Microwave-assisted Pd(OH)2-catalyzed direct C-H arylation of free-(NH2) adenines with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2008.10.021

A direct C-H arylation of free-(NH₂) adenines using Pd(OH)₂/C (Pearlman's catalyst) and stoichiometric amount of copper iodide under ligandless microwave activation is described. This new protocol proved to be highly effective to synthesize a variety of 8-aryladenine derivatives 3 without prior protection of the amino substituent. The arylation reaction takes place rapidly within few minutes and allows the coupling to proceed regioselectively at the 8-position with a wide range of aryl halides including aryl iodides, bromides and the less reactive aryl chlorides.

Full text of DOI:10.1016/j.tetlet.2008.10.021

Tetrahedron Letters 49 (2008) 7279–7283
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted Pd(OH)2-catalyzed direct CÀH arylation of free-(NH2)
adenines with aryl halides
*
Sophian Sahnoun, Samir Messaoudi, Jean-François Peyrat, Jean-Daniel Brion, Mouad Alami
Univ Paris-Sud, CNRS, BioCIS UMR 8076, Laboratoire de Chimie Thérapeutique, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry, F-92296, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A direct CÀH arylation of free-(NH2) adenines using Pd(OH)2/C (Pearlman’s catalyst) and stoichiometric
amount of copper iodide under ligandless microwave activation is described. This new protocol proved to
be highly effective to synthesize a variety of 8-aryladenine derivatives 3 without prior protection of the
amino substituent. The arylation reaction takes place rapidly within few minutes and allows the coupling
to proceed regioselectively at the 8-position with a wide range of aryl halides including aryl iodides,
bromides and the less reactive aryl chlorides.
Received 15 September 2008
Revised 2 October 2008
Accepted 6 October 2008
Available online 11 October 2008
Keywords:
Adenines
Ó 2008 Elsevier Ltd. All rights reserved.
C–H arylation
Palladium
Copper
Aryl chlorides
Microwave irradiation
Substituted purines are important structural elements of thera-
peutic drug molecules, and have been demonstrated to provide
high-affinity ligands for a variety of proteins.1 Many molecules
bearing this heterocycle nucleus are well known to display a wide
variety of interesting biological properties. Some of them are re-
ported as cyclin-dependent kinase inhibitors,2 adenosine receptor
antagonists,3 modulators of multidrug resistance,4 antiviral5 and
antineoplastic agents.6 Recent works demonstrated that C8-substi-
tuted purine derivatives having a C6 free-amino group, such as
PU3, PU24FCl as well as their 8-arylsulfanyl analogues,7 have
emerged as hsp90 inhibitors, an exciting new target in cancer drug
discovery.8
NH2
N
NH2
N
N
N
N
N
N
Cl
N
F
OMe
OMe
OMe
OMe
n
Bu
3
MeO
PU3
NH2
MeO
PU24FCl
NH2
6
N
N
N
1
N
8
Ar
N
In an ongoing medicinal chemistry programme towards hsp90,9
we required a rapid and versatile access to 8-aryladenines of type
3, which includes two centres for introduction of diversity into
adenine molecule. The literature reports a short number of syn-
thetic routes to these compounds. They are usually prepared by
the Pd-catalyzed CÀC cross-coupling of organometallic reagents10
with N-protected 8-bromoadenines. While these reactions are suit-
able methods, they require the preparation of either or both re-
agents using multi-step reaction sequences therefore time-
consuming and economically inefficient. (see Scheme 1)
N
R
N
N
1 R = ribose
2 R = Bn
R
3
Scheme 1.
arylÀaryl bonds. Hocek12 and Fairlamb13 described the direct aryl
functionalization of free-(NH2) adenine nucleosides 1 to give in
moderate to good yields C8-arylated adenine nucleoside deriva-
tives together with a small amount of N-arylation products.12a In
both studies, optimal conditions were found to require Pd(OAc)2
as a catalyst in association with CuI, Cs2CO3 or piperidine as a base
and heating in DMF. Although progress has been made for this
reaction, it requires prolonged reaction times (5–13 h) that can
seriously affect the yield of the C–H arylation and the use of a large
excess of CuI (3 equiv) as additive. Additionally, in most cases, only
Over the past decade, direct CÀH arylation of heteroarenes11
has been intensively studied as an attractive and a simple alterna-
tive to traditional cross-coupling methods for creating hetero-
* Corresponding author. Tel.: +33 1 46 83 58 87; fax: +33 1 46 83 58 28.
