Direct C-H arylation of purines: Development of methodology and its use in regioselective synthesis of 2,6,8-trisubstituted purines

Article abstract of DOI:10.1021/ol062324j

Direct C-H arylation of purines to position 8 by diverse aryl iodides was achieved with Pd catalysis in the presence of CuI and Cs₂CO ₃. The methodology is general and efficient and was applied in the consecutive regioselective synth

Full text of DOI:10.1021/ol062324j

ORGANIC
LETTERS
2006
Vol. 8, No. 23
5389-5392
Direct C−H Arylation of Purines:
Development of Methodology and Its
Use in Regioselective Synthesis of
2,6,8-Trisubstituted Purines
Igor Cˇernˇa, Radek Pohl, Blanka Klepeta´rˇova´, and Michal Hocek*
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the
Czech Republic, FlemingoVo nam. 2, CZ-16610 Prague 6, Czech Republic
hocek@uochb.cas.cz
Received September 21, 2006
ABSTRACT
Direct C−H arylation of purines to position 8 by diverse aryl iodides was achieved with Pd catalysis in the presence of CuI and Cs2CO3. The
methodology is general and efficient and was applied in the consecutive regioselective synthesis of 2,6,8-trisubstituted purines bearing three
different C-substituents in combination with two cross-coupling reactions.
2,6,9-Tri- and 2,6,8,9-tetrasubstituted purines display a wide
range of biological activities, i.e., inhibition of kinases,1
tubulin polymerization,2 antagonist effects to receptors,3 etc.
Combinatorial libraries of these compounds were prepared4
on the solid-phase with regioselective nucleophilic substitu-
tions of dihalopurines. However, regioselective introduction
of C-substituents by cross-coupling reactions5 is more
problematic. While 2,6- and 6,8-dihalopurines give regiose-
lective cross-couplings with most types of organometallics,6
reactions of 2,6,8-trichloropurine proceed unselectively giv-
ing mixtures of products.7 Therefore, we decided to combine
the regioselective cross-couplings of 2,6-dihalopurines with
direct C-H arylation in position 8 to develop a general
selective approach to 2,6,8-trisubstituted purines bearing three
different C-substituents.
C-H activation reactions have received prominent atten-
tion8 in recent years as an alternative to cross-coupling
reactions with use of organometallics. Direct C-H arylation
of arenes and heterocycles has been achieved by using, e.g.,
Rh,9 Ru,10 or Pd11,12 catalysis with different bases and many
types of aryl halides. To the best of our knowledge, the only
(1) (a) Gray, N. S.; Wodicka, L.; Thunnissen, A.-M.; Nornam, T. C.;
Kwon, S.; Espinoza, F. H.; Morgan, D. O.; Barnes, G.; LeClerc, S.; Meijer,
L.; Kim, S.-H.; Lockhart, D. J.; Schultz, P. G. Science 1998, 281, 533-
538. (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.
(2) (a) Rosania, G. R.; Chang, Y.-T.; Perez, O.; Sutherlin, D.; Dong, H.
L.; Lockhart, D. J.; Schultz, P. G. Nature Biotechnol. 2000, 18, 304-308.
(b) Chang, Y.-T.; Wignall, S. M.; Rosania, G. R.; Gray, N. S.; Hanson, S.
R.; Su, A. I.; Merlie, J.; Moon, H. S.; Sangankar, S. B.; Perez, O.; Heald,
R.; Schultz, P. G. J. Med. Chem. 2001, 44, 4497-4500.
(6) Examples: (a) Langli, G.; Gundersen, L.-L.; Rise, F. Tetrahedron
1996, 52, 5625-5638. (b) Nolsoe, J. M. J.; Gundersen, L.-L.; Rise, F. Acta
Chem. Scand. 1999, 53, 366-372. (c) Havelkova´, M.; Dvorˇa´k, D.; Hocek,
M. Synthesis 2001, 1704-1710. (d) Hocek, M.; Dvorˇa´kova´, H. J. Org.
Chem. 2003, 68, 5773-5776. (e) Hocek, M.; Hockova´, D.; Dvorˇa´kova´, H.
Synthesis 2004, 889-894. (f) Sˇilha´r, P.; Pohl, R.; Votruba, I.; Hocek, M.
Collect. Czech. Chem. Commun. 2005, 70, 1669-1695.
(7) Hocek, M.; Pohl, R. Synthesis 2004, 2869-2876.
(8) Reviews: (a) Labinger, J. A.; Bercaw, J. E. Nature 2002, 417, 507-
514. (b) Godula, K.; Sames, D. Science 2006,312, 67-72.
(3) (a) Cocuzza, A. J.; Chidester, D. R.; Culp, S.; Fitzgerald, L.; Gilligan,
P. Bioorg. Med. Chem. Lett. 1999, 9, 1063-1066. (b) Chang, L. C. W.;
Spanjersberg, R. F.; von Frijtag Drabbe Kunzel, J. K.; Mulder-Krieger, T.;
Brussee, J.; IJzerman, A. P. J. Med. Chem. 2006, 49, 2861-2867.
(4) (a) Brill, W. K.-D.; Riva-Toniolo, C.; Mu¨ller, S. Synlett 2001, 1097-
1100. (b) Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J. Am.
Chem. Soc. 2002, 124, 1594-1596. (c) Bork, J. T.; Lee, J. W.; Chang,
Y.-T. QSAR Comb. Sci. 2004, 23, 245-260.
(5) Hocek, M. Eur. J. Org. Chem. 2003, 245-254.
10.1021/ol062324j CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/21/2006

