C-Functionalization of 9-deazapurines by cross-coupling reactions

Article abstract of DOI:10.1016/j.tet.2006.12.008

C-Functionalization of pyrrolo[3,2-d]pyrimidine scaffold in positions 2, 4, and 7 using cross-coupling reactions was performed. Thus, 2-(5-(benzyloxymethyl)-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethanol, a versatile synthetic precursor for 9-deazapurines and?4,6-diazaindoles, was prepared by vinylation of the corresponding iodide followed by hydroboration of the double bond. A synthesis of 9-(1,2-dihydroxyethyl)-9-deazaadenine, a 9-deaza-1′-nor congener to antiviral DHPA, was developed. In addition, an abnormal regioselectivity in methylalumination of the terminal triple bond in position 7 of the pyrrolo[3,2-d]pyrimidine scaffold leading to a transformation into (Z)-prop-1-enyl was observed.

Full text of DOI:10.1016/j.tet.2006.12.008

Tetrahedron 63 (2007) 1589–1601
C-Functionalization of 9-deazapurines by cross-coupling reactions
*
ˇ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Vıtezslav Bambuch, Miroslav Otmar, Radek Pohl, Milena Masojıdkova and Antonın Holy
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
Flemingovo naꢀm. 2, 166 10 Prague 6, Czech Republic
Received 8 September 2006; revised 23 November 2006; accepted 7 December 2006
Abstract—C-Functionalization of pyrrolo[3,2-d]pyrimidine scaffold in positions 2, 4, and 7 using cross-coupling reactions was performed.
Thus, 2-(5-(benzyloxymethyl)-2,4-dichloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethanol, a versatile synthetic precursor for 9-deazapurines
and 4,6-diazaindoles, was prepared by vinylation of the corresponding iodide followed by hydroboration of the double bond. A synthesis
of 9-(1,2-dihydroxyethyl)-9-deazaadenine, a 9-deaza-10-nor congener to antiviral DHPA, was developed. In addition, an abnormal regio-
selectivity in methylalumination of the terminal triple bond in position 7 of the pyrrolo[3,2-d]pyrimidine scaffold leading to a transformation
into (Z)-prop-1-enyl was observed.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
syntheses or are limited only to a very narrow category of
compatible substituents. Therefore, our aim is to assess the
possibilities of routine C-functionalization of pyrrolo[3,2-d]-
pyrimidines by cross-coupling reactions. Our special interest
lies in an effective introduction of a 2-hydroxyethyl group
into position 7, which could enable the construction of
9-deaza congeners of acyclic nucleoside phosphonates of
PME type.21
In recent years, C-substituted purines have become an inten-
sively investigated group of compounds, resulting in some
promising findings of biological activity.1–9 The usual
synthetic approach employing cross-coupling reactions
allowed routine introduction of C-substituents into positions
6, 2, and 8. On the other hand, on 9-deazapurines (pyrrolo-
[3,2-d]pyrimidines), cross-coupling reactions were used
rarely. Only a few examples of Suzuki reaction in position
4 and Sonogashira coupling in position 7 were recently de-
scribed.10,11 However, applying the cross-coupling based
methodology to pyrrolo[3,2-d]pyrimidine scaffold is of high
interest, as many 7-C-substituted pyrrolo[3,2-d]pyrimidines
are potent inhibitors of purine nucleoside phosphorylase
(PNP) or exhibit other biological activities.12–15 Moreover,
it could open the route to a construction of 9-deaza conge-
ners of some biologically active 9-substituted purines and
4,6-diaza congeners of 3-substituted indole containing bio-
molecules. For the preparation of 7-C-substituted pyrrolo-
[3,2-d]pyrimidines, the traditional approach introduced by
Klein and co-workers based on pyrimidine ring construction
on suitably substituted pyrroles is used predominantly.16
There are also some more recent methods—reductive cycli-
zation of 6-cyanomethyl-5-nitropyrimidines,15,17 addition of
an electrophile to a carbanion18 generated by metalation in
position 7, modified Fisher indole synthesis19 as well as Frie-
del–Crafts reaction in hot trifluoromethanesulfonic acid.20
However, the approaches are either based on multiple
2. Results and discussion
2,4-Dichloro-5H-pyrrolo[3,2-d]pyrimidine22,23 (2,6-dichloro-
9-deazapurine, 1), easily available from 6-methyluracil, is an
ideal synthetic precursor for the C-functionalization reaction
(Scheme 1). On reaction with 1 equiv of phenylboronic acid
at 100 ꢀC it gave the phenyl derivative 2 with high regio-
selectivity. To assign the position of the substituent unequiv-
ocally, the remaining chlorine atom was removed by
reduction with RedAl to form compound 3. The position of
the introduced hydrogen atom was determined from proton
coupled 13C NMR spectrum, in which the spin–spin inter-
action between H-2 and C-7a is present whereas no signal
splitting corresponding to the interaction between H-4 and
C-4a was observed. It suggests that the phenyl substituent
is in position 4 and cannot be in position 2. Treatment of
compound 2 with a further equivalent of phenylboronic
acid gave the diphenyl derivative 4, with 2-naphthylboronic
acid gave the 2-(2-naphthyl) derivative 5, and with AlMe3
gave the 2-methyl derivative 6. Reactions of compound 1
with tributyl(thiophen-2-yl)stannane and benzylzinc(II) bro-
mide, respectively, are highly regioselective as well. The
products are 4-C-substituted pyrrolo[3,2-d]pyrimidines 7
and 8. The position of the substituents was assigned using
Keywords: Nucleobase; Nucleoside; 9-Deazaadenine; Carbometalation;
Carboalumination.
* Corresponding author. Tel.: +420 220 183 375; fax: +420 220 183 560;
e-mail: otmar@uochb.cas.cz
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.008

1590
V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
H,C-HMBC, wherein cross-peaks between H-3-thiophene
(8.26 ppm) and C-4a (120.2) in 7, and CH2 (4.35 ppm) and
C-4a (124.9 ppm) in 8 were observed. With the exception
of boronic acids, all the agents were used in 100% excess.
Under these conditions, the reactions were fully compatible
with the free pyrrole NH group.
alkaline conditions in cross-coupling reactions. Thus, by the
treatment of compound 1 with benzyl chloromethyl ether
and sodium hydride the protected derivative 13 was easily
obtained (Scheme 3). However, further reaction with
N-iodosuccinimide (NIS) did not give any product, even
when the reaction time was prolonged to several days. In
contrast, the inverse arrangement of those two steps led to
a satisfactory result. The reaction of unprotected compound
1 with NIS proceeded smoothly affording the 7-iodo deriva-
tive 14 in high yield. Compound 14 was then protected by
the formation of the benzyloxymethyl derivative 15.
Ph
N
Bn
N
H
N
H
N
N
N
Me
Cl
8
6
Cl
Cl
(iv)
65% (vi)
48%
N
H
N
H
N
(iii)
N
N
Ph
N
Ph
Cl
N
93%
H
N
H
H
Cl
N
Cl
N
(i)
(i)
N
N
N
I
1
14
90%
Cl
80%
79%
Ph
Cl
N
Cl
N
(i)
91%
(i)
2
4
1
(iii)
67% (v)
Cl
(ii)
73%
BOM
N
BOM
N
54%
N
Ph
(ii)
H
N
N
N
N
S
N
0%
Cl
N
Cl
N
Ph
H
H
I
N
N
N
13
15
5
Scheme 3. (i) BOM–Cl, NaH, THF, rt; (ii) NIS, THF, rt, 7 days; (iii) NIS,
THF, rt, 1 h.
N
Cl
N
3
7
Scheme 1. (i) PhB(OH)2, Pd(PPh3)4, K2CO3, toluene, 100 ꢀC, 5 h; (ii)
RedAl, toluene, 100 ꢀC, 1 h; (iii) 2-naphthylboronic acid, Pd(PPh3)4,
K2CO3, toluene, 100 ꢀC, 5 h; (iv) Me3Al, Pd(PPh3)4, THF, reflux, 8 h; (v)
tributyl(thiophen-2-yl)stannane, Pd(PPh3)4, toluene, reflux, 4 h; (vi)
BnZnBr, Pd(PPh3)4, toluene, reflux, 8 h.
As a further substrate for the cross-coupling reactions, the
4-dibenzylamino derivative 16 was designed (Scheme 4).
The reason was to increase the solubility in less polar sol-
vents and remove the chlorine atom in position 4, which
could compete with the iodine in position 7. Treatment of
compound 1 with dibenzylamine in refluxing ethanol gave
the 4-substituted derivative 17, whose free NH group was
then protected by the formation of benzyloxymethyl deriva-
tive 18. The following reaction with NIS proceeded with dif-
ficulty. Despite using a large excess of the reagent and
prolonged reaction time, the yield of compound 16 did not
exceed 50%. As in the previous case, reversing the order
of the reaction steps (via iodide 19) resulted in high overall
yield.
Initial experiments on cross-coupling reactions in position 7
were performed on N-benzyl-7-iodo-5H-pyrrolo[3,2-d]pyr-
imidin-4-amine (9) and its bromo congener 10 (Scheme 2).
However, treatment with the same agents as above did not
lead to products of C-substitution even if large excess was
used. Mostly, the product of reductive dehalogenation 11
was isolated besides the unreacted starting compounds.24
In the case of boronic acids, a small amount of the stable
ylide 12 was obtained as well. Regardless of the additional
NH group attached to position 4, the formation of the ylide
12 as well as of the dehalogenated compound 11 indicates
that the tautomerization in the pyrrole ring, if not prevented,
interferes with the formation of C-substituted product.
Therefore, it was decided to protect the 5-NH group in fur-
ther experiments.
NBn2
NBn2
Cl
H
N
H
N
H
N
(iv)
(i)
N
38%
N
N
N
95%
77%
Cl
N
Cl
N
Cl
N
I
17
19
1
(ii)
79%
(ii)
NHBn
NHBn
NHBn
NBn2
NBn2
BOM
H
BOM
N
(i)
H
N
N
N
(ii)
N
N
N
N
(iii)
N
(ii)
43%
49%
N
N
N
Cl
N
18
Cl
N
X
PPh3
11
I
12
16
9 X = I, 95%
10 X = Br, 90%
Scheme 4. (i) Bn2NH, EtOH, reflux, 4 h; (ii) BOM–Cl, NaH, THF, rt, over-
night; (iii) NIS, THF, rt, 7 days; (iv) NIS, THF, rt, 2 h.
Scheme 2. (i) NIS or NBS, THF, 1 h; (ii) PhB(OH)2, Pd(PPh3)4, K2CO3,
80 ꢀC, 8 h.
Reactivity of compound 16 in common cross-coupling reac-
tions, such as Suzuki, Stille, Sonogashira, and Negishi,
was assessed. Thus, treatment of iodide 16 with phenyl-
boronic acid, tributyl(thiophen-2-yl)stannane, ethynylbenz-
ene, and benzylzinc(II) bromide, respectively, resulted in
the formation of 7-C-substituted products 20–23 in high
A construction of the protected precursor for the cross-
coupling in position 7 from compound 1 is very attractive
due to the possibility of an easy potential nucleophilic
replacement of the chlorine atoms. As protecting group,
benzyloxymethyl was chosen, because it is stable under

