having an amide or ester functionality installed in the
3-position.6 Numerous syntheses of such 3-carboxy-func-
tionalized pyrazoles have been reported,7 but the most
prevalent approach relies on the Knorr pyrazole synthesis.8
This classic condensation reaction between R,γ-diketoesters
and hydrazines is hampered by low regioselectivity.9,10
Furthermore, the preparation of R,γ-diketoesters from methyl
ketones limits the diversity of side chains that may be
introduced around the heterocyclic core.
A regioselective approach to heteroaromatic structures,
such as pyrazoles, although less established, is the analogous
addition of hydrazines to an acetylenic ketone.11 This strategy
also works well for acetylenic ketoesters resulting in ester-
functionalized pyrazoles.12 However, acetylenic ketoesters
are scarce synthetic intermediates commonly prepared from
the corresponding aldehydes in two steps.13 Even though
direct addition of activated carboxylic acids to alkynes has
been well-documented over the last few decades,14 to date,
the only useful addition to alkyl propynoates is via a
potentially explosive silver acetylide.15 Moreover, in our
experience, acid chlorides (PhCOCl and AcCl) add to the
analogous lithium acetylide in low yield (Supporting Infor-
mation). Thus, the need for methodology that gives direct
access to acetylenic ketoesters or related structures with equal
reactivity from activated acids is apparent. Hitherto, few
reports16 describe the reaction of Weinreb amides with alkyl
propynoates.
of aqueous HCl (1.0 M) after 96 h. The isolated yields of
3a and 4a after flash chromatography were 25 and 32%,
respectively.]
Tertiary enaminones, such as 3a, preferentially adopt
E-geometry,17 whereas primary and secondary enaminones,
such as 5 and 6, exist predominantly in the Z-form,
energetically favored by intramolecular hydrogen bonding.
In accordance with this, only one geometric isomer could
be detected in the crude reaction mixture, and the E-
stereochemistry of â-enaminoketoester 3a was confirmed by
an X-ray crystal structure determination (Scheme 1) after
Scheme 1. Reaction of Weinreb Amide 2a with Ethyl
Propynoate (1) and ORTEP Plot of the Molecular Structure of
3a
When performing this reaction with the lithium acetylide
derived from ethyl propynoate (1), N-methoxy-N-methylac-
etamide (2a) gave the corresponding â-enaminoketoester 3a
and not the expected ethyl 4-oxo-pent-2-ynoate. [LHMDS
(2.5 mmol, 1.0 M in THF) added to ethyl propynoate (2.25
mmol) in THF (2.5 mL) at -78 °C then addition of MeCON-
(OMe)Me (2.5 mmol, 5.0 M in THF). Quenching by addition
purification.
S.; Rogier, D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J.
N.; Gregory, S. A.; Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen,
A. W.; Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347-1365.
(6) (a) Francisco, M. E. Y.; Seltzman, H. H.; Gilliam, A. F.; Mitchell,
R. A.; Rider, S. L.; Pertwee, R. G.; Stevenson, L. A.; Thomas, B. F. J.
Med. Chem. 2002, 45, 2708-2719. (b) Finn, J.; Mattia, K.; Morytko, M.;
Ram, S.; Yang, Y.; Wu, X.; Mak, E.; Gallant, P.; Keith, D. Bioorg. Med.
Chem. Lett. 2003, 13, 2231-2234. (c) van Herk, T.; Brussee, J.; van den
Nieuwendijk, A. M. C. H.; van der Klein, P. A. M.; Ijzerman, A. P.; Stannek,
C.; Burmeister, A.; Lorenzen, A. J. Med. Chem. 2003, 46, 3945-3951. (d)
Katoch-Rouse, R.; Pavlova, O. A.; Caulder, T.; Hoffman, A. F.; Mukhin,
A. G.; Horti, A. G. J. Med. Chem. 2003, 46, 642-645.
The reaction rate was very dependent on the polarity of
the solvent. Thus, in toluene, the observed reaction was much
slower than that in THF, and no reaction was observed in
hexane. The reaction time required for full conversion was
shortened considerably from the initial 96 to 1.5 h by raising
the temperature of the reaction mixture from -78 to -40
°C and by employing the sodium acetylide instead of lithium
acetylide. The observed reactivity pattern for the sodium
acetylide of ethyl propiolate is contradictory to Herrmann
et al.18 and Midland et al.19 who reported that lithium salts
of alkyl propionates add to ketones in higher yield than their
sodium counterparts, due to the higher basicity of the latter.
The basicity (HSAB) had less significance in the reaction
with a Weinreb amide.
(7) (a) Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org. Chem. 1990, 55,
4144-4153. (b) Washizuka, K.-I.; Nagai, K.; Minakata, S.; Ryu, I.;
Komatsu, M. Tetrahedron Lett. 1999, 40, 8849-8853.
(8) Knorr, L.; Blank, A. Ber. 1885, 18, 311-317.
(9) Schmidt, A.; Habeck, T.; Kindermann, M. K.; Nieger, M. J. Org.
Chem. 2003, 68, 5977-5982.
(10) Martins, M. A. P.; Freitag, R. A.; de Rosa, A.; Flores, A. F. C.;
Zanatta, N.; Bonacorso, H. G. J. Heterocycl. Chem. 1999, 36, 217-220.
(11) (a) Cabarrocas, G.; Ventura, M.; Maestro, M.; Mah´ıa, J.; Villalgordo,
J. M. Tetrahedron: Asymmetry 2000, 11, 2483-2493. (b) Chang, K.-T.;
Choi, Y. H.; Kim, S.-H.; Yoon, Y.-J.; Lee, W. S. J. Chem. Soc., Perkin
Trans. 1 2002, 207-210. (c) Adlington, R. M.; Baldwin, J. E.; Catterick,
D.; Pritchard, G. J.; Tang, L. T. J. Chem. Soc., Perkin Trans. 1 2000, 303-
305.
To test the generality of this reaction and explore the
potential of the technology in array and combinatorial
(17) (a) Ostercamp, D. L. J. Org. Chem. 1970, 35, 1632-1641. (b)
Karpov, A. S.; Mu¨ller, T. J. J. Synthesis 2003, 18, 2815-2826. (c) Kashima,
C.; Aoyama, H.; Yamamoto, Y.; Nishio, T. J. Chem. Soc., Perkin Trans. 2
1975, 665-670.
(18) Herrmann, J. L.; Berger, M. H.; Schlessinger, R. H. J. Am. Chem.
Soc. 1979, 101, 1544-1549.
(19) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980,
45, 28-29.
(12) Adamo, M. F. A.; Adlington, R. M.; Baldwin, J. E.; Pritchard, G.
J.; Rathmell, R. E. Tetrahedron 2003, 59, 2197-2205.
(13) Obrecht, D.; Obrecht, C.; Grieder, A.; Villalgordo, J. M. HelV. Chim.
Acta 1997, 80, 65-72.
(14) Kel’in, A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67, 95-98.
(15) Naka, T.; Koide, K. Tetrahedron Lett. 2003, 44, 443-446.
(16) Trost, B. M.; Crawley, M. L. Chem.sEur. J. 2004, 10, 2237-2252.
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