A facile synthesis of pyrazoles with multi-point structural diversity by 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2010.09.012

We describe the synthesis of diverse pyrazoles by 1,3-dipolar cycloaddition of ethyl diazoacetate with various acetylenes in refluxing toluene. The product pyrazoles are useful starting points for preparing a diverse collection of trisubstituted pyrazole

Full text of DOI:10.1016/j.tetlet.2010.09.012

Tetrahedron Letters 51 (2010) 5915–5918
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A facile synthesis of pyrazoles with multi-point structural diversity by
1,3-dipolar cycloaddition
⇑
Kwai Ming J. Cheung, Jóhannes Reynisson, Edward McDonald
Cancer Research UK Cancer Therapeutics Unit, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2010
Revised 28 July 2010
Accepted 3 September 2010
Available online 15 September 2010
We describe the synthesis of diverse pyrazoles by 1,3-dipolar cycloaddition of ethyl diazoacetate with
various acetylenes in refluxing toluene. The product pyrazoles are useful starting points for preparing
a diverse collection of trisubstituted pyrazole carboxamides. For aryl and heteroaryl alkynes a single
product is obtained while alkyl alkynes afford a ca. 6:1 mixture of regioisomers. The observed regioselec-
tivity for the cycloaddition step and the ease of reaction are consistent with predictions derived from
computing the HOMO–LUMO energies of the reactants.
Keywords:
Pyrazole
Ó 2010 Published by Elsevier Ltd.
1,3-Dipolar cycloaddition
HOMO–LUMO
Substituted pyrazoles are an important class of heterocycles
known to have a range of biological activities. Beside their applica-
tions as potent pesticides1,2 and herbicides,3 they are also widely
used as anti-inflammatory,4–8 anti-bacterial,9 anti-diabetic10–12
and anti-cancer13–17 agents. One of the simple, yet important
methods for pyrazole synthesis is the 1,3-dipolar cycloaddition be-
tween a diazo compound and an alkyne (Scheme 1). It has been re-
ported that the reaction of ethyl diazoacetate with prop-2-yn-1-ol
gave a sole product, ethyl 3-(hydroxymethyl)-1H-pyrazole-5-car-
boxylate18 while with prop-2-ynyl acetate, a mixture of pyrazole
regioisomers, ethyl 3-(acetoxymethyl)-1H-pyrazole-5-carboxylate
(4) (3-isomer) and ethyl 4-(acetoxymethyl)-1H-pyrazole-5-car-
boxylate (5) (4-isomer) was obtained19 (Fig. 1). More recently,
there have been reports on the 1,3-dipolar cycloaddition of diazo-
carbonyl compounds with acetylides;20 diazoalkanes with unsatu-
rated trifluoromethyl ketones21 and fluorinated alkynes;22 as well
as a report that this type of 1,3-dipolar cycloaddition can be cata-
lyzed by InCl3 in water23 and by the zeolite NaY.24
allow additional substituents to be introduced via organometallic
couplings.27
Our synthetic exploration involved reacting ethyl diazoacetate
(2) with various alkynes in refluxing toluene (Table 1). In our
hands, the reaction between ethyl diazoacetate and prop-2-yn-1-
ol (Table 1, entry 7) gave the 3- and 4-isomers in a ratio of 6:1
as shown by the 1H NMR spectrum of the crude product. The struc-
tural assignments are based on the chemical shifts19 of d = 6.90 and
7.94 for H-4 and H-3, respectively, in structures 4 and 5. The
homologous alkyne but-3-yn-1-ol (entry 8) gave a similar yield
and distribution of regioisomers but the overall yield dropped as
R
O
toluene
-N
COOEt
N+
R
+
reflux
N
OEt
N
H
1a-n
2
3a-n
Trisubstituted pyrazoles were ‘hit compounds’25 from a high
throughput screen designed to detect inhibitors of heat shock pro-
tein 90 (HSP90) and potency was increased26 by introducing a car-
boxamide substituent at C-5 (e.g., 6, Fig. 2). For further lead
optimization we required versatile methods for the synthesis of
pyrazole carboxamides and we report herein, one of those routes
using 1,3-dipolar cycloaddition. This method gives access to pyra-
zoles with a variety of functional groups at C-3 while retaining a
carboxylate at C-5 that can be transformed into various carboxam-
ides at a later stage. The vacant C-4 position can be halogenated to
Scheme 1. Synthesis of pyrazoles by 1,3-dipolar cycloaddition.