V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
1591
yields (Scheme 5). The chlorine atom in position 2 was quite
inert. Again, the position of the C-substituents was con-
firmed (in addition to other evidence) by H,C-HMBC,
wherein a correlation between H-6 and substituent carbon
bound to C-7 was observed.
it was mentioned in Section 1, our special interest lays in
functionalization of position 7 with 2-hydroxyethyl group.
Therefore, we employed the regioselectivity of the Stille re-
action for the preparation of vinyl derivative 26 by reaction
with tributyl(vinyl)stannane. Hydroboration of compound
26 followed by oxidation with sodium perborate afforded
the desired 2-hydroxyethyl derivative 27. On the other
hand, the reaction of the iodide 15 with ethynylbenzene
was not selective enough giving an unseparable mixture of
monosubstituted product 28 and disubstituted product 29,
which, however, could be identified by NMR spectroscopy.
In the case of the reaction with benzylzinc(II) bromide, an
unseparable mixture of products was obtained as well.
NBn2
NBn2
BOM
N
BOM
N
N
N
Cl
N
Cl
N
Ph
S
(i)
67%
NBn2
(ii)
21
20
BOM
N
87%
N
Cl
N
NBn2
N
NBn2
(iv)
60%
BOM
N
I
BOM
N
(iii)
In contrast to ethynylbenzene, ethynyltrimethylsilane re-
acted with the iodide 15 regioselectively during the for-
mation of the 7-C-substituted product 30 (Scheme 7). The
trimethysilyl group was removed by tetrabutylammonium
fluoride to give the acetylene 31. Removal of the protecting
group by methanolic ammonia at 120 ꢀC led to the formation
of amine 32 and a small amount of 4-methoxy derivative 33.
Using ethanolic ammonia at the same temperature prevented
the formation of a 4-alkoxy derivative, however, it did not
lead to the removal of the trimethylsilyl group as well, giving
the unprotected amine 34. Compound 34 was also prepared
alternatively by the treatment of the iodide 15 with metha-
nolic ammonia followed by a reaction of the resulting amine
35 with ethynyltrimethylsilane. The trimethylsilyl group of
amine 34 was removed by tetrabutylammonium fluoride to
give the unprotected acetylene 32. Upon treatment with
borane–dimethyl sulfide complex, compound 32 did not
16
N
N
61%
Cl
Cl
N
Bn
22
23
Ph
Scheme 5. (i) PhB(OH)2, Pd(PPh3)4, K2CO3, toluene, 100 ꢀC, 5 h; (ii) tri-
butyl(thiophen-2-yl)stannane, Pd2(dba)3, CuI, AsPh3, DMF, 70 ꢀC, 1 h;
(iii) PhC^CH, Pd(PPh3)4, CuI, (i-Pr)2NEt, THF, 50 ꢀC, 2 h; (iv) BnZnBr,
Pd(PPh3)4, DMF, 75 ꢀC, 1 h.
Precursor 15 bears three potential reaction centers for cross-
coupling reactions. In comparison to compound 16, it has
a relatively reactive chlorine atom in position 4, which can
compete with the iodine in position 7. Additionally, the chlo-
rine in position 2 is more reactive than that in 16, due to the
absence of the electron donating dibenzylamino group in po-
sition 4. Hence, the question was whether the cross-coupling
reactions are selective enough to give the 7-substituted prod-
ucts even in this case. Thus, the reaction of compound 15
with phenylboronic acid and tributyl(thiophen-2-yl)stan-
nane, respectively, under the analogous conditions as above
gave the 7-C-substituted products 24 and 25 (Scheme 6). As
Cl
Cl
Cl
BOM
N
BOM
N
BOM
N
(v)
N
N
N
69%
Cl
N
Cl
Cl
N
Cl
N
I
38
(vii)
39
15
(iii)
HO
(i)
68%
68%
Cl
70%
Cl
Cl
BOM
N
BOM
N
(iv)
N
N
NH2
Cl
N
BOM
N
BOM
N
BOM
N
86%
(ii)
N
N
N
Cl
N
Cl
N
27
OH
Cl
65%
26
Cl
N
Cl
N
31
I
30
35
(i)
(iv)
(ii)
(iii)
47%
80%
SiMe3
60%
Cl
Cl
BOM
BOM
BOM
N
(iii)
+
NH2
OMe
NH2
(i)
BOM
N
N
BOM
(ii)
81%
BOM
N
N
N
N
N
N
N
N
63%
N
46%
21%
Cl
Cl
N
Cl
N
Cl
N
98%
Ph
I
Cl
N
N
Cl
N
S
15
25
24
34
33
32
Ph
(v)
45%
SiMe3
(v)
Cl
BOM
N
BOM
N
NH2
N
NH2
N
N
BOM
N
+
H
N
(vi)
89%
N
N
Cl
N
Cl
N
28%
Ph
41%
Ph
29
Cl
N
28
OH
OH
37
36
HO
HO
Scheme 6. (i) PhB(OH)2, Pd(PPh3)4, K2CO3, toluene, 95 ꢀC, 4 h; (ii) tri-
butyl(thiophen-2-yl)stannane, Pd2(dba)3, AsPh3, CuI, DMF, 50 ꢀC, 2 h;
(iii) tributyl(vinyl)stannane, Pd2(dba)3, AsPh3, CuI, DMF, 75 ꢀC, 2 h; (iv)
(1) 9-BBN, THF, 0 ꢀC to rt, 2 h; (2) NaBO3, H2O, rt, 2 h; (v) PhC^CH,
Pd(PPh3)4, CuI, Et3N, THF, 50 ꢀC, 2 h.
Scheme 7. (i) Me3SiC^CH, PdCl2(PPh3)2, CuI, Et3N, THF, rt, 2 h; (ii)
TBAF, THF, rt, 10 min; (iii) NH3 in MeOH, 120 ꢀC, 12 h; (iv) NH3 in
EtOH, 120 ꢀC, 12 h; (v) (1) BH3$SMe2, THF, 0 ꢀC to rt, 2 h; (2) NaBO3,
H2O, 2 h; (vi) H2/Pd, MeOH, rt, overnight; (vii) AlMe3, Cp2ZrCl2,
CH2Cl2, 0 ꢀC to rt, 2 h.

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V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
react unless more than 3 equiv of the reagent were added.
After oxidation with sodium perborate, a product of double
addition of borane—the diol 36 was obtained. The removal
of the protecting group and chlorine atom in position 2 by
hydrogenation led to the formation of compound 37, which
can be considered as a racemic 9-deaza-10-nor congener
of antiviral 9-(2,3-dihydroxypropyl)adenine (DHPA).25,26
However, the tests on antiviral and antiproliferative activities
were negative.
with Xe, accelerating voltage 8 kV, thioglycerol–glycerol
3:1 mixture or bis(2-hydroxyethyl) disulfide were used as
matrix). 1H and 13C NMR spectra were recorded on Bruker
Avance 400 (1H at 400 MHz and 13C at 100.6 MHz), Varian
Unity 500, and Bruker Avance 500 instruments (1H at
500 MHz and 13C at 125.7 MHz) in CDCl3 (referenced to
TMS as an internal standard) or in DMSO-d6 (referenced
to the solvent signal d¼2.50 and 39.70 ppm, respectively).
Complete assignment is based on heteronuclear correlation
experiments HSQC and H,C-HMBC. Chemical shifts are in
parts per million and coupling constants (J) in hertz. UV
spectra were taken on a Beckman DU-65 spectrophotometer
in methanol solution. IR spectra were obtained on an FTIR
Bruker Equinox IFS 55 spectrometer in chloroform or KBr
pellets. Elemental analyses were carried out on a Perkin–
Elmer CHN Analyser 2400, Series II Sys (Perkin–Elmer,
Norwolk, CT, USA).
Once having the acetylene 31, the conversion of the ethynyl
group to isopropyl was also of interest as it could open the
route to 9-deaza congeners of biologically active 9-iso-
propylpurines, e.g., myoseverin or purvalanol A. Upon treat-
ment of compound 31 with trimethylaluminum in the
presence of bis(cyclopentadienyl)zirconium dichloride, the
addition of the methyl group should, according to literature
precedent,27 take place in the a-position to the heterocycle
by a cis-mechanism. In fact, however, the methyl group
was attached to the terminal carbon of the triple bond during
the formation of the cis-olefin 38 (according Jcis(H,H)¼
11.4 Hz), which is a product of trans-addition. The trans-
mechanism as well as the opposite regioselectivity could
be explainable by a chelation-controlled isomerization28
proceeding via an aluminated intermediate, in which ni-
trogen atom in position 1 is coordinated to aluminum.
Hydroboration of the cis-olefin 38 proceeded regioselec-
tively during the formation of the racemic a-hydroxy
derivative 39.
4.1.1. 2-Chloro-4-phenyl-5H-pyrrolo[3,2-d]pyrimidine
(2). Compound 1 (940 mg, 5 mmol), phenylboronic acid
(760 mg, 6.3 mmol), potassium carbonate (900 mg,
6.5 mmol), and Pd(PPh3)4 (400 mg, 0.35 mmol) in toluene
(40 mL) were heated under argon to 100 ꢀC for 5 h. Then
the reaction mixture was taken into ethyl acetate, washed
with brine, and evaporated. Chromatography on a silica
gel column (hexanes/ethyl acetate, 4:1) followed by crystal-
lization (hexanes/ethyl acetate, 3:1) afforded compound 2
(920 mg, 80%, white crystals, mp 203–204 ꢀC). MS (FAB)
m/z (rel intensity): 232 (37, M[37Cl]+H), 230 (100,
M[35Cl]+H), 196 (22, MꢁCl+2H), 194 (9, MꢁCl). HRMS
(FAB) m/z calcd for C12H937ClN3 (M+H): 232.0455, found:
232.0496; calcd for C12H935ClN3 (M+H): 230.0485, found:
230.0452. MS (EI) m/z (rel intensity): 231 (34, M[37Cl]), 229
(100, M[35Cl]), 194 (35, MꢁCl), 154 (4, M[37Cl]ꢁPh), 152
(10, M[35Cl]ꢁPh), 77 (23, Ph). 1H NMR (500 MHz, DMSO-
d6): 12.26 (br s, 1H, NH-5), 8.05–8.07 (m, 2H, Ph), 8.02 (t,
1H, J¼2.8, H-6), 7.61–7.63 (m, 3H, Ph), 6.69 (d, 1H, J¼2.7,
H-7). 13C NMR (125.7 MHz, DMSO-d6): 153.9 (ddd,
J¼2.9, 6.8, and 9.8, C-7a), 151.2 (s, C-2), 150.0 (t, J¼3.9,
C-4), 136.6 (br dd, J¼9.8 and 188.5, C-6), 134.9 (dd,
J¼5.9 and 7.8, Ph), 131.0 (dt, J¼2ꢂ7.8 and 161.1, Ph),
129.2 (ddd, J¼3.9, 4.9, and 162.1, Ph), 128.9 (ddd, J¼5.9,
7.8, and 161.1, Ph), 122.9 (br dt, J¼2ꢂ4.4 and 7.8, C-4a),
101.5 (ddd, J¼2.9, 7.8, and 178.7, C-7). IR (CHCl3):
3465, 2997, 1609, 1600, 1539, 1421, 1369, 1257, 1173,
893, 864 cmꢁ1. UV (MeOH): 296 (11.00), 249 (12.10).
Anal. Calcd for C12H8ClN3: C, 62.76; H, 3.51; Cl, 15.44;
N, 18.30. Found: C, 61.63; H, 3.44; Cl, 15.70; N, 18.32.
3. Conclusion
To summarize, cross-coupling reactions were proven as a
very good tool for C-functionalization of pyrrolo[3,2-d]-
pyrimidine scaffold in positions 4, 2, and 7. Compound 15,
due to the widely different reactivities of its halogen atoms,
is predestined to be employed in the synthesis of 9-deaza-
purine and 4,6-diazaindole congeners of biomolecules.
The facility of introduction of the (2-hydroxy)ethyl substit-
uent into position 7 opens the route for the construction of
9-deaza congeners of acyclic nucleoside phosphonates of
PME type with various substituents in positions 4 and 2.
Finally, the abnormal carboalumination of compound 31
leading to the attachment of the methyl group to the terminal
carbon of the triple bond by trans-mechanism is a remarkable
finding, which is worth further investigating.
4. Experimental
4.1. General
4.1.2. 4-Phenyl-5H-pyrrolo[3,2-d]pyrimidine (3). To a
solution of compound 2 (230 mg, 1 mmol) in toluene
(40 mL) RedAl (65% solution in toluene, 2.5 mL, 8.3 mmol)
was added and the reaction mixture was heated to 100 ꢀC for
1 h. Water was added, the reaction mixture was taken into
toluene, and washed with water. Chromatography on a silica
gel column (chloroform/methanol, 97:3) followed by crys-
tallization (hexanes/ethyl acetate, 1:1) afforded compound
3 (105 mg, 54%, white crystals, mp 171–173 ꢀC). MS (EI)
m/z (rel intensity): 195 (100, M), 168 (26), 149 (44), 140
(29), 118 (70, MꢁPh+H), 104 (18), 89 (73), 77 (85, Ph).
1H NMR (500 MHz, DMSO-d6): 11.99 (br s, 1H, NH-5),
8.91 (s, 1H, H-2), 8.09–8.11 (m, 2H, Ph), 7.90 (br t, 1H,
J¼2.6, H-6), 7.56–7.63 (m, 3H, Ph), 6.71 (d, 1H, J¼6.71,
Melting points were determined on a Kofler block and are
uncorrected. Analytical TLC was performed on silica gel
pre-coated aluminum plates with fluorescent indicator
(Merck 5554, 60 F254). Spots were visualized with UV light
(254 nm) or by spraying with ninhydrin (1% solution in eth-
anol) followed by a short heating to 300–400 ꢀC. Column
chromatography was carried out on silica gel (Sigma
S-0507, 40–63 mm). Mass spectra were measured on a
ZAB-EQ (Micromass, Manchester, UK) spectrometer
using the EI (electron energy 70 eV) or FAB (ionization

