Solid-phase synthesis of bis-heterocyclic compounds with skeletal diversity from resin-bound 3-propargylamino-2-seleno-ester

Full text of DOI:10.1021/cc900112s

 Copyright 2010 by the American Chemical Society
Volume 12, Number 1
January/February 2010
Report
pounds, it is considered worthwhile to develop a general and
effective method for the construction of a bis-heterocyclic
compounds library.
Solid-Phase Synthesis of Bis-Heterocyclic
Compounds with Skeletal Diversity from
Resin-Bound 3-Propargylamino-2-seleno-ester
Organoselenium resins are ideal linkers and reagents
for solid-phase synthesis because organoselenium com-
pounds are important synthetic intermediates, and the
Se-C bond can be easily broken by various methods.11
Recently several research groups12 including ours13 were
interested in the preparation of heterocyclic libraries from
organoselenium resins. In a continuation of our efforts
toward the solid-phase synthesis of bis-heterocyclic com-
pounds,14 we describe, herein, an efficient approach for
the solid-phase synthesis of a bis-heterocycles system
consisting of uracil/diazepinedione and benzofuran/indole.
The overall strategy is based on the resin-bound interme-
diate 4 (Scheme 1), in which the 3-amino-2-seleno-ester
moiety is transformed to uracil or diazepinedione through
condensation with isocyanate or R-amino-acid and oxida-
tive elimination of selenium linker and the terminal
acetylene moiety is transformed to benzofuran or indole
through a sonogashira/annulation reaction with 2-iodophe-
nol or 2-iodoaniline. The strategy opens the way to the
Jian Cao† and Xian Huang*,†,‡
Department of Chemistry, Zhejiang UniVersity (Xixi
Campus), Hangzhou 310028, P.R. China, and State Key
Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, P.R. China
ReceiVed July 30, 2009
Heterocyclic compounds have attracted considerable at-
tention for being broadly useful as therapeutic agents,
especially privileged heterocycles which are capable of
binding to multiple receptors with high affinity.1 Combination
of two privileged heterocycles in one molecule can construct
a novel system of a bis-heterocycle which may potentially
create new entities with unusual bioproperties through a
synergistic effect. In fact recent reports described libraries
where the most active compound was a bis-heterocycle,2 and
an average six publications in every issue of the Journal of
Medicinal Chemistry reported bis-heterocycles as being the
most potent ones in 2008.3 Uracil,4 benzofuran,5 indole,6 and
diazepinedione7 are privileged heterocycles known for a wide
range of biological activities, which have been found in
clinically accepted drugs as well. Particularly, molecules
containing two of these privileged heterocycles were reported
to show special biological activities. For example, uracil-
benzofuran bis-heterocycle 1 (Figure 1) displayed a potent
anti-HIV-1 activity,8 while uracil-indole 2 was found to be
a potential neoplasm inhibitors9 and 3 was reported to show
serotonergic activity.10 Because of potential biological and
pharmacological applications of these bis-heterocyclic com-
* To whom correspondence should be addressed. E-mail: huangx@
mail.hz.zj.cn.
† Zhejiang University (Xixi Campus).
‡ Chinese Academy of Sciences.
Figure 1
10.1021/cc900112s CCC: $40.75  2010 American Chemical Society
Published on Web 11/06/2009

