A versatile new method for the synthesis of cyclopentenones via an unusual rhodium-catalyzed intramolecular trans hydroacylation of an alkyne

Full text of DOI:10.1021/ja011907f

11492
J. Am. Chem. Soc. 2001, 123, 11492-11493
A Versatile New Method for the Synthesis of
Cyclopentenones via an Unusual Rhodium-Catalyzed
Intramolecular Trans Hydroacylation of an Alkyne
Ken Tanaka and Gregory C. Fu*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed August 7, 2001
Because cyclopentenones serve both as key intermediates in
the synthesis of a wide array of significant bioactive compounds
(e.g., prostaglandins1) and as interesting natural products in their
own right (e.g., jasmone2 and pentenomycins3), the development
of efficient methods for their construction constitutes an important
ongoing challenge. Of the existing approaches to the synthesis
of cyclopentenones, the Pauson-Khand reaction is perhaps the
most well-known.4 This powerful method does, however, suffer
from certain deficiencies, including poor regioselectivity in the
incorporation of the olefin and modest yield in reactions of
unstrained or hindered olefins, as well as internal alkynes. As a
consequence of these considerations, the intramolecular Pauson-
Khand reaction, which furnishes bicyclic compounds, has been
more widely applied than the intermolecular process.
Figure 1. A possible pathway for metal-catalyzed intramolecular
hydroacylations of 4-alkynals.
of 4-alkynals is the need, if the process follows a pathway
analogous to the reactions of 4-alkenals, for a trans addition of a
metal hydride to an alkyne (Figure 1).10
The transition metal-catalyzed intramolecular hydroacylation
of 4-alkenals has become a well-established method for producing
cyclopentanones (eq 1).5-9 In contrast, the corresponding reaction
of 4-alkynals, which are readily available through 1,4-addition
of alkynylmetals to R,â-unsaturated aldehydes, to generate
cyclopentenones has not been described; in fact, Larock has noted
that, under conditions in which 4-alkenals undergo Rh(PAr3)3-
Cl-catalyzed cyclization, a 4-alkynal furnishes no product.6b One
potential difficulty in achieving intramolecular hydroacylations
During a recent investigation of rhodium-catalyzed isomeriza-
tions of allylic alcohols to aldehydes,11 while attempting to convert
allylic alcohol 1 to 4-alkynal 2, we obtained a small amount of
cyclopentenone 3, presumably via 2 (eq 3). In view of the lack
of precedent for such an intramolecular hydroacylation, we
decided to pursue the development of this unanticipated side
reaction into a versatile new route to cyclopentenones.
(1) For reviews, see: (a) Noyori, R.; Suzuki, M. Science 1993, 259, 44-
45. (b) Straus, D. S.; Glass, C. K. Med. Res. ReV. 2001, 21, 185-210. (c)
Corey, E. J. Angew. Chem., Int. Ed. Engl. 1991, 30, 455-465.
(2) For leading references to jasmone and its derivatives, see: (a) Dobbs,
D. A.; Vanhessche, K. P. M.; Brazi, E.; Rautenstrauch, V.; Lenoir, J.-Y.; Geneˆt,
J.-P.; Wiles, J.; Bergens, S. H. Angew. Chem., Int. Ed. 2000, 39, 1992-1995.
(b) Fra`ter, G.; Bajgrowicz, J. A.; Kraft, P. Tetrahedron 1998, 54, 7633-
7703.
(3) For leading references, see: Seepersaud, M.; Al-Abed, Y. Tetrahedron
Lett. 2000, 41, 4291-4293.
(4) For reviews, see: (a) Schore, N. E. Org. React. 1991, 40, 1-90. (b)
Brummond, K. M.; Kent, J. L. Tetrahedron 2000, 56, 3263-3283. (c) Chung,
Y. K. Coord. Chem. ReV. 1999, 188, 297-341.
(5) For examples of intramolecular hydroacylations of 4-alkenals in the
presence of stoichiometric Rh(PPh3)3Cl, see: Sakai, K.; Ide, J.; Oda, O.;
Nakamura, N. Tetrahedron Lett. 1972, 1287-1290.
(6) For examples of intramolecular hydroacylations of 4-alkenals in the
presence of catalytic amounts of rhodium complexes, see: (a) Lochow, C.
F.; Miller, R. G. J. Am. Chem. Soc. 1976, 98, 1281-1283. (b) Larock, R. C.;
Oertle, K.; Potter, G. F. J. Am. Chem. Soc. 1980, 102, 190-197. (c) Sakai,
K.; Ishiguro, Y.; Funakoshi, K.; Ueno, K.; Suemune, H. Tetrahedron Lett.