V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
1593
H-7). 13C NMR (125.7 MHz, DMSO-d6): 151.3–151.6
(m, C-7a), 150.3 (d, J¼200.2, C-2), 147.6 (dt, J¼2ꢂ2.9
and 10.8, C-4), 136.3 (t, J¼6.8, Ph), 134.1 (dd, J¼8.8 and
185.5, C-6), 130.2 (dt, J¼2ꢂ6.8 and 161.1, Ph), 129.1 (dd,
2C, J¼6.8 and 161.1, Ph), 128.7 (dt, 2C, J¼2ꢂ6.8 and
160.2, Ph), 123.7 (ddd, J¼2.9, 5.8, and 6.8, C-4a), 101.8
(ddd, J¼3.9, 7.8, and 176.8, C-7). IR (CHCl3): 3467,
2978, 1609, 1599, 1543, 1490, 1417, 1373, 1364, 1249,
888 cmꢁ1. UV (MeOH): 289 (10.76), 245 (12.26). Anal.
Calcd for C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C,
73.96; H, 4.80; N, 21.34.
(d, 1H, J¼3.2, H-7). 13C NMR (125.7 MHz, DMSO-d6):
155.6 (t, J¼4.9, C-2), 152.6 (ddd, J¼2.9, 6.8, and 9.8),
147.7 (t, J¼4.9, C-4), 136.7 (arom.), 136.6 (arom.), 134.8
(dd, J¼7.8 and 185.6, C-6), 133.7 (arom.), 133.2 (arom.),
130.3 (arom.), 129.1 (3C, arom.), 128.9 (arom.), 128.9
(3C, arom.), 128.0 (arom.), 127.7 (arom.), 126.7 (arom.),
126.4 (arom.), 122.8 (dt, J¼3.9 and 2ꢂ6.8, C-4a), 102.2
(dd, J¼7.8 and 176.8, C-7). IR (CHCl3): 3468, 2977,
1608, 1597, 1544, 1508, 1416, 1378, 1306, 1254 cmꢁ1
.
UV (MeOH): 285 (10.92), 259 (29.34), 223 (15.50). Anal.
Calcd for C22H15N3: C, 82.22; H, 4.70; N, 13.08. Found:
C, 81.78; H, 4.83; N, 12.94.
4.1.3. 2,4-Diphenyl-5H-pyrrolo[3,2-d]pyrimidine (4). A
mixture of compound 1 (280 mg, 1.5 mmol), phenylboronic
acid (730 mg, 6 mmol), potassium carbonate (830 mg,
6 mmol), and Pd(PPh3)4 (350 mg, 0.3 mmol) in toluene
(40 mL) was heated to 100 ꢀC under argon for 5 h, then
was taken into ethyl acetate, washed with water, and evapo-
rated. Chromatography on a silica gel column (chloroform)
followed by crystallization (petroleum ether/ethyl acetate,
3:1) afforded compound 4 (320 mg, 79%) as white crystals,
mp 206–207 ꢀC. MS (FAB) m/z (rel intensity): 272 (100,
M+H), 185 (7), 93 (21). HRMS (FAB) calcd for C18H14N3
4.1.5. 2-Methyl-4-phenyl-5H-pyrrolo[3,2-d]pyrimidine
(6). To a mixture of compound 2 (230 mg, 1 mmol) and
Pd(PPh3)4 (115 mg, 0.1 mmol) in THF (10 mL) trimethyl-
aluminum solution in toluene (2 M, 1 mL) was added under
argon and the reaction mixture was heated to 75 ꢀC for 8 h.
Methanol (3 mL) followed by water (10 mL) was added and
the reaction mixture was evaporated. Chromatography on a
silica gel column (methanol/chloroform, 2:98) followed by
crystallization (petroleum ether/ethyl acetate, 2:1) afforded
compound 6 (100 mg, 48%) as yellowish crystals, mp
188–191 ꢀC. MS (EI) m/z (rel intensity): 209 (100, M),
168 (5), 140 (5), 132 (14, MꢁPh), 106 (16), 89 (12), 77
(7, Ph). HRMS (EI) calcd for C13H11N3 (M): 209.0953,
1
(M+H): 272.1188, found: 272.1155. H NMR (500 MHz,
DMSO-d6): 12.00 (br s, 1H, NH-5), 8.55 (dt, 2H, J¼2ꢂ1.4
and 7.1, Ph), 8.23 (dt, 2H, J¼2ꢂ1.4 and 6.7, Ph), 7.93 (d,
1H, J¼3.1, H-6), 7.66 (tt, 2H, J¼1.6 and 7.3, Ph), 7.61 (tt,
1H, J¼1.6 and 7.2, Ph), 7.52 (tt, 2H, J¼1.5 and 7.1, Ph),
7.45 (tt, 1H, J¼1.6 and 7.3), 6.77 (d, 1H, J¼3.1, H-7).
13C NMR (125.7 MHz, DMSO-d6): 155.6 (t, J¼3.9, C-2),
152.6 (dd, J¼2.9 and 8.8, C-7a), 147.5 (t, J¼3.9), 139.2 (t,
J¼6.8, Ph), 136.5 (t, J¼6.8, Ph), 134.6 (dd, J¼8.8 and
185.5, C-6), 130.3 (dt, J¼2ꢂ7.8 and 161.1, Ph), 129.4 (dt,
J¼2ꢂ7.8 and 160.1, Ph), 129.1 (dd, 2C, J¼7.8 and 161.1,
Ph), 128.8 (dt, 2C, J¼2ꢂ7.8 and 161.2, Ph), 128.6 (dd,
2C, J¼7.8 and 160.1, Ph), 127.6 (dt, 2C, J¼2ꢂ7.8 and
160.2, Ph), 122.7 (dd, J¼5.8 and 6.8, C-4a), 102.2 (dd,
J¼7.8 and 176.8, C-7). IR (CHCl3): 3469, 2977, 1606,
1597, 1544, 1490, 1485, 1416, 1377, 1252, 1026,
891 cmꢁ1. UV (MeOH): 257 (8.94). Anal. Calcd for
C18H13N3: C, 79.68; H, 4.83, N, 15.49. Found: C, 79.36,
H, 4.87, N, 15.17.
1
found: 209.0951. H NMR (500 MHz, DMSO-d6): 11.80
(br s, 1H, NH-5), 8.06 (d, 2H, Ph), 7.86 (t, 1H, J¼3.0,
H-6), 7.58 (m, 3H, Ph), 6.58 (dd, 1H, J¼1.7 and 3.1, H-7),
2.69 (s, 3H, CH3). 13C NMR (125.7 MHz, DMSO-d6):
158.4 (q, J¼6.8, C-2), 152.2 (ddd, J¼2.9, 6.8, and 8.8,
C-7a), 147.4 (t, J¼4.9, C-4), 136.5 (t, J¼7.8, Ph), 133.9
(ddd, J¼2.9, 8.8, and 185.6, C-6), 130.1 (dt, J¼2ꢂ7.8 and
162.1, Ph), 129.0 (dd, 2C, J¼7.8 and 160.2, Ph), 128.7 (dt,
2C, J¼2ꢂ7.8 and 160.2, Ph), 122.1 (ddd, J¼4.9, 5.9, and
6.8, C-4a), 101.2 (ddd, J¼4.9, 7.8, and 175.8, C-7), 25.8
(q, J¼127.0, CH3). IR (CHCl3): 3469, 2966, 1611, 1599,
1543, 1418, 1371, 1245, 871 cmꢁ1. UV (MeOH): 291
(9.50), 242 (11.60). Anal. Calcd for C13H11N3: C, 74.62;
H, 5.30; N, 20.08. Found: C, 74.95; H, 5.16; N, 19.68.
4.1.6. 2-Chloro-4-(thiophen-2-yl)-5H-pyrrolo[3,2-d]-
pyrimidine (7). A mixture of compound 1 (225 mg,
1.2 mmol), Pd(PPh3)4 (115 mg, 0.1 mmol), and tributyl-
(thiophen-2-yl)stannane (0.9 mg, 2.4 mmol) in toluene
(15 mL) was refluxed under argon for 4 h and then the sol-
vent was evaporated. Chromatography on a silica gel column
(chloroform) followed by crystallization (petroleum ether/
ethyl acetate, 3:1) afforded compound 7 (190 mg, 67%) as
white crystals, mp 173–175 ꢀC. MS (EI) m/z (rel intensity):
237 (37, M[37Cl or 34S]), 235 (100, M[35Cl]), 200 (41,
4.1.4. 2-(Naphthalen-2-yl)-4-phenyl-5H-pyrrolo[3,2-d]-
pyrimidine (5). A mixture of compound 2 (210 mg,
0.9 mmol), 2-naphthylboronic acid (310 mg, 1.8 mmol),
potassium carbonate (250 mg, 1.8 mmol), and Pd(PPh3)4
(115 mg, 0.1 mmol) in toluene (20 mL) was heated to
100 ꢀC under argon for 5 h, then was taken into ethyl acetate,
washed with water, and evaporated. Chromatography on a
silica gel column (methanol/chloroform, 1:99) followed by
crystallization (petroleum ether/ethyl acetate, 5:1) afforded
compound 5 (210 mg, 73%) as white crystals, mp 174–
175 ꢀC. MS (EI) m/z (rel intensity): 321 (100, M), 244 (8,
MꢁPh), 217 (9), 190 (6), 168 (6), 160 (10), 158 (10), 140
(7), 127 (21, naphthyl). HRMS (EI) calcd for C22H15N3
(M): 321.1266, found: 321.1280. 1H NMR (500 MHz,
DMSO-d6): 12.04 (br s, 1H, NH-5), 9.10 (br s, 1H, arom.),
8.72 (dd, 1H, J¼1.7 and 8.7, arom.), 8.28 (dt, 2H, J¼1.5
and 6.9, arom.), 8.12–8.14 (m, 1H, arom.), 8.02 (d, 1H,
J¼8.8, arom.), 7.96–7.98 (m, 1H, arom.), 7.96 (d, 1H,
J¼3.2, H-6), 7.68 (tt, 2H, J¼1.4 and 7.0, arom.), 7.63 (tt,
1H, J¼1.3 and 7.2, arom.), 7.54–7.57 (m, 2H, arom.), 6.82
1
MꢁCl). H NMR (500 MHz, DMSO-d6): 12.21 (br s, 1H,
NH), 8.26 (dd, 1H, J¼3.8 and 1.1, H-30), 8.03 (d, 1H,
J¼3.1, H-6), 7.93 (dd, 1H, J¼5.0 and 1.1, H-50), 7.36 (dd,
1H, J¼5.0 and 3.8, H-40), 6.66 (d, 1H, J¼3.1, H-7). 13C
NMR (125.7 MHz, DMSO-d6): 154.1 (C-7a), 150.6 (C-2),
144.1 (C-4), 139.4 (C-20), 136.3 (C-6), 131.8 (C-50), 130.4
(C-30), 129.3 (C-40), 120.2 (C-4a), 101.8 (C-7). IR
(CHCl3): 3459, 2999, 1602, 1539, 1528, 1422, 1369, 1257,
1172, 947 cmꢁ1. UV (MeOH): 333 (16.40), 267 (7.80),
233 (13.80). Anal. Calcd for C10H6ClN3S: C, 50.96; H,
2.57; Cl, 15.04; N, 17.83; S, 13.60. Found: C, 51.07; H,
2.80; Cl, 14.88; N, 17.71; S, 13.84.

1594
V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
1
4.1.7. 4-Benzyl-2-chloro-5H-pyrrolo[3,2-d]pyrimidine
(8). Benzylzinc(II) bromide (solution in THF, 0.5 M,
6 mL) was added under argon to a mixture of compound 1
(280 mg, 1.5 mmol) and Pd(PPh3)4 (115 mg, 0.1 mmol) in
toluene (20 mL), and the reaction mixture was refluxed for
8 h. Methanol (3 mL) followed by water (10 mL) was added,
the reaction mixture was taken into ethyl acetate, washed
with water, and evaporated. Chromatography on a silica gel
column (methanol/chloroform, 99:1) afforded compound 8
(230 mg, 65%) as an amorphous solid. MS (EI) m/z (rel in-
tensity): 245 (33, M[37Cl]), 244 (43), 243 (100, M[35Cl]),
242 (86, M[35Cl]ꢁH), 208 (19, MꢁCl), 206 (16). HRMS
(EI) m/z calcd for C13H10N337Cl (M[37Cl]): 245.0534,
found: 245.0538; calcd for C13H10N335Cl (M[35Cl]):
Bn), 77 (54, Ph). H NMR (500 MHz, DMSO-d6): 11.28
(br s, 1H, NH-5), 8.27 (s, 1H, H-2), 7.69 (d, 1H, J¼2.8, H-
6), 7.60 (t, 1H, J¼5.6, NH), 7.39 (d, 2H, J¼7.4, Ph), 7.34
(t, 2H, J¼7.8, Ph), 7.26 (t, 1H, J¼7.2, Ph), 4.75 (d, 2H,
J¼5.6, CH2). 13C NMR (125.7 MHz, DMSO-d6): 151.1 (d,
J¼197.3, C-2), 149.6 (dq, J¼3ꢂ3.9 and 10.7, C-4), 143.6
(ddd, J¼5.8, 7.8, and 10.7, C-7a), 139.6–139.8 (m, Ph),
128.6 (dd, 2C, J¼7.8 and 160.2, Ph), 127.8 (dm, 2C,
J¼157.2 and SJ¼21.5, Ph), 160.2 (dt, J¼2ꢂ7.8 and
160.2, Ph),127.1 (dd, J¼3.9 and 191.4, C-6), 113.9 (br d,
J¼6.8, C-4a), 89.5 (dd, J¼4.9 and 6.8, C-7), 43.6 (tt,
J¼2.9 and 138.7, CH2). IR (KBr): 3324, 3062, 1629, 1537,
1453, 1405, 1342, 1026, 893, 693 cmꢁ1. UV (MeOH):
286 (12.64), 277 (12.50), 241 (20.16). Anal. Calcd for
C13H11BrN4: C, 51.50; H, 3.66; Br, 26.36; N, 18.48. Found:
C, 51.32; H, 3.67; Br, 26.32; N, 18.30.
1
243.0563, found: 243.0514. H NMR (500 MHz, DMSO-
d6): 12.40 (br s, 1H, NH), 8.04 (t, 1H, J¼2.9, H-6), 7.60
(m, 1H, Ph), 7.40–7.15 (m, 4H, Ph), 6.60 (dd, 1H, J¼2.9
and 1.3, H-7), 4.35 (s, 2H, CH2). 13C NMR (125.7 MHz,
DMSO-d6): 154.1 (C-4), 152.3 (C-7a), 151.0 (C-2), 137.7
(Ph), 135.5 (C-6), 129.1 (2C, Ph), 128.7 (2C, Ph), 126.8
(Ph), 124.9 (C-4a), 101.3 (C-7), 38.8 (CH2). IR (CHCl3):
3451, 2995, 1607, 1539, 1498, 1455, 1421, 1370, 1242,
925, 704 cmꢁ1. UV (MeOH): 280 (6.70). Anal. Calcd for
C13H11N3: C, 64.07; H, 4.14; Cl, 14.55; N, 17.24. Found:
C, 64.25; H, 4.16; Cl, 14.37; N, 17.11.
4.1.10. N-Benzyl-7-(triphenylphosphoranylidene)-7H-
pyrrolo[3,2-d]pyrimidin-4-amine (12). A mixture of com-
pound 9 (200 mg, 0.5 mmol), phenylboronic acid (180 mg,
1.5 mmol), potassium carbonate (210 mg, 1.5 mmol), and
Pd(PPh3)4 (115 mg, 0.1 mmol) in dioxane/water mixture
(4:1, 10 mL) was heated to 80 ꢀC under argon for 8 h and
the solvent was evaporated. Chromatography on a silica
gel column (methanol/chloroform, 1:20) followed by crys-
tallization (petroleum ether/ethyl acetate, 2:1) afforded
unstable compound 12 (105 mg, 43%) as white crystals,
mp 220–230 ꢀC, which decomposes spontaneously (com-
pletely within several days) to N-benzyl-5H-pyrrolo[3,2-d]-
pyrimidin-4-amine and triphenylphosphine. MS (EI) m/z (rel
intensity): 484 (31, M), 407 (5, MꢁPh), 393 (3, MꢁBn), 379
(7, MꢁBnNH+H), 351 (13), 275 (18), 262 (4, PPh3), 217 (4),
183 (20), 129 (10), 108 (13, PPh), 91 (31, Bn), 73 (29), 55
(53), 43 (100). HRMS (EI) calcd for C31H25N4P (M):
4.1.8. N-Benzyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-
4-amine (9). Compound 11 (325 mg, 1.25 mmol) and N-
iodosuccinimide (340 mg, 1.5 mmol) were stirred in THF
(10 mL) for 1 h and the solvent was evaporated. Chromato-
graphy on a silica gel column (methanol/chloroform, 2:98)
followed by crystallization (petroleum ether/ethyl acetate,
3:1) afforded compound 9 (115 mg, 95%) as white crystals,
mp 219–220 ꢀC. MS (EI) m/z (rel intensity): 350 (59, M),
333 (7), 245 (16, MꢁBnNH+H), 224 (27, MꢁI+H), 119
(17), 106 (100, BnNH), 91 (52, Bn). HRMS (EI) calcd for
C13H11N4I (M): 350.0028, found: 350.0017. 1H NMR
(500 MHz, DMSO-d6): 8.46 (br t, 1H, J¼5.6, NH), 8.36
(s, 1H, H-2), 7.79 (s, 1H, H-6), 7.36 (d, 2H, J¼7.5, Ph),
7.33 (t, 2H, J¼7.5, Ph), 7.26 (t, 1H, J¼7.5, Ph), 4.78 (d,
2H, J¼5.6, CH2). 13C NMR (125.7 MHz, DMSO-d6):
149.9 (dq, J¼3ꢂ3.9 and 10.7, C-4), 149.6 (d, J¼201.2,
C-2), 143.6 (t, J¼8.8, C-7a), 138.9–139.1 (m, Ph), 132.6
(d, J¼192.4, C-6), 128.6 (dd, 2C, J¼7.8 and 160.2, Ph),
127.5 (dtt, 2C, J¼2ꢂ3.9, 2ꢂ7.8, and 157.2, Ph), 127.3 (dt,
J¼2ꢂ7.8 and 161.1, Ph), 114.2 (d, J¼6.8, C-4a), 55.6 (d,
J¼6.8, C-7), 43.7 (tt, J¼3.9 and 138.7, CH2). IR (KBr):
3303, 3087, 1627, 1533, 1441, 1402, 1340, 1017, 693,
655 cmꢁ1. UV (MeOH): 286 (12.78), 277 (13.30), 243
(20.74). Anal. Calcd for C13H11IN4: C, 44.59; H, 3.17; I,
36.24; N, 16.00. Found: C, 44.43; H, 3.11; I, 36.40; N, 15.82.
1
484.1817, found: 484.1736. H NMR (500 MHz, CDCl3):
8.37 (s, 1H, H-2), 7.68–7.76 (m, 9H, Ph), 7.57–7.60 (m,
6H, Ph), 7.47 (d, 2H, J¼5.0, Ph), 7.30 (t, 2H, J¼4.5, Ph),
7.22 (t, 1H, J¼4.5, Ph), 7.18 (d, 1H, J¼1.6, H-6), 6.96
(br, 1H, NH), 4.88 (d, 2H, J¼5.7, CH2). 13C NMR
(125.7 MHz, CDCl3): 153.1 (C-4), 151.3 (C-2), 150.5 (d,
JCP¼8.3, C-7a), 144.6 (br d, JCP¼15.1, C-6), 139.4 (Ph),
133.8 (d, JCP¼10.7, PPh3), 133.8 (d, JCP¼4.9, PPh3),
129.6 (d, JCP¼13.2, PPh3), 128.4 (2C, Ph), 127.7 (2C,
arom.), 126.9 (Ph), 122.5 (d, JCP¼92.3, PPh3), 58.8 (d,
JCP¼125.3, C-7), 44.3 (CH2). 31P NMR (80.98 MHz,
CDCl3): 18.12 (s). IR (KBr): 3430, 1626, 1603, 1438,
1188, 1110, 703 cmꢁ1
.
4.1.11. 5-(Benzyloxymethyl)-2,4-dichloro-5H-pyr-
rolo[3,2-d]pyrimidine (13). Sodium hydride (60% disper-
sion in mineral oil, 150 mg, 3.75 mmol) was added to
compound 1 (600 mg, 3.2 mmol) in THF (15 mL) and the
mixture was sonicated for 1 h. Benzyl chloromethyl ether
(1 mL, 5.7 mmol) was added, the reaction mixture was
stirred for 24 h and the solvent was evaporated. Chromato-
graphy on a silica gel column (chloroform) afforded com-
pound 13 (900 mg, 91%) as a colorless oil. MS (EI) m/z
(rel intensity): 309 (12, M[37Cl, 35Cl]), 307 (18, M[35Cl,
35Cl]), 279 (8), 277 (15), 203 (16, M[37Cl, 35Cl]ꢁBnO+H),
201 (22, M[35Cl, 35Cl]ꢁBnO+H), 108 (44, BnOH), 91 (100,
Bn). 1H NMR (400 MHz, CDCl3): 7.60 (d, 1H, J¼3.3, H-6),
7.37–7.20 (m, 5H, Ph), 6.65 (d, 1H, J¼3.3, H-7), 5.79 (s, 2H,
N–CH2–O), 4.51 (s, 2H, CH2–O). 13C NMR (100.6 MHz,
4.1.9. N-Benzyl-7-bromo-5H-pyrrolo[3,2-d]pyrimidin-
4-amine (10). Compound 11 (725 mg, 2.8 mmol) and N-
bromosuccinimide (570 mg, 3.2 mmol) were stirred in THF
(30 mL) for 1 h and the solvent was evaporated. Chromato-
graphy on a silica gel column (methanol/chloroform, 2:98)
followed by crystallization (petroleum ether/ethyl acetate,
3:1) afforded compound 10 (755 mg, 90%) as white crystals,
mp 257–260 ꢀC. MS (EI) m/z (rel intensity): 304 (18,
M[81Br]), 302 (20, M[79Br]), 199 (9, M[81Br]ꢁBnN), 198
(7), 197 (8, M[79Br]ꢁBnN), 196 (7), 172 (7), 144 (7), 131
(8), 117 (26, MꢁBnNHꢁBr), 106 (69, BnNH), 91 (100,

