Novel 1,3-dipolar cycloaddition of diazocarbonyl compounds to alkynes catalyzed by InCl3 in water

Article abstract of DOI:10.1039/b311763d

The first intermolecular 1,3-dipolar cycloaddition of diazocarbonyl compounds with alkynes was developed by using an InCl₃ catalyzed cycloaddition in water. The reaction was found to proceed by a domino 1,3-dipolar cycloaddition-hydrogen (alkyl or aryl) migration.

Full text of DOI:10.1039/b311763d

Novel 1,3-dipolar cycloaddition of diazocarbonyl compounds to alkynes
catalyzed by InCl3 in water
Nan Jianga and Chao-Jun Li*ab
a Department of Chemistry, Tulane University, New Orleans, Louisiana 70118, USA.
E-mail: cjli@tulane.edu; Fax: 504-8655596; Tel: 504-8655573
b Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, Quebec H3A 2K6,
Canada. E-mail: cj.li@mcgill.ca; Fax: 514-3983797; Tel: 514-3988457
Received (in Corvallis, OR, USA) 23rd September 2003, Accepted 15th December 2003
First published as an Advance Article on the web 19th January 2004
The first intermolecular 1,3-dipolar cycloaddition of diazo-
carbonyl compounds with alkynes was developed by using an
InCl3 catalyzed cycloaddition in water. The reaction was found
to proceed by a domino 1,3-dipolar cycloaddition–hydrogen
(alkyl or aryl) migration.
that water as the solvent played a crucial role in this reaction. When
the reaction solvent was CH2Cl2 or benzene (the common solvents
for diazo chemistry) only a trace amount of the target product was
detected.
In order to understand the nature of this reaction, the catalyst was
then applied to various methyl a-diazoarylacetates 4 and methyl
propiolate (Scheme 2) as summarized in Table 1.13 All diazocarbo-
nyl compounds gave two pyrazole products in excellent combined
yields. No cyclopropane or O–H insertion product could be
detected in the crude reaction mixture. The possible mechanism for
the formation of the products 5 and 6 is tentatively illustrated by
Scheme 3: the formation of the minor product 6 proceeds by an
Pyrazoles are known not only as potent insecticides1 and herbi-
cides,2 but also as anti-tumor, anti-inflammatory, anti-microbial
and anti-psychotic agents.3 An important method for their synthesis
is the 1,3-dipolar cycloaddition of diazo compounds4 and other
1,3-dipoles5 to alkynes. Although the 1,3-dipolar cycloaddition of
electron-rich diazo compounds to alkynes is known,6 to the best of
our knowledge, intermolecular 1,3-dipolar cycloaddition of elec-
tron-deficient diazocarbonyl compounds with alkynes has not been
reported.7 This has been elegantly attributed to the increased
HOMO–LUMO energy gap between diazocarbonyl compounds
and alkynes.8 One possible solution to the problem is to lower the
LUMO of the alkyne dipolarophiles, e.g. by a Lewis acid. However,
this could result in the decomposition of the diazocarbonyl
compounds, leading to various well known competing side
reactions,9 such as dimerization, X–H insertion or cyclopropana-
tion. Essentially, these difficulties have prevented the development
of diazocarbonyl compounds as nucleophilic dipoles for alkynes.
To overcome this dilemma, a delicate balance between the catalytic
activity of the Lewis acid for pyrazole formation and the
“carbenoid” reactivity of diazocarbonyl compounds must be
achieved. As part of a continued interest in developing organic
synthesis in aqueous media, herein we wish to report the
intermolecular 1,3-dipolar cycloaddition reaction of a-diazocarbo-
nyl compounds with alkynes catalyzed by InCl3 in water to
synthesize pyrazoles.