E-mail address: mouad.alami@u-psud.fr (M. Alami).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.021

7280
S. Sahnoun et al. / Tetrahedron Letters 49 (2008) 7279–7283
aryl iodide reagents are used. To our knowledge, cheaper and gen-
erally more available aryl chlorides have never been employed.14
Therefore, alternative routes and more reliable procedures for this
transformation are welcome. The remaining challenge is to devel-
op a simple catalytic system for such transformation without com-
promising reagent safety, simplicity, and practicality. Herein we
report our general approach to provide a variety of 8-aryladenine
derivatives 3 from various aryl halides including aryl iodides, bro-
mides as well as the less reactive aryl chlorides. We found that the
use of Pd(OH)2/C (Pearlman’s catalyst) under ligandless microwave
irradiations proves to be an efficient catalyst system allowing the
reaction to take place rapidly (from hours to just few minutes),
even when using a stoichiometric amount of copper salt.
ditions, the target 8-aryladenine 3a was formed in good yield (72%,
entry 6).
Having determined optimal conditions for the formation of 3a
using classical heating, we attempted to use microwave activa-
tion16 in order to enhance the reaction rate and possibly to reduce
the reaction time as well as to increase the yield and the substrate
scope.17 Microwave-assisted organic synthesis has emerged during
the past two decades as another valuable technology for synthetic
organic and medicinal chemists.18 We were pleased to find that di-
rect arylation of 2 under microwave irradiation using similar con-
ditions as those of entry 6 provided 3a in a 76% isolated yield after
only 30 min (entry 7). Under these conditions, replacement of DMF
by DMA produced 3a with a comparable yield (entry 8), whereas
the use of 1,4-dioxane did not promote any coupling reaction (en-
try 9). Among several polar solvents tested, NMP is the unrivaled
solvent choice for this direct CÀH arylation, as 3a was formed in
excellent yield within 30 min (85%, entry 10). Interestingly, a sim-
ilar result was obtained using a stoichiometric amount (1 equiv) of
the CuI additive (84%, not shown in Table). Finally, The best condi-
tions were found to require: 4-iodoanisole (1.5 equiv), Pd(OH)2/C
(5 mol %), CuI (1 equiv), Cs2CO3 (2.0 equiv) in NMP at 160 °C for
15 min; and 3a was formed in 90% yield (entry 11). It should be
noted that attempting to carry out the reaction using traditional
oil bath heating (160 °C, 15 min, sealed tube), resulted in partial
conversion (ca. 20%, entry 12). This result clearly demonstrated
the benefit to use microwave irradiations.
To optimize experimental conditions for the preparation of
target compounds 3, the coupling of unprotected adenine 2 with
4-iodoanisole was selected as a model reaction. The results are
summarized in Table 1.
Initially the reaction was investigated according to Hocek pro-
cedure: Pd(OAc)2 (5 mol %), CuI (3 equiv), piperidine (5 equiv) in
DMF.12a After heating at 120 °C for 20 h, the expected coupling
product 3a was formed in 55% yield (entry 1). Increasing the tem-
perature to 150 °C for 5 h gave a slightly better result (entry 2).