V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
1595
CDCl3): 155.0 (C-7a), 150.8 (C-2), 143.3 (C-4), 138.5
(CH-6), 135.9 (C–i-Ph), 128.5, 128.1, 127.6 (CH–Ph),
122.9 (C-4a), 103.3 (CH-7), 76.6 (N–CH2–O), 70.4 (CH2–
O). IR (CHCl3): 3139, 3112, 3090, 3068, 1591, 1524,
1455, 1384, 1096. UV (MeOH): 282 (4.30). Anal. Calcd
for C14H11Cl2N3O: C, 54.57; H, 3.60; N, 13.64, Cl, 23.01.
Found: C, 54.64; H, 3.65; N, 13.23; Cl, 22.91.
on a silica gel column (ethyl acetate/hexanes, 1:4) followed
by crystallization (ethyl acetate/hexanes, 1:9) afforded
compound 16 (1.5 g, 79%) as yellowish crystals, mp 114–
116 ꢀC. MS (FAB) m/z (rel intensity): 597 (6, M[37Cl]+H),
1
595 (18, M[35Cl]+H), 91 (100, Bn). H NMR (400 MHz,
CDCl3): 7.52 (s, 1H, H-6), 7.31–7.04 (m, 15H, 3Ph); 5.60
(s, 2H, N–CH2–O), 4.51 (s, 4H, CH2–N), 4.28 (s, 2H,
CH2–O). 13C NMR (100.6 MHz, CDCl3): 155.4 (C-4),
154.7 (C-7a), 152.7 (C-2), 138.9 (CH-6), 136.2, 135.9
(C–i-Ph), 128.6, 128.5, 128.5, 128.3, 127.7, 127.5 (CH–Ph),
117.6 (C-4a), 77.0 (N–CH2–O), 71.0 (CH2–O), 60.5 (C-7),
53.2 (CH2–N). IR (CHCl3): 3089, 3012, 2929, 1587, 1571,
1527, 1497, 1455, 1332, 1029, 907. UV (MeOH): 305
(10.50), 260 (8.65). Anal. Calcd for C28H24ClIN4O: C,
56.53; H, 4.07; Cl, 5.96; N, 9.42. Found: C, 57.02; H,
4.17; Cl, 5.92; N, 9.64.
4.1.12. 2,4-Dichloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine
(14). Compound 1 (250 mg, 1.3 mmol) and N-iodosuccin-
imide (340 mg, 1.5 mmol) were stirred in THF (15 mL) for
1 h and the solvent was evaporated. Chromatography on a
silica gel column (methanol/chloroform, 1:99) followed by
crystallization (ethyl acetate/hexanes, 1:4) afforded com-
pound 14 (390 mg, 93%) as yellowish crystals, mp 231–
233 ꢀC. MS (EI) m/z (rel intensity): 317 (10, M[37Cl,
37Cl]), 315 (65, M[37Cl, 35Cl]), 313 (100, M[35Cl, 35Cl]),
35
35
280 (10, M[37Cl, 35Cl]ꢁ Cl), 278 (33, M[35Cl, 35Cl]ꢁ Cl),
4.1.14.2. Method B. Compound 18 (890 mg, 1.5 mmol)
and N-iodosuccinimide (1.0 g, 4.45 mmol) were stirred in
THF (10 mL) for 7 days and the solvent was evaporated.
Chromatography on a silica gel column (ethyl acetate/
hexanes, 1:4) followed by crystallization (ethyl acetate/hex-
anes, 9:1) afforded compound 16 (560 mg, 49%) as yellow-
ish crystals, mp 114–116 ꢀC.
1
243 (31, Mꢁ2Cl). H NMR (500 MHz, DMSO-d6): 13.18
(br s, 1H, NH), 8.28 (s, 1H, H-6). 13C NMR (125.7 MHz,
DMSO-d6): 153.1 (C-7a), 149.5 (C-2), 143.1 (C-4), 140.6
(CH-6), 124.1 (C-4a), 57.9 (C-7). IR (KBr): 3108, 3081,
3030, 1613, 1518, 1487, 1378, 1269, 910, 878. UV (MeOH):
282 (6.75), 239 (20.70). Anal. Calcd for C6H2N3Cl2I: C,
22.96; H, 0.64; N, 13.39; Cl, 22.59. Found: C, 23.25; H,
0.71; N, 13.16; Cl, 21.79.
4.1.15. N,N-Dibenzyl-2-chloro-5H-pyrrolo[3,2-d]pyrimi-
din-4-amine (17). Compound 1 (380 mg, 2 mmol) and di-
benzylamine (1.25 mL, 6.5 mmol) were refluxed in ethanol
(15 mL) for 4 h and the reaction mixture was evaporated.
Chromatography on a silica gel column (methanol/chloro-
form, 1:99) followed by crystallization (petroleum ether/
ethyl acetate, 5:1) afforded compound 16 (540 mg, 77%)
as white crystals, mp 138–139 ꢀC. MS (EI) m/z (rel inten-
sity): 350 (1.6, M[37Cl]), 348 (4, M[35Cl]), 259 (37,
M[37Cl]ꢁBn), 257 (100, M[35Cl]ꢁBn), 221 (6), 194 (5),
154 (7, M[37Cl]ꢁBn2N), 152 (18, M[35Cl]ꢁBn2N), 118
(15, MꢁBn2NꢁCl+H), 91 (79, Bn), 77 (8, Ph). HRMS
(EI) calcd for C20H1735ClN4 (M): 348.1142, found:
4.1.13. 5-(Benzyloxymethyl)-2,4-dichloro-7-iodo-5H-
pyrrolo[3,2-d]pyrimidine (15). Sodium hydride (60%
dispersion in mineral oil, 800 mg, 20 mmol) was added to
compound 14 (5 g, 16 mmol) in THF/DMF mixture (1:1,
80 mL) and the mixture was sonicated for 1 h. Benzyl
chloromethyl ether (2.8 mL, 20 mmol) was added and the
reaction mixture was stirred overnight. The solvent was eva-
porated, the residue was taken into ethyl acetate, and washed
with water. Chromatography on a silica gel column (ethyl
acetate/hexanes, 1:4) followed by crystallization (ethyl
acetate/hexanes, 1:9) afforded compound 15 (6.2 g, 90%)
as white crystals, mp 116–118 ꢀC. MS (EI) m/z (rel inten-
sity): 435 (16, M[37Cl, 35Cl]), 433 (25, M[35Cl, 35Cl]), 405
(15, M[37Cl, 35Cl]ꢁCH2O), 403 (25, M[35Cl, 35Cl]ꢁCH2O),
329 (24, M[37Cl, 35Cl]ꢁBnO), 327 (36, M[35Cl,
1
348.1155. H NMR (400 MHz, DMSO-d6): 11.35 (br s,
1H, NH-5), 7.53 (d, 1H, J¼2.9, H-6), 7.31–7.34 (m, 4H,
Ph), 3.25–7.28 (m, 6H, Ph), 6.41 (d, 1H, J¼2.9, H-7), 4.92
(s, 4H, CH2). 13C NMR (100.6 MHz, DMSO-d6): 151.8–
151.9 (m, C-7a), 151.3 (p, J¼2.9, C-4a), 150.4 (s, C-2),
137.5 (m, 2C, Ph), 130.4 (dd, J¼7.8 and 185.6, C-6),
128.7 (dd, 4C, J¼7.8 and 160.2, Ph), 127.5 (dm, 4C,
J¼161.1, Ph), 127.4 (dt, 2C, J¼2ꢂ7.8 and 161.1, Ph),
111.6 (t, J¼6.8, C-4a), 101.5 (dd, J¼7.8 and 176.7, C-7),
50.0 (tp, 2C, J¼4ꢂ3.9 and 2ꢂ138.7, CH2). IR (KBr):
3435, 1593, 1584, 1530, 1352, 941, 700 cmꢁ1. UV
(MeOH): 293 (13.54), 242 (16.04). Anal. Calcd for
C20H17ClN4: C, 68.86; H, 4.91; Cl, 10.16; N, 16.06. Found:
C, 69.08; H, 4.99; Cl, 10.32; N, 15.55.
1
35Cl]ꢁBnO), 91 (100, Bn). H NMR (400 MHz, CDCl3):
7.64 (s, 1H, H-6), 7.38–7.19 (m, 5H, Ph), 5.80 (s, 2H, N–
CH2–O), 4.55 (s, 2H, CH2–O). 13C NMR (100.6 MHz,
CDCl3): 155.2 (C-7a), 151.9 (C-2), 143.7 (C-4), 141.7
(CH-6), 135.7 (C–i-Ph), 128.6, 128.4, 127.6 (CH–Ph),
123.3 (C-4a), 77.0 (N–CH2–O), 70.6 (CH2–O), 58.4 (C-7).
IR (CHCl3): 3122, 3090, 3069, 1586, 1518, 1498, 1455,
1380, 1094. UV (MeOH): 321 (2.00), 285 (3.85), 243
(12.90). Anal. Calcd for C14H10Cl2IN3O: C, 38.74; H,
2.32; Cl, 16.34; N, 9.68. Found: C, 39.02; H, 2.52; Cl,
16.05; N, 9.47.
4.1.16. N,N-Dibenzyl-5-(benzyloxymethyl)-2-chloro-5H-
pyrrolo[3,2-d]pyrimidin-4-amine (18). Sodium hydride
(60% dispersion in mineral oil, 400 mg, 10.0 mmol) was
added to compound 17 (1.8 g, 5 mmol) in THF (15 mL)
and the mixture was sonicated for 1 h. Benzyl chloromethyl
ether (1.6 mL, 9.0 mmol) was added, the reaction mixture
was stirred for 24 h, and the solvent was evaporated. Chro-
matography on a silica gel column (ethyl acetate/hexanes,
1:9) followed by crystallization (ethyl acetate/hexanes,
4:1) afforded compound 18 (890 mg, 38%) as white crystals,
4.1.14. N,N-Dibenzyl-5-(benzyloxymethyl)-2-chloro-7-
iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine (16).
4.1.14.1. Method A. Sodium hydride (60% dispersion
in mineral oil, 170 mg, 3.8 mmol) was added to compound
19 (1.5 g, 3.2 mmol) in THF (18 mL) and the mixture was
sonicated for 1 h. Benzyl chloromethyl ether (0.7 mL,
4.0 mmol) was added and the reaction mixture was stirred
overnight. The solvent was evaporated, the residue was taken
into ethyl acetate, and washed with water. Chromatography

