ORGANIC
LETTERS
Synthesis of 5-Hydroxycyclopent-2- 2009
Vol. 11, No. 6
enones from Allenyl Vinyl Ketones via 1229-1231
an Interrupted Nazarov Cyclization
Vanessa M. Marx and D. Jean Burnell*
Department of Chemistry, Dalhousie UniVersity, Halifax, NoVa Scotia,
Canada B3H 4J3
[email protected] Received January 7, 2009
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ABSTRACT
Treatment of an allenyl vinyl ketone with trifluoroacetic acid leads to Nazarov cyclization, and the intermediate carbocation is trapped efficiently
by trifluoroacetate. Hydrolysis of the ester with methanol and basic alumina provides, in good to excellent overall yield, a 5-hydroxycyclopent-
2-enone in which the alcohol is predominantly trans to a substituent at C-4.
The Nazarov cyclization has become a powerful tool for the an R oxygen substituent on the allene, as substrates for
construction of substituted cyclopentenones.1 Strong acids are the preparation of a variety of 2-hydroxycyclopent-2-enone
normally required to induce the cyclization with divinyl ketone derivatives 2, which are enolized 1,2-diketones (Scheme
substrates, but the reactivity of the substrate can be enhanced 1).5-7 In addition to the R oxygen, the use of an allene
by electron-donating or electron-withdrawing substituents.
Frontier and co-workers2 have carefully studied experimentally
the electronic effects of substituents. A number of more recent
examples of Nazarov cyclizations employ substrates substituted Scheme 1. Outline of Tius Nazarov Cyclizations with Allenyl
in the R position by an oxygen.3,4 The Tius group has greatly Vinyl Ketones
developed the use of allenyl vinyl ketones 1, activated by
(1) Reviews: (a) Pellissier, H. Tetrahedron 2005, 61, 6479–6517. (b)
Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577–7606. (c) Tius,
M. A. Eur. J. Org. Chem. 2005, 2193–2206.
(2) (a) He, W.; Sun, X.; Frontier, A. J. J. Am. Chem. Soc. 2003, 125,
14278–14279. (b) He, W.; Herrick, I. R.; Atesin, T. A.; Caruana, P. A.;
Kellenberger, C. A.; Frontier, A. J. J. Am. Chem. Soc. 2008, 130, 1003–
1011.
(3) (a) Bee, C.; Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 4927–4930.
(b) Liang, G.; Gradl, S. N.; Trauner, D. Org. Lett. 2003, 5, 4931–4934. (c)
Liang, G.; Trauner, D. J. Am. Chem. Soc. 2004, 126, 9544–9545. (d) Batson,
W. A.; Sethumadhavan, D.; Tius, M. A. Org. Lett. 2005, 7, 2771–2774. (e)
Prandi, C.; Deagostino, A.; Venturello, P.; Occhiato, E. G. Org. Lett. 2005,
7, 4345–4348. (f) Janka, M.; He, W.; Haedicke, I. E.; Fronczek, F. R.;
Frontier, A. J.; Eisenberg, R. J. Am. Chem. Soc. 2006, 128, 5312–5313. (g)
Williams, D. R.; Robinson, L. A.; Nevill, C. R.; Reddy, J. P. Angew. Chem.,
Int. Ed. 2007, 46, 915–918. (h) Rueping, M.; Ieawsuwan, W.; Antonchick,
A. P.; Nachtsheim, B. J. Angew. Chem., Int. Ed. 2007, 46, 2097–2100. (i)
Amere, M.; Blanchet, J.; Lasne, M.-C.; Rouden, J. Tetrahedron Lett. 2008, accelerates cyclization as evidenced by the work of Hashmi
49, 2541–2545. and co-workers,8 who showed that Nazarov cyclization of
10.1021/ol900029d CCC: $40.75 2009 American Chemical Society
Published on Web 02/12/2009
allenyl vinyl ketones that lack an oxygen substituent can take
place during chromatography on silica gel.
Scheme 3. Preparation of Allenyl Vinyl Ketones
The initial, cationic intermediate of the Nazarov cyclization
can be intercepted, or “interrupted,” by a nucleophile.7,9,10 This
process has been cleverly exploited synthetically by West.11
We hypothesized that the cationic intermediate 3 (Scheme
2) derived by the Nazarov cyclization of allenyl vinyl ketones
Scheme 2. Carbocation Intermediate from the Nazarov
Cyclization of an Allenyl Vinyl Ketone
sponding ketones 5a-g, which were accompanied by
significant amounts of impurities that were difficult to
remove. Oxidation of 4a-g with MnO2 was somewhat better,
but the yields of the ketones ranged from only 21% for 5a
might be particularly well suited to intermolecular intercep-
up to 71% for 5f (over the two steps). These ketones have
tion by a nucleophile because termination of the process by
a methyl group in the R position, which should further
proton loss from 3 might be disfavored, as this would lead
stabilize the carbocation intermediate (similar to 3) and make
to a fulvene. However, in order to trap the intermediate
nucleophilic attack at one of the R positions more sterically
carbocation derived from the allenyl vinyl ketone 1 with an
encumbered.