Switching to Fairlamb conditions13 (Cs2CO3 as a base instead of
piperidine, 120 °C, 13 h) gave the target 8-aryladenine 3a, but in
a lower yield (45%, entry 3), even when the reaction was carried
out at 160 °C (25%, entry 4). The palladium source was then ex-
plored. Thus, when running the reaction in DMF at 160 °C with
Pd2(dba)3 instead of Pd(OAc)2, contrary to Fairlamb conditions,13
high rate was observed, and direct CÀH arylation reaction of 2 pro-
vided 3a in 56% yield within 4 h (entry 5). Of the palladium sources
screened, the highest yield was achieved by using Pd(OH)2/C,
clearly indicating that in the present reaction, Pearlman’s cata-
lyst15 proved to be superior to all other choices. Under these con-
Prompted by these results, we subsequently investigated the
substrate scope for the CÀH arylation of 2. Results summarized
in Table 2 show that the optimized conditions described above
proved to be general for the selective C-8 arylation with a large ser-
ies of functionalized aryl halides.19 The reaction worked well with
para electron-rich aryl iodides, bromides as well as the less reactive
aryl chlorides (entries 1–5), even those containing base sensitive
Table 1
Optimization coupling reaction of 2 with 4-iodoanisole under various conditionsa
NH2
NH2
I
OMe
N
N
N
N
OMe
N
N
N
N
[Pd] / CuI, base,
solvent, T ˚C
Bn
Bn
3a
2
Entry
[Pd]b
Base
Solvent
Tj (°
C)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(OH)
Piperidined
Piperidined
Cs CO3e
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
120 (Δ)
150 (
20
5
13
16
4
55
61
45
25
56
72
76
71
0
)
Δ
120 (Δ)
160 (Δ)
Δ
160 (
160 (
)
)
4
Δ
2/C
Pd(OH)
Pd(OH)
Pd(OH)
Pd(OH)2/C
Pd(OH)2/C
160 (MWI)
160 (MWI)
160 (MWI)
160 (MWI)
160 (MWI)g
Δ
0.5
0.5
0.5
0.5
0.25
2/C
2/C
2/C
1,4-Dioxane
NMP
NMP
10
11
12
85f
90h
Cs2CO3
2
Pd(OH)2/C
Cs2CO3
NMP
160 (
)
0.25
ndi
a Unless otherwise stated, all reactions were heated in solvent using 2 (1.0 equiv), 4-iodoanisole (2.0 equiv), [Pd] (5 mol %), CuI (3 equiv) and base (2.5 equiv).
b No reaction occurred without palladium catalyst or copper salt.
c Isolated yields.
d 5 equiv of piperidine were used, Hocek conditions, see Ref. 12a.
e 2.5 equiv of Cs2CO3 were used, Fairlamb conditions, see Ref. 13.
f A 84% yield of 3a was obtained, when using CuI (1 equiv). Partial conversion (ca. 20%) was observed in the presence of a catalytic amount (20 mol %).
g A 74% yield of 3a was obtained when running the reaction at 130 °C for 5 h.
h Best conditions were found to be: 2 (1.0 equiv), 4-iodoanisole (1.5 equiv), Pd(OH)2/C (5 mol %), CuI (1 equiv) and Cs2CO3 (2.0 equiv), MWI, 160 °C, 15 min. For a general
procedure: see, Ref. 19.
i Yield not determined; 20% of conversion was observed.
j D: standard heating, MWI: microwave irradiation.

S. Sahnoun et al. / Tetrahedron Letters 49 (2008) 7279–7283
7281
Table 2
Synthesis of C-8 aryladenine derivatives 3 from 219
Entry
Aryl halide
Time (h)
Product 3
Yielda (%)
90
NH2
N
N
N
1
0.25
2
R = Me
3a
I
OMe
OR
N
Bn
2
3
R = Me
R = H
3a
3b
60
22
Cl
OMe
NH2
N
N
0.25
3c
78
I
Me
Me
N
N
Bn
4
5
1
70b
81
Cl
Me
NH2
N
N
N
1
3d
3e
I
NH2
NH2
N
Bn
NH2
OMe
OMe
N
N
N
6
7
0.50
0.25
55c
I
OMe
OMe
N
OMe
OMe
Bn
NH2
Me
Me
N
N
3f
42
I
N
N
Bn
NH2
N
N
N
8
9
0.25
3g
95
Br
N
Bn
1
85
Cl
I
NH2
N
N
N
10
0.25
3h
3i
68d
CN
CN
N
Bn
NH2
N
N
N
11
0.25
0.25
43
82
Br
Br
NO2
NO2
N
Bn
NH2
N
N
N
12
3j
CF3
N
CF3
Bn
a
Isolated yield.
b
c
No reaction occurred under Hocek or Fairlamb conditions, see: Refs. 12a and 13.