reported example of a direct C-H functionalization of purine
moiety is a Rh-catalyzed alkylation by 3,3-dimethylbut-1-
ene.13 Here we report on the development of novel meth-
odology of arylation of purines to position 8 by direct C-H
arylation.
After some initial unsuccessful attempts on reactions of 1
with p-Tol-I under Rh and Co catalyses using diverse bases,
we have focused on Pd catalysis with Cs salts as bases in
the presence of CuI and PPh3 in analogy to the systems
recently applied to imidazoles.12 Optimization of solvents
(Table 1, entries 1 and 2) showed that DMF is the most
Cs2CO3 (2.5 equiv) at 160 °C were used15 in further
experiments.
When performing larger scale reactions in larger vials, we
have observed formation of some byproducts in isolable
amounts. To rationalize their formation, a set of reactions
of 1 with Tol-I and Ph-I (2 or 10 equiv) in argon-purged
small vials or in bigger vials set up in air was performed
(Table 2). Reactions with 2 equiv of Ar-I in small (nearly
Table 2. Influence of Conditions to Formation of Byproducts
Table 1. Optimization of Direct Coupling of 1 with 4-MePh-I
base
(equiv)
CuI
ligand
(mol %)
yield
(%)
entry
(equiv) solvent
1
2
3
4
5
6
7
Cs2CO3 (1.5)
Cs2CO3 (1.5)
Cs2CO3 (1.5)
CsF (1.5)
Cs2CO3 (2.5)
Cs2CO3 (2.5)
None
0.2
0.2
0.2
0.2
2
othera
DMF
DMF
DMF
DMF
DMF
DMF
PPh3 (20) traces
PPh3 (20) 39
yield (%)
reaction
vessela
ArI
(equiv)
none
none
none
none
none
48
12
87
95b
36
entry
2
3
4
1
2
3
4
5
6
7
A
B
B
A
B
B
C
p-Tol-I (2)
p-Tol-I (2)
p-Tol-I (10)
Ph-I (2)
Ph-I (2)
Ph-I (10)
p-Tol-I (2)
95
87
30
92
88
31
10
traces
6
47
traces
6
54
5
traces
4b
3
3
0
traces
3b
a Dioxane, acetonitrile, or toluene. b 2 equiv of 4-MePhI was used.
0
11b
a A: 0.5 mmol, argon purged sealed 3 mL vial. B: 1 mmol, septum
sealed 20 mL vial set up in air. C: 1 mmol, 20 mL vial opened to air.
b Yields of 4 were recalculated on 0.5 mmol of 1.
suitable, giving product 2a in 39% yield after 60 h.
Surprisingly, the same reaction without phosphine ligand
gave an even better yield of 48% (entry 3) and therefore
other experiments were performed ligandless. The use of CsF
as base led to a decrease of the yield (entry 4). Increasing
the amounts of CuI (2 equiv) and Cs2CO3 (2.5 equiv)
afforded 2a in a good yield of 87% (entry 5). Further increase
of the amounts of Tol-I (2 equiv) and CuI (3 equiv) led to
nearly quantitative yield of the product 2a (entry 6) but still
the reaction was quite slow and required 60 h at 160 °C to
reach full conversion (analogous experiment at 120 °C gave
just 50% conversion). The reaction in the absence of base14
(entry 7) proceeded with a very low conversion of 36%. Thus
the optimized conditions (entry 6) with CuI (3 equiv) and
full) argon-purged sealed vials gave cleanly 8-arylpurines
2a,b in excellent yields (entries 1 and 4). On the other hand,
reactions performed in larger vials (1/4 full) set up in air
and sealed by septum without purging with argon gave two
types of byproducts in 2-6% yields (apparently caused by
traces of oxygen). The first type of byproduct was identified
as the product of double arylation to position 8 and to the
ortho position of the phenyl group in position 6 (compounds
3a,b). The second byproduct was 8,8′-bispurine 4, so far
unprecedented in the literature.16 Its structure was determined
by X-ray diffraction (Figure 1). Reactions with 10 equiv of
(9) (a) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005, 127,
4996-4997. (b) Wiedermann, S. H.; Lewis, J. C.; Ellman, J. A.; Bergman,
R. G. J. Am. Chem. Soc. 2006, 128, 2452-2462. (c) Lewis, J. C.; Wu, J.
Y.; Bergman, R. G.; Ellman, J. A. Angew. Chem., Int. Ed. 2006, 45, 1589-
1591.
(14) Analogy to conditions successfully used for arylation of imidazoles
and benzimidazoles in ref 12c.
(15) General procedure: DMF (6 mL) was added through a septum to
an argon purged vial containing 1 (286 mg, 1 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol, 5 mol %), CuI (571 mg, 3 mmol), aryl halide (2 mmol), and
Cs2CO3 (815 mg, 2.5 mmol). The reaction mixture was heated to 160 °C
for 60 h. The solvent was evaporated and products were isolated by flash
column chromatography (gradient elution hexanes f ethyl acetate/hexanes
1:1). Analytical samples were crystalized from a mixture of CHCl3/heptane.
(16) The only two known related examples of C-H homocoupling of
heterocycles: (a) a Cu-mediated dimerization of benzothiazole: Chodowska-
Palicka, J.; Nilsson, M. Synthesis 1974, 128-129. (b) Recently described
Pd-catalyzed dimerization of bromothiophenes in the presence of AgF:
Takahashi, M.; Masui, K.; Sekiguchi, H.; Kobayashi, N.; Mori, A.;
Funahashi, M.; Tamaoki, N. J. Am. Chem. Soc. 2006, 128, 10930-10933.
(10) Ackermann, L. Org. Lett. 2005, 7, 3123-3125.
(11) (a) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura,
M. Bull. Chem. Soc. Jpn. 1998, 71, 467-473. (b) Lane, B. S.; Sames, D.
Org. Lett. 2004, 6, 2897-2900. (c) Lane, B. S.; Brown, M. A.; Sames, D.
J. Am. Chem. Soc. 2005, 127, 8050-8057.
(12) (a) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. J.
Org. Chem. 2005, 70, 3997-4005. (b) Bellina, F.; Cauteruccio, S.; Mannina,
L.; Rossi, R.; Viel, S. Eur. J. Org. Chem. 2005, 693-703. (c) Bellina, F.;
Cauteruccio, S.; Rossi, R. Eur. J. Org. Chem. 2006, 1379-1382.
(13) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2002, 124, 13964-13965. (b) Tan, K. L.; Park, S.; Bergman, R. G.; Ellman,
J. A. J. Org. Chem. 2004, 69, 7329-7335.
5390
Org. Lett., Vol. 8, No. 23, 2006

