An efficient copper-catalyzed microwave-assisted S-arylation towards the synthesis of 8-arylsulfanyl adenines

Article abstract of DOI:10.1055/s-0031-1289888

We report a microwave-assisted synthetic protocol for the C-S cross-coupling reaction of aryl iodides and 8-mercaptoadenine using CuI and n-Bu₄NBr with NaOt-Bu in DMF. The method is rapid, simple, and cost efficient, and leads in high yields to

Full text of DOI:10.1055/s-0031-1289888

3008
LETTER
An Efficient Copper-Catalyzed Microwave-Assisted S-Arylation towards the
Synthesis of 8-Arylsulfanyl Adenines
S
ynthesis of 8-Arylsulfa
e
nyl
A
denin
i
es lin Sun,a Pallav D. Patel,b Ralph A. Stephani,b Gabriela Chiosis*a
a
Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
Fax +1(646)4220416; E-mail: chiosisg@mskcc.org
b
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John’s University,
Jamaica, NY 11439, USA
Received 24 May 2011
often the narrow scope associated with the use of a copper
catalyst.9
Abstract: We report a microwave-assisted synthetic protocol for
the C–S cross-coupling reaction of aryl iodides and 8-mercaptoad-
enine using CuI and n-Bu4NBr with NaOt-Bu in DMF. The method
is rapid, simple, and cost efficient, and leads in high yields to bio-
logically relevant aryl sulfides.
In spite of increasing interest in the development of cop-
per-catalyzed C–S bond-formation reactions, these efforts
were rarely applied to biologically relevant heterocycles,
potentially because such molecules often contain func-
tionalities that render most catalyst systems impractical
and because these compounds tend to be poorly soluble in
frequently used organic solvents.
Key words: microwave, copper-catalyzed S-arylation, phase-
transfer catalyst
Cross-coupling reactions of aryl halides with various nu-
cleophilic compounds are among the most widely used
synthetic methods for the formation of carbon heteroatom
bonds.1 Amongst them, organosulfur chemistry has re-
ceived increasing attention since sulfur-containing groups
are frequent in organic synthetic sequences.2 They are
also prevalent structural units in numerous natural prod-
ucts and in pharmaceutical compounds with potential
clinical applications in diseases such as diabetes, cancer,
viral and bacterial infections, and Alzheimer’s disease.3
Among the most widely used scaffolds in the synthesis of
biologically active compounds is 8-arylsulfanyl adenine,
a core structure present in several inhibitors of the heat
shock protein 90 (Hsp90).10 Hsp90 is an attractive target
in cancer and neurodegenerative diseases,11 and there is
significant interest over the recent years to develop small-
molecule Hsp90 inhibitors. Our laboratory has discovered
the purine scaffold as a template in the design and devel-
opment of Hsp90 inhibitors and has a long-standing inter-
est in these agents as anticancer and antineuro-
degenerative disease agents.3a,b,10d,12
To construct these molecules, increasing attention has
been given to transition-metal-catalyzed S-arylation.4
Specifically, palladium with diverse organophosphane
ligands has been used in the coupling of aryl halides and
thiols.5 While a versatile reaction, its use is restricted be-
cause (for monodentate phosphines) the reactive sulfur
functionality may displace the metal-bound phosphines
and inactivate the palladium catalyst.4a Even though
strongly coordinating bidentate ligands resist the dis-
placement of thiolates, the dependence of reaction on en-
vironmentally unfriendly PR3 ligands limits the use of this
system. Other transition-metal-catalyst systems, includ-
ing nickel6 and cobalt,7 have also been studied, but the
toxicity and high price of these metals have limited their
use. An iron-based system has recently been reported to
catalyze C–S bond formation.8
The Hsp90-targeted purine-scaffold molecules may com-
bine a core adenine ring having attached an aromatic moi-
ety through a carbon or sulfur linker at the 8-position of
adenine.10d In a previous report,13 we described the utility
of microwave in the synthesis of 8-arylmethyl-9H-purin-
6-amines in one pot from pyrimidine-4,5,6-triamine or
pyrimidine-2,4,5,6-tetraamine and aryl acetic acid deriva-
tives. This procedure enabled the efficient synthesis of
intermediates containing a carbon linker. Efficient forma-
tion of the sulfur-linker compounds, however, remains a
challenge. Here we focus on the development of a new
and more effective method to create the C–S bond in a va-
riety of biologically relevant 8-arylsulfanyl adenine struc-
tures.
