A general strategy for five-membered heterocycle synthesis by cycloeliniination of alkynyl ketones, amides, and thioamides

Full text of DOI:10.1021/jo981542q

7132
J . Org. Chem. 1998, 63, 7132-7133
Sch em e 1
A Gen er a l Str a tegy for F ive-Mem ber ed
Heter ocycle Syn th esis by Cycloelim in a tion of
Alk yn yl Keton es, Am id es, a n d Th ioa m id es
Peter Wipf,* Leera T. Rahman, and Stacey R. Rector
Department of Chemistry, University of Pittsburgh,
Pittsburgh, Pennsylvania 15260
Received August 4, 1998
Furans are common substructures in numerous natural
products, such as the cembranolides lophotoxin,1 kallolides,2
and pukalide.3 These heterocycles are also found in numer-
ous commercial products, including pharmaceuticals, fra-
grances, and dyes. Accordingly, many strategies have been
developed for the preparation of furans.4 Marshall and co-
workers utilized 3-alkynyl allylic alcohols in SN2′ reactions
to provide 2,3-disubstituted furans.5 Another method for the
formation of 2,3-disubstituted furans from the same labora-
tory employed Ag(I)- or Rh(I)-catalyzed cyclizations of allenyl
ketones and aldehydes.6 Palladium catalysis has also been
used for the synthesis of furans. Coupling of terminal
acetylenes and γ-hydroxyalkynoates followed by Pd(II)-
catalyzed cyclization produced 2,4-disubstituted furans.7
Wakabayashi et al. have used Pd(II) to promote intramo-
lecular cyclizations of 3-alkynyl-1,2-diols to give either 2,3-
disubstituted or 2,3,4-trisubstituted furans from â,γ-acety-
lenic ketones.8 Numerous literature protocols for the
formation of furans employ 1,3-dicarbonyl compounds.
Paquette and co-workers used these starting materials to
prepare a 2,3,5-trisubstituted furan as an intermediate in
the total synthesis of gorgiacerone, a furanocembranolide.9
Larock and Cacchi studied the Pd(0)-mediated cyclizations
of 2-propargylic-1,3-dicarbonyl compounds,10 and Tsuji et al.
used Pd(0) catalysis for the formation of furans in the
intramolecular annelation reaction of â-keto esters and
either propargylic carbonates or oxiranes.11 Other strategies
based on dicarbonyl substrates use the Feist-Benary con-
densation of 1,2-dibromoacetate with acetoacetate to provide
2,3-disubstituted furans or the cyclocondensation of acetone
dicarboxylate with 1,4-dibromobut-2-yne to give 2-vinylidene-
hydrofurans.12,13 As part of our approach toward the total
synthesis of lophotoxin, we were interested in a general
protocol for 2-alkenylfurans. In this paper, we present the
first use of unstabilized monocarbonyl systems in the
formation of substituted furans. Our methodology employs
alkynyl ketone enolates which undergo a thermal SN2′
O-alkylation to provide the desired heterocycles. Further-
more, we were able to extend this strategy toward novel
syntheses of 1,3-oxazoles and -thiazoles.
Sch em e 2
The starting materials for our furan synthesis, alkynyl
ketones of type 3, were readily obtained by the BF3‚etherate-
mediated Michael addition of alkynyl boranes to enones
(Scheme 1).14 Since we were interested in studying the effect
of the leaving group, different protective groups (Bn, MOM,
MEM) were installed at the propargylic oxygen.
Treatment of alkynyl ketones
3 with 1.1 equiv of
NaHMDS at -78 °C, followed by warming to -10 °C,
provided the desired alkenylfurans 4 in 47-71% yield after
chromatography on SiO2. Irrespective of the ether protective
groups, substrates 3a -c provided furan 4a in 67-71% yield.