OAc
4
3
AcO
5
COOEt
COOEt
N
N
2
1
N
H
N
H
4
5
⇑
Corresponding author. Tel.: +44 0208 722 4231.
E-mail address: ted.McDonald@icr.ac.uk (E. McDonald).
Figure 1. Pyrazole regioisomers formed from the 1,3-dipolar cycloaddition of ethyl
diazoacetate and prop-2-ynyl acetate.
0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2010.09.012

5916
Kwai Ming J. Cheung et al. / Tetrahedron Letters 51 (2010) 5915–5918
OMe
lem arose when N-propargyl phthalimide (entry 12) was used
and the reaction proceeded readily to give 3l in 60% yield. The low-
er LUMO energy of N-propargyl phthalimide may be a significant
factor. Alkynes with electron-withdrawing groups reacted more
readily than their alkyl counterparts, with higher yields and clea-
ner reactions. In the cases of ethyl propynoate (entry 10), t-butyl
propynoate (entry 11), and heteroaromatic alkynes (entries 4–6),
no 4-isomers were observed. Phenyl and substituted phenyl al-
kynes (entries 1–3) also gave the 3-substituted isomers in 50–
61% yields. The structure of 3a was confirmed by NMR spectral
comparison with a sample prepared by a literature route.20
Cl
HO
CONHEt
HO
N
N
H
The progression of 1,3-dipolar cycloadditions depends on the
energy gap between the HOMO of the dipole and the LUMO of
the dipolarophile. For smaller energy gaps lower activation ener-
gies are predicted with the expectation of easier reactions.28 Simi-
larly, the regioselectivity is expected to correspond to the most
effective overlapping of the relevant frontier molecular orbitals.
We therefore calculated the HOMO energy of the dipole (ethyl
diazoacetate) and the LUMO energies of the dipolarophiles
(alkynes), using the computer program suite CAChe 6.129 (Table 1).
6
Figure 2. A 3,4-disubstituted pyrazole carboxamide HSP90 inhibitor.
the size of the alkyl substituent increased (entry 9). No pyrazole
formation was observed when using propargylamine and t-Boc-
propargylamine (entries 13 and 14). In the former case, thermal
degradation of the propargylamine was suspected, while in the lat-
ter reaction only starting materials were recovered. Neither prob-
Table 1
Yields and frontier orbital energy gaps for the 1,3-dipolar cycloaddition of ethyl diazoacetate (2) with various alkynes
Entry
R
Yield
(%)
Ratio of 3-regioisomer to 4-
regioisomer
AlkyneLUMO
(eV)
Frontier orbital energy gap
(eV)
1
3a
3b
61
50
100:0
100:0
ꢀ0.08
ꢀ0.02
ꢀ9.67
ꢀ9.73
MeO
2
3
F
3c
56
100:0
ꢀ0.66
ꢀ9.09
F
4
5
3d
3e
54
80
100:0
100:0
ꢀ0.40
ꢀ0.43
ꢀ9.35
ꢀ9.32
N
N
N
6
3f
17
100:0
+0.11
ꢀ9.86
N
HO
7
8
9
3g
3h
3i
42
46
11
6:1
+1.73
+1.78
+1.78
ꢀ11.48
ꢀ11.53
ꢀ11.53
HO
HO
4.5:1
5.5:1

Kwai Ming J. Cheung et al. / Tetrahedron Letters 51 (2010) 5915–5918
5917
Table 1 (continued)
Entry
R
Yield
(%)
Ratio of 3-regioisomer to 4-
regioisomer
AlkyneLUMO
(eV)
Frontier orbital energy gap
(eV)
O
10
3j
68
65
100:0
100:0
+0.20
+0.30
ꢀ9.95
EtO
O
O
11
12
3k
ꢀ10.05
O
O
N
3l
60
100:0
+0.52
ꢀ10.27
H2N
13
14
3m
3n
0
0
N/A
N/A
+1.73
+0.86
ꢀ11.48
ꢀ10.61
O
O
N
H
Frontier orbital energy gap = 2aHOMO ꢀ alkyneLUMO
.
aThe HOMO energy of ethyl diazoacetate (2) was calculated to be ꢀ9.75 eV.