1596
V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
mp 84–86 ꢀC. MS (EI) m/z (rel intensity): 469 (4,
M[35Cl]+H), 409 (5), 407 (12), 379 (35, M[37Cl]ꢁBn), 378
(25), 377 (100, M[35Cl]ꢁBn), 349 (8, M[37Cl]ꢁCH2OBn),
347 (22, M[35Cl]ꢁCH2OBn), 271 (9), 269 (23), 91 (95,
4.1.19. N,N-Dibenzyl-5-(benzyloxymethyl)-2-chloro-7-
(thiophen-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(21). Tributyl(thiophen-2-yl)stannane (0.1 mL, 0.3 mmol)
was added under argon to a mixture of compound 16
(150 mg, 0.25 mmol), triphenylarsine (9.2 mg, 0.03 mmol),
copper(I) iodide (5.7 mg, 0.03 mmol), and Pd2(dba)3
(7.8 mg, 0.0075 mmol) in DMF (2 mL). The reaction mix-
ture was heated to 70 ꢀC for 1 h, solvent was evaporated,
the residue was taken into ethyl acetate, and washed with
water. Chromatography on a silica gel column (hexanes/ethyl
acetate, 4:1) followed by crystallization (hexanes/ethyl
acetate, 9:1) afforded compound 21 (120 mg, 87%) as white
crystals, mp 148–150 ꢀC. MS (EI) m/z (rel intensity):
552 (16, M[37Cl]), 551 (15), 550 (33, M[35Cl]), 461
(23, M[37Cl]ꢁBn), 459 (58, M[35Cl]ꢁBn), 431 (32,
M[37Cl]ꢁBnOMe), 429 (76, M[35Cl]ꢁBnOMe), 91 (100,
Bn). 1H NMR (400 MHz, CDCl3): 7.76 (dd, 1H, J¼3.6 and
1.2, H-30), 7.62 (s, 1H, H-6), 7.35–7.22 (m, 11H, 2Ph+H50),
7.16–7.05 (m, 6H, Ph+H40), 5.64 (s, 2H, N–CH2–O),
4.51 (s, 4H, CH2–N), 4.29 (s, 2H, CH2–O). 13C NMR
(100.6 MHz, CDCl3): 155.4 (C-4), 152.2 (C-2), 151.4
(C-7a), 136.4 (C–i-NBn), 136.0 (C–i-OBn), 133.3 (C-20),
130.9 (CH-6), 128.6, 128.5, 128.5, 127.7, 127.6 (CH–
Ph+CH-40), 124.7 (CH-30), 123.4 (CH-50), 118.1 (C-4a),
113.8 (C-7), 76.8 (N–CH2–O), 70.8 (CH2–O), 53.1 (CH2–
N). IR (CHCl3): 3089, 3067, 3033, 1597, 1564, 1527,
1496, 1380, 1103, 933. UV (MeOH): 281 (6.10). Anal. Calcd
for C32H27ClN4OS: C, 69.74; H, 4.94; N, 10.70; Cl, 6.43.
Found: C, 69.68; H, 4.83; N, 10.77; Cl, 6.57.
1
Bn). H NMR (500 MHz, CDCl3): 7.45 (d, 1H, J¼3.3, H-
6), 7.06–7.36 (m, 15H, 3Ph), 6.65 (d, 1H, J¼3.3, H-7), 5.62
(s, 2H, N–CH2–O), 4.52 (s, 4H, CH2–N), 4.25 (s, 2H, CH2–
O). 13C NMR (125.7 MHz, CDCl3): 155.3 (C-4), 154.8
(C-7a), 151.8 (C-2), 136.6, 136.5, 136.2 (C–i-Ph), 135.5
(CH-6), 128.5, 128.5, 128.2, 127.6, 127.5 (CH–Ph), 117.5
(C-4a), 104.9 (C-7), 76.7 (N–CH2–O), 70.5 (CH2–O), 53.1
(CH2–N). IR (CHCl3): 3090, 3033, 3012, 2962, 1600,
1575, 1497, 1455, 1387, 1070. UV (MeOH): 303 (7.10).
Anal. Calcd for C28H25ClN4O: C, 71.71; H, 5.37; N, 11.95;
Cl, 7.56. Found: C, 71.55; H, 5.32; N, 11.78; Cl, 7.43.
4.1.17. N,N-Dibenzyl-2-chloro-7-iodo-5H-pyrrolo[3,2-d]-
pyrimidin-4-amine (19). Compound 17 (2.5 g, 7.2 mmol)
and N-iodosuccinimide (1.8 g, 7.9 mmol) were stirred in
THF (20 mL) for 2 h and the solvent was evaporated. Chro-
matography on a silica gel column (chloroform) followed
by crystallization (ethyl acetate/hexanes, 1:6) afforded
compound 19 (3.2 g, 95%) as white crystals, mp 216–
218 ꢀC. MS (EI) m/z (rel intensity): 474 (7, M[35Cl]), 385
(24, M[37Cl]ꢁBn), 383 (78, M[35Cl]ꢁBn), 259 (18,
M[37Cl]ꢁBnꢁI), 257 (55, M[35Cl]ꢁBnꢁI), 91 (100, Bn).
1H NMR (500 MHz, DMSO-d6): 11.79 (br s, 1H, NH-5),
7.73 (s, 1H, H-6), 7.35–7.22 (m, 10H, 2Ph), 4.91 (s, 4H,
CH2–N). 13C NMR (125.7 MHz, DMSO-d6): 151.7 (C-7a),
151.5 (C-4), 151.2 (C-2), 137.3 (C–i-Ph), 134.6 (CH-6),
128.8, 127.5, 127.5 (CH–Ph), 112.2 (C-4a), 57.8 (C-7),
51.2 (CH2–N). IR (KBr): 3268, 3029, 1590, 1582, 1530,
1451, 1203, 1132, 954, 906. UV (MeOH): 298 (12.10),
251 (14.30). Anal. Calcd for C20H16ClIN4: C, 50.60; H,
3.40; Cl, 7.47; N, 11.80. Found: C, 50.67; H, 3.55; Cl,
7.49; N, 11.32.
4.1.20. N,N-Dibenzyl-5-(benzyloxymethyl)-2-chloro-7-
(phenylethynyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine
(22). A mixture of compound 16 (250 mg, 0.42 mmol),
ethynylbenzene (50 mg, 0.5 mmol), diisopropylethylamine
(1.7 mL), copper(I) iodide (8 mg, 0.042 mmol), and
Pd(PPh3)4 (50 mg, 0.042 mmol) in THF (5 mL) was heated
under argon to 50 ꢀC for 2 h. The solvent was evaporated,
the residue was taken into ethyl acetate, and washed with
water. Chromatography on a silica gel column (hexanes/
ethyl acetate, 92:8) afforded compound 22 (146 mg, 61%)
as colorless oil. MS (EI) m/z (rel intensity): 568 (8,
M[35Cl]), 550 (16), 504 (10), 469 (15, M[37Cl]ꢁPhC^C),
467 (40, M[35Cl]ꢁPhC^C), 431 (28), 429 (60), 361 (23),
4.1.18. N,N-Dibenzyl-5-(benzyloxymethyl)-2-chloro-7-
phenyl-5H-pyrrolo[3,2-d]pyrimidin-4-amine (20). A mix-
ture of compound 16 (340 mg, 0.6 mmol), phenylboronic
acid (290 mg, 2.4 mmol), potassium carbonate (330 mg,
2.4 mmol), and Pd(PPh3)4 (140 mg, 0.1 mmol) in toluene
(30 mL) was heated to 100 ꢀC under argon for 5 h. The sol-
vent was evaporated, the residue was taken into ethyl ace-
tate, and washed with water. Chromatography on a silica
gel column (chloroform) followed by crystallization (hex-
anes/ethyl acetate, 3:1) afforded compound 20 (210 mg,
67%) as white crystals, mp 143–145 ꢀC. MS (FAB) m/z
(rel intensity): 547 (41, M[37Cl]+H), 546 (40), 545 (100,
1
359 (40), 91 (100, Bn). H NMR (400 MHz, CDCl3): 7.68
(s, 1H, H-6), 7.62–7.56, 7.38–7.22, 7.17–7.11, 7.09–7.03
(4 m, 20H, 4Ph), 5.62 (s, 2H, N–CH2O), 4.50 (s, 4H,
CH2N), 4.29 (s, 2H, CH2O). 13C NMR (100.6 MHz,
CDCl3): 155.5 (C-4), 154.1 (C-7a), 152.8 (C-2), 137.7
(CH-6), 136.2 (C–i-NBn), 135.9 (C–i-OBn), 131.7, 128.6,
128.5, 128.3, 128.2, 128.2, 127.7, 127.6 (CH–Ph), 123.3
(C–i-Ph), 117.2 (C-4a), 101.6 (C-7), 93.1 (–C^C–Ph),
79.3 (–C^C–Ph), 76.9 (N–CH2–O), 70.8 (CH2–O), 53.2
(CH2–N). IR (CHCl3): 3089, 3067, 3033, 1581, 1547,
1527, 1496, 1380, 1101, 962. UV (MeOH): 293 (32.20),
276 (30.50). Anal. Calcd for C36H29ClN4O: C, 75.98; H,
5.14; Cl, 6.23; N, 9.84. Found: C, 75.78; H, 5.26; Cl, 5.97;
N, 9.59.
1
M[35Cl]+H), 91 (83, Bn). H NMR (400 MHz, CDCl3):
8.01 (m, 2H, o-H–Ph-7), 7.70 (s, 1H, H-6), 7.45 (m, 2H,
m-H–Ph-7), 7.34–7.23 (m, 11H, 2Ph+p-H–Ph-7), 7.15–
7.06 (m, 5H, Ph), 5.68 (s, 2H, N–CH2–O), 4.52 (s, 4H,
CH2–N), 4.30 (s, 2H, CH2–O). 13C NMR (100.6 MHz,
CDCl3): 155.5 (C-4), 152.2 (C-7a), 152.0 (C-2), 136.5,
136.2 (C–i-Ph), 132.0 (CH-6), 128.7, 128.6, 128.6, 128.5,
128.2, 127.6, 127.6, 126.9, 126.9 (CH–Ph), 118.7 (C-7),
118.4 (C-4a), 76.8 (N–CH2–O), 70.8 (CH2–O), 53.2 (CH2–
N). IR (CHCl3): 3089, 3067, 3033, 1589, 1551, 1523,
1496, 1415, 1382, 1102, 949. UV (MeOH): 303 (4.40),
258 (8.50). Anal. Calcd for C34H29ClN4O: C, 74.92; H,
5.36; Cl, 6.50; N, 10.28. Found: C, 74.79; H, 5.49; Cl,
6.77; N, 9.91.
4.1.21. N,N-7-Tribenzyl-5-(benzyloxymethyl)-2-chloro-
5H-pyrrolo[3,2-d]pyrimidin-4-amine (23). Benzylzinc(II)
bromide (0.65 mL, 0.33 mmol, 0.5 M solution in THF) was
added to a mixture of compound 16 (150 mg, 0.25 mmol)
and Pd(PPh3)4 (30 mg, 0.025 mmol) in DMF (4 mL) and

