Direct B-alkyl suzuki-miyaura cross-coupling of 2-halopurines. Practical synthesis of ST1535, a potent adenosine A2A receptor antagonist

Article abstract of DOI:10.1021/jo101027h

(Figure presented) The scope and limitations of using palladium-catalyzed cross-coupling reactions of diverse butyl metal species with two different 2-halopurines were evaluated. While tributylboranes reacted readily and regioselectively with both 2-chloro-6-dibenzylaminopurines and 2-iodo-6-chloropurines, all the other alkyl metal species were much less reactive and gave very poor yield and/or selectivity of the desired product. This protocol was applied to the synthesis of an important adenosine A _2A receptor antagonist, ST1535.

Full text of DOI:10.1021/jo101027h

pubs.acs.org/joc
anti-Parkinson’s agents, we designed and synthesized new
Direct B-Alkyl Suzuki-Miyaura Cross-Coupling of
2-Halopurines. Practical Synthesis of ST1535, a
Potent Adenosine A2A Receptor Antagonist
scaffolds containing the purine core as the binding motif to
adenosine A2A receptors.5 In particular, we focused our
attention on 2-alkyl-6-amino-8-triazolpurines with ST1535
being the most potent and adenosine selective of a series of
analogues currently in phase II clinical trials.6 The presence
of a nonfunctionalized alkyl chain in position 2 of the
heterocyclic ring makes the structure synthetically challen-
ging to prepare (Figure 1).
Francesca Bartoccini,† Walter Cabri,‡ Diana Celona,‡
Patrizia Minetti,‡ Giovanni Piersanti,*,† and
Giorgio Tarzia†
†Department of Drug and Health Sciences, University of
Urbino “Carlo Bo”, P.zza Rinascimento 6, 61029 Urbino
(PU), Italy, and ‡Chemistry & Analytical Development
Department, Sigma-Tau, Via Pontina Km 30,400, 00040
Pomezia, Roma, Italy
Classical methods for the preparation of 2-alkylpurines are
based on ring-closure reactions/heterocyclization of appro-
priately substituted pyrimidines or imidazoles with carboxylic
acid equivalents and usually involve multistep procedures and
proceed with moderate to low yields.7 More recently, transi-
tion metal-catalyzed cross-coupling reactions involving sp2-
hybridized carbon nucleophiles and aryl and vinylhalides have
altered organic synthesis enormously8 and many highly effi-
cient and mild protocols for C-C bond construction have
emerged and can be considered excellent alternatives. Yet, few
comprehensive studies have been published concerning the
analogous cross-coupling of C(sp3)-hybridized organometal-
lics with aryl halides.9 Perhaps the most utilized C-C bond
forming cross-coupling reactions when an sp3 carbon in the
coupling event is involved are the B-alkyl Suzuki-Miyaura,
Stille, and Negishi reactions. Among them, the Suzuki cou-
pling has gained significant attention due to its mildness,
versatility, and reduced environmental impact. Our interest
in selective adenosine A2A receptor antagonists as new anti-
Parkinson’s agents has focused attention on C2-alkyl-substi-
tuted purine derivatives having a C6-free amino group and a
triazole heterocycle in position 8. A focused library of poten-
tial A2A antagonists has been designed and the Stille reaction
giovanni.piersanti@uniurb.it
Received May 26, 2010
The scope and limitations of using palladium-catalyzed
cross-coupling reactions of diverse butyl metal species with
two different 2-halopurines were evaluated. While tributyl-
boranes reacted readily and regioselectively with both
2-chloro-6-dibenzylaminopurines and 2-iodo-6-chloropur-
ines, all the other alkyl metal species were much less reactive
and gave very poor yield and/or selectivity of the desired
product. This protocol was applied to the synthesis of an
important adenosine A2A receptor antagonist, ST1535.
(5) (a) Minetti, P.; Tinti, M. O.; Carminati, P.; Castorina, M.; Di Cesare,
M. A.; Di Serio, S.; Gallo, G.; Ghirardi, O.; Giorgi, F.; Giorgi, L.; Piersanti,
G.; Bartoccini, F.; Tarzia, G. J. Med. Chem. 2005, 22, 6887–6896. (b)
Piersanti, G.; Giorgi, L.; Bartoccini, F.; Tarzia, G.; Minetti, P.; Gallo, G.;
Giorgi, F.; Castorina, M.; Ghirardi, O.; Carminati, P. Org. Biomol. Chem.
