Intermolecular Pauson-Khand reactions of cyclopropane: A general synthesis of cyclopentanones

Article abstract of DOI:10.1021/ol016505r

(equation presented) The Pauson-Khand reaction of cyclopropene with a variety of terminal alkynes has been studied. The best reaction conditions involve NMO activation in CH₂Cl₂ at -35 °C. In this way, 3-substituted-bicyclo[3.1.0]hex-3-en-2-ones have been obtained in good to excellent yields. As a synthetic application, several types of substituted cyclopentenones have been prepared from these cycloadducts by protocols involving conjugate addition and reductive ring opening.

Full text of DOI:10.1021/ol016505r

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3193-3196
Intermolecular Pauson−Khand Reactions
of Cyclopropene: A General Synthesis
of Cyclopentanones
,†
Iolanda Marchueta, Xavier Verdaguer, Albert Moyano, Miquel A. Perica`s,* and
Antoni Riera*
Departament de Qu´ımica Orga`nica, Mart´ı i Franque`s, 1-11, Barcelona E-08028, Spain
a.riera@qo.ub.es
Received July 27, 2001
ABSTRACT
The Pauson−Khand reaction of cyclopropene with a variety of terminal alkynes has been studied. The best reaction conditions involve NMO
activation in CH Cl2 at −35 °C. In this way, 3-substituted-bicyclo[3.1.0]hex-3-en-2-ones have been obtained in good to excellent yields. As a
2
synthetic application, several types of substituted cyclopentenones have been prepared from these cycloadducts by protocols involving
conjugate addition and reductive ring opening.
One of the most significant characteristics of the Pauson-
Khand (PK) reaction1 is its broad applicability, tolerating
many functional groups. Up to now, a great variety of
structural patterns and functionalities have been described
in intramolecular PK cyclizations, giving rise to a plethora
of structures. In the intermolecular version of the reaction,
however, the diversity of alkynes that have been successfully
used is in sharp contrast with the small number of the alkene
counterparts. It is well-known that only strained alkenes, such
as cyclobutenes, or bicyclic olefins with a norbornane
skeleton are good substrates for intermolecular PK reactions.1
Although substituted ethylenes and some cyclic olefins such
as cyclopentenes or dihydrofuranes can give the reaction,
on most occasions the yields using unstrained olefins are
low. Theoretical [DFT//PM3(tm)] calculations2 provide an
adequate explanation for this behavior and suggest that
cyclopropene should be an excellent substrate for inter-
molecular PK cyclizations. Somewhat surprisingly, there are
only few reports on the use of cyclopropenes in PK
reactions,3 and to the best of our knowledge the simplest
member of this type of compound has never been tested in
the reaction. Bicyclo[n.1.0]alkenones, such as those that
could result from the PK reaction of cyclopropene, are
synthetically useful compounds which, taking advantage of
their ring strain, have been used in a variety of reactions
featuring nucleophilic ring opening or reductive ring expan-
sions.4 We describe herein our results in the study of the
Pauson-Khand reaction of cyclopropene which provide a
useful preparation of bicyclo[3.1.0]hexenones and the regio-
and stereoselective transformation of those systems into
polysubstituted cyclopentanones.
† E-mail: mapericas@qo.ub.es.
Following the procedure described by Binger,5 a solution
of cyclopropene in toluene was prepared by treating a
(1) For selected reviews, see: (a) Pauson, P. L. Tetrahedron 1985, 41,
5855-5860. (b) Pauson, P. L. In Organometallics in Organic Synthesis.
Aspects of a Modern Interdisciplinary Field; de Meijere, A., tom Dieck,
H., Eds.; Springer: Berlin, 1988; pp 233-246. (c) Harrington, P. J.
Transition Metals in Total Synthesis; Wiley: New York, 1990; pp 259-
301. (d) Schore, N. E. Org. React. 1991, 40, 1-90. (e) Schore, N. E. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 5, pp 1037-1064. (f) Chung, Y. K. Coord. Chem. ReV.
1999, 188, 297-341. (g) Sugihara, T.; Yamaguchi, M.; Nishizawa, M. ReV.
Heteroat. Chem. 1999, 21, 179-194. (h) Brummond, K. M.; Kent, J. L.
Tetrahedron 2000, 56, 3263-3283.
(2) Vazquez, J.; Moyano, M.; Perica`s, M. A.; Riera, A., unpublished
results.
(3) (a) Kireev, S. L.; Smit, V. A.; Ugrak, B. I.; Nefedov, O. M. Bull.
Acad. Sci USSR (Engl. Transl.) 1991, 2240-2246. (b) Nu¨ske, H.; Bra¨se,
S.; de Meijere, A. Synlett 2000, 1467-1469. (c) Witulski, B.; Gossmann,
M. Synlett 2000, 1793-1797.
(4) (a) Baird, M. S. Top. Curr. Chem. 1988, 144, 137-209. (b) Padwa,
A.; Fryxell, G. E. AdV. Strain Org. Chem. 1991, 1, 117-166.
10.1021/ol016505r CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/12/2001

