Parallel synthesis of pyrazolines on soluble polymer support

Article abstract of DOI:10.1055/s-2003-40863

An efficient and rapid parallel liquid-phase synthesis of pyrazolines has been developed. The one-pot three-components reaction of polyethylene glycol (PEG)-supported acrylate 1, aldehyde 2 and aryl hydrazine 3 in the presence of chloramine-T in methanol gave the corresponding PEG-supported pyrazolines 5. Cleavage from the support under mild conditions afforded pyrazolines 6 in good yields (69-91%) and high purities (91-100%).

Full text of DOI:10.1055/s-2003-40863

LETTER
1467
Parallel Synthesis of Pyrazolines on Soluble Polymer Support
Parallel Synthesis
a
of Pyrazolin
n
e
s
on Solub
-
le Polym
G
er Support uang Wang,* Jian Zhang, Xu-Feng Lin, Han-Feng Ding
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
Fax +86(571)87951512; E-mail: orgwyg@zju.edu.cn
Received 1 June 2003
COCl
Abstract: An efficient and rapid parallel liquid-phase synthesis of
O
R1
pyrazolines has been developed. The one-pot three-components re-
action of polyethylene glycol (PEG)-supported acrylate 1, aldehyde
2 and aryl hydrazine 3 in the presence of chloramine-T in methanol
gave the corresponding PEG-supported pyrazolines 5. Cleavage
from the support under mild conditions afforded pyrazolines 6 in
good yields (69–91%) and high purities (91–100%).
OH
O
TOA-CH2Cl2 , r.t. 24 h
R1
1
N
R2
R3
R2CHO
N
Key words: pyrazolines, 1,3-dipolar cycloaddition, soluble poly-
mer, liquid-phase synthesis, polyethylene glycol (PEG)
1) TOA, MeOH, r.t., 10 min
2
+
O
2) 1, Chloramine-T, 24 h
R1
R3NHNH2·HCl
O
3
5
In recent years, the liquid-phase synthesis of small hetero-
cyclic molecules has been a subject of intense research ac-
tivity,1 since it represents one of the most promising ways
to generate small molecular libraries in the field of com-
binatorial chemistry.2 It profits from both the advanta-
geous features of homogeneous solution chemistry (high
reactivity, lack of diffusion phenomena and ease of anal-
ysis without following the cleavage-and-check technique)
and of solid-phase methods (use of excess reagents and
easy isolation and purification of products). Among the
various soluble polymers, polyethylene glycol (PEG) is
the most useful and promising.3
N
R2
R3
CH3ONa/CH3OH
r.t. 6 h
N
CO2Me
R1
6
Scheme 1
trile imines generated in situ with PEG-supported dipo-
larophile 1 provided the corresponding PEG-supported
pyrazolines 5 in good yields. Quantitative conversion in
the 1,3-dipolar cycloaddition reaction was verified by 1H
NMR analysis. The reactions carried out in the homoge-
neous phase at room temperature for 24 hours and the syn-
thetic sequences performed in parallel one-pot fashion.
Substituted pyrazolines offer a high degree of structure di-
versity and have proven to be very important in medicinal
chemistry.4 Even though solution methods for their prep-
aration via 1,3-dipolar cycloaddition are well studied,5
there are very limited procedures available for the synthe-
sis of this class of compounds on solid supports and solu-
ble supports.3d,6 In connection with our research on the
PEG-supported liquid-phase synthesis,7 herein we dis-
close our findings pertaining to [3+2] cycloaddition of in
situ generated nitrile imine and polymer-supported acry-
late. Commercially available difunctional PEG 4000 was
chosen as soluble polymer support. Our efforts at obtain-
ing a representative library of pyrazolines, which exploit-
ed three sites of chemical diversity, are presented below.
1
Structural assignments of the cycloadducts rely upon H
NMR analysis. In particular, the proton on C5 of the pyr-
azoline ring of 6d resonates at d = 4.85 ppm as a doublet
of doublets, thus accounting for the depicted regiochemis-
try of the cycloaddition.
The target compounds 6 were released from the PEG by
treatment of the polymer bound products 5 with 0.1 N Me-
ONa in methanol at room temperature. Normally, cleav-
age was completed after stirring in 0.1 N MeONa/MeOH
for 6 hours.
A variety of hydrazones reacted well with the soluble
polymer-supported acrylate under similar reaction condi-
tions to afford the corresponding pyrazolines in good
yields and high purities. The ready availability of alde-
hydes and hydrazines from commercial sources allows the
preparation of large heterocyclic compound libraries. The
proof of the structure of the pyrazolines was provided by
1H NMR, 13C NMR, GC-MS and HRMS spectra. In every
case, only one isomer was obtained. Table 1 summarizes
some of the initial results we have obtained by application
of the above methodology.8
PEG-supported acryloyl esters 1 were easily obtained as
illustrated in Scheme 1 and the conversion of terminal hy-
droxyl groups on PEG was determined by 1H NMR anal-
ysis to be quantitative. Condensation of aldehydes 2 and
aryl hydrazines 3 in methanol at room temperature for 10
minutes gave the hydrazones 4. Then chloramine-T
(CAT) and PEG-supported acryloyl esters 1 were added to
the reaction mixture. The 1,3-dipolar cycloadditions of ni-
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1467,1468,ftx,en;U10103ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

