P. R. Krishna et al. / Tetrahedron Letters 49 (2008) 6768–6772
6771
CO2Et
N2CHCO2Et
a
64 and 53 %
with DABCO
and InCl3
Ph
N
Ph
Method A or B
neat, rt, 12 h
N
H
19
20
O
CO2Et
ref. 17
N2CHCO2Et
EtO
b
EtO2C
N
OEt
EtO2C
Method A
Method B
neat, rt, 2 h
N
H
21
23
O
22 (66%)
Scheme 2. Reaction of phenylacetylene and ethyl propiolate with ethyl diazoacetate under methods A and/or B conditions.
Interestingly, when the [3+2] cycloaddition was performed on
References and notes
simple alkynes such as phenylacetylene 19 and electron-poor
alkyne ethyl propiolate 21, both gave the corresponding pyrazoles
20 and 22 in moderate to good yields. The earlier reported method
did not give the desired products under the Lewis acid conditions
in aqueous medium.16 Herein, while 19 gave 20 under both the
reaction conditions (Methods A and B, Scheme 2, route a) in com-
parable yields, 21 gave the desired product 22 (Scheme 2, route b)
in the presence of Lewis acid (InCl3) alone, and underwent a facile
self coupling reaction to give the undesired diethyl-2E-en-4-yn-
1,6-dioate17 (23) under Method A conditions as the only product
(Scheme 2, route b). The 1H NMR spectrum of 20 and 22 revealed
the lone aromatic proton at d 7.08 ppm and at d 7.27 ppm, respec-
tively. Though, the regiochemical disposition of the substituents in
20 cannot be conclusively proved through its spectral data at this
point of time, we believe the cycloaddition reaction follows a path-
way similar to that followed by other substrates.
1. (a) Craig, P. N.. In Comprehensive Medicinal Chemistry; Drayton, C. J., Ed.;
Pergamon Press: New York, 1991; Vol. 8, (b) Southton, I. W.; Buckingham, J. In
Dictionary of Alkaloids; Saxton, J. E., Ed.; Chapman and Hall: London, 1989; (c)
O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446.
2. Synthetic applications of 1, 3-dipolar cycloaddition chemistry toward
heterocycles and natural products: Padwa, A., Pearson, W. H., Eds.; Wiley:
Hoboken, 2003.
3. (a) Radha Krishna, P.; Kannan, V.; Ilangovan, A.; Sharma, G. V. M. Tetrahedron:
Asymmetry 2001, 12, 829–837; (b) Radha Krishna, P.; Raja Sekhar, E.; Kannan, V.
Tetrahedron Lett. 2003, 44, 4973–4975; (c) Radha Krishna, P.; Kannan, V.;
Sharma, G. V. M. Synth. Commun. 2004, 34, 55–64; (d) Radha Krishna, P.;
Manjuvani, A.; Kannan, V.; Sharma, G. V. M. Tetrahedron Lett. 2004, 45, 1183–
1185; (e) Radha Krishna, P.; Raja Sekhar, E.; Kannan, V. Synthesis 2004, 857–
860; (f) Radha Krishna, P.; Kannan, V.; Narasimha Reddy, P. V. Adv. Synth. Catal.
2004, 346, 603–606.
4. (a) Radha Krishna, P.; Narsingam, M.; Kannan, V. Tetrahedron Lett. 2004, 45,
4773–4775; (b) Radha Krishna, P.; Narsingam, M.; Srinivas Reddy, P.;
Srinivasulu, G.; Kunwar, A. C. Tetrahedron Lett. 2005, 46, 8885–8888; (c)
Radha Krishna, P.; Narsingam, M. J. Comb. Chem. 2007, 9, 62–69.
5. Nair, V.; Menon, R. S.; Sreekanth, A. R.; Abhilash, N.; Biju, A. T. Acc. Chem. Res.
2006, 39, 520–530.
6. See synthesis and biological activity of pyrazoles: Qi, X.; Ready, J. M. Angew.
Chem., Int. Ed. 2007, 46, 3242–3244. and references cited therein.
7. See for information of pyrazolines: Lévai, A. Chemistry of Heterocyclic
Compounds 1997, 33, 647–659.
8. (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.
9. Kanemasa, S.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1993, 66, 2685–2693.
10. Yamauchi, M.; Yajima, M. Chem. Pharm. Bull. 2001, 49, 1638–1639.
11. Yadav, J. S.; Subba Reddy, B. V.; Geetha, V. Synlett 2002, 513–515.
12. Noels, A. F.; Braham, J. N.; Hubert, A. J.; Teyssie, Ph. Tetrahedron 1978, 34, 3495–
3497.
