L. Bosch et al. / Tetrahedron Letters 53 (2012) 1358–1362
1361
2004, 69, 5473–5475; (c) Terrazas, M.; Ariza, X.; Vilarrasa, J. Tetrahedron Lett.
2005, 46, 5127–5130; (d) Terrazas, M.; Ariza, X.; Vilarrasa, J. Org. Lett. 2005, 7,
2477–2479; (e) Caner, J.; Vilarrasa, J. J. Org. Chem. 2010, 75, 4880–4883.
5. There are exceptions, however, depending on the nucleophile and medium. For
an update, see: (a) Liu, J.; Robins, M. J. J. Am. Chem. Soc. 2007, 129, 5962–5968,
and references cited therein; (b) we have confirmed in our lab that, with a
commercially available solution of NH3 in 1,4-dioxane (0.5 M), it was easy to
introduce an amino group at C6, either at 50 °C (overnight) or 80 °C (for 2 h)
from 1–3 in a closed vial, without affecting at all bromine and iodine atoms at
C2, that is, the reactions were very clean and, in spite of using 5 equiv of NH3,
no substitution at C2 was observed; the chlorine atom of 6-chloro-2-cyano and
6-chloro-2-(benzylamino)carbonyl derivatives had been replaced by us under
identical conditions (see: Bosch, L.; Vilarrasa, J. Tetrahedron Lett. 2011, 52, 753–
756); (c) in our hands, ammonia in anhydrous dioxane does not cleave the ester
groups of the monosaccharide ring (see Robins, M. J.; Uznanski, B. Can. J. Chem.
1981, 59, 2608–2611, for related observations in DME); the amino-
dechlorination reactions were almost quantitative.
plete but a partial decomposition of the carbamate group was
noted (the isolated yield was around 60%).21
Only the activation of the 2-Cl substituent of 1 (and of 11–13)
remained a challenge. We had attempted this replacement by forc-
ing the reaction conditions in refluxing 1,4-dioxane but the crude
contained many decomposition products. However, the conversion
of 1 into the dibenzamido derivative, 6, could be achieved in tolu-
ene at 108–110 °C (bath temperature), in 90% isolated yield, within
6 h, with 2.5 mol % of Pd2(dba)3, 7.5 mol % of Xantphos and
110 mol % of Cs2CO3.
In summary, Pd0 and Xantphos are very suitable partners for the
coupling of halopurine nucleosides with amides (either carboxam-
ides, carbamates or nosylamides). The regioselectivity–reactivity
order is 2-I > 2-Br > 6-Cl ꢀ 2-Cl (the 2-I > 2-Br > 2-Cl order was ex-
pected, but the point was to establish the ‘position’ of 6-Cl). We
have achieved the replacement of the iodine atom of 6-iodo-2-
chloro derivative 3 (and other similar iodo derivatives) at 0 °C, a
temperature at which the bromine of 2 is not substituted at all.
Such a reactivity order permits to manipulate 2,6-dihalopurines
in a proper way to attach protected amine groups either at C2 or
C6. Via Pd-catalysed processes, it is also feasible to prepare differ-
ently N2,N6-disubstituted diaminopurines (potential nucleoside
conjugates). Finally, even the more reluctant 2-Cl substituent can
be replaced by a benzamido group, in toluene at 110 °C, with a
minimum amount of Cs2CO3 and reaction times as short as possi-
ble to avoid byproducts coming from the decomposition or sapon-
ification of sensitive substrates (protected purine nucleosides).
6. (a) Piguel, S.; Legraverend, M. J. Org. Chem. 2007, 72, 7026–7029; also see: (b)
Vandromme, L.; Legraverend, M.; Kreimerman, S.; Lozach, O.; Meijer, L.;
Grierson, D. S. Bioorg. Med. Chem. 2007, 15, 130–141; (c) Li, X.; Vince, R. Bioorg.
Med. Chem 2006, 14, 5742–5755; (d) Ibrahim, N.; Legraverend, M. J. Comb. Chem
2009, 11, 658–666; for other Pd-catalysed aminations and amidations of
purines and purine nucleosides see Ref. 1.
7. Dichloro derivative 1 was prepared according to Refs.4e,5 as well as from the 2-
amino-6-chloropurine nucleoside by diazotisation and halo-dediazoniation
(tert-butyl nitrite or isopentyl nitrite, Me3SiCl, CH2Cl2); see: (a) Francom, P.;
Robins, M. J. J. Org. Chem. 2003, 68, 666–669; 2-bromo-6-chloro derivative 2
was also obtained by the last procedure (with Me3SiBr and CH2Br2 instead). We
prepared 6-chloro-2-iodo derivative
3 by a related procedure, viz., by
treatment of the amine with isopentyl nitrite, I2, CH2I2 and CuI in THF; see:
(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) Nair,
V.; Richardson, S. G. Synthesis 1982, 670–672.
8. For a review, see: Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M. Chem.
Soc. Rev. 2009, 38, 1099–1118.