solution of allyl chloride in toluene at reflux with sodium
bis(trimethylsilyl)amide and trapping the gas in toluene at
-78 °C. On the other hand, the hexacarbonyl-dicobalt
complexes 2 were prepared by treatment of the corresponding
alkyne 1 with octacarbonyl dicobalt in hexanes at room
temperature (Scheme 1).
the reaction: Due to the high reactivity of cyclopropene, a
further olefin insertion competes with the normal CO
insertion, leading to a cyclopentenone.9 Disappointingly, the
cobalt complex derived from 1-hexyne did not afford any
cycloadduct under the same reaction conditions.
Since the reaction was taking place near the onset
temperature for cyclopropene polymerization, we reasoned
that, to improve the yield, the PK reaction should proceed
as fast as possible. Perhaps the low solubility of the NMO
in the mixture of toluene and methylene chloride at -30 °C
could be responsible for the low rate and consequently for
low yields. The reaction conditions were thus modified
again: Cyclopropene was condensed neat, dissolved in
CH2Cl2, and added to a mixture of NMO and cobalt complex
2a in CH2Cl2 at -35 °C. The reaction took place in only 5
min, yielding enone 3a in 93% yield. Under these optimized
conditions, the standard PK adducts 3b and 3c could be
finally obtained, although in both cases small amounts of
the tricyclic products 4b and 4c were also formed (Table
1).
Scheme 1
The Pauson-Khand reaction between cyclopropene and
tert-butylacetylene was first attempted under purely thermal
conditions. A solution of cyclopropene in toluene was added
to a solution of hexacarbonyl dicobalt complex 2a (R ) t-Bu)
in toluene at -78 °C, and the mixture was slowly allowed
to warm with stirring. However, no trace of PK cycloadducts
was observed in the crude by TLC. Since it is known that
cyclopropene polymerizes at temperatures above -30 °C,
we reasoned that the reaction had to be performed below
this temperature and that N-oxide promotion could help in
this task.6,7 Thus, a solution of cyclopropene in toluene
(aproximately 5-7 equiv) was added to a stirred solution of
2a in methylene chloride at -78 °C and a solution of NMO
(6 equiv) in methylene chloride was next added. The mixture
was allowed to warm to -30 °C and stirred until the starting
complex was consumed. In this way, a moderate 42% yield
of 3-tert-butylbicyclo[3.1.0]hex-3-en-2-one (3a) could be
isolated by chromatography of the reaction crude (Scheme
2). However, under the same reaction conditions, the cobalt
Table 1. Pauson-Khand Reaction of Cyclopropene with
Hexacarbonyl-Dicobalt Complexes 2 Derived from Terminal
Alkynes 1a
starting complex, R )
4, % yield
3, % yield
2a
2b
2c
2d
2e
2f
tert-butyl
phenyl
n-hexyl
Ph3Si
PhCH3C(OH)
p-tolyl
93
50
60
82
45
26
51
15
10
23
2h
(CH3)2C(OH)
a Reaction conditions. A solution of the hexacarbonyl-dicobalt complex
2 in CH2Cl2 was cooled to -35 °C. To this solution were sequentially added,
via cannula, 6 equiv of NMO (2 M solution in CH2Cl2) and 7 equiv of
cyclopropene (ca. 6-10 M solution in CH2Cl2). After 5 min of stirring at
-35 °C, the mixture was filtered through Celite and evaporated. The crude
was chromatographed on silica gel, eluting with EtOAc/hexanes.
These optimized conditions were tested on a series of
cobalt complexes 2d-h derived from commercially available
terminal alkynes. In the case of bulky substituents (2a,d),
the yields of bicyclo[3.1.0]hex-3-en-2-ones are very high.
The cobalt complex of p-tolylacetylene exhibits the lowest
yield of bicyclic adducts due to the significant amount of
tricyclononanone 4h formed in the reaction. In summary,
the Pauson-Khand of cyclopropene with bulky terminal
alkynes gives good to excellent yields of cycloadducts,
whereas in the case of aromatic and n-alkyl-substituted
alkynes the yields are good to moderate.
Scheme 2
(6) At this temperature, the purely thermal dissociative loss of CO
required for the reaction is extremely slow and NMO-promoted dissociation
can provide an appropriate reaction rate.
complex 2b (R ) Ph) prepared from phenylacetylene
afforded the tricyclic ketone 4b in 50% yield as a main
product. This unprecedented adduct8 should arise from the
abnormal evolution of the key cobaltacycle intermediate of
(7) (a) Shambayati, S.; Crowe, W. E.; Schreiber, S. L. Tetrahedron Lett.
1990, 31, 5289-5292. (b) Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.;
Yoo, S. E. Synlett 1991, 204-206.
(8) Only one stereoisomer of 4b was observed by 1H and 13C NMR.
The stereochemistry of this adduct could not be unambiguously established.
(9) For a complete theoretical study of the mechanism, see: Yamanaka,
M.; Nakamura, E. J. Am. Chem. Soc. 2001, 123, 1703-1708.
(5) Binger, P.; Wedemann, P.; Goddard, R.; Brinker, U. H. J. Org. Chem.
1996, 61, 6462-6464.
3194
Org. Lett., Vol. 3, No. 20, 2001

