Synthesis of 2-alkylidenecyclopentanones via palladium-catalyzed cross-coupling of 1-(1-alkynyl)cyclobutanols and aryl or vinylic halides

Article abstract of DOI:10.1021/ol000219i

(matrix presented) The palladium-catalyzed cross-coupling of aryl or vinylic halides and 1-(1-alkynyl)cyclobutanols affords good yields of stereoisomerically pure 2-arylidene-or 2-(2-alkenylidene)cyclopentanones, respectively, by a process involving (1) o

Full text of DOI:10.1021/ol000219i

ORGANIC
LETTERS
2
000
Vol. 2, No. 21
325-3327
Synthesis of
-Alkylidenecyclopentanones via
Palladium-Catalyzed Cross-Coupling of
-(1-Alkynyl)cyclobutanols and Aryl or
3
2
1
Vinylic Halides
Richard C. Larock* and Ch. Kishan Reddy
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received August 4, 2000
ABSTRACT
The palladium-catalyzed cross-coupling of aryl or vinylic halides and 1-(1-alkynyl)cyclobutanols affords good yields of stereoisomerically pure
-arylidene- or 2-(2-alkenylidene)cyclopentanones, respectively, by a process involving (1) oxidative addition of the organic iodide to Pd(0), (2)
2
carbopalladation of the triple bond of the 1-(1-alkynyl)cyclobutanol, (3) regio- and stereoselective ring expansion to form a novel palladiacycle,
and (4) reductive elimination to the 2-alkylidenecyclopentanone with simultaneous regeneration of the Pd(0) catalyst.
6
The synthesis of 2-alkylidenecyclopentanones is important,
because some natural products bearing this functionality
exhibit significant biological activity. A number of reactions
clization to produce unsaturated bicyclic ketones. 2-(1-
Alkynyl)-2-hydroxycyclobutanones undergo palladium(II)-
catalyzed ring expansion to 2-alkylidene-1,3-cyclopentane-
1
7
of palladium reagents and four-membered ring compounds
have been previously shown to undergo novel processes to
produce ketones. For example, methylenecyclobutanes un-
dergo palladium(II)-catalyzed ring expansion to cyclopen-
diones. 1-(3-Methoxycarbonyloxy-1-propynyl)cyclobutanols
undergo palladium(0)-catalyzed ring expansion in the pres-
ence of phenols to produce 2-(1-aryloxyvinyl)cyclopen-
tanones. Finally, 1-allenylcyclobutanols react with aryl or
vinylic halides in the presence of a palladium catalyst by a
8
2
tanones. The reaction of cyclobutanols and catalytic amounts
3
of Pd(OAc)
2
generates 3-alkenones. The analogous pal-
ladium(0)-catalyzed reaction of cyclobutanols and aryl
halides affords 4-arylalkanones. Recently, 1-vinylcyclo-
(5) (a) Clark, G. R.; Thiensathit, S. Tetrahedron Lett. 1985, 26, 2503.
(b) Demuth, M.; Pandey, B.; Wietfeld, B.; Said, H.; Viader, J. HelV. Chim.
Acta 1988, 71, 1392. (c) de Almeida Barbosa, L.-C.; Mann, J. J. Chem.
Soc., Perkin Trans. 1 1990, 177. (d) Nemoto, H.; Nagamochi, M.; Fukumoto,
K. J. Chem. Soc., Perkin Trans. 1 1993, 2329. (e) Nemoto, H.; Nagamochi,
M.; Ishibashi, H.; Fukumoto, K. J. Org. Chem. 1994, 59, 74. (f) Nemoto,
H.; Miyata, J.; Fukumoto, K. Tetrahedron 1996, 52, 10363. (g) Nemoto,
H.; Miyata, J.; Ihara, M. Tetrahedron Lett. 1999, 40, 1933.
4
butanols or the corresponding silyl ethers have been shown
to react with palladium(II) salts to produce ring-expanded
palladiocyclopentanones, which undergo either hydride
5
elimination to unsaturated cyclopentanones or further cy-
(6) (a) Nemoto, H.; Shiraki, M.; Fukumoto, K. Synlett 1994, 599. (b)
Nemoto, H.; Miyata, J.; Yoshida, M.; Raku, N.; Fukumoto, K. J. Org. Chem.
1997, 62, 7850. (c) Nemoto, H.; Yoshida, M.; Fukumoto, K.; Ihara, M.
Tetrahedron Lett. 1999, 40, 907.
(7) (a) Liebeskind, L. S.; Mitchell, D.; Foster, B. S. J. Am. Chem. Soc.
1987, 109, 7908. (b) Liebeskind, L. S.; Chidambaram, R.; Mitchell, D.;
Foster, B. S. Pure Appl. Chem. 1988, 60, 27. (c) Mitchell, D.; Liebeskind,
L. S. J. Am. Chem. Soc. 1990, 112, 291.
(
1) See: Liebeskind, L. S.; Chidambaram, R.; Mitchell, D. Pure Appl.
Chem. 1988, 60, 27 and references therein.
2) Boontanonda, P.; Grigg, R. J. Chem. Soc., Chem. Commun. 1977,
83.
(
5
2
(3) Nishimura, T.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 1999, 121,
645.
(4) Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 11010.
(8) Yoshida, M.; Nemoto, H.; Ihara, M. Tetrahedron Lett. 1999, 40, 8583.
1
0.1021/ol000219i CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/28/2000