2 equiv of 3,4,5-trimethoxyiodobenzene were used.
A 7% of benzamide compound was isolated as a side product.
d

7282
S. Sahnoun et al. / Tetrahedron Letters 49 (2008) 7279–7283
References and notes
NH2
NH2
R
N
N
Br
(1.5 equiv)
N
N
1. (a) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987–4006; (b)
Baraldi, P. G.; Tabrizi, M. A.; Gessi, S.; Borea, P. A. Chem. Rev. 2008, 108, 238–
263.
Pd(OH)2/C (5 mol%)
CuI (2 equiv)
Cs2CO3 (2 equiv)
NMP 160 °C, MWI
N
N
R
N
N
Bn
Bn
2. (a) Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc, S.; Meijer, L. Bioorg. Med.
Chem. Lett. 1998, 8, 793–798; (b) 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; (c) Imbach, P.; Capraro, H. G.; Furet,
P.; Mett, H.; Meyer, T.; Zimmermann, J. Bioorg. Med. Chem. Lett. 1999, 9, 1–96;
(d) Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc, S.; Meijer, L.; Giocanti, N.;
Sadri, R.; Favaudon, V. Bioorg. Med. Chem. 1999, 7, 1281–1293; (e) 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; (f) Sielecki, T. M.;
Boylan, J. F.; Benfield, P. A.; Trainor, G. L. J. Med. Chem. 2000, 43, 1–18; (g)
Ducrot, P.; Legraverend, M.; Grierson, D. S. J. Med. Chem. 2000, 43, 4098–
4108.
3. (a) Wanner, M. J.; Von Frijtag Drabbe Künzel, J. K.; Ijzerman, A. P.; Koomen, G.-J.
Bioorg. Med. Chem. Lett. 2000, 10, 2141–2144; (b) Abiru, T.; Miyashita, T.;
Watanabe, Y.; Yamaguchi, T.; Machida, H.; Matsuda, A. J. Med. Chem. 1992, 35,
2253–2260; (c) 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.
4. Dhainaut, A.; Regnier, G.; Tizot, A.; Pierre, A.; Leonce, S.; Guilbaud, N.; Kraus-
Berthier, L.; Atassi, G. J. Med. Chem. 1996, 39, 4099–4108.
4
2
a : R = C6H5 (55%)
Scheme 2.
groups without their prior protection (entry 5). Substrate 3,4,5-tri-
methoxyiodobenzene reacted reasonably well giving 3e in accept-
able yield (entry 6). On switching the substituents to the ortho
position, the coupled product 3f was formed in a lower yield
(42%, entry 7), indicating that steric hindrance appears to play an
important role. However, the use of 1-halonaphthalene (bromo
or chloro derivative), as the arene coupling partner, gave the ex-
pected arylation product 3g in excellent yields (entries 8 and 9).
Electron-deficient aryl iodides, bromides also reacted with adenine
2 to provide 3h-j in moderate to good yields with substitution
being tolerated at each of the meta and para positions (entries
10–12).
Although the reactivity of aryl chlorides was moderate in com-
parison with their corresponding iodo and bromo derivatives, as it
requires longer reaction times (1–2 h instead of 15 min), the yields
of CÀH arylation were equally effective with either iodo, bromo
and chloro reagents (compare entries 1, 3, 8 and 2, 4, 9, respec-
tively). The lower yield observed with 4-chloroanisole (entry 2)
is due to the formation of side product 3b (22%) resulting from
deprotection of the methoxy substituent under the reaction condi-
tions employed (160 °C, 2 h). Because of the excellent results ob-
served using aryl chlorides as coupling partners, we attempted to
compare the efficiency of our new catalytic system with those of
the literature. Thus, when running the reaction of 2 with 4-tolyl
chloride under Hocek or Fairlamb conditions, no reaction occurred
and only starting material was recovered. These results clearly
indicated that our conditions are a highly effective protocol and
general for the C–H arylation of adenine substrates.