Initially, the CuI and neocuproine with NaOt-Bu in DMF
system was used in our laboratory for the synthesis of the
purine-scaffold S-arylated Hsp90 inhibitors. It coupled 8-
mercaptoadenine with 5-iodobenzo[1,3]dioxole in moder-
ate yield (58%).3a While this reaction led to the desired
product it needed an excess of aryl iodide (3 equiv)3a to
completely consume the 8-mercaptoadenine. It was also
limited by the technical difficulty of separating neocu-
proine from the product. Further, when 5-iodobenzo-
[1,3]dioxole was replaced with 6-iodo-2,3-dihydrobenzo-
furan, the reaction resulted in only trace amounts of prod-
The copper metal remains the preferred catalyst for S-aryl-
ation because of its efficiency, low-cost, and little toxici-
ty. A variety of copper-catalyzed systems have been
studied to develop a general and efficient protocol to pre-
pare aryl sulfides. In particular, these efforts aimed to lim-
it the long reaction times, harsh reaction conditions, and
SYNLETT 2011, No. 20, pp 3008–3012
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Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289888; Art ID: S04711ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 8-Arylsulfanyl Adenines
3009
uct, as indicated by LC-MS analysis (Table 1, entry 1). gested that we should move to another system. The phase-
These limitations prompted us to explore alternative cou- transfer catalyst n-Bu4NBr, proposed to keep the CuI spe-
pling conditions.
cies in solution, has been used for the S-arylation of thiols
with aryl iodides.14c When the CuI, n-Bu4NBr and K3PO4
system was heated at 110 °C for 12 hours, it gave the de-
sired product but in low yield. Increasing the temperature
to 130 °C and extending the reaction time to 24 hours
failed to improve the yield (Table 1, entry 7). In addition,
we observed that the benzofuran side product appeared
and accumulated as the reaction time increased. We there-
fore concluded that shorter reaction times were desired in
order to prevent side-product formation.
In an initial screening effort, we investigated several con-
ditions for the coupling of 8-mercaptoadenine and 6-iodo-
2,3-dihydrobenzofuran (Table 1). When the PdCl2(dppf)-
catalyzed coupling conditions were used, the reaction
could not be completed even with considerable amounts
of catalyst (30 mol%) and extended reaction times of up
to 48 hours (Table 1, entry 2). We next attempted the
Bolm’s iron-catalyzed S-arylation. This method – cou-
pling thiols with aryl iodides – was reported to work with
heterocyclic thiols such as imidazoles and benzothiaz- Microwave irradiation is reported15 to accelerate transfor-
oles.8 It uses the FeCl3 and DMEDA with NaOt-Bu cata- mation of reactants to products with great synthetic versa-
lyst system and toluene as a solvent. Because 8- tility compared to conductive heating experiments. When
mercaptoadenine is poorly soluble in toluene, we attempt- microwave irradiation was applied in conjunction with the
ed to replace it with DMF. No product was observed un- CuI, n-Bu4NBr and K3PO4 system, we obtained improved
der either set of conditions in our hands (Table 1, entry 3 yields in a shorter reaction time (Table 1, entry 8). To im-
and 4).