V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
1597
the reaction mixture was heated under argon to 75 ꢀC for 1 h.
The solvent was evaporated, the residue was taken into ethyl
acetate, and washed with water. Chromatography on a silica
gel column (hexanes/ethyl acetate, 93:7) followed by crys-
tallization (hexanes/ethyl acetate, 9:1) afforded compound
23 (85 mg, 60%) as white crystals, mp 85–87 ꢀC. MS (EI)
m/z (rel intensity): 560 (7, M[37Cl], 558 (19, M[35Cl]), 469
(17, M[37Cl]ꢁBn), 467 (48, M[35Cl]ꢁBn), 439 (13,
M[37Cl]ꢁBnOMe), 437 (32, M[35Cl]ꢁBnOMe), 461 (20),
359 (40), 91 (100, Bn). 1H NMR (400 MHz, CDCl3):
7.37–7.21, 7.12–7.01 (2 m, 20H, 4Ph), 6.97 (t, 1H, J¼1.1,
H-6), 5.51 (s, 2H, N–CH2–O), 4.51 (s, 4H, CH2–N), 4.17
(s, 2H, CH2–O), 4.09 (d, 2H, J¼1.1, CH2-7). 13C NMR
(100.6 MHz, CDCl3): 155.2 (C-4), 153.6 (C-7a), 151.6 (C-
2), 140.1 (C–i-Bn-7), 136.7 (C–i-NBn), 136.3 (C–i-OBn),
133.8 (CH-6), 129.0, 128.6, 128.5, 128.5, 128.4, 128.1,
127.6, 127.5, 126.2 (CH–Ph), 119.1 (C-7), 117.8 (C-4a),
76.5 (N–CH2–O), 70.5 (CH2–O), 53.1 (CH2–N), 29.8
(CH2-7). IR (CHCl3): 3088, 3067, 3032, 1593, 1550, 1524,
1496, 1454, 1102, 962. UV (MeOH): 304 (9.00), 257
(8.90). Anal. Calcd for C35H31ClN4O: C, 75.19; H, 5.59;
N, 10.02; Cl, 6.34. Found: C, 75.25; H, 5.58; N, 9.98;
Cl, 6.41.
MS (EI) m/z (rel intensity): 391 (38, M[37Cl, 35Cl]), 389 (54,
M[35Cl, 35Cl]), 361 (32, M[37Cl, 35Cl]ꢁCH2O), 359 (46,
1
M[35Cl, 35Cl]ꢁCH2O), 91 (100, Bn). H NMR (400 MHz,
CDCl3): 7.71 (dd, 1H, J¼3.6 and 1.2, H-30), 7.70 (s, 1H,
H-6), 7.36–7.22 (m, 6H, H-50+Ph), 7.11 (dd, J¼3.6
and 5.1, H-40), 5.81 (s, 2H, N–CH2–O), 4.55 (s, 2H, CH2–
O). 13C NMR (100.6 MHz, CDCl3): 151.3 (C-7a), 151.3
(C-2), 143.5 (C-4), 135.9 (C–i-Ph), 133.8 (CH-6), 131.9
(C-20), 128.6 (o-CH–Ph), 128.5 (CH-40), 127.8 (CH–p-Ph),
127.7 (CH–m-Ph), 125.2 (CH-30), 124.0 (CH-50), 123.4
(C-4a), 112.5 (C-7), 76.7 (N–CH2–O), 70.8 (CH2–O).
IR (CHCl3): 3090, 3069, 3035, 1603, 1512, 1456, 1417,
1380, 1337, 1087. UV (MeOH): 278 (16.25), 272 (15.90).
Anal. Calcd for C18H13Cl2N3OS: C, 55.39; H, 3.36;
N, 10.77; Cl, 18.17. Found: C, 55.56; H, 3.73; N, 10.67;
Cl, 18.50.
4.1.24. 5-(Benzyloxymethyl)-2,4-dichloro-7-vinyl-5H-
pyrrolo[3,2-d]pyrimidine (26). Tributyl(vinyl)stannane
(3.2 mL, 11 mmol) was added under argon to a mixture
of compound 15 (4.3 g, 10 mmol), Pd2(dba)3 (180 mg,
0.2 mmol), triphenylarsine (250 mg, 0.8 mmol), and cop-
per(I) iodide (2.25 g, 12 mmol) in DMF (30 mL) and the
reaction mixturewas heated to 75 ꢀC for 2 h. The solvent was
evaporated, the residue was taken into ethyl acetate and
washed with water. Chromatography on a silica gel column
(hexanes/ethyl acetate, 92:8) followed by crystallization
(hexanes/ethyl acetate, 5:1) afforded compound 26 (2.7 g,
80%) as white crystals, mp 92–95 ꢀC. MS (EI) m/z (rel inten-
sity): 335 (25, M[37Cl, 35Cl]), 333 (35, M[35Cl, 35Cl]), 305
(44, M[37Cl, 35Cl]ꢁCH2O), 303 (48, M[35Cl, 35Cl]ꢁCH2O),
247 (18), 91 (100, Bn). 1H NMR (500 MHz, CDCl3): 7.55 (s,
1H, H-6), 7.35–7.22 (m, 5H, Ph), 6.75 (dd, 1H, Jtrans¼17.7,
Jcis¼11.3, –CH]CH2), 6.21 (dd, 1H, Jtrans¼17.7, Jgem¼1.5,
–CH]CHaHb), 5.78 (s, 2H, N–CH2–O), 5.40 (dd, 1H,
Jcis¼11.3, Jgem¼1.5, –CH]HaHb), 4.52 (s, 2H, CH2–O).
13C NMR (125.7 MHz, CDCl3): 152.6 (C-7a), 151.1 (C-2),
143.30 (C-4), 136.0 (C–i-Ph), 135.6 (CH-6), 128.6 (CH–
m-Ph), 128.3 (CH–p-Ph), 127.7 (CH–o-Ph), 124.7
(CH]CH2), 123.6 (C-4a), 116.6 (CH]CH2), 115.9 (C-7),
76.6 (N–CH2–O), 70.6 (CH2–O). IR (CHCl3): 3069, 3034,
3011, 1637, 1594, 1511, 1417, 1352, 1087. UV (MeOH):
330 (2.90), 279 (5.30), 249 (26.65). Anal. Calcd for
C16H13Cl2N3O: C, 57.50; H, 3.92; N, 12.57; Cl, 21.22.
Found: C, 57.20; H, 3.97; N, 12.47; Cl, 21.39.
4.1.22. 5-(Benzyloxymethyl)-2,4-dichloro-7-phenyl-5H-
pyrrolo[3,2-d]pyrimidine (24). A mixture of compound
15 (220 mg, 0.5 mmol), phenylboronic acid (80 mg,
0.65 mmol), potassium carbonate (90 mg, 0.65 mmol), and
Pd(PPh3)4 (70 mg, 0.06 mmol) in toluene (12 mL) was
heated under argon to 95 ꢀC for 4 h. The solvent was evap-
orated, the residue was taken into ethyl acetate, and washed
with water. Chromatography on a silica gel column (hexanes/
ethyl acetate, 9:1) followed by crystallization (hexanes/ethyl
acetate, 9:1) afforded compound 24 (120 mg, 63%) as white
crystals, mp 101–103 ꢀC. MS (EI) m/z (rel intensity): 385
(29, M[37Cl, 35Cl]), 383 (42, M[35Cl, 35Cl]), 355 (27,
M[37Cl, 35Cl]ꢁCH2O), 353 (40, M[35Cl, 35Cl]ꢁCH2O), 91
1
(100, Bn). H NMR (400 MHz, CDCl3): 7.94 (m, 2H, H–
o-Ph-7), 7.79 (s, 1H, H-6), 7.45 (m, 2H, H–m-Ph-7), 7.35–
7.22 (m, 6H, H–p-Ph-7+Ph), 5.85 (s, 2H, N–CH2–O), 4.56
(s, 2H, CH2O). 13C NMR (100.6 MHz, CDCl3): 152.2
(C-7a), 151.1 (C-2), 143.5 (C-4), 136.0 (C–i-Bn), 134.9
(CH-6), 130.8 (C–i-Ph-7), 128.9 (CH–m-Ph-7), 128.6 (CH–
m-Bn), 128.3 (CH–p-Bn), 127.7 (CH–o-Ph-7), 127.5 (CH–
p-Ph-7), 126.9 (CH–o-Bn), 123.7 (C-4a), 117.4 (C-7), 76.8
(N–CH2–O), 70.8 (CH2–O). IR (CHCl3): 3085, 3068, 3034,
1596, 1551, 1510, 1489, 1423, 1358, 1087, 1030. UV
(MeOH): 255 (22.65). Anal. Calcd for C20H15Cl2N3O: C,
62.51; H, 3.93; N, 10.94; Cl, 18.45. Found: C, 62.14; H,
3.73; N, 10.54; Cl, 18.28.
4.1.25. 2-[5-(Benzyloxymethyl)-2,4-dichloro-5H-pyr-
rolo[3,2-d]pyrimidin-7-yl]ethanol (27). Compound 26
(2.3 g, 6.9 mmol) in THF (10 mL) was added gradually
under argon at 0 ꢀC to a solution of 9-BBN (0.5 M in THF,
27 mL, 13.8 mmol) and the reaction mixture was stirred at
0 ꢀC for 15 min and then 2 h at room temperature. Sodium
perborate (tetrahydrate, 4.2 g, 27.5 mmol) in water (28 mL)
was added and the reaction mixture was left to stand for
additional 2 h. The solvent was evaporated, the residue
was taken into ethyl acetate and washed with water. Chroma-
tography on a silica gel column (chloroform/methanol, 98:2)
afforded compound 27 (2.1 g, 86%) as colorless oil. MS (EI)
m/z (rel intensity): 353 (4, M[37Cl, 35Cl]), 351 (6, M[35Cl,
35Cl]), 335 (8, M[37Cl, 35Cl]ꢁH2O), 333 (10, M[35Cl,
35Cl]ꢁH2O), 323 (51, M[37Cl, 35Cl]ꢁCH2O), 321
(78, M[35Cl, 35Cl]ꢁCH2O), 202 (30), 200 (40), 91 (100,
4.1.23. 5-(Benzyloxymethyl)-2,4-dichloro-7-(thiophen-2-
yl)-5H-pyrrolo[3,2-d]pyrimidine (25). Tributyl(thiophen-
2-yl)stannane (0.23 mL, 0.73 mmol) was added under argon
to a mixture of compound 15 (250 mg, 0.6 mmol), triphenyl-
arsine (21.3 mg, 0.07 mmol), copper(I) iodide (13.3 mg,
0.07 mmol), and Pd2(dba)3 (18 mg, 0.017 mmol) in DMF
(4 ml) and the reaction mixture was heated to 50 ꢀC for
2 h. The solvent was evaporated, the residue was taken
into ethyl acetate, and washed with water. Chromatography
on a silica gel column (hexanes/ethyl acetate, 94:6) followed
by crystallization (hexanes/ethyl acetate, 5:1) afforded com-
pound 25 (180 mg, 81%) as white crystals, mp 103–106 ꢀC.
1
Bn). H NMR (400 MHz, DMSO-d6): 8.10 (s, 1H, H-6),

