SNAr iodination of 6-chloropurine nucleosides: Aromatic finkelstein reactions at temperatures below -40°C1

Article abstract of DOI:10.1021/ol048987n

(Equation Presented) Mesitoyl or toluoyl esters of inosine and 2′-deoxyinosine were deoxychlorinated at C6 to give the crystalline 6-chloropurine nucleoside derivatives, which underwent quantitative conversion to the 6-iodo analogues with Nal/TFA/butanone

Full text of DOI:10.1021/ol048987n

ORGANIC
LETTERS
2004
Vol. 6, No. 17
2917-2919
SNAr Iodination of 6-Chloropurine
Nucleosides: Aromatic Finkelstein
Reactions at Temperatures Below
1
−40 °C
Jiangqiong Liu, Zlatko Janeba, and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602-5700
morris_robins@byu.edu
Received June 1, 2004
ABSTRACT
Mesitoyl or toluoyl esters of inosine and 2′-deoxyinosine were deoxychlorinated at C6 to give the crystalline 6-chloropurine nucleoside derivatives,
which underwent quantitative conversion to the 6-iodo analogues with NaI/TFA/butanone at −50 to −40 °C. The 6-iodo compounds were
efficient substrates for SNAr, Sonogashira, and Suzuki−Miyaura reactions, in contrast with the 6-chloro analogues, and gave good to high
yields of C−N and C−C coupled products.
Natural purine bases play central roles in many biological
processes. Purine derivatives with various substituents at C6
have received considerable recent attention due to their broad
spectrum of biological activities,2-5 and certain 6-aryl- and
6-alkynylpurine derivatives have been reported to possess
cytostatic activity.6 Advances in the synthesis of C6 modified
purines have employed Sonogashira,7,8 Suzuki-Miyaura,9,10
and SNAr11 reactions, and the area of organometallic cross-
coupling with purine and purine nucleoside derivatives has
been reviewed.12 Ve´liz and Beal11 reported that 6-bromo-
purine nucleosides were more reactive than their 6-chloro
analogues in SNAr reactions with arylamines, whereas
Lakshman and co-workers10 found that the 6-chloro ana-
logues usually provided better yields than 6-bromopurine
(1) Nucleic Acid Related Compounds. 123. Paper 122: Janeba, Z.; Lin,
X.; Robins, M. J. Nucleosides Nucleotides Nucleic Acids 2004, 23, 137-
147.
(2) Brathe, A.; Gundersen, L.-L.; Rise, F.; Eriksen, A. B.; Vollsnes, A.
V.; Wang, L. Tetrahedron 1999, 55, 211-228.
(7) Matsuda, A.; Shinozaki, M.; Yamaguchi, T.; Homma, H.; Nomoto,
R.; Miyasaka, T.; Watanabe, Y.; Abiru, T. J. Med. Chem. 1992, 35, 241-
252.
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K.-N.; Cristalli, G. J. Med. Chem. 2002, 45, 3271-3279.
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43, 1817-1825.
(10) Lakshman, M. K.; Hilmer, J. H.; Martin, J. Q.; Keeler, J. C.; Dinh,
Y. Q. V.; Ngassa, F. N.; Russon, L. M. J. Am. Chem. Soc. 2001, 123, 7779-
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2001, 44, 2683-2686.
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(6) (a) Hocek, M.; Votruba, I.; Dvora´kova´, H. Tetrahedron 2003, 59,
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Spilsberg, B. Bioorg. Med. Chem. Lett. 2003, 13, 877-880.
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(12) Hocek, M. Eur. J. Org. Chem. 2003, 245-254.
10.1021/ol048987n CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/20/2004

