Regiospecific N9 alkylation of 6-(heteroaryl)purines: Shielding of N7 by a proximal heteroaryl C-H

Article abstract of DOI:10.1021/jo061759h

Purine alkylations have been plagued with formation of mixtures of N9 (usually desired), N7, and other regioisomers. We have developed methods for synthesis of 6-(azolyl)purine derivatives whose X-ray crystal structures show essentially coplanar conformations of the linked azole-purine rings. Such ring orientations position the C-H of the azole above N7 of the purine, which results in protection of N7 from alkylating agents. Treatment of 6-(2-butylimidazol-1- yl)-2-chloropurine (9) with sodium hydride in DMF followed by addition of ethyl iodide resulted in exclusive formation of 6-(2-butylimidazol-1-yl)-2-chloro-9- ethylpurine (10), whereas identical treatment of 2-chloro-6-(4,5- diphenylimidazol-1-yl)purine (11) produced a regioisomeric mixture 12/13 (N9/N7, ～5:1). The linked imidazole and purine rings are coplanar in 9 (the butyl side chain is extended away from the purine ring and C-H is over N7) but are rotated ～57° in 11, and the more bulky azole substituent in 11 did not prevent formation of the minor N7 regioisomer 13. Access to various regioisomerically pure 9-alkylpurines is now readily available.

Full text of DOI:10.1021/jo061759h

Regiospecific N9 Alkylation of 6-(Heteroaryl)purines: Shielding of
N7 by a Proximal Heteroaryl C-H1
Minghong Zhong and Morris J. Robins*
Department of Chemistry and Biochemistry, Brigham Young UniVersity, ProVo, Utah 84602-5700
morris_robins@byu.edu
ReceiVed August 25, 2006
Purine alkylations have been plagued with formation of mixtures of N9 (usually desired), N7, and other
regioisomers. We have developed methods for synthesis of 6-(azolyl)purine derivatives whose X-ray
crystal structures show essentially coplanar conformations of the linked azole-purine rings. Such ring
orientations position the C-H of the azole above N7 of the purine, which results in protection of N7
from alkylating agents. Treatment of 6-(2-butylimidazol-1-yl)-2-chloropurine (9) with sodium hydride
in DMF followed by addition of ethyl iodide resulted in exclusive formation of 6-(2-butylimidazol-
1-yl)-2-chloro-9-ethylpurine (10), whereas identical treatment of 2-chloro-6-(4,5-diphenylimidazol-1-yl)-
purine (11) produced a regioisomeric mixture 12/13 (N9/N7, ∼5:1). The linked imidazole and purine
rings are coplanar in 9 (the butyl side chain is extended away from the purine ring and C-H is over N7)
but are rotated ∼57° in 11, and the more bulky azole substituent in 11 did not prevent formation of the
minor N7 regioisomer 13. Access to various regioisomerically pure 9-alkylpurines is now readily available.
Introduction
methyl}guanine was reported.5 A requisite step for the prepara-
tion of all of these compounds is alkylation at N9 of a purine
ring. Polypeptide nucleic acids (PNAs) have good chemical and
enzymatic stability and bind strongly with oligonucleotides to
produce double- and triple-stranded structures with potential
applications in antisense and related diagnosis and therapeutic
strategies.6 The polypeptide backbone units of PNAs also are
linked to N9 of the purine bases.
Alkylation of purine nucleobases and analogues is rarely
regiospecific, and mixtures of N9 and N7 isomers are usually
obtained. The desired N9 compound is normally the major
product, but formation of significant amounts of the N7 isomer,7
as well as other alkylation products,8 is often observed. Ratios
of regioisomers formed can vary with different purine substrates
Acyclic analogues of nucleosides (acyclonucleosides) have
remained major biomedical research targets since the discovery
of the potent antiviral activity of 9-[(2-hydroxyethoxy)methyl]-
guanine (acyclovir, ACV),2 the standard drug for the treatment
of herpes viral infections. Additional acyclonucleosides have
been prepared and found to have such activity including
2-amino-9-(4-hydroxybutyl)purine (substrate for HSV-1 and
HSV-2 thymidine kinases),3 9-[4-acetoxy-3-(acetoxymethyl)-
butyl]-2-aminopurine, and 2-amino-9-[4-hydroxy-3-(hydroxy-
methyl)butyl]purine.4 More recently, the potent antiherpetic
activity of 9-{[(1S,2R)-1,2-bis(hydroxymethyl)cycloprop-1-yl]-
(1) Nucleic Acid Related Compounds. 140. (Patent application filed.)
Paper 139 is: Nowak, I.; Robins, M. J. J. Org. Chem., in press.
(2) Schaeffer, H. J.; Beauchamp, L.; de Miranda, P.; Elion, G. B.; Bauer,
D. J.; Collins, P. Nature 1978, 272, 583-585.
(5) Sekiyama, T.; Hatsuya, S.; Tanaka, Y.; Uchiyama, M.; Ono, N.;
Iwayama, S.; Oikawa, M.; Suzuki, K.; Okunishi, M.; Tsuji, T. J. Med. Chem.
1998, 41, 1284-1298.
(6) Nielsen, P. E.; Haaima, G. Chem. Soc. ReV. 1997, 26, 73-78.
(7) Ogilvie, K. K.; Cheriyan, U. O.; Radatus, B. K.; Smith, K. O.;
Galloway, K. S.; Kennell, W. L. Can. J. Chem. 1982, 60, 3005-3010.
(8) Estep, K. G.; Josef, K. A.; Bacon, E. R.; Carabateas, P. M.; Rumney,
S., IV; Pilling, G. M.; Krafte, D. S.; Volberg, W. A.; Dillon, K.; Dugrenier,
N.; Briggs, G. M.; Canniff, P. C.; Gorczyca, W. P.; Stankus, G. P.; Ezrin,
A. M. J. Med. Chem. 1995, 38, 2582-2595.
(3) Keller, P. M.; Fyfe, J. A.; Beauchamp, L.; Lubbers, C. M.; Furman,
P. A.; Schaeffer, H. J.; Elion, G. B. Biochem. Pharmacol. 1981, 30, 3071-
3077.
(4) (a) Harnden, M. R.; Jarvest, R. L.; Bacon, T. H.; Boyd, M. R. J.