The initial investigation started with the reaction of ethyl
diazoacetate and ethyl propiolate (Scheme 1). In the presence of
20% InCl3 in water under an air atmosphere at room temperature
for 24 h, pyrazole 3 was obtained in 87% yield after flash
chromatography. It should be noted that the catalyst InCl3, which
stayed in the aqueous phase after the work-up, could be reused for
two additional times without loss of catalytic activity (yields, 89%
and 90% for second and third run respectively). The formation of 3
can be explained by an initial 1,3-dipolar cycloaddition to form 3H-
pyrazole, which undergoes a spontaneous 1,3-hydrogen migration
leading to thermodynamically more stable pyrazole 3. It should be
noted that the formation of five-membered rings by a 6p-electro-
cyclization is well precedented and represents an important
principle in heterocyclic chemistry.10 Although in recent years,
indium reagents have evolved as mild and water-tolerant Lewis
acids imparting high regio-, chemo- and stereoselectivity in various
chemical transformations,11 indium has seldom been used as a
catalyst for diazo chemistry12 when compared to other transition
metals, such as copper, rhodium, palladium, and silver. It was found
initial 1,3-dipolar cycloaddition followed by
a subsequent
1,3(5)-carboxylate shift of the initially formed 3,5-dicarboxylate-
3-aryl-3H-pyrazole; the formation of the major product 5 could
proceed by three steps: an initial 1,3-dipolar cycloaddition, a
subsequent 1,5-aryl shift of initially formed 3,5-dicarboxylate-
3-aryl-3H-pyrazole to give the intermediate 4H-pyrazole, and a
1,3-hydrogen shift of the 4H-pyrazole intermediate. The aryl
migration product 5 predominates in all cases, and a small
electronic effect of the substituent on the aryl group was observed.
An aryl group with electro-donating substituents has a higher
Scheme 2
Table 1 1,3-Dipolar cycloaddition reaction of methyl a-diazoarylacetates
and methyl propiolate catalyzed by InCl3 in water
Yield of
5 (%)b
Yield of
6 (%)b,c
Entry
Diazo
5 : 6a
1
2
3
4
5
6
a, X = H
91 : 9
92 : 8
94 : 6
89 : 11
88 : 12
86 : 14
82
81
90
80
77
83
7
8
4
10
12
9
b, X = m-MeO
c, X = p-MeO
d, X = p-F
e, X = m-Br
f, X = m-CF3
a Determined by 1H NMR of the crude product mixture. b Isolated yield by
flash chromatography. c Position of NCO2Me in the minor product 6 is
arbitrarily assigned since we can not differentiate reliably between the two
tautomers.
Scheme 1
Scheme 3
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C h e m . C o m m u n . , 2 0 0 4 , 3 9 4 – 3 9 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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migratory aptitude, and this trend suggests that the aryl group is
migrating to an electron-deficient carbon.
In conclusion, an efficient InCl3-catalyzed 1,3-dipolar cycload-
dition of diazocarbonyl compounds and alkynes to synthesize
pyrazoles has been achieved in water.14 The process is simple and
can be used to generate a wide range of pyrazoles. The reaction is
applicable to various a-diazocarbonyl compounds and alkynes with
a carbonyl group at the neighboring position and the success of the
reaction has been rationalized by decreasing the HOMO–LUMO
gap with InCl3. The scope, mechanism, and synthetic applications
via this reaction are under investigation.
We are grateful to the NSF and the NSF–EPA joint program for
a sustainable environment for support of our research. CJL is a
Canada Research Chair (Tier I) in Green Chemistry at McGill
University.
The catalyst was then applied to various a-diazocarbonyl
compounds and alkynes as summarized in Table 2. All the alkynes
with a carbonyl group at the neighboring position reacted smoothly
with ethyl diazoacetate to give the target pyrazole products in good
yields (entries 1, 2, 3, 5); however, phenylacetylene failed to give
the desired product even in a trace amount, which suggests that
InCl3 actually activates the alkynes by coordinating its neighboring
carbonyl group and thus lowers the LUMO8 of the alkyne moiety
(instead of a-diazocarbonyl compounds that traditionally occurred
in diazo chemistry).
On the other hand, all the a-diazocarbonyl compounds can react
with alkynes bearing a carbonyl group at the neighboring position
to afford the pyrazoles in mild to excellent yields (entries 5–12).