1598
V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
7.29–7.18 (m, 5H, Ph), 5.84 (s, 2H, N–CH2–O), 4.74 (t, 1H,
JOH;CH ¼5:4, OH), 4.53 (s, 2H, CH2–O), 3.65 (td, 2H,
4.1.28. 5-(Benzyloxymethyl)-2,4-dichloro-7-ethynyl-5H-
pyrrolo[3,2-d]pyrimidine (31). Tetrabutylammonium fluo-
ride (1.1 M solution in THF, 17.5 mL, 19.4 mmol) was
added to compound 30 (7.1 g, 17.5 mmol) and the reaction
mixture was left to stand for 10 min. The solvent was evapo-
rated, the residue was taken into ethyl acetate, and washed
with water. Chromatography on a silica gel column (hexanes/
ethyl acetate, 88:12) followed by crystallization (hexanes/
ethyl acetate, 4:1) afforded compound 31 (3.8 g, 65%) as
white crystals, mp 100–102 ꢀC. MS (EI) m/z (rel intensity):
333 (18, M[37Cl, 35Cl]), 331 (20, M[35Cl, 35Cl]), 303 (16,
M[37Cl, 35Cl]ꢁCH2O), 301 (20, M[35Cl, 35Cl]ꢁCH2O),
256 (68), 239 (25), 91 (100, Bn). 1H NMR (500 MHz,
CDCl3): 7.75 (s, 1H, H-6), 7.35–7.27 (m, 3H, H–m,p-Ph),
7.24 (m, 2H, H–o-Ph), 5.79 (s, 2H, N–CH2–O), 4.54 (s, 2H,
CH2–O), 3.30 (s, 1H, C^CH). 13C NMR (125.7 MHz,
CDCl3): 154.8 (C-7a), 152.1 (C-2), 144.1 (C-4), 140.9 (CH-
6), 135.6 (C–i-Ph), 128.6 (CH–m-Ph), 128.4 (CH–p-Ph),
127.7 (CH–o-Ph), 122.6 (C-4a), 99.3 (C-7), 82.4 (C^CH),
76.9 (N–CH2–O), 72.3 (C^CH), 70.9 (CH2–O). IR (CHCl3):
3306, 3105, 2123, 1594, 1517, 1421, 1357, 1236, 1092. UV
(MeOH): 321 (2.00), 278 (2.75), 239 (14.90). Anal. Calcd
for C16H11Cl2N3O: C, 57.85; H, 3.34; N, 12.65; Cl, 21.35.
Found: C, 57.66; H, 3.28; N, 12.38; Cl, 21.21.
2
Jvic¼7.0, JCH ;OH¼5:4, CH2–OH), 2.80 (t, 2H, Jvic¼7.0,
2
CH2–C7). 13C NMR (100.6 Hz, DMSO-d6): 154.0 (C-7a),
148.9 (C-2), 142.4 (C-4), 139.6 (CH-6), 137.4 (C–i-Ph),
128.3 (CH–m-Ph), 127.7 (CH–p-Ph), 127.6 (CH–o-Ph),
122.6 (C-4a), 113.3 (C-7), 76.9 (N–CH2–O), 69.9 (CH2–
O), 60.5 (CH2–OH), 26.9 (CH2). IR (CHCl3): 3390, 3091,
1601, 1515, 1455, 1384, 1234, 1108, 1075. UV (MeOH):
307 (4.60), 283 (7.30). Anal. Calcd for C16H15Cl2N3O2: C,
54.56; H, 4.29; N, 11.93; Cl, 20.13. Found: C, 54.50; H,
4.62; N, 11.69; Cl, 19.92.
4.1.26. Mixture (3:2) of 5-(benzyloxymethyl)-2,4-di-
chloro-7-(phenylethynyl)-5H-pyrrolo[3,2-d]pyrimidine
(28) and 5-(benzyloxymethyl)-2-chloro-4,7-bis(phenyl-
ethynyl)-5H-pyrrolo[3,2-d]pyrimidine (29). A mixture of
compound 15 (430 mg, 1.0 mmol), ethynylbenzene (120 mg,
1.2 mmol), triethylamine (0.2 mL, 1.5 mmol), copper(I)
iodide (11 mg, 0.06 mmol) and Pd(PPh3)4 (70 mg,
0.06 mmol) in THF (6 mL) was heated under argon to
50 ꢀC for 2 h. The solvent was evaporated, the residue was
taken into ethyl acetate, and washed with water. Chromato-
graphy on a silica gel column (hexanes/ethyl acetate, 92:8)
afforded an unseparable mixture (300 mg, 3:2) of com-
pounds 28 and 29. Compound 28: MS (EI) m/z: 409 (33,
M[37Cl, 35Cl]), 407 (48, M[35Cl, 35Cl]), 379 (36, M[37Cl,
4.1.29. 5-(Benzyloxymethyl)-2-chloro-7-ethynyl-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine (32).
1
35Cl]ꢁCH2O), 377 (55, M[35Cl, 35Cl]ꢁCH2O). H NMR
4.1.29.1. Method A. Tetrabutylammonium fluoride
(1.1 M in THF, 1.6 mL, 1.8 mmol) was added to a solution
of compound 34 (620 mg, 1.6 mmol) in THF (10 mL) and
left to stand for 10 min. The solvent was evaporated, the resi-
due was taken into ethyl acetate, and washed with water.
Chromatography on a silica gel column (chloroform/metha-
nol, 98:2) followed by crystallization (hexanes/ethyl acetate,
4:1) afforded compound 32 (500 mg, 98%) as white crystals,
mp 202–204 ꢀC. MS (EI) m/z (rel intensity): 314 (26,
M[37Cl]), 312 (73, M[35Cl]), 282 (28, M[35Cl]ꢁCH2O),
277 (18, MꢁCl), 91 (100, Bn). 1H NMR (400 MHz,
CDCl3): 7.42–7.35 (m, 3H, H–m,p-Ph), 7.34 (s, 1H, H-6),
7.28 (m, 2H, H–o-Ph), 6.24 (br s, 2H, NH2), 5.48 (s, 2H,
N–CH2–O), 4.58 (s, 2H, CH2O), 3.24 (s, 1H, HC^C). 13C
NMR (100.6 MHz, CDCl3): 153.9 (C-2), 152.8 (C-7a),
152.1 (C-4), 135.6 (CH-6), 134.6 (C–i-Ph), 128.9 (CH–p-
Ph), 128.9 (CH–m-Ph), 128.5 (CH–o-Ph), 113.2 (C-4a),
98.22 (C-7), 81.2 (C^CH), 77.0 (N–CH2–O), 73.7
(C^CH), 70.4 (CH2–O). IR (KBr): 3408, 3311, 3158,
2119, 1647, 1594, 1531, 1359, 1095. UV (MeOH): 293
(9.40), 240 (26.90). Anal. Calcd for C16H13ClN4O: C,
61.44; H, 4.19; N, 17.91. Found: C, 61.65; H, 4.18; N, 17.80.
(500 MHz, CDCl3): 7.78 (s, 1H, H-6), 7.59–7.25 (m, 10H,
CH–Ph), 5.81 (s, 2H, N–CH2–O), 4.55 (s, 2H, CH2O).
Compound 29: MS (EI) m/z: 475 (4, M[37Cl, 35Cl]), 473
(10, M[35Cl, 35Cl]). 1H NMR (500 MHz, CDCl3): 7.81
(s, 1H, H-6), 7.59–7.25 (m, 15H, CH–Ph), 5.98 (s, 2H,
N–CH2–O), 4.58 (s, 2H, CH2–O).
4.1.27. 5-(Benzyloxymethyl)-2,4-dichloro-7-[(trimethyl-
silyl)ethynyl]-5H-pyrrolo[3,2-d]pyrimidine (30). A mix-
ture of compound 15 (10.9 g, 25 mmol), copper(I) iodide
(290 mg, 1.5 mmol), triethylamine (5.2 mL, 37.5 mmol)
and PdCl2(PPh3)2 (530 mg, 0.75 mmol) in THF (40 mL)
was stirred under argon for 10 min, ethynyltrimethylsilane
(4 mL, 28.8 mmol) in THF (15 mL) was added gradually
and the reaction mixture was stirred at room temperature
for 2 h. The solvent was evaporated, the residue was taken
into ethyl acetate and washed with water. Chromatography
on a silica gel column (hexanes/ethyl acetate, 92:8) followed
by crystallization (hexanes/ethyl acetate, 9:1) afforded
compound 30 (7.10 g, 70%) as white crystals, mp 76–
78 ꢀC. MS (FAB) m/z (rel intensity): 406 (42, M[37Cl,
35Cl]+H), 404 (42, M[35Cl, 35Cl]+H), 366 (60), 364 (84),
336 (30), 334 (32), 91 (100, Bn). 1H NMR (500 MHz,
CDCl3): 7.78 (s, 1H, H-6), 7.37–7.29 (m, 3H, H–m,p-Ph),
7.26 (m, 2H, H–o-Ph), 5.79 (N–CH2–O), 4.52 (CH2O),
0.29 (s, 9H, Me3Si). 13C NMR (125.7 MHz, CDCl3): 154.4
(C-7a), 152.0 (C-2), 144.0 (C-4), 141.2 (CH-6), 135.6
(C–i-Ph), 128.7 (CH–m-Ph), 128.4 (CH–p-Ph), 127.7
(CH–o-Ph), 122.4 (C-4a), 100.5 (C-7), 99.7 (C^C–Si),
92.8 (C^C–Si), 76.8 (N–CH2–O), 70.7 (CH2–O), ꢁ0.1
(Me3Si). IR (CHCl3): 3093, 3069, 3035, 2901, 2164, 1594,
1517, 1456, 1373, 1251, 1091. UV (MeOH): 319 (4.60),
278 (6.80), 248 (47.70). Anal. Calcd for C19H19Cl2N3OSi:
C, 56.44; H, 4.74; N, 10.93; Cl, 17.54. Found: C, 56.27;
H, 4.63; N, 10.85; Cl, 17.26.
4.1.29.2. Method B. Compound 30 (700 mg, 1.7 mmol)
was dissolved in methanolic ammonia (10 M, 40 mL) and
heated to 120 ꢀC in autoclave for 12 h. The solvent was
evaporated, the residue was taken into ethyl acetate, and
washed with water. Chromatography on a silica gel column
(chloroform/methanol, 100:0 to 98:2) afforded compound
33 (120 mg, 21%), white crystals, mp 147–148 ꢀC (hex-
anes/ethyl acetate, 9:1) and compound 32 (250 mg,
46%), white crystals, mp 202–204 ꢀC (hexanes/ethyl
acetate, 4:1).
4.1.30. 5-(Benzyloxymethyl)-2-chloro-7-ethynyl-4-meth-
oxy-5H-pyrrolo[3,2-d]pyrimidine (33). The compound

V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
1599
was obtained as a side-product in the preparation of
compound 32 (see Section 4.1.29.2). MS (EI) m/z (rel inten-
sity): 329 (8, M[37Cl]), 327 (26, M[35Cl]), 299 (7,
M[37Cl]ꢁCH2O), 297 (22, M[35Cl]ꢁCH2O), 223 (8,
M[37Cl]ꢁBnO), 221 (28, M[35Cl]ꢁBnO), 91 (100, Bn). 1H
NMR (400 MHz, CDCl3): 7.58 (s, 1H, H-6), 7.36–7.26 (m,
3H, H–m,p-Ph), 7.22 (m, 2H, H–o-Ph), 5.66 (s, 2H, N–
CH2–O), 4.47 (s, 2H, CH2–O), 4.12 (s, 3H, MeO), 3.25 (s,
1H, HC^C). 13C NMR (100.6 MHz, CDCl3): 156.9 (C-4),
152.9 (C-7a), 151.9 (C-2), 136.9 (CH-6), 136.2 (C–i-Ph),
128.5 (CH–m-Ph), 128.1 (CH–p-Ph), 127.6 (CH–o-Ph),
113.8 (C-4a), 99.1 (C-7), 81.3 (C^CH), 77.1 (N–CH2–O),
73.6 (C^CH), 70.5 (CH2–O), 54.6 (MeO). IR (CHCl3):
3306, 3091, 2121, 1606, 1543, 1462, 1415, 1363, 1090.
UV (MeOH): 289 (5.50), 263 (5.20). Anal. Calcd for
C17H14ClN3O2: C, 62.30; H, 4.31; N, 12.80; Cl, 10.82.
Found: C, 62.10; H, 4.34; N, 12.61; Cl, 11.07.
white crystals, mp 197–199 ꢀC. MS (EI) m/z (rel intensity):
416 (20, M[37Cl]), 414 (60, M[35Cl]), 259 (14, M[37Cl]ꢁ
1
CH2OꢁI), 257 (40, M[35Cl]ꢁCH2OꢁI), 91 (100, Bn). H
NMR (500 MHz, DMSO-d6): 7.90 (s, 1H, H-6), 7.35–7.16
(m, 7H, NH2+Ph), 5.73 (s, 2H, N–CH2–O), 4.49 (s, 2H,
CH2–O). 13C NMR (125.7 MHz, DMSO-d6): 152.5 (C-2),
152.4 (C-4), 151.9 (C-7a), 137.9 (CH-6), 136.9 (C–i-Ph),
128.4, 128.0, 127.9 (CH–Ph), 113.2 (C-4a), 77.7 (N–CH2–
O), 69.8 (CH2–O), 57.4 (C-7). IR (KBr): 3480, 3361, 3031,
1625, 1585, 1536, 1417, 1354, 1072. UV (MeOH): 291
(6.90), 243 (16.30). Anal. Calcd for C14H12ClIN4O: C,
40.55; H, 2.92; N, 13.51; Cl, 8.55. Found: C, 39.99; H,
2.86; N, 13.32; Cl, 8.88.
4.1.33. 1-[4-Amino-5-(benzyloxymethyl)-2-chloro-5H-
pyrrolo[3,2-d]pyrimidin-7-yl]ethane-1,2-diol (36). A so-
lution of compound 32 (500 mg, 1.6 mmol) in THF (4 mL)
was added gradually under argon to a solution of borane–
dimethyl sulfide complex (1 M solution in dichloromethane,
4.8 mL, 4.8 mmol) and the reaction mixture was stirred
at 0 ꢀC for 15 min and then at room temperature for 2 h.
Sodium perborate (tetrahydrate, 1.7 g, 11 mmol) in water
(8 mL) was added and the reaction mixture was left to stand
for additional 2 h. The solvent was evaporated, the residue
was taken into ethyl acetate, and washed with water. Chro-
matography on a silica gel column (chloroform/methanol,
97:3) followed by crystallization (hexanes/ethyl acetate,
3:1) afforded compound 36 (250 mg, 45%) as white crystals,
mp 176–178 ꢀC. MS (EI) m/z (rel intensity): 332 (12,
M[37Cl]ꢁH2O), 331 (12), 330 (22, M[35Cl]ꢁH2O), 319
(20), 318 (30, M[35Cl]ꢁCH2O), 317 (52), 304 (9), 302
4.1.31. 5-(Benzyloxymethyl)-2-chloro-7-[(trimethylsilyl)-
ethynyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine (34).
4.1.31.1. Method A. Ethynyltrimethylsilane (0.28 mL,
2 mmol) in THF (1.5 mL) was added gradually under argon
to a mixture of compound 35 (570 mg, 1.5 mmol), copper(I)
iodide (18 mg, 0.09 mmol), PdCl2(PPh3)2 (32 mg,
0.045 mmol), and triethylamine (0.3 mL, 2.2 mmol) in
THF (3 mL) and the reaction mixture was stirred for 2 h.
The solvent was evaporated, the residue was taken into ethyl
acetate, and washed with water. Chromatography on a silica
gel column (chloroform) followed by crystallization (hex-
anes/ethyl acetate, 6:1) afforded compound 34 (260 mg,
47%) as white crystals, mp 90–92 ꢀC. MS (FAB) m/z (rel
intensity): 387 (6, M[37Cl]+H), 385 (20, M[35Cl]+H), 91
1
(28), 91 (100, Bn). H NMR (500 MHz, DMSO-d6): 7.58
1
(35, Bn), 73 (100, SiMe3). H NMR (400 MHz, CDCl3):
(br s, 1H, H-6), 7.35–7.20 (m, 5H, Ph), 7.05 (br s, 2H,
NH2), 5.70 (br s, 2H, N–CH2–O), 5.10 (br d, 1H, JOH,CH¼3.7,
7.41–7.36 (m, 3H, H–m,p-Ph), 7.35 (s, 1H, H-6), 7.27 (m,
2H, H–o-Ph), 6.47 (br s, 2H, NH2), 5.47 (s, 2H, N–CH2–
O), 4.56 (s, 2H, CH2–O), 0.26 (s, 9H, Me3Si). 13C NMR
(100.6 MHz, CDCl3): 153.7 (C-2), 152.2 (C-7a), 152.2
(C-4), 136.1 (CH-6), 134.7 (C–i-Ph), 128.9 (CH–m-Ph),
128.8 (CH–p-Ph), 128.4 (CH–o-Ph), 113.1 (C-4a), 99.4
(C-7), 98.0 (C^C–Si), 94.5 (C^C–Si), 77.1 (N–CH2–O),
70.2 (CH2–O), 0.1 (Me3Si). IR (CHCl3): 3479, 3360,
2902, 2159, 1626, 1594, 1533, 1424, 1356, 1251. UV
(MeOH): 296 (8.00), 245 (31.70). Anal. Calcd for
C19H21ClN4OSi: C, 59.28; H, 5.50; N, 14.55; Cl, 9.21.
Found: C, 59.02; H, 5.41; N, 14.33; Cl, 9.53.
OH), 4.77 (br m, 1H, CH–OH), 4.75 (br t, 1H, JOH;CH ¼5:9,
2
OH), 4.45 (s, 2H, CH2Ph), 3.70, 3.45 (2br dt, 2H, Jgem¼11.1,
Jvic¼6.4, JCH ;OH¼5:9, CH2OH). 13C NMR (125.7 MHz,
2
DMSO-d6): 152.2 (C-4), 151.3 (C-2), 149.3 (C-7a), 137.1
(C–i-Ph), 132.6 (CH-6), 128.5 (CH–m-Ph), 128.0 (CH–p-
Ph), 127.9 (CH–o-Ph), 117.2 (C-7), 112.8 (C-4a), 77.4 (N–
CH2–O), 69.5 (CH2Ph), 66.9 (CH–OH), 66.3 (CH2–OH).
IR (KBr): 3401, 3295, 3120, 3035, 1647, 1604, 1529, 1435,
1363, 1088. UV (MeOH): 283 (7.05), 238 (18.90). Anal.
Calcd for C16H17ClN4O3: C, 55.10; H, 4.91; N, 16.06. Found:
C, 54.84; H, 4.91; N, 15.81.
4.1.31.2. Method B. Compound 30 (1.1 g, 3 mmol) was
dissolved in ethanolic ammonia (2 M, 50 mL) and heated to
120 ꢀC in autoclave for 12 h. The solvent was evaporated,
the residue was taken into ethyl acetate, and washed with
water. Chromatography on a silica gel column (chloroform)
followed by crystallization (hexanes/ethyl acetate, 6:1)
afforded compound 34 (620 mg, 60%) as white crystals,
mp 90–92 ꢀC.
4.1.34. 1-(4-Amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-
ethane-1,2-diol (37). Compound 36 (250 mg, 0.72 mmol)
in methanol (100 mL) was acidified by the addition of meth-
anolic hydrogen chloride (1 M, 3 mL) and hydrogenated
under slight overpressure in the presence of Pd–C catalyst
(10 wt%, 40 mg) overnight. The catalyst was filtered off
through a Celite pad and the filtrate was evaporated. Chro-
matography on a silica gel column (chloroform/methanol,
97:3 to 90:10) followed by crystallization (ethyl acetate/
methanol, 4:1) afforded compound 37 (125 mg, 89%) as
white crystals, mp>300 ꢀC. MS (EI) m/z (rel intensity):
4.1.32. 5-(Benzyloxymethyl)-2-chloro-7-iodo-5H-pyr-
rolo[3,2-d]pyrimidin-4-amine (35). Compound 15 (2.0 g,
4.6 mmol) was dissolved in methanolic ammonia (10 M,
40 mL) and heated to 120 ꢀC in autoclave for 12 h. The sol-
vent was evaporated, the residue was taken into ethyl acetate,
and washed with water. Chromatography on a silica gel
column (chloroform) followed by crystallization (hexanes/
ethyl acetate, 6:1) afforded compound 35 (1.2 g, 68%) as
1
178 (14, MꢁH2O). H NMR (500 MHz, DMSO-d6): 12.79
(br s, 1H, NH), 8.94 (br s, 2H, NH2), 8.43 (s, 1H, H-2),
7.74 (d, 1H, JH6,NH¼2.8, H-6), 5.49 (br s, 1H, OH),
4.85 (t, 1H, Jvic¼5.9, CH–OH), 3.61, 3.56 (2 dd, 2H,
Jgem¼11.0, Jvic¼5.9, CH2–OH). 13C NMR (125.7 MHz,
DMSO-d6): 152.6 (C-4), 145.0 (CH-2), 132.5 (C-7a),