Med. Chem. 1987, 30, 1636-1642. (b) Harnden, M. R.; Jarvest, R. L.; Boyd,
M. R.; Sutton, D.; Vere Hodge, R. A. J. Med. Chem. 1989, 32, 1738-
1743.
10.1021/jo061759h CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/18/2006
J. Org. Chem. 2006, 71, 8901-8906
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Zhong and Robins
and also with the nature of the alkylating species.9 It has been
noted that N9/N7 alkylation ratios were influenced significantly
by the size of the substituent at C6 on purine rings. Increased
N9/N7 ratios were observed with larger groups at C6,10 and
bulky protecting groups have been installed to improve the N9
alkylation selectivity.11 Geen et al. reported that N9/N7 alky-
lation ratios changed from 1.8:1 with 2-amino-6-methoxypurine
to 25:1 with the more sterically demanding 2-amino-6-isopro-
poxypurine (in DMF with K2CO3 as the base),10 and Reese and
co-workers found that treatment of 2-amino-6-[(4-chlorophenyl)-
sulfanyl]purine with 4-acetoxy-3-(acetoxymethyl)butyl mesylate
(K2CO3/DMF) gave the N9 isomer in 80% yield (with 89%
regioselectivity).12 We had developed a methodology for re-
giospecific N9 glycosylation (and alkylation with a reactive
R-bromoether) of 2-acetamido-6-(N,N-diphenylcarbamoyloxy)-
purine,13 but others noted that its alkylation with methyl
bromoacetate (DIPEA as base) gave limited regioselectivity (N9/
N7, ∼71:15).14 Efficient N9 alkylation with potassium tert-
butoxide/18-crown-6/DMF at 0 °C was achieved with our
carbamoyloxy derivative,15 and problems reported with other
reagents and conditions16,17 can be attributed to the limited
stability of the diphenylcarbamoyloxy group at C6.18
synthesis of 6-(imidazol-1-yl)purine derivatives.22,23 Mintas24
and others25 used pyrrol-1-yl24 and 1,2,4-triazol-4-yl25 rings as
sterically demanding 6-substituents to inhibit alkylation at N7
of 2-aminopurine. However, a minor amount of the N7 isomer
was formed (in addition to the desired N9 product) upon
alkylation of the sodium salt of 6-(pyrrol-1-yl)purine with
propylene carbonate in hot DMF,24a and alkylation of 6-(thien-
2-yl)purine with an epoxide in DMSO (or its sodium salt in
DMF) produced the N3 isomer as well as the N9 product.8 Our
6-(imidazol-1-yl)purine derivatives are more stable than the
6-(1,2,4-triazol-4-yl)purine counterparts, but both triazole and
imidazole substituents are more readily displaced (much less
basic) than a pyrrole anion. Favorable π-electron interactions
(and possibly nonclassical hydrogen bonding, C-H‚‚‚N7)
stabilize coplanar orientations of azole-aromatic ring-linked
systems.26 We reasoned that such preferred conformations of
6-(azolyl)purines (with C-H on the azole ring positioned above
N7 of the purine ring) would provide more effective shielding
of N7 than time-averaged steric interference by bulky substit-
uents at C6. In addition, any contribution of nonclassical
hydrogen bonding (C-H‚‚‚N7) would decrease the nucleophi-
licity of N7. Our X-ray crystal structures of 6-(azolyl)purine
derivatives23 are consistent with the calculations,26 and we are
pleased to report that alkylations of sodium (NaH/DMF) and
potassium (K2CO3/DMF) salts of 6-(imidazol-1-yl)- and 6-(1,2,4-
triazol-4-yl)purines under controlled conditions produce N9 alkyl
products exclusively. The N7 regioisomers were not contami-
nants in purified products, and they were not detected in crude
reaction mixtures (TLC, NMR).
Lewis acid catalyzed alkylations (SN1-type) are an alternative
to SN2-type methods. Alkylation at N7 occurs more rapidly than
at N9 under SN1 conditions, but the N7 compounds can undergo
isomerization to the more thermodynamically stable N9 prod-
ucts. Thus, TMSOTf-catalyzed alkylation of silylated guanine
derivatives with 2-acetoxy-4-(benzyloxymethyl)tetrahydrofuran
gave increased N9/N7 ratios (from 1:1 to 15:1) with extended
reaction times.19 Treatment with (2-acetoxyethoxy)methyl ac-
etate at 100-110 °C for 80 h gave a ratio of ∼24:1 (N9/N7),
but it was suggested that the high regioselectivity might have
resulted from the combination of specific reagents.20
Results and Discussion
The sodium salt of 6-(1,2,4-triazol-4-yl)purine21 (1) (Scheme
1) was generated with sodium hydride in dried DMF at ambient
temperature. Treatment of the sodium purinate with methyl
iodide gave a single isomer (1H NMR, TLC) that was purified
by filtration through silica gel to give 9-methyl-6-(1,2,4-triazol-
4-yl)purine (2a) (90%) (identical to the compound obtained by
triazole ring elaboration with 9-methyladenine21). Similar treat-
ment with other primary (ethyl, butyl, and benzyl) iodoalkanes
gave the respective 9-alkyl products 2b (93%), 2c (84%), and
2d (98%) exclusively. Because 2d was obtained in 64% yield
with benzyl chloride, benzyl iodide was generated in situ by
stirring a solution of sodium iodide and benzyl chloride in DMF
prior to addition of the purinate salt. Regiospecific alkylation
of the sodium purinate also occurred efficiently with secondary
iodides (iodocyclopentane, 2-iodopropane, and 2-iodooctane)
to give the 9-cyclopentyl 2e (87%), 9-(1-methylethyl) 2f (99%),
We have elaborated 6-amino groups on the purine base and
nucleoside derivatives into the readily displaced 6-(1,2,4-triazol-
4-yl) substituent21 and developed alternative methods for the
(9) Hockova, D.; Budesinsky, M.; Marek, R.; Marek, J.; Holy, A. Eur.
J. Org. Chem. 1999, 2675-2682. In this paper, it was reported that
alkylation of 6-N-[(dimethylamino)methylene]adenine with chloroacetoni-
trile, ethyl bromoacetate, and 1,1,1-trifluoro-2-iodoethane (with NaH or DBU
as basic promoters) gave 7-alkyl derivatives (32-51% isolated yields).