Table 3. Arylation of Purines to Position 8 by Optimized
Procedure
Figure 1. Crystals structures of 2a (a, CCDC 617551) and 4 (b,
CCDC 617550). Thermal ellipsoids at the 50% probability level.
Ar-I set up in air gave rise to diarylated products 3a or 3b
in ca. 50% yields. To further examine the influence of an
excess of oxygen, an experiment fully opened to air was also
performed (entry 7). The conversion was quite low (ca 26%)
but the ratio of 2a and dimer 4 was ca. 1:1 showing the
crucial importance of oxygen for the side reaction. The
mechanism of this reaction will be a subject of further studies
but we suppose that it may consist of oxidative dimerization
of 8-organocopper purine intermediates.
a Accompanied by 4% 9-benzyl-6,8-bis(p-tolyl)purine (9).
The optimized procedure was then used for introduction
of diverse aryl groups to position 8 of several purines (Table
3). Arylation with substituted iodobenzenes proceeded very
smoothly to give desired products 2a-e in high yields around
90%. For comparison, p-Tol-Br underwent the reaction with
significantly lower yield of 62% (entry 2). Reactions with
iodopyridines proceeded with lower conversions to give
products 2f,g in 42% and 48%, respectively. Also 9-benzyl-
6-methylpurine (5) underwent C-H activation selectively
in position 8 to give product 7 in 82% yield (entry 9). Then
we have tried a reaction of 6-unsubstituted 9-benzylpurine
6 to check whether the C-H in position 8 will still be
preferentially substituted in competition with C-H in posi-
tion 6. This reaction gave quite selectively the 8-arylpurine
8 in 86% accompanied by only a very minor amount (4%)
of 6,8-diarylated product 9 confirming that C-H in position
8 is the most easily substituted.
(Table 4). 9-Benzyl-2,6-dichloropurine (10) was reacted
successively in one pot with two different arylboronic acids6c
Table 4. Consecutive Synthesis of 2,6,8-Trisubstituted Purines
entry
R1
R2
R3
product
yield (%)
1
2
Ph
Me
4-MeOPh
Ph
p-Tol
p-Tol
11
12
65a
56b
a The first two steps were done in one pot, then the mixture was filtered
and evaporated and the crude residue was directly used for the third step.
b After the first step, the intermediate was isolated and used for the second
step and then the reaction mixture was just filtered and evaporated and the
crude residue was used for the last step.
Finally, the optimized experimental conditions for direct
C-H arylation of purines in position 8 were applied to a
sequential three-step synthesis of 2,6,8-trisubstituted purines
Org. Lett., Vol. 8, No. 23, 2006
5391

