electronegativity of the 7-halogen substituents (Fig. 3). In aqueous solution, 7-halogenated 2’-
deoxyribonucleosides show an approximately 70% S population (Fig. 2 and Table 1).
Introduction. – The 7-halogenated 7-deazapurine (pyrrolo[2,3-d]pyrimidine)
nucleosides have gained attention since some of them exhibit a broad spectrum of
biological activity [1 – 10]. The 7-iodotubercidin (1) (purine numbering is used
throughout the general section) is a potent inhibitor of adenosine kinase [11][12].
The 2’-C-methyl derivative 2 of 7-fluorotubercidin is one of the most potent and
selective inhibitors of HCV polymerase [13]. The 7-fluorinated 2’-deoxytubercidin 3
and its 2’-fluoroarabinofuranosyl derivative [14] were synthesized, and X-ray analyses
were performed showing the influence of the fluoro substituent on the nucleoside
conformation [15][16]. Several halogenated pyrrolo[2,3-d]pyrimidine nucleosides have
been incorporated into oligonucleotides enhancing DNA-duplex stability compared to
their unmodified counterparts [17 – 19]. The synthesis and properties of 7-deazapurine
ribonucleosides and 7-deazapurine 2’-deoxyribonucleosides have been reviewed
recently [20].
Although a series of 7-halogenated 7-deazapurine 2’-deoxyribonucleosides have
been already synthesized [21 – 28], the number of 7-fluorinated compounds is limited
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 91 (2008)
[14][29]. As the F-atom is the substituent with the highest electronegativity (3.98 vs.
3.44 of the O-atom) [30] but with the smallest size [31] of the halogen substituents,
various positive effects on the biological activity of nucleosides are observed [13][32].
Thus, we became interested in 7-fluorinated 7-deazapurine nucleosides related to 2’-
deoxyisoguanosine, 2’-deoxyxanthosine, 2-amino-2’-deoxyadenosine, and 2-chloro-2’-
deoxyadenosine which are all unknown.
Earlier, we have shown that 2-substituents introduced into purine and 7-
deazapurine nucleosides change the base-paring properties due to the presence of a
bulky 2-substituent or the absence of the N(7)-atom [33][34], a phenomenon which
has been also recognized by others [35][36]. So, 2-halogenated 7-deazapurines neither
form Watson– Crick nor Hoogsteen base pairs [33]. Here, we report the 7-fluorination
of the 2,6-dichloro-7-deazapurine and its stereoselective glycosylation giving access to
the 7-fluorinated nucleosides 4b – 6b, 9b, and 10b related to 2’-deoxyisoguanosine, 2’-
deoxyxanthosine, and 2-chloro-2’-deoxyadenosine, while the 7-fluorinated 2-amino-2’-
deoxyadenosine related 7b and the intermediate 8 were prepared from an already
known precursor [14]. The 7-halogenated 7-deazapurine 2’-deoxynucleosides 5c, 6c –
6e, 9c – 9e, and 10c – 10e containing chloro, bromo, or iodo substituents were also
synthesized as well as the corresponding 7-nonfunctionalized compounds 6a [25], 9a
[37], and 10a. The spectroscopic and physicochemical properties, which include pKa
data and the influence of the electronegativity of the 7-halogen substituents on the
13C-NMR chemical shifts of the 7-deazapurine moieties, are reported. The sugar
conformation of the halogenated nucleosides is determined in aqueous solution by
using the 3J(H,H) coupling constants and applying the program PSEUROT [38].
Results and Discussion. – 1. Synthesis of 7-Halogenated 7-Deazapurine 2’-
Deoxyribonucleosides. The 7-halogenated 7-deazapurine nucleosides can be prepared
either by the regioselective halogenation of an appropriately protected nucleoside
[20][39] or from a halogenated 7-deazapurine which is glycosylated afterwards
[14][40]. Here, the halogenation was performed on the nucleobase level. The 2,6-
dichloro-7-deazapurine (11a) [41] (Scheme 1) was chosen as the starting material, since
the selective displacement of the chloro substituents makes various NH2- and OH-
substituted derivatives accessible. Moreover, it was expected that a 7-fluoro substitu-
ent, as in 11b, can be introduced by an electrophilic fluorination of compound 11a with
the hazard-free source Selectfluor [42a] in a similar manner as it was already reported
for the 6-chloro-7-deazapurine (¼4-chloro-7H-pyrrolo[2,3-d]pyrimidine) [32]. How-
ever, the reaction conditions employed for 6-chloro-7-deazapurine (20% AcOH/
MeCN (1:5), 708, 14 h) [32] led to the decomposition of 11a. Thus, the fluorination
reaction was investigated in more detail leading to the observation that much milder
conditions (50 – 608, 5 h, and 10% AcOH/MeCN (1:10)) had to be employed.
However, in all cases the formation of compound 11b was inevitably accompanied
by the chloro compound 11c. Therefore, a mixture of 11b/11c was obtained in yields of
around 54% with an 11b/11c ratio of 3 :1 (Scheme 1). This ratio was determined by 1H-
and 13C-NMR spectra as well as HPLC analysis (Fig. 1). At first, we thought that the
starting material 11a contains already the trichloro compound 11c as both compounds
show similar retention factors on TLC. However, according to the 1H-NMR spectrum,
only traces of 11c could be detected in the reaction mixture purified by flash

Helvetica Chimica Acta – Vol. 91 (2008)
1085
chromatography. Thus, the main amount of the corresponding protected trichloro
nucleoside 11c must be formed during the fluorination reaction. It is likely that the
introduction of the 7-chloro substituent results from a partial decomposition of the
starting material 11a which together with the fluorination reagent (Selectfluor) can
form electrophilic Clþ, a route which has been described for other cases [42a]. As
compounds 11b and 11c can hardly be separated on a preparative scale employing flash
column chromatography or recrystallization, the nucleobase mixture 11b/11c was used
for the glycosylation procedure without further purification. An analytical amount of
pure 11b was obtained after HPLC purification (Exper. Part). Other halogen
substituents (Cl, Br, and I) were introduced selectively into the 7-position of 11a
employing N-halogenosuccinimides to yield the halogenated bases 11c – 11e in 66 –
87% yields (Scheme 1).
Next, the nucleobase-anion glycosylation [23][42b] of 11a – 11e was performed.
The reactions were carried out under standard conditions with 2-deoxy-3,5-di-O-(4-

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Scheme 1
i) Selectfluor, MeCN, AcOH, 608. ii) NCS, DMF (!11c), NBS, CH2Cl2 (!11d), or NIS, CH2Cl2
(!11e).
Fig. 1. Reversed-phase HPLC (RP-18) profiles of a) products obtained from the fluorination reaction; b)
anartificial mixture of compounds 11a – 11e. The mixtures were analyzed by reversed-phase HPLC at
260 nm on a RP-18 column (250 ꢀ 4 mm). Gradient: 30% MeCN, 70% buffer (buffer: 0.1m Et3NH · OAc
(pH 7.0)/MeCN 95 :5). Flow rate 0.7 ml/min.
toluoyl)-a-d-erythro-pentofuranosyl chloride (12) [43] as sugar component, MeCN as
solvent, and powdered KOH/TDA-1 (TDA-1 ¼ tris[2-(2-methoxyethoxy)ethyl]amine)
to generate the nucleobase anion. The protected nucleosides 13a – 13e were isolated in
60 – 73% yield (Scheme 2). For the preparation of sufficient amounts of 13b, a mixture
11b/11c was glycosylated as described above to yield 13b/13c which was used for the
deprotection procedures without further purification (Scheme 2; Exper. Part).
From the intermediates 13b/13c, the 7-fluorinated 2’-deoxyisoguanosine and 2’-
deoxyxanthosine derivatives were prepared. For that, the NH2 and MeO groups had to

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1087
Scheme 2
i) KOH, TDA-1, MeCN.
be introduced. Thus, the nucleosides 13b/13c were deprotected in MeONa/MeOH or
NH3/MeOH (Scheme 3). Treatment of 13b/13c in 0.5m MeONa at 608 (autoclave)
afforded the dimethoxy nucleosides 9b and 9c, which were separated from each other
by flash chromatography. When 13b/13c was treated with NH3/MeOH (sat. at 08) at
room temperature overnight, the monomethoxy compounds 10b and 10c were
obtained. Treatment with NH3/MeOH (1008, autoclave) converted 13b/13c to the 2-
chloro-2’-deoxyadenosine derivatives 6b and 6c. The fluoro compounds (b series) and
chloro derivatives (c series) were isolated in a ratio of ca. 3 :1. The exact individual
yields of the free nucleosides were determined on the basis of the F/Cl contents of the
starting material, the overall yield was in the range of 80 – 90%, slightly changing
according to the 3 :1 ratio of the staring material 13b/13c (Scheme 3).
In the same way as described for the fluoro and chloro compounds, the other
halogenated and the nonfunctionalized intermediates 13a and 13c – 13e were converted
to the corresponding free nucleosides 6, 9, and 10 as shown in Scheme 4. In the case of
the conversion 13a ! 10a, compound 10a (48%) was formed together with 14 (30%).
Therefore, the 6-chloro substituent can partially be retained under these conditions
when no halogen atom is present at the 7-position. On the contrary, the 7-halogenated
nucleosides 13b – 13e were always displaced at the 6-position (Schemes 3 and 4).
To access the ꢁisoguanosineꢂ derivatives, 2,6-diamino nucleosides are normally used
as starting materials which undergo NH2 ! OH displacement by selective diazotization
at the 2-position [40]. However, attempts to prepare the 2,6-diamino compound 7b

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Helvetica Chimica Acta – Vol. 91 (2008)
Scheme 3
i) 0.5m MeONa, 608, overnight. ii) NH3/MeOH, r.t., overnight. iii) NH3/MeOH, 1008, 12 h.
from compound 13b encountered difficulties. As described above, treatment of 13a –
13e with NH3/MeOH (sat. at 08) can only displace the 6-Cl substituent by a MeO or
NH2 group, leaving the 2-chloro substituent untouched (!10 and 6). Efforts to
complete the reaction by increasing the temperature, prolonging the reaction time, or
employing aqueous NH3 solution resulted in no further conversion. Thus, we chose
another starting material, namely compound 15 [14] (Scheme 5). For the displacement
of the 6-chloro substituent by an NH2 group, harsh conditions are required. Treatment
with NH3/MeOH or NH3/H2O in a steel vessel at elevated temperature removes the
pivaloyl protecting group accompanied by the displacement of the 6-choro substituent.
These reaction conditions worked well with other halogenated derivatives [40][44] but
failed to access compound 7b due to decomposition. Thus, conditions were elaborated
(708, 5 d) to perform the reaction without significant decomposition of the molecule.
Under those moderate conditions, compound 7b was formed together with 8 and 16 as
by-products (Scheme 5). Unfortunately, the selective NH2 ! OH exchange on
compound 7b failed as the acidic diazotization conditions led to the decomposition