2007, 16, 2567–2571.
(6) (a) Belcastro, V.; Tozzi, A.; Tantucci, M.; Costa, C.; Di Filippo, M.;
Autuori, A.; Picconi, B.; Siliquini, S.; Luchetti, E.; Borsini, F.; Calabresi, P.
The biological importance of purine bases has long been
recognized.1 Furthermore, substituted purines are important
structural elements of drug molecules and have been demon-
strated to provide high-affinity ligands for a variety of
proteins/receptors and enzymes.2-4 In particular, purines
bearing alkyl substituents attached to ring carbon atoms
dramatically influence their base-pairing ability, selective
binding to target cells, and stability toward enzymatic de-
gradation/metabolism. Thus, efficient and selective ways to
introduce an alkyl chain on the purine core are highly
desirable. As a part of our research in the field of adenosine
A2A receptor antagonists as attractive nondopaminergic
ꢀ
Exp. Neurol. 2009, 1, 231–234. (b) Galluzzo, M.; Pintor, A.; Pezzola, A.;
Grieco, R.; Borsini, F.; Popoli, P. Eur. J. Pharmacol. 2008, 579, 149–152. (c)
Tronci, E.; Simola, N.; Borsini, F.; Schintu, N.; Frau, L.; Carminati, P.;
Morelli, M. Eur. J. Pharmacol. 2007, 566, 94–102. (d) Rose, S.; Ramsay,
C. N.; Jenner, P. Brain Res. 2007, 1, 110–114. (e) Stasi, M. A.; Borsini, F.;
Varani, K.; Vincenzi, F.; Di Cesare, M. A.; Minetti, P.; Ghirardi, O.;
Carminati, P. Int. J. Neuropsychopharmacol. 2006, 5, 575–584.
(7) (a) Shaw, G. In Comprehensive Heterocyclic Chemistry ; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: New York, 1984; Vol. 5, pp
501-597. (b) Ewing, D. F.; Mackenzie, G. In Second Supplements to the 2nd
ed. of Rodds Chemistry of Carbon Compounds; Sainsbury, M., Ed.; Elsevier
Science: New York, 1999; Vol. IV, pp 127-179. (c) Legraverend., M.
Tetrahedron 2008, 64, 8585–8603.
(8) For an overview on metal-catalyzed cross-coupling reactions, see: (a)
Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F.,
Eds.; Wiley-VCH: New York, 2004.
(9) For representative references, see: Negishi coupling: (a) Boudier, A.;
Knochel, P. Tetrahedron Lett. 1999, 40, 687–690. (b) Dai, C.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 2719–2724. (c) Kondolff, I.; Doucet, H.; Santelli, M.
Organometallics 2006, 25, 5219–5222. (d) Melzig, L.; Gavryushin, A.;
Knochel, P. Org. Lett. 2007, 9, 5529–5532. Suzuki-Miyaura coupling: (e)
Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G. A. J. Am.
Chem. Soc. 2008, 130, 9257–9259. and references cited therein. Stille
coupling: Imperato, G.; Vasold, R.; Kc-nig, B. Adv. Synth. Catal. 2006,
348, 2243–2247. and references cited therein.
(1) Rosemeyer, H. Chem. Biodiversity 2004, 1, 361–401. and references
cited therein..
(2) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987–
4006.
(3) Schmidt, A. P.; Lara, D. R.; Souza, D. O. Pharmacol. Ther. 2007, 116,
401–416.
€
(4) Ertl, P.; Jelfs, S.; Muhlbacher, J.; Schuffenhauer, A.; Selzer, P. J. Med.
Chem. 2006, 49, 4568–4573.
5398 J. Org. Chem. 2010, 75, 5398–5401
Published on Web 07/02/2010
DOI: 10.1021/jo101027h
r
2010 American Chemical Society

Bartoccini et al.
JOCNote
have been reported in a few cross-coupling reactions.14 Gratify-
ingly, when commercially available tri-n-butylborane with 2 mol
% Pd(dppf)Cl2, Cs2CO3 (2 equiv), and chloropurine 1 was used,
satisfactory conversion and yield of the desired product 2a was
obtained (entry 11). Optimization of the reaction conditions in
terms of catalyst loading, base, and solvent (data not shown)
achieved complete conversion and very good yield (entry 12).