nucleosides for Suzuki-Miyaura couplings. Compari-
sons between 6-chloro- and 6-iodopurine nucleosides for
Sonogashira, Suzuki-Miyaura, and SNAr reactions have not
been evaluated systematically. Aryl chlorides are usually
much less reactive than the corresponding iodides for
transition metal-catalyzed reactions with aromatic sys-
tems,12,13 and Plenio and co-workers recently communicated
a more efficient catalyst system for the Sonogashira coupling
of aryl chlorides.14
6-chloropurine nucleosides 3a and 3b and the 2′-deoxy-
nucleoside 3c in good to high yields (Scheme 1). It is
noteworthy that these new 6-chloropurine nucleoside deriva-
tives are crystalline, in contrast with the amorphous esters
obtained with acetyl or benzoyl protection.
Scheme 1a
Syntheses of 6-chloro- and bromopurine nucleoside de-
rivatives are considerably less problematic11,15,16 than prepa-
ration of their 6-iodo analogues. An earlier procedure for
conversion of 6-chloro- to 6-iodopurines employed HI/H2O
at ice-bath temperature.17 The large excess of aqueous HI at
this temperature limits its utility with acid-labile compounds,
especially with the important 2′-deoxynucleosides. Roberts
and co-workers used 15N NMR to identify protonation sites
on purines and nucleosides with trifluoroacetic acid (TFA)
in DMSO,18 and applications of enhanced purine SNAr
reactivity with TFA have been noted.19 Diazotive iodo-
deamination of aminopurine nucleosides is an alternative
methodology,7,16,20 but this approach has limitations, includ-
ing poor to moderate yields, byproduct formation, and
expensive reagents.
Klapars and Buchwald13 recently communicated a copper-
catalyzed aromatic Finkelstein reaction, which converted aryl
bromides into iodides at 110 °C. We now report highly
efficient transformations of 6-chloropurine nucleoside and
2′-deoxynucleoside derivatives into their 6-iodo analogues
via an acid-catalyzed aromatic Finkelstein reaction at tem-
peratures below -40 °C. We also report the first direct
comparisons of the utility of the corresponding chloro- and
iodopurine nucleoside derivatives in C-C and C-N bond-
forming reactions at C6 via Sonogashira, Suzuki-Miyaura,
and SNAr processes.
Sugar hydroxyl groups on the inosine nucleosides were
protected21,22 as mesitoyl (2,4,6-trimethylbenzoic acid and
trifluoroacetic anhydride in CH2Cl2) or p-toluoyl (4-methyl-
benzoyl chloride/pyridine) esters because they crystallize
much more readily.22 These protected inosine and 2′-
deoxyinosine derivatives 2a-c were treated with POCl3
under our previously developed conditions15,23 to give the
a 2-4: a, R ) Mst, R′ ) OMst; b, R ) Tol, R′ ) OTol; c, R
) Tol, R′ ) H.
Minimal iodo product formation was observed upon
treatment of solutions of 3a or 3b with excess sodium iodide
in acetone, acetonitrile, or butanone at ambient temperature.
Dark-colored solutions were formed upon heating. Addition
of TFA at ambient temperature resulted in separation of a
fine precipitate (NaCl), but these acid-catalyzed SNAr reac-
tions did not proceed beyond ∼65% replacement of Cl by I.
Reaction mixtures became darker upon standing, and heating
resulted in further darkening and decomposition (TLC). We
reasoned that the solubility of NaCl in butanone would be
minimal at low temperatures but that the addition-elimina-
tion of halides at C6 would proceed at reasonable rates with
protonated purine cations in equilibrium with TFA.18
We were gratified to observe quantitative conversions
(>98% by 1H NMR24) of the 6-chloropurine nucleosides into
their iodo analogues upon treatment of 3a and 3b with 5
equiv of TFA and 20 equiv of NaI in butanone at -50 to
-40 °C for 5 h. The iodo products were purified and isolated
as crystalline solids [4a (80%) and 4b (73%)]. These
remarkably mild and convenient reaction conditions were
then applied to iodide exchange with the 2′-deoxynucleoside
3c, and 4c was produced quantitatively (>98% by 1H NMR,
66% crystalline). This represents the first synthesis of a
6-iodopurine 2′-deoxynucleoside by an aromatic Finkelstein
process.
(13) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844-
14845.
(14) Ko¨llhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed. 2003,
42, 1056-1058.
(15) Janeba, Z.; Francom, P.; Robins, M. J. J. Org. Chem. 2003, 68,
989-992.
(16) Francom, P.; Janeba, Z.; Shibuya, S.; Robins, M. J. J. Org. Chem.
2002, 67, 6788-6796.
(17) (a) Elion, G. B.; Hitchings, G. H. J. Am. Chem. Soc. 1956, 78, 3508-
3510. (b) Tanji, K.; Higashino, T. Chem. Pharm. Bull. 1988, 36, 1935-
1941.
(18) (a) Markowski, V.; Sullivan, G. R.; Roberts, J. D. J. Am. Chem.
Soc. 1977, 99, 714-718. (b) Gonnella, N. C.; Nakanishi, H.; Holtwick, J.
B.; Horowitz, D. S.; Kanamori, K.; Leonard, N. J.; Roberts, J. D. J. Am.
Chem. Soc. 1983, 105, 2050-2055.
(19) Whitfield, H. J.; Griffin, R. J.; Hardcastle, I. R.; Henderson, A.;
Meneyrol, J.; Mesguiche, V.; Sayle, K. L.; Golding, B. T. Chem. Commun.
2003, 2802-2803.
The Sonogashira reaction is valuable for the synthesis of
6-alkynylpurine nucleosides, which serve as intermediates
(20) Nair, V.; Richardson, S. G. Synthesis 1982, 670-672.
(21) Parish, R. C.; Stock, L. M. J. Org. Chem. 1965, 30, 927-929.
(22) Robins, M. J.; Barr, P. J.; Giziewicz, J. Can. J. Chem. 1982, 60,
554-557.
(23) Robins, M. J.; Uznanski, B. Can. J. Chem. 1981, 59, 2601-2607.
(24) Robins, M. J.; Sarker, S.; Wunk, S. F. Nucleosides Nucleotides 1998,
17, 785-790.
2918
Org. Lett., Vol. 6, No. 17, 2004

