Regioselective Sonogashira cross-coupling reactions of 6-chloro-2,8-diiodo- 9-THP-9H-purine with alkyne derivatives

Article abstract of DOI:10.1016/j.tetlet.2010.11.033

Lithiation of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine with LiTMP, gave access to 6-chloro-2,8-dihalogenated purine derivatives. In particular, the 6-chloro-2,8-diiodopurine derivative is an interesting new intermediate which gave regioselectively various 2-alkynylated compounds or 2,8-dialkynylated purines by using an excess of alkyne.

Full text of DOI:10.1016/j.tetlet.2010.11.033

Tetrahedron Letters 52 (2011) 305–307
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Tetrahedron Letters
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Regioselective Sonogashira cross-coupling reactions of
6-chloro-2,8-diiodo-9-THP-9H-purine with alkyne derivatives
⇑
Nada Ibrahim, Franciane Chevot, Michel Legraverend
UMR176 CNRS/Institut Curie, Bât. 110, Centre Universitaire Paris XI, Orsay 91405, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Lithiation of 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine with LiTMP, gave access to 6-chloro-2,8-
dihalogenated purine derivatives. In particular, the 6-chloro-2,8-diiodopurine derivative is an interesting
new intermediate which gave regioselectively various 2-alkynylated compounds or 2,8-dialkynylated
purines by using an excess of alkyne.
Received 15 September 2010
Revised 4 November 2010
Accepted 8 November 2010
Available online 29 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Purine
Metallation
Lithiation
Regioselective functionalization
1. Introduction
not been synthesized from 6-chloropurine before, although Nolsoe
obtained a 6-chloro-2,8-dibromopurine derivative in very low
Metallation reactions remain as very useful methods for the
regioselective functionalization of heterocycles. Thus, lithiation of
purine nucleosides with n-BuLi or lithium diisopropylamide
(LDA), followed by reaction with various electrophiles has led to
the synthesis of 8-substituted purine derivatives (methyl, ethyl,
formyl, etc).1,2 The 8-methoxycarbonyl derivative of adenosine or
inosine2 and 8-halogeno purine derivatives was also obtained by
this methodology.3–6 From these pioneering works, it can be stated
that lithiation of a 6-N,N-dimethylaminopurine derivative with n-
BuLi1 or of 6-chloropurine derivatives with LDA2,5 occurs exclu-
sively at the C-8 position, the reason being that the C-8 hydrogen
is more acidic than the C-2 hydrogen. Tanaka’s group was the first
to obtain 2-tributylstannyl-purine derivatives, using lithium tetra-
methyl piperidylamide (LiTMP) as a lithiation agent. The mecha-
nism involved an initial lithiation of the 6-chloropurine
nucleoside with LiTMP at the 8-position. However, reaction of
the 8-lithiated species with tin and silicon electrophiles furnished
2-functionalized products, which resulted from an anionic transfer
of the stannyl or silyl group from the 8- to the 2-position.5 In a later
study, the authors suggested that direct C-2 lithiation becomes a
feasible event once C-8 is substituted with a stable triisopropylsilyl
group, permitting thereby to skip the C-2 stannylation step.7 In
these examples, direct lithiation was achieved with the purpose
of obtaining C-2 or C-8-substituted purines. However, to the best
of our knowledge 2,6,8-trihalogenated purine derivatives have
yield (<5%),8 whereas Hocek and Pohl,9 reported the preparation
of a 2,6,8-trichloropurine by 8-lithiation (LDA) followed by chlori-
nation (C2Cl6) of 2,6-dichloro-9-THP-purine. Following these
works, our interest was to synthesize in one step 2,8-disubstituted
purines as 6-chloro-2,8-dibromo- and 6-chloro-2,8-diiodo-purines.
These intermediates are attractive to synthesize variously func-
tionalized purine derivatives of potential biological interest.10 Fur-
thermore, our hypothesis was that cross-coupling reactions with 6-
chloro-2,8-diiodopurine intermediate would show selectivity for
alkynylation at C2, although the selectivity of previously described
Suzuki-Miyaura cross-coupling reaction with 2,6,8-trichloro-9-
THP-purine was quite low.9 In this context, we report in this com-
munication the synthesis of new 2,8-dibromo- and 2-8-diiodopu-
rine derivatives from 6-chloropurine and show that they can be
used in regioselective cross-coupling reactions.
2. Results and discussion
For the purpose of functionalizing the 2- and 8-positions in one
pot, 6-chloropurine derivative 111 was treated with 5 equiv of LiT-
MP, followed by addition of various electrophiles. This led to various
2,8-disubstituted purines 2 as outlined in Scheme 1. It should be no-
ticed that the yield decreased when using less than 5 equiv of LiTMP.
On the other hand, treatment of the 8-phenyl derivative 5 with
5 equiv of LiTMP, followed by an excess of I2, led to the 2-iodopurine
derivative 6 in 51% yield, confirming that lithiation occurred at po-
sition 2 (Scheme 2). Again, the yield of this reaction decreased with
less than 5 equiv of LiTMP as already observed.7 When DMF was
⇑
Corresponding author. Tel.: +33 169 86 30 85; fax: +33 169 07 53 81.
E-mail address: Michel.legraverend@curie.u-psud.fr (M. Legraverend).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.033

