General Method for the Synthesis of 8-Arylsulfanyl Adenine Derivatives

Article abstract of DOI:10.1021/jo049875c

We report a general method for the synthesis of 8-arylsulfanyl adenine derivatives using a mild protocol of coupling 8-mercaptoadenine with a variety of aryl iodides.

Full text of DOI:10.1021/jo049875c

Gen er a l Meth od for th e Syn th esis of
-Ar ylsu lfa n yl Ad en in e Der iva tives
8-mercaptopurines with aryl iodides, but to our knowl-
edge there is no literature precedent on the feasibility of
this reaction. Literature on formation of aryl-sulfur
bonds has usually lagged behind publications reporting
formation of aryl-nitrogen and aryl-oxygen bonds. One
of the first reactions of aryl halides with thiols was
8
Huazhong He, Laura Llauger, Neal Rosen, and
Gabriela Chiosis*
Departments of Medicine and Cell Biology,
Memorial Sloan-Kettering Cancer Center,
275 York Avenue, New York, New York 10021
7
published by Migita using Pd catalyst. Since then, sub-
stantial contributions were reported, using Pd(0) and
Ni(0) catalysts.8 Recently, an elegant method using
copper catalyst was reported independently by Venkat-
araman9 and Buchwald. Venkataraman used CuI in
the presence of neocuproine and NaOt-Bu to create a
variety of aryl sulfides from aryl iodides and aryl/
alkylthiols. The method presented by Buchwald utilized
1
chiosisg@mskcc.org
10
Received J anuary 22, 2004
Abstr a ct: We report a general method for the synthesis of
-arylsulfanyl adenine derivatives using a mild protocol of
8
2 3
CuI, ethylene glycol, and K CO to generate aryl sulfides.
coupling 8-mercaptoadenine with a variety of aryl iodides.
Unfortunately, these methods were not reported to work
with heterocyclic moieties such as purines. Herein, we
present the formation of 8-arylsulfanyl adenine deriva-
tives from 8-mercaptoadenine and aryl iodides using
copper catalysis.
Our initial exploration into the optimization of the
reaction conditions started with studying the cross-
coupling of 8-mercaptoadenine with 4-iodo-anisole (Table
1). Due to the poor solubility of 8-mercaptoadenine in
most solvents, we were left trying the feasibility of DMSO
and DMF as solvents for coupling. Several reactions were
performed in the presence of catalyst (CuI and neocu-
The purine skeleton is part of many naturally occurring
ligands, and derivatives of purine nucleosides have been
extensively studied as biological ligands involved in
mediating metabolic processes and signaling pathways
1
in all living organisms. However, the use of the purine
moiety as a skeleton for the creation of chemical libraries
has been only recently explored. As such, large libraries
of 2,6,9-purines have been synthesized by Schultz and
co-workers2 and the activity of these compounds as
inhibitors of many biological processes has been demon-
strated.3 On our part, we are interested in creating
libraries of 2,6,8,9-purines as selective inhibitors of the
2 3 3 4
proine), varying the type of base (K CO , K PO , or NaOt-
Bu) in either DMF or DMSO. CuI was chosen as the
source of copper catalyst due to its stability in air. As
4
molecular chaperone Hsp90. Although there is extensive
8
chemical literature on the purine moiety, substitution at
the C8 position has been only minimally explored.
Formation of a C-C, C-O, or C-N bond at this position
previously reported, the presence of neocuproine was
essential for accelerating the reaction. Both DMF and
5
has been previously reported; however, a survey of the
(5) (a) Young, R. C.; J ones, M.; Milliner, K. J .; Rana, K. K.; Ward,
J . G. J . Med. Chem. 1990, 33, 2073. (b) Gonnella, N. C.; Nakanishi,
H.; Holtwick, J . B.; Horowitz, D. S.; Kanamori, K. J . Am. Chem. Soc.
existing literature does not offer a straightforward syn-
thetic route to a wide variety of 8-arylsulfanyl purines.
Coupling of 8-bromo adenine with thiophenols in the
presence of a base has been reported as an alternative
1
983, 105, 2050. (c) Draminsky, M.; Frass, E. Pol. J . Chem. 1987, 61,
901. (d) Chiosis, G.; Lucas, B.; Shtil, A.; Huezo, H.; Rosen, N. Bioorg.
Med. Chem. 2002, 11, 3555. (e) Lucas, B.; Rosen, N.; Chiosis, G. J .
Comb. Chem. 2001, 3, 518. (f) Camaioni, E.; Di Francesco, E.; Vittori,
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6
method. This strategy is less attractive due to thiophe-
nols’ commercial unavailability, stench, and tendency to
quickly oxidize. An attractive method would be coupling
6
29.
6) Kasibhatla, S. R.; Zhang, L.; Boehm, M.; Fan, J .; Hong, K.; Shi,
(
(
1) Purines in Cellular Signaling: Targets for New Drugs; J acobson,
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Activity. WO03037860, 2003.
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Kosugi, M. Bull. Chem. Soc. J pn. 1980, 53, 1385. (b) Kosugi, M.; Ogata,
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(
Kwon, S.; Norman, T. C.; Sarohia, R.; Leost, M.; Meijer, L.; Schultz,
P. G. Chem. Biol. 1999, 6, 361. (b) Ding, S.; Gray, N. S.; Ding, Q.;
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Org. Chem. 2002, 67, 3643. (f) Hartwig, J . F. Acc. Chem. Res. 1998,
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A. H.; Curtin, N. J .; Endicott, J . A.; Garman, E. F.; Gibson, A. E.;
Golding, B. T.; Grant, S.; Griffin, R. J .; J ewsbury, P.; J ohnson, L. N.;
Lawrie, A. M.; Newell, D. R.; Noble, M. E.; Sausville, E. A.; Schultz,
R.; Yu, W. J . Med. Chem. 2000, 43, 2797. (c) Harmse, L.; van Zyl, R.;
Gray, N.; Schultz, P.; Leclerc, S.; Meijer, L.; Doerig, C.; Havlik, I.
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P. G.; Wong, C. H. J . Am. Chem. Soc. 2002, 124, 14524. (e) Chang, Y.
T.; Choi, D.; Bae, Y. S.; Burdett, M.; Moon, H. S.; Lee, J . W.; Gray, N.
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1
0.1021/jo049875c CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/01/2004
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230
J . Org. Chem. 2004, 69, 3230-3232