Variation of the organoborane was also carried out, using
tri-n-ethylborane, which gave the desired product 2b in com-
parable yield (entry 13). Thus, this procedure can replace the
Stille coupling in the synthesis of ST1535 that can be obtained
by using the sequence already reported.5a The existing synthe-
sis of ST1535 presents some limitations other than the C-C
bond formation, however, such as the use of very expensive
2,6-dichloropurine as the starting material, the need to first
introduce the protected amino group in the more reactive C6
position, and, consequently, the problematic final deprotection
with triflic acid.
To further improve the overall efficiency of the synthesis of
ST1535 and explore the scope and limitations of this B-alkyl
Suzuki coupling with trialkylborane, the more challenging and
readily available substrate 6-chloro-2-iodo-9-methylpurine
was chosen, since regioselectivity in the alkylation step had to
be taken into account.15 According to the literature,16 the C2
position should be the most reactive position in palladium-
catalyzed cross-coupling reactions, whereas the C6 position
should be the most reactive position in nucleophilic substitu-
tion reactions. Thus, the C-C coupling must be carried out
first, which opens the possibility of further derivatization of
such compounds at the 6-position to give biologically relevant
compounds. As expected by using the optimal conditions
reported above, the reaction proceeded with high regioselec-
tivity and afforded 2-butyl-6-chloro-9-methylpurine in good
yield (Table 2, entry 1). Only trace amounts of bis-alkylated
product (<3%) were found. Decreasing the catalyst loading or
the amount of organoborane led to lower conversion and poor
yields (entries 2 and 3). As expected, variation of the nucleo-
phile with tri-n-ethylborane gave coupling product 4b in
excellent yield (entry 13). Notably, B-alkyl Suzuki coupling
also on this substrate with use of conventional butylboronic
acid and butyltrifluoroborate provided very low yields under
different conditions (entries 4-7). No highly toxic thallium
compounds (TlOH or Tl2CO3) or other additives were utilized
for the reaction. The Negishi cross-coupling with BuZnBr did
not proceed in a satisfactory manner and low conversions in
different experimental conditions were found (entries 10-12).
However, the use of highly reactive alkylzinc reagents with aryl
or heteroaryl halides has been reported.17 Thus, we cannot
exclude that further optimization of the reaction conditions
and/or in situ generation of the air- and moisture-sensitive zinc
reagents could improve the yield of the cross-coupling product.
On the contrary, the Stille coupling with a toxic stannane
FIGURE 1. General structure of A2A antagonist and ST1535.
has been used to introduce different alkyl chains.5a Despite the
fact that the Stille reaction was very useful to introduce alkyl
chains in the less reactive 2-position of the purine, it had
several drawbacks, including toxicity of the reagents and
byproduct, low turnover number (TON) and turnover fre-
quency (TOF), harsh reaction conditions, and problematic
final purification. Herein, we report on the scope and limita-
tions of the utilization of different butyl metal reagents in the
synthesis of 2-butyl-substituted purines as an alternative
synthetic methodology to the Stille reaction and its application
in the synthesis of ST1535.10 First, we tried to optimize the
catalytic system and reaction conditions of 6-dibenzylamino-
2-chloro-9-methylpurine, previously reported by us, with dif-
ferent butyl metal species. Results of the cross-coupling reac-
tions are reported in Table 1.
Although there are several reports of Negishi couplings on
2-halopurines11 and it is probably the most convenient way to
introduce alkyl groups onto N-alkylated purines, no reaction
occurred on 1 using commercially available 1 M BuZnBr in
THF under standard reaction conditions (entry 2). Butyl zinc
bromide generated from BuLi or BuMgBr and ZnBr2 with
Pd(dppf)Cl2 also did not afford the coupling reaction (entry 3).
We then turned our attention to stable and commercially
available alkyl boron derivates such as butyl boronic acid and
butyl trifluoroborates.12 Because of their unique reactivity and
benign features, both of these seemed to be promising reagents
for the direct introduction of alkyl groups to the C2 position of
purines. Unfortunately, only trace amounts of product were
found with both reagents (entries 4-9). Only in the case of tri-
fluoroborate using the best conditions reported by Molander13
was 11% of the product obtained (entry 10). The small success
of the B-alkyl Suzuki-Miyaura reactions with potassium alkyl-
trifluoroborates and alkyl boronic acids did not discourage us to
test other alkyl metal reagents based on boron. Normally,
B-alkyl-9BBNs are used but must be prepared and used in situ.