306
N. Ibrahim et al. / Tetrahedron Letters 52 (2011) 305–307
R
R
Cl
N
Cl
N
N
N
7
6
N
Cl
I
N
Cl
N
Cl
N
N
N
N
N
1
2
N
N
N
i, ii
ii
i
E
CHO
8
N
N
N
N
9
E
OHC
N
N
I
N
3
N
N
N
O
O
O
I
O
O
O
R
1
2a: E = I (80%)
2b: E = Br (45%)
2c: E = Cl (60%)
3
8a: R = Ph (56%)
2a
7a: R = Ph
8b: R = p-Cl-Ph (70%)
8c: R = p-Me-Ph (63%)
8d: R = p-OMe-Ph (54%)
8e: R = m-Me-Ph (74%)
(48%)
2d: E = CHOH-Ph (70%)
2e: E = Si(i-Pr)3 (80%)
7b: R = p-Cl-Ph
(29%)
7c: R = p-Me-Ph
(41%)
Scheme 1. Reagents and conditions: (i) LiTMP, 5 equiv, ꢀ78 °C, THF, 2 h; (ii)
electrophile: (a) I2, (b) 1,3-dibromo-5,5-dimethyl-hydantoin, (c) CCl3CCl3, (d)
PhCHO, (e) (i-PrSi)3OTf, ꢀ78 °C?rt.
7d: R = p-OMe-Ph
(22%)
7e: R = m-Me-Ph
(51%)
Cl
N
Cl
N
Cl
N
Scheme 3. Reagents and conditions: (i) alkyne, 1.05 equiv, CuI, 12 mol %,
Pd[(PPh)3]4, 25 mol %, Cs2CO3, 1 equiv, DMF, 24 h; (ii) alkyne, 3 equiv, CuI,
12 mol %; Pd[(PPh)3]4, 6 mol %, Cs2CO3, 3 equiv; DMF, 2–3 h.
N
N
N
N
N
N
N
N
N
I
i
ii
I
O
O
O
4
5
6
N
Cl
N
Scheme 2. Reagents and conditions: (i) PhB(OH)2, K2CO3, anhydrous toluene,
Pd(PPh3)4, 100 °C, 24 h, under Argon; (ii) (a) LiTMP, ꢀ78 °C, THF, 30 min, (b) I2,
ꢀ78 °C?rt.
N
Cl
N
N
N
i
N
I
N
O
used as an electrophile, 2,8-diformylated compound 3 was obtained
but the chlorine atom was substituted by a dimethylamino group
resulting from the reaction of organolithium species with DMF.
The synthesis of 8-iodopurine derivative 4 was performed from 1
with LDA/I2 at ꢀ78 °C, in 80% yield as described.7,8
O
59 %
7a
9
Particularly interesting is the formation of diiodo purine 2a in
high yield (80%) which was never described before, to our best
knowledge. 2,8-Dibromo- and 2,8-dichloropurines 2b and 2c were
obtained in moderate yield with mild reagents such as 1,3-dibro-
mo-3,5-dimethylhydantoin and hexachloroethane, respectively.
Use of Br2 as a brominating agent did not lead to 2b but to the
decomposition of 1.
Scheme 4. Reagents and conditions: (i) alkyne, 1.05 equiv, CuI, 12 mol %,
Pd[(PPh)3]4, 6 mol %, Cs2CO3, 1 equiv, DMF, 2 h.
3. Conclusions
In conclusion, we report in this communication a new method
for the synthesis of 2,6,8-trihalogenated purine derivatives. Preli-
minary results indicate that regioselective cross-coupling at posi-
tion 2 can be obtained with 6-chloro-2,8-diiodopurine. It should
also be noted that in all these experiments, the chlorine at position
6 remained unsubstituted and available for further functionaliza-
tion. Additional functionalization at position 9 is also possible after
acidic hydrolysis of the THP group.12,13
We next examined the regioselective Sonogashira alkynylation
of di-iodopurine 2a.
Using 1 equiv of alkyne under Sonogashira conditions gave the
monoalkynylated derivative 7a–e in 22–51% yield, whereas more
than 1 equiv of alkyne (2–3 equiv) led to the dialkynylated deriva-
tive 8 in 54–74% yield (Scheme 3). C2 and C8 resonances in 1 (13
C
NMR signals at 151.9 ppm and 143 ppm respectively) are shifted
upfield in the bis-iodo derivative 2a to 116.8 ppm (C2-I) and
106.3 ppm (C8-I). In the monoalkynylated compounds 7, the C8-I
signal around 106 ppm remains present, whereas the C2-I signal
at 116.8 ppm11 is not observed. Further evidence of C2 monoalky-
nylation was given by the presence of a correlation between THP
H10 and C8-I. The moderate yield of the monoalkynylated com-
pounds 7b,d is due, in part, to some homocoupling of the alkyne
reactant. In addition to trace amounts of bis-alkynylated com-
pounds (8b,d) (<5%), unreacted starting compounds (<5%) as well
as some other minor unidentified compounds were observed in
these experiments. However, the regioselectivity of the alkynyla-
tion under controlled conditions is interesting since it allows a fur-
ther nucleophilic aromatic substitution or cross-coupling reaction
on the 8-position, resulting in different substituents on the 2 and
8 positions of 2a. Thus 7a was used in a supplementary Sonogash-
ira coupling at position 8, using meta-tolyl acetylene (Scheme 4).
The second cross-coupling leading to the bis-alkynylated purine
9 was faster (2 h, Scheme 4) than the first couplings at C2 (24 h,
Scheme 3, 2a ? 7).
Acknowledgments
The authors would like to thank Institut Curie (IC fellowship for
NI) and the French Ministry of Research (MENRT fellowship for FC).
Supplementary data
Supplementary data associated with (detailed experimental
procedures, and compound characterization data for all new com-
pounds) this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.11.033.
References and notes
1. Barton, H. R.; Hedgecock, C. J. R.; Lederer, E.; Motherwell, W. B. Tetrahedron Lett.
1979, 20, 279–280.
2. Hayakawa, H.; Haraguchi, K.; Tanaka, H.; Miyasaka, T. Chem. Pharm. Bull. 1987,
35, 72–79.
3. Moriarty, R. M.; Epa, W. R.; Awasthi, A. K. Tetrahedron Lett. 1990, 31, 5877–
5880.