Although, 3-substituted bicyclo[3.1.0]hex-3-en-2-ones such
as the PK adducts reported here are relatively unknown
compounds,10 other substances, either synthetic11 or natural,12
with the same bicyclic skeleton but with a different substitu-
tion pattern have been described in the literature. Most of
these compounds have been prepared by photochemical
rearrangement of enones13 or phenols14 and are used in
mechanistic studies related to the photochemical conversion
of santonin into lumisantonin.15
Once a practical procedure for the synthesis of 3-substi-
tuted bicyclo[3.1.0]hex-3-en-2-ones 3 was developed, their
synthetic potential was subsequently explored. The photo-
chemical behavior leading the corresponding ortho-substi-
tuted phenols is discussed in detail in the following Letter.21
The combination of conjugate addition and ring expansion
reactions also has potential applications for the synthesis of
substituted cycloalkanones. The conjugate addition was
studied on substrate 3a, which by treatment either with
Bu2Cu(CN)Li2 or Ph2CuLi2 afforded respectively the bicyclic
cyclopentanones 5aa or 5ab in excellent yields (Scheme 3).
was established by NOESY experiments and in the case of
5aa was assigned by analogy. As expected, the conjugate
addition took place from the less hindered exo face of the
bicyclic structure, trans to the cyclopropane methylene group.
The relative stereochemistry of the tert-butyl group was also
determined to be trans to the phenyl. Semiempirical calcula-
tions using AM116 confirmed that this structure is the
thermodynamically most stable isomer. Conjugate addition
of the same cuprates on other adducts also gave excellent
yields of cyclopentanones and followed the same stereo-
chemical course. For instance, triphenylsilyl derivative 3d
afforded 5da and 5db in 90 and 70% yields, respectively.
Compound 5ab was used to explore ring opening reactions
of the cyclopropane moiety. Unfortunately, all of our attempts
to hydrogenate the cyclopropane ring under a variety of
hydrogenation conditions (Pd/C or Pt2O)17 failed, leading to
the recovery of unchanged starting material. Identical results
were obtained by treatment with Zn in methanol in the
presence of zinc chloride.17 Quite gratifyingly, however, the
reductive photoinduced electron transfer (hν 254 nm, Et3N,
LiClO4, CH3CN)18 provided the methylcyclopentanone 6ab
in 60% yield. An even better yield was obtained by reductive
cleavage using samarium iodide,19 which afforded 6ab in
74% yield. In both cases, the reduction took place with
complete regioselectivity R to carbonyl exo-cyclic bond
(Scheme 4). Even more surprising was the fact that electro-
Scheme 3
Scheme 4
The reaction was totally stereoselective, affording only one
isomer. The stereochemistry of 5ab (depicted in Scheme 3)
(10) Williamson, B. L.; Tykwinski, R. R.; Stang, P. J. J. Am. Chem.
Soc. 1994, 116, 93-98.
(11) (a) Parziale, P. A.; Berson, J. A. J. Am. Chem. Soc. 1991, 113,
4595-4606. (b) Dolbier, W. R., Jr.; Garza, O. T. J. Org. Chem. 1978, 43,
3848. (c) Baraldi, P. G.; Pollini, G. P.; Simoni, D.; Barco, A.; Benetti, S.
Tetrahedron 1984, 40, 761-764. (d) Padwa, A.; Chiacchio, U.; Fairfax,
D. J.; Kassir, J. M.; Litrico, A.; Semones, M. A.; Xu, S. L. J. Org. Chem.
1993, 58, 6429-6437.
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1151. (b) Barber, L.; Chapman, O. L.; Lassila, J. D. J. Am. Chem. Soc.
1968, 90, 5933-5934. (c) Adams, R. P.; Zanoni, T. A.; Lara, A.; Barrero,
A. F.; Cool, L. G. J. Essent. Oil Res. 1997, 9, 303-309. (d) Malizia, R.
A.; Cardell, D. A.; Gonzalez, S.; Guerra, P.; Grou, R. J. J. Essent. Oil Res.
2000, 12, 59-63.
(13) (a) Zimmerman, H. E.; Schuster, D. I. J. Am. Chem. Soc. 1961, 83,
4486-4488. (b) Schultz, A. G.; Lavieri, F. P.; Macielag, M. Tetrahedron
Lett. 1986, 27, 1481-1484. (c) Schultz, A. G. Pure Appl. Chem. 1988, 60,
981-988. (d) Zimmerman, H. E.; Lynch, D. C. J. Am. Chem. Soc. 1985,
107, 7745-7756. (e) Quinkert, G.; Kleiner, E.; Freitag, B. J.; Glenneberg,
J.; Billhardt, U. M.; Cech, F.; Schmieder, K. R.; Schudok, C.; Steinmetzer,
H. C.; Bats, J. W.; Zimmermann, G.; Du¨rner, G.; Rehm, D.; Paulus, E. F.
HelV. Chim. Acta 1986, 69, 469-537.
(14) (a) Kakiuchi, K.; Ue, M.; Yamaguchi, B.; Nishimoto, A.; Tobe, Y.
Bull. Chem. Soc. Jpn. 1991, 64, 3468-3470. (b) Baeckstro¨m, P.; Jacobsson,
U.; Koutek, B.; Norin, T. J. Org. Chem. 1985, 50, 3728-3732.
(15) Schuster, D. I. Acc. Chem. Res. 1978, 11, 65-73.
philic ring opening of 6ab using the conditions developed
by Dieter20 (trimethylsilyl chloride/NaI/CH3CN) afforded
iodide 7ab in 92% yield.
The Pauson-Khand adducts of silylacetylenes such as 5d
can be used as a precursors of 3,4-disubstituted cyclopen-
tanones through a sequence of conjugate addition, TBAF
(16) As implemented in SPARTAN, version 4.1.1, Wavefunction, Inc.
(17) Attah-Poku, S. K.; Antzak, K.; Alward, S. J.; Fallis, A. G. Can. J.
Chem. 1984, 62, 1717-1721. (b) Attah-Poku, S. K.; Alward, S. J.; Fallis,
A. G. Tetrahedron Lett. 1983, 24, 681-684.
(18) (a) Cossy, J.; BouzBouz, S. Tetrahedron Lett. 1997, 38, 1931-
1932. (b) Cossy, J.; Furet, N. Tetrahedron Lett. 1993, 34, 8107-8110. (c)
Bischof, E. W.; Mattay, J. J. Photochem. Photobiol, A: Chem. 1992, 63,
249-251.
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Org. Lett., Vol. 3, No. 20, 2001
3195