However, the corresponding silyl ether 2 did not convert to
furan even at elevated temperatures. Whereas aliphatic
ketones with R′ ) alkyl groups (e.g., 3d and 3e) reacted
analogously to the aromatic ketones, replacement of the R
substituent with alkyl groups or hydrogen led to unreactive
substrates 3f and 3g that did not provide any furans upon
exposure to NaHMDS or other bases. Even replacement of
the propargylic ether substituents with better leaving groups
such as benzoates and mesylates or the use of Pd(0) catalysts
did not facilitate furan formation.
In contrast, cycloelimination of ketones 3 with R ) H or
alkyl groups was possible if an additional electron-with-
drawing group was attached R to the carbonyl group
(Scheme 2). â-Keto esters 6a and 6b were obtained by
alkylation with propargylic alcohols 5a and 5b, respectively,
and converted smoothly to furans 7a and 7b upon treatment
with 5 mol % of Pd(OAc)2 and 6 mol % of (diphenylphos-
(1) Fenical, W.; Okeeda, R. K.; Basnadurraga, M. M.; Culver, P.; J acobs,
R. S. Science 1981, 212, 1512.
(2) Look, S. A.; Burch, M. T.; Fenical, W.; Qi-tai, Z.; Clardy, J . J . Org.
Chem. 1985, 50, 5741.
(3) Missakian, M. G.; Burreson, B. J .; Scheuer, P. J . Tetrahedron 1975,
31, 2513.
(4) Eberbach, W. In Heteroarenes I, Part 1, 4th ed.; Kreher, R. P., Ed.;
Georg Thieme Verlag: Stuttgart, 1994; Vol. E6a, pp 16-185d.
(5) Marshall, J . A.; Bennett, C. E. J . Org. Chem. 1994, 59, 6110.
(6) Marshall, J . A.; Wang, X.-J . J . Org. Chem. 1991, 56, 960.
(7) Trost, B. M.; McIntosh, M. C. J . Am. Chem. Soc. 1995, 117, 7255.
(8) Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.; Nozaki,
H. Tetrahedron 1985, 41, 3655.
(9) (a) Paquette, L. A.; Doherty, A. M.; Rayner, C. M. J . Am. Chem. Soc.
1992, 114, 3910. (b) Rayner, C. M.; Astles, P. C.; Paquette, L. A. J . Am.
Chem. Soc. 1992, 114, 3926.
(10) Arcadi, A.; Cacchi, S.; Larock, R. C.; Marinelli, F. Tetrahedron Lett.
1993, 34, 2813.
(11) Minami, I.; Yuhara, M.; Watanabe, H.; Tsuji, J . J . Organomet. Chem.
1987, 334, 225.
(12) Cambie, R. C.; Moratti, S. C.; Rutledge, P. S.; Woodgate, P. D. Synth.
Commun. 1990, 20, 1923.
(13) Lavoisier-Gallo, T.; Rodriguez, J . J . Org. Chem. 1997, 62, 3787.
(14) Sinclair, J . A.; Brown, H. C. J . Org. Chem. 1976, 41, 1078.
S0022-3263(98)01542-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/23/1998

Communications
J . Org. Chem., Vol. 63, No. 21, 1998 7133
Sch em e 3
Sch em e 5
Sch em e 6
Sch em e 4
basic conditions the cycloelimination does not readily epimer-
ize base-labile stereocenters. As in the furan case, the
preparation of more highly substituted alkenyl heterocycles
is possible. A 3:1 E/Z ratio of disubstituted alkenyl oxazoles
19 was obtained from the secondary benzyl ether 18 (Scheme
5).
Further extension of this novel methodology to thioamide
analogues of 15 provided directly the vinylthiazolines 21
after coupling of amine 12 with dithiobenzoic or dithioiso-
butyric acid, and none of the putative thioamide intermedi-
ates 20 were observed (Scheme 6).17 Interestingly, as a
consequence of the greater nucleophilicity of the thioamide
function, spontaneous cyclization onto the triple bond had
occurred. Treatment of 21a with NaHMDS for 1 h provided
a ca. 1:1 mixture of thiazole 22a and vinylthiazole 23,
whereas the thiazoles 22a and 22b were obtained as the sole
products in 76-82% yield after prototropic rearrangement
of 21a and 21b in the presence of DBU.