Moreover, the preparation of B-alkyl-9BBNs bearing lower
alkyl groups is inconvenient as it involves hydroboration of
volatile alkenes (in our case butene) or other tedious operations.
On the other hand, some tri-n-alkylboranes are commercially
available or conveniently prepared from Grignard reagents and
(10) For reviews on the syntheses of purines based on transition metal-
catalyzed cross-coupling reactions, see: (a) Hocek, M. Eur. J. Org. Chem.
2003, 245–254. (b) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev.
2003, 103, 1875–1891. (c) Lakshman, M. K. J. Organomet. Chem. 2002, 653,
234–251.
(11) (a) Wang, Y.; Shakespeare, W. C.; Huang, W.-S.; Sundaramoorthi,
R.; Lentini, S.; Das, S.; Liu, S.; Banda, G.; Wen, D.; Zhu, X.; Xu, Q.; Keats,
J.; Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J. T.; Broudy, M. I.;
Russian, K.; Dalgarno, D.; Clackson, T.; Sawyer, T. K. Bioorg. Med. Chem.
Lett. 2008, 18, 4907–4912. (b) Braendvang, M.; Gundersen, L.-L. Bioorg.
Med. Chem. 2007, 22, 7144–7165.
(15) (a) Norman, T. C.; Gray, N. S.; Koh, J. T.; Schultz, P. G. J. Am. Chem.
Soc. 1996, 118, 7430–7431. (b) Matsuda, A.; Shinozaki, M.; Yamaguchi, T.;
Homma, H.; Nomoto, R.; Miyasaka, T.; Watanabe, Y.; Abiru, T. J. Med.
Chem. 1992, 35, 241–252. (c) Legraverend, M.; Ludwig, O.; Bisagni, E.; Leclerc,
S.; Meijer, L.; Giocanti, N.; Sadri, R.; Favaudon, V. Bioorg. Med. Chem. 1999,
7, 1281–1293.
(16) Piguel, S.; Legraverend, M. J. Org. Chem. 2007, 72, 7026–7029.
(17) (a) Huo, S. Org. Lett. 2003, 5, 423–425. (b) Chacko, A. M.; Qu, W.;
Kung, H. F. J. Org. Chem. 2008, 73, 4874–4881. (c) Thaler, T.; Haag, B.;
Gavryushin, A.; Schober, K.; Hartmann, E.; Gschwind, R. M.; Zipse, H.;
Mayer, P.; Knochel, P. Nat. Chem. 2010, 2, 125–130.
(12) Doucet, H. Eur. J. Org. Chem. 2008, 2013–2030.
(13) (a) Molander, G. A.; Yun, C.-S.; Ribagorda, M.; Biolatto, B. J. Org.
Chem. 2003, 68, 5534–5539. (b) Dreher, S. D.; Lim, S.-E.; Sandrock, D. L.;
Molander, G. A. J. Org. Chem. 2009, 74, 3626–3631.
(14) (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 4544–4568. (b) Sun, H. X.; Sun, Z. H.; Wang, B.
Tetrahedron Lett. 2009, 50, 1596–1599.
J. Org. Chem. Vol. 75, No. 15, 2010 5399

Bartoccini et al.
JOCNote
TABLE 1. Cross Coupling of 1 with Different Alkyl Metal Species
entry
alkyl-M (2 equiv)
Bu4Sn
BuZnBr
BuLi or BuMgBr/ZnBr2
BuB(OH)2
BuB(OH)2
BuB(OH)2
BuB(OH)2
BuB(OH)2
BuBF3K
reaction conditions
conversion (%)a
yield (%)b
79
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(PPh3)4 (20%), NMP, 120 °C, 48 h
100
Pd(PPh3)4 (20%), THF, 60 °C, 20 h
NRc
NRc
trace
NRc
trace
NRc
trace
15
Pd(dppf)Cl2 (20%), THF, 60 °C, 20 h
Pd(PPh3)4 (10%), K3PO4, dioxane, 100 °C, 20 h
Pd2(dba)3 (1.5%), Cs2CO3, IPr HCl (3%), dioxane, 80 °C, 20 h
3
Pd2(dba)3 (1.5%), Cs2CO3, L (3%),d dioxane, 80 °C, 24 h
Pd(PPh3)4 (5%), Na2CO3, EtOH/DME/H2O, 45 W, 80 °C, 4 min
Pd(OAc)2 (0.4%), Na2CO3, TBAB, H2O/DME, 100 W, 160 °C, 5 min
PdCl2(dppf) (10%), Cs2CO3, THF, H2O, 60 °C, 20 h
Pd(OAc)2 (10%), RuPhos, K2CO3, 10:1 toluene/H2O, 80 °C, 20 h
PdCl2(dppf) (2%), Cs2CO3, THF, 60 °C, 20 h
10
11
63
85
87
BuBF3K
Bu3B
Bu3B
Et3B
17
80
100
100
PdCl2(dppf) (6%), Cs2CO3, THF, 60 °C, 16 h
PdCl2(dppf) (6%), Cs2CO3, THF, 60 °C, 16 h
aDetermined by HPLC. bYield of isolated product (average of two experiments). cNo reaction. dL = 2-(di-tert-butylphosphino)biphenyl.
