DABCO catalyzed facile synthesis of highly functionalized pyrazolines from Baylis-Hillman acetates and ethyl diazoacetate

Article abstract of DOI:10.1016/j.tetlet.2010.10.006

A convenient synthesis of pyrazolines is reported via DABCO mediated reaction of ethyl diazoacetate (EDA) with Baylis-Hillman acetates. The products were obtained in good to excellent yields (70-95%).

Full text of DOI:10.1016/j.tetlet.2010.10.006

Tetrahedron Letters 51 (2010) 6507–6510
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DABCO catalyzed facile synthesis of highly functionalized pyrazolines from
Baylis–Hillman acetates and ethyl diazoacetate
⇑
Palakodety Radha Krishna , Y. Lakshmi Prapurna
D-211, Discovery Laboratory, Organic Chemistry Division-III, Indian Institute of Chemical Technology, Hyderabad 500607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of pyrazolines is reported via DABCO mediated reaction of ethyl diazoacetate
(EDA) with Baylis–Hillman acetates. The products were obtained in good to excellent yields (70–95%).
Ó 2010 Elsevier Ltd. All rights reserved.
Received 17 August 2010
Revised 28 September 2010
Accepted 1 October 2010
Available online 8 October 2010
Keywords:
Baylis–Hillman acetates
Ethyl diazoacetate (EDA)
DABCO
Reattack of acetate ion (acetate
rearrangement)
Pyrazolines1 show a wide range of biological activity and play
an important role in the pharmaceutical and agrochemical indus-
tries. The pyrazolines have been reported to show antidepressant,
anticancer, and antibacterial activity.2 Owing to the high impor-
tance of pyrazolines a number of synthetic approaches have been
developed.3 The diazo compounds have been extensively em-
ployed as a carbene4 source, undergo 1,3-dipolar cycloaddition5
to form five-membered heterocyclic rings, as reagents for carbonyl
homologation,6 and acid esterification.7
rearrangement of –OAc group. Unlike most of the cycloadditions
(i.e., concerted) the reaction was thought to proceed through reac-
tive intermediates to afford the products. The products were sepa-
rated into individual components and their structures identified as
regioisomeric pyrazolines 1a and 1b, respectively, from the spec-
tral data. Accordingly 1H NMR of 1a shows the benzylic CH proton
at d 5.83 ppm as a singlet integrating for one proton, NH proton as
a singlet at d 4.02 ppm (D2O exchangeable), CH2 protons as AB-
doublets at d 3.68 and at d 3.13 ppm (J = 19.49 Hz), while 1b shows
a doublet at d 6.18 ppm (J = 9.35 Hz), a doublet at d 5.34 ppm
(J = 9.35 Hz) and benzylic CH2 protons as AB-doublets at d 3.41
and at d 3.13 ppm (J = 19.49 Hz).
Over the past few years, we have investigated the Baylis–Hill-
man reaction8 and showcased the versatile utility of adducts.9
Continuing our interest, we conducted
a
1,4-diazabicy-
clo[2.2.2]octane (DABCO) catalyzed reaction between ethyl diazo-
acetate (EDA) and Baylis–Hillman acetate derived from 4-
nitrobenzaldehyde (1, Scheme 1) in CH2Cl2.
To our delight the reaction proceeded smoothly in 1 h to afford
two chromatographically separable products in 1:9 ratio. The prod-
ucts can be rationalized through the DABCO catalyzed cycloaddi-
tion of EDA to the olefin of the BH-adduct with a simultaneous
Next, reaction optimization studies were performed between 1
and EDA using different solvents and bases (Table 1). After screen-
ing, DABCO was selected as the base and CH2Cl2 as the solvent for
all further reactions (entry 1, Table 1). The optimum catalyst load-
ing was found to be 20 mol % of DABCO. The ratio of major and
minor products remained the same in all the cases. There was no
temperature effect on the product distribution or on the rate of
OAc
O
AcO
EtO2C
AcO
NO2
NO2
CO2Et
EtO2C
O
(20 mol%)
DABCO
CH2Cl2, rt
NH
N
1
O2N
N2
1a
EtO2C
1b
EtO2C
1:9
N
N
Scheme 1. Reaction of BH acetate derived from 4-nitrobenzaldehyde and EDA under optimal conditions.
⇑
Corresponding author. Tel.: +91 40 27160123; fax: +91 40 27160387.