prove the synthesis, we next screened several bases and
found that NaOt-Bu gave the highest conversion and yield
(Table 1, entries 8–10). In addition to being efficient, this
optimized protocol (CuI, n-Bu4NBr, NaOt-Bu, MW)16 is
also cost effective as it uses only one equivalent of aryl
iodide to entirely consume the 8-mercaptoadenine. At-
tempts to reduce the amount of n-Bu4NBr from 20% to
5% resulted in the incomplete conversion of the starting
material (Table 1, entries 10–12). We next demonstrated
that the procedure is scalable; when attempted on 0.58 g
of aryl iodide, the reaction resulted in the desired product
in 53% recovered yield, somewhat lower than the yield
obtained on the 16 mg scale (92%, Table 2, entry 1).
Table 1 Screening Conditions for the Coupling of 8-Mercaptoade-
nine and 6-Iodo-2,3-dihydrobenzofuran
NH2
NH2
N
N
N
N
SH
+
I
S
N
H
O
N
H
N
N
O
Entry Reagentsa
Temp TimeP/
(°C) (h) SMb
110 12 2:98
120 48 40:60
135 24 0:100
135 24 0:100
100 12 0:100
80 24 0:100
130 24 10:90
1
2
3
4
5
6
7
8
9
CuI, neocuproine, NaOt-Bu3a
PdCl2(dppf), Cs2CO3
To evaluate the scope of the optimized coupling condi-
tions,16 a variety of aryl iodides with electron-donating,
electron-neutral, and electron-withdrawing groups were
synthesized and coupled with 8-mercaptoadenine
(Table 2). Both electron-rich and electron-neutral aryl
iodides coupled efficiently. For example, iodides with sat-
urated benzofused heterocyclic rings (Table 2, entries 1–
5,) and indole (Table 2, entry 6) gave good to excellent
yields. Other heterocyclic iodides (Table 2, entries 7, 8,
10, and 11,) gave C–S coupled products in moderate
yields. We were able to successfully couple sterically hin-
dered iodides that contained functionalities in the ortho
position, such as amino (Table 2, entries 3 and 4,), chloro
(Table 2, entry 12), and ethyl (Table 2, entry 13). Elec-
tron-withdrawing groups at this position, such as nitro,
limited the product formation (Table 2, entry 14), poten-
tially by decreasing the reactivity of the aryl iodide to-
wards S-arylation.
FeCl3, DMEDA, NaOt-Bu, PhMe8
FeCl3, DMEDA, NaOt-Bu
9
CuI, NMP, K2CO3
CuI, EG, K2CO3, i-PrOH14a
14c
CuI, n-Bu4NBr (20 mol%), K3PO4
CuI, n-Bu4NBr (20 mol%), K3PO4, MW
CuI, n-Bu4NBr (20 mol%), Cs2CO3, MW 190
190
1.5 70:30
1.5 20:80
1.5 100:0
1.5 50:50
1.5 10:90
10 CuI, n-Bu4NBr (20 mol%), NaOt-Bu, MW 190
11 CuI, n-Bu4NBr (10 mol%), NaOt-Bu, MW 190
12 CuI, n-Bu4NBr (5 mol%), NaOt-Bu, MW 190
a DMF was used as solvent unless indicated otherwise.
b P/SM is the ratio of the sulfide product (P) to starting material (SM)
aryl iodide according to LC analysis; dppf = 1,1′-bis(diphenylphos-
phino)ferrocene, EG = ethylene glycol.
When the aryl iodide contained multiple electron-with-
drawing halogens, the reaction resulted in several side
products, as determined by LC-MS analysis. Milder con-
ditions (150 °C for 1 h), however, overcame this limita-
tion and offered the desired product in moderate to good
yields (Table 2, entries 15–18). Dichloro-substituted aryl
iodide (Table 2, entry 15) gave the highest yield when
compared to bromo- and iodo-substituted aryl iodide
No product was observed when the reaction was per-
formed using a ligand-free copper catalyst9 (Table 1, en-
try 5) or when ethylene glycol was used as a ligand14a
(Table 1, entry 6). The CuI–PEG system14b led to low
yields (data not shown). This limitation, added to the dif-
ficulty of removing PEG in the workup procedure, sug-
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W. Sun et al.
