Trifunctionalization of the purine scaffold using Mg and Zn organometallic intermediates

Article abstract of DOI:10.1021/ol103057k

Starting from an appropriate 6-chloro-2-TMS-purine derivative, a regioselective functionalization of the purine scaffold was achieved successively at positions 8, 6, and 2 via zinc and magnesium intermediates which were generated either by a direct zincat

Full text of DOI:10.1021/ol103057k

ORGANIC
LETTERS
2011
Vol. 13, No. 4
792–795
Trifunctionalization of the Purine Scaffold
Using Mg and Zn Organometallic
Intermediates
Silvia Zimdars, Xavier Mollat du Jourdin, Franc-ois Crestey, Thomas Carell, and
Paul Knochel*
€
Department Chemie & Biochemie, Ludwig-Maximilians-Universitat Munchen,
€
Butenandtstrasse 5-13, 81377 Mu€nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received December 17, 2010
ABSTRACT
Starting from an appropriate 6-chloro-2-TMS-purine derivative, a regioselective functionalization of the purine scaffold was achieved succes-
sively at positions 8, 6, and 2 via zinc and magnesium intermediates which were generated either by a direct zincation with TMPZnCl LiCl or by an
I/Mg exchange with iPrMgCl.
3
The purine scaffold functionalization is of great impor-
tance since several biologically active compounds bear this
heterocyclic unit.1 For example, purine derivatives 1 and 2
are potential kinase inhibitors2 or display immunosup-
pressant3 activity (Figure 1). Large combinatorial libraries
of several types of substituted purines have been prepared
by heterocyclizations,4 direct C-H arylations,5 or regio-
selective nucleophilic substitutions of dihalopurines with
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Figure 1. Biologically active purines and metalation precursor of
type 3.
amines in combination with cross-coupling reactions.6 Pd-
catalyzed cross-couplings as well as Fe-catalyzed alkyla-
tions provide access to various simple 6,8-difunctionalized
(3) Neagu, I.; Diller, D.; Kingsbury, C.; Bohnstedt, A. C.; Ohlmeyer,
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D.; Dvorakova, H. Synthesis 2004, 889.
r
10.1021/ol103057k
Published on Web 01/19/2011
2011 American Chemical Society

