Azoles as suzuki cross-coupling leaving groups: Syntheses of 6-arylpurine 2′-deoxynucleosides and nucleosides from 6-(lmidazol-1-yl)- and 6-(1,2,4-triazol-4-yl)purine derivatives

Article abstract of DOI:10.1021/ol048490d

(Chemical Equation Presented) 6-(lmidazol-1-yl)-, 6-(benzimidazol-1-yl)-, and 6-(1,2,4-triazol-4-yl)purine nucleosides undergo a nickel-mediated C-C cross-coupling of azole-substituted purine derivatives with arylboronic acids to give good yields of 6-ary

Full text of DOI:10.1021/ol048490d

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3421-3423
Azoles as Suzuki Cross-Coupling
Leaving Groups: Syntheses of
6-Arylpurine 2′-Deoxynucleosides and
Nucleosides from 6-(Imidazol-1-yl)- and
6-(1,2,4-Triazol-4-yl)purine Derivatives1
Jiangqiong Liu and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity,
ProVo, Utah 84602-5700
morris_robins@byu.edu
Received July 30, 2004
ABSTRACT
6-(Imidazol-1-yl)-, 6-(benzimidazol-1-yl)-, and 6-(1,2,4-triazol-4-yl)purine nucleosides undergo a nickel-mediated C−C cross-coupling of azole-
substituted purine derivatives with arylboronic acids to give good yields of 6-arylpurine nucleosides.
Modified purines and purine nucleoside derivatives play a
major role in biology, biochemistry, and pharmaceutics.2
Recently, 6-arylpurine ribonucleosides have been shown to
possess cytostatic activity.3 Classic methodology for the
synthesis of biaryls by the Suzuki-Miyaura protocol involves
the Pd/Ni-mediated cross-coupling of haloaromatic or aryl-
sulfonate derivatives with arylboronic acids.3,4
We recently demonstrated that 6-iodopurine nucleoside
derivatives are markedly superior to their 6-chloropurine
analogues as substrates for the Suzuki-Miyaura and other
cross-coupling procedures.1 However, syntheses of such
6-halopurine 2′-deoxynucleosides from naturally occurring
2′-deoxy(inosine/adenosine) are problematic, and high yields
are obtained only with considerable care and persistence.1,5
By contrast, 6-(imidazol-1-yl)purine (2′-deoxy)nucleoside
derivatives can be prepared readily in excellent yields from
(2′-deoxy)inosine.6 Because of these considerations, we have
probed the unexplored utility of 6-(imidazol-1-yl)purine
nucleosides as substrates for cross-coupling with arylboronic
acids. Such couplings would provide a new avenue for
modifications at C6 of purine nucleosides from readily
accessible 6-azolyl precursors.
(1) Nucleic Acid Related Compounds. 124. Paper 123: Liu, J.; Janeba,
Z.; Robins, M. J. Org. Lett. 2004, 6, 2917-2919.
(2) (a) Brathe, A.; Gunderesen, L.-L.; Rise, F.; Eriksen A. B.; Vollsnes,
A. V.; Wang, L. Tetrahedron 1999, 55, 211-228. (b) Perez, O. D.; Chang
Y.-T.; Rosania, G.; Sutherlin, D.; Schultz, P. G. Chem. Biol. 2002, 9, 475-
483.
(3) (a) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med. Chem.
2000, 43, 1817-1825. (b) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova,
H. Collect. Czech. Chem. Commun. 2000, 65, 1683-1697. (c) Hocke, M.;
Holy, A.; Votruba, I.; Dvorakova, H. Collect. Czech. Chem. Commun. 2001,
66, 483-499.
(4) Lakshman, M. K.; Thomson, P. F.; Nuqui, M. A.; Hilmer, J. H.;
Sevova, N.; Boggess, B. Org. Lett. 2002, 4, 1479-1482.
Our initial attempts to couple 4-methoxyphenylboronic
acid and 6-(imidazol-1-yl)purine nucleoside derivatives with
palladium-based catalyst systems were not successful. Hartwig
(5) (a) Robins, M. J.; Uznanski, B. Can. J. Chem. 1981, 59, 2601-
2607. (b) Nair, V.; Richardson, S. G. Synthesis 1982, 670-672. (c) Francom,
P.; Janeba, Z.; Shibuya, S.; Robins, M. J. J. Org. Chem. 2002, 67, 6788-
6796. (d) Janeba, Z.; Francom, P.; Robins, M. J. J. Org. Chem. 2003, 68,
989-992 and references therein.
(6) Lin, X.; Robins, M. J. Org. Lett. 2000, 2, 3497-3499.
10.1021/ol048490d CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/26/2004