9. 6-Benzamido-2-chloro-9-(20,30,50-tri-O-acetyl-b-
D-ribofuranosyl)-purine (4):
white foam; 1H NMR (CDCl3, 400 MHz) d 2.07 (s, 3H), 2.12 (s, 3H), 2.15 (s,
3H), 4.39 (d, J = 3.6 Hz, 2H), 4.45 (m, 1H), 5.58 (dd, J = 4.1, 5.5, 1H), 5.80 (t,
J = 5.7, 1H), 6.24 (d, J = 5.9, 1H), 7.49 (t, J = 7.7, 2H), 7.59 (t, J = 7.4, 1H), 8.00 (d,
J = 7.3, 2H), 8.18 (s, 1H), 9.09 (br s, 1H); 13C NMR (CDCl3, 100.6 MHz) d 20.3
(CH3), 20.5 (CH3), 20.7 (CH3), 63.0 (CH2), 70.6 (CH), 73.1 (CH), 80.6 (CH), 85.8
(CH), 122.8 (C), 128.0 (CH), 128.8 (CH), 132.6 (C), 133.1 (CH), 141.3 (CH), 150.6
(C), 153.6 (C), 153.8 (C), 164.4 (C), 169.3 (C), 169.5 (C), 170.2 (C); HRMS (ESI) m/
Acknowledgments
L.B. thanks TRIoH (EU, contract LHSB-CT2003 503480) and Fun-
dació Privada Cellex of Barcelona (June 2009–June 2010) for sti-
pends; he is currently a postdoc at CSIC (Barcelona). I.C. was a
student funded by TRIoH and currently via Fundació Bosch Gim-
pera. J.C. thanks TRIoH (2007) and Fundació Cellex (June 2009–June
2010) for a fellowship; he is currently a postdoc of the Nagoya Uni-
versity. M.T. had a studentship from TRIoH and was later ‘‘Ajudant
LOU’’ in our Department; she is currently a postdoc at the IRBB of
Barcelona.
z
calcd for [C23H2335ClN5O8]+ (M+H+) 532.1235 and [C23H2235ClN5NaO8]+
(M+Na+) 554.1055, found 532.1228 and 554.1046.
10. 2-Benzamido-6-chloro-9-(20,30,50-tri-O-acetyl-b-
-ribofuranosyl)purine
D
(5):
white solid foam; mp 70–71 °C; 1H NMR (CDCl3, 400 MHz) d 2.07 (s, 3H),
2.11 (s, 3H), 2.17 (s, 3H), 4.53 (m, 3H), 5.95 (m, 2H), 6.16 (d, J = 3.9, 1H), 7.50 (t,
J = 7.5, 2H), 7.58 (t, J = 7.4, 1H), 7.96 (d, J = 7.2, 2H), 8.14 (s, 1H), 8.91 (br s, 1H);
13C NMR (CDCl3, 100.6 MHz) d 20.4 (CH3), 20.5 (CH3), 20.7 (CH3), 63.5 (CH2),
70.8 (CH), 73.6 (CH), 80.6 (CH), 87.5 (CH), 127.5 (CH), 128.8 (CH), 129.0 (C),
132.5 (CH), 133.9 (C), 143.2 (CH), 151.6 (C), 152.0 (C), 152.2 (C), 164.1 (C),
169.5 (C), 169.5 (C), 169.6 (C); HRMS (ESI) m/z calcd for [C23H2335ClN5O8]+
(M+H+) 532.1235 and [C23H2235ClN5NaO8]+ (M+Na+) 554.1055, found 532.1239
and 554.1060.
References and notes
11. 2,6-Dibenzamido-9-(20,30,50-tri-O-acetyl-b-
D-ribofuranosyl)purine (6): white
1. For recent reviews, see: (a) Maiti, D.; Fors, B. P.; Henderson, J. L.; Nakamura, Y.;
Buchwald, S. L. Chem. Sci. 2011, 2, 57–68; (b) Sadig, J. E. R.; Willis, M. C.
Synthesis 2011, 1–22 (synthesis of heterocycles); (c) Surry, D. S.; Buchwald, S. L.
Angew. Chem., Int. Ed 2008, 47, 6338–6361; (d) Hartwig, J. F. Acc. Chem. Res.
2008, 41, 1534–1544; (e) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036–1045;
(f) Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006,
348, 23–39; (g) Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245–
2267; (h) Lakshman, M. K. Curr. Org. Synth. 2005, 2, 83–112; for very recent
references on the Pd-catalysed amidations or aminations, see: (i) Vimolratana,
M.; Simard, J. L.; Brown, S. P. Tetrahedron Lett. 2011, 52, 1020–1022 (bidentate
phosphines, 2-chloropyrimidine); (j) Thomson, P. F.; Lagisetty, P.; Balzarini, J.;
De Clercq, E.; Lakshman, M. K. Adv. Synth. Catal. 2010, 352, 1728–1735
(Xantphos as the best ligand).
