A novel one-pot method for the preparation of pyrazoles by 1,3-dipolar cycloadditions of diazo compounds generated in situ

Article abstract of DOI:10.1021/jo0268409

A convenient one-pot procedure for the preparation of pyrazoles by 1,3-dipolar cycloaddition of diazo compounds generated in situ has been developed. Diazo compounds derived from aldehydes were reacted with terminal alkynes to furnish regioselectively 3,5-disubstituted pyrazoles. Furthermore, the reaction of N-vinylimidazole and diazo compounds derived from aldehydes gave exclusively 3-substituted pyrazoles in a one-pot process.

Full text of DOI:10.1021/jo0268409

SCHEME 1. P r op osed Syn th esis of P yr a zoles
Usin g Dia zo Com p ou n d s Gen er a ted in Situ
A Novel On e-P ot Meth od for th e
P r ep a r a tion of P yr a zoles by 1,3-Dip ola r
Cycloa d d ition s of Dia zo Com p ou n d s
Gen er a ted in Situ
Varinder K. Aggarwal,*,† J avier de Vicente,† and
Roger V. Bonnert‡
School of Chemistry, Bristol University, Cantock’s Close,
Bristol BS8 1TS, U.K., and AstraZeneca R&D Charnwood,
Medicinal Chemistry, Bakewell Road, Loughborough, Leics
LE11 5RH, U.K.
carbonyl compounds,7 cyclopropanation of alkenes,8 and
homologation of aldehydes.9 We were therefore keen to
examine whether this new process could solve some of
the traditional problems inherent in the 1,3-dipolar
cycloaddition approach to pyrazoles. In this paper, we
report our success in achieving this goal and the develop-
ment of a new user-friendly one-pot procedure for the
preparation of pyrazoles from aldehydes in which not only
the diazo compound but also the tosylhydrazone is
generated in situ.
We proposed two different routes to pyrazoles using
diazo compounds generated in situ: first, direct 1,3-
dipolar cycloaddition of diazo compounds onto alkynes
(route A, Scheme 1), or second, employing an olefin
bearing a leaving group X, which would afford the
pyrazole after an elimination/aromatization of the cy-
cloadduct intermediate (route B, Scheme 1).10 The diazo
compounds involved in these [3 + 2] approaches to
pyrazoles would be generated in situ from tosylhydrazone
salts.
Preliminary experiments showed that diazo compounds
could also be generated in situ from aldehydes in a one-
pot process. Condensation of tosylhydrazine with ben-
zaldehyde followed by treatment with an aqueous solu-
tion of sodium hydroxide led to a solution of benzaldehyde
tosylhydrazone sodium salt, which upon warming to 50
°C gave a reddish solution of phenyldiazomethane. Prior
to warming the reaction mixture, phenylacetylene was
added and the desired 3,5-diphenylpyrazole was obtained
in good yield as a single regioisomer (entry 1, Table 1).
This new procedure for the preparation of a pyrazole from
v.aggarwal@bristol.ac.uk
Received December 11, 2002
Abstr a ct: A convenient one-pot procedure for the prepara-
tion of pyrazoles by 1,3-dipolar cycloaddition of diazo com-
pounds generated in situ has been developed. Diazo com-
pounds derived from aldehydes were reacted with terminal
alkynes to furnish regioselectively 3,5-disubstituted pyra-
zoles. Furthermore, the reaction of N-vinylimidazole and
diazo compounds derived from aldehydes gave exclusively
3-substituted pyrazoles in a one-pot process.
The synthesis of pyrazoles remains of great interest
due to the wide applications of such heterocycles in the
pharmaceutical and agrochemical industry.1,2 The most
important methods for preparing this class of hetero-
cycles are the reaction between hydrazines with â-di-
functional compounds3 and 1,3-dipolar cycloadditions of
diazo compounds onto triple bonds.4 The former process,
considered to be the best method for the preparation of
pyrazoles, involves the double condensation of 1,3-di-
ketones with hydrazine or its derivatives.5 This method
has a wide scope not only because of the readily avail-
ability of 1,3-diketones but also because one carbonyl of
the diketone starting material can be replaced by an
acetal, a hemiacetal, a chlorovinyl group, dihalides, etc.3
The cycloaddition approach to pyrazoles has been es-
sential in the mechanistic understanding of the 1,3-
dipolar cycloaddition reactions but to date is second in
importance for preparative purposes due the need to
prepare and handle diazo compounds which are known
to be toxic and potentially explosive. We recently reported
a new method for generating aryldiazomethanes from
stable tosylhydrazone derivatives. This procedure has
proven to be a highly effective and safe alternative to
handling aryldiazomethanes6 and has been employed in
the sulfur ylide-mediated synthesis of epoxides from
(6) Aryldiazomethanes have been prepared by vacuum pyrolysis of
the hydrazone salt. See: Creary, X. Org. Synth. 1986, 64, 207. We have
carried out the Creary preparation a large number of times over a
5-year period but on three occasions experienced minor explosions. We
therefore sought methods for generating the diazo compound in situ
to avoid the need to carry out the vacuum pyrolysis.
(7) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M.
J .; Porcelloni, M.; Studley, J . R. Angew. Chem., Int. Ed. 2001, 40, 1430-
1433.
(8) Aggarwal, V. K.; de Vicente, J .; Bonnert, R. V. Org. Lett. 2001,
3, 2785-2788.
(9) Aggarwal, V. K.; de Vicente, J .; Pelotier, B.; Holmes, I. P.;
Bonnert, R. V. Tetrahedron Lett. 2000, 52, 10327-10331.
(10) The formation of pyrazoles from pyrazolines by elimination
reactions has been previously described. For eliminations of H2O, see:
Singh, S. P.; Kumar, D.; J ones, B. G.; Threadgill, M. D. J . Fluorine
Chem. 1999, 94, 199-203. Flores, A. F. C.; Martins, H. A. P.; Rosa,
A.; Flores, D. C.; Zannatta, N.; Bonacorso, H. G. Synth. Commun. 2002,
32, 1585-1594. For eliminations of HBr, see: Chandrasekhar, S.;
Rajaiah, G.; Srihari, P. Tetrahedron Lett. 2001, 42, 6599-6601. J iang,
B.; Xu, J . Y. J . Fluorine Chem. 1994, 67, 83-86. For eliminations of
p-TolSOH, see: Midura, W. H.; Krysiah, J . A.; Mikolajczyk, M.
Tetrahedron 1999, 55, 14791-14802. For eliminations of HNO2, see:
Mancera, M.; Rodriguez, E.; Roffe, I.; Galbis, J . A. Carbohydr. Res.
1994, 253, 307-316.
† Bristol University.
‡ AstraZeneca R&D Charnwood.
(1) Elguero, J . In Comprenhensive Heterocyclic Chemistry; Katritzky,
A., Ed.; Pergamon Press: Oxford, 1984; Vol. 5, pp 277-282.
(2) Elguero, J . In Comprenhensive Heterocyclic Chemistry II; Shin-
kai, I., Ed.; Elseiver: Oxford, 1996; Vol. 3, pp 3-75.
(3) Kost, A. N.; Grandberg, I. I. Adv. Heterocycl. Chem. 1966, 6, 347-
429.
(4) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; J ohn Wiley &
Sons: New York, 1984; Vol. I.
(5) Wiley, R. H.; E., H. P. Org. Synth. 1951, 31, 43-44.
10.1021/jo0268409 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/24/2003
J . Org. Chem. 2003, 68, 5381-5383
5381