for the preparation of highly substituted 6-arylpurine nucleo-
sides that are not readily accessible by standard coupling
reactions.25 No cross-coupling product was detected upon
treatment of the 6-chloro analogue 3b (Scheme 2) with
for 10 h gave the aryl substitution product 6 in 70% yield.
By comparison, the 6-iodo analogue 4b gave 6 in 83% after
5 h under identical conditions.
SNAr displacement reactions provide convenient access to
biologically important N-aryl-modified nucleosides. No
product was observed upon treatment of the 6-chloro
compound 3b with aniline in CH3CN at 70 °C for 3 h. In
contrast, parallel treatment of the 6-iodo analogue 4b gave
the substitution product 7 in 80% yield. Ve´liz and Beal11
had noted that such substitution reactions did not proceed
with 6-chloro- or 6-bromopurine nucleosides with arylamines
in acetonitrile, and Lakshman et al.10,26 had resorted to
palladium-catalyzed coupling of 6-chloropurine compounds
with arylamines.
Scheme 2a
In summary, a remarkable aromatic Finkelstein reaction
that proceeds readily at temperatures below -40 °C provides
a simple, efficient, and cheap procedure for the preparation
of synthetically important 6-iodopurine nucleosides and 2′-
deoxynucleosides. Our examples demonstrate that these
6-iodopurine nucleosides are excellent substrates for SNAr
reactions with an arylamine as well as certain transition
metal-catalyzed cross-coupling reactions. In all of these
processes, the 6-iodo compounds proved to be markedly
superior to their 6-chloropurine analogues. Further systematic
comparisons are in progress, which include SNAr reactions
of the corresponding 6-fluoro- and 6-bromopurine nucleoside
analogues and different nitrogen, oxygen, and sulfur nucleo-
philes.
a R ) 2′,3′,5′-tri-O-(4-methylbenzoyl)-â-D-ribofuranosyl.
1-hexyne/Pd(PPh3)4/CuI/TEA for 10 h at ambient tempera-
ture. In contrast, parallel treatment of the 6-iodo compound
4b gave the coupling product 5 in 92% yield after 20 min.
Analogous treatment of 3b with 1-hexyne at ambient
temperature in DMF for 16 h gave 40% yield of 5, whereas
the conversion of 4b to 5 was complete in 10 min under
these conditions.
The Suzuki-Miyaura procedure has been used to prepare
6-phenylpurine nucleosides.12 Treatment of 3b with 4-meth-
oxyphenylboronic acid/Pd(PPh3)4/K2CO3/toluene at 100 °C
Acknowledgment. Pharmaceutical company gift funds
in support of this research (M.J.R.) and the award of a Roland
K. Robins Graduate Research Fellowship by Brigham Young
University (J.L.) are gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048987N
(25) Turek, P.; Kotora, M.; Hocek, M.; C´ısarova´, I. Tetrahedron Lett.
2003, 44, 785-788.
(26) Lakshman, M. K.; Gunda, P. Org. Lett. 2003, 5, 39-42.
Org. Lett., Vol. 6, No. 17, 2004
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