LETTER
Table 2 Microwave-Assisted C–S Cross-Coupling of Aryl Iodides
and 8-Mercaptoadenine (continued)
(Table 2, entries 16–18), potentially due to competition of
the several halides for coupling with the thiol.
NH2
NH2
CuI, n-Bu4NBr
NaOt-Bu, DMF
Table 2 Microwave-Assisted C–S Cross-Coupling of Aryl Iodides
and 8-Mercaptoadenine
N
N
N
N
+
ArI
SH
S
Ar
microwave
190 °C, 1.5 h
N
H
N
H
NH2
NH2
N
N
N
CuI, n-Bu4NBr
NaOt-Bu, DMF
N
N
N
N
Entry
9
Product
Yield (%)b
+
ArI
SH
S
Ar
microwave
190 °C, 1.5 h
N
H
N
H
N
NH2
Yield (%)b
92
N
Entry
1
Product
N
N
25
S
N
H
NH2
N
N
N
S
S
NH2
N
H
O
N
10
58
N
S
N
NH2
N
H
N
N
N
N
2
65
NH2
N
N
H
N
N
11
12
40
N
S
S
Br
Br
Ac
N
H
N
NH2
H2N
N
N
N
N
3
4
80
84
N
42a
S
O
N
H
N
H
N
Cl
NH2
N
H2N
NH2
N
N
13
14
15
N
49
5
S
S
Br
N
H
N
N
H
N
NH2
N
NH2
O2N
N
N
N
5
6
S
O
70
53
S
N
H
N
N
H
N
N
Me
NH2
Cl
NH2
N
54a
Br
N
N
S
S
N
N
N
N
H
S
Cl
Cl
N
H
NH2
N
PMB
N
40a
34a
16a
N
N
16
17
18
NH2
N
N
H
N
N
S
N
Br
Br
7
8
48
47
N
H
NH2
N
N
N
S
Cl
Br
N
H
Br
I
NH2
NH2
N
N
N
N
N
N
N
S
N
S
PMB
N
H
N
H
Br
a Reaction conditions: MW, 150 °C, 1 h.
b Isolated yields.
Synlett 2011, No. 20, 3008–3012 © Thieme Stuttgart · New York

LETTER
Synthesis of 8-Arylsulfanyl Adenines
3011
B.; Soullez, D.; Girault, S.; Maes, L.; Landry, V.; Davioud-
Charvet, E.; Sergheraert, C. Bioorg. Med. Chem. 2000, 8, 95.
(4) (a) Kondo, T.; Mitsudo, T.-A. Chem. Rev. 2000, 100, 3205.
(b) Procter, D. J. J. Chem. Soc., Perkin Trans. 1 2001, 335.
(c) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,
43, 5400.
(5) (a) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587.
(b) Fernández-Rodríguez, M. A.; Shen, Q.; Hartwig, J. F.
J. Am. Chem. Soc. 2006, 128, 2180. (c) Murata, M.;
Buchwald, S. L. Tetrahedron 2004, 60, 7397.
(d) Mispelaere-Canivet, C.; Spindler, J.-F.; Perrio, S.;
Beslin, P. Tetrahedron 2005, 61, 5253.
(6) (a) Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org. Lett. 2007, 9,
3495. (b) Jammi, S.; Barua, P.; Rout, L.; Saha, P.;
Punniyamurthy, T. Tetrahedron Lett. 2008, 49, 1484.
(c) Taniguchi, N. J. Org. Chem. 2004, 69, 6904.