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Scheme 4
i) 0.5m MeONa, 608, overnight. ii) NH3/MeOH, r.t., overnight. iii) NH3/MeOH, 1008, overnight.
of the nucleosides. Therefore, another approach was chosen. As reported earlier,
isoguanine nucleosides are accessible from 2-halogenated adenosine derivatives by a
photochemically catalyzed nucleophilic displacement reaction [45]. Consequently, the
7-fluorinated nucleoside 6b was irradiated in aqueous solution in a quartz reactor for

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Helvetica Chimica Acta – Vol. 91 (2008)
Scheme 5
i) NH3/MeOH, 708, 5 d. ii) 0.1% NH3/H2O, hn.
1 h. Purification by means of a Serdolit-AD-4 column afforded nucleoside 4b in 35%
yield (Scheme 5).
Next, the conversion of 9b and 9c into the xanthosine derivatives 5b and 5c was
studied. Different protocols have been described for the conversion of the MeO to
C¼O groups in nucleosides: a) acidic cleavage, HBr/AcOH in absolute THF [37]; b)
Me3SiCl/NaI in MeCN [46]; c) 2n NaOH, reflux [46]. Efforts to use protocols a) and b)
for the cleavage of 9b failed due to the decomposition of the compounds. Therefore, 9b
was treated according to protocol c) with 2n NaOH under reflux to yield a new product,
17b. NMR Spectra (see Exper. Part and Table 4 (below)) showed that this compound
still carries one MeO group but is different from the 6-methoxy compound 18
(Scheme 6). Thus, the structure of a 2-methoxy nucleoside was assigned to 17b.
Extension of the reaction time did not improve the situation. In the same way, the
dimethoxy compounds 9a and 9c – 9e were converted into the corresponding mono-
methoxy derivatives 17a and 17c – 17e (Scheme 6). With only one MeO group,
compound 17b is more likely to be converted to 5b by using protocol b) compared to 9b
which has two MeO substituents. Protocol b) was successfully employed for compounds
17b and 17c. Milder conditions (lower concentration of the reactant, see Exper. Part)
must be used to avoid the decomposition and halogen exchange as reported [46].
Compounds 5b and 5c were obtained in 69 and 65% yields, respectively (Scheme 6).
This reaction carried out under the same conditions was also performed with compound
18 as starting material which was obtained from 16 [14] by diazotization (63%). The
monomethoxy nucleoside 18 was converted to 5b in 66% yield (Scheme 6).

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1091
Scheme 6
i) 2n NaOH, reflux. ii) Me3SiCl, NaI, MeCN. iii) NaNO2, AcOH.
2. Conformational Analysis. The conformation of oligonucleotides is believed to
depend strongly upon the conformation of the nucleotide monomers that constitute
them. Thus, a conformational analysis of the sugar moiety of nucleosides 5a – 5e and
7a – 7e was performed with the aid of the PSEUROT program (version 6.3) [38]. In this
program, a minimization of the differences between the experimental and calculated
coupling constants is accomplished by a nonlinear Newton– Raphson minimization; the
quality of the fit is expressed by the root-mean-square (rms) difference. This procedure
presupposes the existence of a two-state N/S equilibrium in aqueous solution (Fig. 2)
[47]. The input contained the following coupling constants: J(1’,2’), J(1’,2’’), J(2’,3’),
J(2’’,3’), and J(3’,4’) (2’’ ¼ short form of H’ꢁC(2’)). During the iterations, either the
puckering parameters (P, ymax) of the minor conformer (N) or the puckering
amplitudes of both conformers were constrained. The coupling constants and the
pseudorotational parameters are shown in Table 1. From the data given in Table 1, it is
apparent that all nucleosides are in the N > S equilibrium in aqueous solution showing
a preferred S (71 – 74% S) conformer population. Halogenation bias the equilibrium
slightly towards N. However, little difference was observed for the various halogen-
substituted nucleosides.
3. UV/VIS Spectra and pKa Values. All compounds are characterized by UV/VIS
spectra (Table 2 and Exper. Part). The UV/VIS spectra of compounds 9a – 9e, 10a – 10e,
11a – 11e, and 17a – 17e were measured in MeOH and indicate that 7-halogen

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Fig. 2. N and S Conformation of the Nucleosides
Table 1. 3J(H,H) Coupling Constants of the Sugar Moiety and Conformer Population of Nucleosidesa)
3J(H,H) [Hz] Pseudorotational parametersb)
1’,2’
1’,2’’c)
2’,3’
2’’,3’c)
3’,4’
% N
% S
PS [8]
YS [8]
rms [Hz]
5a
5b
5c
5d
5e
6a
6b
7a
7b
7c
7d
7e
8
6.90
6.92
7.17
7.05
6.89
7.64
7.00
7.64
7.75
6.99
6.92
6.99
6.99
6.31
6.53
6.47
6.60
5.90
6.43
6.51
6.43
6.31
6.57
6.46
6.62
6.81
6.22
6.18
6.07
6.40
5.81
6.16
6.51
6.16
6.27
6.54
6.52
6.52
6.60
2.89
3.22
3.16
3.20
2.75
2.89
3.04
2.89
3.13
3.13
3.18
3.18
3.26
2.90
3.20
3.09
3.10
3.00
3.34
3.25
3.34
3.43
3.52
3.54
3.49
3.52
26
29
28
28
27
26
27
26
27
28
29
28
28
74
71
72
72
73
74
73
74
73
72
71
72
72
168.0
165.8
165.4
162.9
168.3
152.7
158.0
152.7
148.9
153.3
153.5
154.7
154.3
29.1
29.6
30.8
28.4
31.8
31.0
27.6
31.0
32.4
27.6
28.1
27.6
26.8
0.35
0.22
0.19
0.18
0.53
0.14
0.24
0.14
0.09
0.20
0.25
0.17
0.10
a) Measured in D2O at 258. b) PN ¼ 188 and YN ¼ 388 were fixed during the final minimization. c) 2’’ ¼
short form of H’ꢁC(2’).
substituents induce a bathochromic shift of ca. 1 – 13 nm (Table 2) as in 7-deazaade-
nosines and 7-deazainosines [48]. The spectra of compounds 9a and 9c – 9e, show two
peaks in the range of 260 – 280 nm which are poorly resolved. In the case of the fluoro
compound 9b, there is only one broad peak with an absorbance maximum at 269 nm.

Helvetica Chimica Acta – Vol. 91 (2008)
1093
Moreover, it is also interesting to notice that the Cl-, Br-, and I-substituents reduce the
extinction coefficient of the nucleosides as observed in other cases [48], while the F-
substituent enhances the absorbance, especially in nucleosides 9b and 10b (Table 2).
Table 2. UV Absorption Maxima and Extinction Coefficients of Nucleosides and Basesa)
lmax (e)
lmax (e)
9a
9b
9c
9d
9e
10a
10b
10c
10d
10e
257 (7500), 272 (7800)
269 (20100)
264 (5900), 273 (6100)
264 (6100), 274 (6300)
264 (7300), 275 (7700)
271 (8500)
273 (26100)
282 (6500)
281 (6900)
284 (5800)
11a
11b
11c
11d
11e
17a
17b
17c
17d
17e
289 (4100)
302 (3900)
305 (3100)
307 (2900)
312 (2600)
255 (9500)
255 (10000)
258 (8800)
259 (9500)
261 (8400)
a) Measured in MeOH at 258.
Protonation and deprotonation influence base-pairing selectivity and mismatch
formation of DNA and RNA duplexes. The addition of a phosphate to form nucleotides
raises the nucleoside pKa values by 0.2 – 0.6 pH units. In oligonucleotides, a further
increase is observed. The negatively charged phosphate group attracts the ionizable
proton and thus raises the pKa. Therefore, pKa values of the nucleosides 4 – 8 and 14
were determined by spectrophotometric titration [49] (pH 1.0 – 13.5) at 220 – 400 nm.
As shown in Table 3, xanthosine derivatives are already deprotonated under slightly
acidic conditions (pKa 6.2 for 5b and 6.1 for 5c), the 2-chloroadenosine derivatives
have very low pKa values for protonation (2.0 for 6a and 1.6 for 6b – 6e). The pKa value
of the dichloro nucleoside 14 is even lower and cannot be detected in aqueous solution.
In contrast, the pKa value of the diamino compound 7b (5.0) is in the range of that of 2’-
deoxytubercidin (5.08 [14]), while that of the 2-amino-6-chloro derivative 8 is
significantly lower (4.2). Thus, as expected, electron-donating substituents such as the
2-amino group increase the basicity of the 7-deazapurine moiety, while a 2-chloro group
Table 3. pKa Values of the Nucleosidesa)b)
c
Wavelength [nm]
pKac)d)
Wavelength [nm]
pKa
)
4a
4b
5a
5b
5c
7a
7b
305
279
255
257
259
230
234
4.6, 10.5
3.6, 10.1
6.7
6.2
6.1
6a
6b
6c
6d
6e
8
232
234
239
240
312
310
248
2.0
1.6
1.6
1.6
1.6
4.2
5.7
5.0
14
< 1
a) Measured in phosphate buffer (0.1m NaH2PO4) from pH 1 to pH 13. b) Wavelength with the most
significant absorbance change. c) Protonation. d) Deprotonation.