process involving carbopalladation of the allene and subse-
quent ring expansion of the resulting π-allylpalladium
intermediate to generate unsaturated cyclopentanones (eq 1).
Table 1. Palladium-Catalyzed Cross-Coupling of
9
a
1-(1-Alkynyl)cyclobutanols and Aryl or Vinylic Iodides
Despite the fact that we have carried out a large number
of carbopalladation reactions on 1-(1-alkynyl)cycloalkanols
bearing five- or six-membered rings without any involvement
of the carbocyclic ring, this latter process involving allenyl-
cyclobutanols encouraged us to examine the possibility that
1
-(1-alkynyl)cyclobutanols might undergo an analogous
cross-coupling process with aryl or vinylic halides to afford
-alkylidenecyclopentanones. We now wish to report the
2
success of that process.
With a wide variety of 1-(1-alkynyl)cyclobutanols readily
available, we focused our initial studies on the reaction of
1-(phenylethynyl)cyclobutanol (1) and iodobenzene as our
model system (eq 2). An examination of the effect of several
different palladium catalysts [Pd(PPh
Pd(dba) ], various inorganic and organic bases, two different
chloride sources [LiCl and n-Bu NCl (TBAC)], and the
ligand PPh on the yield of cyclopentanone 2 afforded the
following optimized procedure: 10 mol % of Pd(OAc) , 20
mol % of PPh , 2 equiv of aryl or vinylic iodide, 2 equiv of
diisopropylethylamine as the base, and 2 equiv of n-Bu NCl
3 4 2
) , Pd(OAc) , and
2
4
3
2
3
4
are allowed to react in DMF as the solvent at 80 °C. This
procedure afforded a 70% yield of cyclopentanone 2 after a
12 h reaction time (Table 1, entry 1).
With a standard procedure in hand, we explored the scope
and limitations of this novel route to 2-alkylidenecyclopen-
tanones by examining a wide variety of 1-(1-alkynyl)-
cyclobutanols and aryl or vinylic iodides as shown in Table
1
. The reaction of 1-(phenylethynyl)cyclobutanol (1) and the
electron-rich o-iodoanisole provided the corresponding
-arylidenecyclopentanone as a single stereoisomer in good
2
yield (entry 2). A high yield was also obtained from the
electron-poor o-iodonitrobenzene (entry 3). Neither electronic
effects nor steric hindrance thus appear to cause any
problems. Under our standard reaction conditions for aryl
iodides, phenyl triflate failed to produce any of the expected
cyclopentanone product.
We also examined the possibility of employing vinylic
iodides in this process. The reaction of 1-(phenylethynyl)-
cyclobutanol (1) and (E)-1-iodo-1-hexene under our standard
conditions afforded the single isomeric product 5 in 40%
a
Unless otherwise stated, all reactions were carried out under an argon
atmosphere using 1 equiv of cyclobutanol (0.5 mmol), 2 equiv of organic
halide (1.0 mmol), 10 mol % of Pd(OAc)2 (0.05 mmol), 20 mol % of PPh3
(
(
0.1 mmol), 2 equiv of n-Bu4NCl (TBAC, 1.0 mmol), 2 equiv of i-Pr2NEt
1.0 mmol), and DMF (5 mL) at 80 °C for 12 h. b These reactions were
(
9) (a) Nemoto, H.; Yoshida, M.; Fukumoto, K. J. Org. Chem. 1997,
carried out for 6 h at 80 °C.
6
2, 6450. (b) Yoshida, M.; Sugimoto, K.; Ihara, M. Tetrahedron Lett. 2000,
1, 5089.
4
3326
Org. Lett., Vol. 2, No. 21, 2000