E-mail address: prkgenius@iict.res.in (P. Radha Krishna).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.006

6508
P. Radha Krishna, Y. L. Prapurna / Tetrahedron Letters 51 (2010) 6507–6510
Table 1
H
OAc O
N
Optimization of reaction conditions
(20 mol%)
DABCO
N
CO2Et
N2
Solvent Time (h) Yield (%)a
O
Entry Base
EtO2C
CH2Cl2, rt
CO2Et
5a
5
1
2
DABCO
CH2Cl2
CH2Cl2
1
3
95
56
1,8-Diazabicyclo[5,4,0] undec-7-
Scheme 2. Reaction of BH acetates derived from acetaldehyde and EDA under
ene
optimal conditions.
3
4
5
6
7
8
Imidazole
N,N-Diisopropylethyl amine
DABCO
DABCO
DABCO
DABCO
CH2Cl2
CH2Cl2
THF
MeOH
CH3CN
Neat
2.5
2
3
3
2
67
70
75
50
56
48b
Table 3
Reaction of aliphatic BH acetates with EDA under optimal conditions
1
Entry BH acetate
Time Products
(h)
Yield
(%)
a
The ratio of major and minor products is almost 1:9 ratio in all cases.
Product was isolated along with mixture of undesired products.
b
OAc
O
H
N
N
1
0.5
0.6
0.8
0.5
75
70
71
76
the reaction. A blank reaction without a catalyst did not give the
desired products.
O
EtO2C
CO2Et
H
5
5a
To extend the scope of this methodology, various Baylis–Hillman
acetates (2–4) derived from benzaldehyde, 4-cyanobenzaldehyde,
and 4-fluorobenzaldehyde under the standardized conditions affor-
ded thecorrespondingproducts (1a–4a)in minorquantities(8–10%)
and theirisomericcounterparts(1b–4b) in excellentyields (Table 2).
But interestingly, when aliphatic Baylis–Hillman acetates were
the substrates different products were obtained (Scheme 2). The
first example chosen was the Baylis–Hillman acetate (5) derived
from acetaldehyde under standard reaction conditions.
OAc
O
N
N
2
3
4
O
EtO2C
CO2Et
6
6a
OAc
H
O
N
N
3
O
O
EtO2C
4
CO2Et
7a
7
OAc
H
N
The product 5a was obtained in good yield (75%) within 20 min
as the only product and it was characterized by its spectral data.
For instance, 1H NMR shows olefinic protons as a double doublet
O
N
EtO2C
CO2Et
8
8a
at
d 6.01 ppm (J = 10.57, 17.37 Hz), a multiplet at d 5.40–
5.23 ppm, CH2 protons appeared as AB-doublets at d 3.53 and at
d 2.94 ppm (J = 17.37 Hz). The reason for this unusual result was
explained at a later stage. The relative stereochemistry of the sub-
stituents (of the major and minor products) and hence the diaste-
reomeric ratio could not be ascertained from the NMR data.
Next, the versatility of this reaction was studied with various
aliphatic Baylis–Hillman acetates derived from butyraldehyde,
hexanaldehyde, and propionaldehyde as shown in Table 3.
The plausible mechanism is as shown in Scheme 3 (part i). At
first the EDA activated by DABCO (triazene intermediate)10 attacks
BH acetate via the Michael addition pathway resulting in interme-
diate A which can isomerise to B.11 Then the reattack of acetate ion
on A and B promotes the cyclization to afford pyrazolines 1a and
1b in 1:9 ratio, respectively. The major products arising from inter-
mediate B are sterically more favored. The formation of 5a (and the
related products as in Table 3) can be explained invoking a similar
mechanism (Scheme 3, part ii). However, the basic difference is
that due to the presence of a
c-proton and its participation in
the trapping of the ‘acetoxy ion’ results in the cyclization followed
by 1,3-H shift to afford a 5-vinyl pyrazoline unlike the earlier sub-
strates. Expectedly, we did not obtain a 5-alkenyl pyrazoline prod-
uct when the acetate of formaldehyde BH-adduct was exposed to
the same reaction conditions thus proving the participation of
the c-proton.