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Helvetica Chimica Acta – Vol. 91 (2008)
reduces the basic character. In the case of the related antimalignant 2-chloro-2’-
deoxyadenosine (pKa 1.4), a similar trend was observed [50]. However, this molecule
became extremely labile under acidic condition as the protonation site changed from
N(7) to N(1). This is not observed for compound 6a which is extraordinarily stable, due
to the pyrrolo[2,3-d]pyrimidine system. The X-ray structure of compound 4a shows that
the molecule adopts the HꢁN(1), C(2)¼O form as indicated in the formula [51]. The
7-halogen substituents decrease the pKa values of the functionalized compounds
compared to those of nonfunctionalized nucleosides (5a – 5c and 6a – 6e).
4. NMR Spectra and Influence of the 7-Substituent Electronegativity on 13C-NMR
Chemical Shifts. The nucleosides and the intermediates were characterized by 1H-, 13C-,
and 19F-NMR spectra as well as by elemental analysis or mass spectra. The 13C-NMR
chemical shifts of all new compounds, were measured in (D6)DMSO apart from 13a –
13c and 13e which were measured in CDCl3 due to their poor solubility in (D6)DMSO
(Table 4). The d(C) of the 7-unsubstituted compounds 6a, 9a, 11a, and 13a were
assigned according to references [25][37][41] which report the corresponding chemical
shifts. The C-atoms of the 7-halogenated heterocycles were assigned according to the
1
influence of the halogen substituents as well as on the basis of H/13C-NMR gated-
decoupled spectra. The chemical shifts of the sugar moieties of the deprotected
nucleosides were assigned according to [20][46] and on the basis of 1H/13C-NMR gated-
decoupled spectra of compounds 10b and 10d (Table 5).
Table 4 shows that the 7-halogen substituents shifts the C(5), C(7), and C(8)
signals significantly, while other C-atoms are not affected. Compared to the non-
functionalized base or nucleosides (a series), the C(7) signals of the 7-fluoro
derivatives (b series) are shifted strongly downfield (by ca. 40 ppm), while the 7-
chloro compounds (c series) show only minor downfield shifts of 3 – 5 ppm. The other
halogen substituents induce upfield shifts of 12 – 13 ppm for the bromo compounds (d
series) and of 47 – 49 ppm for iodo derivatives (e series). This trend is also observed for
other ring systems such as for 5-halogenated uracil derivatives [52] and 7-halogenated
inosine derivatives [48]. The atoms C(5) and C(8) also experience chemical shift
changes due to the halogen substituents. The F-substituent biases the C(5) signals
upfield by ca. 10 ppm and C(8) by 17.5 ppm. Other halogen atoms induce chemical-shift
changes of C(5) and C(8), e.g., a value of ca. 2 – 4 ppm is observed for Cl (upfield) and I
(downfield).
A dependence of the chemical shifts on the electronegativity of the halogen
substituents is observed. This is demonstrated for C(5), C(7), and C(8) in Fig. 3. The
graphs correlate the chemical shifts vs. the electronegativity of the 7-halogen
substituents for two series, compounds 6b – 6e (Fig. 3,a) and 10b – 10e (Fig. 3,b); a
similar correlation is found for the other halogenated compounds (Table 4). The
chemical shift of C(7) is increasing almost linearly with increasing electronegativity of
the substituents. For C(8) and C(5), the effect is lower relative to that of C(7).
Additionally, the chemical shifts of C(8) and C(5) decrease linearly with increasing
electronegativity of the C(7) substituents.
To confirm the position of halogenation (C(7) vs. C(8)), the 13C,19F coupling
constants J(C,F) of the fluorinated compounds were calculated (Table 5). Moreover,
1
gated-decoupled H/13C-NMR spectra of the 7-fluoro nucleoside 10b and 7-bromo
compound 10d which were selected as representative examples were measured. The

Helvetica Chimica Acta – Vol. 91 (2008)
1095
Table 4. 13C-NMR Chemical Shifts (d [ppm]) of Nucleosides and Precursorsa)b)
C(2)c) C(6)c) C(5)
C(7) C(8) C(4)c) C(1’) C(2’) C(3’) C(4’) C(5’)
C(2)
C(4)
C(4a) C(5) C(6) C(7a)
11a [41] 150.9
150.1
147.6
150.6
150.7
150.2
152.2
147.5
150.7
151.6
151.5
163.4
162.8
163.6
163.6
163.6
162.9
162.1
162.8
162.9
162.9
159.3
157.2
157.9
158.3
158.3
156.0
156.2
159.5
157.7
158.4
158.2
156.7
157.6
157.8
158.2
156.2
150.0
150.5
163.1
115.8
104.9
112.0
113.1
115.1
117.0
106.6
113.3
114.0
116.3
100.2
90.6
99.4 129.5 152.8
140.0 112.1 149.3
102.3 127.1 150.9
86.6 129.6 150.9
52.6 134.7 151.4
101.5 126.6 152.8
141.9 109.1 151.5
106.4 123.6 152.8
88.5 126.5 151.6
53.4 131.8 153.6
98.8 122.3 152.9
142.1 104.5 148.6
103.2 119.5 151.8
87.1 121.9 152.3
51.8 127.1 152.9
99.4 125.1 151.0
141.5 107.6 147.3
103.3 122.1 151.9
87.1 124.6 151.2
52.1 129.6 152.0
103.0 119.2 147.7
145.4 101.5 143.7
106.6 116.2 146.8
90.9 118.9 147.5
54.7 123.9 147.7
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
11b
11c
11d
11e
150.9
151.6
152.0
152.7
152.0
153.1
150.7
151.2
152.3
–
13ad)
13bd)
13cd)
13d
84.2c) 38.5
84.3c) 38.5
84.3c) 38.7
75.0
74.8
74.9
74.6
75.0
70.9
70.9
71.0
70.9
70.9
70.9
70.7
70.7
70.7
70.7
71.2
71.0
71.0
71.2
71.0
71.1
71.1
70.8
70.6
70.7
70.8
70.8
70.8
71.9
70.8
71.0
71.1
70.8
70.8
82.7c) 64.2
82.8c) 64.0
83.0c) 63.9
83.8
36.3
81.8
64.0
13ed)
84.5c) 38.8
83.1c) 64.0
9a [37] 161.0
82.9
82.5
82.9
82.9
82.8
83.1
82.7
83.1
83.2
83.1
82.8
82.4
82.7
82.9
82.7
83.4
82.5
85.5
85.1
85.5
82.7
82.2
82.7
82.8
82.7
81.7
82.2
82.0
82.8
39.4
87.1
87.3
87.5
87.5
87.4
87.5
87.6
87.7
87.7
87.6
87.3
87.4
87.5
87.6
87.5
87.2
87.2
87.3
87.4
87.6
87.1
87.3
87.5
87.5
87.5
86.8
87.3
87.8
87.2
61.9
61.9
61.9
61.8
61.8
61.8
61.7
61.6
61.6
61.6
62.1
61.9
61.9
62.0
61.9
62.0
62.1
61.4
61.4
61.4
61.8
61.8
61.7
61.7
61.7
62.1
62.0
61.6
61.8
e
9b
9c
9d
161.6
161.5
161.3
161.0
152.1
152.0
150.6
151.6
151.3
155.2
155.5
155.7
155.7
155.2
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
)
e
98.1
99.4
e
e
9e
101.9
104.0
93.9
101.6
103.0
105.6
102.7
92.7
e
10a
10b
10c
10d
10e
17a
17b
17c
17d
17e
e
e
e
e
e
e
e
99.9
e
101.5
102.8
92.6
e
e
4a [24] 153.9
4b 153.5
5a [37] 150.7
100.8 118.9 152.6
f
f
e
)
144.2 100.6
)
99.4
89.5
96.3
101.3
91.0
103.1 117.6 138.0
145.7 99.9 134.8
40.0
e
5b
5c
150.5
150.6
)
)
e
107.3 114.7 137.9
99.9 121.6 152.6
142.7 104.4 146.3
103.6 119.2 153.6
87.3 121.8 153.4
52.6 127.1 152.9
6a [17] 150.3
38.5
e
6b
6c
6d
6e
7b
8
153.8
149.4
149.9
150.6
160.5
159.5
151.2
160.1
)
)
)
)
)
)
)
)
e
98.5
99.6
101.8
86.2
98.9
116.6
e
e
e
144.0
99.2 149.1
e
141.8 105.3 149.6
e
14
18
100.3 129.4 151.7
f
f
e
)
142.6 102.7
)
a) Measured in (D6)DMSO at 258. b) First heading row ¼ purine numbering, second heading row ¼
systematic numbering. c) Tentative. d) Measured in CDCl3 at 258. e) Superimposed by DMSO signal.
f) Not detected.
1
19F,13C couplings indicate a J(C(7),FꢁC(7)) value of ca. 250 Hz for all fluorinated
2
2
compounds, and J(C(8),FꢁC(7)) and J(C(5),FꢁC(7)) amount to ca. 25 and 15 Hz,
respectively. Moreover, for some compounds, i.e., 6b, 8, 9b – 10b, 13b, and 17b, long-
3
3
range couplings J(C(4),FꢁC(7)) and J(C(6),FꢁC(7)) are observed (Table 5). The

1096
Helvetica Chimica Acta – Vol. 91 (2008)
Fig. 3. 13C-NMR Chemical shift of C(5), C(7), and C(8) vs. halogen-substituent electronegativity for a)
compounds 6b – 6e, and b) compounds 10b – 10e. Chemical-shift data from Table 4 and electronegativity
data from [30].
Table 5. J(C,F) and J(C,H) Coupling Constants of 7-Halogenated Nucleosidesa)b)
1J(C(7),FꢁC(7)) 2J(C(8),FꢁC(7)) 2J(C(5),FꢁC(7)) 3J(C(4),FꢁC(7)) 3J(C(6),FꢁC(7))
d
d
4b 245.9
5b 245.6
6b 246.2
7b 243.5
25.8
26.9
26.8
26.9
27.4
27.2
26.8
25.7
21.7
26.8
24.7
16.4
16.7
16.5
16.9
15.9
16.4
15.8
14.3
14.9
14.0
16.0
)
)
)
)
d
d
3.1
2.8
1.7
1.7
3.0
3.2
d
)
8
247.5
3.7
3.1
2.8
9b 246.1
10b 247.6
11b 247.1
13bc) 255.7
17b 245.4
d
d
)
)
4.2
3.4
1.4
2.8
d
d
18
245.5
)
)
1J(C(8),HꢁC(8)) 2J(C(7),HꢁC(8)) 3J(C(4),HꢁC(8)) 3J(C(4),HꢁC(1’)) 3J(C(8),HꢁC(1’))
d
10b 194.0
)
8.6
2.6
5.0
10d 196.1
3.5
8.2
2.5
4.8
3J(C(5),HꢁC(8)) 4J(C(6),HꢁC(8)) 1J(C(1’),HꢁC(1’)) 1J(C(4’),HꢁC(4’)) 1J(C(3’),HꢁC(3’))
10b 6.2
3.9
167.4
147.7
148.6
10d 6.9
4.1
167.2
147.3
149.1
a) Data taken from measurements in (D6)DMSO at 258. b) Data are given in Hz. c) Data taken from
measurements in CDCl3 at 258. d) Not detected.
gated-decoupled spectra of 10b and 10d showed a three-bond coupling of the
heterocyclic C(8) with the anomeric HꢁC(1’) with 3J (C(8),HꢁC(1’)) of 5.0 (10b) and
4.8 (10d) Hz. Furthermore, the angular C-atom C(4) is coupled with HꢁC(8) by
3J(C(4),HꢁC(8) values of 8.6 (10b) and 8.2 (10d) Hz. Therefore, position C(7) is
1
confirmed as halogenation site. J(C,H) coupling constants of sugar C-atoms are also