yield (entry 4). The 2D NOSEY spectrum of the product
was only consistent with the carbonyl group and the new
vinylic moiety being trans to each other. Surprisingly, the
analogous reaction with the vinylic triflate 4-phenylcyclohex-
Scheme 1
1
1
-enyl triflate afforded a higher yield, but the product was a
:1 mixture of stereoisomers, which proved to be rather
unstable (entry 5).
The reaction of 1-(prop-1-ynyl)cyclobutanol (7) and iodo-
benzene under our standard conditions again gave the single
isomer product 8 (Table 1, entry 6). The product was
characterized by 1D and 2D NMR HMQC, COSEY, and
NOSEY spectroscopy. The spectra are only consistent with
the structure 8 with the phenyl group trans to the carbonyl.
Further examples of the reaction of 1-(prop-1-ynyl)cyclo-
butanol (7) and an aryl iodide or a vinylic iodide produced
analogous ring-expanded products in slightly lower yields
than those obtained with 1-(phenylethynyl)cyclobutanol (1)
(entries 7 and 8). In both cases, a single stereoisomeric
product was obtained. Good results were also obtained in
the reaction between 3-phenyl-1-(phenylethynyl)cyclobutanol
of the Pd(0) catalyst. Ring expansion to a palladiacycle nicely
explains the fact that the aryl or vinylic group arising from
the organic iodide always ends up trans to the carbonyl
carbon. Were the cyclobutanol carbon to migrate so as to
effect a direct backside displacement of the vinylic palladium,
one would expect the opposite stereochemistry in the final
product.
(
11) and the electron-deficient aryl iodide ethyl p-iodo-
benzoate (entry 9).
To gain a better mechanistic understanding of this inter-
esting process, we carried out reactions with two un-
symmmetrical bicyclic alkynols. The reaction between
6-(phenylethynyl)bicyclo[3.2.0]hept-2-en-6-ol (13) and o-
iodoanisole under our standard reaction conditions gave the
single regioisomeric product 14 in good yield whose spectra
are only consistent with an electron-deficient intermediate
being generated in which the more substituted carbon of the
cyclobutanol has undergone migration (entry 10). Similarly,
the reaction of 1-methyl-7-(phenylethynyl)bicyclo[4.2.0]-
octan-7-ol (15) and iodobenzene gave a good yield of the
bicyclononanone 16 in which the more substituted neighbor-
ing carbon of the cyclobutanol has undergone exclusive
In conclusion, a variety of highly substituted 2-alkyl-
idenecyclopentanones have been prepared by the reaction
of aryl or vinylic iodides and 1-(1-alkynyl)cyclobutanols in
the presence of a palladium catalyst. These products are
formed regio- and stereoselectively in moderate yields. The
process appears to involve a novel ring expansion to a
palladiacyclohexanone and subsequent reductive elimination.
It would be quite difficult to prepare such products by any
other present methodology.
migration.
On the basis of the above results and previous work,8,9
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, for partial support of this
research, Kawaken Fine Chemicals Co., Ltd. for donation
of the palladium acetate, and Merck Co., Inc. for an
Academic Development Award in Chemistry.
we believe that this novel ring expansion process proceeds
as shown in Scheme 1 by a sequence involving (1) reduction
of Pd(OAc) to the actual Pd(0) catalyst, (2) oxidative
2
addition of the aryl or vinylic iodide or triflate to Pd(0), (3)
vinylic or arylpalladium coordination to the carbon-carbon
triple bond of the alkynylcyclobutanol and subsequent regio-
and stereoselective insertion of the alkynylcyclobutanol to
form a vinylpalladium intermediate, (4) release of the
cyclobutane ring strain by migration of the more highly
substituted, electron-rich carbon of the cyclobutanol to
palladium to produce a palladiacyclohexanone, and (5)
reductive elimination to afford a single stereoisomeric
Supporting Information Available: The preparations of
all starting 1-(1-alkynyl)cyclobutanols, the standard pal-
1
13
ladium-catalyzed cross-coupling procedure, and H and
C
NMR spectra for all starting cyclobutanols and cyclopen-
tanone products in Table 1. This material is available free
of charge via the Internet at http://pubs.acs.org.
2-alkylidenecyclopentanone with simultaneous regeneration
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