Traceless solid-phase synthesis of 2,6,9-trisubstituted purines from resin bound 6-thiopurines

Article abstract of DOI:10.1016/S0040-4020(02)00905-5

The preparation of 6-chloro-2-iodo-9-tetrahydropyranylpurine (2), was achieved in three high yield steps from 6-chloropurine. This derivative was then selectively substituted at C-6 by reaction with a benzylthiol to give 3, a versatile intermediate for the synthesis of 2,6,9-trisubstituted purines. Reaction of 3 in palladium-catalyzed cross-coupling reactions, (including Sonogashira coupling at room temperature), as well as nucleophilic substitutions with amines occurred selectively at C-2. The 6-thiobenzyl substituent was activated through oxidation to the corresponding sulfone and replaced by various benzyl or phenyl amines. This strategy was subsequently adapted to solid support, wherein 23 is connected to Merrifield resin via a 6-thiovaleric ester linker. The presence of the linker, in combination with the use of palladacycle type catalysts improved the yield of palladium(0)-catalyzed Suzuki and Sonogashira cross-coupling reactions. This strategy opens a new route to combinatorial chemistry library synthesis of trisubstituted purines on the solid support.

Full text of DOI:10.1016/S0040-4020(02)00905-5

Tetrahedron 58 (2002) 7911–7923
Traceless solid-phase synthesis of 2,6,9-trisubstituted purines
from resin bound 6-thiopurines
*
Virginie Brun, Michel Legraverend and David S. Grierson
ˆ
Section de biologie, Institut Curie, Centre Universitaire, UMR 176 CNRS, Batiment 110-112, 91405 Orsay Cedex, France
Received 17 May 2002; accepted 23 July 2002
Abstract—The preparation of 6-chloro-2-iodo-9-tetrahydropyranylpurine (2), was achieved in three high yield steps from 6-chloropurine.
This derivative was then selectively substituted at C-6 by reaction with a benzylthiol to give 3, a versatile intermediate for the synthesis of
2,6,9-trisubstituted purines. Reaction of 3 in palladium-catalyzed cross-coupling reactions, (including Sonogashira coupling at room
temperature), as well as nucleophilic substitutions with amines occurred selectively at C-2. The 6-thiobenzyl substituent was activated
through oxidation to the corresponding sulfone and replaced by various benzyl or phenyl amines. This strategy was subsequently adapted to
solid support, wherein 23 is connected to Merrifield resin via a 6-thiovaleric ester linker. The presence of the linker, in combination with the
use of palladacycle type catalysts improved the yield of palladium(0)-catalyzed Suzuki and Sonogashira cross-coupling reactions. This
strategy opens a new route to combinatorial chemistry library synthesis of trisubstituted purines on the solid support. q 2002 Elsevier
Science Ltd. All rights reserved.
1. Introduction
In the course of our synthetic efforts toward the construction
of purine libraries using solid support technology, we
needed to introduce various amine, acetylenyl and aryl
substituents selectively at the 2-position of the purine ring
with the subsequent option to effect further nucleophilic
substitution at the C-6 position. Keeping in mind that
2-iodo(or bromo- or chloro)-6-chloropurines always react
initially at the 6-position with ammonia15,16,20,21 and
primary/secondary amines,15,18,22,23 whereas the corre-
sponding reactions of 2-fluoro-6-chloropurines produce
either 6-mono-substituted-2-fluoropurines24,25 or mixtures
of 2 or 6-monosubstituted purines,25–30 we chose to connect
the purine ring to the resin via a sulfur atom at C-6. Indeed,
it was predicted that the C6–S bond in such thiopurine
derivatives would be stable to the conditions used to
functionalize the 2 and 9-positions of the purine ring, as well
as to a variety of acidic, basic, nucleophilic, mild
electrophilic and oxophilic reaction conditions which are
classically used in solid phase synthesis. Furthermore, the
same sulfur atom would react as a good leaving group after
activation through conversion to the corresponding
sulfone.31 This step serves also to liberate the fully
functionalized purine from the polymer support.
Modified purines bearing substituents at the 2-, 6- and/or 9
positions have been associated with a wide variety of
interesting biological properties. For instance, they find
application as cyclin-dependent kinase inhibitors,1–8 ade-
nosine receptor antagonists,9–11 modulators of multidrug
resistance,12 and as antiviral13 and antineoplastic agents.14
2,6,9-Trisubstituted purines are generally obtained from the
corresponding 2,6-dihalo-purines. These intermediates react
with amine (alkyl, or aryl) and oxygen nucleophiles at C-6
prior substitution at the C-2 position.15 –18 Recently,
palladium-catalyzed cross-coupling reactions between 2,6-
dichloropurines have been explored, showing that in Stille
couplings regioselective functionalization at the 6-position
is achieved at 70–858C, whereas at higher temperature
(1208C) reaction occurs at both C-2 and C-6. Further, it has
also been shown that the regioselectivity in Stille couplings
is governed by the nature of the halogen leaving group,
since for 2-bromo or 2-iodo-6-chloropurine selective
coupling at the 2-position is achieved under mild conditions
(40–608C).19 Similar C-2 regioselectivity was observed in
Sonogashira cross-coupling reactions between 6-chloro-2-
iodo purines and various acetylenic derivatives carried out
at room temperature.10,11
In the present paper we present our results on the
development of this strategy.32–34 This involved initial
optimization of the synthetic operations in solution using
2-iodo-6-thiobenzyl-purine derivatives to mimic the resin
bound purine substrate. This chemistry, which includes Pd-
catalyzed cross-coupling reactions to produce 2-alkynylated
purine derivatives11,35,36 was, subsequently adapted to the
Keywords: 6-chloro-2-iodo-9-THP-purine; palladium-catalyzed cross-
coupling; solid-support.
*
Corresponding author. Fax: þ33-1-69-07-53-81;
e-mail: michel.legraverend@curie.u-psud.fr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00905-5

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V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
Scheme 1. (a) Benzyl thiol, ethanol, 608C; (b) RNH2, N,N-dimethylacetamide, N(nPr)3, 100–1208C; (c) m-CPBA, CH2Cl2, 08C, or rt, #10 min;
(d) benzylamine, ethanol.
solid phase. The objective of this work was to propose a
general method for the synthesis of 2,6,9-trisubstituted
purines on solid support which is compatible with
palladium-catalyzed cross-coupling reaction at C-2. As
demonstrated, the key feature of our approach is the
possibility to effect reaction at all three positions (2, 6 and
9) while the purine is on the solid support. Other reported
methods to prepare trifunctionalized purines either require
one step in the liquid phase,37 or are limited by the necessity
to make attachment of one of the amine components to the
resin before connection of the purine.38–41
mediated stannyl transfer process followed by 2-tributyl-
stannyl–iodine exchange as described by Kato and
colleagues.43 We found that the presence of the 9-tetra-
hydropyran (THP) protecting group was required in order to
obtain the 2-stannylated purine intermediate in high yield.
Indeed, in our hands, the corresponding reaction of 9-alkyl
purines did not proceed. Chelation of the 8-lithio inter-
mediate by the THP oxygen might explain this result. A
further interest for the use of tetrahydropyran group is that it
is easily removed under mild acidic condition. In this way
the 6-chloro-2-iodopurine derivative (2) was obtained in
high yield from inexpensive 6-chloropurine (in contrast to
2,6-dichloropurine which although frequently employed in
purine synthesis3,29,44,45 is cost prohibitive). Selective
substitution of the 6-chloro atom in 2 by benzylthiol was
achieved upon simple heating (608C), and led to 3 (Scheme
1) without any substitution of the 2-iodo atom.
2. Results and discussion
The 6-chloro-2-iodo-9-tetrahydropyranylpurine 2 (Scheme
1) was obtained from 6-chloro purine42 1 via a lithiation-

V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
7913
Scheme 2. (a) Benzyl thiol, t-BuOK, ethanol, rt; (b) o-iodo phenol, Pd(PPh3)4, CuI, THF.
In order to generate a small C-2 amine library, intermediate
3 was reacted with a series of primary/secondary amines to
give compounds 4a–f. (Scheme 1) The 6-benzylthio ether
motif in compounds 4b, e and f was then readily and cleanly
converted to the corresponding sulfone. This oxidation
reaction does not produce any 6-oxopurine or side chain
oxidized side-products provided that the dichloromethane
solution of m-CPBA was previously dried. Final reaction of
compounds 5 with the appropriate amine provided the
trisubstituted purine products 6a–c.
6-thiobenzyl susbstituent was not detrimental to this
reaction. The conditions for this reaction are similar to
those used for the Stille coupling of 6-chloro-2-stannylated
purines.43 The 2-iodo purine derivative 3 was in turn
subjected to Sonogashira cross-coupling reactions with
acetylene derivatives (Scheme 3). In this case, the 2-sub-
stituted acetylenic derivatives (10a, b) were obtained in
good yield at room temperature. Thus, the reactivity of the
2-iodopurine 3 containing a 6-benzylthio substituent was
comparable to the reactivity of 6-chloro-2-iodopurine.11
Note that a Sonogashira cross-coupling at 2 would require
higher temperatures in the presence of a 6-amino sub-
stituent.46 Finally, Pd(0) catalyzed Suzuki cross-coupling
reactions of iodopurine 3 with boronic acids provided a
further means for introducing aromatic substituents at C-2
(13a–d) (Scheme 4).
By treating the stannylated intermediate 7 (precursor of 2)
with benzylthiol at room temperature the 6-benzylthio
purine derivative 8 was obtained (Scheme 2). Stille cross-
coupling reaction of 8 with o-iodophenol then afforded 9 in
good yield, demonstrating that the presence of the
Scheme 3. Alkyne, (PPh3)2PdCl2, CuI, Et3N/THF; m-CPBA, CH2Cl2, 08C or rt, #10 min; (c) RNH2, rt or 808C.
Scheme 4. ArB(OH)2, Pd(PPh3)4 (3 mol%), Na2CO3, DMF, D, 24; (b) m-CPBA, CH2Cl2, rt; (c) PhCH2NH2, tert-BuOH, 608C.

7914
V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
The strategy outlined in Schemes 2–4 therefore provides an
efficient means for the creation of a C–C bond involving the
purine C-2 position, while leaving the C-6 position
unaffected. The subsequent displacement of the sulfur
substituent at C-6 in compounds 10a, b and 13a–d by
amines (aryl, benzyl,…) via the two-step oxidation SNAr
reaction protocol again proved straightforward and high
yielding. In this context it is pertinent to note that the
6-benzylthio substituent behaves as a temporary C-6
‘protecting group’, which is inert under a variety of reaction
conditions including SNAr and particularly various
palladium-catalyzed cross-coupling reactions (Sonogashira,
Suzuki, Stille).
b from 3 no reaction occurred on solid support, even by
adding 1 equiv. of palladium reagent and a large excess of
CuI and acetylene. In all cases, the resin rapidly turned
black, indicating that the palladium metal was precipitating
onto the resin surface. In addition, no purine could be
recovered after performing the two-step procedure (S-oxi-
dation and reaction with a benzylamine) used for product
release. However, employing the more coordinating
bidentate phosphine ligand ‘dppe’, the resin remained
only slightly colored, and the alkynylated derivative 22
was obtained in 25% yield. This reaction was further
improved in terms of the amount of palladium reagent, CuI
and acetylene required through use of Herrmann’s catalyst47
(catalytic quantities). In a Suzuki reaction involving resin
18, 0.5 equiv. of palladium tetrakis, an excess of base
(3 equiv.) and boronate (3 equiv.), the yield of 19 remained
low as judged by the yield (10%) of the cleaved compound
(21).
Having validated the 6-thiobenzylpurine approach to the
synthesis of 2,6,9-trisubstituted purines in solution, the next
step was to adapt this chemistry to the solid phase. The resin
bound purine 18 was thus prepared (purine directly
connected at 6 to a Merrifield-SH resin) and subjected to
two palladium-catalyzed cross-coupling reactions (Scheme
5). Under conditions that led to alkynylated derivatives 10a,
To decrease the effect of steric crowding and its probable
influence on catalyst destruction (and hence reaction yield)
Scheme 5. (a) TFA 20 equiv. dropwise in DCM then 5 min, rt; (b) P(Ph)3 1 equiv., DIAD 1 equiv., THF, 2508C, 10 min, i-PrOH 1 equiv., 10 min, then rt 2
days; (c) merrifield resin-SH 1 mmol/g 3 g in DMF, tert-BuOK 1 equiv., stirring 15 min under Ar then 17 3 equiv., 808C, 24 h; (d) resin 18,1 mmol 200 mg,
DMF, Pd(0) 0.5 equiv., DIEA 3 equiv., 4-methoxyphenylboronic acid 3 equiv., 1008C 3 days; (e) resin 18,1 mmol 200 mg, DMF, PdCl2(dppe) 1.1 equiv., CuI
2.2 equiv., ,DIEA 30 equiv., 3-methyl-pentyn-3-ol 20 equiv., 808C, 36 h; (f) m-CPBA, CH2Cl2, rt, 24 h; (g) RNH2, 708C.