Table 2
Reaction of various aromatic BH acetates with EDA under optimal conditions
Entry
BH acetate
Time (h)
Products
Yield (%)
10:85
OAc
O
AcO
EtO2C
NO2
AcO
NO2
EtO2C
1
O
1
NH
NH
NH
1b
2b
3b
4b
N
N
N
N
1a
2a
3a
EtO2C
1
EtO2C
O2N
N
N
N
N
N
OAc
O
AcO
EtO2C
AcO
EtO2C
2
3
4
2
9:80
8:86
9:86
O
EtO2C
EtO2C
2
N
OAc
O
AcO
EtO2C
CN
CN
EtO2C
AcO
1.2
1.5
O
3
EtO2C
NC
EtO2C
N
OAc
O
AcO
EtO2C
AcO
F
F
EtO2C
O
NH 4a
4
EtO2C
EtO2C
F
N

P. Radha Krishna, Y. L. Prapurna / Tetrahedron Letters 51 (2010) 6507–6510
6509
EtO2C
EtO2C
EtO2C
DABCO
N
N N
N
N
N
N
H
H
H
OAc
O
Part (i) Aromatic BH acetates
O
O2N
N
N N
EtO2C
CO2Et
N
CO2Et
N
N
N
N
N
O2N
O2N
B
A
CO2Et
CO2Et
Attack of acetate ion
N
OAc
CO2Et
N
CO2Et
N
N
N
N
O2N
O2N
CO2Et
OAc
CO2Et
AcO
EtO2C
AcO
EtO2C
EtO2C
AcO
NO2
NO2
NO2
1,3-Hshift
N
1b
NH
1a
N
EtO2C
EtO2C
Part (ii) Aliphatic BH acetates
OAc
EtO2C
N
N
N
H
N
O
N
CO2Et
N
N
1,3-Hshift
N
N
OAc
EtO2C
O
EtO2C
N
CO2Et
H
CO2Et
5a
CO2Et
N
N
N
EtO2C
Scheme 3. Plausible mechanism.
5. Mass, G. In Padwa, A., Pearson, W. H., Eds.; Heterocyclic Compounds: 1,3-
Dipolar Cycloaddition; John Wiley and Sons: New York, 2002; Vol. 59, pp 541–
621.
6. (a) Gutsche, C. D. Org. React. 1954, 8, 364–429; (b) Maruoka, K.; Concepcion, A.
B.; Yamamoto, H. J. Org. Chem. 1994, 59, 4725–4726.
In conclusion, we have demonstrated a new and efficient meth-
odology for the synthesis of pyrazolines.12,13 The reaction is simple,
convenient with lower reaction times, and the starting compounds
are easy to prepare, which makes it a useful and attractive process
for the preparation of pyrazolines. Overall, a facile synthesis of
densely functionalized pyrazolines has been reported.
7. Regitz, M.; Mass, G. Diazo Compounds Properties and Synthesis; Academic Press:
Orlando, 1986.
8. (a) Radha Krishna, P.; Sharma, G. V. M. Mini-Rev. Org. Chem. 2006, 3, 137–153;
(b) Radha Krishna, P.; Sachwani, R.; Reddy, P. S. Synlett 2008, 2897–2912.
9. (a) Radha Krishna, P.; Kannan, V.; Sharma, G. V. M. Synth. Commun. 2004, 34,
55–64; (b) Radha Krishna, P.; Narsingam, M.; Reddy, P. S.; Srinivasulu, G.;
Kunwar, A. C. Tetrahedron Lett. 2005, 46, 8885–8888; (c) Radha Krishna, P.; Raja
Sekhar, E.; Mongin, F. Tetrahedron Lett. 2008, 49, 6768–6772; (d) Radha Krishna,
P.; Prapurna, Y. L. Synlett 2009, 2613–2616.
Acknowledgement
One of the authors (Y.L.P.) thanks UGC, New Delhi for the finan-
cial support in the form of a fellowship.
10. Bräse, S. Acc. Chem. Res. 2004, 37, 805–816.
11. The formation of B from A is preferred due to allylic hydrogen shift which may
de induced by DABCO (shown below) that further results in stereochemically
favorable major products 1b–4b.
References and notes
N
1. Lévai, A. Chem. Heterocycl. Compd. 1997, 33, 647–659.
2. (a) Johnson, M.; Younglove, B.; Lee, L.; LeBlanc, R.; Holt, H., Jr.; Hills, P.; Mackay,
H.; Brown, T.; Mooberry, S. L.; Lee, M. Bioorg. Med. Chem. Lett. 2007, 17, 5897–
5901; (b) Oezdemir, Z.; Kandilci, H. B.; Guemuesel, B.; Calis, U.; Bilgin, A. A. Eur.
J. Med. Chem. 2007, 42, 373–379; (c) Nauduri, D.; Reddy, G. B. Chem. Pharm. Bull.
1998, 48, 1254–1260.
