Synthesis of 5-hydroxycyclopent-2-Enones from allenyl vinyl ketones via an interrupted Nazarov cyclization

Article abstract of DOI:10.1021/ol900029d

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 excellen

Full text of DOI:10.1021/ol900029d

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1229-1231
Synthesis of 5-Hydroxycyclopent-2-
enones from Allenyl Vinyl Ketones via
an Interrupted Nazarov Cyclization
Vanessa M. Marx and D. Jean Burnell*
Department of Chemistry, Dalhousie UniVersity, Halifax, NoVa Scotia,
Canada B3H 4J3
jean.burnell@dal.ca
Received January 7, 2009
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
construction of substituted cyclopentenones.1 Strong acids are
normally required to induce the cyclization with divinyl ketone
substrates, but the reactivity of the substrate can be enhanced
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
in the R position by an oxygen.3,4 The Tius group has greatly
developed the use of allenyl vinyl ketones 1, activated by
an R oxygen substituent on the allene, as substrates for
the preparation of a variety of 2-hydroxycyclopent-2-enone
derivatives 2, which are enolized 1,2-diketones (Scheme
1).5-7 In addition to the R oxygen, the use of an allene
Scheme 1
.
Outline of Tius Nazarov Cyclizations with Allenyl
Vinyl Ketones
(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,
49, 2541–2545.
accelerates cyclization as evidenced by the work of Hashmi
and co-workers,8 who showed that Nazarov cyclization of
10.1021/ol900029d CCC: $40.75
Published on Web 02/12/2009
2009 American Chemical Society

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
up to 71% for 5f (over the two steps). These ketones have
a methyl group in the R position, which should further
stabilize the carbocation intermediate (similar to 3) and make
nucleophilic attack at one of the R positions more sterically
encumbered.
might be particularly well suited to intermolecular intercep-
tion by a nucleophile because termination of the process by
proton loss from 3 might be disfavored, as this would lead
to a fulvene. However, in order to trap the intermediate
carbocation derived from the allenyl vinyl ketone 1 with an
amine, Tius and co-workers7 were obliged to conduct the
Nazarov cyclization in the absence of solvent and in the
presence of silica gel and the amine. Thus, it was our
intention to examine the Nazarov cyclizations of some allenyl
vinyl ketones under more conventional conditions with the
expectation that these would lead to interrupted reactions.
Our studies began with the preparation of a series of allenyl
vinyl ketones (Scheme 3). An indium-mediated Barbier-type
coupling reaction12,13 was employed to react 1-bromo-2-
butyne with a variety of R,ꢀ-unsaturated aldehydes to furnish
allenyl alcohols 4a-g efficiently. However, Dess-Martin
periodinane oxidation gave very low yields of the corre-
Conditions to effect Nazarov cyclizations were surveyed with
the allenyl vinyl ketone 5d, and the results are summarized in
Table 1. In contrast with the examples of Hashmi and Tius,7,8
treatment of 5d with silica gel failed to provide any cyclized
product. Indeed, 5a-g were purified successfully by column
chromatography on silica gel. Whereas concentrated HCl
gave no Nazarov cyclization product (entry 1), other Brønsted
acids (entries 2-4) provided an oxygen-trapped compound
6 as a single diastereomer in modest to excellent yields. No
product with an exocyclic double bond was isolated. The
relative stereochemistry of 6 was confirmed by X-ray
crystallography. Of the triflates tested (entries 6-8),
Cu(OTf)2 slowly destroyed 5d, but Sc(OTf)3 and Yb(OTf)3
both yielded 6 also. Yb(OTf)3 uniquely gave the alcohol
product as an epimeric mixture.
(4) Two computational studies of Nazarov cyclizations confirm the
facilitation of Nazarov cyclization by an R oxygen substituent: (a) Cavalli,
A.; Masetti, M.; Recanatini, M.; Prandi, C.; Guarna, A.; Occhiato, E. G.
Chem. Eur. J. 2006, 12, 2836–2845. (b) Polo, V.; Andre´s, J. J. Chem. Theory
Comput. 2007, 3, 816–823.
White and West11b had observed the trapping of a Nazarov
intermediate by chloride when a cyclization had been promoted
by TiCl4. Treatment of 5d with TiCl4 led to the destruction of
the substrate, and the result was the same with AlCl3 and FeCl3
(entries 9-11). Compound 5d was rapidly transformed in the
(5) Tius, M. A. Acc. Chem. Res. 2003, 36, 284–290, and references
therein.
(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)
delos Santos, D. B.; Banaag, A. R.; Tius, M. A. Org. Lett. 2006, 8, 2579–
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–
12473. (b) Dhoro, F.; Kristensen, T. E.; Stockmann, V.; Yap, G. P. A.;
Tius, M. A. J. Am. Chem. Soc. 2007, 129, 7256–7257. (c) Basak, A. K.;
Tius, M. A. Org. Lett. 2008, 10, 4073–4076.
(11) Recent examples by West: (a) Browder, C. C.; Marmsa¨ter, F. P.;
West, F. G. Can. J. Chem. 2004, 82, 375–385. (b) White, T. D.; West,
F. G. Tetrahedron Lett. 2005, 46, 5629–5632. (c) Giese, S.; Mazzola, R. D.,
Jr.; Amann, C. M.; Arif, A. M.; West, F. G. Angew. Chem., Int. Ed. 2005,
44, 6546–6549. (d) Grant, T. N.; West, F. G. J. Am. Chem. Soc. 2006, 128,
9348–9349. (e) Rostami, A.; Wang, Y.; Arif, A. M.; McDonald, R.; West,
F. G. Org. Lett. 2007, 9, 703–706. (f) Mahmoud, B.; West, F. G.
Tetrahedron Lett. 2007, 48, 2091–5094. (g) Grant, T. G.; West, F. G. Org.
Lett. 2007, 9, 3789–3792. (h) Rieder, C. J.; Fradette, R. J.; West, F. G.
Chem. Commun. 2008, 1572–1574.
(8) Hashmi, A. S.; Bats, J. W.; Choi, J.-H.; Schwarz, L. Tetrahedron
Lett. 1998, 39, 7491–7494. This use of an allene in a Nazarov cyclization
was preceded by the following report, in which an oxygen-substituted allene
underwent Nazarov cyclization during workup: Tius, M. A.; Kwok, C.-K.;
Gu, X.; Zhao, C. Synth. Commun. 1994, 24, 871–885.
(9) (a) Shoppee, C. W.; Cooke, B. J. A. J. Chem. Soc., Perkin Trans. 1
1972, 2271, 2276. (b) Binet du Jassonneix, C. Bull. Soc. Chim. Fr. 2 1974,
758–769. (c) Hirano, S.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1974,
1429–1430. (d) de Lera, A. R.; Rey, J. G.; Hrovat, D.; Iglesias, B.; Lo´pez,
S. Tetrahedron Lett. 1997, 38, 7425–7428. (e) Nair, V.; Bindu, S.;
Sreekumar, V.; Chiaroni, A. Org. Lett. 2002, 4, 2821–2823.
(10) Photochemical Nazarov cyclizations involve trapping of the
intermediate by solvent: Habermas, K. L.; Denmark, S. E.; Jones, T. K.
Org. React. 1994, 45, 1–158, and references therein.
(12) (a) Isaac, M. B.; Chan, T.-H. J. Chem. Soc., Chem. Commun. 1995,
1003–1004. (b) Alcaide, B.; Almendros, P.; Rodr´ıgues-Acebes, R. J. Org.
Chem. 2005, 70, 3198–3204.
(13) Yields with indium seem to be better than via the tin compound.
For instance, 4d synthesized via the propargyltin was produced in 21%
yield, as a 94:6 mixture with the corresponding acetylenic alcohol:
Masuyama, Y.; Watabe, A.; Ito, A.; Kurusu, Y. Chem. Commun. 2000,
2009–2010.
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Org. Lett., Vol. 11, No. 6, 2009