TABLE 1. Yield s a n d Regioselectivities of
3,5-Disu bstitu ted P yr a zoles F or m ed fr om Alk yn es a n d
Ald eh yd es
TABLE 2. Yield s of 3-Su bstitu ted P yr a zoles F or m ed
fr om Rea ction of N-Vin ylim id a zole a n d Ald eh yd es
entry
R
yielda (%)
1
2
3
4
5
6
7
8
Ph
56
47
62
79
71
33
32
32
yielda ratio of regioisomers
(%)
o-MeC6H4
p-MeOC6H4
p-CNC6H4
p-ClC6H4
2-furyl
entry
R1
R2
(3,5/3,4)b
1
2
3
4
5
6
7
8
Ph
p-CNC6H4
p-MeOC6H4 Ph
3-pyridyl
Ph
p-CNC6H4
Ph
Ph
61
67
51
33
36
19
54
24
99.8:0.2
99.8:0.2
99.8:0.2
97:3
2-thienyl
3-pyridyl
Ph
3-pyridyl
3-pyridyl
97:3
99.8:0.2
99.8:0.2
95:5
a
Isolated yields.
p-MeOC6H4 3-pyridyl
3-pyridyl 3-pyridyl
SCHEME 2. P r ep a r a tion of 3-P h en ylp yr a zolea
a
b
Isolated yields. Determined by GC-MS.
an aldehyde and an alkyne was tested with a selection
of four aromatic aldehydes as precursors of diazo com-
pounds and two alkynes as dipolarophiles, phenylacety-
lene (entries 1-4, Table 1) and 3-ethynylpyridine (entries
2-8, Table 1). The desired pyrazoles were obtained in
moderate to high yield with excellent regioselectivity in
favor of the 3,5-disubstituted pyrazoles. The yields of
these reactions can be improved by preforming the
corresponding tosylhydrazone sodium salt, e.g., the yield
obtained in entry 1 was increased up to 71% starting from
benzaldehyde tosylhydrazone salt. Clearly, the process
can be applied to the generation of a library of pyrazoles
as a large variety of the starting aldehydes and acety-
lenes are readily available. The high regioselectivity
observed in these 1,3-dipolar cycloadditions is in keeping
with previous literature reports involving cycloadditions
onto arylacetylenes.11 This can be explained by both the
steric interaction of the substituents of the reactants and
the atomic orbital coefficients of the HOMO (diazo
compound)-LUMO (alkyne) favored interaction expected
for this type of cycloaddition.4
The 1,3-dipolar cycloaddition of diazo compounds onto
acetylene would lead to 3-substituted pyrazoles.12 How-
ever, acetylene is a very inconvenient dipolarophile to use
due to the difficulties in handling this volatile alkyne,
whose boiling point at atmospheric pressure is -83 °C.
We therefore decided to explore the use of monosubsti-
tuted alkenes bearing a potential leaving group as an
acetylene equivalent in the newly developed one-pot 1,3-
dipolar cycloaddition of diazo compounds generated in
situ from aldehydes. The choice of leaving group (X) was
considered to be critical. It had to be a good enough
leaving group for elimination to occur rapidly, thus
avoiding extrusion of nitrogen with formation of the
a
Reagents and conditions: (a) BnEt3NCl (0.1 equiv), vinyl
acetate (20 equiv), 1,4-dioxane, 30 °C, 48 h; (b) BnEt3NCl (0.1
equiv), N-vinylimidazole (5 equiv), 1,4-dioxane, 30 °C, 48 h, 81%.
corresponding cyclopropane, but at the same time if H-X
was too acidic it would protonate the hydrazone salt and
inhibit formation of the diazo compound. Considering
these issues, two acetylenes equivalents were tested:
N-vinylimidazole and vinyl acetate. However, the reac-
tion of tosylhydrazone salt 1 with vinyl acetate gave a
complex mixture of products (2, 3, 4, and 5). In addition
to the hydrazone itself, the benzylated hydrazone 513 was
formed together with some of the desired pyrazole 2 and
the acyl pyrazole 3. Clearly, the elimination of acetic acid
caused significant side reaction and protonation of the
hydrazone salt itself. In contrast, the desired pyrazole 2
was obtained in good yield using N-vinylimidazole as the
substrate. The imidazole byproduct, being less acidic than
acetic acid, did not interfere in any side reaction, and it
was easily removed from the crude reaction by an
aqueous workup. Indeed, the process generated exclu-
sively water-soluble byproducts, sodium p-toluenesulfi-
nate, and imidazole, and after aqueous wash, the pyra-
zole was isolated in essentially pure form. The possible
cycloadduct intermediates of the initial dipolar cyclo-
addition were never detected by TLC or GC-MS, sug-
gesting that the elimination was occurring under the
reaction conditions.
The effectiveness of this procedure for the preparation
of 3-substituted pyrazoles is illustrated by the use of a
series of diazo precursors derived from aromatic and
heteroaromatic aldehydes (entries 2-8, Table 2). Al-
though yields can again be improved by starting from
the preformed hydrazone salt (route b, Scheme 2), the
operational simplicity and speed of the current protocol
may outweigh the issue concerning the moderate yields
obtained.
(11) Bastide, J .; Henri-Rousseau, O. Bull. Soc. Chim. Fr. 1973,
2294-2296. 1,3-Dipolar cycloadditions onto electron-rich acetylenes
form the 3,4-regioisomer and cycloaddition onto electronically neutral
acetylenes (alkyl substituted) give regioisomeric mixtures of pyrazoles.
See ref 4.
(12) 3-Substituted pyrazoles can also be prepared by cycloaddition
of diazomethane with monosubstituted acetylenes. See: Kirmse, H.
J ustus Liebigs Ann. Chem. 1958, 614, 1.
(13) The formation of side product 5 could be formed by reaction of
the tosylhydrazone salt 1 with phenyldiazomethane in the presence
of a protic source.
In conclusion, we have developed a simple one-pot
procedure for the preparation of 1H-pyrazoles by the
5382 J . Org. Chem., Vol. 68, No. 13, 2003

