Copper-promoted cycloaddition of diazocarbonyl compounds and acetylides

Article abstract of DOI:10.1002/anie.200700069

(Chemical Equation Presented) HOMO-logous: The copper-mediated cycloaddition of alkynes with diazo carbonyl compounds to give pyrazoles is reminiscent of the copper-catalyzed cycloaddition of alkynes and azides. The formation of the copper acetylide is proposed to narrow the energy gap between the highest occupied molecular orbital (HOMO) of the alkyne and the lowest unoccupied molecular orbital (LUMO) of the diazo compound.

Full text of DOI:10.1002/anie.200700069

Communications
DOI: 10.1002/anie.200700069
Dipolar Cycloaddition Reactions
Copper-Promoted Cycloaddition of Diazocarbonyl Compounds and
Acetylides**
Xiangbing Qi and Joseph M. Ready*
1
,3-Dipolar cycloaddition reactions provide convenient
The pyrazole substructure appears in small molecules
which possess a wide range of biological activities, and
accordingly represents a valuable target for organic syn-
access to carbocyclic and heterocyclic five-membered ring
[
1]
systems. In some cases, 1,3-dipoles react with dipolarophiles
without activation of either component. For example, the
ozonolysis of olefins and the addition of nitrile oxides to
alkynes often proceed without added promoters. With many
substrate combinations, however, no cycloadduct is formed
when the dipole and dipolarophile are simply mixed. To
accelerate these types of reactions, two complementary
strategies focus on modulating the reactivity of the dipolar-
ophile (Scheme 1). In the first, Lewis acids are included to
[
7]
thesis. A common tactic for the preparation of pyrazoles 1
[
8]
relies on the condensation of b-diketones with hydrazines.
[
2]
[9]
Alternatively, the cyclization reaction of diazoalkenes or
[
10]
unsaturated hydrazines
provides improved control of
regiochemistry relative to the dicarbonyl/hydrazine conden-
sation, although the precursors are more challenging to
prepare. A direct approach to pyrazoles involves the cyclo-
addition of diazo compounds with alkynes. In this regard,
electron-rich diazo compounds (such as diazomethane) react
[
11]
under mild conditions with electron-deficient alkynes. In
contrast, Lewis acids are required to promote the cyclo-
addition between electron-deficient alkynes and diazocar-
[
12]
bonyl compounds. However, simple alkyl or aryl acetylenes
generally fail to react with diazocarbonyl compounds under
thermal conditions or in the presence of Lewis acids. To
identify an alternative mode of activation, we evaluated metal
acetylides in cycloaddition reactions with diazocarbonyl
compounds.
When lithium phenylacetylide was treated successively
with various copper(I) sources and benzyl diazoacetate (2),
pyrazole 1a was formed along with benzyl alcohol (BnOH,
Table 1). In all cases, the conversion of the diazoester reached
completion, and, with one exception, more than 90% of the
mass balance was accounted for by 1a, BnOH, and recovered
alkyne. Fumarate and maleate side products were observed in
less than 5% yield, which allowed the use of equimolar
quantities of reagents. An alkali-metal acetylide was required,
and in the absence of copper, no pyrazole was formed.
Scheme 1. Activation of alkynes and alkenes by metals for 1,3-dipolar
cycloaddition reactions. LUMO=lowest unoccupied molecular orbital,
HOMO=highest occupied molecular orbital, M=metal.
[
3]
lower the energy of the LUMO of the dipolarophile. Under
such conditions the dipole reacts through its HOMO to
[
4]
generate the cycloaddition product. Alternatively, additives
that increase the electron density of the dipolarophile can
accelerate cycloaddition through
a
HOMO(dipolarophile)–
LUMO(dipole) interaction. This approach is less common than
Systematic variation of the copper source, base, and additive
[
5]
[13]
the methods based on Lewis acids, but is most notably
operative in the copper-catalyzed synthesis of triazoles from
led to the discovery that CuCN·6LiCl
minimized the
formation of BnOH and maximized the yield of the pyrazole
[
6]
[14]
alkynes and azides. Here we report a new example of
dipolar cycloaddition reactions with an inverse electron
demand: the synthesis of pyrazoles from the cycloaddition
of copper acetylides with diazocarbonyl compounds [Eq. (1)].