Helvetica Chimica Acta – Vol. 91 (2008)
1097
given in Table 5. The coupling constant for C(1’) is ca. 20 Hz larger than that of C(4’)
and C(3’), due to the electron-withdrawing effect of the base moiety, a phenomenon
observed in ribonucleosides by Seela and Bussmann [53]. For further coupling
constants, see Table 5.
Conclusions. – A 7-fluoro substituent was introduced to 2,6-dichloro-7-deazapurine
by Selectfluor affording a mixture 11b/11c of the fluorinated and chlorinated
nucleobases. It was not possible to perform the fluorination reaction without formation
of the 7-chloro compound 11c as by-product. As this mixture was difficult to separate,
nucleobase-anion glycosylation reaction was performed with 11b/11c yielding a mixture
of the nucleosides 13b/13c. The 2-chloro and 6-chloro substituents were displaced under
simultaneous deprotection of the sugar moiety yielding a series of 7-deazapurine
nucleosides related to 2-amino-2’-deoxyadenosine, 2’-deoxyxanthosine, and 2’-deoxy-
isoguanosine. The 7-fluorination induces instability of the nucleosides. Therefore, much
milder conditions have to be used in these cases to avoid the decomposition of the
molecules. Other halogen substituents were introduced to the same base, and various
new 7-chloro, 7-bromo, and 7-iodo derivatives were synthesized. The 7-halogen
substituents decrease the basicity of the 7-deazapurine nucleosides and bias the sugar
conformation towards N, while UV/VIS data show an auxochromic effect of the
halogen substituents. NMR Studies confirmed the halogenation position and showed
that the chemical shifts of C(5), C(7), and C(8) have an almost linear dependency on
the electronegativity of the halogen substituents.
Experimental Part
General. All chemicals were purchased from Acros, Fluka, or Sigma-Aldrich. Solvents were distilled
from technical-grade solvents. The used petroleum ether had b.p. 40 – 608. Quartz reactor: 30-W
germicidal lamp (Philips, Netherlands). In the irradiation reaction, the light was passed through a 2-mm
layer of 20% AcOH to avoid transmission below 230 nm. TLC: aluminium sheets, silica gel (SiO2) 60
F254 (0.2 mm; VWR International, Darmstadt, Germany). Flash chromatography (FC): 0.4 bar, SiO2 60
(VWR International). M.p.: Electrothermal 9200; not corrected. UV Spectra: U-3200 UV/VIS
spectrometer (Hitachi, Japan); lmax (e) in nm. NMR Spectra: Avance-PX-50 or -DPX-300 spectrometers
(Bruker, Germany); d values in ppm rel. to Me4Si as internal standard, J values in Hz. Elemental
analyses: Mikroanalytisches Laboratorium Beller, Gçttingen, Germany. ESI-TOF-MS: MicrOTOF
Bruker Daltonics spectrometer; electropositive mode; in m/z.
2,4-Dichloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (11b). To a suspension of 11a [41] (1.13 g,
6 mmol) and Selectfluor (3.18 g, 9 mmol) in anh. MeCN (60 ml) was added glacial AcOH (6 ml). The
mixture was kept stirring at 608 and became clear gradually. After 5 h, the mixture was cooled to r.t. and
diluted with CH2Cl2 (150 ml). The org. layer was washed with 5% aq. NaHCO3 soln., dried (Na2SO4),
and concentrated and the residue subjected to FC (SiO2, 15 ꢀ 2.5 cm column, CH2Cl2/AcOEt 15 :1): 11b/
11c (0.67 g, ca. 54%) as colorless solid which was used for the next step without further purification. An
anal. sample (100 mg) of 11b/11c was purified by HPLC (RP-18 column (250 ꢀ 4 mm), MeCN/buffer 3 :7
(buffer: 0.1m Et3NH · OAc (pH 7.0)/MeCN 95 :5), flow rate 0.7 ml/min). The fractions containing 11b
were concentrated, and the residue was subjected to FC (SiO2, 8 ꢀ 2.5 cm column, CH2Cl2/AcOEt 15 :1):
11b (60 mg) as colorless solid which was recrystallized from CH2Cl2. Colorless needles. M.p. 2348. TLC
(SiO2, CH2Cl2/AcOEt 15 :1): Rf 0.46. UV (MeOH): 230 (35400), 273 (3800), 302 (3900). 1H-NMR
((D6)DMSO): 7.76 (s, HꢁC(6)); 12.71 (s, HꢁN(7)). 19F-NMR ((D6)DMSO): ꢁ 170.58. Anal. calc. for
C6H2Cl2FN3 (206.00): C 34.98, H 0.98, N 20.40; found: C 35.42, H 1.03, N 19.95.

1098
Helvetica Chimica Acta – Vol. 91 (2008)
2,4,5-Trichloro-7H-pyrrolo[2,3-d]pyrimidine (11c). To a soln. of 11a [41] (261 mg, 1.39 mmol) in anh.
DMF (4 ml) was added N-chlorosuccinimide (NCS; 278 mg, 2.09 mmol). The mixture was stirred at r.t.
for 2 d. The soln. was concentrated and the residue subjected to FC (SiO2, 8 ꢀ 2.5 cm column), CH2Cl2/
AcOEt 15 :1): 11c (203 mg, 6%) as colorless solid which was recrystallized from CH2Cl2. Colorless
needles. M.p. 2258. TLC (SiO2, CH2Cl2/AcOEt 15 :1): Rf 0.46. UV (MeOH): 234 (27900), 274 (3300),
1
305 (3100). H-NMR ((D6)DMSO): 7.95 (s, HꢁC(6)); 12.94 (s, HꢁN(7)). Anal. calc. for C6H2Cl3N3
(222.46): C 32.39, H 0.91, N 18.89; found: C 32.60, H 1.03, N 18.90.
5-Bromo-2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (11d). To a suspension of 11a [41] (564 mg,
3 mmol) in CH2Cl2 (20 ml) was added N-bromosuccinimide (NBS; 640 mg, 3.6 mmol). The suspension
was stirred at r.t. overnight (TLC: complete conversion to 11d). The solid was filtered and washed with
CH2Cl2 (3 ml) to afford 11d as pale yellow solid (320 mg). The filtrate was evaporated and the residue
subjected to FC (SiO2, column 8 ꢀ 2.5 cm, CH2Cl2/AcOEt 15 :1) to afford another 230 mg of 11d as
colorless solid. The combined solid gave 550 mg (69%) of 11d which was recrystallized from CH2Cl2.
Colorless needles. M.p. 2268. TLC (SiO2, CH2Cl2/AcOEt 15 :1): Rf 0.48. UV (MeOH): 234 (29400), 273
(3200), 307 (2900). 1H-NMR ((D6)DMSO): 7.98 (s, HꢁC(6)); 13.18 (s, HꢁN(7)). Anal. calc. for
C6H2BrCl2N3 (266.91): C 27.00, H 0.76, N 15.74; found: C 27.12, H 0.80, N 15.75.
2,4-Dichloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (11e). As described for 11d, with 11a [41] (200 mg,
1.06 mmol), CH2Cl2 (10 ml), and N-iodosuccinimide (NIS; 287 mg 1.28 mmol): 11e (288 mg, 87%) as
colorless solid which was recrystallized from CH2Cl2. Colorless needles. M.p. 2248. TLC (SiO2, CH2Cl2/
AcOEt 15 :1): Rf 0.49. UV (MeOH): 238 (27600), 272 (3500), 312 (2600). 1H-NMR ((D6)DMSO): 7.96
(s, HꢁC(6)); 13.14 (s, HꢁN(7)). Anal. calc. for C6H2Cl2IN3 (313.91): C 22.96, H 0.64, N 13.39; found: C
23.05, H 0.70, N 13.50.
2,4-Dichloro-7-[2-deoxy-3,5-bis-O-(4-methylbenzoyl)-b-d-erythro-pentofuranosyl]-5-fluoro-7H-pyr-
rolo[2,3-d]pyrimidine (13b). To a stirred suspension of powdered KOH (35 mg, 80%, 0.5 mmol) and
TDA-1 (0.01 ml, 0.03 mol) in MeCN (3 ml), 11b (50 mg, 0.24 mmol) was added. After 5 min stirring, 2-
deoxy-3,5-bis-O-(4-methylbenzoyl)-a-d-erythro-pentofuranosyl chloride (12) [43] (116 mg, 0.3 mmol)
was added within 15 min ( ! thick suspension). Stirring was continued for another 10 min, the mixture
filtered, and the solid washed with MeCN (2 ml). The filter cake and the funnel were washed with CH2Cl2
(20 ml). The CH2Cl2 soln. was concentrated affording 13b as colorless solid. Recrystallization from
AcOEt/petroleum ether gave 13b (80 mg, 60%). Colorless needles M.p. 2058. TLC (SiO2, petroleum
ether/AcOEt 6 :1): Rf 0.24. UV (MeOH): 235 (52500), 274 (4900), 309 (3500). 1H-NMR (CDCl3): 2.43
(s, Me); 2.45 (s, Me); 2.62 – 2.83 (m, 2 HꢁC(2’)); 4.60 – 4.75 (m, HꢁC(4’), 2 HꢁC(5’)); 5.70 – 5.72 (m,
HꢁC(3’)); 6.80 (t, J ¼ 6.8, HꢁC(1’)); 7.14 (s, HꢁC(6)); 7.19 – 7.98 (m, 8 arom. H). 19F-NMR (CDCl3):
165.93. Anal. calc. for C27H22Cl2FN3O5 (558.38): C 58.08, H 3.97, N 7.53; found: C 58.01, H 4.00, N 7.52.
2,4,5-Trichloro-7-[2-deoxy-3,5-bis-O-(4-methylbenzoyl)-b-d-erythro-pentofuranosyl]-7H-pyrro-
lo[2,3-d]pyrimidine (13c). As described for 13b, with 11c (900 mg, 4.05 mmol), 12 [43] (2.04 g,
5.25 mmol), KOH (840 mg, 80%, 12 mmol), and TDA-1 (0.15 ml, 0.47 mmol): 13c as colorless needles
(1.7 g, 73%) after recrystallization from AcOEt/petroleum ether. M.p. 1678. TLC (SiO2, petroleum ether/
1
AcOEt 6 :1): Rf 0.25. UV (MeOH): 237 (61500), 304 (3900). H-NMR (CDCl3): 2.43 (s, Me); 2.45 (s,
Me); 2.63 – 2.82 (m, 2 HꢁC(2’)); 4.60 – 4.78 (m, 2 HꢁC(4’), 2 HꢁC(5’)); 5.70 – 5.71 (m, HꢁC(3’)); 6.75
(t, J ¼ 6.5, HꢁC(1’)); 7.37 (s, HꢁC(6)); 7.27 – 7.98 (m, 8 arom. H). Anal. calc. for C27H22Cl3N3O5 (574.84):
C 56.41, H 3.86, N 7.31; found: C 56.33, H 3.80, N 7.22.
5-Bromo-2,4-dichloro-7-[2-deoxy-3,5-bis-O-(4-methylbenzoyl)-b-d-erythro-pentofuranosyl]-7H-
pyrrolo[2,3-d]pyrimidine (13d). As described for 13b, with 11d (295 mg, 1.1 mmol), 12 [43] (556 mg,
1.43 mmol), KOH (154 mg, 80%, 2.2 mmol), and TDA-1 (0.02 ml, 0.06 mmol): 13d as colorless needles
(500 mg, 73%) after recrystallization from AcOEt/petroleum ether. M.p. 1788. TLC (SiO2, petroleum
ether/AcOEt 6 :1): Rf 0.26. UV (MeOH): 238 (55400), 273 (4800), 305 (3900). 1H-NMR ((D6)DMSO):
2.36 (s, Me); 2.39 (s, Me); 2.74 – 2.80 (m, HaꢁC(2’)); 3.02 – 3.10 (m, HbꢁC(2’)); 4.57 – 4.64 (m, HꢁC(4’),
2 HꢁC(5’)); 5.72 – 5.73 (m, HꢁC(3’)); 6.67 (t, J ¼ 6.6, HꢁC(1’)); 7.28 – 7.94 (m, 8 arom. H); 8.23 (s,
HꢁC(6)). Anal. calc. for C27H22BrCl2N3O5 (619.29): C 52.36, H 3.58, N 6.79; found: C 52.48, H 3.68, N
6.65.
2,4-Dichloro-7-[2-deoxy-3,5-bis-O-(4-methylbenzoyl)-b-d-erythro-pentofuranosyl]-5-iodo-7H-pyr-
rolo[2,3-d]pyrimidine (13e). As described for 13b, with 11e (460 mg, 1.47 mmol), 12 [43] (683 mg,