X-Ray crystal structures showed that conformations of the electron-donating
amidine group [(CH3)2NCHdN-] at C6 were distal to N7, and the enhanced
basicity of N7 with this substituent at C6 was indicated by 13C NMR.
(10) Geen, G. R.; Grinter, T. J.; Kincey, P. M.; Jarvest, R. L. Tetrahedron
1990, 46, 6903-6914.
(11) Breipohl, G.; Will, D. W.; Peyman, A.; Uhlmann, E. Tetrahedron
1997, 53, 14671-14686.
(12) Brand, B.; Reese, C. B.; Song, Q.; Visintin, C. Tetrahedron 1999,
55, 5239-5252.
(21) (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.
(13) (a) Zou, R.; Robins, M. J. Can. J. Chem. 1987, 65, 1436-1437.
(b) Robins, M. J.; Zou, R.; Guo, Z.; Wnuk, S. F. J. Org. Chem. 1996, 61,
9207-9212.
(22) (a) Lin, X.; Robins, M. J. Org. Lett. 2000, 2, 3497-3499. (b) Janeba,
Z.; Lin, X.; Robins, M. J. Nucleosides, Nucleotides, Nucleic Acids 2004,
23, 137-147.
(14) Timar, Z.; Kovacs, L.; Kovacs, G.; Schmel, Z. J. Chem. Soc., Perkin
Trans. 1 2000, 19-26.
(15) Lazrek, H. B.; Taourirte, M.; Barascut, J. L.; Imbach, J. L. Bull.
Soc. Chim. Belg. 1996, 105, 391-395.
(23) Zhong, M.; Nowak, I.; Cannon, J. F.; Robins, M. J. J. Org. Chem.
2006, 71, 4216-4221.
(16) Onishi, T.; Matsuzawa, T.; Nishi, S.; Tsuji, T. Tetrahedron Lett.
1999, 40, 8845-8847.
(24) (a) Raic, S.; Pongracic, M.; Vorkapic-Furac, J.; Vikic-Topic, D.;
Hergold-Brundic, A.; Nagl, A.; Mintas, M. Nucleosides Nucleotides 1996,
15, 937-960. (b) Dzolic, Z.; Kristafor, V.; Cetina, M.; Nagl, A.; Hergold-
Brundic, A.; Mrvos-Sermek, D.; Burgemeister, T.; Grdisa, M.; Slade, N.;
Pavelic, K.; Balzarini, J.; De Clercq, E.; Mintas, M. Nucleosides, Nucle-
otides, Nucleic Acids 2003, 22, 373-389.
(17) Cheung, A. W.-H.; Sidduri, A.; Garofalo, L. M.; Goodnow, R. A.,
Jr. Tetrahedron Lett. 2000, 41, 3303-3307.
(18) Zhong, M.; Robins, M. J. Tetrahedron Lett. 2003, 44, 9327-9330
and references therein.
(19) Geen, G. R.; Kincey, P. M.; Spoors, P. G. Tetrahedron Lett. 2001,
42, 1781-1784.
(20) Singh, D.; Wani, M. J.; Kumar, A. J. Org. Chem. 1999, 64, 4665-
4668.
(25) Alarcon, K.; Martelli, A.; Demeunynck, M.; Lhomme, J. Tetrahe-
dron Lett. 2000, 41, 7211-7215.
(26) Carra, C.; Bally, T.; Albini, A. J. Am. Chem. Soc. 2005, 127, 5552-
5562.
8902 J. Org. Chem., Vol. 71, No. 23, 2006

Regiospecific N9 Alkylation of 6-(Heteroaryl)purines
SCHEME 1. Alkylation of 6-(1,2,4-Triazol-4-yl)purine
SCHEME 3. Alkylation of 2-Amino-6-(imidazol-1-yl)purine
gave 2-amino-9-butyl-6-(imidazol-1-yl)purine (6a) (62%) plus
a 9-butyl-2-butylamino-6-(imidazol-1-yl)purine byproduct (8%).
More of that byproduct was formed with larger excesses of butyl
iodide and/or longer reaction times, and purified 6a was
converted into the dibutyl compound under the same conditions.
Treatment of the sodium purinate with benzyl iodide (generated
in situ from benzyl chloride and sodium iodide in acetonitrile)
gave 2-amino-9-benzyl-6-(imidazol-1-yl)purine (6b) (77%) as
the only detected monobenzyl product, and minor byproducts
were removed by chromatography. Standard treatment of the
purinate with cyclopentyl iodide gave 2-amino-9-cyclopentyl-
6-(imidazol-1-yl)purine (6c) (58% after chromatography). Be-
cause NaH-mediated alkylations of 5 did not proceed to
completion and were not as clean as parallel reactions of 1 or
3, we tried K2CO3/DMF. Treatment of a suspension of 5/K2-
CO3/DMF with butyl iodide gave 6a as the only observed
product (81% after chromatography). Cyclopentyl iodide/5/K2-
CO3/DMF gave 6c (99% after chromatography). Benzylation
of 5 gave 6b (68%) as the only regioisomer but did not proceed
to completion with this procedure. Treatment of the sodium salt
of 5 with the reactive (2-acetoxyethoxy)methyl bromide gave
9-[(2-acetoxyethoxy)methyl]-2-amino-6-(imidazol-1-yl)purine
(6d) (56% after chromatography), and the K2CO3/DMF system
also produced bis(2-acetoxyethoxy)methyl byproducts in addi-
tion to 6d (50%).
Regiospecific alkylation of 2-chloro-6-(imidazol-1-yl)purine
(7) (Scheme 4) with butyl iodide, benzyl iodide, and cyclopentyl
iodide (NaH/DMF) gave 9-butyl-2-chloro-6-(imidazol-1-yl)-
purine (8a) (88%), 9-benzyl-2-chloro-6-(imidazol-1-yl)purine
(8b) (85%), and 2-chloro-9-cyclopentyl-6-(imidazol-1-yl)purine
(8c) (84%), respectively. Treatment of 6-(2-butylimidazol-1-
yl)-2-chloropurine (9) with NaH/DMF followed by addition of
ethyl iodide resulted in quantitative conversion to 2-chloro-9-
ethyl-6-(2-butylimidazol-1-yl)purine (10). In contrast, identical
treatment of 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (11)
produced the ethylated regioisomers 12 and 13 (N9/N7, ∼5:1).