3. (a) Eleguero, J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Potts, K. T., Eds.; Pergamon: Oxford, 1984; Vol. 5, p 167; (b) Eleguero, J. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E.
F., Eds.; Pergamon Press: Oxford, 1996; Vol. 3, pp 1–75; (c) Kanemasa, S.;
Kobayashi, S. Bull. Chem. Soc. Jpn 1993, 66, 2685–2693; (d) Yamauchi, M.;
Yajima, M. Chem. Pharm. Bull. 2001, 49, 1638–1639; (e) Yadav, J. S.; Subba
Reddy, B. V.; Geetha, V. Synlett 2002, 513–515.
N
R
R
N
N
N
N
N
N
H
O2N
O2N
B
A
R
CO2Et
4. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; John Wiley & Sons: New York, 1998.
12. General experimental procedure: To a solution of EDA (1.0 mmol), and DABCO
(0.2 mmol) in CH2Cl2 (3.0 mL), Baylis–Hillman acetate (1.0 mmol) was added

6510
P. Radha Krishna, Y. L. Prapurna / Tetrahedron Letters 51 (2010) 6507–6510
and stirred for 0.5–2 h at rt. After completion of the reaction as indicated by
142.1, 145.6, 160.0, 170.9, 171.3. IR (KBr): 3339, 2896, 2932, 2229, 1750, 1710,
1520, 1335, 1261, 1171, 1010, 856 cmÀ1. ESI-MS: 410 [M+Na]+. Anal. Calcd for
TLC, water (5.0 mL) was added and the product was extracted with CH2Cl2
(2 Â 10 mL). The combined organic layers were washed with brine (10 mL),
dried (Na2SO4), and purified by column chromatography (silica gel, 60–120
mesh, EtOAc:n-hexane, 1:9–2:8) to afford the products.
C
19H21N3O6: C, 58.91, H, 5.46, N, 10.85. Found: 58.94, H, 5.43, N, 10.88.
Compound 3b: 1H NMR (400 MHz, CDCl3): d 7.63 (d, 2H, J = 8.05 Hz, Ar–H), 7.39
(d, 2H, J = 8.48 Hz, Ar–H), 6.16 (d, 1H, J = 9.33 Hz, CH), 5.24 (d, 1H, J = 9.33 Hz),
4.32 (q, 2H, J = 7.20 Hz, O–CH2), 4.26 (q, 2H, J = 7.20 Hz, O–CH2), 3.40 (d, 1H,
J = 19.50 Hz, H–CH2), 3.22 (d, 1H, J = 19.10 Hz, H–CH2), 2.46 (s, 3H, CH3), 1.39–
1.25 (m, 6H, 2 Â CH3). 13C NMR (100 MHz, CDCl3): d 13.7, 13.8, 22.5, 42.2, 62.1,
62.8, 74.5, 77.1, 112.1, 118.1, 128.3, 131.9, 143.2, 145.4, 160.0, 168.0, 173.9. IR
(KBr): 2983, 2928, 2229, 1742, 1678, 1255, 1094, 756 cmÀ1. ESI-MS: 410
[M+Na]+. Anal. Calcd for C19H21N3O6: C, 58.91, H, 5.46, N, 10.85. Found: 58.89,
H, 5.48, N, 10.88. Compound 5a: 1H NMR (300 MHz, CDCl3): d 6.80 (s, 1H, NH),
6.01 (dd, 1H, J = 10.57, 17.37 Hz, olefinic), 5.40–5.23 (m, 2H, olefinic), 4.30–4.19
(m, 4H, 2 Â O–CH2) 3.53 (d, 1H, J = 17.37 Hz, H–CH2), 2.94 (d, 1H, J = 17.37 Hz,
H–CH2), 1.37–1.20 (m, 6H, 2 Â CH3). 13C NMR (75 MHz, CDCl3): d 13.9, 14.1,
41.0, 61.2, 62.3, 74.4, 116.9, 135.6, 142.3, 161.9, 172.1. IR (KBr): 3435, 2981,
2934, 1713, 1654, 1255, 1086, 1047, 714 cmÀ1. ESI-MS: 263 [M+Na]+. Anal.