V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
7915
Scheme 6. (a) 5-Mercaptovaleric acid 1.2 equiv., DMF, NaH 1.2 equiv., stirring 15 min, rt, then 17 1 equiv. 2 h; (b) merrifield resin 1 mmol/g, 1 g, DMF,
cesium carbonate 3 equiv., KI 0.5 equiv., 17 1.5 mmol; (c) resin 24,1 mmol 200 mg, DMF, Pd(0) 0.5 equiv., DIEA 3 equiv., 4-methoxyphenylboronic acid
3 equiv., 1008C 3 days. (Path A) resin 24,1 mmol 200 mg, DMF, PdCl2(dppe) 1.1 equiv., CuI 2.2 equiv., DIEA 30 equiv., 3-methyl-pentyn-3-ol 20 equiv.,
808C, 36 h. (Path B) resin 24 1 mmol/g 200 mg, NMP, Herrmann’s catalyst 20 mol%, CuI 5 mol%, DIEA 3.6 equiv., 3-methyl-pentyn-3-ol 3.9 equiv., 808C,
36 h; (d) m-CPBA, CH2Cl2, rt, 24 h; (e) RNH2, 708C.
through ‘irreversible’ coordination of Pd metal to the purine
N7 and the sulfur atom at 6, the 6-chloro-2-iodopurine
substrate 17 was connected to the Merrifield-Cl resin (35–
75 mm; 1 mmol/g) via a 5-thiovaleric acid linker (Scheme
6). Indeed, Waldmann et al.48 have recently shown that a
wide range of Pd(0) coupling reactions are highly efficient
when the substrate and polymer support are separated by a
linker. Interestingly, the formation of compound 23 was
always accompanied by small quantities (up to 15%) of the
2,6-disubstituted compound 25. After condensation of
intermediate 23 to the resin via CsCO3 promoted ester
formation, the resin bound substrate 24 was reacted with
3-methyl-1-pentyn-3-ol using the stoechiometric
Pd(dppe)Cl2–CuI system (Scheme 6). After cleavage of
the coupling product from the resin via S-oxidation with
m-CPBA and reaction of the derived sulfone with
p-methoxybenzylamine, the trisubstituted purine derivative
22 was isolated in 64% overall yield (three steps from 24).
More pertinent, conducting the same reaction using a
catalytic amount of Herrmann’s catalyst (20 mol%) pro-
vided compound 22 in 50% isolated yield after the three-
step sequence. The conditions previously used for the
Suzuki cross-coupling on resin 18, were then applied to
resin 24 ((Pd(PPhe3)4 (0.5 equiv.); DIEA 3 equiv.; boronic
acid 3 equiv.). Although not optimized with respect to the
catalyst, the presence of the linker led to significant
improvement in the yield of product 21 (10% without
linker to 35% with the linker). These experiments
demonstrate the advantage of incorporating a linker
between the resin and the purine substrate.
at the purine 2, 6 and 9 positions on solid support, and is
compatible with a variety of Pd(0) coupling protocols for
functionalization at C-2. In a recent article, Schultz et al.56
reported a closely related strategy using a 2-fluoro-6-
mercapto-polystyrene resin for the preparation of 2,6-
diamino substituted purine libraries. However, in its present
form their approach, where the purine is directly linked to
the resin, may be limited with respect to the diversity of the
chemistry that can be carried out at C-2.
3. Experimental
3.1. Material and methods
Melting points are uncorrected. NMR spectra were recorded
on either 200 (Varian, AC200) or 300 (Bruker, Avance 300)
MHz spectrometers. (Prime numbers refer to numbering of
THP protons.) MS were measured by chemical ionization
(CI, NH3), or by electrospray. Microanalyses were
performed by the Service de microanalyses, ICSN, CNRS,
Gif sur Yvette. Anhydrous solvents were freshly distilled
before use: tetrahydrofuran (THF) from sodium /benzo-
phenone under argon, N,N-dimethylacetamide and N,N-
dimethylformamide from P2O5. Flash chromatographies
were performed on silica gel 60 (SDS, 35–70 mm) columns
under pressure (5–10 bars).
3.1.1. 6-Chloro-9-(tetrahydro-pyran-2-yl)-2-tributyl-
stannanyl-9H-purine (7). The 6-chloro-9-(tetrahydro-
pyran-2-yl)-9H-purine (1) (7.5 g, 31 mmol, 1 equiv.) in
THF (30 mL),was added dropwise to a THF (200 mL)
solution of LTMP (lithium tetramethylpiperidine) (1.4 mol,
4.7 equiv.) under inert atmosphere (Argon), while main-
taining the reaction temperature below 2708C. The mixture
was stirred for 1 h, Bu3SnCl (25 mL, 93 mmol, 3 equiv.)
was added slowly, and stirring was continued for 0.5 h at
2788C. The reaction was quenched by adding aqueous
NH4Cl. The aqueous layer was extracted with dichloro-
methane, the organic layers (THF, CH2Cl2) were washed
In summary, we have demonstrated the versatility of our
strategy to build 2,6,9-trisubstituted purines in liquid as well
as in solid phase synthesis. This methodology should open
the route to the construction of more diverse purine libraries.
Although ignored in the present work, the potential of the
Mitsunobu reaction for introduction of diversity at the N-9
position of the purine ring has been clearly demonstrated by
several groups in both solution49–54 and solid phase
synthesis.55 Our method permits independent substitutions

7916
V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
with brine, dried (MgSO4), evaporated and chromato-
graphed on a silica gel column (heptane/EtOAc¼9/1–
7/3). This afforded the desired compound (7) as a colorless
oil (15.7 g, 95%). MS (CI/NH3): m/z 527 (M)þ; m/z 528
(MH)þ; m/z 445 (M2THP)þ; 1H NMR (CDCl3, 300 MHz)
d 0.8–0.86 (t, J¼7.31 Hz, 9H, CH2CH3); 1.1–1.40 (2m,
12H, 3£CH2CH2CH3); 1.52–1.7 and 2.0–2.15 (2m, 12H,
mercaptan (2 equiv.) in ethanol (25 mL) containing
sodium terbutoxide was stirred under inert atmosphere
(Ar) at room temperature for 10 min. A solution of 6-chloro-
9-(tetrahydro-pyran-2-yl)-2-tributylstannanyl-9H-purine
(7) in ethanol (5 mL) was then added and the mixture was
stirred at room temperature for 2 h. After evaporation of the
volatile material in vacuo, workup (CH2Cl2 extraction,
water washing and MgSO4 drying of the organic phase) was
followed by column chromatography (SiO2) which provided
pure material as a colorless oil in 85% yield: MS (CI/NH3):
m/z 615 (M)þ; m/z 616 (MH)þ; 1H NMR: (CDCl3,
200 MHz): d 0.7–1 (t, 9H, J¼7.2 Hz, CH3); 1–1.5 (2m,
12H, 3£CH2CH2CH3); 1.5–2.15 (m, 12H, 3£CH2Sn and
0
0
0
3£CH2Sn and H2 ,3 ,4 ); 3.65–3.78 (td, J¼2.82, 10.97 Hz,
0
0
1H, H5 ); 4.09–4.15 (m, 1H, H5 ); 5.70–5.76 (dd, J¼2.81,
9.9 Hz, 1H, H1 ); 8.02 (s, 1H, H8); 13C NMR (CDCl3,
0
0
75.47 MHz): d 8.9 (CH3); 14.1 (CH3CH2); 23.0 (C3 ); 25.2
0
(C4 ); 27.6 (CH3CH2CH2); 29.4 (CH2Sn); 32.1 (C2 ); 69.1
0
0
0
(C5 ); 82.9 (C1 ); 130.6 (C5); 141.9 (C8); 149.5 (C4); 150.4
(C6); 181.1 (C2). Anal. calcd for C22H37N4OClSn: C, 50.07;
H, 7.06; N, 10.61. Found: C, 50.6; H, 6.7; N, 10.2.
0
0
0
0
00
H2 3 4 ); 3.6–3.8 (m, 1H, H5 ); 4.05–4.2 (m, 1H, H5 ); 4.67
0
(s, 2H, CH2Ph); 5.65–5.85 (m, 1H, H1 ); 7.1–7.5 (2m,
2þ3H, Ph); 8.06 (s, 1H, H8); 13C NMR: (CDCl3,
0
75.47 MHz) d 7.1 (CH3); 13.6 (CH2CH3); 22.6 (C3 ); 24.7
3.1.2. 6-Chloro-2-iodo-9-(tetrahydro-pyran-2-yl)-9H-
purine (2). A solution of 6-chloro-9-(tetrahydro-pyran-2-
yl)-2-tributylstannanyl-9H-purine (7) (12.2 g, 23.1 mmol)
in THF (220 mL) containing iodine (7.4 g, 27.7 mmol,
1.2 equiv.) was stirred at room temperature until dis-
appearance of the stannanyl-purine (as judged by TLC
heptane/EtOAc 1/1). The reaction was quenched by adding
a saturated solution of NaS2O3. The aqueous layer was
extracted with dichloromethane, the organic layers were
washed with brine, dried (MgSO4) and evaporated. Silica
gel chromatography column (heptane/EtOAc¼8/2) of the
residue gave compound (2) as a white solid, which was
recrystallized from heptane in 79% yield; MS (CI/NH3): m/z
365 (MH)þ; m/z 364 (M)þ; 1H NMR (CDCl3, 200 MHz): d
0
(C4 ); 27.7 (CH2CH2CH3); 28.9 (CH2Sn); 31.5 (C2 ); 31.9
0
0
(CH2Ph); 68.4 (C5); 81.2 (C4 ); 126.8, 128.2, 128.8, 138.2
(Ph); 129.8 (C5); 139.2 (C8); 146.9 (C4); 157.2 (C6); 179.7
(C2). Anal. calcd for C23H29N5O2S: C, 56.59; H, 7.20; N,
9.10; S, 5.2. Found: C, 56.66; H, 7.41; N, 9.11; S, 5.04.
3.1.5. 6-Chloro-2-iodo-(9H)-purine (16). To a solution of
2 (2.5 g, 6.8 mmol) in 100 mL of CH2Cl2, were added
slowly 20 equiv. (10.5 mL) of a 50% solution of TFA in
CH2Cl2 at room temperature. The mixture turned rapidly
red, and the reaction was complete in a few min. The solvent
was evaporated and the residue solubilized in AcOEt and
washed with an aqueous solution of NaHCO3. After silica
gel chromatography (heptane/AcOEt: 1/1–3/7) pure 16 was
obtained after crystallization from CH2Cl2/heptane in 84%
yield. Mp 2548C; 1H NMR (DMSO-d6): d 8.63 (s, 1H, H8);
14.01 (broad s, 1H, NH). 13C NMR (CDCl3, 75.47 MHz): d
117.6 (C2); 129.5 (C5); 147.0 (C8); 147.3 (C4); 155.9 (C6).
Anal. calcd for C5H2N4ClI: C, 21.41; H, 0.72; N, 19.98; Cl,
12.64; I, 45.25. Found: C, 21.41; H, 0.48; N, 20.11; Cl,
12.70; I, 45.49.
0
0
0
1.55–2.2 (m, 6H, H2 ,3 ,4 ); 3.6–3.85 (dt, J¼3.61, 10.29 Hz,
0
0
1H, H5 ); 4.05–4.2 (m, 1H, 1H5 ); 5.6–5.8 (dd, J¼2.06,
9.81 Hz, 1H1 ); 8.21 (s, 1H, H8); 13C NMR (CDCl3,
0
0
0
0
50 MHz): d 22.5 (C3 ); 24.7 (C4 ); 32.1 (C2 ); 68.9 (C5 );
0
0
82.3 (C1 ); 116.6 (C2); 131.6 (C5); 143.0 (C8); 150.3 (C4);
151.6 (C6). Anal. calcd for C10H10ClIN4O: C, 32.95; H,
2.76; N, 15.37; I, 34.81. Found: C, 33.14; H, 2.76; N, 15.12;
I, 35.05.
3.1.3. 6-Benzylsulfanyl-2-iodo-9-(tetrahydro-pyran-2-
yl)-9H-purine (3). A solution of 6-chloro-2-iodo-9H-9-
tetrahydropyranylpurine (2) in ethanol (15 mL) containing
triethylamine (2 equiv.) and benzylmercaptan (2 equiv.)
was stirred under inert atmosphere (Ar) at 608C for 4 h. The
mixture was cooled to room temperature, filtered. The solid
compound was washed with ethanol and recrystallised from
ethanol. The filtrate was evaporated to dryness before
purification by column chromatography eluting with
heptane/ethylacetate (4/6) to give a further amount of pure
3. Desired compound was obtained in 93% yield; mp 186–
3.2. Preparation of resin bound 2-iodo-9-isopropyl-(9H)-
purine (18)
A suspension of Merrifield-SH resin57 (1 mmol/g; 2 g) in
DMF under argon was treated with 1 equiv. of Potassium
tert-butoxide. The yellowish-orange suspension was stirred
mechanically and slowly for 15 min at room temperature.
The purine 175 (3 equiv.) was then added and the suspension
was stirred for 24 h at 808C under argon. The resin 18 was
filtrated and washed successively with THF, CH2Cl2, water,
EtOH, THF, acetone, CH2Cl2 and dried in vacuo.
1
1878C; MS (CI/NH3): m/z 452 (M)þ; m/z 453 (MH)þ; H
0
0
0
NMR (CDCl3; 200 MHz): d 1.55–2.25 (2m, 6H, H2 ,3 ,4 );
3.3. Preparation of resin bound 2-iodo-9-isopropyl-(9H)-
purine (24)
0
3.65–3.9 (td, J¼2.85, 11.1 Hz, 1H, H5 ); 4.05–4.3 (m, 1H,
0
H5 ); 4.55 (s, 2H, CH2Ph); 5.6–5.8 (dd, 1H, J¼1.9, 8.0 Hz,
13
0
H1 ); 7.15–7.4 and 7.4–7.6 (2m, 5H, Ph); 8.04 (s, 1H, H8);
A suspension of Merrifield resin (1 mmol/g; 1 g) in DMF
under argon was treated with 3 equiv. of cesium carbonate
(977 mg), KI (0.5 equiv., and purine 23 (630 mg,
1.5 equiv.). The suspension was stirred for 24 h at 808C
under argon. The resin 23 was filtrated and washed
successively with DMF, THF, EtOH, water, EtOH, THF,
CH2Cl2 and dried in vacuo. Quantitative yield according to
elemental analysis (Anal. calcd for: N, 4.04; S, 2.30. Found:
N, 4.23; S, 2.42).
0
C NMR: d 22.6 (C3 ); 24.8 (C4 ); 32.1 (C2 ); 33.3 (CH2Ph);
0
0
0
0
68.8 (C5 ); 81.8 (C1 ); 118.4 (C2); 127.4, 128.4, 129.4, 137.2
(Ph); 131.1 (C5); 140.3 (C8); 148.4 (C4); 161.6 (C6). Anal.
calcd for C17H17IN4OS: C, 45.14; H, 3.79; N, 12.39; S, 7.09.
Found: C, 44.81; H, 3.71; N, 12.14; S, 7.21.
3.1.4. 6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-2-tri-
butylstannanyl-9H-purine (8). A solution of benzyl-