1984, 25, 961-964. (d) Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7,
936-945.
(7) For examples of catalytic enantioselective intramolecular hydroacyla-
tions of 4-alkenals, see: (a) James, B. R.; Young, C. G. J. Chem. Soc., Chem.
Commun. 1983, 1215-1216. James, B. R.; Young, C. G. J. Organomet. Chem.
1985, 285, 321-332. (b) Taura, Y.; Tanaka, M.; Funakoshi, K.; Sakai, K.
Tetrahedron Lett. 1989, 30, 6349-6352. Tanaka, M.; Imai, M.; Fujio, M.;
Sakamoto, E.; Takahashi, M.; Eto-Kato, Y.; Wu, X. M.; Funakoshi, K.; Sakai,
K.; Suemune, H. J. Org. Chem. 2000, 65, 5806-5816. (c) Barnhart R. W.;
Wang, X.; Noheda, P.; Bergens, S. H.; Whelan, J.; Bosnich, B. J. Am. Chem.
Soc. 1994, 116, 1821-1830. Bosnich, B. Acc. Chem. Res. 1998, 31, 667-
674 and references therein.
(8) For examples of intramolecular hydroacylations of 4-alkenals in the
presence of catalytic amounts of ruthenium complexes, see: Eilbracht, P.;
Gersmeier, A.; Lennartz, D.; Huber, T. Synthesis 1995, 330-334.
(9) For examples of intramolecular hydroacylations of 4-alkenals in the
presence of catalytic amounts of cobalt complexes, see: (a) Vinogradov, M.
G.; Tuzikov, A. B.; Nikishin, G. I.; Shelimov, B. N.; Kazansky, V. B. J.
Organomet. Chem. 1988, 348, 123-134. (b) Lenges, C. P.; Brookhart, M. J.
Am. Chem. Soc. 1997, 119, 3165-3166.
Among the phosphines (e.g., binap, dppf, and dcpe) and
solvents (e.g., CH2Cl2, THF, benzene, and CH3NO2) that we have
examined, the combination of Rh/dppe and acetone has proved
to be the most effective. Under these conditions, we can achieve
the intramolecular hydroacylation of a broad range of 4-alkynals
to produce cyclopentenones in good yield (eq 4).
(10) While attempting to decarbonylate an aldehyde with RhCl(PPh3)3,
Nicolaou observed a novel intramolecular hydroacylation of a 5-alkynal to
generate a cyclohexenone (78% yield based on 50% conversion). To the best
of our knowledge, this single example (a stoichiometric process: 2.5 equiv
of RhCl(PPh3)3 were used, relative to isolated cyclohexenone) is the only report
to date of an intramolecular hydroacylation of an acetylenic aldehyde. See:
Nicolaou, K. C.; Gross, J. L.; Kerr, M. A. J. Heterocycl. Chem. 1996, 33,
735-746.
(11) Tanaka, K.; Qiao, S.; Tobisu, M.; Lo, M. M.-C.; Fu, G. C. J. Am.
Chem. Soc. 2000, 122, 9870-9871.
10.1021/ja011907f CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/25/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 46, 2001 11493
Table 1. [Rh(dppe)]2(BF4)2-Catalyzed Synthesis of
Cyclopentenones via the Intramolecular Hydroacylation of
4-Alkynals
As illustrated in Table 1, a wide array of 4-alkynals cleanly
cyclize upon treatment with catalytic [Rh(dppe)]2(BF4)2.12 5-Alkyl
(entries 1-3)-, 5-aryl (entries 4-5)-, 5-alkenyl (entry 6)-, and
5-alkynyl-substituted (entry 7) aldehydes are suitable substrates
for this process.13 The intramolecular hydroacylation proceeds in
the presence of substitution in the â (entries 2, 4, 5, and 6) and
the R (entry 3) positions. The effective cyclization of the
potentially labile tertiary propargylic ether depicted in entry 5 is
worthy of note.