The 4,5-diphenylimidazole moiety in 11 is more bulky and
would be expected to shield the proximal N1 and N7 regions
of space more effectively if conformationally averaged steric
effects were more important. However, the phenyl groups on
the imidazole ring in 11 impede coplanar orientations of the
linked imidazole-purine system (a departure of 56.5° from
coplanarity was measured in an X-ray crystal structure23), which
also would disrupt nonclassical hydrogen bonding. In contrast,
the alkyl substituent at C2 of the imidazole ring in 9 does not
interfere with coplanarity of the imidazole-purine system
because the butyl group is extended away from the purine N1
region of space (a deviation of only 3.4° between the planes of
the imidazole and purine rings was measured in our X-ray
crystal structure23 of 9). The C-H of the coplanar imidazole
moiety in 9 is held above N7 of the purine ring, which would
SCHEME 2. Alkylation of 6-(Imidazol-1-yl)purine
and 9-(1-methylheptyl) 2g (83%) derivatives, respectively.
Formation of byproduct 6-alkoxy-9-alkylpurines was observed
(and byproducts were isolated in some cases). Extended reaction
times and/or excess alkyl iodide resulted in greater byproduct
formation [displacement of iodide by OH- (from adventitious
H2O and NaH) would produce an alcohol, which would react
with NaH to generate an alkoxide nucleophile].
Alkylation yields with 6-(imidazol-1-yl)purine23 (3) (Scheme
2) were comparable to those with 1. Selective alkylation at N9
of the purinate salt was effected with 1.5 equiv of benzyl iodide,
but both the imidazole N3 and the purine N9 positions were
benzylated with 4.5 equiv. NMR and mass spectral data were
consistent with a 3′,9-dibenzyl structure.27 Dialkylated byprod-
ucts were not observed with 3 equiv of other alkyl iodides (or
even with 5 equiv of cyclopentyl iodide). Anhydrous potassium
carbonate is a much more convenient base than sodium hydride
dispersed in mineral oil, and K2CO3/DMF was equivalent or
superior to NaH/DMF for some alkylations. The 6-(imidazol-
1-yl)purines have lower SNAr reactivity than their triazole
analogues, which makes them less sensitive to byproduct
formation and purification procedures. Benzylation of the
appended imidazole produces an imidazolium cation that is more
readily displaced by nucleophiles.27 Exclusive N9 alkylation
followed by SNAr displacements21,22 or cross-coupling reac-
tions28 makes a wide range of regiochemically pure 9-alkylpu-
rines readily available.
We then probed access to 9-alkyl-2-(substituted)purines with
2-amino-6-(imidazol-1-yl)purine (5) (Scheme 3). Treatment of
5 with NaH/DMF followed by addition of excess butyl iodide
(27) Zhong, M.; Nowak, I.; Robins, M. J. J. Org. Chem., 2006, 71, 7773-
7779.
(28) Liu, J.; Robins, M. J. Org. Lett. 2004, 6, 3421-3423.
J. Org. Chem, Vol. 71, No. 23, 2006 8903

Zhong and Robins
Experimental Section29
SCHEME 4. Alkylation of 2-Chloro-6-(imidazol-1-yl)purines
The 6-(1,2,4-triazol-4-yl)purine21 (1), 6-(imidazol-1-yl)purine23
(3), 2-amino-6-(imidazol-1-yl)purine23 (5), 2-chloro-6-(imidazol-
1-yl)purine23 (7), 2-chloro-6-(2-butylimidazol-1-yl)purine23 (9), and
2-chloro-6-(4,5-diphenylimidazol-1-yl)purine23 (11) were prepared
and characterized as described.
General Method 1. Sodium hydride (60% w/w dispersion in
mineral oil) was added to a stirred solution of the 6-(azolyl)purine
in DMF (5 mL) under N2, and stirring was continued at ambient
temperature for ∼1 h. The respective iodoalkane was added, and
stirring was continued until conversion of the starting was essentially
complete (TLC). For alkylations of: 1 (190 mg, 1.02 mmol) and
NaH (60 mg of 60% dispersion, 1.5 mmol); 3 (93 mg, 0.50 mmol)
and NaH (23 mg of 60% dispersion, 0.58 mmol); 5 (100 mg, 0.5
mmol) and NaH (25 mg of 60% dispersion, 0.63 mmol); and 7
(110 mg, 0.50 mmol) and NaH (25 mg of 60% dispersion, 0.63
mmol).
Traces of 6-alkoxy-9-alkylpurine byproducts resulting from
nucleophilic replacement of triazole by the alkoxide derived from
the respective iodoalkane were observed.
General Method 2. Anhydrous potassium carbonate (230 mg,
1.67 mmol) and the 6-(azolyl)purine (0.5 mmol) in DMF (5 mL)
were stirred under N2. The respective iodoalkane was added to the
suspension, and stirring was continued at ambient temperature
overnight.
9-Methyl-6-(1,2,4-triazol-4-yl)purine21 (2a). Treatment of 1 by
general method 1 with MeI (0.09 mL, 210 mg, 1.5 mmol),
evaporation of volatiles in vacuo, and chromatography of the residue
(MeOH/CH2Cl2, 1:14) gave a solid. This material was washed (H2O)
to give 2a (180 mg, 90%): UV max 210, 277 nm (ꢀ 27 300,
12 700), min 235 nm (ꢀ 2600); 1H NMR (300 MHz, DMSO-d6) δ
9.67 (s, 2H), 8.95 (s, 1H), 8.79 (s, 1H), 3.93 (s, 3H); LRMS (EI)
m/z 201 (M+ [C8H7N7] ) 201).
A solution of 2a in Me2NH/H2O (40% w/w, 20 mL) was stirred
at ambient temperature until the displacement was complete (TLC).
Volatiles were evaporated in vacuo, and the residue was chromato-
graphed (MeOH/CH2Cl2, 1:40) to give 9-methyl-6-dimethylami-
nopurine21 (150 mg, 86%): 1H NMR δ 8.30 (s, 1H), 7.64 (s, 1H),
3.74 (s, 3H), 3.47 (br s, 6H); LRMS (EI) m/z 177 (M+ [C8H11N5]
) 177).
effectively shield this volume of space and also might decrease
the nucleophilicity of N7. Thus, our alkylation results, X-ray
crystal structures,23 and theoretical calculations26 are in harmony
with the coplanar conformation-restriction hypothesis.