TABLE 2. Cross Coupling of 3 with Different Alkyl Metal Species
entry
alkyl-M
reaction conditions
conversion (%)a
yield (%) (4a,b)b
1
2
3
4
5
Bu3B (2 equiv)
Bu3B (2 equiv)
Bu3B (1.1 equiv)
BuB(OH)2 (1.1 equiv)
BuB(OH)2 (1.2 equiv)
BuB(OH)2 (1.5 equiv)
BuBF3K (1.1 equiv)
Bu4Sn (2 equiv)
Bu4Sn (1.1 equiv)
BuZnBr (1.2 equiv)
BuZnBr (1.2 equiv)
BuZnBr (1.2 equiv)
Et3B (1.1 equiv)
PdCl2(dppf) (6%), Cs2CO3, THF, 60 °C, 6 h
PdCl2(dppf) (2%), Cs2CO3, THF, 60 °C, 20 h
PdCl2(dppf) (6%), Cs2CO3, THF, 60 °C, 20 h
Pd2(dba)3 (2%), P(t-Bu)3, Cs2CO3, dioxane, 100 °C, 24 h
Pd(OAc)2 (4%), XPhos, Cs2CO3, toluene, 100 °C, 24 h
Pd(OAc)2 (4%), XPhos, K3PO4, toluene, 100 °C, 24 h
PdCl2(dppf) (10%), Cs2CO3, THF, H2O, 60 °C, 20 h
Pd(PPh3)4 (20%), NMP, 90 °C, 48 h
100
66
40
66
48
27
NRe
NRe
NRe
5
6
7
3
8c
9
100
60
56
51c
41
Pd(PPh3)4 (20%), NMP, 90 °C, 48 h
10
11
12
13
Pd(PPh3)4 (5%), THF, 50 °C, 20 h
44
NDd
Pd(OAc)2 (5%), XPhos, THF, 50 °C, 20 h
PdCl2(PPh3)2 (5%), XPhos, THF, 50 °C, 20 h
PdCl2(dppf) (6%), Cs2CO3, THF, 60 °C, 3 h
27
NRe
100
77
aDetermined by HPLC. bYield of isolated product (average of two experiments). cFormation of 5 (29%). dNot determined. eNo reaction; XPhos =
2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
reagent worked very well; however, a large amount of the bis-
alkylated product 5 was obtained (entry 8).
material are additional advantages. Application of the protocol
allowed a novel, practical, protecting-group-free synthesis of
ST1535, a promising molecule for the treatment of Parkinson’s
disease.
Thus, with coupling product 4a in our hands, an easy,
simple, protecting group free synthesis of ST1535 was ac-
complished via a simple three-step sequence: (i) amination
with aqueous ammonia, (ii) regioselective bromination of
C8, and (iii) bromide displacement with triazole to afford
ST1535 in good overall yield without using hazardous reagents
and protecting groups (Scheme 1).