TABLE 1. Rea ction Con d ition s Op tim iza tion for th e Cou p lin g of 8-Mer ca p toa d en in e w ith Ar yl Iod id es
Sa
B
I
DMSO
K2CO3
DMF
K3PO4
NaO-t-Bu
K3PO4
K2CO3
NaO-t-Bu
1.2
22.9
2
57.0
3
43.5
1.2
17.6
2
30.0
3
27.9
1.2
12.8
2
32.4
3
44.2
1.2
18.0
2
25.3
3
35.9
1.2
12.9
2
21.3
3
24.2
1.2
32.4
2
58.4
3
63.4
b
Y
a
S ) solvent (2 mL); B ) base (2 equiv); I ) aryl iodide (equiv); Y ) yield (%). b Yield estimated by HPLC.
TABLE 2. Rea ction s of 8-Mer ca p toa d en in e w ith Ar yl Iod id es
a
Isolated yield. b With 25% neocuproine
DMSO afforded the expected product, suggesting that the
polarity of the solvent was not critical for the reaction.
Interestingly, higher yields were obtained in DMSO when
sphere. It is noteworthy that the reaction does not require
the use of dry solvents or special handling of the reagents.
On the basis of these observations, we tested the
coupling of 8-mercaptoadenine with several aryl iodides
using CuI/neocuproine as a catalyst and NaOt-Bu/DMF
as the base/solvent combination (Table 2).
Our optimized reaction conditions utilize 10 mol % CuI,
10 mol % neocuproine, NaOt-Bu (2 equiv), and aryl iodide
(3 equiv) in reagent-grade DMF at 110 °C under nitrogen.
These conditions resulted in the expected product without
noticeable byproducts. It is noteworthy that neither
3 4
the base was K PO , while in DMF, NaOt-Bu seemed to
perform better. The use of an excess of aryl iodide also
improved yields and conversions. Somewhat surprising,
the reaction yields reached a plateau value of 60-70%.
The TLC and HPLC reaction analyses showed a clean
transition from 8-mercaptoadenine to product. However,
further analysis of reactant stability under the coupling
conditions concluded that decomposition of 8-mercap-
toadenine was a cause to reduced yields. An observed
increase in the reaction yields when 25% neocuproine was
used (entry 2, Table 2) suggests that coordination of
copper by the adenine starting material and/or product
derivatives may additionally contribute to lowered yields.
To reduce the probability of any disulfide byproduct
formation, reactions were performed in an inert atmo-
coupling of the C6-NH
2
with the aryl iodides nor
disulfide formation has been detected.
The reaction could be used to couple in reasonable
yields 8-mercaptoadenine with aryl iodides (Table 2),
tolerating diverse substituents at the ortho-, meta-, and
para-positions of the aryl moiety. No particular sensitiv-
ity to the presence of deactivating functionalities was
J . Org. Chem, Vol. 69, No. 9, 2004 3231

seen. As such, electron-rich rings (entries 1-4, 9, and 10,
Table 2) allowed for coupling in yields comparable to
electron-deficient aromatic moieties (entries 5, 6, and 8,
Table 2). Steric hindrance was additionally permitted;
the presence of methoxy, methyl, or hydroxymethyl ortho
to iodide had minimal to no effect on reaction yields.
In summary, we have developed an efficient Cu-cata-
lyzed formation of 8-arylsulfanyl purines. Considering the
ever increasing number of aryl iodides available com-
mercially, the reaction could be used to generate a library
of 8-thioarylpurines as potentially useful biological ligands.
Ack n ow led gm en t. The work was funded in part by
NIH-NCI (1U01CA91178-03), AACR-Cancer Research
and Prevention Foundation, and a generous donation
from the Taub Foundation.
Su p p or tin g In for m a tion Ava ila ble: Synthetic proce-
dures and characterization data for products listed in Table
2
. This material is available free of charge via the Internet at
http://pubs.acs.org.
J O049875C
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232 J . Org. Chem., Vol. 69, No. 9, 2004