Summary and Conclusions
Treatment of 6-(1,2,4-triazol-4-yl)purine, 6-(imidazol-1-yl)-
purine, 2-amino-6-(imidazol-1-yl)purine, and 2-chloro-6-(imi-
dazol-1-yl)purine with NaH/DMF followed by alkyl iodides
gave regiospecific N9 alkylation (N7 isomers were not detected,
even in crude reaction mixtures). Anhydrous K2CO3/DMF was
a convenient alternative to NaH/DMF in some cases. Byproduct
6-alkoxy-9-alkylpurines were presumably formed by displace-
ment of iodide from the iodoalkanes by hydroxide (adventitious
H2O and NaH) to give alcohols, deprotonation by NaH to give
alkoxides, and alkoxide displacement of the azole at C6. Larger
excesses of alkyl iodides and/or longer reaction times increased
byproduct formation. We attribute the N9 regiospecificity to
the coplanarity of the linked azole-purine rings, which positions
the C-H of the azole above N7 of the purine. Treatment of the
sodium salt of 6-(2-butylimidazol-1-yl)-2-chloropurine (coplanar
azole-purine rings) with ethyl iodide gave the 9-ethyl isomer
exclusively, whereas identical treatment of sodium 2-chloro-6-
(4,5-diphenylimidazol-1-yl)purinate (greater steric bulk, but
rotated ∼57° from coplanarity) gave both N9 and N7 regioi-
somers (∼5:1). A broad array of regioisomerically pure
6-substituted-9-alkylpurines and 9-alkylpurines with substituents
at both C2 and C6 are now readily accessible. Although not
investigated, 6-(heteroaryl)-8-(substituted)purines also would be
expected to undergo alkylation regiospecifically at N9 because
steric effects of groups at C8 should disfavor reactions at N7
that would generate products with three contiguous substituents
(at C6, N7, and C8).
9-Ethyl-6-(1,2,4-triazol-4-yl)purine (2b). Treatment of 1 by
general method 1 with EtI (0.12 mL, 230 mg, 1.4 mmol),
evaporation of volatiles in vacuo, and chromatography of the residue
(MeOH/CH2Cl2, 1:40 f 1:30 f 1:20) gave a solid (228 mg) that
was dissolved in CH2Cl2 and washed (H2O). The aqueous phase
was back-extracted with CH2Cl2, and the combined organic phase
was dried (Na2SO4). Volatiles were evaporated in vacuo to give a
solid (205 mg, 93%) that was recrystallized (CH2Cl2/hexanes) to
give 2b: mp 218.5-220.5 °C; UV max 212, 277 nm (ꢀ 25 400,
1
13 100), min 235 nm (ꢀ 2600); H NMR δ 9.67 (s, 2H), 8.88 (s,
1H), 8.25 (s, 1H), 4.46 (q, J ) 7.3 Hz, 2H), 1.66 (t, J ) 7.3 Hz,
3H); 13C NMR δ 154.2, 152.4, 145.3, 143.4, 141.2, 122.8, 39.8,
15.6; HRMS (EI) m/z 215.0911 (M+ [C9H9N7] ) 215.0919). Anal.
Calcd for C9H9N7: C, 50.23; H, 4.22; N, 45.56. Found: C, 50.45;
H, 4.32; N, 45.70.
9-Benzyl-6-(1,2,4-triazol-4-yl)purine (2d). A. Treatment of 1
by general method 1 with BnCl (0.17 mL, 190 mg, 1.5 mmol) and
evaporation of volatiles in vacuo gave a residue that was partitioned
(H2O/CH2Cl2). The aqueous layer was extracted (CH2Cl2), and the
combined organic phase was dried (Na2SO4). Volatiles were
evaporated, and the residue was dissolved in a small amount of
CH2Cl2. Precipitation with Et2O gave solid 2d (180 mg, 64%).
B. BnCl (0.17 mL, 190 mg, 1.5 mmol) was added to a stirred
solution of NaI (450 mg, 3.0 mmol) in CH3CN (3 mL). Precipitation
of NaCl occurred, and stirring was continued for ∼1 h at ambient
temperature (the resulting solution of BnI was used without
(29) General experimental items are in the Supporting Information.
8904 J. Org. Chem., Vol. 71, No. 23, 2006

Regiospecific N9 Alkylation of 6-(Heteroaryl)purines
purification). Treatment of 1 by general method 1 with the crude
BnI, evaporation of volatiles in vacuo, and chromatography of the
residue (MeOH/CH2Cl2, 1:20) gave a solid (276 mg, 98%) that
was recrystallized (CH2Cl2/hexanes) to give 2d: mp 218-218.8
°C; UV max 211, 277 nm (ꢀ 33 300, 13 700), min 238 nm (ꢀ 3200);
1H NMR δ 9.66 (s, 2H), 8.91 (s, 1H), 8.20 (s, 1H), 7.42-7.29
(m, 5H), 5.55 (s, 2H); 13C NMR δ 154.4, 152.8, 145.6, 143.5, 141.1,
134.7, 129.6, 129.5, 129.3, 128.3, 122.6, 48.1; HRMS (EI)
m/z 277.1075 (M+ [C14H11N7] ) 277.1076). Anal. Calcd for
C14H11N7: C, 60.64; H, 4.00; N, 35.36. Found: C, 60.81; H, 3.98;
N, 35.30.
of the residue (MeOH/CH2Cl2, 1:40) gave a solid (123 mg, 97%)
that was recrystallized (CH2Cl2/hexanes) to give 4e: mp 117.5-
119 °C; UV max 283, 293 nm (ꢀ 16 500, 12 300), min 240, 291
nm (ꢀ 3800, 11 700); 1H NMR δ 9.21 (s, 1H), 8.80 (d, J ) 1.5 Hz,
1H), 8.43 (s, 1H), 8.17 (s, 1H), 7.28 (s, 1H), 5.07 (quint, J ) 7.1
Hz, 1H), 2.41-2.35 (m, 2H), 1.86-2.13 (m, 6H); 13C NMR δ
154.0, 152.1, 145.9, 143.0, 137.9, 130.9, 123.1, 117.6, 56.8, 32.9,
24.1; HRMS m/z 254.1291 (M+ [C13H14N6] ) 254.1280). Anal.
