New cobalt-catalyzed cycloisomerization of ε-acetylenic β-keto esters. Application to a powerful cyclization reactions cascade

Article abstract of DOI:10.1021/jo9600619

The full details of investigations into the cobalt(I)-catalyzed ene type reaction of ε-acetylenic β-keto esters to form highly functionalized methylenecyelopentanes are described. The observed regio-, chemo-, and stereoselectivities support a process of cycloisomerization which controls the relative stereochemistry of two contiguous stereogenic centers. An efficient route to the basic skeleton of the phyllocladane family has been achieved via a one-pot sequence of cyclizations: ene type, [2 + 2 + 2], [4 + 2]. This new cascade created six carbon-carbon bonds and four rings in a totally stereoselective manner from an easily accessible acyclic polyunsaturated precursor.

Full text of DOI:10.1021/jo9600619

J . Org. Chem. 1996, 61, 2699-2708
2699
New Coba lt-Ca ta lyzed Cycloisom er iza tion of E-Acetylen ic â-Keto
Ester s. Ap p lica tion to a P ow er fu l Cycliza tion Rea ction s Ca sca d e
Paul Cruciani, Robert Stammler, Corinne Aubert, and Max Malacria*
Universite´ Pierre et Marie Curie, Paris VI, Laboratoire de Chimie Organique de Synthe`se, associe´ au
CNRS, tour 44-54, B. 229, 4, Place J ussieu, 75252 - Paris Cedex 05, France
Received J anuary 9, 1996X
The full details of investigations into the cobalt(I)-catalyzed ene type reaction of ꢀ-acetylenic â-keto
esters to form highly functionalized methylenecyclopentanes are described. The observed regio-,
chemo-, and stereoselectivities support a process of cycloisomerization which controls the relative
stereochemistry of two contiguous stereogenic centers. An efficient route to the basic skeleton of
the phyllocladane family has been achieved via a one-pot sequence of cyclizations: ene type, [2 +
2 + 2], [4 + 2]. This new cascade created six carbon-carbon bonds and four rings in a totally
stereoselective manner from an easily accessible acyclic polyunsaturated precursor.
In tr od u ction
tion of ꢀ-acetylenic â′-alkyl â-keto esters with the dia-
stereoselective generation of highly functionalized meth-
ylenecyclopentanes8,9 enhancing the synthetic utility of
this thermal10 or Lewis acid11 -catalyzed reaction and the
basic carbopalladation reaction.12
Transition-metal-mediated cyclizations of substrates
containing two or more unsaturations have provided new
catalytic strategies for the construction of polycyclic
molecules.1,2 Toward this aim, the use of cobalt com-
plexes has seen many applications during the past fifteen
years.3 For instance, the [2 + 2 + 2] cocyclization of
alkynes affords a versatile entry to the total synthesis of
natural compounds.4 In addition, the intramolecular
version including the use of enediynes or triynes led to
new syntheses of natural or unnatural steroids5 as well
as various important sesquiterpenes6 and tetracyclic
diterpenes.7
Here, we present full details of the scope, limitations,
and the investigations into the mechanism of such a new
cobalt(I)-mediated ene type reaction and its application
in the field of cascade chemistry.13 By using only one
transition-metal, we disclosed a new one-pot combination
of reactions: ene type reaction, [2 + 2 + 2] cyclization,
and intramolecular [4 + 2] reaction to afford the basic
skeleton of a tetracyclic diterpene of the phyllocladane
family in a totally controlled manner.14 This one-pot
sequence created six carbon-carbon bonds and four rings