1468
Y.-G. Wang et al.
LETTER
Table 1 One-Pot Liquid-Phase Synthesis of Pyrazolines
References
Com- R1
pound
R2
R3
Yield Purity
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(%)a
70
87
84
75
79
88
84
75
69
90
85
81
91
87
88
80
83
77
(%)b
89
94
92
92
98
91
94
95
93
98
97
98
100
99
100
96
95
97
6a
6b
6c
6d
6e
6f
H
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
Ph
Ph
H
p-CH3C6H4
p-FC6H4
Ph
H
H
H
Ph
p-CH3C6H4
p-FC6H4
Ph
H
Ph
6g
6h
6i
H
2-Furyl
2-Furyl
2-Furyl
p-CH3OC6H4
p-CH3OC6H4
p-CH3OC6H4
Ph
H
p-CH3C6H4
p-FC6H4
Ph
H
6j
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
6k
6l
p-CH3C6H4
p-FC6H4
Ph
(7) (a) Shang, Y. J.; Wang, Y. G. Tetrahedron Lett. 2002, 43,
2247. (b) Xia, M.; Wang, Y. G. Tetrahedron Lett. 2002, 43,
7703. (c) Lin, X. F.; Zhan, J.; Wang, Y. G. Tetrahedron Lett.
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6m
6n
6o
6p
6q
6r
Ph
p-CH3C6H4
p-FC6H4
Ph
Ph
(8) Typical Procedure for Pyrazoline Synthesis: After
combining aldehyde (1.0 mmol), hydrazine hydrochloride
(1.0 mmol) and trioctylamine (TOA, 1.0 mmol) in MeOH (8
mL) at r.t. for 10 min, PEG-supported acryloyl ester (0.25
mmol) and chloramine-T (1.0 mmol) were added and the
mixture was stirred for 24 h under N2. Upon completion of
the reaction, cold Et2O (30 mL) was added to the reaction
mixture to precipitate the PEG-bound pyrazoline. The
precipitate was then collected on a sintered glass funnel and
thoroughly washed with Et2O (10 mL × 3). PEG-bound
pyrazoline was then dried under vacuum. Finally, the
resulting PEG-bound pyrazoline was cleaved by 0.1 N
MeONa in MeOH (5 mL) at r.t. for 6 h. Cold Et2O (30 mL)
was added to precipitate the detached PEG-OH. The
polymer was filtered and the combined filtrate was flash
passed through a short column to remove trace amount of
PEG and MeONa. The solvent was removed to give the
corresponding crude product. All compounds listed in
Table 1 give satisfactory 1H NMR, 13C NMR, GC-MS and
HRMS data. For compound 6p is as follows: 1H NMR (500
MHz, CDCl3): d = 1.64 (s, 3 H), 3.24 (d, J = 16.7 Hz, 1 H),
3.65 (d, J = 16.7 Hz, 1 H), 3.76 (s, 3 H), 6.49 (s, 1 H), 6.60
(d, J = 3.4 Hz, 1 H), 6.90 (t, 1 H), 7.08 (d, J = 8.0 Hz, 2 H),
7.24 (m, 2 H), 7.5 (s, 1 H). 13C NMR (125 MHz, CDCl3):
d = 174.3, 148.0, 143.7, 143.3, 137.9, 129.3, 120.6, 115.0,
111.9, 109.6, 68.9, 53.3, 48.1, 21.3. MS (EI): m/z = 284.
HRMS calcd for C16H16N2O3 ([M + H]+): 285.1161. Found:
285.1170.
2-Furyl
2-Furyl
2-Furyl
p-CH3C6H4
p-FC6H4
a Yields refer to product cleaved from PEG.
b Purities were determined by GC-MS analysis. GC purity was con-
sistent with the purity determined by 1H NMR.
In summary, we have demonstrated that liquid-phase
methodology can be applied efficiently in parallel synthe-
sis of pyrazoline library, which exploited three sites of
chemical diversity. All reactions involved here are highly
efficient in giving the desired compounds at room temper-
ature. Crude products are usually obtained in high purity
and high yield just by simple precipitation and washings,
so they could be directly used in primary biological assays
without further purification. The synthesis of large pyr-
azoline libraries is presently under investigation.
Acknowledgment
This work was financially supported by the National Natural Sci-
ence Foundation of China (No. 20272051) as well as the Teaching
and Research Award Program for Outstanding Young Teachers in
Higher Education Institutions of MOE, P.R.C.
Synlett 2003, No. 10, 1467–1468 © Thieme Stuttgart · New York