Calcd for C13H14N6: C, 61.40; H, 5.55; N, 33.05. Found: C, 61.21;
H, 5.32; N, 33.13.
B. Treatment of 3 (98 mg, 0.5 mmol) by general method 2 with
iodocyclopentane (174 µL, 295 mg, 1.5 mmol) and workup as in
A gave 4e (123 mg, 97%).
9-Cyclopentyl-6-(1,2,4-triazol-4-yl)purine (2e). Treatment of
3 by general method 1 with iodocyclopentane (0.3 mL, 509 mg,
2.6 mmol) (conversion not complete, TLC), evaporation of volatiles
in vacuo, and chromatography of the residue (MeOH/CH2Cl2, 1:40)
gave a solid (226 mg, 87%) that was recrystallized (CH2Cl2/
hexanes) to give 2e: mp 181-182.5 °C; UV max 211, 278 nm (ꢀ
2-Amino-9-butyl-6-(imidazol-1-yl)purine (6a). A. Treatment
of 5 by general method 2 (complete in 28 h, TLC) with BuI (0.25
mL, 404 mg, 2.20 mmol), evaporation of volatiles in vacuo, and
chromatography (MeOH/CH2Cl2, 1:60) of the residue gave 6a (103
mg, 81%; the only product eluted): mp 156.5-157 °C; UV max
1
28 900, 13 700), min 236 nm (ꢀ 3000); H NMR δ 9.66 (s, 2H),
1
8.86 (s, 1H), 8.26 (s, 1H), 5.10 (quint, J ) 7.3 Hz, 1H), 2.46-2.34
(m, 2H), 2.17-1.84 (m, 6H); 13C NMR δ 154.4, 152.1, 144.2, 143.3,
141.2, 123.1, 57.1, 32.9, 24.2; HRMS (EI) m/z 255.1228 (M+
[C12H13N7] ) 255.1232). Anal. Calcd for C12H13N7: C, 56.46; H,
5.13; N, 38.41. Found: C, 56.70; H, 5.18; N, 38.40.
227, 321 nm (ꢀ 33 800, 9000), min 281 nm (ꢀ 1400); H NMR
(500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.24-8.23 (m, 2H), 7.19-
7.18 (m, 1H), 6.80 (s, 2H), 4.08 (t, J ) 7.3 Hz, 2H), 1.78 (quint,
J ) 7.3 Hz, 2H), 1.27 (sext, J ) 7.3 Hz, 2H), 0.90 (t, J ) 7.3 Hz,
3H); 13C NMR (125 MHz, DMSO-d6) δ 160.6, 156.5, 145.6, 143.8,
137.2, 130.6, 117.7, 115.7, 43.3, 31.8, 20.0, 14.1; HRMS m/z
9-Ethyl-6-(imidazol-1-yl)purine (4b). A. Treatment of 3 by
general method 1 with EtI (0.06 mL, 117 mg, 0.75 mmol),
evaporation of volatiles in vacuo, and chromatography of the residue
(MeOH/CH2Cl2, 1:40) gave a solid (101 mg, 95%) that was
recrystallized (CH2Cl2/hexanes) to give 4b (97 mg, 91%): mp
125.5-127 °C; UV max 212, 282, 292 nm (ꢀ 24 000, 15 900,
257.1378 (M+ [C12H15N7]
C12H15N7: C, 56.02; H, 5.88; N, 38.11. Found: C, 55.82; H, 6.01;
N, 37.88.
) 257.1389). Anal. Calcd for
B. Treatment of 5 by general method 1 (complete in 5.5 h, TLC)
with BuI (0.25 mL, 404 mg, 2.20 mmol), evaporation of volatiles
in vacuo, and chromatography of the residue (MeOH/CH2Cl2, 1:96
f 1:60) gave 6a (80 mg, 62%) plus 9-butyl-2-butylamino-6-
(imidazol-1-yl)purine (12 mg, 8%): mp 134.5-135 °C; UV max
232, 333 nm (ꢀ 35 400, 7600), min 212, 287 nm (ꢀ 13 600, 3200);
1H NMR (500 MHz, CDCl3) δ 9.08 (s, 1H), 8.33 (s, 1H), 7.72 (s,
1H), 7.22 (s, 1H), 5.13 (s, 1H), 4.13 (t, J ) 7.3 Hz, 2H), 3.50 (q,
J ) 7.0 Hz, 2H), 1.88 (quint, J ) 7.3 Hz, 2H), 1.67 (quint, J ) 7.3
Hz, 2H), 1.47 (sext, J ) 7.3 Hz, 2H), 1.40 (sext, J ) 7.3 Hz, 2H),
0.98-1.01 (m, 6H); 13C NMR (125 MHz, CDCl3) δ 159.4, 156.2,
146.1, 141.4, 137.7, 130.4, 117.6, 116.4, 43.4, 41.9, 31.99, 31.97,
20.4, 20.1, 14.1, 13.8; HRMS m/z 313.2007 (M+ [C16H23N7] )
313.2015). Anal. Calcd for C16H23N7: C, 61.32; H, 7.40; N, 31.28.
Found: C, 61.16; H, 7.46; N, 31.14.
1
11 800), min 235, 290 nm (ꢀ 2900, 11 700); H NMR δ 9.18 (s,
1H), 8.79 (s, 1H), 8.40 (t, J ) 1.2 Hz, 1H), 8.13 (s, 1H), 7.25 (d,
J ) 0.5 Hz, 1H), 4.39 (q, J ) 7.3 Hz, 2H), 1.61 (t, J ) 7.3 Hz,
3H); 13C NMR δ 153.8, 152.3, 145.9, 144.2, 137.9, 130.9, 122.8,
117.6, 39.6, 15.6; HRMS m/z 214.0959 (M+ [C10H10N6] )
214.0967). Anal. Calcd for C10H10N6: C, 56.07; H, 4.70; N, 39.23.
Found: C, 56.31; H, 4.52; N, 39.08.
Extended reaction times and/or more iodoethane resulted in the
formation of 6-ethoxy-9-ethylpurine: 1H NMR δ 8.55 (s, 1H), 7.94
(s, 1H), 4.68 (q, J ) 7.1 Hz, 2H), 4.32 (q, J ) 7.3 Hz, 2H), 1.57
(t, J ) 7.3 Hz, 3H), 1.54 (t, J ) 7.3 Hz, 3H); LRMS m/z 192 (M+
[C9H12N4O] ) 192), 177 (M - CH3 [C8H9N4O] ) 177).