N. Ibrahim et al. / Tetrahedron Letters 52 (2011) 305–307
307
4. Liu, F.; Dalhus, B.; Gundersen, L.-L.; Rise, F. Acta Chem. Scand. 1999, 53, 269–279.
9. Hocek, M.; Pohl, R. Synthesis 2004, 2869–2876.
5. Kato, K.; Hayakawa, H.; Tanaka, H.; Kumamoto, H.; Shindoh, S.; Shuto, S.;
Miyasaka, T. J. Org. Chem. 1997, 62, 6833–6841.
10. Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987–4006.
11. Brun, V.; Legraverend, M.; Grierson, D. S. Tetrahedron 2002, 58, 7911–7923.
6. Ghosh, A. K.; Lagisetty, P.; Zajc, B. J. Org. Chem. 2007, 72, 8222–8226.
7. Kumamoto, H.; Tanaka, H.; Tsukioka, R.; Ishida, Y.; Nakamura, A.; Kimura, S.;
Hayakawa, H.; Kato, K.; Miyasaka, T. J. Org. Chem. 1999, 64, 7773–7780.
8. Nolsoe, J. M. J.; Gundersen, L.-L.; Rise, F. Synth. Commun. 1998, 28, 4303–4315.
12. Brun, V.; Legraverend, M.; Grierson, D. S. Tetrahedron Lett. 2001, 42, 8165–
8167.
13. Brun, V.; Legraverend, M.; Grierson, D. S. Tetrahedron Lett. 2001, 42, 8169–
8171.