1a (entry 8, Table 1). The relationship between the com-
ponents of the reaction mixture and the product distribution
was found to be complex. For example, while the inclusion of
LiCl did not improve the reactions which involved CuI
(entry 1 versus 3, Table 1), small but reproducible enhance-
[
*] X. Qi, Prof. J. M. Ready
Department of Biochemistry
University of Texas Southwestern Medical Center at Dallas
Dallas, TX 75390-9038 (USA)
Fax: (+1)214-648-0320
ments in the 1a/BnOH ratio were observed when up to six
equivalents of LiCl were added to the reaction mixtures that
contained CuCN (entries 5–9, Table 1). Similarly, whereas
complexmixtures were produced from 1:1 molar ratios of CuI
and alkyne, optimal results were obtained when the lower-
order cuprate derived from CuCN·6LiCl was used (entry 1
versus 2, and 4 versus 5; Table 1).
The cycloaddition reaction displayed substantial general-
ity with respect to both the alkyne and diazocarbonyl
component, and in all cases the product was formed as a
single regioisomer (Scheme 2). Electron-poor and electron-
E-mail: joseph.ready@utsouthwestern.edu
Homepage: http://www.swmed.edu/readylab/
[
**] We acknowledge financial support from the NIGMS (GM074822)
and UT Southwestern (J.M.R is a Southwestern Medical Foundation
Scholar in Biomedical Research).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
3
242
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 3242 –3244

Angewandte
Chemie
Table 1: Influence of copper source and LiCl on the cycloaddition
[
a]
reaction of lithium phenylacetylide with benzyl diazoacetate.
I
I
[b]
Entry
Cu
Equiv Cu
Ratio 1a/BnOH
1
2
CuI
CuI
0.5
1.0
1.5:1
–
[
c]
3
4
5
6
7
8
9
CuI·2LiCl
0.5
0.9:1
CuCN
CuCN
0.5
1.0
1.0
1.0
1.0
1.0
2.0:1
4.0:1
5.4:1
5.9:1
6.0:1
5.4:1
CuCN·2LiCl
CuCN·4LiCl
CuCN·6LiCl
CuCN·8LiCl
[
a] Complete conversion of diazoester was observed in all cases. Mass
1
balances were >90% as determined by H NMR spectroscopy relative to
an internal standard (except entry 2). [b] Determined by H NMR
1
spectroscopy of the crude reaction mixture. [c] Complex mixture.
rich aryl acetylenes performed well in the cycloaddition.
Alkyl-substituted terminal alkynes reacted cleanly, and
halides, tertiary amino groups, esters, and nitriles were
tolerated. The reaction was not limited to benzyl diazoacetate
as the ethyl and tert-butyl diazoesters and Weinreb amides
performed similarly in the cycloaddition. In many cases, the
pyrazoles could be isolated in greater than 90% purity by
trituration with hexanes; in all cases, analytically pure product
could be isolated after column chromatography on silica gel.
Comparisons between the present cycloaddition reaction
Scheme 2. Copper-promoted reaction of lithium acetylides with diazo carbonyl
compounds. chex=cyclohexyl, p-tol=para-tolyl.
and two known reactions are striking. First, Suµrez and Fu
I
described
a
Cu -catalyzed alkynylation of diazoesters
merize under the reaction conditions (Scheme 3). This
proposal accounts for several important observations: First,
the fact that the reaction rate is similar in THF, ether, and
[
15]
[
Eq. (2)]
in which no pyrazole was formed under the
neutral conditions. Likewise, the reaction of ethyl dizaoace-
tate with PhCCLi/CuCN·6LiCl gave no observable alkynyl
ester. The critical difference between the two systems is likely
the protonation state of the alkyne; alkynyl anions were used
in the cycloaddition reaction whereas neutral alkynes were
involved in the reaction reported by Suµrez and Fu. The
amount of copper used in the reaction does not appear to
have been significant, as even catalytic amounts of CuI was
found to promote the cycloaddition of lithium phenylacety-
lene and benzyl diazoacetate.