Helvetica Chimica Acta – Vol. 91 (2008)
1099
1.76 mmol), KOH (210 mg, 80%, 3 mmol), and TDA-1 (0.02 ml, 0.06 mmol): 13e as colorless needles
(700 mg, 71%) from AcOEt/petroleum ether. M.p. 1858. TLC (SiO2, petroleum ether/AcOEt 6 :1): Rf
0.27. UV (MeOH): 240 (52500), 310 (3000). 1H-NMR (CDCl3): 2.43 (s, Me); 2.45 (s, Me); 2.63 – 3.01 (m,
2 HꢁC(2’)); 4.61 – 4.79 (m, 2 HꢁC(4’), 2 HꢁC(5’)); 5.72 – 5.73 (m, HꢁC(3’)); 6.76 (t, J ¼ 6.5, HꢁC(1’));
7.55 (s, HꢁC(6)); 7.27 – 7.98 (m, 8 arom. H). Anal. calc. for C27H22BrCl2N3O5 (666.29): C 48.67, H 3.33, N
6.31; found: C 48.54, H 3.33, N 6.18.
Glycosylationof 11b/11c to 13b/13c. As described for 13b, with 11b/11c (800 mg), 12 [43] (2.48 g,
6.39 mmol), KOH (560 mg, 80%, 8 mmol), and TDA-1 (0.1 ml, 0.3 mmol): 13b/13c (1.62 g). Colorless
solid which was used for the next steps (see below) without further purification.
2-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (6a). A sus-
pension of 13a [25] (540 mg, 1 mmol) in NH3/MeOH (100 ml; sat. at 08) was introduced into an autoclave
and stirred at 1008 overnight. The clear soln. was concentrated to give a solid residue which was subjected
to FC (SiO2, 10 ꢀ 2.5 cm column, CH2Cl2/MeOH (20 :1 ! 10 :1). The obtained colorless solid, was
recrystallized from MeOH/CH2Cl2: 6a (250 mg, 88%). Colorless crystals. Anal. data: identical to those
published earlier [25].
2,5-Dichloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (6c). As
described for 6a, with 13c (480 mg, 0.84 mmol) and NH3/MeOH (80 ml). FC and recrystallization of the
obtained colorless solid from MeOH/CH2Cl2 afforded 6c (225 mg, 84%). Colorless crystals. M.p. 1958
1
(dec.). TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.33. UV (MeOH): 280 (10500). H-NMR ((D6)DMSO):
2.13 – 2.22 (m, HaꢁC(2’)); 2.36 – 2.47 (m, HbꢁC(2’)); 3.45 – 3.57 (m, 2 HꢁC(5’)); 3.79 – 3.80 (m,
HꢁC(4’)); 4.30 – 4.31 (m, HꢁC(3’)); 4.94 (t, J ¼ 5.4, OHꢁC(5’)); 5.29 (d, J ¼ 4.2, OHꢁC(3’)); 6.40 (t, J ¼
6.80, HꢁC(1’)); 7.34 (br. s, NH2); 7.59 (s, HꢁC(6)). Anal. calc. for C11H12Cl2N4O3 (319.14): C 41.40, H
3.79, N 17.56; found: C 40.97, H 3.72, N 17.78.
2-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-4-amine
(6b) and 2,5-Dichloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
(6c). As described for 6a, with 13b/13c (730 mg) and NH3/MeOH (120 ml; sat. at 08). FC (SiO2, 12 ꢀ
2.5 cm column, CH2Cl2/MeOH 20 :1 ! 10 :1) resulted in two compounds. The slower-migrating zone
yielded 6b as colorless solid (240 mg) which was recrystallized from MeOH/CH2Cl2. Colorless crystals.
M.p. 2128. TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.28. UV (MeOH): 279 (9800). 1H-NMR ((D6)DMSO):
2.14 – 2.17 (m, HaꢁC(2’)); 2.32 – 2.37 (m, HbꢁC(2’)); 3.50 (m, 2 HꢁC(5’)); 3.78 – 3.79 (m, HꢁC(4’));
4.28 – 4.29 (m, HꢁC(3’)); 4.91 (t, J ¼ 5.3, OHꢁC(5’)); 5.28 (d, J ¼ 3.6, OHꢁC(3’)); 6.42 (t, J ¼ 6.9,
HꢁC(1’)); 7.27 (s, HꢁC(6)); 7.52 (br. s, NH2). 19F-NMR ((D6)DMSO): ꢁ 167.03. Anal. calc. for
C11H12ClFN4O3 (302.69): C 43.65, H 4.00, N 18.51; found: C 43.65, H 4.01, N 18.30.
The faster-migrating zone yielded 6c (100 mg). Anal. data: identical to those shown above.
5-Bromo-2-chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine
(6d). As described for 10a, with 13d (300 mg, 0.48 mmol) and NH3/MeOH (80 ml). FC resulted in a
colorless solid which was recrystallized from MeOH/CH2Cl2: 6d (145 mg, 83%). Colorless crystals. M.p.
1778 (dec.). TLC (SiO2 , CH2Cl2/MeOH 10 :1): Rf 0.36. UV (MeOH): 281 (5800). 1H-NMR
((D6)DMSO): 2.14 – 2.19 (m, HaꢁC(2’)); 2.37 – 2.45 (m, HbꢁC(2’)); 3.45 – 3.58 (m, 2 HꢁC(5’)); 3.79 –
3.80 (m, HꢁC(4’)); 4.30 – 4.31 (m, HꢁC(3’)); 4.94 (t, J ¼ 5.3, OHꢁC(5’)); 5.29 (d, J ¼ 3.9, OHꢁC(3’));
6.40 (t, J ¼ 6.7, HꢁC(1’)); 7.24 (br. s, NH2); 7.64 (s, HꢁC(6)). Anal. calc. for C11H12BrClN4O3 (363.59): C
36.34, H 3.33, N 15.41; found: C 36.41, H 3.20, N 15.41.
2-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (6e).
As described for 6a, with 13e (350 mg, 0.53 mmol) and NH3/MeOH (80 ml). FC yielded a colorless solid
which was recrystallized from MeOH/CH2Cl2: 6e (180 mg, 83%). Colorless crystals. M.p. 1738 (dec.).
1
TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.36. UV (MeOH): 283 (10500). H-NMR ((D6)DMSO): 2.14 –
2.18 (m, HaꢁC(2’)); 2.40 – 2.45 (m, HbꢁC(2’)); 3.45 – 3.56 (m, 2 HꢁC(5’)); 3.79 – 3.80 (m, HꢁC(4’));
4.30 – 4.31 (m, HꢁC(3’)); 4.93 (t, J ¼ 5.0, OHꢁC(5’)); 5.28 (d, J ¼ 4.0, OHꢁC(3’)); 6.38 (t, J ¼ 6.8,
HꢁC(1’)); 7.22 (br. s, NH2); 7.67 (s, HꢁC(6)). Anal. calc. for C11H12ClIN4O3 (410.60): C 32.18, H 2.95, N
13.65; found: C 32.20, H 2.80, N 13.65.
4-Amino-7-(2-deoxy-b-d-erythro-pentofuranosyl)-5-fluoro-3,7-dihydro-2H-pyrrolo[2,3-d]pyrimidin-
2-one (4b). A soln. of 6b (91 mg, 0.3 mmol) in 0.1% aq. NH3 soln. (200 ml) was irradiated in a quartz
reactor for 1 h. The soln. was concentrated to 20 ml and subjected to a Serdolit-AD-4 column (20 ꢀ 2 cm).