In summary, we have developed facile microwave-irradi-
ated C–S cross-coupling conditions to prepare several 8-
arylsulfanyl adenines. Given that C–S bond formation is
of great significance to medicinal chemistry, this micro-
wave-assisted catalytic system offers a rapid, simple, and
efficient procedure to prepare a wide range of biologically
relevant heterocyclic aryl sulfides.
Acknowledgment
This work was supported in part by the National Institute of Allergy
and Infectious Diseases (1R21AI090501), the National Cancer In-
stitute (1R01CA155226-01), and the National Institute on Aging
(1U01AG032969).
(d) Millois, C.; Diaz, P. Org. Lett. 2000, 2, 1705.
(7) Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006,
8, 5613.
(8) Correa, A.; Carril, M.; Bolm, C. Angew. Chem. Int. Ed.
2008, 47, 2880.
(9) Sperotto, E.; van Klink, G. P. M.; de Vries, J. G.; van Koten,
G. J. Org. Chem. 2008, 73, 5625.
(10) (a) Kasibhatla, S. R.; Hong, K.; Zhang, L.; Biamonte, M. A.;
Boehm, M. F.; Shi, J.; Fan, J. WO 03037860, 2003.
(b) Bajji, A. C.; Kim, S.-H.; Tangallapally, R.; Markovitz,
B.; Trovatao, R.; Anderson, M. B.; Wettstein, D.;
Shenderovich, M. WO 2009065035, 2009. (c) Chen, J.;
Sperl, G.; Gullo, V.; Sista, L.; Hughes, D.; Peng, Y.;
Pierceall, W.; Weiskopf, A.; Dushin, R. G.; Kevin, J. I.
WO 2008049105, 2008. (d) Taldone, T.; Chiosis, G. Curr
Top Med. Chem. 2009, 9, 1436.
References and Notes
(1) (a) Hartwig, J. F. In Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 1; Negishi, E., Ed.;
Wiley-Interscience: New York, 2002, 1051. (b) Muci, A.
R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
(c) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B.
Tetrahedron 2002, 58, 2041. (d) Kondo, T.; Mitsudo, T.-A.
Chem. Rev. 2000, 100, 3205. (e) Hartwig, J. F. Acc. Chem.
Res. 1998, 31, 852. (f) Beletskaya, I. P.; Ananikov, V. P.
Eur. J. Org. Chem. 2007, 3431.
(2) For general reviews on sulfides, see: Comprehensive
Organic Chemistry, Vol. 3; Jones, D. N., Ed.; Pergamon
Press: Oxford, 1979.
(3) (a) He, H.; Zatorska, D.; Kim, J.; Aguirre, J.; Llauger, L.;
She, Y.; Wu, N.; Immormino, R. M.; Gewirth, D. T.;
Chiosis, G. J. Med. Chem. 2006, 49, 381. (b) Chiosis, G.;
Timaul, M. N.; Lucas, B.; Munster, P. N.; Zheng, F. F.;
Sepp-Lorenzino, L.; Rosen, N. A. Chem. Biol. 2001, 8, 289.
(c) Wang, Y.; Chackalamannil, S.; Hu, Z.; Clader, J. W.;
Greenlee, W.; Billard, W.; Binch, H.; Crosby, G.; Ruperto,
V.; Duffy, R. A.; McQuade, R.; Lachowicz, J. E. Bioorg.
Med. Chem. Lett. 2000, 10, 2247. (d) Nielsen, S. F.;
Nielsen, E. O.; Olsen, G. M.; Liljefors, T.; Peters, D. J. Med.
Chem. 2000, 43, 2217. (e) De Martino, G.; Edler, M. C.;
La Regina, G.; Cosuccia, A.; Barbera, M. C.; Barrow, D.;
Nicholson, R. I.; Chiosis, G.; Brancale, A.; Hamel, E.;
Artico, M.; Silvestri, R. J. Med. Chem. 2006, 49, 947.