V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
7917
1
3.3.1. 5-(2-Iodo-9-isopropyl-9H-purin-6-yl sulfanyl)-
pentanoic acid (23) and 5-[2-(4-carboxy-butylsulfanyl)-
9-isopropyl-9H-purin-6-yl sulfanyl)-pentanoic acid (25).
NaH (60%) (721 mg, 8.5 mmol) in DMF (10 mL) was
added to a solution of 5-mercaptovaleric acid58,59 (1.4 g,
8.5 mmol) in DMF (20 mL). The mixture was stirred for
15 min at room temperature and 6-chloro-2-iodo-9-iso-
propyl (9H)-purine (17)5 (2.3 g, 7.13 mmol) in DMF
(20 mL) was added. After 2 h at room temperature, solvent
was evaporated, the residue was solubilized in water
(50 mL) and acidified (pH 1). After extraction of the
aqueous phase with AcOEt (5£20 mL) the combined
organic phases were washed with water and dried over
MgSO4 before evaporation. Silica gel chromatography led
to 23 after crystallization from a mixture of CH2Cl2/heptane
in 62% yield. Mp 189–1908C; MS (CI/NH3): m/z 419
1078C; MS (CI/NH3): m/z 426 (MH)þ; m/z 425 (M)þ; H
NMR (CDCl3, 200 MHz) d 1.5–1.85 and 1.85–2.35 (m,
0
0 0
5Hþm, 5H, H2 3 4 and 2£CH2CH2N); 3.6–3.95 (m, 5H,
0
CH2OH, CH2N, H5 ); 4.05–4.2 (m, 1H, H5 ); 4.2–4.35 (m,
00
1H, CHCH2OH); 4.5–4.65 (d, J¼7.32 Hz, 2H, CH2Ph);
0
5.4–5.5 (m, 1H, H5 ); 7.15–7.35 and 7.35–7.5 (2m, 5H,
Ph); 7.76–7.78 (d, 1H, 1H8). (2 diastereoisomers); 13C
0
NMR (CDCl3, 75.47 MHz): d 23.2 (C3 ); 24.4 (C4 ); 25.2
0
(CH2CH2N); 30.2 (CH2CHN); 31.1 (C2 ); 31.6 (CH2Ph); 33
(CH2N); 49.5 (CH2OH); 61.6 (CHN); 69.0 (C5 ); 82.5 (C1 );
124.7 (C5); 127.5, 128.8, 129.3, 137.6 (Ph); 138.1 (C8);
150.3 (C4); 158.0 (C2); 162.5 (C6). Anal. calcd for
C22H27N5O2S: C, 62.09; H, 6.4; N, 16.46; S, 7.54. Found:
C, 62.11; H, 6.49; N, 16.45; S, 7.39.
0
0
0
3.4.2. {1-[6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-yl]-piperidin-2-yl}-methanol (4b). Com-
pound 3 was treated with 2-piperidinemethanol according
to method A to afford compound 4b in 68% yield: mp 718C;
MS (electrospray): m/z 440 (MH)þ; m/z 462 (MþNa)þ; 1H
NMR (CDCl3, 300 MHz): d 1.45–1.75 (m, 8H) and 1.95–
1
(M21)þ; H NMR: (CDCl3): d 1.56–1.58 (d, J¼6.8 Hz,
6H, 2CH3); 1.81–1.84 (m, 4H, CH2CH2CH2CH2); 2.41–
2.46 (t, J¼6.79 Hz, 2H, CH2COOH); 3.31–3.36 (t,
J¼6.77 Hz, 2H, CH2S); 4.79–4.88 (sept, J¼6.8 Hz, 1H,
CH(CH3)2); 7.93 (s, 1H, H8); 13C NMR: (DMSO) d 22.3
(CH(CH3)2); 23.9 (CH2CH2S); 28.3 (CH2 CH2COOH); 28.9
(CH2S); 33.5 (CH2COOH); 47.5 (CH(CH3)2); 119.1 (C2);
131.2 (C5); 143.0 (C8); 149.2 (C4); 161.1 (C6); 174.6
(COOH). Anal. calcd for C13H17N4IO2S: C, 37.15; H, 4.08;
N, 13.33; S, 7.66. Found: C, 36.91; H, 4.05; N, 13.02; Cl,
12.70; S, 7.66.
0
0
0
2.1 (m, 4H) (H2 ,3 ,4 and 3£CH2 piperidine); 2.95–3.05 (m,
0
1H, CH2N); 3.63–3.76 (m, 2H, H5 and 1H, CH2OH); 3.90–
0
3.97 (m, 1H, CH2OH); 4.0–4.15 (m, 1H, H5 ); 4.4–4.56 (m,
2H, CH2Ph); 4.65–4.80 (m, 1H, CHN); 4.93–5.01 (m, 1H,
0
CHN); 5.47–5.52 (m, 1H, H1 ); 7.2–7.29 and 7.39–7.45
(2m, 5H, Ph); 7.78 (s, 1H, H8); 13C NMR (CDCl3,
0
d 20.2 (CH2 piperidine); 23.2 (C4 ); 25.3
300 MHz):
0
0
A minor compound was then eluted from the column in 15%
yield which was identified as the bis-2,6-substituted purine
25. Mp 152–1538C. MS (CI/NH3): m/z 427 (M)þ; m/z 449
(Mþ2þNa)þ; m/z 471 (Mþ2Na)þ 1H NMR: (DMSO): d
1.52–1.54 (d, J¼6.76 Hz, 6H, 2CH3); 1.61–1.77 (m, 8H,
2£CH2CH2CH2CH2); 2.21–2.28 (t, J¼6.97 Hz, 4H, CH2-
COOH); 3.15–3.20 (t, J¼6.87 Hz, 2H, CH2S); 3.28–3.33
(t, J¼6.76 Hz, 2H, CH2S); 4.70–4.79 (sept, J¼6.76 Hz, 1H,
CH(CH3)2); 8.38 (s, 1H, H8); 12.03 (broad s, 2H,
2£COOH); 13C NMR: (DMSO) d 22.3 (CH(CH3)2);
24.0–24.21 (2£CH2CH2S); 27.9–29.0 (2£CH2 CH2-
COOH); 30.7–31 (2£CH2S); 33.5–33.6 (2£CH2COOH);
47.5 (CH(CH3)2); 128.9 (C5); 142.0 (C8); 149.2 (C4); 159.9
(C6); 162.2 (C2); 74.6 (COOH). Anal. calcd for
C18H26N4O4S2: C, 50.68; H, 6.14; N, 13.13; S, 15.03.
Found: C, 50.41; H, 6.23; N, 13.41; S, 15.02.
(CH2 piperidine); 26.1 (C3 ); 31.6 (C2 ); 33.0 (CH2Ph); 35.5
(CH2 piperidine); 40.4 (CH2N); 53.4 (CHN); 63.2 (CH2OH);
0
0
68.9 (C5 ); 81.8 (C1 ); 124.6 (C5); 127.5, 128.8, 129.8, 138.1
(Ph); 137.8 (C8); 150.3 (C4); 159.6 (C2); 160.5 (C6). Anal.
calcd for C23H29N5O2S: C, 62.84; H, 6.65; N, 15.93; S, 7.29.
Found: C, 62.53; H, 6.93; N, 15.55; S, 7.11.
3.4.3. 2-[6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-ylamino]ethanol (4c). Compound 3 was
treated with ethanolamine according to method A to afford
compound 4c in 68% yield: mp 50–588C (decomposition);
MS (electrospray): m/z 386 (MH)þ; m/z 408.2 (MþNa)þ;
m/z 793.4 (2MþNa)þ; H NMR (CDCl3): d 1.4–1.75 and
1
0
0
0
1.90–1.98 (m, 3H, and m, 3H, H2 ,3 ,4 ); 3.5–3.7 (2m,
0
2Hþ1H, CH2N, H5 ); 3.7–3.8 (t, J¼5.16 Hz, 2H, CH2OH);
0
4.0–4.1 (m, 1H, H5 ); 4.44 (s, 2H, CH2Ph); 5.35–5.45 (m,
0
1H, H1 ); 5.6 (s broad, 1H, NH); 7.1–7.4 (2m, 5H, Ph); 7.72
0
0
3.4. General procedure for the preparation of
compounds 4a–f (SNAr). Method A
(s, 1H, H8); 13C NMR (CDCl3): d 22.7 (C3 ); 25.2 (C4 ); 31.6
0
(C2 ); 32.9 (CH2Ph); 45.3 (CH2N); 63.5 (CH2OH); 68.9
0
0
(C5 ); 81.9 (C1 ); 125.1 (C5); 127.5, 128.5, 129.3, 137.7 (Ph);
138.0 (C8); 150.1 (C4); 159.4 (C2); 161.5 (C6). Anal. calcd
for C19H23N5O2S: C, 59.20; H, 6.01; N, 18.17; S, 8.32.
Found: C, 58.91; H, 6.08; N, 18.23; S, 8.12.
A mixture of 6-benzylsulfanyl-2-iodo-9-(tetrahydro-pyran-
2-yl)-9H-purine (3) (1.1 mmol) in N,N-dimethylacetamide
(8 mL) containing tripropylamine (3 equiv.) and 3 equiv. of
the appropriate amine was stirred under inert atmosphere
(Ar) at 1208C for 12–20 h. After evaporation of the volatile
material in vacuo, workup (CH2Cl2 extraction, water
washing and MgSO4 drying of the organic phase) was
followed by column chromatography (SiO2) which provided
pure material after crystallisation from heptane or
cyclohexane.
3.4.4. 2-{[6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-yl]-ethyl-amino}ethanol (4d). Compound 3
was treated with 2-(ethylamino)ethanol according to the
method A, to afford compound 4d in 70% yield: mp 1228C
(white crystals); MS (electrospray): m/z 414 (MH)þ; m/z
1
436 (MþNa)þ; H NMR (CDCl3, 300 MHz): d 1.04–1.09
(t, J¼6.9 Hz, 3H, CH3); 1.45–1.63 and 1.80–1.95 (m, 3H
0
0
0
0
and m, 3H, H2 ,3 ,4 ); 3.53–3.69 (m, 5H, H5 , 2£CH2N);
3.4.1. {(R)-1-[6-Benzylsulfanyl-9-(tetrahydro-pyran-2-
yl)-9H-purin-2-yl]-pyrrolidin-2-yl}-methanol (4a). Com-
pound 3 was treated with 2-piperidinemethanol according to
method A to afford compound 4a in 68% yield: mp 106–
3.74–3.80 (t, J¼4.7 Hz, 2H, CH2OH); 3.85–4.05 (m,
0
1H, H5 ); 4.45 (s, 2H, CH2Ph); 5.35–5.40 (dd, J¼3.5,
0
9 Hz, 1H, H1 ); 7.10–7.2 and 7.25–7.35 (2m, 5H, Ph); 7.67