amine, Tius and co-workers7 were obliged to conduct the
Nazarov cyclization in the absence of solvent and in the Conditions to effect Nazarov cyclizations were surveyed with
presence of silica gel and the amine. Thus, it was our the allenyl vinyl ketone 5d, and the results are summarized in
intention to examine the Nazarov cyclizations of some allenyl Table 1. In contrast with the examples of Hashmi and Tius,7,8
vinyl ketones under more conventional conditions with the treatment of 5d with silica gel failed to provide any cyclized
expectation that these would lead to interrupted reactions. product. Indeed, 5a-g were purified successfully by column
chromatography on silica gel. Whereas concentrated HCl
Our studies began with the preparation of a series of allenyl
gave no Nazarov cyclization product (entry 1), other Brønsted
vinyl ketones (Scheme 3). An indium-mediated Barbier-type
acids (entries 2-4) provided an oxygen-trapped compound
coupling reaction12,13 was employed to react 1-bromo-2-
6 as a single diastereomer in modest to excellent yields. No
butyne with a variety of R,β-unsaturated aldehydes to furnish
product with an exocyclic double bond was isolated. The
allenyl alcohols 4a-g efficiently. However, Dess-Martin
relative stereochemistry of 6 was confirmed by X-ray
periodinane oxidation gave very low yields of the corre-
crystallography. Of the triflates tested (entries 6-8),
Cu(OTf)2 slowly destroyed 5d, but Sc(OTf)3 and Yb(OTf)3
(4) Two computational studies of Nazarov cyclizations confirm the
facilitation of Nazarov cyclization by an R oxygen substituent: (a) Cavalli, both yielded 6 also. Yb(OTf)3 uniquely gave the alcohol
A.; Masetti, M.; Recanatini, M.; Prandi, C.; Guarna, A.; Occhiato, E. G. product as an epimeric mixture.
Chem. Eur. J. 2006, 12, 2836–2845. (b) Polo, V.; Andrés, J. J. Chem. Theory White and West11b had observed the trapping of a Nazarov
Comput. 2007, 3, 816–823.
(5) Tius, M. A. Acc. Chem. Res. 2003, 36, 284–290, and references intermediate by chloride when a cyclization had been promoted
therein. by TiCl4. Treatment of 5d with TiCl4 led to the destruction of
(6) (a) Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171–1174. (b) Forest,
J.; Bee, C.; Cordaro, F.; Tius, M. A. Org. Lett. 2003, 5, 4069–4072. (c) the substrate, and the result was the same with AlCl3 and FeCl3
delos Santos, D. B.; Banaag, A. R.; Tius, M. A. Org. Lett. 2006, 8, 2579– (entries 9-11). Compound 5d was rapidly transformed in the
2582. (d) Banaag, A. R.; Tius, M. A. J. Am. Chem. Soc. 2007, 129, 5328–
5329. (e) Banaag, A. R.; Tius, M. A. J. Org. Chem. 2008, 73, 8133–8141.
(7) (a) Dhoro, F.; Tius, M. A. J. Am. Chem. Soc. 2005, 127, 12472– (11) Recent examples by West: (a) Browder, C. C.; Marmsäter, F. P.;
12473. (b) Dhoro, F.; Kristensen, T. E.; Stockmann, V.; Yap, G. P. A.; West, F. G. Can. J. Chem. 2004, 82, 375–385. (b) White, T. D.; West,
Tius, M. A. J. Am. Chem. Soc. 2007, 129, 7256–7257. (c) Basak, A. K.; F. G. Tetrahedron Lett. 2005, 46, 5629–5632. (c) Giese, S.; Mazzola, R. D.,
Tius, M. A. Org. Lett. 2008, 10, 4073–4076. Jr.; Amann, C. M.; Arif, A. M.; West, F. G. Angew. Chem., Int. Ed. 2005,
(8) Hashmi, A. S.; Bats, J. W.; Choi, J.-H.; Schwarz, L. Tetrahedron 44, 6546–6549. (d) Grant, T. N.; West, F. G. J. Am. Chem. Soc. 2006, 128,
Lett. 1998, 39, 7491–7494. This use of an allene in a Nazarov cyclization 9348–9349. (e) Rostami, A.; Wang, Y.; Arif, A. M.; McDonald, R.; West,
was preceded by the following report, in which an oxygen-substituted allene F. G. Org. Lett. 2007, 9, 703–706. (f) Mahmoud, B.; West, F. G.
underwent Nazarov cyclization during workup: Tius, M. A.; Kwok, C.-K.; Tetrahedron Lett. 2007, 48, 2091–5094. (g) Grant, T. G.; West, F. G. Org.
Gu, X.; Zhao, C. Synth. Commun. 1994, 24, 871–885. Lett. 2007, 9, 3789–3792. (h) Rieder, C. J.; Fradette, R. J.; West, F. G.
(9) (a) Shoppee, C. W.; Cooke, B. J. A. J. Chem. Soc., Perkin Trans. 1 Chem. Commun. 2008, 1572–1574.