In summary, tributylborane was found to be an excellent
reagent for cross-coupling reactions with two different 2-halo-
purines under Pd catalysis. This protocol, to the best of our
knowledge, is the first direct, mild, and regioselective B-alkyl-
Suzuki-Miyaura cross coupling of 2-halopurines, which are
well-known challenging substrates in Pd-mediated cross-cou-
pling chemistry. Thus, it is especially useful for the incorpora-
tion of lower n-alkyl chains to the less reactive C2 position of
2-halopurine. The reasonable catalyst loading, relatively short
reaction time, as well as the commercially available starting
Experimental Section
General Procedure. To a mixture of the appropiate 2-halopu-
rine (1.0 mmol), Cs2CO3 (977 mg, 3.0 mmol), and Pd (dppf)Cl2
3
CH2Cl2 (49 mg, 6 mol %) in a Schlenk tube under Ar atmosphere
was added freshly distilled THF (2.0 mL). To the stirred suspension
was added tributylborane (1 M solution in THF) or triethylborane
(1 M solution in hexane) in one portion, and the mixture was
refluxed for the appropriate time. To the cooled reaction mixture
was added 50% aq HOAc (2 mL) and the whole was refluxed for
1 h. The cooled solution was basified with a saturated solution
of NaHCO3 and then extracted with dichloromethane (3ꢀ10 mL).
The combined organic layer was washed successively with water
andbrine, dried(Na2SO4), filtered, and concentrated under reduced
pressure. The residue was purified by silica gel flash column
chromatography (dichloromethane/MeOH, 99:1).
5400 J. Org. Chem. Vol. 75, No. 15, 2010

Bartoccini et al.
JOCNote
SCHEME 1. Novel Synthesis of ST1535a
reduced pressure. The residue was purified by flash chromatog-
raphy (gradient dichloromethane-methanol 98:2 and 93:7).
Yield 72%; mp 146-148 °C; MS (ESI) 206 (M þ 1); 1H NMR
(200 MHz, CDCl3) δ 0.95 (t, J = 7.3 Hz, 3H), 1.37-1.49 (m,
2H), 1.72-1.84 (m, 2H), 2.82 (t, J = 8.0 Hz, 2H), 3.82 (s, 3H),
7.73 (s, 1H); 13C NMR (50 MHz, CDCl3) δ 14.0, 22.7, 29.8, 31.4,
36.2, 117.7, 140.7, 151.2, 154.8, 165.9. Anal. Calcd for C10H15N5
(205.13): C, 58.51; H, 7.37; N, 34.12. Found: C, 58.63; H, 7.25;
N, 34.08.
aReagents: (i) NH3(aq)/dioxane, 70 °C 16 h; (ii) Br2 acetate buffer pH 4,
10 min; (iii) 1H-1,2,3-triazole, Cs2CO3, DMF, 80 °C 16 h.
8-Bromo-2-butyl-9-methyl-9H-purin-6-amine (7): Bromine
(300 μL, 5.8 mmol) was added dropwise, at -15 °C, to 6 (123
mg, 0.6 mmol) dissolved in a mixture of MeOH (1.6 mL), THF
(1.6 mL), and acetate buffer pH 4 (1.6 mL) (obtained by
dissolving 4 g of sodium acetate in 100 mL of water and by
adjusting to pH 4 with glacial acetic acid). The reaction was
stirred at -15 °C for 10 min and at room temperature for 30 min.
An excess of bromine was eliminated with sodium metabisulfite
and the reaction was brought to pH 8 by addition of a saturated
solution of NaHCO3. The aqueous phase was extracted with
dichloromethane. The organic phases were dried over anhy-
drous sodium sulfate and evaporated under reduced pressure, in
order to give a residue (yield 80%) that was used for the
following reaction without further purification.
2-Butyl-9-methyl-8-(2H-1,2,3-triazol-2-yl)-9H-purin-6-amine
(ST1535): To a solution of 7 (34 mg, 0.12 mmol) in anhydrous
DMF (1 mL) were added Cs2CO3 (59 mg, 0.18 mmol) and then
1H-1,2,3-triazole (10 μL, 0.18 mmol). The mixture was stirred
overnight at 90 °C. The solvent was evaporated under reduced
pressure and the residue obtained was suspended in water
and extracted with dichloromethane (4 ꢀ50 mL). The combined
organic phases were dried over anhydrous sodium sulfate and
evaporated under reduced pressure, to give a residue that was
purified by flash chromatography (dichloromethane-methanol
95:5). The solid obtained was crystallized by ethanol. Yield
30%; mp 182 °C; MS (ESI) 273 (M þ 1); 1H NMR (200 MHz,
CDCl3) δ 0.97 (t, J = 7.25 Hz, 3H), 1.3-1.5 (m, 2H), 1.7-1.9
(m, 2H), 2.85 (t, J = 7.9 Hz, 2H), 4.07 (s, 3H), 5.56 (br, 2H), 8.00
(s, 2H); 13C NMR (50 MHz, CDCl3) δ 14.0, 22.6, 31.1, 31.2,
39.3, 115.2, 136.9, 141.9, 151.4, 155.1, 166.8. Anal. Calcd for
C12H16N8 (272.15): C, 52.93; H, 5.92; N, 41.15. Found: C, 52.87;
H, 6.03; N, 41.02.