7918
V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
1
(s, 1H, H8); 13C NMR (CDCl3, 75.47 MHz): d 13.3 (CH3);
1158C; H NMR (CDCl3, 300 MHz): d 1.06–1.27 (t, 3H,
J¼7.40 Hz, CH3CH2); 1.64 (s, 3H, CH3); 1.52–2.28 (m,
0
23.1 (C3 ); 25.2 (C4 ); 31.4 (C2 ); 32.9 (CH2Ph); 44.9
0
0
0
(CH2CH2N); 51.7 (CH2OH); 64.0 (CH3CH2N); 68.9 (C5 );
0
82.1 (C1 ); 124.6 (C5); 127.5, 128.8, 129.1, 137.5 (Ph); 138.0
(C8); 150.1 (C4); 158.9 (C2); 161.0 (C6). Anal. calcd for
C21H27N5O2S: C, 60.99; H, 6.58; N, 16.93; S, 7.75. Found:
C, 60.91; H, 6.67; N, 17.21; S, 7.81.
0
0
0
8H, H2 ,3 ,4 and CH2CH3); 3.66–3.82 (td, J¼3.74, 11.82 Hz,
0
0
1H, H5 ). 4.06–4.18 (dd, J¼3.84, 10.29 Hz, 1H, H5 ); 4.62
0
(s, 2H, CH2Ph); 5.71–5.80 (dd, J¼2.18, 10.30 Hz, 1H, H1 );
7.14–7.33 and 7.41–7.53 (5H, m, Ph); 8.17 (s, 1H, H8); 13
C
0
NMR (CDCl3, 75.47 MHz): d 9.0 (CH3CH2); 22.6 (C4 );
0
0
24.8 (C3 ); 28.9 (CH2CH3); 32.2 (C2 ); 33.0 (CH2Ph); 36.4
0
0
3.4.5. 6-Benzylsulfanyl-2-morpholin-4-yl-9-(tetrahydro-
pyran-2-yl)-9H-purine (4e). Compound 3 was treated with
morpholine according to method A to afford compound 4e
in 91% yield: mp 1288C; MS (electrospray): m/z 412
(MH)þ; m/z 434 (MþNa)þ; 1H NMR (CDCl3, 300 MHz): d
(CH3); 68.7 (C5 ); 69.9 (C–OH); 81.6 (C1 ); 82.8 (C2–C);
89.8 (C–C–OH); 129.3, 128.4, 127.2 (Ph); 130.1 (C5);
137.4 (Ph); 141.2 (C8); 145.2 (C2); 147.7 (C4); 160.6 (C6).
Anal. calcd for C23H26N4O2S: C, 65.38; H, 6.20; N, 13.26;
S, 7.59. Found: C, 65.08; H, 6.31; N, 13.09; S, 7.43.
0
0 0
1.50–1.75 and 1.79–1.99 (2£m, 3Hþ3H, H2 3 4 ); 3.60–
0
3.75 (m, 1H, H5 ); 3.65–3.73 and 3.75–3.79 (2£m, 4Hþ4H,
3.5.2. 4-[6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-yl]-2-methyl-but-3-yn-2-ol (10b). Treatment
of 3 with 2-methyl-3-butyn-2-ol according to method B
afforded compound 10b in 74% yield: mp 65–728C
(decomposition); MS (electrospray): m/z 409.1 (MH)þ;
m/z 431.1 (MþNa)þ; 1H NMR (CDCl3, 300 MHz): d 1.55–
0
2CH2N, 2CH2O); 4.04–4.1 (m, 1H, H5 ); 4.49 (s, 2H,
0
CH2Ph); 5.47–5.52 (m, 1H, H1 ); 7.15–7.24 and 7.34–7.37
(2£m, 5H, Ph); 7.79 (s, 1H, H8); 13C NMR (CDCl3,
0
0
0
75.47 MHz): d 23.2 (C3 ); 25.2 (C4 ); 31.7 (C2 ); 32.9
0
(CH2Ph); 45.3 (2CH2N); 67.1 (2CH2O); 68.9 (C5 ); 81.7
0
(C1 ); 124.9 (C5); 127.4, 128.7, 129.1, 138.2 (Ph); 138.1
(C8); 150.4 (C4); 158.4 (C2); 160.3 (C6). Anal. calcd for
C21H25N5O2S: C, 61.29; H, 6.12; N, 17.02; S, 7.79. Found:
C, 61.02; H, 6.17; N, 16.96; S, 7.61.
0
0
0
1.80 and 2.02–2.20 (2£m, 3Hþ3H, H2 ,3 ,4 ); 1.71 (s, 6H,
2CH3); 2.42 (s broad, 1H, OH); 3.65–3.85 (td, J¼2.83,
0
0
11.1 Hz, 1H, H5 ); 4.10–4.23 (m, 1H, H5 ); 4.65 (s, 2H,
0
CH2Ph); 5.73–5.81 (dd, J¼2.15, 10.3 Hz, 1H, H1 ); 7.20–
7.35 and 7.45–7.52 (2m, 5H, Ph); 8.21 (s, 1H, H8); 13C
0 0
NMR (CDCl3, 75.47 MHz): d 23.1 (C4 ); 25.2 (C3 ); 31.5
3.4.6. 6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-9H
purin-2-yl]-(3-methoxybenzyl)-amine (4f). Compound 3
was treated with 3-methoxybenzylamine according to
method A to afford compound 4f in 52% yield: mp 1138C;
0
(CH3); 32.6 (C2 ); 33.6 (CH2Ph); 65.80 (C–OH); 69.2 (C5 );
0
0
82.0 (C2–C); 82.1 (C1 ); 91.3 (C–C–OH); 127.7, 128.9,
129.8 (Ph); 130.4 (C5); 137.6 (Ph); 141.7 (C8); 145.6 (C2);
148.13 (C4); 161.2 (C6). Anal. calcd for C22H24N4O2S: C,
64.68; H, 5.92; N, 13.71; S, 7.85. Found: C, 64.76; H, 6.09;
N, 13.53; S, 7.89.
1
MS (electrospray): m/z 484 (MþNa)þ; H NMR (CDCl3,
0
0
0
300 MHz): d 1.50–1.65 and 1.88–1.99 (2£m, 6H, H2 ,3 ,4 );
0
3.65–3.76 (m, 1H, H5 ) and (s, 3H, OMe); 4.10–4.18 (m,
0
1H, H5 ); 4.51 (s, 2H, CH2Ph); 4.65–4.67 (d, 3H, J¼5.7 Hz,
0
1H, CH2Ar); 5.50–5.56 (m, 2H, H1 þNH); 6.78–6.82 (m,
3.6. General procedure for the preparation of
compounds 13a–d (Suzuki coupling). Method C
1H) and 6.91–6.96 (m, 2H) (Ar); 7.17–7.30 (m, 4H) and
7.35–7.38 (m, 2H) (Ar); 13C NMR (CDCl3, 75.47 MHz): d
0
22.9 (C3 ); 25.0 (C4 ); 31.5 (C2 ); 32.7 (CH2Ph); 46.2
0
0
Dimethylformamide (5 mL) was added to an argon purged
flask containing 6-benzylsulfanyl-2-iodo-9-(tetrahydro-
0
0
(NCH2Ar); 55.3 (OCH3); 68.7 (C5 ); 81.6 (C1 ); 112.6,
113.2, 119.9 (Ar); 125.2 (C5); 127.2, 128.5, 129.1, 129.7
(Ar); 137.7 (C8); 137.9–141.3 (Ar); 150.1 (C4); 158.4 (C2);
159.9 (C–OMe); 160.7 (C6). Anal. calcd for C25H27N5O2S:
C, 65.05; H, 5.90; N, 15.17; S, 6.95. Found: C, 64.79; H,
5.91; N, 15.17; S, 6.71.
pyran-2-yl)-9H-purine
(3)
(0.33 mmol),
K2CO3
(1.5 equiv.), appropriate substituted phenylboronic acid
(1.5 equiv.) and tetrakis(triphenylphosphine) palladium
(5 mol%). The mixture was stirred under argon at 1008C
for 48 h. After cooling to ambient temperature, the mixture
was evaporated in vacuo and the residue was chomato-
graphed on a silica gel column (heptane/ethylacetate 9/1–
7/3). Pure compounds were obtained after recrystallisation
from heptane or cyclohexane.
3.5. General procedure for the preparation of
compounds 10a,b (Sonogashira coupling). Method B
A solution of 6-benzylsulfanyl-2-iodo-9-(tetrahydro-pyran-
2-yl)-9H-purine (3) (1.1 mmol), CuI (1/20 equiv. mol),
bistriphenylphosphine palladium dichloride (1/5 equiv.
mol), triethylamine (1.2 equiv.) and the appropriate alkyne
(1.2 equiv.) in dried tetrahydrofuran (20 mL) was stirred
under inert atmosphere (Ar) at room temperature in the dark
for 8–20 h (until disappearance of the iodopurine as judged
by TLC in heptane/ethylacetate to dryness and subjected to
silica gel column chromatography (heptane/ethylacetate
9/1–7/3). Compounds were obtained as pure solids after
crystallization from heptane.
3.6.1. 6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-2-p-
tolyl-9H-purine (13a). p-Tolyl derivative 13a was obtained
from 3, according to method C, in 40% yield as white
needles after crystallization from cyclohexane and a few
drops of heptane: mp 148–1498C; MS (electrospray): m/z
417.2 (MH)þ; m/z 439.1 (MþNa)þ; 1H NMR (CDCl3,
0
0
0
300 MHz): d 1.4–1.7 and 1.8–2.0 (2£m, 6H, H2 ,3 ,4 ); 2.23
0
(s, 3H, CH3); 3.65–3.75 (td, J¼2.7, 11.3 Hz, 1H, H5 ); 4.0–
0
4.1 (m, 1H, H5 ); 4.67 (s, 2H, CH2Ph); 5.71–5.75 (dd,
0
J¼2.9, 10.00 Hz, 1H, H1 ); 7.05–7.30 and 7.35–7.41 (2£m,
5Hþ2H, SCH2Ph, 2CHAr); 8.03 (s, 1H, H8); 8.30–8.35 (d,
J¼8.21 Hz, 2H, 2CHAr); 13C NMR (CDCl3, 75.47 MHz): d
3.5.1. [6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-9H-
purin-2-yl]-3-methyl-pent-1-yn-3-ol (10a). 2-Iodo deriva-
tive 3 was treated with 3-methyl-1-pentyn-3-ol according to
Method B to afford compound 10a in 80% yield: mp 113–
0
21.9 (CH3); 23.2 (C3 ); 25.3 (C4 ); 32.3 (C2 ); 33.1 (CH2Ph);
0
0
0
0
69.1 (C5 ); 82.3 (C1 ); 127.6, 128.7, 128.9, 129.4, 129.6 (Ph,
Ar); 129.9 (C5); 135.7 (C2); 138.3–140.8 (Ar); 140.9 (C8);