(f) Kadlor, S. W.; Kalish, V. J.; Davies, J. F.; Shetty, B. V.;
Fritz, J. E.; Appelt, K.; Burgess, J. A.; Campanale, K. M.;
Chirgadze, N. Y.; Clawson, D. K.; Dressman, B. A.; Hatch,
S. D.; Khalil, D. A.; Kosa, M. B.; Lubbehusen, P. P.;
Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.;
Tatlock, J. H. J. Med. Chem. 1997, 40, 3979. (g) Marcincal-
Letebvre, A.; Gesquiere, C.; Lemer, C.; Dupuis, B. J. Med.
Chem. 1981, 24, 889. (h) Liu, G.; Link, J. T.; Pei, Z.; Reilly,
E. B.; Leitza, S.; Nguyen, B.; Marsh, K. C.; Okasinski, G. F.;
von Geldem, T. W.; Ormes, M.; Fowler, K.; Gallatin, M.
J. Med. Chem. 2000, 43, 4025. (i) Gangjee, A.; Zeng, Y.;
Talreja, T.; McGuire, J. J.; Kisliuk, R. L.; Queener, S. F.
J. Med. Chem. 2007, 50, 3046. (j) Jarkas, N.; McConathy,
J.; Voll, R. J.; Goodman, M. M. J. Med. Chem. 2005, 48,
4254. (k) Liu, L.; Stelmach, J. E.; Natarajan, S. R.; Chen,
M.-H.; Singh, S. B.; Schwartz, C. D.; Fitzgerald, C. E.;
O’Keefe, S. J.; Zaller, D. M.; Schmatz, D. M.; Doherty, J. B.
Bioorg. Med. Chem. Lett. 2003, 13, 3979. (l) Beard, R. L.;
Colon, D. F.; Song, T. K.; Davies, P. J. A.; Kochhar, D. M.;
Chandraratna, R. A. S. J. Med. Chem. 1996, 39, 3556.
(m) Nagai, Y.; Irie, A.; Nakamura, H.; Hino, K.; Uno, H.;
Nishimura, H. J. Med. Chem. 1982, 25, 1065. (n) Bonnet,
(11) (a) Chiosis, G.; Kang, Y.; Sun, W. Expert Opin. Drug
Discovery 2008, 3, 99. (b) Workman, P.; Burrows, F.;
Neckers, L.; Rosen, N. Ann. N. Y. Acad. Sci. 2007, 1113,
202. (c) Luo, W.; Rodina, A.; Chiosis, G. BMC Neurosci.
2008, 9, S7; Suppl. 2. (d) Luo, W.; Sun, W.; Taldone, T.;
Rodina, A.; Chiosis, G. Mol. Neurodegener. 2010, 5, 24.
(12) (a) Llauger, L.; He, H.; Kim, J.; Aguirre, J.; Rosen, N.;
Peters, U.; Davies, P.; Chiosis, G. J. Med. Chem. 2005, 48,
2892. (b) Luo, W.; Dou, F.; Rodina, A.; Chip, S.; Kim, J.;
Zhao, Q.; Moulick, K.; Aguirre, J.; Wu, N.; Greengard, P.;
Chiosis, G. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 9511.
(c) Cerchietti, L. C.; Lopes, E. C.; Yang, S. N.; Hatzi, K.;
Bunting, K. L.; Tsikitas, L. A.; Malik, A.; Robles, A. I.;
Walling, J.; Varticovski, L.; Shaknovich, R.; Bhalla, K. N.;
Chiosis, G.; Melnick, A. Nat. Med. 2009, 15, 1369.
(d) Caldas-Lopes, E.; Cerchietti, L.; Ahn, J. H.; Clement,
C. C.; Robles, A. I.; Rodina, A.; Moulick, K.; Taldone, T.;
Gozman, A.; Guo, Y.; Wu, N.; de Stanchina, E.; White, J.;
Gross, S. S.; Ma, Y.; Varticovski, L.; Melnick, A.; Chiosis,
G. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 8368.