Interestingly, both the b-hydroxy and b-amino a-diazocarbonyl
compounds reacting with methyl propiolate generated 1H-pyr-
azole-3,5-dicarboxylic acid 3-ethyl ester and 5-methyl ester (the
same product from ethyl diazoacetate reacting with methyl
propiolate) and benzaldehyde as by-product. This could be
explained by an initially formed 3,3-disubstituted-3H-pyrazole
from 1,3-dipolar cycloaddition undergoing a spontaneous retro-
aldol reaction to give thermodynamically more stable pyrazole and
benzaldehyde. However, a 1,3-dicarbonyl diazo compound failed
to give the target product even at 100 °C, possibly due to the even
larger HOMO–LUMO energy gap in this case (entry 13).
Notes and references
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4 A. Padwa, 1,3-Dipolar Cycloaddition Chemistry, John Wiley & Sons;
New York, 1984; Vol. I.
5 For examples, see: A. Ponti and G. Molteni, J. Org. Chem., 2001, 66,
5252–5255; K. I. Washizuka, K. Nagai, S. Minakata, I. Ryu and M.
Komatzu, Tetrahedron Lett., 2000, 41, 691–695.
Table 2 InCl3-promoted 1,3-dipolar cycloaddition of a-diazo compounds to
alkynes in water
6 K. Bowden and E. R. H. Jones, J. Chem. Soc., 1946, 953–954.
7 Two examples for silver-catalyzed intramolecular 1,3-dipolar cycload-
dition of acetylenic a-diazoketones(esters) have been reported, see: (a)
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1091–1160.
Entry
1
Diazo
Alkyne
Product
Yield (%)a
87
2
3
81
93
10 (a) E. C. Taylor and I. J. Turchi, Chem. Rev., 1979, 79, 181–231; (b) R.
Huisgen, Angew. Chem., Int. Ed. Engl., 1980, 19, 947.
11 T.-P. Loh, J. Pei and M. Lin, Chem. Commun., 1996, 2315; C. J. Li and
T. H. Chan, Tetrahedron, 1999, 55, 11149; C. J. Li and T. H. Chan,
Organic Reactions in Aqueous Media; John Wiley & Sons: New York,
1997.
4
5
6
7
8
—
79
43
71
47
12 (a) S. Sengupta and S. Mondal, Tetrahedron Lett., 1999, 40, 8685–8688;
(b) S. Sengupta and S. Mondal, Tetrahedron Lett., 2000, 41,
6245–6248.
1
13 The H NMR of 5a (in CDCl3) showed an active hydrogen (d 13.13),
which disappeared completely when one drop of D2O was added. The
two OMe showed one single peak (d 3.81) in the presence of D2O. The
IR of 5a showed only a single peak at 1721 cm21 between 1650 and
1900 cm21. Thus the two carboxylate groups at C-3 and C-5 in the
pyrazole are equivalent, and the phenyl group is connected to C-4 and a
hydrogen is connected to one of the two nitrogens in the pyrazole. The
structure of 6a was determined based on literature data, however the
position of N–CO2Me in the pyrazole is arbitrarily assigned since we
can not differentiate reliably between the two tautomers, see: A.
Alberola, L. Calvo, A. G. Ortega, M. L. Sadaba, S. G. Granda and E. G.
Rodriguez, Heterocycles, 1999, 51, 2675–2686; V. K. Aggarwal, J. De
Vicente and R. V. Bonnert, J. Org. Chem., 2003, 68, 5381–5383; A.
Dornow and K. Peterlein, Ber., 1949, 82, 257.
9
37
10
20 (74)b
11
12
88
54
14 General experimental procedure: To a solution of InCl3 (46 mg, 0.2
mmol) in 2 mL water was added diazo compound (1.1 mmol) and alkyne
(1.0 mmol) under an air atmosphere. The reaction mixture was capped
and stirred at ambient temperature for 24–72 h, and extracted with ether.
The organic phase was dried over MgSO4 and concentrated in vacuo.
The residue was purified by flash chromatography on silica gel (eluent:
methylene chloride and ether).
13
—
a Isolated yield after flash chromatography. b Yield based on the recovered
starting material.
C h e m . C o m m u n . , 2 0 0 4 , 3 9 4 – 3 9 5
395