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Helvetica Chimica Acta – Vol. 91 (2008)
The resin was washed with H2O (200 ml) followed by H2O/i-PrOH 9 :1 (200 ml). The nucleoside-
containing fractions were combined and evaporated to give 4b (30 mg, 35%). Brownish solid. TLC
(SiO2, i-PrOH/H2O/NH3OH (25%) 7:2 :1): Rf 0.63. UV (MeOH): 225 (19100), 258 (5600), 290 (4100).
1H-NMR ((D6)DMSO): 2.00 – 2.07 (m, HaꢁC(2’)); 2.20 – 2.27 (m, HbꢁC(2’)); 3.47 – 3.50 (m, 2
HꢁC(5’)); 3.73 – 3.74 (m, HꢁC(4’)); 4.24 – 4.25 (m, HꢁC(3’)); 4.99 (br. s, OHꢁC(5’)); 5.21 (br. s,
OHꢁC(3’)); 6.27 (t, J ¼ 6.4, HꢁC(1’)); 6.87 (s, HꢁC(6)); 7.39 (br. s, NH2); 7.67 (s, HꢁC(6)); 10.81 (br. s,
NH).19F-NMR ((D6)DMSO): ꢁ 167.73. ESI-TOF-MS: 285.0996 ([M þ 1]þ, C11H14FN4Oþ4 ; calc.
285.0999).
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-2,4-dimethoxy-7H-pyrrolo[2,3-d]pyrimidine (9a). A sus-
pension of 13a [25] (370 mg, 0.68 mmol) in 0.5m MeONa (10 ml) was introduced into an autoclave and
stirred at 608 overnight. The clear mixture was concentrated and the residue subjected to FC (SiO2, 10 ꢀ
2.5 cm column, CH2Cl2/MeOH 20 :1): 9a (160 mg, 79%). Colorless solid. Anal. data: identical to those
published earlier [37].
5-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-2,4-dimethoxy-7H-pyrrolo[2,3-d]pyrimidine (9c).
As described for 9a, with 13c (350 mg, 0.61 mmol) and 0.5m MeONa (20 ml). FC gave 9c as colorless
solid (180 mg, 89%). TLC (SiO2, CH2Cl2/MeOH 20 :1): Rf 0.24. UV (MeOH): 223 (27200), 264 (5900),
274 (6100). 1H-NMR ((D6)DMSO): 2.14 – 2.19 (m, HaꢁC(2’)); 2.42 – 2.51 (m, HbꢁC(2’)); 3.47 – 3.54 (m,
2 HꢁC(5’)); 3.79 – 3.80 (m, HꢁC(4’)); 3.91 (s, MeO); 4.00 (s, MeO); 4.33 (s, HꢁC(3’)); 4.93 (t, J ¼ 5.4,
OHꢁC(5’)); 5.30 (d, J ¼ 4.0, OHꢁC(3’)); 6.47 (t, J ¼ 6.7, HꢁC(1’)); 7.55 (s, HꢁC(6)). Anal. calc. for
C13H16ClN3O5 (329.74): C 47.35, H 4.89, N 12.74; found: C 47.41, H 4.80, N 12.65.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-5-fluoro-2,4-dimethoxy-7H-pyrrolo[2,3-d]pyrimidine (9b)
and 5-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-2,4-dimethoxy-7H-pyrrolo[2,3-d]pyrimidine (9c).
As described for 9a, with 13b/13c (600 mg) and 0.5m MeONa (20 ml). FC resulted in two colorless
compounds. The slower-migrating zone gave 9b (232 mg) as colorless solid. TLC (SiO2, CH2Cl2/MeOH
20 :1): Rf 0.24. UV (MeOH): 223 (29200), 269 (20100). 1H-NMR ((D6)DMSO): 2.14 – 2.20 (m,
HaꢁC(2’)); 2.37 – 2.46 (m, HbꢁC(2’)); 3.47 – 3.53 (m, 2 HꢁC(5’)); 3.79 – 3.81 (m, HꢁC(4’)); 3.91 (s,
MeO); 4.00 (s, MeO); 4.31 – 4.33 (m, HꢁC(3’)); 4.92 (t, J ¼ 5.3, OHꢁC(5’)); 5.29 (d, J ¼ 3.8,
OHꢁC(3’)); 6.52 (t, J ¼ 6.2, HꢁC(1’)); 7.33 (d, J ¼ 1.8, HꢁC(6)). 19F-NMR ((D6)DMSO): ꢁ 167.73.
Anal. calc. for C13H16FN3O5 (313.28): C 49.84, H 5.15, N 13.41; found: C 49.73, H 5.10, N 13.33.
The faster-migrating zone gave 9c (80 mg). Anal. data: identical to those reported above.
5-Bromo-7-(2-deoxy-b-d-erythro-pentofuranosyl)-2,4-dimethoxy-7H-pyrrolo[2,3-d]pyrimidine (9d).
As described for 9a, with 13d (200 mg, 0.32 mmol) and 0.5m MeONa (20 ml). FC gave 9d as colorless
solid (100 mg, 83%). TLC (SiO2, CH2Cl2/MeOH 20 :1): Rf 0.25. UV (MeOH): 223 (27200), 261 (6100),
275 (6300). 1H-NMR ((D6)DMSO): 2.13 – 2.21 (m, HaꢁC(2’)); 2.49 – 2.53 (m, HbꢁC(2’)); 3.46 – 3.58 (m,
2 HꢁC(5’)); 3.80 – 3.82 (m, HꢁC(4’)); 3.92 (s, MeO); 4.01 (s, MeO); 4.39 (s, HꢁC(3’)); 4.94 (t, J ¼ 5.1,
OHꢁC(5’)); 5.29 (d, J ¼ 3.6, OHꢁC(3’)); 6.50 (t, J ¼ 8.4, HꢁC(1’)); 7.59 (s, HꢁC(6)). Anal. calc. for
C13H16BrN3O5 (374.19): C 41.73, H 4.31, N 11.23; found: C 41.82, H 4.22, N 11.22.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-5-iodo-2,4-dimethoxy-7H-pyrrolo[2,3-d]pyrimidine (9e).
As described for 9a, with 13e (240 mg, 0.36 mmol) and 0.5m MeONa (20 ml). FC gave 9e as colorless
solid (140 mg, 92%). TLC (SiO2, CH2Cl2/MeOH 20 :1): Rf 0.25. UV (MeOH): 223 (33400), 262 (7300),
275 (7700). 1H-NMR ((D6)DMSO): 2.14 – 2.19 (m, HaꢁC(2’)); 2.45 – 2.55 (m, HbꢁC(2’)); 3.43 – 3.54 (m,
2 HꢁC(5’)); 3.80 – 3.82 (m, HꢁC(4’)); 3.92 (s, MeO); 4.01 (s, MeO); 4.34 – 4.35 (m, HꢁC(3’)); 4.94 (t,
J ¼ 5.2, OHꢁC(5’)); 5.30 (d, J ¼ 3.7, OHꢁC(3’)); 6.46 (t, J ¼ 6.7, HꢁC(1’)); 7.61 (s, HꢁC(6)). Anal. calc.
for C13H16IN3O5 (421.19): C 37.07, H 3.83, N 9.98; found: C 37.06, H 4.33, N 9.85.
2-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (10a)
and 2,4-Dichloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (14). A suspen-
sion of 13a [25] (300 mg, 0.56 mmol) in NH3/MeOH (30 ml, sat. at 08) was stirred at r.t. overnight. The
clear mixture was concentrated, and the residue subjected to FC (SiO2, 10 ꢀ 2.5 cm column, CH2Cl2/
MeOH 20 :1 to afford two compounds. The faster-migrating zone yielded 10a as colorless solid which was
recrystallized from MeOH/CH2Cl2: 10a (80 mg, 48%). Colorless crystals. M.p. 1858. TLC (SiO2, CH2Cl2/
1
MeOH 15 :1): Rf 0.29. UV (MeOH): 225 (21300), 270 (8500). H-NMR ((D6)DMSO): 2.19 – 2.28 (m,
HaꢁC(2’)); 2.44 – 2.55 (m, HbꢁC(2’)); 3.49 – 3.61 (m, 2 HꢁC(5’)); 3.83 – 3.84 (m, HꢁC(4’)); 4.05 (s,
MeO); 4.35 – 4.36 (m, HꢁC(3’)); 4.97 (t, J ¼ 5.4, OHꢁC(5’)); 5.36 (d, J ¼ 4.2, OHꢁC(3’)); 6.50 (t, J ¼ 7.0,