5. Gao, H.; Mitra, A. K. Synthesis 2000, 329–351.
6. Bonnet, P. A.; Robins, R. K. J. Med. Chem. 1993, 36, 635–653.
7. (a) Chiosis, G.; Lucas, B.; Shtil, A.; Huezo, H.; Rosen, N. Bioorg. Med. Chem. 2002,
10, 3555–3564; (b) Chiosis, G.; Timaul, M. N.; Lucas, B.; Munster, P. N.; Zheng, F.
F.; Sepp-Lorenzino, L.; Rosen, N. Chem. Biol. 2001, 8, 289–299; (c) Vilenchik, M.;
Solit, D.; Basso, A.; Huezo, H.; Lucas, B.; He, H.; Rosen, N.; Spampinato, C.;
Modrich, P.; Chiosis, G. Chem. Biol. 2004, 11, 787–797; (d) Biamonte, M. A.; Shi,
J.; Hong, K.; Hurst, D. C.; Zhang, L.; Fan, J.; Busch, D. J.; Karjian, P. L.; Maldonado,
A. A.; Sensintaffar, J. L.; Yang, Y. C.; Kamal, A.; Lough, R. E.; Lundgren, K.;
Burrows, F. J.; Timony, G. A.; Boehm, M. F.; Kasibhatla, S. R. J. Med. Chem. 2006,
49, 817–828.
8. (a) Messaoudi, S.; Peyrat, J.-F.; Brion, J.-B.; Alami, M. Anti-Cancer Agents Med.
Chem 2008, 8, 761–782; (b) Messaoudi, S.; Peyrat, J.-F.; Brion, J.-B.; Alami, M.
Anti-Cancer Agents Med. Chem., 2008, 8, 761–782.
9. (a) LeBras, G.; Radanyi, C.; Peyrat, J. -F.; Brion, J. -D.; Alami, M.; Marsaud, V.; Stella,
B.; Renoir, J.-M. J. Med. Chem. 2007, 50, 6189–6200; (b) Radanyi, C.; Le Bras, G.;
Messaoudi, S.; Bouclier, C.; Peyrat, J.-F.; Brion, J.-D.; Marsaud, V.; Renoir, J.-M.;
Alami, M. Bioorg. Med. Chem. Lett. 2008, 18, 2495–2498; (c) Radanyi, C.; Le Bras,
G.; Marsaud, V.; Peyrat, J.-F.; Messaoudi, S.; Catelli, M. G.; Brion, J.-D.; Alami, M.;
Renoir, J.-M. Cancer Lett., doi:10.1016/j.canlet.2008.09.001.
10. (a) Firth, A.-G.; Fairlamb, I. J. S.; Darley, K.; Baumann, C.-G. Tetrahedron Lett.
2006, 47, 3529–3533; (b) Capek, P.; Pohl, R.; Hocek, M. Org. Biomol. Chem 2006,
4, 2278–2284; (c) Collier, A.; Wagner, G. Org. Biomol. Chem. 2006, 4, 4526–
4532; (d) Collier, A.; Wagner, G. Chem. Commun. 2008, 178–180.
11. For a recent review, see: Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174–238.
Having successfully generated 8-aryladenines
3 from aryl
halides, we have tried to extend the CÀH arylation reaction of
free-(NH2) adenine 2 to vinyl halides. These reagents would lead
to compounds 4 which are vinylogous of our target structures 3.
A preliminary experiment, depicted below, showed that b-(E)-
bromostyrene reacted with 2, under our optimized conditions, to
give stereoselectively the coupling product 4a, as a unique E-iso-
mer. It should be mentioned that it was necessary to add more cop-
per iodide (2 equiv) to obtain a satisfactory yield (55%, Scheme 2).
In conclusion, we have developed an efficient and regioselective
arylation of free-(NH2) adenines based on the use of Pearlman’s
catalyst under ligandless microwave activation. The reaction took
place rapidly within few minutes even using a stoichiometric
amount of copper salt. Accordingly, a variety of aryl iodides, bro-
mides as well as chlorides have been successfully employed, to
provide rapid access to C-8 substituted adenines in good to excel-
lent yields. This new protocol appears to be general, and applica-
tions of our new catalytic system to other substituted
heterocycles are under investigation. The synthesis of a library of
new adenine derivatives 3 as well as 4 as potential hsp90 inhibitors
will be reported in due course.