2
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Reports
Table 1. Synthesis of Bis-Heterocycles of Uracil and
Benzofuran/Indole 10a-n
Scheme 1
product
R1
R3
X
yield (%)a purity (%)b
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
n-Bu
Ph
Ph
p-tol
p-tol
p-tol
3-MeC6H4
4-MeOC6H4
n-Bu
Ph
Ph
p-tol
p-tol
H
H
O
O
O
O
O
O
O
O
NMs
NMs
NMs
NMs
43
45
41
53
46
56
44
51
42
46
40
47
39
37
82
89
86
91
84
92
83
86
80
84
81
85
78
79
Me
H
Me
t-Bu
H
H
H
H
Cl
H
Scheme 2a
Me
H
NMs
NSO2Ph
Ph
a Yield of the crude product based on the loading of the resin 5.
b Determined by HPLC.
Scheme 4a
a Reagents and conditions: (a) 2-iodophenol or 2-iodoaniline, Pd(PPh3)4,
CuI, Et3N, DMF, 65 °C, 24 h; (b) H2O2, THF, rt, 1 h.
a Reagents and conditions: (a) ZnCl2, methyl acrylate, CH2Cl2, rt, 0.5 h,
then propargylamine, 24 h; (b) K2CO3, R1NCO, DMF, 65 °C, 5 h; (c) Fmoc-
R-amino-acid, DIC, THF, rt, 24 h; (d) piperidine/CH2Cl2 (1:4), rt, 12 h.
Table 2. Synthesis of Bis-Heterocycles of Diazepinedione and
Benzofuran/Indole 12a-j
product
R-amino-acid
R3
X
yield (%)a purity (%)b
Scheme 3a
12a
12b
12c
12d
12e
12f
12g
12h
12i
glycine
glycine
D-phenylalanine
L-alanine
L-isoleucine
glycine
glycine
glycine
D-phenylalanine
H
Me
H
Me
H
H
Me NMs
Cl
H
O
O
O
O
O
39
42
45
49
52
38
44
35
31
81
83
85
84
90
80
86
77
76
NMs
a Reagents and conditions: (a) 2-iodophenol or 2-iodoaniline, Pd(PPh3)4,
CuI, Et3N, DMF, 65 °C, 24 h; (b) H2O2, THF, rt, 1 h.
NMs
NSO2Ph
a Yield of the crude product based on the loading of the resin 5.
b Determined by HPLC.
construction of a bis-heterocyclic compounds library with
skeletal diversity (four different heterocycles).
resin 4 was condensed with Fmoc-R-amino-acids to form
1,4-diazepane-2,5-diones 8 under standard peptide synthesis
conditions. Resin 4 was reacted smoothly with Fmoc-R-
amino-acids and DIC (N,N′-diisopropylcarbodiimide) to form
the corresponding amides 7. Then the amides 7 were
deprotected and spontaneously cyclized in piperidine/CH2Cl2
to form the 1,4-diazepane-2,5-diones 8, which exhibited a
strong peak at 1661-1673 cm-1 and a weaker peak at
1689-1700 cm-1. Oxidative cleavage of a small aliquot of
Results and Discussion
Resin-bound 3-propargylamino-2-seleno-ester 4 was pre-
pared according to our previous report.13k Polystyrene-
supported selenenyl bromide (resin 5) (Br: 1.18 mmol/g) was
smoothly reacted with methyl acrylate in the presence of
ZnCl2 at room temperature to afford the corresponding resin-
bound 3-bromo-2-seleno ester, which was reacted with
propargylamine in one pot to give the corresponding yellow
resin 4 (Scheme 2). The Fourier transform infrared (FT-IR)
spectrum showed a strong peak of the carbonyl absorptions
at 1730 cm-1.
With resin 4 in hand, we performed cyclization reactions
with isocyanates and R-amino-acids to afford the dihydrou-
racils 6 and 1,4-diazepane-2,5-diones 8. First, in the presence
of K2CO3, resin 4 was reacted with isocyanates in DMF at
65 °C for 5 h to afford the corresponding resin-bound N1-
propargyl 5,6-dihydrouracils 6.13k The FT-IR spectrum
showed two strong peaks for the carbonyl absorptions at
1729-1734 and 1665-1679 cm-1, respectively. Second,
1
resins 6 and 8 with 30% H2O2 and subsequent H NMR
spectroscopic analysis of the products showed that the steps
above succeeded.
We then sought to construct the benzofuran and indole
moiety. It is well-known that benzofuran and indole could
be synthesized through a sonogashira/annulation reaction
with 2-iodophenol or 2-iodoaniline and terminal acetylene,15
and the method has been applied to solid-phase synthesis
successfully with various linkers16 including the selenium
linker.12e Therefore we performed the sonogashira/annulation
reaction to form the benzofuran and indole moiety. Under
classical Pd/Cu and Et3N catalytic condition, resins 6 were

Reports
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 3
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reacted with 2-iodophenol smoothly to afford bis-heterocycle
9 (Scheme 3). After 24 h, IR analysis revealed the complete
disappearance of the terminal alkyne C-H vibration (3297
cm-1), and oxidative cleavage of resins 9 with 30% H2O2
showed the sonogashira/annulation reaction succeeded and
no uncyclized 2-ethynylphenol was found. Screening the
reaction conditions showed that other conditions (catalyst,
base, and temperature) did not improve the yields and purities
dramatically. Then a series of isocyanates and 2-iodophenols
were chosen to perform the reaction (Table 1, products
10a-10h). The results were satisfactory for various 2-io-
dophenols. Both alkyl and aryl isocyanates worked well.
Thus, bis-heterocycles of uracil and benzofuran were con-
structed successfully.
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Inspired by the results above, we performed the sono-
gashira/annulation reaction to form the indole moiety. For
activating the amino group,16a N-sulfonyl-2-iodoanilines were
chosen to react with resins 6. The reaction proceeded
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similar to benzofuran (Table 1, products 10i-10n). Both
alkyl and aryl sulfonyl-2-iodoanilines worked well, and R3
could be H, alkyl, and Cl. Unfortunately, replacing the
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Finally, bis-heterocycles of diazepinedione and benzofuran/
indole were constructed through the sonogashira/annulation
reaction with resins 8 and 2-iodophenol or 2-iodoaniline
(Scheme 4). The results were satisfactory for various
R-amino-acids (Table 2). Because of the ready availability
of chiral R-amino-acid, this methodology was suited for the
synthesis of optically pure products. To demonstrate that the
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maintained throughout all four synthetic steps, the product
12c was then analyzed by chiral HPLC, compared with the
racemic product, and found to be optically pure (ee >99%).
In summary, we have developed an efficient solid-phase
parallel synthetic route to a bis-heterocycles library of uracil/
diazepinedione and benzofuran/indole from resin-bound
3-propargylamino-2-seleno-ester. Efforts to construct a li-
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Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Project Nos. 20672095 and
20732005), National Basic Research Program of China (973
Program, 2009CB825300), and CAS Academician Founda-
tion of Zhejiang Province for financial support.
Supporting Information Available. General procedures
1
for the synthesis of the library, spectral data, H NMR and
13C NMR spectra of all the products, and parts of HPLC
spectra of 10d, 10n, 12d, and 12i. This material is available
free of charge via the Internet at http://pubs.acs.org.
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CC900112S