Dibenzyl(2-n-butyl-9-methyl-9H-purin-6-yl)amine (2a): yield
1
85%; mp 72-73 °C; MS (ESI) 386 (M þ 1); H NMR (200
MHz, CDCl3) δ 0.91 (t, J = 8.0 Hz, 3H), 1.33-1.44 (m, 2H),
1.76-1.84 (m, 2H), 2.88 (t, J = 7.6 Hz, 2H), 3.84 (s, 3H),
5.11-5.82 (br, 4H), 7.30 (s, 10H), 7.65 (s, 1H); 13C NMR (50
MHz, CDCl3) δ 14.1, 22.6, 29.8, 31.0, 39.3, 49.46, 49.48, 117.7,
127.1, 128.1, 128.5, 138.4, 138.7, 152.4, 154.5, 165.3. Anal. Calcd
for C24H27N5 (385.23): C, 74.77; H, 7.06; N, 18.17. Found: C,
74.89; H, 7.02; N, 18.26.
Dibenzyl(2-n-ethyl-9-methyl-9H-purin-6-yl)amine (2b): yield
1
87%; MS (ESI) 358 (M þ 1); H NMR (200 MHz, CDCl3) δ
1.35 (t, J = 8.0 Hz, 2H), 2.88 (q, J = 8.0 Hz, 2H), 3.82 (s, 3H),
5.14-5.47 (br, 4H), 7.31 (s, 10H), 7.66 (s, 1H); 13C NMR (50
MHz, CDCl3) δ 13.1, 29.7, 32.7, 49.1, 49.4, 117.8, 127.1, 128.1,
128.5, 138.4, 138.7, 152.4, 154.5, 166.1. Anal. Calcd for C22H23N5
(357.20): C, 73.92; H, 6.49; N, 19.59. Found: C, 73.88; H, 6.60; N,
19.72.
2-n-Butyl-6-chloro-9-methyl-9H-purine (4a): yield 66%; mp
1
53-54 °C; MS (ESI) 225-227 (M þ 1); H NMR (200 MHz,
CDCl3) δ 0.96 (t, J = 7.3 Hz, 3H), 1.33-1.48 (m, 2H), 1.77-1.88
(m, 2H), 3.02 (t, J = 7.7 Hz, 2H), 3.91 (s, 3H), 8.02 (s, 1H); 13
C
NMR (50 MHz, CDCl3) δ 13.9, 22.5, 30.1, 31.2, 38.9, 116.7,
129.3, 150.5, 152.7, 166.3. Anal. Calcd for C10H13ClN4 (224.08):
C, 53.45; H, 5.83; N, 24.94. Found: C, 53.32; H, 5.67; N, 24.99.
2-n-Ethyl-6-chloro-9-methyl-9H-purine (4b): yield 77%; mp
100-101 °C; MS (ESI) 197-199 (M þ 1); 1H NMR (200 MHz,
CDCl3) δ 1.40 (t, J = 8.0 Hz, 3H), 3.05 (q, J = 8.0 Hz, 2H), 3.91
(s, 3H), 8.03 (s, 1H); 13C NMR (50 MHz, CDCl3) δ 13.1, 30.1,
32.4, 129.3, 145.0, 150.5, 152.7, 167.0. Anal. Calcd for C8H9ClN4
(196.05): C, 48.86; H, 4.61; N, 28.49. Found: C, 48.91; H, 4.55; N,
28.38.
2-Butyl-9-methyl-9H-purin-6-amine (6): To a solution of 4a
(174 mg, 0.85 mmol) in dioxane (1.3 mL) was added 30% w/w
water solution of ammonia (2.6 mL). The reaction mixture was
stirred overnight in an autoclave at 70 °C. The solution was
evaporated at atmospheric pressure at 50 °C and then under
Supporting Information Available: Experimental proce-
dures, characterization data, and NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5401