treatment to remove the silyl group, and reductive ring
opening. In Scheme 5 is shown the transformation of 5da
These synthetic sequences provide a new strategy for the
modular construction of substituted cyclopentanones which
is currently being studied in our group. Thus, di- or
trisubtituted cyclopentenones would be constructed from an
alkyne, cyclopropene, carbon monoxide, and cuprate reagent
as represented in Figure 1.
Scheme 5
and 5db into 3-substituted 4-methylcyclopentanones in
excellent overall yields.
In summary, we have found that cyclopropene is an
excellent substrate for PK reactions. The appropriate condi-
tions consist of performing the reaction in CH2Cl2 at -35
°C in the presence of NMO. The resulting 3-substituted
bicyclo[3.1.0]-3-hexen-2-ones 3 are interesting intermediates
that can be easily converted into di- or trisubstituted
cyclopentanones in a totally controlled regio- and stereo-
selective manner by protocols involving conjugate addition,
reductive ring opening, and silyl group removal.
Figure 1.
Acknowledgment. Financial support from MEC (Grant
PB98-1246) and DURSI (Grant 2000SGR00019) is gratefully
acknowledged. I. Marchueta thanks University of Barcelona
for a fellowship.
OL016505R
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Org. Lett., Vol. 3, No. 20, 2001