1600
V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
129.1 (CH-6), 114.0 (C-7), 112.8 (C-4a), 66.7 (CH–OH),
66.4 (CH2–OH). IR (KBr): 3401, 3204, 2906, 1648, 1537,
1458, 1417, 1082, 1029. UV (MeOH): 272 (4.65). Anal.
Calcd for C8H10N4O2: C, 49.48; H, 5.19; N, 28.85. Found:
C, 49.72; H, 5.25; N, 28.45.
(C-4a), 120.8 (C-7), 77.0 (N–CH2–O), 69.9 (CH2–O), 65.8
(CH–OH), 30.3 (CH2), 10.0 (CH3). IR (CHCl3): 3607,
3445, 3031, 1600, 1513, 1455, 1383, 1088. UV (MeOH):
280 (4.05). Anal. Calcd for C17H17Cl2N3O2: C, 55.75; H,
4.68; N, 11.47; Cl, 19.36. Found: C, 55.50; H, 4.37; N,
11.57; Cl, 19.46.
4.1.35. (Z)-5-(Benzyloxymethyl)-2,4-dichloro-7-(prop-1-
enyl)-5H-pyrrolo[3,2-d]pyrimidine (38). Trimethylalumi-
num (2 M solution in toluene, 20 mL, 40 mmol) and a solu-
tion of compound 31 (3.4 g, 10.2 mmol) in dichloromethane
(10 mL) were added under argon to a solution of Cp2ZrCl2
(3.0 g, 10.2 mmol) in dichloromethane and the reaction mix-
ture was stirred at 0 ꢀC for 15 min and then at room temper-
ature for 2 h. The reaction was quenched by pouring onto
water with ice (100 mL), chloroform was added, the organic
layer was washed with water, and evaporated. Chromato-
graphy on a silica gel column (hexanes/ethyl acetate, 92:8)
followed by crystallization (hexanes/ethyl acetate, 5:1)
afforded compound 38 (2.4 g, 68%) as white crystals, mp
127–129 ꢀC. MS (EI) m/z (rel intensity): 349 (48, M[37Cl,
35Cl]), 347 (74, M[35Cl, 35Cl]), 319 (23, M[37Cl,
35Cl]ꢁCH2OH), 317 (34, M[35Cl, 35Cl]ꢁCH2OH), 228
(48, M[37Cl, 35Cl]ꢁBnOMe), 226 (76, M[35Cl,
35Cl]ꢁBnOMe), 91 (100, Bn). 1H NMR (500 MHz,
CDCl3): 7.61 (s, 1H, H-6), 7.35–7.22 (m, 5H, Ph), 6.65
Acknowledgements
This work, which is a part of the Institute research project no.
Z4 055 0506, was supported by the Centre for New Anti-
virals and Antineoplastics (1M0508) of the Ministry of
Education, Youth and Sports of the Czech Republic and by
Gilead Sciences, Inc. We also thank Professor M. Kotora
for fruitful discussion.
References and notes
ˇ
1. Silhar, P.; Pohl, R.; Votruba, I.; Klepetarova, B.; Hocek, M.
ˇ
ꢀ
ꢀ
Collect. Czech. Chem. Commun. 2006, 71, 788–803.
ꢀ
ˇ
2. Capek, P.; Pohl, R.; Hocek, M. Org. Biomol. Chem. 2006, 4,
2278–2284.
ˇ
ꢀ
3. Silhar, P.; Pohl, R.; Votruba, I.; Hocek, M. Collect. Czech.
Chem. Commun. 2005, 70, 1669–1695.
ˇ
(dqd, 1H, Jcis¼11.4, JCH;CH ¼1:8, JCH;H-6¼0:8, CH]
4. Hocek, M.; Naus, P.; Pohl, R.; Votruba, I.; Furman, P. A.;
3
CH–CH3), 5.92 (dq, 1H, Jcis¼11.4, JCH;CH ¼7:1, CH]
Tharnish, P. M.; Otto, M. J. J. Med. Chem. 2005, 48, 5869–5873.
5. Hocek, M.; Pohl, R. Synthesis 2004, 2869–2876.
6. Turek, P.; Kotora, M.; Hocek, M.; Votruba, I. Collect. Czech.
Chem. Commun. 2005, 70, 339–349.
7. Naus, P.; Votruba, I.; Hocek, M. Collect. Czech. Chem.
Commun. 2004, 69, 1955–1970.
3
CH–CH3), 5.83 (s, 2H, N–CH2–O), 4.54 (s, 2H, CH2–O),
1.92 (dd, 3H, J¼7.1 and 1.8, CH3). 13C NMR (125.7 MHz,
CDCl3): 153.7 (C-7a), 150.8 (C-2), 143.2 (C-4), 136.0 (C–
i-Ph), 135.8 (CH-6), 128.6 (CH–m-Ph), 128.3 (CH–p-Ph),
127.7 (CH–o-Ph), 127.3 (CH]CH–CH3), 122.7 (C-4a),
117.0 (CH]CH–CH3), 114.7 (C-7), 76.6 (N–CH2–O),
70.6 (CH2–O), 15.6 (CH3). IR (CHCl3): 3068, 3034, 1626,
1594, 1511, 1416, 1381, 1357, 1089. UV (MeOH): 319
(3.05), 281 (6.35), 243 (29.60). Anal. Calcd for
C17H15Cl2N3O: C, 58.63; H, 4.34; N, 12.07. Found: C,
58.75; H, 4.22; N, 11.83.
ˇ
ˇ
8. Hocek, M.; Hockova, D.; Stambasky, J. Collect. Czech. Chem.
ꢀ
Commun. 2003, 68, 837–848.
ꢀ
9. Hocek, M. Eur. J. Org. Chem. 2003, 245–254.
10. Norman, M. H.; Chen, N.; Chen, Z.; Fotsch, C.; Hale, C.; Han,
N.; Hurt, R.; Jenkins, T.; Kincaid, J.; Liu, L.; Lu, Y.; Moreno,
O.; Santora, V. J.; Sonnenberg, J. D.; Karbon, W. J. Med.
Chem. 2000, 43, 4288–4312.
4.1.36. 1-[5-(Benzyloxymethyl)-2,4-dichloro-5H-pyr-
rolo[3,2-d]pyrimidin-7-yl]propan-1-ol (39). Compound
38 (1.8 g, 5.2 mmol) in THF was added gradually under
argon at 0 ꢀC to a solution of borane–dimethyl sulfide com-
plex (2 M in toluene, 7.5 mL, 15 mmol) and the reaction
mixture was stirred at 0 ꢀC for 15 min and then at room tem-
perature for 2 h. Then sodium perborate (tetrahydrate, 4.5 g,
30 mmol) in water (15 mL) was added and the reaction mix-
ture was stirred for additional 2 h. The solvent was evapo-
rated, the residue was taken into ethyl acetate, and washed
with water. Chromatography on a silica gel column (chloro-
form) afforded compound 39 (1.3 g, 69%) as colorless oil.
MS (EI) m/z (rel intensity): 367 (2, M[37Cl, 35Cl]), 365
(4, M[35Cl, 35Cl]), 349 (10), 347 (14, M[35Cl, 35Cl]ꢁH2O),
338 (54, M[37Cl, 35Cl]ꢁCH3CH2), 336 (84, M[35Cl,
35Cl]ꢁCH3CH2), 308 (24), 306 (36, M[35Cl, 35Cl]ꢁ
OCH2CH2CH3), 91 (100, Bn). 1H NMR (400 MHz,
DMSO-d6): 8.15 (s, 1H, H-6), 7.29–7.18 (m, 5H, Ph), 5.87
(s, 2H, N–CH2–O), 5.25 (br s, 1H, OH), 4.81 (dd, 1H,
Jvic¼7.2 and 5.0, CH–OH), 4.52 (s, 2H, CH2–O), 1.88,
1.75 (2 m, 2H, CH2), 0.86 (t, 3H, Jvic¼7.4, CH3).
13C NMR (100.6 MHz, DMSO-d6): 152.2 (C-7a), 148.9
(C-2), 142.5 (C-4), 138.6 (CH-6), 137.3 (C–i-Ph), 128.3
(CH–m-Ph), 127.7 (CH–p-Ph), 127.6 (CH–o-Ph), 122.8
11. Seela, F.; Shaikh, K. I.; Budow, S.; Jawalekar, A. M.
Nucleosides, Nucleotides Nucleic Acids 2005, 24, 851–854.
12. Gandhi, V.; Kilpatrick, J. M.; Plunkett, W.; Ayres, M.; Harman,
L.; Du, M.; Bantia, S.; Davisson, J.; Wierda, W. G.; Faderl, S.;
Kantarjian, H.; Thomas, D. Blood 2005, 106, 4253–4260.
13. Schramm, V. L. Nucleosides, Nucleotides Nucleic Acids 2004,
23, 1305–1311.
14. Schramm, V. L.; Tyler, P. C. Curr. Top. Med. Chem. 2003, 3,
525–540.
ꢀ
ꢀ
ꢀ
15. Otmar, M.; Masojıdkova, M.; Votruba, I.; Holy, A. Bioorg.
Med. Chem. 2004, 12, 3187–3195.
16. Lim, M.-I.; Ren, W.-Y.; Otter, B. A.; Klein, R. S. J. Org. Chem.
1983, 48, 780–788.
ˇˇ
ꢀ
ꢀ
ꢀ
17. Otmar, M.; Masojıdkova, M.; Budesınsky, M.; Holy, A.
ꢀ
ꢀ
Tetrahedron 1998, 54, 2931–2940.
18. Evans, G. B.; Furneaux, R. H.; Hausler, H.; Larsen, J. S.; Tyler,
P. C. J. Org. Chem. 2004, 69, 2217–2220.
19. Trejo, A.; Arzeno, H.; Browner, M.; Chanda, S.; Cheng, S.;
Comer, D. D.; Dalrymple, S. A.; Dunten, P.; Lafargue, J.;
Lovejoy, B.; Freire-Moar, J.; Lim, J.; Mcintosh, J.; Miller, J.;
Papp, E.; Reuter, D.; Roberts, R.; Sanpablo, F.; Saunders, J.;
Song, K.; Villasenor, A.; Warren, S. D.; Welch, M.; Weller,
P.; Whiteley, P. E.; Zeng, L.; Goldstein, D. M. J. Med. Chem.
2003, 46, 4702–4713.

V. Bambuch et al. / Tetrahedron 63 (2007) 1589–1601
1601
ˇ
24. Capek, P.; Otmar, M.; Masojıdkova, M.; Votruba, I.; Holy, A.
ꢀ
Collect. Czech. Chem. Commun. 2003, 68, 779–791.
ꢀ
ꢀ
20. Shih, H.; Cottam, H. B.; Carson, D. A. Chem. Pharm. Bull.
2002, 3, 364–367.
ꢀ
21. De Clercq, E.; Holy, A. Nat. Rev. Drug Discov. 2005, 4,
928–940.
ꢀ
25. De Clercq, E.; Descamps, J.; De Somer, P.; Holy, A. Science
1978, 200, 563–564.
22. Girgis, N. S.; Cottam, H. B.; Larson, S. B.; Robins, R. K.
J. Heterocycl. Chem. 1987, 24, 821–827.
23. Modnikova, G. A.; Titkova, R. M.; Glushkov, R. G.; Sokolova,
A. S.; Silin, V. A.; Chernov, V. A. Khim.-Farm. Zh. 1988, 22,
185–191.
26. Buchanan, J. G.; Craven, D. A.; Whihtman, R. H.; Harnden,
M. R. J. Chem. Soc., Perkin Trans. 1 1991, 195–202.
27. Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. J. Org.
Chem. 1981, 46, 4096–4097.
28. Ma, S.; Negishi, E. J. Org. Chem. 1997, 62, 784–785.