novel 1,3-dipolar cycloaddition reactions of diazo com-
pounds generated in situ from aldehydes. 1H-3-Substi-
tuted pyrazoles were easily prepared by 1,3-dipolar
cycloadditions of diazo compounds, generated from vari-
ous aldehydes, with N-vinylimidazole as an acetylene
equivalent. Diazo compounds, generated in situ from
aldehydes, reacted regioselectively with monosubstituted
alkynes, providing a convergent method for the prepara-
tion of 3,5-disubstituted pyrazoles.
further 20 min. The dipolarophile (7.5 mmol) was added,
and the mixture was stirred at 50 °C for 48 h. The
volatiles were evaporated under reduced pressure, and
the residue was dissolved in a 1:1 mixture of water-ethyl
acetate (70 mL). The organic layer was separated and
dried over MgSO4. After filtration and removal of the
solvent under reduced pressure, the crude material was
purified by flash chromatography.
Ack n ow led gm en t . We gratefully thank Astra-
Zeneca for support of a studentship (J .V.).
Exp er im en ta l Section
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Su b-
stitu ted P yr a zoles (Ta bles 1 a n d 2). The aldehyde (1.5
mmol) was added to a solution of p-toluenesulfonyl
hydrazide (279 mg, 1.5 mmol). After the mixture was
stirred for 3 h at rt, a solution 5 N NaOH (300 µL, 1.5
mmol) was added and the mixture was stirred for a
Su p p or tin g In for m a tion Ava ila ble: General methods
and representative procedures for the synthesis of pyrazoles,
as well as characterization data of the pyrazoles synthesized.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0268409
J . Org. Chem, Vol. 68, No. 13, 2003 5383