12. (a) Cerna, I.; Pohl, R.; Hocek, M. Chem. Commun. 2008, 4729–4730; (b) Cerna, I.;
Pohl, R.; Klepetarova, B.; Hocek, M. Org. Lett. 2006, 23, 5389–5392.
13. Storr, T.-E.; Firth, A.-G.; Wilson, K.; Darley, K.; Baumann, C.-G.; Fairlamb, I. J. S.
Tetrahedron 2008, 64, 6125–6137.
14. For the direct arylation of electron rich-heterocycles with aryl chlorides, see:
(a) Iwasaki, M.; Yorimitsu, H.; Oshima, K. Chem. Asian J. 2007, 2, 1430–1435; (b)
Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449–1451. For intramolecular
process, see: (c) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 581–590; (d) Leclerc, J.-P.; André, M.; Fagnou, K. J. Org. Chem.
2006, 71, 1711–1714.
15. For intra and intermolecular arylation reaction using pearlman’s catalyst, see:
Parisien, M.; Valette, D.; Fagnou, K. J. Org. Chem. 2005, 70, 7578–7584.
16. Microwave heating was ineffective for direct arylation of adenine nucleosides
due to significant decomposition, see: Ref. 13.
17. (a) LeBras, G.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett.
2006, 47, 5497–5501; (b) Giraud, A.; Provot, O.; Peyrat, J.-F.; Alami, M.; Brion,
J.-D. Tetrahedron 2006, 62, 7667–7673; (c) L’Hermite, N.; Giraud, A.; Provot, O.;
Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron 2006, 62, 11994–12002; (d)
LeBras, G.; Hamze, A.; Messaoudi, S.; Provot, O.; Le Calvez, P. B.; Brion, J.-D.;
Alami, M. Synthesis 2008, 1607–1611.
18. (a) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284; (b) Kappe, C.
O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry; Wiley-VCH:
Weinheim, 2005; (c) Loupy, A., Ed., Microwaves in Organic Synthesis, 2nd
ed; Wiley-VCH: Weinheim, 2006; (d) Larhed, M.; Hallberg, A. Drug Discov.
Today 2001, 6, 406–416; (e) Wathey, B.; Tierney, J.; Lidstrom, P.; Westman,
J. Drug Discov. Today 2002, 7, 373–380; (f) Al-Obeidi, F.; Austin, R. E.;
Okonya, J. F.; Bond, D. R. S. Mini-Rev. Med. Chem. 2003, 3, 449–460; (g)
Shipe, W. D.; Wolkenberg, S. E.; Lindsley, C. W. Drug Discov. Today: Technol.
2005, 2, 155–161; (h) Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Discov.
2006, 5, 51–63.
Acknowledgements
19. General procedure for Pd-catalyzed couplings of N-bezyladenine 2 with various
The CNRS is gratefully acknowledged for financial support of
this research and the MNSER for a doctoral fellowship to S.S.
arylhalides:
A flame-dried resealable 2–5 mL Pyrex reaction vessel was
charged with the solid reactant(s): Pd(OH)2/C (20% on carbon) (5.0 mol %),

S. Sahnoun et al. / Tetrahedron Letters 49 (2008) 7279–7283
7283
CuI (1.0 mmol), N-benzyladenine 2 (1.0 mmol), aryl halide (1.5 mmol) and
Cs2CO3 (2.0 mmol). The reaction vessel was capped with a rubber septum,
evacuated and backfilled with argon; this evacuation/backfill sequence was
repeated one additional time. The liquid reactant(s) and NMP (6 mL per
mmol) were added through the septum. The septum was replaced with a
Teflon screwcap. The reaction vessel was sealed, then placed in the Emrys
Optimizer and exposed to microwave irradiation according to the following
specifications: temperature: 160 °C; time: (see Tables); fixed hold time: on;
sample absorption: high; pre-stirring: 60 s. The resulting suspension was
cooled to room temperature and filtered through a pad of Celite eluting with
CH2Cl2/MeOH (7:3), and the inorganic salts were removed. The filtrate was
concentrated and purification of the residue by silica gel column
chromatography gave the desired product.