V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
7919
149.3 (C4); 158.8 (Ph); 160.2 (C6). Anal. calcd for
C24H24N4OS: C, 69.20; H, 5.81; N, 13.45; S, 7.70. Found:
C, 68.99; H, 5.98; N, 12.98; S, 7.33.
6-benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-2-tributylstan-
nanyl-9H-purine (8) (0.81 mmol), CuI (20 mol%), tetrakis-
triphenylphosphine palladium (5 mol%) and 2-iodophenol
(3 equiv.). The mixture was stirred under argon at 808C in
the dark for 16 h. After cooling to room temperature, the
mixture was evaporated in vacuo. After workup (CH2Cl2
extraction, water washing and MgSO4 drying of the organic
phase), the residue was purified on silica gel column
(heptane/ethylacetate 9/1–7/3). The compound was recrys-
tallized from heptane to give white pure crystals in 70%
yield: mp 1498C; MS (CI/NH3): m/z 419 (M)þ; m/z 420
(MH)þ; 1H NMR (CDCl3, 300 MHz): d 1.56–1.84 (m, 3H)
3.6.2. 6-Benzylsulfanyl-2-(4-methoxyphenyl)-9-(tetra-
hydro-pyran-2-yl)-9H-purine (13b). p-Methoxyphenyl
derivative 13b was obtained from compound 3, according
to method C, in 93% yield: mp 1178C; MS (electrospray):
1
m/z 433 (MH)þ; m/z 455.1 (MþNa)þ; H NMR (CDCl3,
300 MHz): d 1.50–1.65 and 1.85–1.99 (2£m, 3Hþ3H,
0
H2 ,3 ,4 ); 3.70–3.87 (m, 1H, H5 ); 3.87 (s, 3H, OCH3); 4.11–
0
0
0
0
4.22 (m, 1H, H5 ); 4.76 (s, 2H, CH2Ph); 5.76–5.87 (dd,
0
0 0 0
J¼2.9, 9.8 Hz, 1H1 ); 6.93–7.04 (d, J¼8.9 Hz, 2H, 2CHAr);
and 1.92–2.20 (m, 3H) (H2 3 4 ); 3.64–3.81 (td, J¼3.08,
0 0
11.09 Hz, 1H, H5 ); 4.03–4.21 (m, 1H, H5 ); 4.65 (s, 2H,
7.16–7.34 (m, 3H, Ph) and 7.41–7.53 (m, 2H, Ph); 8.12 (s,
1H, H8); 8.42–8.56 (d, J¼8.9 Hz, 2CHAr); 13C NMR
CH2Ph); 5.59–5.73 (dd, J¼2.78, 9.81 Hz, 1H, H1 ); 6.83–
0
0
(CDCl3, 75.47 MHz): d 22.8 (C3 ); 24.9 (C4 ); 31.8 (C2 );
0
0
7.02 (m, 2H, Hphenol); 7.11–7.49 (m, 6H, Phþ1Hphenol);
8.09 (s, 1H, H8); 8.43–8.57 (m, 1H, Hphenol); 13C NMR: d
0
0
35.4 (CH2Ph); 55.4 (OCH3); 68.7 (C5 ); 81.8 (C1 ); 113.7,
127.2, 128.5, 128.9 (Ph); 129.3 (C5); 129.9 (Ar); 130.7 (C2);
137.9 (Ar); 140.4 (C8); 148.9 (C4); 158.2 (Ar); 159.7 (C6);
161.5 (Ar). Anal. calcd for C24H24N4O2S: C, 66.64; H, 5.59;
N, 12.95; S, 7.41. Found: C, 66.46; H, 5.69; N, 12.86; S,
7.41.
0
23.2 (C3 ); 25.3 (C4 ); 32.1 (C2 ); 34.0 (CH2Ph); 69.2 (C5 );
0
0
0
0
82.9 (C1 ); 118.1, 119.6, 119.7 (Cphenol); 128.0, 129.1, 129.4
(Ph); 129.9–133.1 (Cphenol); 136.6 (C5); 141.3 (C8); 147.2
(C2); 159.3 (C4); 160.16 (C–OH); 161.2 (C6). Anal. calcd
for C23H22N4O2S: C, 66.01; H, 5.30; N, 13.39; S, 7.66.
Found: C, 66.19; H, 5.39; N, 13.31; S, 7.61.
3.6.3. 4-[6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-yl]benzaldehyde (13c). According to method
C, this compound was obtained in 70% yield: mp 1768C;
3.7. General procedure for the oxidation of sulfur to the
sulfone derivative. Method D
1
MS (electrospray): m/z 453 (MþNa)þ; H NMR (CDCl3,
0
0
0
300 MHz): d 1.4–1.9 and 1.9–2.2 (2£m, 3Hþ3H, H2 ,3 ,4 );
A solution of m-CPBA (2.2 equiv.) in CH2Cl2 was dried
(MgSO4) and added to the purine in CH2Cl2 (5 mL) at room
temperature. The mixture was stirred until disappearance of
the sulfur as judged by TLC on silica gel in CH2Cl2/EtOH
99/1 (2–10 min). Water was added and after workup
(CH2Cl2 extraction, water washing and MgSO4 drying of
the organic phase), the residue was chromatographed on a
silica gel column (heptane/ethylacetate 1/1–3/7). Com-
pounds could be recrystallized from heptane but were
sufficiently pure after chromatography to be used directly in
the next step.
0
3.75–3.85 (td, J¼2.8, 11.3 Hz, 1H, H5 ); 4.15–4.22 (m, 1H,
0
H5 ); 4.76 (s, 2H, CH2Ph); 5.82–5.87 (dd, J¼2.8, 10.02 Hz,
0
1H, H1 ); 7.1–7.35 (m, 3H) and 7.46–7.50 (m, 2H) (Ph);
7.95–7.98 (d, J¼8.3 Hz, 2H, 2CHAr); 8.19 (s, 1H, H8);
13
8.65–8.68 (d, J¼8.3 Hz, 2H, 2CHAr); 10.09 (s, 1H, CHO);
0
C NMR (CDCl3, 75.47 MHz): d 22.3 (C3 ); 24.9 (C4 );
0
0
0
0
31.9 (C2 ); 32.9 (CH2Ph); 68.8 (C5 ); 82.0 (C1 ); 127.3,
128.6, 128.8, 128.0, 129.7 (Ar); 130.2 (C5); 137.2 (Ar);
137.5 (C–CO); 141.4 (C8); 143.4 (C2); 148.7 (C4); 156.8
(C–C2); 160.4 (C6); 192.1 (CO). Anal. calcd for
C24H22N4O2S: C, 66.96; H, 5.15; N, 13.01; S, 7.45.
Found: C, 66.81; H, 5.19; N, 13.04; S, 7.35.
3.7.1. {1-[6-Benzylsulfonyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-yl]-piperidin-2-yl}-methanol (5b). According
to method D, this compound was obtained from 4b in 74%
yield: mp: 75–858C (decomposition); MS (electrospray):
m/z 494.1 (MþNa)þ; 1H NMR (CDCl3, 300 MHz): d 1.50–
3.6.4. 1-{4-[6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-yl]phenyl}-ethanone (13d). According to
method C, this compound was obtained from 3 in 73%
yield: mp: 1548C; MS (electrospray): m/z 467 (MþNa)þ;
m/z 468 (MHþNa)þ; 1H NMR (CDCl3, 300 MHz): d 1.60–
0
0 0
2.03 (2m, 12H, H2 3 4 and 3CH2 piperidine); 2.96–3.1 (m, 1H,
0
CH2N); 3.66–3.82 (m, 3H, H5 þCH2OH); 4.05–4.15 m,
0
0
0
1.90 and 1.92–2.20 (2£m, 6H, H2 ,3 ,4 ); 2.65 (s, 3H, CH3);
0
1H, H5 ); 4.67–4.79 (m, 1H, 1CH2N); 4.79 (s, 2H, CH2Ph);
0
3.75–3.85 (td, J¼2.81, 11.3 Hz, 1H, H5 ); 4.15–4.25 (m,
0
4.99 (m, 1H, CHCH2OH); 5.56–5.61 (m, 1H, H1 ); 7.22–
7.35 (m, 5H, Ph); 8.06 (s, 1H, H8). 13C NMR (CDCl3,
0
1H, H5 ); 4.76 (s, 2H, CH2Ph); 5.82–5.86 (dd, J¼2.8,
0
10.05 Hz, 1H, H1 ); 7.19–7.35 and 7.45–7.50 (2£m,
0
75.47 MHz): d 19.5 (CH2 piperidine); 22.7 (C4 ); 24.8
3Hþ2H, Ph); 8.02–8.07 (d, J¼8.6 Hz, 2H, 2CHAr); 8.19
(s, 1H, H8); 8.57–8.62 (d, J¼8.6 Hz, 2H, 2CHAr); 13C NMR
0
0
(CH2 piperidine); 25.2 (CH2 piperidine); 25.4 (C3 ); 31.4 (C2 );
40.4 (CH2N); 52.9 (CHCH2OH); 59.4 (CH2Ph); 61.7
0
(CDCl3, 75.47 MHz): d 23.2 (C3 ); 25.3 (C4 ); 27.2 (CH3);
0
0
0
(CH2OH); 68.7 (C5 ); 81.7 (C1 ); 122.4 (C5); 126.9, 128.7,
128.8, 131.2 (Ph); 142.1 (C8); 153.2 (C2); 155.6 (C4); 158.8
(C6).
0
0
0
32.2 (C2 ); 35.8 (CH2Ph); 69.2 (C5 ); 82.5 (C1 ); 127.7,
128.83, 128.85, 128.9, 129.31 (Ar); 130.5 (C5); 137.9 (Ph);
138.5 (C2); 141.6 (C8); 142.5 (C–CvO); 148.9, 157.8
(Ar); 198.3 (CvO). Anal. calcd for C24H22N4O2S: C,
67.54; H, 5.44; N, 12.60; S, 7.21. Found: C, 67.49; H, 5.41;
N, 12.42; S, 7.12.
3.7.2. 6-Benzylsulfonyl-2-morpholin-4-yl-9-(tetrahydro-
pyran-2-yl)-9H-purine (5e). Compound 4e was treated
with m-CPBA according to method D to afford compound
5e with 63% yield: mp: 1778C; MS (electrospray): m/z 466.1
1
(MþNa)þ; H NMR (CDCl3, 300 MHz): d 1.54–1.67 and
3.6.5. 2-[6-Benzylsulfanyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-yl]-phenol (9) (Stille). Dried tetrahydrofuran
(12 mL) was added to an argon purged flask containing
0
1.90–1.98 (2m, 6H, H2 ,3 ,4 ); 3.61–3.78 (2m, 5H,
0
0
0
0
H5 þ2CHN, 2CHO); 4.01–4.07 (m, 1H, H5 ); 4.73 (s, 2H,