(e) Marubayashi, S.; Koppikar, P.; Taldone, T.; Abdel-
Wahab, O.; West, N.; Bhagwat, N.; Caldas-Lopes, E.; Ross,
K. N.; Gonen, M.; Gozman, A.; Ahn, J. H.; Rodina, A.;
Ouerfeli, O.; Yang, G.; Hedvat, C.; Bradner, J. E.; Chiosis,
G.; Levine, R. L. J. Clin. Invest. 2010, 120, 3578.
(13) Tao, H.; Kang, Y.; Taldone, T.; Chiosis, G. Bioorg. Med.
Chem. Lett. 2009, 19, 415.
(14) (a) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517.
(b) She, J.; Jiang, Z.; Wang, Y. Tetrahedron Lett. 2009, 50,
593. (c) Buranaprasertsuk, P.; Chang, J. W. W.; Chavasiri,
W.; Chan, P. W. H. Tetrahedron Lett. 2008, 49, 2023.
(15) (a) Bagley, M. C.; Davis, T.; Dix, M. C.; Fusillo, V.;
Pigeaux, M.; Rokicki, M. J.; Kipling, D. J. Org. Chem. 2009,
74, 8336. (b) Friden-Saxin, M.; Pemberton, N.;
da Silva Andersson, K.; Dyrager, D.; Friberg, A.; Grotli, M.;
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W. Sun et al.
LETTER
Luthman, K. J. Org. Chem. 2009, 74, 2755. (c) Al-Saleh,
B.; El-Apasery, M. A.; Hilmy, N. M.; Elnagdi, M. H.
J. Heterocycl. Chem. 2006, 43, 1575. (d) Bargiggia, F. C.;
Murray, W. V. J. Org. Chem. 2005, 70, 9636. (e) Xu, Y.;
Guo, Q.-X. Heterocycles 2004, 63, 903.
compound 8-(2,3-dihydrobenzofuran-6-ylthio)-9H-purin-6-
amine (25 mg, 92%, Table 2, entry 1) as a yellow solid.
Analytical Data
1H NMR (500 MHz, MeOH-d4): d = 8.14 (s, 1 H), 7.24 (d,
J = 7.6 Hz, 1 H), 7.07 (d, J = 7.3 Hz, 1 H), 6.97 (s, 1 H), 4.62
(t, J = 8.7 Hz, 2 H), 3.25 (t, J = 8.7 Hz, 2 H). ESI-MS: m/z =
285.9 [M + H]+. ESI-HRMS: m/z [M + H]+ calcd for
C13H12N5OS: 286.0763; found: 286.0768. HPLC analyses
were performed on a Waters Autopurification system with
PDA, MicroMass ZQ and ELSD detector and a reversed-
phase column (Waters X-Bridge C18, 4.6 × 150 mm, 5 mm).
The mobile phase was the mixture of 5–95% MeCN–H2O
with 0.1% TFA having a flow rate at 1.2 mL/min for 12 min;
tR = 7.47 min; purity, 99%; HRMS data were collected using
Waters LCT Premier XE.
(16) General Procedure for the Microwave Coupling
Reaction
In a conical-bottomed Biotage microwave vial, the mixture
of 8-mercaptoadenine (16 mg, 0.1 mmol), 6-iodo-2,3-
benzofuran (24 mg, 0.1 mmol), CuI (3.6 mg, 0.02 mmol),
NaOt-Bu (28 mg, 0.3 mmol) and TBAB (6.4 mg, 0.02 mmol)
in DMF (2 mL) was charged. The sealed vial was irradiated
in the microwave for 1.5 h at 190 °C. After cooling, the
reaction mixture was condensed in vacuo and purified by
flash chromatography (CH2Cl2–MeOH = 10:1) to yield
Synlett 2011, No. 20, 3008–3012 © Thieme Stuttgart · New York

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