Table 1. Nazarov Cyclization of 5d to 6a
entry
acid
yield (%) of 6b
1
HCl
0c
2
3
4
5
6
7
8
9
p-TsOH
Amberlyst-15
CF3CO2H
BF3·Et2O
Cu(OTf)2
Sc(OTf)3
Yb(OTf)3
TiCl4
71
30
96
0d
0d
54
70e
0d
10
11
12
AlCl3
FeCl3
AuCl3
0d
0d
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
completely consumed, but only intractable material was produced. e A 1:1
mixture of the cis and the trans isomers.
Figure 1. Products of the interrupted Nazarov cyclizations of
5a-c,e-g (with yields).
presence of AuCl3 (entry 12), but in this case a modest amount
of a cyclized product was recovered, and the identity of this
product was shown by NMR and MS to be the chloride-trapped
compound 7 as a single diastereomer.
In summary, a variant of the Nazarov cyclization has been
presented in which the intermediate from an allenyl vinyl ketone
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
generally amenable to interrupted Nazarov cyclizations. Re-
search in this direction is currently underway.
Trifluoroaceticacid was clearly the best acid for the formation
of 6. The origin of the alcohol oxygen of 6 was trifluoroacetate.
This was obvious from the NMR data of the cyclization product,
the ester 8, prior to chromatography on basic alumina. The
remaining allenyl vinyl ketones 5a-c,e-g were reacted using
CF3CO2H. The trifluoroacetate esters were not purified, but
chromatography on basic alumina afforded the 5-hydroxycy-
clopent-2-enones 9-14 with good to excellent yields (Figure
1).14 The trans stereochemistry was assigned to the major
product 10a (from 5b) and to 11-14 on the basis of the
similarity of the coupling constants in their 1H NMR data with
the corresponding data for 6. That only 5b gave a significant
amount of cis alcohol 10b suggests that the stereochemistry
develops as a result of steric interactions with the substituent
at C-4. The reactions of 5f and 5g were slower than the reactions
of the other allenyl vinyl ketones, and the yields of the
corresponding cyclized products 13 and 14 were lower than
the yields of 6 and 9-12 as a result of the production of less
polar byproducts, which were not characterized.
Acknowledgment. We thank Prof. T. Stanley Cameron
for the X-ray crystal structure. We are grateful to the Natural
Sciences and Engineering Research Council of Canada and
the Killam Foundation for financial support.
Supporting Information Available: Experimental pro-
cedures and characterization data; 1H and 13C NMR spectra
of compounds 4a-g, 5a-g, and 6-14; ORTEP plot and
CIF file for the X-ray analysis of 6. This material is available
free of charge via the Internet at http://pubs.acs.
org.
OL900029D
(14) Compound (-)-9 has been isolated from the fermentation broth of
ascomycete strain A23-98: Weidler, M.; Rether, J.; Anke, T.; Erkel, G.;
Sterner, O. J. Antibiot. 2001, 54, 679–681.
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