In conclusion, we have been able to establish a novel
general strategy for the preparation of five-membered
heterocycles. 3-Aryl-substituted γ,δ-acetylenic ketones un-
dergo a formal intramolecular SN2′ O-alkylation with a
variety of ether-type leaving groups to provide 2,4,5-trisub-
stituted vinylfurans. Furthermore, these heterocycles can
also be formed from the corresponding â-keto esters by a
different mechanistic pathway that requires higher temper-
atures but is independent of an aryl substituent at the
(propargylic) ketone â-carbon. In addition to furans, ox-
azoles and thiazoles are readily obtained under analogous
reaction conditions from propargylic amides and thioamides.
In the latter case, the alkynylamine-derived thioamide
spontaneously cyclizes onto the triple bond under the
reaction conditions of thioamide formation, and only vinyl-
thiazoline intermediate is isolated. Subsequent alkene
isomerization provides the aromatic thiazole. We are cur-
rently studying further variations of this new heterocyclic
chemistry as well as its extension to imidazoles.
phino)ferrocene in THF or with 1 equiv of K2CO3 in DMF.
In either case, heating to 70 °C was necessary to effect
cycloelimination to the furan, and no reaction occurred with
ether leaving groups in place of the carbonate.
Since the presence of a phenyl substituent at the R
position in ketones 3 significantly accelerates the cyclo-
elimination to furans, we propose a mechanism for these
substrates that involves cumulene 8 as a reactive intermedi-
ate (Scheme 3). Elimination of 3 to the cumulene is
facilitated by the R-anion-stabilizing effect of the phenyl ring,
and subsequent thermodynamically controlled enolization,
cyclization, and furan formation are fast compared to the
initial elimination reaction. An elimination at the preformed
enolate stage leading directly to cumulene 9 is also possible.
With stabilized enolates derived from â-keto esters 6, a more
traditional pathway involving a direct SN2′ reaction of the
enolate oxygen on the propargylic leaving group provides
an alternative route to alkenyl furans 7.13,15 Obviously, the
latter pathway is also amenable to Pd(0) catalysis.
Either the mechanism invoked in Scheme 3 or a more
traditional intramolecular SN2′ O-alkylation should be per-
tinent to the formation of other five-membered heterocycles.
Accordingly, we prepared amides 14 and 15 from butynediol
derivative 11 and subjected them to NaHMDS (Scheme 4).
In both cases, clean oxazole formation was observed, and
the desired heterocycles were obtained in good yields.16
A
Ack n ow led gm en t . This work was supported by the
National Science Foundation, the National Institutes of
Health, and the Sloan and Camille Dreyfus Foundations.
single diastereomer of oxazole 16 was isolated for (S)-
isoleucine-derived 14, a clear indication that despite the
Su p p or tin g In for m a tion Ava ila ble: Experimental details
and characterization for all new compounds. Copies of 1H and
13C NMR spectra (78 pages).
(15) MaGee, D. I.; Leach, J . D. Tetrahedron Lett. 1997, 38, 8129.
(16) In prior work, we have observed the formation of an alkenyl
oxazoline from a π-allylcopper complex: (a) Wipf, P.; Fritch, P. C. J . Org.
Chem. 1994, 59, 4875. For the related Pd(0)-catalyzed cyclization of 1,4-
disubstituted cyclopentene derivatives to give bicyclic oxazolines and other
examples of amide cyclizations onto a π-allylpalladium complex, see: (b)
Hansel, J .-G.; O’Hogan, S.; Lensky, S.; Ritter, A. R.; Miller, M. J .
Tetrahedron Lett. 1995, 36, 2913. (c) Cook, G. R.; Shanker, P. S. Tetrahedron
Lett. 1998, 39, 3405.
J O981542Q
(17) Thionation of amide 15 with Lawesson’s reagent led, in lower yield,
to the identical vinylthiazoline, and no thioamide intermediate was observed
in this reaction either.