Helvetica Chimica Acta – Vol. 91 (2008)
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HꢁC(1’)); 6.61 (d, J ¼ 3.6, HꢁC(5’)); 7.67 (d, J ¼ 3.7, HꢁC(6)). Anal. calc. for C12H14ClN3O4 (299.71): C
48.09, H 4.71, N 14.02; found: C 47.99, H 4.70, N 14.10.
The second zone yielded 14 as colorless solid (50 mg, 30%) which was recrystallized from MeOH.
M.p. 1648. TLC (SiO2, CH2Cl2/MeOH 15 :1): Rf 0.28. UV (MeOH): 231 (29400), 282 (4800). 1H-NMR
((D6)DMSO): 2.26 – 2.32 (m, HaꢁC(2’)); 2.46 – 2.57 (m, HbꢁC(2’)); 3.51 – 3.63 (m, 2 HꢁC(5’)); 3.85 –
3.86 (m, HꢁC(4’)); 4.37 – 4.38 (m, HꢁC(3’)); 5.00 (t, J ¼ 5.2, OHꢁC(5’)); 5.39 (d, J ¼ 4.2, OHꢁC(3’));
6.53 (t, J ¼ 6.8, HꢁC(1’)); 6.78 (d, J ¼ 3.7, HꢁC(5)); 8.00 (d, J ¼ 3.7, HꢁC(6)). Anal. calc. for
C11H11Cl2N3O3 (304.13): C 43.44, H 3.65, N 13.82; found: C 43.40, H 3.60, N 13.95.
2,5-Dichloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (10c).
As described for 10a, with 13c (250 mg, 0.43 mmol) and NH3/MeOH (30 ml). FC resulted in a colorless
solid which was recrystallized from CH2Cl2/MeOH: 10c (124 mg, 86%). Colorless needles. M.p. 1608.
TLC (SiO2 , CH2Cl2/MeOH 15 :1): Rf 0.29. UV (MeOH): 227 (24100), 281 (6500). 1H-NMR
((D6)DMSO): 2.18 – 2.27 (m, HaꢁC(2’)); 2.41 – 2.46 (m, HbꢁC(2’)); 3.45 – 3.61 (m, 2 HꢁC(5’)); 3.82 –
3.83 (m, HꢁC(4’)); 4.07 (s, MeO); 4.33 – 4.34 (m, HꢁC(3’)); 4.96 (t, J ¼ 5.3, OHꢁC(5’)); 5.33 (d, J ¼
4.2, OHꢁC(3’)); 6.49 (t, J ¼ 6.8, HꢁC(1’)); 7.86 (s, HꢁC(6)). Anal. calc. for C12H13Cl2N3O4 (334.15):
C 43.13, H 3.92, N 12.58; found: C 43.10, H 3.86, N 12.50.
2-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-5-fluoro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine
(10b) and 2,5-Dichloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimi-
dine (10c). As described for 10a, with 13b/13c (270 mg) and NH3/MeOH (30 ml). FC afforded two
colorless compounds. The slower-migrating zone gave 10b as colorless solid (101 mg) which was
recrystallized from CH2Cl2/MeOH. Needles. M.p. 1578. TLC (SiO2, CH2Cl2/MeOH 15 :1): Rf 0.27. UV
1
(MeOH): 225 (22800), 273 (26100). H-NMR ((D6)DMSO): 2.22 – 2.26 (m, HaꢁC(2’)); 2.39 – 2.44 (m,
HbꢁC(2’)); 3.49 – 3.55 (m, 2 HꢁC(5’)); 3.80 – 3.83 (m, HꢁC(4’)); 4.05 (s, MeO); 4.32 – 4.33 (m,
HꢁC(3’)); 4.93 (s, OHꢁC(5’)); 5.31 (d, J ¼ 3.7, OHꢁC(3’)); 6.52 (t, J ¼ 6.0, HꢁC(1’)); 7.65 (s, HꢁC(6)).
19F-NMR ((D6)DMSO): ꢁ 167.07. Anal. calc. for C12H13ClFN3O4 (317.70): C 45.37, H 4.12, N 13.23;
found: C 45.36, H 4.07, N 13.12.
The faster-migrating zone yielded 10c as colorless solid (35 mg). Anal. data: identical to those
reported above.
5-Bromo-2-chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine
(10d). As described for 10a, with 13d (300 mg, 0.48 mmol) and NH3/MeOH (35 ml). FC yielded a
colorless solid which was recrystallized from CH2Cl2/MeOH: 10d (163 mg, 89%). Colorless needles M.p.
1658. TLC (SiO2, CH2Cl2/MeOH 15 :1): Rf 0.31. UV (MeOH): 228 (26600), 281 (6900). 1H-NMR
((D6)DMSO): 2.18 – 2.25 (m, HaꢁC(2’)); 2.42 – 2.49 (m, HbꢁC(2’)); 3.52 – 3.62 (m, 2 HꢁC(5’)); 3.81 –
3.83 (m, HꢁC(4’)); 4.06 (s, MeO); 4.32 – 4.33 (m, HꢁC(3’)); 4.96 (t, J ¼ 4.9, OHꢁC(5’)); 5.32 (d, J ¼
3.4, OHꢁC(3’)); 6.48 (t, J ¼ 6.6, HꢁC(1’)); 7.88 (s, HꢁC(6)). Anal. calc. for C12H13BrClN3O4 (378.61):
C 38.07, H 3.46, N 11.10; found: C 38.45, H 3.80, N 11.00.
2-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-5-iodo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine
(10e). As described for 10a, with 13e (400 mg, 0.60 mmol) and NH3/MeOH (40 ml). FC resulted in a
colorless solid which was recrystallized from CH2Cl2/MeOH: 10e (204 mg, 80%). Colorless crystals M.p.
1688 (dec.). TLC (SiO2, CH2Cl2/MeOH 15 :1): Rf 0.31. UV (MeOH): 232 (25000), 284 (5800). 1H-NMR
((D6)DMSO): 2.18 – 2.23 (m, HaꢁC(2’)); 2.42 – 2.49 (m, HbꢁC(2’)); 3.41 – 3.59 (m, 2 HꢁC(5’)); 3.82 –
3.83 (m, HꢁC(4’)); 4.06 (s, MeO); 4.32 – 4.33 (m, HꢁC(3’)); 4.96 (t, J ¼ 4.9, OHꢁC(5’)); 5.31 (d, J ¼
3.8, OHꢁC(3’)); 6.46 (t, J ¼ 6.7, HꢁC(1’)); 7.88 (s, HꢁC(6)). Anal. calc. for C12H13ClIN3O4 (424.96):
C 33.86, H 3.08, N 9.87; found: C 33.69, H 3.15, N 9.85.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-2-methoxy-4H-pyrrolo[2,3-d]pyrimidin-4-one
(17a). A suspension of 9a (100 mg, 0.35 mmol) in 2n NaOH (8 ml) was stirred under reflux for 3 h. The
clear soln. was cooled, diluted with H2O (10 ml), and neutralized with 1n aq. AcOH. The soln. was
concentrated, and the residue subjected to FC (SiO2, 8 ꢀ 2.5 cm column, CH2Cl2/MeOH 20 :1 ! 10 :1).
The obtained colorless solid was recrystallized from MeOH: 17a (85 mg, 89%). Colorless crystals. M.p.
2058 (dec.). TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.35. UV (MeOH): 255 (9500), 272 (sh, 6600).
1H-NMR ((D6)DMSO): 2.15 – 2.20 (m, HaꢁC(2’)); 2.32 – 2.40 (m, HbꢁC(2’)); 3.44 – 3.56 (m, 2
HꢁC(5’)); 3.79 – 3.80 (m, HꢁC(4’)); 3.91 (s, MeO); 4.33 – 4.34 (m, HꢁC(3’)); 4.90 (br. s, OHꢁC(5’));

