An improved synthesis of pyrazolines from aryl azides and acrylic esters

Article abstract of DOI:10.1055/s-2002-20482

Substituted pyrazoline derivatives are synthesized in high yields through the cycloaddition reactions of azides with acrylates under Baylis-Hillman reaction conditions. Improved yields and enhanced rates are obtained using DABCO as the base.

Full text of DOI:10.1055/s-2002-20482

LETTER
513
An Improved Synthesis of Pyrazolines from Aryl Azides and Acrylic Esters1
I
mprove
d
.Synthesis of
S
P
yrazolines . Yadav,* B. V. Subba Reddy, V. Geetha
Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91(40)7170512; E-mail: yadav@iict.ap.nic.in
Received 4 January 2002
1,4-disubstituted 2-triazolines. Triazolines with electron
withdrawing substituents in the 4-position are known to
isomerize to the open-chain diazocompounds which on
addition of a second molecule of olefin resulted in the for-
mation of 3,5-disubstituted 2-pyrazolines.8 However,
this isomerisation involves longer reaction times (days to
months), low to moderate yields, low regioselectivity and
also the formation of a mixture of products9 comprising
of: triazolines, aziridines and enamines along with the de-
sired pyrazolines. Therefore, there is a need to develop a
practical and efficient protocol for this transformation.
Abstract: Substituted pyrazoline derivatives are synthesized in
high yields through the cycloaddition reactions of azides with acry-
lates under Baylis–Hillman reaction conditions. Improved yields
and enhanced rates are obtained using DABCO as the base.
Key words: azides, Baylis–Hillman reaction, cycloaddition reac-
tions, pyrazolines
1,2,3-Triazole and 1,2-pyrazole derivatives are known to
exhibit a wide range of biological activities such as plant
growth regulators,2 fungicides3 and herbicides.4 The most
common method for the preparation of 1,2,3-triazoles is
the 1,3-dipolar cycloaddition reaction of azides with sub-
stituted acetylenes.5–7 The analogous reaction of azides
with electron-deficient olefins leads to the formation of
In this communication, we wish to report a facile synthe-
sis of pyrazolines from azides and acrylates under Baylis–
Hillman conditions (Scheme 1).
Scheme 1
Scheme 2
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0513,0515,ftx,en;D21701ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

