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Table 3 Coupling of various aryl halides to adeninea,b
Coupling of purines with aryl chlorides and sterically hindered
aryl halides remains a challenge. A notable aspect is the pre-
dictable and generally high selectivity observed for arylation of
one specific position in the presence of several other potential
alkylation positions. Arylation at the N9-position was generally
preferred, but this preference was altered in a predictable
manner by the presence of adjacent groups. The robustness
of the reaction is demonstrated not only by the broad substrate
scope, but also by a good performance in several different
solvent systems. Although DMF/H2O was chosen as the standard
for the reactions reported herein, the EtOH/H2O system might be
more suitable for up-scaling, where the cost and environmental
impact become important factors.
We are grateful for financial support from the Danish Council
for Independent Research, Technology and Production, Grants
274-08-056 and 09-070364.
a
Reaction conditions: 4a–f (0.50 mmol), aryl halide (PhX, 0.75 mmol),
Notes and references
1 (a) H. Rosemeyer, Chem. Biodiversity, 2004, 1, 361; (b) M. E. Welsch,
S. A. Snyder and B. R. Stockwell, Curr. Opin. Chem. Biol., 2010,
14, 347.
2 (a) M. Legraverend and D. S. Grierson, Bioorg. Med. Chem., 2006,
14, 3987; (b) N. Kato, T. Sakata, G. Breton, K. G. Le Roch, A. Nagle,
C. Andersen, B. Bursulaya, K. Henson, J. Johnson, K. A. Kumar,
F. Marr, D. Mason, C. McNamara, D. Plouffe, V. Ramachandran,
M. Spooner, T. Tuntland, Y. Zhou, E. C. Peters, A. Chatterjee,
P. G. Schultz, G. E. Ward, N. Gray, J. Harper and E. A. Winzeler,
Nat. Chem. Biol., 2008, 4, 347; (c) F. Di Virgilio, Cancer Res., 2012,
72, 5441.
KOH (1.0 mmol), CuBr (5 mol%), L3 (10 mol%), NaAsc (10 mol%), DMF/
b
H2O (1 mL, 4 : 1 v/v), 120 1C, 21 h (X = I) or 48 h (X = Br). Isolated
yields, yields of the other (N7) regioisomers are given in parentheses.
c
e
d
t = 48 h. No added NaAsc; the solvent was DMSO/H2O (1 mL, 4 : 1 v/v).
f
t = 6 h. t = 32 h.
94% and 60% yields, respectively, but with complete selectivity
for the N9-position over the three other potential coupling
positions in the molecule (N7 and the two amino groups). The
exclusive selectivity for the N9- over the N7-position in both
adenine and 2,6-diaminopurine indicates that the 6-amino
group blocks N7-arylation. In contrast, theophylline (4c) couples
with iodo- and bromobenzene to give 79% and 78% yields,
respectively, of the exclusively N7-arylated product, which can
be rationalised by steric hindrance of the N9-position by the
N3-methyl substituent. The reaction of 8-methyltheophylline
(4d) with iodo- and bromobenzene results in the isolation of
the N7-arylated product in only 10–12% yield, indicating detri-
mental steric interactions between the C8-methyl and the
Cu-ligand complex.
3 L. Aguado, H. J. Thibaut, E.-M. Priego, M.-L. Jimeno, M.-J. Camarasa,
´
´
J. Neyts and M.-J. Perez-Perez, J. Med. Chem., 2009, 53, 316.
4 A. K. Bakkestuen, L.-L. Gundersen and B. T. Utenova, J. Med. Chem.,
2005, 48, 2710.
5 N. Kode, L. Chen, D. Murthy, D. Adewumi and S. Phadtare,
Eur. J. Med. Chem., 2007, 42, 327.
6 (a) I. P. Beletskaya and A. V. Cheprakov, Organometallics, 2012,
31, 7753; (b) T. R. M. Rauws and B. U. W. Maes, Chem. Soc. Rev.,
2012, 41, 2463; (c) G. Evano, N. Blanchard and M. Toumi, Chem.
Rev., 2008, 108, 3054.