7920
V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
(d, J¼9.09 Hz, 2H, 2CHAr). 13C NMR (CDCl3,
0
CH2Ph); 5.49–5.54 (dd, J¼9.07, 2.29 Hz, 1H, H1 ); 8.06 (s,
13
0
1H, H8). C NMR (CDCl3): d 22.7 (C3 ); 24.8 (C4 ); 31.5
0
0 0 0
75.47 MHz): d 20.7 (C3 ); 23.0 (C4 ); 32.3 (C2 ); 55.8
0
(C2 ); 44.8 (CHN); 59.2 (CH2Ph); 66.8 (CHO); 68.8 (C5 );
0
81.7 (C1 ); 122.9 (C5); 126.8, 128.7, 128.8, 131.2 (Ph); 142.5
(C8); 153.6 (C2); 155.6 (C4);157.8 (C6).
0
0
0
(OCH3); 60.8 (CH2Ph); 69.3 (C5 ); 82.7 (C1 ); 114.4 (CHAr);
127.1 (Ph); 128.4 (C5); 129.1–129.2 (Ph); 129.3 (C2); 130.7
(CHAr); 132.4 (Ph);145.9 (C8); 153.5 (C2–C); 154.9 (C4);
159.1 (C6); 162.6 (C–OMe).
3.7.3. 6-Benzylsulfonyl-9-(tetrahydro-pyran-2-yl)-9H-
purin-2-yl]-(3-methoxy-benzyl)-amine (5f). According to
method D, this compound was obtained from 4f with 74%
3.8. General procedure for sulfone substitution by
various amines. Method E
1
yield as an oil: MS (electrospray): m/z 516 (MþNa)þ; H
NMR (CDCl3, 300 MHz): d 1.41–1.68 and 1.69–1.98 (2m,
A mixture of the sulfone in ethanol or t-BuOH containing
1.2–2.5 equiv. of the appropriate amine was stirred at 25–
808C for 0.5–20 h. After evaporation of the volatile material
in vacuo, workup (CH2Cl2 extraction, water washing and
MgSO4 drying of the organic layer) was followed by
column chromatography (SiO2) which provided pure
material after crystallisation from heptane, cyclohexane or
heptane/CH2Cl2.
0
6H, H2 3 4 ); 3.94 (s, 3H, OMe); 3.71–3.93 (m, 1H, H5 );
0
0
0
0
4.08–4.13 (m, 1H, H5 ); 4.61 (s, 2H, SO2CH2Ph); 4.80 (s
0
broad, 2H, NHCH2Ph); 5.55–5.58 (m, 1H, H1 ); 6.0 (s
broad, 1H, NH); 6.73–6.83 (m, 1H); 6.85–7.0 (m, 2H);
7.12–7.46 (m, 5H) (Ar); 8.10 (s, 1H, H8). 13C NMR
0
(CDCl3, 75.47 MHz): d 22.6 (C3 ); 24.8 (C4 ); 31.3 (C2 );
0
0
0
46.1 (SO2CH2Ph); 55.2 (OCH3); 59.3 (CH2NH); 68.7 (C5 );
0
81.9 (C1 ); 112.6, 113.3, 119.83 (Ar); 123.5 (C5); 126.7,
128.6, 128.7, 129.6, 131.2, 140.3 (Ar); 142.2 (C8); 153.7
(C4); 155.6 (C2); 158.8 (C6); 159.8 (Ar).
3.8.1. {1-[6-Butylamino-9-(tetrahydro-pyran-2-yl)-9H-
purin-2-yl]-piperidin-2-yl}-methanol (6a). According to
method E, compound 5b was treated with butylamine
(2.5 equiv.) at room temperature for 5 h to afford compound
6a with 89% yield: mp: 50–608C (decomposition); MS
3.7.4. 2-[6-Benzylsulfonyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-yl]3-methyl-pent-1-yn-3-ol (11a). Compound
10a was treated with m-CPBA according to method D to
afford compound 11a with 63% yield: mp: 1008C; MS
(CI/NH3): m/z 355 (M-THP); 1H NMR (CDCl3, 300 MHz):
d 1.05–1.25 (t, J¼7.40 Hz, 3H, CH3CH2); 1.65 (s, 3H,
1
(electrospray): m/z 411.1 (MþNa)þ; m/z 389 (MH)þ; H
NMR (CDCl3, 300 MHz): d 0.86–0.96 (t, J¼7.20 Hz, 3H,
CH3); 1.36–1.48 (hex, J¼7.2 Hz, 2H, CH2CH3); 1.49–2.15
0
0 0
(m, 14H, CH3CH2CH2, 3CH2 piperidine and H2 3 4 ); 3.04–
3.13 (m, 1H, NCH2); 3.40–3.60 (m, 2H, CH2NH); 3.66–
0
0 0
CH3); 1.55–2.25 (8H, m, H2 3 4 and q, J¼7.40 Hz,
0
CH2CH3); 3.65–3.9 (m, 1H, H5 ); 4.1–4.3 (m, 1H, H5 );
0
0
0
3.77 (m, 2H, H5 and CH2OH); 4.04–4.15 (m, 2H, H5 and
CH2OH); 4.71–4.77 (m, 1H, NCH2); 4.96–5.01 (m, 1H,
0
4.92 (s, 2H, CH2Ph); 5.75–5.95 (m, 1H, H1 ); 7.2–7.5 (m,
5H, Ph); 8.48 (s, 1H8). 13C NMR (CDCl3, 75.47 MHz): d 8.9
0
CHCH2OH); 5.46–5.51 (m, 1H, H1 ); 6.8 (s large, 1H, NH);
7.63 (s, 1H, H8). 13C NMR (CDCl3, 75.47 MHz): d 13.8
0
(CH3CH2); 22.4 (C4 ); 24.6 (C3 ); 28.7 (CH3); 32.1 (C2 );
0
0
0
36.2 (CH2CH3); 59.04 (CH2Ph); 68.9 (C5 þC–OH); 81.7
0
(CH3); 20.08 (CH2CH3); 20.1 (CH2 piperidine); 23.0 (C3 );
0
(C2–C); 82.3 (C1 ); 92.6 (C–C–OH); 126.0, 126.03, 126.3,
0
0
25.2–25.0 (2CH2 piperidine); 26.5 (C4 ); 31.4 (C2 ); 31.8
(CH3CH2CH2); 40.08 (NCH2); 40.12 (CH2NH); 53.3
131.1 (Ph); 131.4 (C5);145 (C2); 146.5 (C8); 153.4 (C4);
153.5 (C6).
0
0
(CHCH2OH); 60.40 (CH2OH); 68.5 (C5 ); 81.3 (C1 );
113.4 (C5); 134.5 (C8); 150.2 (C4); 154.6 (C2); 160.6 (C6).
Anal. calcd for C20H32N6O2: C, 61.83; H, 8.30; N, 21.63.
Found: C, 61.61; H, 8.53; N, 21.43.
3.7.5. 4-[6-Benzylsulfonyl-9-(tetrahydro-pyran-2-yl)-
9H-purin-2-yl]-2-methyl-but-3-yn-2-ol (11b). Compound
10b was treated with m-CPBA according to method D to
afford compound 11b with 78% yield: mp: 96–1008C
(decomposition); MS (electrospray): m/z 463.1 (MþNa)þ;
1H NMR (CDCl3, 300 MHz): d 1.69 (s, 6H, 2CH3); 1.67–
3.8.2. (4-Chloro-benzyl)-[2-morpholin-4-yl-9-(tetra-
hydro-pyran-2-yl)-9H-purin-6-yl]-amine (6b). According
to method E, treatment of 5e with 2 equiv. of p-chloro-
benzylamine in t-BuOH at 808C for 16 h afford compound
6b with 67% yield: mp: 2058C; MS (electrospray): m/z
429.2 (MH)þ; m/z 451.1 (MþNa)þ; 1H NMR (CDCl3,
300 MHz): d 1.59–1.77 (m, 3H) and 1.99–2.10 (m, 3H)
0
2.13 (2m, 6H, H2 3 4 ); 3.5–3.80 (m, 1H, H5 ); 4.15–4.22 (m,
0
0
0
0
1H, H5 ); 4.91 (s, 2H, CH2Ph); 5.82–5.86 (dd, J¼2.33,
0
10.4 Hz, 1H, H1 ); 7.25–7.30 and 7.36–7.41 (2m, 5H, Ph);
8.51 (s, 1H, H8). 13C NMR (CDCl3, 75.47 MHz): d 22.9
0
(C3 ); 25.0 (C4 ); 31.3 (2CH3); 32.5 (C2 ); 59.5 (CH2Ph);
0
0
0
0
0
(H2 ,3 ,4 ); 3.74 (s, 8H, 2CH2N and 2CH2O); 3.69–3.75 (m,
0
0
65.8 (C–OH); 69.3 (C5 ); 81.0 (C2–C); 82.7 (C1 ); 93.7
(C–C–OH); 126.7 (C5); 129.1, 129.3, 131.7 (Ph); 145.4
(C2); 146.9 (C8); 153.6 (C6); 153.9 (C4).
0
1H, H5 ); 4.11–4.16 (m, 1H, H5 ); 4.91 (s, 2H, CH2Ph);
0
0
5.50–5.56 (m, 1H, H1 ); 6.16 (s broad, 1H, NH); 7.26 (s, 4H,
Ph); 7.62 (s, 1H, H8). 13C NMR (CDCl3, 75.47 MHz): d 23.4
0
(C3 ); 25.3 (C4 ); 31.8 (C2 ); 44.1 (CH2Ph); 45.3 (CH2N);
0
0
3.7.6. 6-Benzylsulfonyl-2-(4-methoxy-phenyl)-9-(tetra-
hydro-pyran-2-yl)-9H-purine (14). This compound was
obtained from 13b, according to method D, in 94% yield:
mp 153–1558C; MS (electrospray) m/z 487.1 (MþNa)þ; 1H
NMR (CDCl3, 300 MHz): d 1.5–1.9 and 2.0–2.25 (2£m,
0
0
67.3 (CH2O); 68.9 (C5 ); 81.6 (C1 ); 114.1 (C5); 128.9,
129.2, 133.2 (Ph); 135.5 (C8); 138.2 (C–Cl); 151.2 (C4);
154.6 (C6); 159.6 (C2). Anal. calcd for C21H25N6O2Cl: C,
58.81; H, 5.87; N, 19.59; O, 7.46; Cl, 8.27. Found: C, 58.86;
H, 5.92; N, 19.36; Cl, 8.31.
0
0
0
0
6H, H2 ,3 ,4 ); 3.72–3.82 (td, J¼2.83, 11.19 Hz, 1H, H5 );
0
3.86 (s, 3H, OMe); 4.12–4.21 (m, 1H, H5 ); 4.92 (s, 2H,
3.8.3. N6-(4-Ethoxy-benzyl)-N2-(3-methoxy-benzyl)-9-
(tetrahydro-pyran-2-yl)-9H-purine-2,6-diamine
0
CH2Ph); 5.81–5.86 (dd, J¼2.46 Hz, 10.21 Hz, 1H, H1 );
(6c).
According to method E, treatment of 5f in ethanol with
2 equiv. of p-ethoxybenzylamine at 558C for 8 h afford 6c as
6.95–7.15 (d, J¼9.09 Hz, 2H, 2CHAr); 7.19–7.23 and
7.31–7.37 (2£m, 3Hþ2H, Ph); 8.35 (s, 1H, H8); 8.44–8.48