Calcd for C11H16N2O4: C, 54.99, H, 6.71, N, 11.66. Found: 54.96, H, 6.69, N,
11.64. Compound 6a: 1H NMR (300 MHz, CDCl3): d 6.71 (s, 1H, NH), 5.82–5.71
(m, 1H, olefinic), 5.63–5.53 (m, 1H, olefinic), 4.32–4.18 (m, 4H, O–CH2), 3.56 (d,
1H, J = 17.75 Hz, H–CH2), 2.87 (d, 1H, J = 17.75 Hz, H–CH2), 2.13–2.02 (m, 2H,
CH2), 1.40–1.23 (m, 6H, 2 Â CH3), 1.00 (t, 3H, J = 7.55 Hz). 13C NMR (75 MHz,
CDCl3): d13.0, 14.03, 14.2, 25.4, 41.2, 61.2, 62.2, 74.2, 126.8, 135.0, 142.2, 162.2,
172.6. IR (KBr): 3350, 2964, 2926, 1735, 1706, 1243, 1118, 1032, 751 cmÀ1. ESI-
MS: 269 [M+H]+. Anal. Calcd for C13H20N2O4: C, 58.19; H, 7.51; N, 10.44. Found:
C, 58.16; H, 7.55; N, 10.41.
13. Spectral data for selected compounds: Compound 1a: 1H NMR (400 MHz, CDCl3):
d 8.17 (d, 2H, J = 8.57 Hz, Ar–H), 7.47 (d, 2H, J = 8.57 Hz, Ar–H), 5.83 (s, 1H, CH),
4.41–4.19 (m, 4H, 2 Â O–CH2), 4.02 (s, 1H, NH), 3.68 (d, 1H, J = 19.49 Hz, H–
CH2), 3.13 (d, 1H, J = 19.49 Hz, H–CH2), 2.30 (s, 3H, CH3), 1.35–1.25 (m, 6H,
2 Â CH3). 13C NMR (75 MHz, CDCl3): d 13.9, 21.8, 38.5, 62.3, 63.0, 69.4, 72.9,
123.1, 127.8, 143.8, 145.7, 147.8, 160.5, 170.9, 171.4. IR (KBr): 3317, 2986,
1753, 1713, 1653, 1525, 1345, 1261, 1171, 1010, 857 cmÀ1
. ESI-MS: 408
[M+H]+. Anal. Calcd for C18H21N3O8: C, 53.07, H, 5.20, N, 10.31. Found: 53.09, H,
5.22, N, 10.33. Compound 1b: 1H NMR (400 MHz, CDCl3): d 8.21 (d, 2H,
J = 8.57 Hz, Ar–H), 7.46 (d, 2H, J = 8.57 Hz, Ar–H), 6.18 (d, 1H, J = 9.35 Hz, CH),
5.34 (d, 1H, J = 9.35 Hz, CH), 4.32 (q, 2H, J = 7.40 Hz, O–CH2), 4.22 (q, 2H,
J = 7.01 Hz, O–CH2), 3.41 (d, 1H, J = 19.49 Hz, H–CH2), 3.24 (d, 1H, J = 19.49 Hz,
H–CH2), 2.45 (s, 3H, CH3), 1.36 (t, 3H, J = 7.79 Hz, CH3), 1.31 (t, 3H, J = 7.79 Hz,
CH3). 13C NMR (75 MHz, CDCl3): d 13.9, 14.0, 22.7, 42.6, 61.5, 63.1, 74.8, 75.6,
123.5, 128.6, 129.7, 141.6, 145.2, 160.1, 168.11, 174.3. IR (KBr): 2984, 2931,
1744, 1671, 1524, 1349, 1257, 1093, 755 cmÀ1. ESI-MS: 408 [M+H]+. Anal.
Calcd for C18H21N3O8: C, 53.07, H, 5.20, N, 10.31. Found: 53.10, H, 5.23, N,
10.28. Compound 3a: 1H NMR (300 MHz, CDCl3): d 7.60 (d, 2H, J = 8.30 Hz, Ar–
H), 7.37 (d, 2H, J = 8.30 Hz, Ar–H), 5.76 (s, 1H, CH), 4.38–4.18 (m, 4H, 2 Â CH2),
3.98 (s, 1H, NH), 3.64 (d, 1H, J = 19.26 Hz, H–CH2), 3.09 (d, 1H, J = 19.26 Hz, H–
CH2), 2.28 (s, 3H, CH3), 1.37–1.19 (m, 6H, 2 Â CH3). 13C NMR (75 MHz, CDCl3): d
14.1, 21.4, 38.3, 62.4, 62.9, 69.7, 73.2, 112.5, 118.6, 127.6, 128.7, 132.0, 132.2,