B. Treatment of 3 (98 mg, 0.5 mmol) by general method 2 with
EtI (80 µL, 159 mg, 1.0 mmol) and workup as in A gave 4b (98
mg, 92%).
Greater excesses of BuI produced more of the dibutylated
product, and treatment of 6a with BuI by general method 1 also
produced the dibutyl compound.
9-Benzyl-6-(imidazol-1-yl)purine (4d). A. Treatment of 3 by
general method 1 with BnI [prepared from BnCl (0.086 mL, 95
mg, 0.75 mmol) and NaI (0.25 g, 1.67 mmol) in CH3CN (2 mL)],
evaporation of volatiles in vacuo, and chromatography of the residue
(MeOH/CH2Cl2, 1:40) gave a solid (133 mg, 96%) that was
recrystallized (CH2Cl2/hexanes) to give 4d: mp 195.5-196.5 °C;
UV max 282, 292 nm (ꢀ 16 800, 12 700), min 238, 290 nm (ꢀ 3600,
2-Amino-9-cyclopentyl-6-(imidazol-1-yl)purine (6c). A. Treat-
ment of 5 by general method 2 with iodocyclopentane (0.30 mL,
0.509 g, 2.57 mmol), evaporation of volatiles in vacuo, and
chromatography of the residue (MeOH/CH2Cl2, 1:30) gave 6c (133
mg, 99%): mp 183.5-184.5 °C; UV max 228, 320 nm (ꢀ 31 900,
1
8500), min 210, 281 nm (ꢀ 12 800, 1800); H NMR (500 MHz,
1
12 300); H NMR δ 9.21 (s, 1H), 8.86 (d, J ) 1.2 Hz, 1H), 8.85
CDCl3) δ 9.08 (s, 1H), 8.32 (s, 1H), 7.84 (s, 1H), 7.22 (s, 1H),
5.01 (s, 2H), 4.85 (quint, J ) 7.3 Hz, 1H), 2.27-2.32 (m, 2H),
1.92-2.03 (m, 4H), 1.79-1.87 (m, 2 H); 13C NMR (125 MHz,
CDCl3) δ 159.2, 156.0, 146.3, 140.2, 137.7, 130.5, 117.6, 117.5,
55.9, 32.8, 24.1; HRMS m/z 269.1383 (M+ [C13H15N7] ) 269.1389).
Anal. Calcd for C13H15N7: C, 57.98; H, 5.61; N, 36.41. Found: C,
57.91; H, 5.87; N, 36.28.
B. Treatment of 5 by general method 1 (incomplete; minor
byproducts, TLC) with iodocyclopentane (0.30 mL, 0.509 g, 2.59
mmol), and workup as in A gave 6b (80 mg, 59%).
(s, 1H), 8.11 (s, 1H), 7.29-7.43 (m, 6H), 5.52 (s, 2H); 13C NMR
δ 154.0, 152.7, 146.0, 144.5, 137.9, 135.0, 131.0, 129.5, 129.1,
128.2, 122.6, 117.6, 47.9; HRMS m/z 276.1122 (M+ [C15H12N6]
) 276.1123). Anal. Calcd for C15H12N6: C, 65.21; H, 4.38; N,
30.42. Found: C, 65.22; H, 4.31; N, 30.66.
B. Increasing the ratio of BnI/3 from 1.5:1 (in A) to 3:1 (in B)
gave 4d (20 mg, 14%) plus 3-benzyl-1-(9-benzylpurin-6-yl)-
imidazolium iodide (179 mg, 73%): 1H NMR δ 10.57-10.59 (m,
1H), 8.76 (s, 1H), 8.66 (s, 1H), 8.60-8.61 (m, 1H), 8.06-8.08
(m, 1H), 7.64-7.69 (m, 2H), 7.24-7.41 (m, 8H), 6.01 (s, 2H),
5.57 (s, 2H); 13C NMR δ 154.8, 151.9, 147.9, 141.5, 135.6, 134.7,
132.5, 129.8-128.5 (overlap), 124.4, 122.8, 120.0, 54.4, 48.1. The
second benzylation could be driven to completion with BnI/3 ratios
of g5:1.
9-Butyl-2-chloro-6-(imidazol-1-yl)purine (8a). Treatment of 7
by general method 1 (4 h; complete, TLC) with BuI (0.35 mL,
566 mg, 3.1 mmol), evaporation of volatiles in vacuo, and
chromatography of the residue (MeOH/CH2Cl2, 1:60) gave 8a (122
mg, 88%): mp 150-150.5 °C; UV max 220, 290, 300 nm (ꢀ
1
9-Cyclopentyl-6-(imidazol-1-yl)purine (4e). A. Treatment of
3 by general method 1 with iodocyclopentane (290 µL, 492 mg,
2.5 mmol), evaporation of volatiles in vacuo, and chromatography
29 000, 15 600, 12 600), min 239, 297 nm (ꢀ 2900, 11 100); H
NMR (500 MHz, DMSO-d6) δ 9.15 (t, J ) 1.1 Hz, 1H), 8.35 (t, J
) 1.4 Hz, 1H), 8.07 (s, 1H), 7.25 (dd, J ) 1.5, 0.9 Hz, 1H), 4.29
J. Org. Chem, Vol. 71, No. 23, 2006 8905

Zhong and Robins
(t, J ) 7.4 Hz, 2H), 1.93 (quint, J ) 7.5 Hz, 2H), 1.41 (sext, J )
7.3 Hz, 2H), 0.99 (t, J ) 7.0 Hz, 3H); 13C NMR (125 MHz, DMSO-
d6) δ 155.4, 153.9, 146.5, 145.1, 138.0, 131.2, 121.6, 117.6, 44.4,
32.1, 20.1, 13.7; HRMS m/z 276.0889 (M+ [C12H13ClN6] )