2. For a very recent review on purvalanol A, a cyclin-dependent kinase inhibitor,
see: (a) Tanowitz, H. B.; Machado, F. S. Cancer Biol. Ther. 2010, 10, 326–328; for
reviews on nelarabine (drug approved against T-cell acute lymphoblastic
leukemia), see: (b) Roecker, A. M.; Stockert, A.; Kisor, D. F. Clin. Med. Insights:
Oncol. 2010, 4, 133–141; (c) Robak, T.; Korycka, A.; Lech-Maranda, E.; Robak, P.
Molecules 2009, 14, 1183–1226; for entries to purine nucleosides and
analogues with cytotoxic or cytostatic activity, see: (d) Ottria, R.; Casati, S.;
Manzocchi, A.; Baldoli, E.; Mariotti, M.; Maier, J. A. M.; Ciuffreda, P. Bioorg. Med.
Chem. 2010, 18, 4249–4254; (e) Naus, P.; Pohl, R.; Votruba, I.; Dzubak, P.;
Hajduch, M.; Ameral, R.; Birkus, G.; Wang, T.; Ray, A. S.; Mackman, R.; Cihlar, T.;
Hocek, M. J. Med. Chem. 2010, 53, 460–470; also see the following review: (f)
Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987–4006.
3. For an entry to the subject, see the following reviews: (a) Elzein, E.; Zablocki, J.
Expert Opin. Investig. Drugs 2008, 17, 1901–1910; (b) Tosh, D. K.; Jacobson, K. A.;
Jeong, L. S. Drugs Future 2009, 34, 43–52.
solid foam; mp 109–110 °C; 1H NMR (CDCl3, 400 MHz) d 2.06 (s, 3H), 2.10 (s,
3H), 2.15 (s, 3H), 4.50 (m, 3H), 5.99 (m, 2H), 6.16 (d, J = 2.5, 1H), 7.48 (m, 4H),
7.54 (m, 2H), 8.00 (m, 4H), 8.05 (s, 1H), 9.21 (br s, 1H), 9.34 (br s, 1H); 13C NMR
(CDCl3, 100.6 MHz) d 20.4 (CH3), 20.5 (CH3), 20.7 (CH3), 63.4 (CH2), 70.8 (CH),
73.4 (CH), 80.3 (CH), 86.9 (CH), 120.7 (C), 127.6 (CH), 127.9 (CH), 128.6 (CH),
128.7 (CH), 132.1 (CH), 132.7 (CH), 133.2 (C), 134.2 (C), 141.0 (CH), 150.1 (C),
152.5 (C), 152.6 (C), 164.7 (C), 164.7 (C), 169.5 (C), 169.6 (C), 170.4 (C); HRMS
(ESI) m/z calcd for [C30H29N6O9]+ (M+H+) 617.1996 and [C30H28N6NaO9]+,
(M+Na+) 639.1815, found 617.1992 and 639.1822.
12. Palladium diacetate, provided that it was previously reduced to Pd0 by heating
with a small amount of water and a biarylphosphine, was very recently
recommended for the coupling of aryl chlorides with carboxamides or ureas.
See: (a) Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008, 10,
3505–3508; (b) Fors, B. P.; Dooleweert, K.; Zeng, Q.; Buchwald, S. L. Tetrahedron
2009, 65, 6576–6583; (c) Breitler, S.; Oldenhuis, N. J.; Fors, B. P.; Buchwald, S. L.
Org. Lett 2011, 13, 3262–3265.
13. [Pd(dba)Xantphos] may be the predominant species according to studies on
the nature of bidentate phosphine–Pd complexes: (a) Amatore, C.; Broeker, G.;
Jutand, A.; Khalil, F. J. Am. Chem. Soc. 1997, 119, 5176–5185; (b) Klingensmith,
L. M.; Strieter, E. R.; Barder, T. E.; Buchwald, S. L. Organometallics 2006, 25, 82–
91.
14. There are several examples, however, of efficient Kumada–Corriu couplings
(RMgX, ArX, Pd) even below 0 °C: (a) Bonnet, V.; Mongin, F.; Trécourt, F.;
Quéguiner, G.; Knochel, P. Tetrahedron Lett. 2001, 42, 5717–5720; (b) Bonnet,
V.; Mongin, F.; Trécourt, F.; Quéguiner, G.; Knochel, P. Tetrahedron 2002, 58,
4429–4438; (c) Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Hadei, N.; Nasielski, J.;
O’Brien, C. J.; Valente, C. Chem. Eur. J. 2007, 13, 150–157; (d) Martin, R.;
Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3844–3845; there is one example
(ArCl, morpholine, LiHMDS, SPhos-Pd0, ꢂ10 °C, DME) of amination below rt;
(e) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 6686–
4. (a) Ariza, X.; Bou, V.; Vilarrasa, J. J. Am. Chem. Soc. 1995, 117, 3665–3673; (b)
Terrazas, M.; Ariza, X.; Farràs, J.; Guisado-Yang, J. M.; Vilarrasa, J. J. Org. Chem.