The geometries of the reactants were optimized by MM330 prior to
calculation of the wave functions for the HOMO and LUMO orbitals
and their energies using the PM331 semi-empirical method. Table 1
shows how the energy gaps between the HOMO of ethyl diazoace-
tate (2HOMO) and the LUMO of the alkynes (alkyneLUMO) are related
to the observed yields. Compounds having a smaller energy gap
tended to give better yields (entries 1–5, 10 and 11) with the
exception of entry 6. Additional calculations, not shown herein,
confirmed that the energy gaps between the HOMOs of the alkynes
(alkyneHOMO) and the LUMO of ethyl diazoacetate (2LUMO) are sig-
nificantly larger. Therefore the latter orbitals are not relevant for
predicting the course of the reactions.
F
2
1
F
1c
N
1d
3'
2'
N+
1'
-N
Also, the observed regioselectivity corresponds to the most
effective overlapping of the atomic contributions in the frontier
molecular orbitals of ethyl diazoacetate and the alkynes. The
atomic contributions for diazoacetate 2 and some selected al-
kynes (1c, 1d, 1g, and 1j) are shown in Figure 3. For acetylenes
with electron-withdrawing and aromatic groups (1c, 1d, and 1j),
the atomic contribution of C-1 is relatively larger than that of
C-2: hence, the more favorable atomic orbital overlapping would
be C-1 and C-2 of the acetylene to C-30 and N-10 of ethyl diazo-
acetate, respectively. Experimentally, for these cases only 3-iso-
mer was obtained. On the other hand, when the alkyne
substituents are alkyl groups, as in 1g, the atomic contributions
at C-1 and C-2 of the acetylene are similar. Therefore a mixture
of isomers would be expected and this is reflected in the exper-
imental results for 3g–i.
O
HO
O
2
1g
1j
O
O
Figure 3. Diagrams illustrating atomic contributions in the frontier orbitals of ethyl
diazoacetate 2 and various alkynes.
In conclusion, a facile synthesis of pyrazoles with multi-point
structural diversity by 1,3-dipolar cycloaddition was achieved. A
wide range of pyrazoles can be generated by simply refluxing ethyl
diazoacetate and various substituted alkynes in toluene. The meth-
od accommodates alkynes with aliphatic, aromatic and heteroaro-
matic groups. Computation of the HOMO and LUMO energies of the
dipoles and dipolarophiles, using the PM3 method, allows predic-
tion of the regioselectivity of this 1,3-dipolar cycloaddition.
Acknowledgments
This work was supported by Cancer Research UK [CUK] Grant
number CA309/2187. The authors wish to thank Dr. Amin Mirza
and Mr. Meirion Richards for their expert assistance in the collec-
tion of NMR and MS data. We also wish to acknowledge the use of
the EPSRC Chemical Database Service at Daresbury.32

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14. Kreusch, A.; Han, S.; Brinker, A.; Zhou, V.; Choi, H.; He, Y.; Lesley, S. A.; Caldwell,
Supplementary data
J.; Gu, X. Bioorg. Med. Chem. Lett. 2005, 15, 1475.
15. Baraldi, P. G.; Beria, I.; Cozzi, P.; Geroni, C.; Espinosa, A.; Gallo, M. A.; Entrena,
A.; Bingham, J. P.; Hartley, J. A.; Romagnoli, R. Bioorg. Med. Chem. 2004, 12,
3911.
16. Rostom, S. A. F.; Shalaby, M. A.; El-Demellawy, M. A. Eur. J. Med. Chem. 2003, 38,
959.
17. Abadi, A. H.; Eissa, A. A. H.; Hassan, G. S. Chem. Pharm. Bull. 2003, 51, 838.
18. Mugnaini, E.; Grunanger, P. Atti. Accad. Nazl. Lincei, Rend., Classe Sci. Fis., Mat.
Nat. 1953, 14, 95.
19. Akhrem, A. A.; Kvasyuk, E. I.; Mikhailopulo, I. A. Zh. Obshch. Khim. 1975, 45,
1401.
20. Qi, X.; Ready, J. M. Angew. Chem., Int. Ed. 2007, 46, 3242.
21. Nenajdenko, V. G.; Statsuk, A. V.; Balenkova, E. S. Chem. Heterocycl. Compd.
2003, 39, 598.