and 2,6,8-trifunctionalized purine derivatives.5b,6b,6c The
partial functionalization of purines via lithiation,7 mag-
nesiation,8 or zincation9 has also been reported. The suc-
cessive functionalization ofpositions 8, 6, and2 ofthesame
purine scaffold with use of organometallic intermediates
is complicated and depends highly on the appropriate
choice of the masked functional groups A, B, and C at
these positions as well as the protecting group (PG) of
purine 3 (Figure 1). After extensive experimentation, we
report herein an optimum combination of A, B, C, and PG
allowing the successive generation of Zn or Mg intermedi-
ates at positions 8, 6, and 2, which finally provides access to
a wide range of new polyfunctional purines.
Table 1. Functionalization of Position 8 via Zincated Purine 5
Scheme 1. General Reaction Scheme
a Isolated, analytically pure product. b Obtained after addition of 5%
CuCN 2LiCl. c Obtained by Pd-catalyzed acylation reaction with 2%
3
Pd(PPh3)4. d Obtained by Pd-catalyzed cross-coupling reaction with 2%
Pd(dba)2 and 4% P(o-furyl)3 as catalyst. e Obtained from 6a by Pd-
catalyzed coupling reaction with 1.2 equiv of NEt3, 4% CuI, 2%
Pd(dba)2, and 4% P(o-furyl)3.
(TMP = 2,2,6,6-tetramethylpiperidide)11 within 15 min at
25 °C leading to the zincated purine 5 (Scheme 1). Iodolysis
of 5 produces the expected 8-iodopurine (6a) in 77% yield
(entry 1 of Table 1). Copper(I)-catalyzed allylation12 (5%
CuCN 2LiCl) with 3-bromocyclohexene (-30 to 25 °C, 10 h)
3
leads to the 8-allylated purine (6b) in 91% yield (entry 2).
Pd-catalyzed acylation (2% Pd(PPh3)4)13 with 2-furoyl
chloride (0 to 25 °C, 6 h) gave ketone 6c in 55% yield
(entry 3). Negishi cross-coupling reactions14 with various
Starting from 6-chloropurine, we have prepared the
6-chloro-9-methoxymethyl-2-trimethylsilyl-9H-purine (4)
according to the procedure of Tanaka.10 Thus, this purine
is readily zincated in position 8 by using TMPZnCl LiCl
3
15
aryl iodides using 2% Pd(dba)2 and 4% P(o-furyl)3
afford 8-arylated purines (6d-g) in 72-91% yield
(entries 4-9). An alkynyl group was also introduced via
Sonogashira coupling16 by preparing in situ the iodide 6a.
Its reaction with p-anisylacetylene (1.2 equiv of NEt3, 4%
CuI, 2% Pd(dba)2, 4% P(o-furyl)3, 25 °C, 3 h) provided
the 8-alkynylated purine 6h in 75% yield. The chloro-
substituent in position 6 is then removed by using a
Pd-catalyzed reduction with HCO2NH4 (20 wt % Pd/C,
MeOH/EtOH or MeOH/THF, 45 °C, 15-30 min). Under
(7) (a) Leonard, N. J.; Bryant, D. J. J. Org. Chem. 1979, 44, 4612.
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P.; Zajc, B. J. Org. Chem. 2007, 72, 8222.
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Tobrman, T.; Dvorak, D. Collect. Czech. Chem. Commun. 2006, 71,
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Ed. 1999, 38, 379.
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(9) (a) Stevenson, T. M.; Prasad, A. S. B.; Citineni, J. R.; Knochel, P.
Tetrahedron Lett. 1996, 37, 8375. (b) Prasad, A. S. B.; Stevenson, T. M.;
Citineni, J. R.; Nyzam, V.; Knochel, P. Tetrahedron 1997, 53, 7237.
(c) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837.
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T. Tetrahedron Lett. 1995, 36, 6507.
(11) (a) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837.
(b) Mosrin, M.; Bresser, T.; Knochel, P. Org. Lett. 2009, 11, 3406.
(c) Mosrin, M.; Monzon, G.; Bresser, T.; Knochel, P. Chem. Commun.
2009, 37, 5615. (d) Bresser, T.; Mosrin, M.; Monzon, G.; Knochel, P. J.
Org. Chem. 2010, 75, 4686. (e) Bresser, T.; Monzon, G.; Mosrin, M.;
Knochel, P. Org. Process Res. Dev. 2010, 14, 1299.
Chem. 1988, 53, 2390. (b) Dubner, F.; Knochel, P. Angew. Chem., Int.
Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181.
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Org. Lett., Vol. 13, No. 4, 2011
793