V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
7921
an oil with 74% yield: MS (electrospray): m/z 489.2 (MH)þ;
m/z 511.1 (MþNa)þ; 1H NMR (CDCl3, 300 MHz): d 1.20–
1.25 (t, J¼6.9 Hz, 3H, CH3CH2); 1.40–1.57 (m, 3H) and
1948C; MS (electrospray): m/z 416.2 (MH)þ; m/z 438.2
1
(MþNa)þ; H NMR (CDCl3, 300 MHz): d 1.60–1.90 and
0
0
0
1.93–2.14 (2m, 6H, H2 ,3 4 ); 3.70–3.84 (m, 1H, H5 ); 3.86
0
0
0
0
0
0
(s, 3H, OMe); 4.15–4.21 (m, 1H, H5 ); 4.99 (s broad, 2H,
1.77–1.82 (m, 3H, H2 3 4 ); 3.50–3.60 (m, 1H, H5 ); 3.58 (s,
0
3H, OMe); 3.78–3.85 (q, J¼6.9 Hz, 2H, CH2CH3); 3.91–
CH2Ph); 5.78–5.83 (dd, J¼2.76, 9.92 Hz, 1H, H1 ); 6.15 (s
0
3.93 (m, 1H, H5 ); 4.43–4.46 (d, J¼5.9 Hz, 2H, HNCH2-
broad, 1H, NH); 6.94–6.97 (d, J¼8.9 Hz, 2H, 2CHAr);
7.25–7.44 (2m, 5H, Ph); 7.91 (s, 1H, H8); 8.42–8.45 (d,
J¼8.9 Hz, 2H, 2CHAr). 13C NMR (CDCl3, 75.47 MHz): d
0 0 0
22.9 (C3 ); 25.6 (C4 ); 31.9 (C2 ); 44.5 (CH2Ph); 55.3
(OCH3); 68.7 (C5 ); 81.6 (C1 ); 113.5 (CHAr); 118.1 (C5);
127.3, 127.8, 128.6 (Ph); 129.7 (CHAr); 131.6 (C2); 137.6
(C8); 139.2 (Ph); 150.1 (C4); 154.2 (C2–C); 159.1 (C6);
161.1 (C–OMe). Anal. calcd for C24H25N5O2: C, 69.38; H,
6.06; N, 16.86. Found: C, 69.24; H, 6.15; N, 17.03.
ArOEt); 4.49 (s broad, 2H, HNCH2ArOMe); 5.20–5.24 (t,
0
J¼5.9 Hz, 1H, NHCH2ArOEt); 5.32–5.37 (m, 1H, H1 );
6.21 (s broad, 1H, NHCH2ArOMe); 6.58–6.64 (m, 3H);
6.76–6.79 (m, 2H); 7.00–7.06 (m, 3H) (Ar); 7.38 (s, 1H,
H8). 13C NMR (CDCl3, 75.47 MHz): d 15.2 (CH2CH3); 23.3
0
0
0
(C3 ); 27.3 (C4 ); 31.8 (C2 ); 44.2 (CH2Ar); 46.4 (CH2Ar);
0
0
0
0
55.5 (OCH3); 63.7 (OCH2CH3); 68.9 (C5 ); 81.6 (C1 );
112.7, 113.8, 114.8, 120.3, 129.4, 129.7, 131.5, 142.4,
155.2, 160.1 (Ar); 114.5 (C5); 135.0 (C8); 151.1 (C4); 158.5
(C6); 160.0 (C2). Anal. calcd for C27H32N6O3·1/2H2O: C,
65.17; H, 6.68; N, 16.89; O, 11.25. Found: C, 65.25; H,
6.65; N, 16.84; O, 11.24.
3.8.7. 4-Methoxybenzyl-[2-(4-methoxy-phenyl)-9-(iso-
propyl)-9H-purin-6-yl]-amine (21). To a suspension of
resin 18 or resin 24 (,1 mmol) in dry DMF (6 mL) was
added Pd(PPh3)4 (0.5 equiv.), DIEA (3 equiv.) and
4-methoxyphenylboronic acid (3 equiv.). The mixture was
stirred mechanically for 3 days at 1008C. The resin was then
filtrated and washed with THF, EtOH, water, THF, CH2Cl2
and finally dried under vacuo. The resin was treated with
m-CPBA according to method D and cleavage of the
product was carried out according to method E with
4-methoxybenzylamine (5 equiv.) in THF. The resin was
filtrated and washed with THF and CH2Cl2. The filtrate and
washing were evaporated, chromatographed on silica gel
column (heptane/AcOEt: 9/1–3/7), and finally crystallized
from heptane to yield 10% of 21 from resin 18 or 35% of 21
from resin 24. Mp 1308C; MS (electrospray): m/z 404.1
(MH)þ; m/z 427.1 (MþNa)þ; 1H NMR (CDCl3, 300 MHz)
d 1.61–1.63 (d, J¼6.79 Hz, 6H, 2CH3); 3.76 (s, 3H, OMe);
3.83 (s, 3H, OMe); 4.85–4.93 (m, J¼6.79 Hz, 1H,
CH(CH3)2 and 4.85–5.05 (m, 2H, CH2Ph); 6.82–6.85 (d,
J¼8.94 Hz, 2H, m-CHAr); 6.94–6.97 (d, J¼8.9 Hz, 2H,
m-CHAr); 7.34–7.37 (d, J¼8.9 Hz, 2H, o-CHAr); 7.76 (s,
1H, H8); 8.44–8.47 (d, J¼8.94 Hz, 2H, o-CHAr); 13C NMR
(CDCl3, 75.47 MHz): d 23.1 (CH3); 44.5 (CH2Ph); 47.1
(CH(CH3)2); 55.6 (OMe); 56.0 (OMe); 113.9–114.4 (Ph);
119.1 (C5); 129.6, 130.0, 131.8, 132.2 (Ph); 137.7 (C8);
150.6 (C4); 154.6 (C2); 158.9 (C6); 159.3 and 161.4 (2£C–
OMe). Anal. calcd for C23H25N5O2: C, 68.47; H, 6.25; N,
17.36. Found: C, 68.34; H, 6.23; N, 17.38.
3.8.4. (3R,S)-1-[6-(4-Methoxy-benzylamino)-9-(tetra-
hydro-pyran-2-yl)-9H-purin-2-yl]-3-methyl-pent-1-yn-
3-ol (12a). According to method E, treatment of 11a in
ethanol with p-methoxybenzylamine at room temperature
for 25 min afford compound 12a in quantitative yield: mp:
1548C; 1H NMR (CDCl3, 200 MHz): d 1.05–1.15 (t,
J¼7.3 Hz, 3H, CH2CH3); 1.6 (s, 3H, CH3); 1.55–2.25 (m,
0
0 0
8H, H2 3 4 þCH2CH3); 2.68 (s broad, 1H, OH); 3.79 (s, 3H,
0
OMe); 3.65–3.85 (m, 1H5 ); 4.1–4.15 (m, 1H5 ); 4.82 (s,
0
0
2H, CH2Ph); 5.65–5.75 (m, 1H, H1 ); 6.75–6.9 (d,
J¼8.35 Hz, 2H, 2CH, Ph); 7.2–7.35 (d, J¼8.35 Hz, 2H,
2CH, Ph); 7.95 (s, 1H, H8). 13C (CDCl3, 50 MHz): d 9.0
0
0
0
(CH2CH3); 22.8 (C4 ); 24.9 (C3 ); 28.9 (CH3); 32.2 (C2 );
0
36.3 (CH2CH3); 44.3 (CH2Ph); 55.2 (OCH3); 68.7 (C5 );
0
81.2 (C1 ); 83.3 (C2–C); 88.4 (C–C–OH); 113.9 (Ph);
118.7 (C5); 129.3 (Ph); 130.4 (C8); 138.2 (Ph); 146.25 (C6);
148.6 (C2); 154.2 (C4);158.9 (C–OMe). Anal. calcd for
C24H29N5O3: C, 66.19; H, 6.71; N, 16.08. Found: C, 66.32;
H, 6.72; N, 16.26.
3.8.5. (3R,S)-4-[6-(4-Methoxy-phenylamino)-9-(tetra-
hydro-pyran-2-yl)-9H-purin-2-yl]-2-methyl-but-3-yn-2-
ol (12b). According to method E, treatment of 11b in
t-BuOH with 2.5 equiv. of p-ethoxyaniline at 808C for 16 h
afford compound 12b (recrystallized from cyclohexane)
with 67% yield: mp: 2388C; MS (electrospray): m/z 408.1
(MH)þ; m/z 430 (MþNa)þ; 1H NMR (CDCl3, 300 MHz): d
3.8.8. (3R,S)-1-[9-Isopropyl-6-(4-methoxy-benzyl-
amino)-9H-purin-2-yl]-3-methyl-pent-1-yn-3-ol (22). To
a suspension of resin 18 (,1 mmol) in dry DMF (6 mL)
was added dichloro(1,2-bis(diphenylphosphino)ethane)-
palladium(II) (Strem) (1.1 equiv.), DIEA (30 equiv.), CuI
(2.2 equiv.) and 3-methyl-pent-1-yn-3-ol (20 equiv.). The
mixture was stirred mechanically for 36 h at 808C. The resin
was then filtrated and washed with THF, EtOH, water,
EtOH, THF, CH2Cl2 and finally dried under vacuo. The
resin was treated with m-CPBA according to method D and
cleavage of the product was carried out according to method
E with 4-methoxybenzylamine (5 equiv.) in THF. The resin
was filtrated and washed with THF and CH2Cl2. The filtrate
and washing were evaporated, chromatographed on silica
gel column (heptane/AcOEt: 9/1–3/7), and finally crystal-
lized from heptane to yield 25% of 22 from resin 18. From
resin 24, the yield was improved to 64% using the same
conditions as above. The yield of 22 raised to 50% from
0
0 0
1.66 (s, 6H, 2CH3); 1.65–2.16 (m, 6H, H2 3 4 ); 3.71–3.82
0
(m, 1H, H5 ); 3.82 (s, 3H, OMe); 4.13–4.18 (m, 1H, H5 );
0
0
5.76–5.80 (dd, J¼2.26, 10.4 Hz, 1H, H1 ); 6.91–6.94 (d,
J¼9.0 Hz, 2H, 2CHAr); 7.65–7.68 (d, J¼9.0 Hz, 2H,
2CHAr); 7.88 (s large, 1H, NH); 8.08 (s, 1H, H8). 13C
0
0
NMR (CDCl3, 75.47 MHz): d 22.7 (C3 ); 24.9 (C4 ); 31.1
0
(2CH3); 32.3 (C2 ); 55.5 (OCH3); 65.4 (C–OH); 68.9 (C5 );
0
0
81.6 (C1 ); 82.3 (C2–C); 90.9 (C–C–OH); 118.7 (C5);
114.3, 122.3, 131.3 (Ar); 138.7 (C8); 145.1 (C2); 148.6 (C4);
151.6 (C6);156.4 (C–OMe). Anal. calcd for C22H25N5O3:
C, 64.85; H, 6.18; N, 17.19; O, 11.78. Found: C, 64.90; H,
6.30; N, 16.87; O, 11.92.
3.8.6. Benzyl-[2-(4-methoxy-phenyl)-9-(tetrahydro-
pyran-2-yl)-9H-purin-6-yl]-amine (15). According to
method E, treatment of 14 in t-BuOH with benzylamine at
608C for 10 h afforded compound 15 with 68% yield: mp:

7922
V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
19. Langli, G.; Gundersen, L.-L.; Rise, F. Tetrahedron 1996, 52,
5625–5638.
resin 24 when the catalyst used was trans-di(m-acetato)-
bis[o-(di-o-tolylphosphino)benzyldipalladium] (20 mol%),
CuI (20 mol%), DIEA (3.5 equiv.) and 3.9 equiv. of alcyne,
in NMP as solvent, instead of DMF. Mp 134–1368C. H
NMR was identical to the spectrum previously reported for
a sample synthesized in liquid phase.6
20. Nair, V.; Young, D. A. J. Org. Chem. 1985, 50, 406–408.
21. Huang, M.-C.; Avery, T. L.; Blakley, R. L.; Secrist, III.; J. A.;
Montgomery, J. A. J. Med. Chem. 1984, 27, 800–802.
22. Kim, H. O.; Schinazi, R. F.; Nampalli, S.; Shanmuganathan,
K.; Cannon, D. L.; Alves, A. J.; Jeong, L. S.; Beach, J. W.;
Chu, C. K. J. Med. Chem. 1993, 36, 30–37.
1
23. Nandanan, E.; Jang, S.-Y.; Moro, S.; Kim, H. O.; Siddiqui,
M. A.; Russ, P.; Marquez, V. E.; Busson, R.; Herdewijn, P.; K,
H. T.; Boyer, J. L.; Jacobson, K. A. J. Med. Chem. 2000, 43,
829–842.
Acknowledgements
Financial support from the ‘Association pour la Recherche
sur le Cancer’ (ARC, Subvention No 5313) is gratefully
acknowledged as well as a MENRT scholarship for V. B.
24. Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett. 1997,
38, 1161–1164.
25. Trivedi, B. K.; Bruns, R. F. J. Med. Chem. 1989, 32,
1667–1673.
26. Jeong, L. S.; Schinazi, R. F.; Warren Beach, J.; Kim, H. O.;
Shanmuganathan, K.; Nampalli, S.; Chun, M. W.; Chung,
W.-K.; Choi, B. G.; Chu, C. K. J. Med. Chem. 1993, 36,
2627–2638.
References
1. Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc, S.; Meijer,
L. Bioorg. Med. Chem. Lett. 1998, 8, 793–798.
2. Chang, Y. T.; Gray, N. S.; Rosania, G. R.; Sutherlin, D. P.;
Kwon, S.; Norman, T. C.; Sarohia, R.; Leost, M.; Meijer, L.;
Schultz, P. G. Chem. Biol. 1999, 6, 361–375.
3. Imbach, P.; Capraro, H. G.; Furet, P.; Mett, H.; Meyer, T.;
Zimmermann, J. Bioorg. Med. Chem. Lett. 1999, 9, 91–96.
4. Furet, P.; Zimmermann, J.; Capraro, H. G.; Meyer, T.; Imbach,
P. J. Comput.-Aided Mol. Des. 2000, 14, 403–409.
5. Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc, S.; Meijer,
L.; Giocanti, N.; Sadri, R.; Favaudon, V. Bioorg. Med. Chem.
1999, 7, 1281–1293.
27. Lee, K.; Choi, Y.; Gullen, E.; Schlueter-Wirtz, S.; Schinazi,
R. F.; Cheng, Y.-C.; Chu, C. K. J. Med. Chem. 1999, 42,
1320–1328.
28. Wang, P.; Bolon, P. J.; Newton, M. G.; Chua, C. K.
Nucleosides Nucleotides 1999, 18, 2819–2835.
29. Kim, H. O.; Schinazi, R. F.; Shanmuganathan, K.; Jeong, L. S.;
Beach, J. W.; Nampalli, S.; Cannon, D. L.; Chu, C. K. J. Med.
Chem. 1993, 36, 519–528.
30. Jeong, L. S.; Schinazi, R. F.; Beach, J. W.; Kim, H. O.;
Nampalli, S.; Shanmuganathan, K.; Alves, A. J.; McMillan,
A.; Chu, C. K.; Mathis, R. J. Med. Chem. 1993, 22, 181–195.
31. Gayo, L. M.; Suto, M. J. Tetrahedron Lett. 1997, 38, 211–214.
32. Brun, V.; Legraverend, M.; Grierson, D. S. Tetrahedron Lett.
2001, 42, 8169–8171.
6. Legraverend, M.; Tunnah, P.; Noble, M.; Ducrot, P.; Ludwig,
O.; Grierson, D. S.; Leost, M.; Meijer, L.; Endicott, J. J. Med.
Chem. 2000, 43, 1282–1292.
33. Brun, V.; Legraverend, M.; Grierson, D. S. Tetrahedron Lett.
2001, 42, 8165–8167.
7. Sielecki, T. M.; Boylan, J. F.; Benfield, P. A.; Trainor, G. L.
J. Med. Chem. 2000, 43, 1–18.
34. Brun, V.; Legraverend, M.; Grierson, D. S. Tetrahedron Lett.
2001, 42, 8161–8164.
8. Ducrot, P.; Legraverend, M.; Grierson, D. S. J. Med. Chem.
2000, 43, 4098–4108.
35. Cristalli, G.; Camaioni, E.; Vittori, S.; Volpini, R.; Borea,
P. A.; Conti, A.; Dionisotti, S.; Ongini, E.; Monopoli, A.
J. Med. Chem. 1995, 38, 1462–1472.
9. Wanner, M. J.; Von Frijtag Drabbe Ku¨nzel, J. K.; Ijzerman,
A. P.; Koomen, G.-J. Bioorg. Med. Chem. Lett. 2000, 10,
2141–2144.
36. Rieger, J. M.; Brown, M. L.; Sullivan, G. W.; Linden, J.;
Macdonald, T. L. J. Med. Chem. 2001, 44, 531–539.
37. Nugiel, D. A.; Cornelius, L. A. M.; Corbett, J. W. J. Org.
Chem. 1997, 62, 201–203.
10. Abiru, T.; Miyashita, T.; Watanabe, Y.; Yamaguchi, T.;
Machida, H.; Matsuda, A. J. Med. Chem. 1992, 35,
2253–2260.
11. Harada, H.; Asano, O.; Hoshino, Y.; Yoshikawa, S.;
Matsukura, M.; Kabasawa, Y.; Niijima, J.; Kotake, Y.;
Watanabe, N.; Kawata, T.; Inoue, T.; Horizoe, T.; Yasuda,
N.; Minami, H.; Nagata, K.; Murakami, M.; Nagaoka, J.;
Kobayashi, S.; Tanaka, I.; Abe, S. J. Med. Chem. 2001, 44,
170–179.
38. Ding, S.; Gray, N. S.; Ding, Q.; Schultz, P. G. J. Org. Chem.
2001, 66, 8273–8276.
39. Norman, T. C.; Gray, N. S.; Koh, J. T.; Schultz, P. G. J. Am.
Chem. Soc. 1996, 118, 7430–7431.
40. Dorff, P. H.; Garigipati, R. S. Tetrahedron Lett. 2001, 42,
2771–2773.
12. Dhainaut, A.; Regnier, G.; Tizot, A.; Pierre, A.; Leonce, S.;
Guilbaud, N.; Kraus-Berthier, L.; Atassi, G. J. Med. Chem.
1996, 39, 4099–4108.
41. Brill, W. K.-D.; Riva-Toniolo, C.; Mu¨ller, S. Synlett 2001(7),
1097–1100.
42. Robins, R. K.; Godefroi, E. F.; Taylor, E. C.; Lewis, L. R.;
Jackson, A. J. Am. Chem. Soc. 1961, 83, 2574–2579.
43. Kato, K.; Hayakawa, H.; Tanaka, H.; Kumamoto, H.; Shindo,
S.; Shuto, S.; Miyasaka, T. J. Org. Chem. 1997, 62,
6833–6841.
13. Gao, H.; Mitra, A. K. Synthesis 2000, 329–351.
14. Bonnet, P. A.; Robins, R. K. J. Med. Chem. 1993, 36,
635–653.
15. Montgomery, J. A.; Holum, L. B. J. Am. Chem. Soc. 1958, 80,
404–408.
44. Fiorini, M. T.; Abell, C. Tetrahedron Lett. 1998, 39,
1827–1830.
16. Sutcliffe, E. Y.; Robins, R. K. J. Org. Chem. 1963, 28,
1662–1666.
17. Robins, M. J.; Uznanski, B. Can. J. Chem. 1981, 59,
2601–2607.
18. Nair, V.; Fasbender, A. J. Tetrahedron 1993, 49, 2169–2184.
45. Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J. Am.
Chem. Soc. 2002, 124, 1594–1596.
46. Matsuda, A.; Shinozaki, M.; Yamaguchi, T.; Homma, H.;

V. Brun et al. / Tetrahedron 58 (2002) 7911–7923
7923
Nomoto, R.; Miyasaka, T.; Watanabe, Y.; Abiru, T. J. Med.
Chem. 1992, 35, 241–252.
53. Wang, P.; Schinazi, R.; Chu, C. K. Bioorg. Med. Chem. Lett.
1998, 8, 1585–1588.
¨
47. Herrmann, W. A.; Brossmer, C.; Ofele, K.; Reisinger, C.-P.;
54. Jenny, T. F.; Previsani, N.; Benner, S. A. Tetrahedron Lett.
1991, 32, 7029–7032.
Priermeier, T.; Beller, M.; Fischer, H. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1844–1848.
55. Choo, H.; Chong, Y.; Chu, C. K. Org. Lett. 2001, 3,
1471–1473.
48. Stieber, F.; Grether, U.; Waldmann, H. Angew. Chem., Int. Ed.
Engl. 1999, 38, 1073–1077.
56. Ding, S.; Gray, N.; Ding, Q. M.; Wu, X.; Schultz, P. G.
J. Comb. Chem. 2002, 4, 183–186.
49. Wachtmeister, J.; Classohn, B.; Samuelsson, B. Tetrahedron
1995, 51, 2029–2038.
57. Frechet, J.-M.; de Smet, M. D.; Farrall, M. J. Polymer 1979,
20, 675–680.
50. Peterson, M. L.; Vince, R. J. Med. Chem. 1991, 34,
2787–2797.
58. Danehy, J. P.; Egan, C. P.; Switalski, J. J. Org. Chem. 1971,
36, 2530–2534.
51. Kotra, L. P.; Newton, M. G.; Chu, C. K. Carbohydr. Res. 1998,
306, 69–80.
59. Urquhart, G. G.; Gates, J. W.; Connor, R. Organic Synthesis;
Horning, E. C., Ed.; Wiley: New York, 1955; Collect. Vol. III,
pp 363–365.
52. Toyota, A.; Katagiri, N.; Kaneko, C. Chem. Pharm. Bull.
1992, 40, 1039–1041.