22. Zheng, J.; Wang, Z.; Shen, Y. J. Fluorine Chem. 1993, 61, 17.
23. Jiang, N.; Li, C.-J. Chem. Commun. 2004, 394.
24. Kobayashi, K.; Igura, Y.; Imachi, S.; Masui, Y.; Onaka, M. Chem. Lett. 2007, 36, 60.
25. Cheung, K.-M.; Matthews, T. P.; James, K.; Rowlands, M. G.; Boxall, K. J.; Sharp,
S. Y.; Maloney, A.; Roe, S. M.; Prodromou, C.; Pearl, L. H.; Aherne, G. W.;
McDonald, E.; Workman, P. Bioorg. Med. Chem. Lett. 2005, 15, 3338.
26. Dymock, B. W.; Barril, X.; Brough, P. A.; Cansfield, J. E.; Massey, A.; McDonald,
E.; Hubbard, R. E.; Surgenor, A.; Roughley, S. D.; Webb, P.; Workman, P.;
Wright, L.; Drysdale, M. J. J. Med. Chem. 2005, 48, 4212.
27. Li, J. J.; Gribble, G. W. In Palladium in Heterocyclic Chemistry; Baldwin, J. E.,
Williams, R. M., Eds., 1st ed.; Tetrahedron Organic Chemistry Series; Pergamon:
Oxford, UK, 2000; Vol. 20,.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.012.
References and notes
1. Sammelson, R. E.; Caboni, P.; Durkin, K. A.; Casida, J. E. Bioorg. Med. Chem. 2004,
12, 3345.
2. Shiga, Y.; Okada, I.; Ikeda, Y.; Takizawa, E.; Fukuchi, T. J. Pestic. Sci. 2003, 28,
313.
3. Vassilev, G. N.; Terebenina, A. V.; Dimcheva, Z. P.; Kostova, K. V.; Jordanov, N.;
Jordanov, B. I.; Kouzmanova, R. B.; Borissov, G. Doklady Bolgarskoi Akademii
Nauk 1981, 34, 591.
4. Li, J.; Lynch, M. P.; DeMello, K. L.; Sakya, S. M.; Cheng, H.; Rafka, R. J.; Bronk, B.
S.; Jaynes, B. H.; Kilroy, C.; Mann, D. W.; Haven, M. L.; Kolosko, N. L.; Petras, C.;
Seibel, S. B.; Lund, L. A. Bioorg. Med. Chem. 2005, 13, 1805.
5. Bekhit, A. A.; Abdel-Aziem, T. Bioorg. Med. Chem. 2004, 12, 1935.
6. Maggio, B.; Daidone, G.; Raffa, D.; Plescia, S.; Mantione, L.; Cutuli, V. M. C.;
Mangano, N. G.; Caruso, A. Eur. J. Med. Chem. 2001, 36, 737.
7. Farghaly, A. M.; Soliman, F. S. G.; El Semary, M. M. A.; Rostom, S. A. F. Pharmazie
2001, 56, 28.
8. Tsuji, K.; Nakamura, K.; Konishi, N.; Tojo, T.; Ochi, T.; Senoh, H.; Matsuo, M.
Chem. Pharm. Bull. 1997, 45, 987.
9. Jain, R.; Srivastava, M. K.; Gupta, S. J. Indian Chem. Soc. 1996, 73, 493.
10. Bebernitz, G. R.; Argentieri, G.; Battle, B.; Brennan, C.; Balkan, B.; Burkey, B. F.;
Eckhardt, M.; Gao, J.; Kapa, P.; Strohschein, R. J.; Schuster, H. F.; Wilson, M.; Xu,
D. D. J. Med. Chem. 2001, 44, 2601.
28. Fleming, I. Frontier Orbitals and Organic Chemical Reactions; John Wiley & Sons:
Chicester, 1976.
29. CAChe 6.1, Fijitsu Limited, 2000–2003.
30. Lii, J. H.; Allinger, N. L. J. Am. Chem. Soc. 1989, 111, 8576.
31. Stewart, J. J. P. J. Comput. Chem. 1989, 10, 221.
11. Soliman, R.; Feid-Allah, H. M.; El Sadany, S. K.; Mohamed, H. F. J. Pharm. Sci.
1981, 70, 606.
32. The United Kingdom Chemical Database Service Fletcher, D. A.; McMeeking, R.
F.; Parkin, D. J. Chem. Inf. Comput. Sci. 1996, 36, 746.
12. Soliman, R.; Darwish, S. A. S. J. Med. Chem. 1983, 26, 1659.
13. Naito, H.; Ohsuki, S.; Atsumi, R.; Minami, M.; Mochizuki, M.; Hirotani, K.;
Kumazawa, E.; Ejima, A. Chem. Pharm. Bull. 2005, 53, 153.