276.0890). Anal. Calcd for C12H13ClN6: C, 52.08; H, 4.74; N,
30.37. Found: C, 51.96; H, 4.86; N, 30.12.
mg, 0.145 mmol) and NaH (8.6 mg, 60% w/w dispersion in mineral
oil, 0.21 mmol) in DMF was stirred at ambient temperature under
N2 for 1 h. EtI (0.05 mL, 98 mg, 0.63 mmol) was added, and stirring
was continued (3 h; incomplete, TLC). Volatiles were evaporated
in vacuo, and the residue was chromatographed (MeOH/CH2Cl2,
1:30) to give 12 and 13 (∼5:1). Compound 12: UV max 278 nm
1
2-Chloro-9-cyclopentyl-6-(imidazol-1-yl)purine (8c). Treatment
of 7 by general method 1 (7 days; incomplete, TLC) with
iodocyclopentane (0.3 mL, 509 mg, 2.6 mmol), evaporation of
volatiles in vacuo, and chromatography of the residue (MeOH/CH2-
Cl2, 1:60) gave 8c as a solid (121 mg, 84%): mp 182-182.5 °C;
UV max 221, 290, 301 nm (ꢀ 30 800, 15 600, 12 700), min 242,
(ꢀ 16 300), min 268 nm (ꢀ 15 700); H NMR (500 MHz, DMSO-
d6) δ 8.86 (s, 1H), 8.78 (s, 1H), 7.20-7.48 (m, 10H), 4.28 (q, J )
7.3 Hz, 2H), 1.45 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz, DMSO-
d6) δ 154.7, 150.8, 147.6, 145.9, 139.0, 138.8, 133.4, 130.6, 130.4,
128.23, 128.16, 128.1, 127.2, 127.0, 126.8, 124.1, 40.0, 14.6;
NOESY cross peaks were present for (CH2, H8), (CH2, CH3), (CH2,
Ph), (CH3, H8), and (CH3, Ph); HRMS m/z 400.1207 (M+ [C22H17-
ClN6] ) 400.1203). Anal. Calcd for C22H17ClN6: C, 65.92; H, 4.27;
N, 20.96. Found: C, 66.00; H, 4.50; N, 20.83. Compound 13: 1H
NMR (500 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.46 (s, 1H), 7.20-
7.52 (m, 10H), 4.05 (q, J ) 7.3 Hz, 2H), 1.20 (t, J ) 7.3 Hz, 3H);
NOE difference effects when CH2 was irradiatied, H8 (1.9%), H2
of 6-(imidazol-1-yl) (3.6%), Ph (2.9%), and CH3 (4.8%); NOESY
cross peaks were present for (CH2, H8), [CH2, H2 of 6-(imidazol-
1-yl)], (CH2, CH3), (CH2, Ph), (CH3, H8), [CH3, H2 of 6-(imidazol-
1-yl)], and (CH3, Ph); 13C NMR (125 MHz, DMSO-d6) δ 166.1,
153.6, 151.7, 147.6, 142.1, 139.3, 139.0, 134.2, 130.8, 129.5, 129.2,
129.0, 127.9, 127.5, 120.6, 42.9, 15.8; HRMS m/z 400.1212 (M+
[C22H17ClN6 ) 400.1203]).
1
298 nm (ꢀ 3600, 12 200); H NMR (500 MHz, CDCl3) δ 9.02 (s,
1H), 8.85 (s, 1H), 8.33 (s, 1H), 7.27 (s, 1H), 4.97 (quint, J ) 7.3
Hz, 1H), 2.20-2.26 (m, 2H), 2.00-2.07 (m, 2H), 1.87-1.95 (m,
2H), 1.70-1.78 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 155.7,
152.2, 146.9, 146.0, 137.7, 131.5, 122.2, 118.1, 56.9, 32.6, 24.2;
HRMS m/z 288.0888 (M+ [C13H13ClN6] ) 288.0890). Anal. Calcd
for C13H13ClN6: C, 54.08; H, 4.54; N, 29.11. Found: C, 54.30; H,
4.65; N, 29.14.
6-(2-Butylimidazol-1-yl)-2-chloro-9-ethylpurine (10). A mix-
ture of 9 (50 mg, 0.18 mmol) and NaH (11.2 mg, 60% w/w
dispersion in mineral oil, 0.28 mmol) in DMF was stirred at ambient
temperature under N2 for 1 h. EtI (0.09 mL, 179 mg, 1.15 mmol)
was added, and stirring was continued (4 h; complete, TLC).
Volatiles were evaporated in vacuo, and the residue was chromato-
graphed (MeOH/CH2Cl2, 1:30) to give 10 (quantitative): mp
104.5-105 °C; UV max 218, 289 nm (ꢀ 23 700, 13 300), min 240
Acknowledgment. We gratefully acknowledge pharmaceuti-
cal company unrestricted gift funds (M.J.R.) and Brigham
Young University for financial support including a Roland K.
Robins Graduate Research Fellowship (M.Z.). We thank Dr.
Ireneusz Nowak for helpful discussions and for reviewing the
manuscript.
1
nm (ꢀ 1500); H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J ) 1.0
Hz, 1H), 8.45 (t, J ) 1.3 Hz, 1H), 7.07 (t, J ) 1.5 Hz, 1H), 4.31
(q, J ) 7.3 Hz, 2H), 3.12 (t, J ) 7.3 Hz, 3H), 1.68 (quint, J ) 7.3
Hz, 2H), 1.47 (t, J ) 7.3 Hz, 2H), 4.31 (sext, J ) 7.3 Hz, 2H),
0.91 (t, J ) 7.3 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 154.8,
150.9, 149.6, 146.8, 146.7, 128.2, 122.3, 120.3, 38.9, 29.5, 29.4,
21.9, 14.7, 13.6; HRMS m/z 327.1105 (MNa+ [C14H17ClN6Na )
327.1101]). Anal. Calcd for C14H17ClN6: C, 55.17; H, 5.62; N,
27.57. Found: C, 55.01; H, 5.72; N, 27.57.
Supporting Information Available: General experimental
items, procedures, and characterization data for 2c, 2f, 2g, 4a, 4c,
4f, 6b, 6d, and 8b and NMR spectra of compounds for which
elemental analyses were not obtained. This material is available
free of charge via the Internet at http://pubs.acs.org.
2-Chloro-9-ethyl-6-(4,5-diphenylimidazol-1-yl)purine (12) and
2-Chloro-7-ethyl-6-(4,5-diphenylimidazol-1-yl)purine (13). A
mixture of 2-chloro-6-(4,5-diphenylimidazol-1-yl)purine (11) (54
JO061759H
8906 J. Org. Chem., Vol. 71, No. 23, 2006