We have begun to explore the mechanism of this intriguing
rhodium-catalyzed hydroacylation process. Our working hypoth-
esis is that the reaction follows the pathway outlined in Figure
1.14 First, in analogy with the well-studied cyclization of 4-al-
kenals, oxidative addition of the aldehyde C-H bond to Rh(I)
furnishes a Rh(III) acyl hydride (A).15 Next, in an unusual step,
the rhodium hydride adds in a trans fashion to the coordinated
alkyne to generate a six-membered rhodium metalacyclohexene
(A);16 in contrast, the intramolecular hydroacylation of alkenes
proceeds via a conventional cis addition to the carbon-carbon
multiple bond.15,17 Finally, reductive elimination occurs, producing
the cyclopentenone and regenerating the Rh(I) catalyst.
Our preliminary mechanistic data are consistent with this path-
way. For example, we have demonstrated that the aldehyde hydro-
gen (deuterium) of the starting material is indeed transferred
cleanly to the â position of the cyclopentenone (eq 5). Further-
more, through a crossover experiment, we have established that
this transfer proceeds intramolecularly; thus, treatment of a 1:1
mixture of 2-methylundec-4-ynal (4) and 1-deuterio-3-methylun-
dec-4-ynal (5) with [Rh(dppe)]2(BF4)2 furnishes 2-n-hexyl-5-
methyl-2-cyclopentenone (6) and 3-deuterio-2-n-hexyl-4-methyl-
2-cyclopentenone (7) exclusively (eq 6).18
a Isolated yields, average of two runs. b CH3CN (10 equiv) was
added; 100 °C. c Room temperature. d 100 °C.
of a rhodium hydride to an alkyne, compares favorably with other
approaches to the construction of this important family of com-
pounds. Additional synthetic and mechanistic investigations of
this ring-forming process are underway.
Acknowledgment. Support has been provided by Mitsubishi Chemical
(postdoctoral fellowship support for K.T.), Bristol-Myers Squibb, Merck,
Novartis, and Pfizer.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA011907F
(13) Notes: (a) For the cyclization of 4-alkynals that bear an alkyl group
in the 5-position, the addition of CH3CN (10 equiv) leads to a more effective
reaction (entries 1-3). (b) Under the same conditions, cyclization of a
4-alkynal that lacks a 5-substituent does not proceed cleanly.
(14) For the sake of simplicity, the elementary steps are drawn as
irreversible.
(15) For mechanistic studies of the rhodium-catalyzed cyclization of
4-alkenals to cyclopentanones, see: (a) Campbell, R. E., Jr.; Miller, R. G. J.
Organomet. Chem. 1980, 186, C27-C31. Campbell, R. E., Jr.; Lochow, C.
F.; Vora, K. P.; Miller, R. G. J. Am. Chem. Soc. 1980, 102, 5824-5830. (b)
Fairlie, D. P.; Bosnich, B. Organometallics 1988, 7, 946-954.
(16) The rhodium-catalyzed intermolecular hydroacylation of alkynes with
aldehydes proceeds via cis addition of the rhodium hydride to the alkyne. For
example, see: (a) Lee, H.; Jun, C.-H. Bull. Korean Chem. Soc. 1995, 16,
1135-1138. (b) Kokubo, K.; Matsumasa, K.; Miura, M.; Nomura, M. J. Org.
Chem. 1997, 62, 4564-4565. (c) Kokubo, K.; Matsumasa, K.; Nishinaka,
Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1999, 72, 303-311.
(17) For the isolation of a cis-hydridopent-4-enoylrhodium(III) complex,
see: Milstein, D. J. Chem. Soc., Chem. Commun. 1982, 1357-1358.
(18) In a preliminary experiment, we have measured kH/kD ≈ 1.5 (100 °C)
for the [Rh(dppe)]2(BF4)2-catalyzed intramolecular hydroacylation of 3-
methylundec-4-ynal (1-H- vs 1-D-).
In conclusion, we have demonstrated that the rhodium-catalyzed
intramolecular hydroacylation of 4-alkynals represents a versatile
new catalytic method for the synthesis of cyclopentenones. This
method, which appears to proceed via an unusual trans addition
(12) Sample experimental (Table 1, entry 4): In the air, [Rh(dppe)]2(BF4)2
(34.1 mg, 0.0581 mmol) was placed into a Schlenk tube, which was then
filled with argon. Under a positive pressure of argon, 3-methyl-5-phenylpent-
4-ynal (100 mg, 0.581 mmol) and acetone (5 mL) were added. The Schlenk
tube was closed, and the mixture was stirred at room temperature for 48 h.
Then, CH3CN (1 mL) was added, solvents were removed, and the reaction
mixture was purified by flash chromatography (pentane:Et2O ) 3:1), which
furnished 4-methyl-2-phenylcyclopent-2-enone (88 mg, 88%) as a colorless
oil.