these conditions, the 6-chloropurines 6d,e led to the de-
chlorinated products 7a,b in 90-95% yield (Scheme 1).
of iodide 9b followed by a Pd-catalyzed cross-coupling with
N-allyl-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide19
affords the 6-alkynylated purine 9i in 75% yield (entry 9).
Table 2. Functionalization of Position 6 via Zincated Purines 8a,b
Table 3. Functionalization of Position 2 via Magnesiated Pur-
ines 11a,b
a Isolated, analytically pure product. b Obtained after addition of
25% CuCN 2LiCl. c Obtained by Pd-catalyzed cross-coupling reaction
3
with 2% Pd(dba)2 and 4% P(o-furyl)3 as catalyst. d Obtained from 9b by
Pd-catalyzed coupling reaction with 1.5 equiv of NEt3, 4% CuI, 2%
Pd(dba)2, and 4% P(o-furyl)3.
a Isolated, analytically pure product. b Obtained after addition of
25% CuCN 2LiCl. c Obtained after transmetalation with 1.6 equiv of
ZnCl2 by Pd-catalyzed cross-coupling reaction with 2% Pd(dba)2 and
4% P(o-furyl)3 as catalyst.
3
Purines of type 7 are readily metalated at position 6.
Thus, treatment of 7a with TMPZnCl MgCl2 LiCl
(1.5 equiv) leads to a complete zincation under microwave
irridation11,17 (sealed vessel, 90 °C, 1 h) providing the
6-zincated purine 8a (E1 = 3-methoxyphenyl). The purine
7b, which proved to be more acidic at position 6 than 7a,
3
3
After having functionalized positions 8 and 6, we have
converted the 2-TMS-substituent of 9d and 9g to the
corresponding 2-iodopurines (10a,b) by treatment with I2
(1.4 equiv, 1:1 CH3CN:THF, microwave irradiation,
sealed vessel, 110-130 °C, 12 h) in the presence of CsF
(2 equiv) in 49-80% yield.20 I/Mg exchange of 10a,b
with iPrMgCl (1.5 equiv, THF, -78 °C, 1 h) furnishes the
Mg- reagents 11a,b. Their reaction with various electrophiles
such as allyl bromides (entry 1 of Table 3), aldehydes (entry
2), immonium reagents21 (entry 3) or a range of functiona-
lized aryl and heteroaryl iodides (entries 4-7) provides the
fully 2,6,8-substituted purines in 55-94% yield.
reacts with TMPZnCl LiCl (prepared in the absence of
3
MgCl2) leading to 8b (E1 = 4-carbethoxyphenyl, 90 °C,
2 h). The resulting zinc reagents (8a,b) react with a range
of electrophiles (Table 2). Thus, iodolysis produces the
6-iodopurines 9a,b in 64-76% yield (entries 1 and 2 of
Table 2). The copper-catalyzed allylation of 8b with ethyl
(2-bromomethyl)acrylate18 leads to purine 9c in 68% yield
(entry 3). A range of aryl iodides bearing either electron-
withdrawing substituents (CO2Et, CF3, Cl), electron-
donating substituents (NBu2), or a heterocyclic backbone
(2-thienyl) undergo Negishi cross-coupling14 with 8a,b
(25 °C, 8-40 h) affording the 2,6-bis-arylated purines
9d-h in 43-64% yield (entries 4-8). In situ generation
In summary, we have described a novel triple functionali-
zation sequence of the purine scaffold starting from the
readily available 6-chloropurine 4 via 8-zincated, 6-zincated,
and 2-magnesiated intermediates using either a selective
(19) Patel, M. C.; Livinghouse, T.; Pagenkopf, B. L. Org. Synth.
2003, 80, 93.
(17) The kinetic basicity of TMPZnCl LiCl can be increased by
3
(20) (a) Latouche, R.; Texier-Boullet, F.; Hamelin, J. Tetrahedron
Lett. 1991, 32, 1179. (b) Furin, G. G.; Vyazankina, O. A.; Gostevsky,
B. A.; Vyazankin, N. S. Tetrahedron 1988, 44, 2675. (c) Clark, J. H.
Chem. Rev. 1980, 80, 429.
adding MgCl2 (1 equiv), see: Wunderlich, S. H.; Knochel, P. Angew.
Chem., Int. Ed. 2007, 46, 7685.
ꢁ
ꢁ
(18) (a) Rambaud, M.; Villieras, J. Synthesis 1984, 406. (b) Villieras,
J.; Rambaud, M. Org. Synth. 1988, 66, 220.
(21) Kinast, G.; Tietze, L. F. Angew. Chem., Int. Ed. 1976, 15, 239.
794
Org. Lett., Vol. 13, No. 4, 2011

zincation with TMPZnCl LiCl11 or an I/Mg exchange trig-
under the European Community’s Seventh Framework
Programme (FP7/2007-2013) ERC grant agreement no.
227763, from the DFG (SFB 749), and from the Alexander
von Humboldt Foundation. We thank Chemetall GmbH
(Frankfurt) and W. C. Heraeus GmbH for the generous
gift of chemicals.
3
gered by iPrMgCl. Besides cross-coupling reactions, our new
functionalization approach of the purine skeleton allows the
performance of novel functionalizations such as allylations,
acylations, and aminomethylations. In conclusion, this new
method offers access to a large variety of highly functionalized
purine derivatives. Further applications to prepare biologi-
cally active, valuable purines are underway in our laboratory.
Supporting Information Available. Experimental pro-
cedures and characterization data of all compounds are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. The research leading to these results
has received funding from the European Research Council
Org. Lett., Vol. 13, No. 4, 2011
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