Scheme 3. Proposed cycloaddition reaction of copper acetylide with
diazo carbonyl compounds. L=ligand.
toluene is consistent with a concerted cycloaddition process
but is not consistent with the stepwise formation of charged
intermediates. Second, the observed regioselectivity is con-
sistent with theoretical predictions for cycloadditions featur-
[
4]
ing HOMO(dipolarophile)–LUMO(dipole) interactions. Third, elec-
tron-withdrawing groups on the alkyne qualitatively slow the
reaction. These groups should lower the energy of the HOMO
of the alkyne and therefore increase the gap between the
HOMO and LUMO energy levels. Fourth, diazomethane
does not react with lithium acetylides under the reaction
conditions, which is presumably a reflection of its high-energy
LUMO relative to that of the diazoesters. Finally, deuterium-
labeling experiments support the proposed tautomerization,
The copper-mediated cycloaddition of alkynyl anions with
diazoesters is also reminiscent of the copper-catalyzed cyclo-
[
16]
addition of terminal alkynes with azides. Accordingly, we
suspect a similar reaction mechanism is operative in both
cases. Copper may serve as an electron-donating group and
raise the energy of the HOMO of the alkyne. A cycloaddition
that involves the LUMO of the diazocarbonyl compound
generates a (pyrazolyl)Cu intermediate 3 which can tauto-
Angew. Chem. Int. Ed. 2007, 46, 3242 –3244
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3243

Communications
in that the copper-mediated cycloaddition reaction with the a- Experimental Section
deuterated benzyl diazoacetate [D]-2 yielded [D]-1a with
substantial deuterium incorporation on the pyrazole ring
BuLi (1.0 mmol) was added to a solution of alkyne (1.0 mmol) in THF
(4 mL) at À788C. After 1 h this solution was transferred into a
solution of CuCN·6LiCl (1.0 mmol) in THF (6 mL). The reaction
mixture was warmed to À178C (dry ice/brine) and stirred for 1 h. A
solution of diazo compound (1.0 mmol) in THF (4 mL) was added.
[
Eq. (3)]. Additionally, recovered phenylacetylene was parti-
ally deuterated, which likely reflects deprotonation of the
[
17]
initial cycloadduct 3 by the alkynyl anion.
After stirring for 2–4 h at RT, aq NH Cl and diethyl ether were added.
4
The aqueous layer was extracted with diethyl ether and the combined
organic phases were concentrated and purified by flash chromatog-
raphy. The data for full characterization of the products can be found
in the Supporting Information.
Received: January 6, 2007
Published online: March 22, 2007
Keywords: acetylides · copper · cycloaddition ·
.
diazo compounds · heterocycles
The origin of the BnOH side product is not clear at
present, although several mechanisms for its formation can be
ruled out. The generation of BnOH requires use of a general
base and not acetylides or copper salts specifically: benzyl
[1] Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products (Eds: A. Padwa,
W. H. Pearson), Wiley, Hoboken, 2003.
[2] T. M. V. D. Pinho e Melo, Curr. Org. Chem. 2005, 9, 925 – 958.
[3] K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98, 863 – 909.
[4] a) R. Sustmann, Tetrahedron Lett. 1971, 12, 2717 – 2720; b) J.
Bastide, N. C. O. Henri-Rousseau, Tetrahedron Lett. 1972, 13,
diazoacetate reacted completely with butyllithium, [Li Cu(n-
2
C H ) CN], lithium phenylacetylide, or lithium diisopropyla-
4
9 2
mide (LDA) to yield BnOH as the major product under mild
conditions. These results, and the fact that the pyrazole is
stable under the reaction conditions, implicate benzyl diazo-
acetate as the source of BnOH. In principle, direct
4225 – 4228; c) K. N. Houk, Acc. Chem. Res. 1975, 8, 361 – 369.
[5] J. Barluenga, C. ValdØs, G. Beltrµn, M. Escribano, F. Aznar,
Angew. Chem. 2006, 118, 7047 – 7050; Angew. Chem. Int. Ed.
2006, 45, 6893 – 6896.
E elimination of alkoxide from benzyl diazoacetate could
2
[
6] a) F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodle-
account for the formation of BnOH. If so, a reduction in the
man, K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005, 127,
[
18]
kinetic acidity of 2a might increase the ratio of 1a/BnOH.