recently prepared three-coordinate arylpalladium amido
complexes, which were subjected to reductive elimination
to give N-coupled arylamines.7 However, the precursor three-
coordinate arylpalladium amido complexes were prepared
by treatment of an arylpalladium bromide complex with the
potassium salt of a diarylamine. This is drastically different
from palladium insertion into the C-N bond of a 6-(imida-
zol-1-yl)purine. Nickel catalysts have been used successfully
in a wide variety of Suzuki reactions, which provide ample
precedent for transmetalations with arylboronic acids.8 Our
challenge was to identify a catalytic complex that could insert
readily into the purine-imidazole (C6-N) bond.
Table 1. Cross-Coupling Reaction Conditions and Yieldsa
entry
catalyst
ligand
base
5 (%)
1
2
3
4b
5
6
7
8c
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Ni(dppp)Cl2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
none
SIPr
SIPr
SIPr
SIPr
SIPr
SIPr
SIPr
IPr
K2CO3
K3PO4
K3PO4
K3PO4
KF
<5
<5
<5
30
<5
64
83
<5
<5
CsF
K3PO4
K3PO4
K3PO4
9
Imidazolium carbene ligands (Figure 1) have been used
successfully in various cross-coupling reactions.9 On the basis
a Reaction conditions: 1.0 equiv of 3, 2.0 equiv of 4, 10 mol % of
catalyst, 10 mol % of ligand, 3.0 equiv of base, 60 °C, 8 h. b BuLi (0.4
equiv) was used to reduce Ni(II) to Ni(0). c Ambient temperature instead
of 60 °C.
high yield (83% isolated) (entry 7). Heating (60 °C) was
required to achieve reasonable reaction rates (entry 8).
Replacement of Ni(COD)2 by palladium catalysts in analo-
gous coupling reaction mixtures did not give coupling
products in meaningful yields.
The superior reaction efficiency observed with the Ni(0)‚
SIPr system and K3PO4 as base prompted additional evalu-
ation with this catalytic combination. Potential electronic
effects on the coupling of 6-(imidazol-1-yl)purine nucleosides
by the aryl substituent of the boronic acids was then
investigated. Both electron-rich and electron-poor arylboronic
acids underwent coupling with 3 in good yields (Schemes 1
and 2) (Table 1, entry 7; Table 2, entries 1-3).
Figure 1. Structures of the imidazolium carbene ligands IPr (1)
and SIPr (2).
of the studies of Blakey and MacMillan,10 we examined Ni-
(COD)2 as a catalyst with addition of IPr‚HCl for the cross-
coupling of 6-(imidazol-1-yl)-9-[2,3,5-tri-O-(4-methylbenzoyl)-
â-D-ribofuranosyl]purine (3) and 4-methoxyphenylboronic
acid (4) (Scheme 1). However, none of the coupling product,
Scheme 2. Coupling Reactions with Varied Substrates
Scheme 1. Model Coupling Reaction
This methodology is efficient for conversions of inosine
into various 6-arylpurine ribonucleosides, but alternative
cross-coupling reactions with 6-halopurine nucleosides pro-
vide comparatively convenient approaches. However, syn-
theses of 6-halopurine 2′-deoxynucleosides are more chal-
6-(4-methoxyphenyl)-9-[2,3,5-tri-O-(4-methylbenzoyl)-â-D-
ribofuranosyl]purine (5), was detected (Table 1, entry 9).
Next, we investigated the catalyst complex resulting from
Ni(COD)2 and SIPr‚HCl in the presence of K3PO4. We were
delighted that the cross-coupled adduct 5 was produced in
(9) (a) Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290-1309.
(b) Grasa, G. A.; Viciu, M. S.; Huang, J. Zhang, C.; Trudell, M. L.; Nolan,
S. P. Organometallics 2002, 21, 2866-2873. (c) Ma, Y.; Song, C.; Jiang,
W.; Wu, Q.; Wang, Y.; Liu, X.; Andrus, M. B. Org. Lett. 2003, 5, 3317-
3319. (d) Ma, Y.; Song, C.; Jiang, W.; Xue, G.; Cannon, J. F.; Wang, X.;
Andrus, M. B. Org. Lett. 2003, 5, 4635-4638. (e) Altenhoff. G.; Goddard,
R.; Lehmann, C. W.; Glorius, F. Angew. Chem., Int. Ed. 2003, 42, 3690-
3693.
(7) Yamashita, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5344-
5345.
(8) (a) Saito, S.; Oh-tani, S.; Miyaura, N. J. Org. Chem. 1997, 62, 8024-
8030. (b) Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. J. Org.
Chem. 2004, 69, 3447-3452. (c) Zhou, J.; Fu, G. C. J. Am. Chem. Soc.
2004, 126, 1340-1341. (d) Tang, Z.-Y.; Hu, Q.-S. J. Am. Chem. Soc. 2004,
126, 3058-3059.
(10) Blakey, S. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125,
6046-6047.
3422
Org. Lett., Vol. 6, No. 19, 2004