514
J. S. Yadav et al.
LETTER
Table One-Pot Synthesis of Pyrazolines from Aryl Azides and
The reaction of phenyl azide with methyl acrylate in the
presence of 10 mol% DABCO in refluxing THF afforded
the corresponding 5-phenyl aminomethyl-3,5-dicarbe-
thoxy- 2-pyrazoline in 87% yield. Similarly, the treat-
ment of several substituted phenyl azides with methyl or
ethyl acrylate in the presence of DABCO gave the corre-
sponding pyrazolines in high yields (75–90%). The con-
versions are clean and complete in short reaction time (3–
7 h). The reactions proceeded smoothly in the presence of
catalytic amount of DABCO in refluxing THF to give the
products in excellent yields. However, at room tempera-
ture the conversions required longer reaction times (8–14
h) to obtain comparable yields than those obtained under
thermal conditions. Further, the reactions are very slow
(3–7 days) at room temperature in the absence of catalyst
and gave a mixture containing triazolines, open chain di-
azo compounds, aziridines and enamines along with the
desired pyrazolines. The best results were obtained when
THF was used as solvent. The reaction may proceed
through the formation of triazole as intermediate that
isomerizes to diazoester followed by the cycloaddition of
the olefin resulting in the formation of pyrazolines
(Scheme 2).
Acrylic Estersa
Entry Azide 1
Acrylate 2
Reaction Yieldb
time (h)
(%)
a
4.5
87
b
6.0
7.0
5.0
3.5
6.0
4.0
90
78
89
90
81
87
c
d
e
f
g
Among various bases like DBU, DBN and Et3N used for
this reaction, DABCO was found to be more effective
with respect to yield and reaction rate. Several examples
illustrating this novel and efficient protocol for the synthe-
sis of pyrazolines are listed in the Table.
h
i
5.5
6.0
7.0
80
89
86
In summary, we have demonstrated an improved protocol
for the synthesis of 3,5-disubstituted pyrazolines involv-
ing 1,3-dipolar cycloaddition of aryl azides with acrylic
esters followed by rearrangement and subsequent cy-
cloaddition using a catalytic amount of DABCO in THF
under reflux conditions. Improved yields, enhanced reac-
tion rates, cleaner reaction products, milder reaction con-
ditions, greater regioselectivity, simple experimental and
work-up procedures are the main advantages of this pro-
cedure over existing ones.
j
k
l
3.0
5.0
90
75
General procedure for the synthesis of pyrazolines:
a All products were characterized by 1H NMR, IR and mass spectra.
b Isolated and unoptimized yields.
A mixture of azide (5 mmol) ethyl or methyl acrylate (15 mmol) and
DABCO (10 mol% w/w of azide) in THF (15 mL) was stirred under
reflux for an appropriate time (Table). After completion of the reac-
tion as indicated by TLC, the reaction mixture was diluted with wa-
ter (10 mL) and extracted with ethyl acetate (2 15 mL). The
combined organic layers were dried (Na2SO4), concentrated in vac-
uo and purified by column chromatography on silica gel (Merck,
100–200 mesh, ethyl acetate–hexane, 2:8) to afford the pure 3,5-
disubstituted pyrazoline.
Spectral data of compounds: 3b: Viscous liquid, 1H NMR (CDCl3)
: 1.50 (t, 3 H, J = 6.8 Hz), 1.80 (t, 3 H, J = 7.0 Hz), 3.10 (d, 1 H, J
= 16.8 Hz), 3.45 (d, 1 H, J = 16.8 Hz), 3.60 (d, 2 H, 2.2 Hz), 4.20
(q, 2 H, J = 7.0 Hz), 4.30 (q, 2 H, J = 7.0 Hz), 4.65 (br s, NH), 6.70
(t, 1 H, J = 7.5 Hz), 6.75 (d, 1 H, J = 7.5 Hz), 7.10 (t, 1 H, J = 7.5
Hz), 7.30 (t, 1 H, J = 7.5 Hz). 13C NMR (CDCl3 proton decoupled)
: 13.7, 13.9, 37.4, 48.6, 61.1, 62.3, 73.0, 111.5, 118.0, 119.4,
127.9, 129.0, 143.0, 152.6, 161.5, 173.3. FABMS: 353 (M+), 308,
NMR (CDCl3) : 3.10 (d, 1 H, J = 16.7 Hz), 3.40 (d, 1 H, J = 16.7
Hz), 3.60 (d, 2 H, J = 2.2 Hz), 3.75 (s, 3 H), 3.80 (s, 3 H), 4.65 (br
s, NH), 6.75 (s, 1 H, J = 7.3 Hz), 7.0 (br s, NH), 7.30 (s, 1 H, J = 7.3
Hz). 13C NMR (CDCl3 proton decoupled) : 171.3, 162.8, 152.3,
142.9, 129.1, 127.8, 122.7, 120.3, 112.4, 73.2, 53.2, 52.2, 49.0,
38.8. FABMS: 395, 363, 208, 186, 153, 139, 101, 67, 59. 3e: Vis-
cous liquid, 1H NMR (CDCl3) : 3.10 (d, 1 H, J = 16.7 Hz), 3.45 (d,
1 H, J = 16.7 Hz), 3.65 (d, 2 H, J = 2.2 Hz), 3.80 (s, 3 H), 3.85 (s, 3
H), 4.70 (br s, NH), 7.10 (t, 1 H, J = 7.3 Hz), 7.30 (d, 1 H, J = 7.3
Hz). 13C NMR (CDCl3 proton decoupled) : 172.4, 161.6, 152.0,
142.7, 128.9, 127.5, 122.5, 120.1, 112.1, 73.0, 53.0, 51.3, 48.8, 38.6
FABMS: 338 (M+), 326, 154, 140, 133, 121, 109, 95, 81, 69. 3f:
Viscous liquid 1H NMR (CDCl3) : 2.25 (s, 3 H), 3.10 (d, 1 H, J =
16.8 Hz), 3.40 (d, 1 H, J = 16.8 Hz), 3.50 (d, 2 H, J = 2.3 Hz), 3.80
(s, 3 H), 3.85 (s, 3 H), 6.55 (d, 2 H, J = 7.5 Hz), 6.90 (br s, NH), 7.0
(d, 1 H, J = 7.5 Hz). 13C NMR (CDCl3 proton decoupled) : 173.5,
1
227, 167, 153, 140, 119, 109, 95, 81, 69. 3c: Viscous liquid, H
Synlett 2002, No. 3, 513–515 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Improved Synthesis of Pyrazolines
515
162.0, 151.8, 143.1, 132.6, 128.4, 127.8, 119.4, 111.0, 73.3, 53.5,
52.8, 49.7, 38.5, 20.8. 3j: Viscous liquid, 1H NMR (CDCl3) : 3.10
(d, 1 H, J = 16.7 Hz), 3.35 (d, 1 H, J = 16.7 Hz), 3.45 (d, 2 H, J =
2.2 Hz), 3.70 (s, 3 H), 3.75 (s, 3 H), 4.10 (br s, NH), 3.45 (d, 2 H, J
= 7.3 Hz), 6.55 (d, 1 H, J = 7.3 Hz), 6.60 (d, 1 H, J = 7.3 Hz), 7.0 (t,
1 H, J = 7.3 Hz). 13C NMR (CDCl3 proton decoupled) : 172.8,
161.7, 152.5, 142.9, 130.2, 129.0, 127.8, 120.5, 112.2, 73.1, 53.3,
52.5, 49.4, 38.7. FABMS: 261, 153, 127, 121, 66, 43. 3l: Viscous
liquid, 1H NMR (CDCl3) : 0.9 (t, 3 H, J = 6.8 Hz), 0.95 (t, 3 H, J =
6.8 Hz), 1.30–1.45 (m, 4 H), 1.60–1.75 (m, 4 H), 3.05 (d, 1 H, J =
16.5 Hz), 3.45 (d, 1 H, J = 16.5 Hz), 3.60 (d, 2 H, J = 2.3 Hz), 4.15
(q, 2 H, J = 6.8 Hz), 4.25 (q, 2 H, J = 6.8 Hz), 4.65 (br s, NH), 6.70
(t, 1 H, J = 7.4 Hz), 6.80 (t, 1 H, J = 7.4 Hz), 6.90 (br s, NH), 7.10
(t, 1 H, J = 7.4 Hz), 7.25 (d, 1 H, J = 7.4 Hz). 13C NMR (CDCl3 pro-
ton decoupled) : 13.1, 13.2, 18.6, 18.7, 29.9, 30.1, 38.3, 48.4, 64.7,
65.8, 72.9, 111.3, 117.8, 119.3, 127.3, 128.8, 142.2, 152.9, 161.5,
172.1.
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Acknowledgement
BVS and VG thank CSIR, New Delhi for the award of fellowships.
(9) Broeckx, W.; OverBergh, N.; Samyn, C.; Smets, G.; Labbe,
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Synlett 2002, No. 3, 513–515 ISSN 0936-5214 © Thieme Stuttgart · New York