210 – 216; b) V. D. Bock, H. Hiemstra, J. H. van Maarseveen,
In practice, however, reactions with 2 or [D]-2 gave nearly
identical ratios of 1a/BnOH [compare entry 8, Table 1 and
Eq. (3)]. Additionally, since the recovered phenylacetylene
was only partially deuterated, the deprotonation could not
account for all of the BnOH formation. Direct addition to the
carbonyl group could release BnOH, yet such a pathway is not
supported by the results. In particular, phenylacetylene was
recovered after the reaction, and no addition products are
observed in the crude reaction mixtures. Furthermore, the
similar yields of pyrazoles obtained with small (ethyl) and
large (tert-butyl) diazoester groups does not support a
competing mechanism that involves addition to the carbonyl
group. Finally, simple ester hydrolysis appears unlikely.
Specifically, the reactions performed with varying substoi-
chiometric amounts of water yielded similar amounts of
BnOH, while excess water was found to inhibit the reaction.
Furthermore, the amount of BnOH produced was inversely
related to the amount of LiCl (a possible source of water) that
was included in the reaction mixture.
The copper-promoted cycloaddition reaction of acetylides
with diazocarbonyl compounds offers a direct and efficient
approach to the synthesis of pyrazoles. The method is
operationally simple and tolerates substantial variation in
the two reacting partners. Furthermore, as a rare example of
an inverse-electron-demand cycloaddition, it represents a
conceptually novel approach to this important class of
heterocycles. Ongoing studies seek clarification of the mech-
anisms responsible for pyrazole and side-product formation
with an aim to identify reaction parameters which favor the
former over the latter.
Eur. J. Org. Chem. 2006, 51 – 68.
[7] For examples of biologically active pyrazoles, see the Supporting
Information.
[
8] For lead references: S. T. Heller, S. R. Natarajan, Org. Lett. 2006,
, 2675 – 2678.
9] A. Padwa, Y. S. Kulkarni, Z. Zhang, J. Org. Chem. 1990, 55,
144 – 4153.
10] R. Martꢀn, M. R. Rivero, S. L. Buchwald, Angew. Chem. 2006,
18, 7237 – 7240; Angew. Chem. Int. Ed. 2006, 45, 7079 – 7082.
8
[
4
[
1
[11] a) D. R. Sauer, S. W. Schneller, J. Org. Chem. 1990, 55, 5535 –
5538; b) V. K. Aggarwal, J. de Vicente, R. B. Bonnert, J. Org.
Chem. 2003, 68, 5381 – 5383; c) G. Maas in Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products (Eds.: A. Padwa, W. H. Pearson), Wiley,
Hoboken, 2003, pp. 623 – 680.
12] a) N. Jiang, C.-J. Li, Chem. Commun. 2004, 394 – 395; b) for
intramolecular versions, see: A. S. Kende, M. Journet, Tetrahe-
dron Lett. 1995, 36, 3087; c) G. Maas, V. Gettwert, Tetrahedron
2000, 56, 4139 – 4147.
13] For reactions with CuCN·2LiCl, see: P. Knochel, M. C. P. Yeh,
S. C. Berk, J. Talbert, J. Org. Chem. 1988, 53, 2390 – 2392.
14] For selected optimization studies, see the Supporting Informa-
tion.
15] A. Suµrez, G. Fu, Angew. Chem. 2004, 116, 3664 – 3666; Angew.
Chem. Int. Ed. 2004, 43, 3580 – 3582.
[
[
[
[
[16] a) F. Himo, T. Lovell, R. Hilgraf, V. V. Rostovtsev, L. Noodle-
man, K. B. Sharpless, V. V. Fokin, J. Am. Chem. Soc. 2005, 127,
210 – 216; b) V. D. Bock, H. Hiemstra, J. H. van Maarseveen,
Eur. J. Org. Chem. 2006, 51 – 68.
[
17] When the reaction was quenched with DCl, over 90% of
deuterated recovered alkyne and 79% of deuterated [D]-1a
were afforded.
[18] H. J. Bestmann, F. M. Soliman, Angew. Chem. 1979, 91, 1012 –
1013; Angew. Chem. Int. Ed. Engl. 1979, 18, 947 – 948.
3
244
www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 3242 –3244