Compound 3d: Yield: 81%; TLC: Rf 0.19 (CH2Cl2/MeOH 95:5); mp = 170–172 °C;
IR (neat): 3127, 1654, 1606, 1451, 1331, 1300, 1184, 835, 729, 695; 1H NMR
(CDCl3, 300 MHz): 5.46 (s, 2H), 5.58 (s, 2H), 6.60 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H,
J = 7,30 Hz), 7.25 (m, 5H), 7.36 (d, 2H, J = 8.4 Hz), 8.13 (s, 1H); 13C NMR (CDCl3,
75 MHz): 46.1, 113.3 (2C), 118.4, 116.4, 126.2 (2C), 127.3, 128.0 (2C), 128.6 (2C),
137.3, 150.3, 151.0, 151.3, 152.0, 155.3; m/z MS (ES+) 317.0 (M+H)+.
Compound 3g: Yield: 95%; TLC: Rf 0.32 (CH2Cl2/MeOH 95:5); mp = 184–186 °C;
IR (neat): 3337, 3164, 1610, 1606, 1572, 1496, 1454, 1450, 1432, 1322, 1315,
800, 775, 722, 695; 1H NMR (CDCl3, 300 MHz): 5.13 (s, 2H), 6.11 (s, 2H, NH), 6.71
(m, 2H), 7.00 (m, 3H), 7.40 (m, 5H), 7.84 (d, 1H, J = 8.2 Hz), 7.92 (d, 1H, J = 8.2 Hz),
8.36 (s, 1H); 13C NMR (CDCl3, 75 MHz): 46.9, 119.2, 124.9 (2C), 126.6, 126.9,
127.4 (3C), 127.7, 128.4 (2C), 128.5, 128.8, 130.8, 131.9, 133.5, 136.0, 150.3,
151.2, 153.1, 155.3; m/z MS (ES+) 352.0 (M+H)+.
Compound 3a: Yield: 90%; TLC: Rf 0.33 (CH2Cl2/MeOH 95:5); mp = 104–
106 °C; IR (neat): 3157, 1661, 1606, 1530, 1458, 1332, 1298, 1266, 1179,
1031, 834, 727, 694; 1H NMR (CDCl3, 300 MHz): 3.78 (s, 3H), 5.39 (s, 2H),
5.85 (s, 2H, NH), 6.88 (d, 2H, J = 8.5 Hz), 7.01 (m, 2H), 7.21 (m, 3H), 7.45 (d,
2H, J = 8.5 Hz), 8.32 (s, 1H); 13C NMR (CDCl3, 75 MHz): 47.0, 55.4, 114.3 (2C),
119.2, 121.8, 126.6 (2C), 127.8, 128.9 (2C), 130.6 (2C), 136.5, 151.8, 152.0,
152.8, 155.0, 161.1; m/z MS (ES+) 332.0 (M+H)+.
Compound 3h: Yield: 68%; TLC: Rf 0.31 (CH2Cl2/MeOH 95:5); mp = 215–217 °C;
IR (neat): 3373, 3168, 2228, 1648, 1593, 1580, 1527, 1490, 1461, 1408, 1310,
1302, 1277, 1110, 1065, 1019, 849, 720, 714, 694; 1H NMR (CDCl3, 300 MHz):
5.43 (s, 2H), 6.00 (bs, 2H, NH), 6.96–6.99 (m, 2H), 7.19–7.24 (m, 3H), 7.66 (s, 4H),
8.35 (s, 1H); 13C NMR (CDCl3, 75 MHz): 47.1, 113.9, 118.0, 126.4 (2C), 128.2,
129.1 (2C), 129.6 (2C), 132.5 (2C), 134.0, 135.9, 149.4, 152.2, 153.6, 155.5; m/z
MS (ES+) 327.0 (M+H)+.