1972, 2271, 2276. (b) Binet du Jassonneix, C. Bull. Soc. Chim. Fr. 2 1974, (12) (a) Isaac, M. B.; Chan, T.-H. J. Chem. Soc., Chem. Commun. 1995,
758–769. (c) Hirano, S.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1974, 1003–1004. (b) Alcaide, B.; Almendros, P.; Rodrı́gues-Acebes, R. J. Org.
1429–1430. (d) de Lera, A. R.; Rey, J. G.; Hrovat, D.; Iglesias, B.; López, Chem. 2005, 70, 3198–3204.
S. Tetrahedron Lett. 1997, 38, 7425–7428. (e) Nair, V.; Bindu, S.; (13) Yields with indium seem to be better than via the tin compound.
Sreekumar, V.; Chiaroni, A. Org. Lett. 2002, 4, 2821–2823. For instance, 4d synthesized via the propargyltin was produced in 21%
(10) Photochemical Nazarov cyclizations involve trapping of the yield, as a 94:6 mixture with the corresponding acetylenic alcohol:
intermediate by solvent: Habermas, K. L.; Denmark, S. E.; Jones, T. K. Masuyama, Y.; Watabe, A.; Ito, A.; Kurusu, Y. Chem. Commun. 2000,
Org. React. 1994, 45, 1–158, and references therein. 2009–2010.
1230 Org. Lett., Vol. 11, No. 6, 2009
Table 1. Nazarov Cyclization of 5d to 6a
entry acid yield (%) of 6b
1 HCl 0c
2 p-TsOH 71
3 Amberlyst-15 30
4 CF3CO2H 96
5 BF3·Et2O 0d
6 Cu(OTf)2 0d
7 Sc(OTf)3 54
8 Yb(OTf)3 70e
9 TiCl4 0d
10 AlCl3 0d
11 FeCl3 0d
12 AuCl3 32 (of7)
a
0.01 M solutions of 5d. b Isolated yields. c Products of the addition of
HCl across the π bonds of the allene were obtained. d Compound 5d was Figure 1. Products of the interrupted Nazarov cyclizations of
completely consumed, but only intractable material was produced. e A 1:1 5a-c,e-g (with yields).
mixture of the cis and the trans isomers.
presence of AuCl3 (entry 12), but in this case a modest amount
of a cyclized product was recovered, and the identity of this In summary, a variant of the Nazarov cyclization has been
product was shown by NMR and MS to be the chloride-trapped presented in which the intermediate from an allenyl vinyl ketone
compound 7 as a single diastereomer. has been trapped by trifluoroacetate. Al2O3-promoted hydrolysis
then provided a 5-hydroxycyclopent-2-enone. When there was
a substituent at C-4 in the product, the predominant stereo-
chemistry of the product was trans. This intermolecular trapping
of a Nazarov cyclization by an oxygen nucleophile offers an
opportunity for the production of a variety of cyclopent-2-enones
bearing oxygen functionality at the 5-position in good to
excellent yield. In addition, the trapping of a similarly derived
cation with chloride suggests that allenyl vinyl ketones may be
Trifluoroaceticacid was clearly the best acid for the formation generally amenable to interrupted Nazarov cyclizations. Re-
of 6. The origin of the alcohol oxygen of 6 was trifluoroacetate. search in this direction is currently underway.
This was obvious from the NMR data of the cyclization product,
the ester 8, prior to chromatography on basic alumina. The Acknowledgment. We thank Prof. T. Stanley Cameron
remaining allenyl vinyl ketones 5a-c,e-g were reacted using for the X-ray crystal structure. We are grateful to the Natural
CF3CO2H. The trifluoroacetate esters were not purified, but Sciences and Engineering Research Council of Canada and
chromatography on basic alumina afforded the 5-hydroxycy- the Killam Foundation for financial support.
clopent-2-enones 9-14 with good to excellent yields (Figure
1).14 The trans stereochemistry was assigned to the major Supporting Information Available: Experimental pro-
product 10a (from 5b) and to 11-14 on the basis of the cedures and characterization data; 1H and 13C NMR spectra
similarity of the coupling constants in their 1H NMR data with of compounds 4a-g, 5a-g, and 6-14; ORTEP plot and
the corresponding data for 6. That only 5b gave a significant CIF file for the X-ray analysis of 6. This material is available
amount of cis alcohol 10b suggests that the stereochemistry free of charge via the Internet at http://pubs.acs.
develops as a result of steric interactions with the substituent org.
at C-4. The reactions of 5f and 5g were slower than the reactions
OL900029D
of the other allenyl vinyl ketones, and the yields of the
corresponding cyclized products 13 and 14 were lower than
(14) Compound (-)-9 has been isolated from the fermentation broth of
the yields of 6 and 9-12 as a result of the production of less ascomycete strain A23-98: Weidler, M.; Rether, J.; Anke, T.; Erkel, G.;
polar byproducts, which were not characterized. Sterner, O. J. Antibiot. 2001, 54, 679–681.
Org. Lett., Vol. 11, No. 6, 2009 1231