and then, without isolation, the reaction mixture was just
filtered, evaporated, and directly used for C-H arylation with
p-tolyl iodide. The first aryl group was introduced to position
6, the second to position 2, and the third one to position 8
to give the desired product 11 in good total yield (65% over
three steps). Analogously, 10 was methylated selectively to
position 6 by Fe-catalyzed reaction with MeMgCl,6d followed
by the Suzuki cross-coupling with phenylboronic acid in
position 2 and C-H arylation with p-tolyl iodide in position
8 to give 12 in 56% yield.
In conclusion, a general Pd-catalyzed arylation of purines
with aryl iodides by C-H activation in position 8 was
developed by using Cs2CO3 and CuI as additives. Though
the reaction conditions are rather harsh, the method can be
efficiently applied in the synthesis of diverse 8-arylpurines
and, in combination with regioselective cross-coupling
reactions6 of 2,6-dichloropurines, of 2,6,8-trisubstituted pu-
rines bearing three different C-substituents, analogues of
important biologically active compounds.
Acknowledgment. This work was supported by research
project Z4 055 0506, by the Centre for Chemical Genetics
(LC06077), by GACR (203/05/0043), and by Gilead Sci-
ences.
Supporting Information Available: Experimental pro-
cedures, analytical and spectral data, crystallographic data
for 2a and 4, HMBC analysis of 3a, and copies of NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062324J
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Org. Lett., Vol. 8, No. 23, 2006