7 (a) A. K. Bakkestuen and L.-L. Gundersen, Tetrahedron Lett., 2003,
44, 3359; (b) M. F. Jacobsen, M. M. Knudsen and K. V. Gothelf, J. Org.
Chem., 2006, 71, 9183; (c) L. Tao, Y. Yue, J. Zhang, S.-Y. Chen and
ˇ´
´
Guanine (4e) and hypoxanthine (4f) both couple with iodo-
and bromobenzene with a lower preference for the N9-position
over the N7-position compared to purine, reflecting a directing
effect on the N7-position by the adjacent carbonyl group. The
preference for the N9-position was enhanced by changing the
solvent to DMSO/H2O and omitting sodium ascorbate. For both
purines, this resulted in a ratio of isolated N9/N7-arylated
product of 3 : 1 with iodobenzene and 9 : 2 with bromobenzene.
In the case of hypoxanthine, arylation at N1 in addition to N9
was seen, and the reaction time was shortened to prevent over-
arylation, resulting in somewhat lower yields compared to
guanine, where no diarylated products were observed.
X.-Q. Yu, Helv. Chim. Acta, 2008, 91, 1008; (d) R. Keder, H. Dvorakova
ˇ´
and D. Dvorak, Eur. J. Org. Chem., 2009, 1522; (e) H.-Y. Niu, C. Xia,
G.-R. Qu, Q. Zhang, Y. Jiang, R.-Z. Mao, D.-Y. Li and H.-M. Guo, Org.
ˇ
ˇ
´ˇ ´
Biomol. Chem., 2011, 9, 5039; ( f ) I. Cerna, R. Pohl, B. Klepetarova
and M. Hocek, J. Org. Chem., 2008, 73, 9048; (g) S. Ding, N. S. Gray,
Q. Ding and P. G. Schultz, Tetrahedron Lett., 2001, 42, 8751;
(h) E. Kiselgof, D. B. Tulshian, L. Arik, H. Zhang and A. Fawzi,
Bioorg. Med. Chem. Lett., 2005, 15, 2119; (i) I. Dreier, S. Kumar,
H. Søndergaard, M. L. Rasmussen, L. H. Hansen, N. H. List,
J. Kongsted, B. Vester and P. Nielsen, J. Med. Chem., 2012, 55, 2067.
8 (a) J. C. Antilla, J. M. Baskin, T. E. Barder and S. L. Buchwald, J. Org.
Chem., 2004, 69, 5578; (b) M. N. Soltani Rad, S. Behrouz, M. M.
Doroodmand and N. Moghtaderi, Synthesis, 2011, 3915.
9 J. Engel-Andreasen, B. Shimpukade and T. Ulven, Green Chem.,
2013, 15, 336.
10 (a) S. Ueda and S. L. Buchwald, Angew. Chem., Int. Ed., 2012,
51, 10364; (b) N. T. Jui and S. L. Buchwald, Angew. Chem., Int. Ed.,
2013, 52, 11624.
In conclusion, we have identified N4,N7-bis(2-hydroxyethyl)-
1,10-phenanthroline-4,7-diamine (L3, BHPhen) as an enabling
ligand for selective, direct copper-catalysed arylation of various
common purines with aryl iodides and aryl bromides in moderate
to excellent yields. Direct coupling of guanine and hypoxanthine
with aryl halides were achieved for the first time. This is also the
first report of direct coupling of purines with aryl bromides.
11 (a) A. Agarwal and P. M. S. Chauhan, Synth. Commun., 2004,
ˇ
ˇ
´
´
ˇ´
34, 2925; (b) L. Cechova, P. Jansa, M. Sala, M. Dracınsk´y, A. Hol´y
and Z. Janeba, Tetrahedron, 2011, 67, 866; (c) T. P. Petersen,
A. F. Larsen, A. Ritzen and T. Ulven, J. Org. Chem., 2013, 78, 4190.
´
12 A control reaction without CuBr gave only 7% conversion after 48 h,
indicating that nucleophilic aromatic substitution only makes a
minor contribution to the yield of 3i.
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Chem. Commun., 2014, 50, 4997--4999 | 4999