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5.30 (br. s, OHꢁC(3’)); 6.34 – 6.39 (m, HꢁC(1’), HꢁC(5)); 7.13 (d, J ¼ 3.6, HꢁC(6)); 11.84 (br. s, NH).
Anal. calc. for C12H15N3O5 (281.26): C 51.24, H 5.38, N 14.94; found: C 51.33, H 3.35, N 15.00.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-5-fluoro-3,7-dihydro-2-methoxy-4H-pyrrolo[2,3-d]pyri-
midin-4-one (17b). As described for 17a, with 9b (125 mg, 0.40 mmol) and 2n NaOH (10 ml). FC
afforded a colorless solid which was recrystallized from MeOH: 17b (108 mg, 90%). Colorless crystals
M.p. 1408 (dec.). TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.33. UV (MeOH): 255 (10000), 275 (sh, 6800).
1H-NMR ((D6)DMSO): 2.12 – 2.18 (m, HaꢁC(2’)); 2.32 – 2.40 (m, HbꢁC(2’)); 3.44 – 3.50 (m, 2
HꢁC(5’)); 3.77 – 3.78 (m, HꢁC(4’)); 3.90 (s, MeO); 4.29 – 4.30 (m, HꢁC(3’)); 4.90 (t, J ¼ 4.9,
OHꢁC(5’)); 5.29 (d, J ¼ 3.3, OHꢁC(3’)); 6.36 (t, J ¼ 6.9, HꢁC(1’)); 7.06 (s, HꢁC(6)); 12.00 (br. s,
NH). 19F-NMR ((D6)DMSO): ꢁ 166.54. Anal. calc. for C12H14FN3O5 (299.26): C 48.16, H 4.72, N 14.04;
found: C 48.26, H 4.62, N 14.00.
5-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-2-methoxy-4H-pyrrolo[2,3-d]pyri-
midin-4-one (17c). As described for 17a, with 9c (100 mg, 0.30 mmol) and 2n NaOH (10 ml). FC afforded
a colorless solid which was recrystallized from MeOH: 17c (85 mg, 90%). Colorless crystals M.p. 2058
1
(dec.). TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.35. UV (MeOH): 258 (8800). H-NMR ((D6)DMSO):
2.16 – 2.18 (m, HaꢁC(2’)); 2.35 – 2.44 (m, HbꢁC(2’)); 3.43 – 3.50 (m, 2 HꢁC(5’)); 3.77 – 3.78 (m,
HꢁC(4’)); 3.90 (s, MeO); 4.29 – 4.30 (m, HꢁC(3’)); 4.92 (t, J ¼ 4.9, OHꢁC(5’)); 5.29 (d, J ¼ 3.2,
OHꢁC(3’)); 6.36 (t, J ¼ 6.9, HꢁC(1’)); 7.27 (s, HꢁC(6)); 12.00 (br. s, NH). Anal. calc. for C12H14ClN3O5
(315.71): C 45.65, H 4.47, N 13.31; found: C 45.51, H 4.70, N 13.15.
5-Bromo-7-(2-deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-2-methoxy-4H-pyrrolo[2,3-d]pyri-
midin-4-one (17d). As described for 17a, with 9d (150 mg, 0.40 mmol) and 2n NaOH (12 ml). FC
afforded a colorless solid which was recrystallized from MeOH: 17d (125 mg, 87%). Colorless crystals
M.p. 2128 (dec.). TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.38. UV (MeOH): 259 (9500), 276 (sh, 7600).
1H-NMR ((D6)DMSO): 2.14 – 2.18 (m, HaꢁC(2’)); 2.39 – 2.45 (m, HbꢁC(2’)); 3.48 – 3.54 (m, 2
HꢁC(5’)); 3.79 – 3.80 (m, HꢁC(4’)); 3.91 (s, MeO); 4.30 – 4.31 (m, HꢁC(3’)); 4.93 (t, J ¼ 5.1,
OHꢁC(5’)); 5.29 (d, J ¼ 3.5, OHꢁC(3’)); 6.36 (t, J ¼ 7.0, HꢁC(1’)); 7.32 (s, HꢁC(6)); 12.00 (br. s,
NH). Anal. calc. for C12H14BrN3O5 (360.16): C 40.02, H 3.92, N 11.67; found: C 40.10, H 3.65, N 11.65.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-3,7-dihydro-5-iodo-2-methoxy-4H-pyrrolo[2,3-d]pyri-
midin-4-one (17e). As described for 13a, with 9e (210 mg, 0.5 mmol) and 2n NaOH (20 ml). FC afforded
a colorless solid which was recrystallized from MeOH: 17e (150 mg, 74%). Colorless crystals. M.p. 1968
1
(dec.). TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.41. UV (MeOH): 261 (8400), 277 (sh, 6800). H-NMR
((D6)DMSO): 2.15 – 2.18 (m, HaꢁC(2’)); 2.40 – 2.49 (m, HbꢁC(2’)); 3.45 – 3.54 (m, 2 HꢁC(5’)); 3.79 –
3.80 (m, HꢁC(4’)); 3.90 (s, MeO); 4.31 – 4.32 (m, HꢁC(3’)); 4.92 (t, J ¼ 5.2, OHꢁC(5’)); 5.29 (d, J ¼
3.6, OHꢁC(3’)); 6.36 (dd, J ¼ 6.1, 7.9, HꢁC(1’)); 7.34 (s, HꢁC(6)); 11.96 (br. s, NH). Anal. calc. for
C12H14IN3O5 (407.16): C 35.40, H 3.47, N 10.32; found: C 35.36, H 3.58, N 10.15.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-5-fluoro-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
(5b). From 17b. To a soln. of 17b (100 mg, 0.33 mmol) in MeCN (20 ml) were added NaI (60 mg,
0.4 mmol) and Me3SiCl (76 ml, 0.6 mmol) at r.t. while stirring. Stirring was continued for 1 h. The reaction
was stopped by addition of MeOH (5 ml), and the soln. was concentrated. The residue was subjected to
FC (SiO2, 2 ꢀ 10 cm column, CH2Cl2/MeOH 20 :1 and 10 :1): 5b (63 mg, 66%). Pale yellow solid.
From 18. As described above, with 18 (80 mg, 0.27 mmol), MeCN (20 ml), NaI (30 mg, 0.2 mmol),
and Me3SiCl (40 ml, 0.31 mmol). FC afforded compound 5b (52 mg, 68%). Pale yellow solid. TLC (SiO2,
CH2Cl2/MeOH 20 :1 ! 10 :1): Rf 0.18. UV (0.1m NaH2PO4 buffer, pH 7.0): 253 (8400), 285 (5300).
1H-NMR ((D6)DMSO): 2.14 – 2.26 (m, 2 HꢁC(2’)); 3.46 – 3.56 (m, 2 HꢁC(5’)); 3.80 (d, J ¼ 2.6,
HꢁC(4’)); 4.28 – 4.29 (m, HꢁC(3’)); 5.26 (d, J ¼ 3.5, OHꢁC(3’)); 5.38 (br. s, OHꢁC(5’)); 6.11 (t, J ¼ 6.8,
HꢁC(1’)); 6.89 (s, HꢁC(6)); 10.76 (s, NH); 11.85 (br. s, NH). 19F-NMR ((D6)DMSO): ꢁ 167.28. ESI-
TOF-MS: 308.0656 ([M þ Na]þ, C11H12FN3NaO5þ ; calc. 308.0659).
5-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-1H-pyrrolo[2,3-d]pyrimidine-2,4(3H,7H)-dione
(5c). As described for 5b, with 17c (80 mg, 0.25 mmol), MeCN (20 ml), NaI (40 mg, 0.26 mmol), and
Me3SiCl (70 ml, 0.55 mmol). FC resulted in 5c (50 mg, 65%). Pale yellow solid. TLC (SiO2, CH2Cl2/
MeOH 10 :1): Rf 0.19. UV (0.1m NaH2PO4 buffer, pH 7.0): 256 (8000), 285 (5100). 1H-NMR
((D6)DMSO): 2.11 – 2.32 (m, 2 HꢁC(2’)); 3.52 – 3.62 (m, 2 HꢁC(5’)); 3.81 – 3.82 (m, HꢁC(4’)); 4.29 –

Helvetica Chimica Acta – Vol. 91 (2008)
1103
4.30 (m, HꢁC(3’)); 5.29 (d, J ¼ 3.5, OHꢁC(3’)); 6.13 (t, J ¼ 6.8, HꢁC(1’)); 7.10 (s, HꢁC(6)); 10.76 (s,
NH); 11.58 (br. s, NH). ESI-TOF-MS: 324.0361 ([M þ Na]þ, C11H12ClN3NaO5þ ; calc. 324.0363).
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (7b)
and 4-Chloro-7-(2-deoxy-b-d-erythro-pentofuranosyl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidin-2-amine
(8). A suspension of 15 [14] (800 mg, 1.28 mmol) in NH3/MeOH (150 ml; sat. at 08) was introduced
into an autoclave and stirred at 708 for 5 d. The clear soln. was concentrated and the residue subjected to
FC (SiO2, 13 ꢀ 2.5 cm column, CH2Cl2/MeOH 20 :1 ! 10 :1): 16 [38] (80 mg, 21%), 8, and 7b. The
slowest-migrating zone gave 7b as a pale yellow solid (120 mg, 33%) which was recrystallized from
MeOH/CH2Cl2: light yellow crystals. M.p. 1808 (dec.). TLC (SiO2, CH2Cl2/MeOH 5 :1): Rf 0.45. UV
1
(MeOH): 233 (19100), 266 (10500), 289 (sh, 6900). H-NMR ((D6)DMSO): 1.99 – 2.05 (m, HaꢁC(2’));
2.23 – 2.34 (m, HbꢁC(2’)); 3.34 – 3.47 (m, 2 HꢁC(5’)); 3.71 – 3.72 (m, HꢁC(4’)); 4.24 – 4.25 (m,
HꢁC(3’)); 4.96 (s, OHꢁC(5’)); 5.18 (d, J ¼ 3.6, OHꢁC(3’)); 5.79 (s, NH2); 6.38 (t, J ¼ 6.9, HꢁC(1’));
6.54 (s, NH2); 6.82 (s, HꢁC(6)). 19F-NMR ((D6)DMSO): ꢁ 168.15 (FꢁC(5)). Anal. calc. for
C11H14FN5O3 (283.26): C 46.64, H 4.98, N 24.72; found: C 46.72, H 5.02, N 24.58.
The second migrating zone yielded 8 as colorless solid (100 mg, 26%). Recrystallization from
MeOH/CH2Cl2 gave colorless crystals. M.p. 1658. TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.30. UV
1
(MeOH): 233 (19100), 285 (7500). H-NMR ((D6)DMSO): 2.08 – 2.14 (m, HaꢁC(2’)); 2.30 – 2.36 (m,
HbꢁC(2’)); 3.46 – 3.51 (m, 2 HꢁC(5’)); 3.74 – 3.79 (m, HꢁC(4’)); 4.28 – 4.30 (m, HꢁC(3’)); 4.92 (t, J ¼
5.4, OHꢁC(5’)); 5.26 (d, J ¼ 3.7, OHꢁC(3’)); 6.45 (t, J ¼ 6.9, HꢁC(1’)); 6.94 (s, NH2); 7.32 (d, J ¼ 1.77,
HꢁC(6)). 19F-NMR ((D6)DMSO): ꢁ 170.23. Anal. calc. for C11H12ClFN4O3 (302.69): C 43.65, H 4.00, N
18.51; found: C 43.97, H 3.72, N 18.21.
7-(2-Deoxy-b-d-erythro-pentofuranosyl)-5-fluoro-3,7-dihydro-4-methoxy-2H-pyrrolo[2,3-d]pyri-
midin-2-one (18). To a soln. of 16 [14] (150 mg, 0.5 mmol) in 10% aq. AcOH soln. (25 ml), a soln. of
NaNO2 (83 mg, 1.2 mmol) in H2O (4 ml) was added dropwise while stirring. Stirring was continued for
20 min. The soln. was neutralized with 2n NaOH under cooling and concentrated. The residue was
subjected to FC (SiO2, 8 ꢀ 2.5 cm column, CH2Cl2/MeOH 20 :1 ! 10 :1): 18 (94 mg, 63%). Colorless
solid. TLC (SiO2, CH2Cl2/MeOH 10 :1): Rf 0.29. UV (MeOH): 222 (24300), 248 (5200), 285 (5900).
1H-NMR ((D6)DMSO): 2.13 – 2.17 (m, HaꢁC(2’)); 2.26 – 2.33 (m, HbꢁC(2’)); 3.49 – 3.53 (m, 2
HꢁC(5’)); 3.75 – 3.78 (m, HꢁC(4’)); 3.97 (s, MeO); 4.28 – 4.30 (m, HꢁC(3’)); 5.25 (br. s, OHꢁC(3’),
OHꢁC(5’)); 6.41 (t, J ¼ 6.6, HꢁC(1’)); 7.19 (s, HꢁC(6)). 19F-NMR ((D6)DMSO): ꢁ 167.78. Anal. calc.
for C12H14FN3O5 (299.26): C 48.16, H 4.72, N 14.04; found: C 47.98, H 4.71, N 13.98.
We thank Dr. Simone Budow and Mrs. Padmaja Chittepu for the NMR spectra. We also thank Dr.
Peter Leonard for helpful discussions. We gratefully acknowledge financial support by Roche Diagnostics
GmbH, Penzberg, and ChemBiotech, Münster, Germany.
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Received January 23, 2008