The formation of the products can be explained based on the
plausible mechanism as depicted in Figure 1. Thus, while the Lewis
acid-catalyzed cycloaddition followed the standard reaction path-
way,18 the attack of Lewis base (DABCO) promoted activation of
EDA presumably occurs to generate ‘triazene intermediate’19a
A
(Pathway A, Fig. 1), which later undergoes Michael addition on
electron-poor olefin (1) to result in adduct ‘B’ followed by its
ring-closure with simultaneous release of the Lewis base (DABCO)
giving ‘C’. Intermediate ‘C’ then undergoes a 1, 3-H shift forming a
more stable, desired product (5). In an effort to understand the role
of DABCO in the cycloaddition reaction, an experiment between
DABCO and EDA was conducted. Even though the proposed inter-
mediate A could not be detected from the NMR studies,19b we
believe that it maybe the most likely intermediate.
On the other hand, the alternative pathway ‘B’ explains the for-
mation of regioisomeric products (3, 4-disubstituted pyrazolines)
through the Michael addition of DABCO on the olefin as the first
step (Baylis–Hillman type mechanism), followed by the concurrent
steps. The Pathway B is discounted, since the products obtained are
different to those described in the present protocol.
13. Doyle, M. P.; Colsman, M. R.; Dorow, R. L. J. Heterocycl. Chem. 1983, 20, 943–
946.
14. (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron 1996, 52, 8001–8062; (b)
Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana, T. Chem. Rev. 2003, 103,
811–891.
15. The authors are thankful to the referee who suggested the cylcoaddition
experiments with either (E)- and (Z)-ethyl crotonate or fumarate, and to test
whether any dual activation mode existed when DABCO and InCl3 were used
together.
16. Jiang, N.; Li, C.-J. Chem. Commun. 2004, 394–395.
17. Ramachandran, P. V.; Rudd, M. T.; Reddy, M. V. R. Tetrahedron Lett. 2005, 46,
2547–2549.
18. Gothelf, K. V.; JØrgensen, K. A. Chem. Rev. 1998, 98, 863–910.
19. (a) Bräse, S. Acc. Chem. Res. 2004, 37, 805–816; (b) Upon referee’s suggestion,
attempts were made to detect the formation of condensation product A by
NMR studies. At this point of time, we do not have any evidence for the
triazene-like intermediate A.
In conclusion, a simple, general one-pot protocol for the synthe-
sis of heterocyclic 3, 5-disubstituted pyrazolines and pyrazoles20,21
was developed from different type of electron-poor olefins/alkynes
including Baylis–Hillman adducts and EDA under mild conditions
in good to excellent yields. Alkynes also provided the desired prod-
ucts. A variety of Lewis bases such as hexamethylenetetramine
(HMTA), NMM, and DBU and Lewis acids like BF3ꢀOEt2, FeCl3 apart
from DABCO and InCl3 were also screened during the standardiza-
tion of cycloaddition reaction.
20. General experimental procedure: Method A: Activated olefin, ethyl acrylate 1
(0.1 g, 1 mmol), ethyl diazoacetate (0.114 g, 1.0 mmol), and DABCO (0.011 g,
0.1 mmol) were stirred for 2 h at ambient temperature until completion of
reaction (tlc). The reaction mixture was purified by column chromatography
(Silica gel, 60–120 mesh, EtOAC/hexane, 2:8) to afford pure 5 in 97% yield.
Method B: A mixture of activated olefin, ethyl acrylate 1 (0.1 g, 1 mmol), ethyl
diazoacetate (0.114 g, 1.0 mmol), and InCl3 (0.022 g, 0.1 mmol) were stirred at
ambient temperature for 4 h. The mixture was purified by column
chromatography to afford 5 in 80% yield.
Acknowledgment
21. Spectral data for selected compounds: Compound 5: Yellow oil; 1H NMR
(200 MHz, CDCl3): d 6.72 (br s, 1H, NH), 4.40 (dd, 1H, J = 6.0, 12.8 Hz, H-5),
4.34–4.15 (m, 4H, 2 ꢃ –OCH2), 3.30 (ddd, 1H, J = 1.5, 5.8, 18.8 Hz, H-4), 3.17
(dd, 1H, J = 12.6, 18.8 Hz, H-40), 1.50-1.20 (m, 6H, 2 ꢃ CH3); 13C NMR (75 MHz,
One of the authors (E.R.S.) thanks the CSIR, New Delhi, India, for
financial support in the form of a fellowship.