corresponding 6-(azolyl)purine analogues6 is buttressed by
our methodology for elaboration of the amino group of
6-aminopurine (2′-deoxy)nucleosides into their 6-(1,2,4-
triazol-4-yl)purine counterparts.11 Thus, such 6-(azolyl)purine
(2′-deoxy)nucleosides are readily available by convenient
transformations of the natural products (2′-deoxy)adenosine11
and (2′-deoxy)inosine,6 as well as for other naturally occur-
ring and synthetic analogues. A brief investigation of the
6-(1,2,4-triazol-4-yl)purine system was then undertaken
(Scheme 3, Table 3).
Table 2. Yields of Coupling Products with Varied Substrates
entry
R1
R2
yield (%)
1
2
3
4
5
6
7
OTol
OTol
OTol
H
H
H
H
CH3
F
73
81
78
68
61
75
65
H
CH3
OCH3
F
H
lenging because of the markedly less stable glycosyl linkage
of the 2′-deoxy analogues, which can result in cleavage under
even mildly acidic conditions.1,5 Our modified Appel meth-
odology provides convenient conversions of 2′-deoxyinosine
derivatives into 6-(imidazol-1-yl)purine 2′-deoxynucleoside
analogues in excellent yields (>90%) with virtually no
glycosyl bond cleavage.6 Application of the present coupling
protocol to such protected 2′-deoxynucleosides gave the
corresponding 6-arylpurine products in good isolated yields
(Table 2, entries 4-7).
Table 3. Yields of 8 with 6-(1,2,4-Triazol-4-yl)purine 7
entry
R
8 (%)
1
2
3
4
H
80
78
85
75
CH3
OCH3
F
The noted reaction conditions were applied to a cross-
coupling of 9-(3,5-di-O-acetyl-2-deoxy-â-D-erythro-pento-
furanosyl)-6-(1,2,4-triazol-4-yl)purine11 (7) and 4-methoxy-
phenylboronic acid (4). Two products, 8c/9c (45:55), were
obtained. Fortunately, the use of IPr‚HCl as ligand and CsF
as base gave the desired cross-coupling product 8c in high
yield (85%), with the oxygen-insertion byproduct 9c detected
as a minor impurity (∼5%). This coupling also was found
to be tolerant with respect to substituents on the arylboronic
acid component [with trace oxygen-insertion byproduct
formation (e5%)].
Sensitivity to the azole substituent was probed with the
6-(benzimidazol-1-yl)purine nucleoside derivative 6 (Figure
2) (also prepared in excellent yield by our modified Appel
In summary, we now report nickel-based systems with
imidazolium carbene ligands, which catalyze efficient Suzuki
cross-coupling of arylboronic acids and 6-(imidazol-1-yl)-,
6-(benzimidazol-1-yl)-, and 6-(1,2,4-triazol-4-yl)purine (2′-
deoxy)nucleoside derivatives to provide the corresponding
6-arylpurine (2′-deoxy)nucleosides. Different ligand/base
combinations give better results with imidazole versus
triazole substrates. Novel 6-(aryloxy)purine 2′-deoxynucleo-
sides, oxygen-insertion byproducts, were observed with the
6-(1,2,4-triazol-1-yl)purine derivatives. Further studies are
in progress with different substrates and catalytic systems.
Figure 2. Nucleoside derivative 6.
procedure6). Coupling of 6 (under the noted conditions) gave
5 (80% isolated yield), which demonstrated that azoles other
than imidazole could be used.
Our modified-Appel approach for quantitative conversion
of 6-oxopurine (2′-deoxy)nucleoside derivatives into the
Acknowledgment. We gratefully acknowledge pharma-
ceutical company gift funds in support of this research
(M.J.R.) and the award of a Roland K. Robins Graduate
Research Fellowship (J.L.) by Brigham Young University.
We thank Professor M. B. Andrus and co-workers for
generous gifts of the ligands IPr (1) and SIPr (2).
Scheme 3. Couplings with 6-(1,2,4-Triazol-4-yl)purine 7
Supporting Information Available: Experimental de-
tails, characterization data, and 1H NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL048490D
(11) (a) Samano, V.; Miles, R. W.; Robins, M. J. J. Am. Chem. Soc.
1994, 116, 9331-9332. (b) Miles, R. W.; Samano, V.; Robins, M. J. J.
Am. Chem. Soc. 1995, 117, 5951-5957.
Org. Lett., Vol. 6, No. 19, 2004
3423