from an acyclic polyunsaturated precursor.
Recently, we disclosed a new (η5-cyclopentadienyl)-
dicarbonyl cobalt [CpCo(CO)2]-catalyzed cycloisomeriza-
X Abstract published in Advance ACS Abstracts, March 15, 1996.
(1) For Pd-catalyzed cycloisomerizations, see: (a) Trost, B. M Acc.
Chem. Res. 1990, 23, 34-42. (b) Trost, B. M. J anssen Chim. Acta 1991,
9, 3-9. (c) Trost, B. M.; Pfrengle, W.; Urabe, H.; Dumas, J . J . Am.
Chem. Soc. 1992, 114, 1923-1924. (d) Trost, B. M.; Shi, Y. Ibid. 1992,
114, 791-792. (e) Negishi, E.-I.; Harring, L. S.; Owczarczyk, Z.;
Mohamud, M. M.; Ay, M. Tetrahedron Lett. 1992, 33, 3253-3256. (f)
Meyer, F. E.; Henniges, H.; de Meijere, A. Ibid. 1992, 33, 8039-8042.
(g) Takacs, J . M.; Zhu, J .; Chandramouli, S. J . Am. Chem. Soc. 1992,
114, 773-774. (h) Kucera, D. J .; O’Connor, S. J .; Overman, L. E. J .
Org. Chem. 1993, 58, 5304-5306. (i) Brown, S.; Clarkson, S.; Grigg,
R.; Sridharan, V. Tetrahedron Lett. 1993, 34, 157-160. (j) Trost, B.
M.; Gelling, O. J . Ibid. 1993, 34, 8233-8236. (k) Trost, B. M.; Czeskis,
B. A. Ibid. 1994, 35, 211-214. (l) Takacs, J . M.; Chandramouli, S. V.
Ibid. 1994, 35, 9165-9168.
(2) For Rh-catalyzed cyclizations, see: Grigg, R.; Scott, R.; Steven-
son, R. J . Chem. Soc., Perkin Trans. 1 1988, 1357-1364. For Fe-
catalyzed version, see: (a) Takacs, J . M.; Weidner, J . J .; Takacs, B. E.
Tetrahedron Lett. 1993, 34, 6219-6222. (b) Takacs, J . M.; Myoung,
Y.-C.; Anderson, L. G. J . Org. Chem. 1994, 59, 6928-6942. For Zr-
catalyzed version: (a) Negishi E.-I. In Comprehensive Organic Syn-
thesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, pp 1163-1184. (b) Agnel, G. Negishi, E.-
I. J . Am. Chem. Soc. 1991, 113, 7424-7426. For Ni-catalyzed version,
see: Tamao, K.; Kobayashi, K.; Ito, Y. Synlett 1992, 539-546.
(3) (a) Shore N. E. In Comprehensive Organic Synthesis, Trost, B.
M., Fleming, I., Paquette, L. A., Eds.; Pergamon Press: Oxford, 1991;
Vol. 5, pp 1037-1064 and pp 1129-1162. (b) Lautens, M.; Tam, W.;
Edwards, L. G. J . Org. Chem. 1992, 57, 8-9.
(4) (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23,
534-556. (b) Gotteland, J .-P.; Malacria, M. Tetrahedron Lett. 1989,
30, 2541-2544. (c) Gotteland, J .-P.; Malacria, M. Synlett 1990, 667-
669. (d) Aubert, C.; Gotteland, J .-P.; Malacria, M. J . Org. Chem. 1993,
58, 4298-4305.
(5) (a) Vollhardt, K. P. C. Pure Appl. Chem. 1995, 57, 1819-1826.
(b) Lecker, S. H.; Nguyen, N. H.; Vollhardt, K. P. C. J . Am. Chem.
Soc. 1986, 108, 856-858. (c) Butenscho¨n, H.; Winkler, M.; Vollhardt,
K. P. C. J . Chem. Soc., Chem. Commun. 1986, 388-390.
(6) J ohnson, E. P.; Vollhardt, K. P. C. J . Am. Chem. Soc. 1991, 113,
381-382.
(7) Germanas, J .; Aubert, C.; Vollhardt, K. P. C. J . Am. Chem. Soc.
1991, 113, 4006-4008.
Resu lts a n d Discu ssion
Scop e, Lim ita tion s, a n d Mech a n istic Asp ects.
The ꢀ-acetylenic â-keto ester 1 was prepared in 90% yield
by alkylation of the methyl acetoacetate sodium enolate
with 5-bromo-1-pentyne according to an usual proce-
dure.15 When a xylenes solution of 1 was heated to reflux
(137-140 °C) in the presence of 5 mol % CpCo(CO)2, a
fast reaction afforded a 3:1 mixture of compounds 2 and
3 in 92% yield (Scheme 1).
The migration of the double bond, already described,4d
seems to result from a partial decomposition of the
catalyst at high temperature which generates more
electrophilic cobalt species. As expected, when the reac-
(8) Stammler, R.; Malacria, M. Synlett 1994, 92.
(9) Cruciani, P.; Aubert, C.; Malacria, M. Tetrahedron Lett. 1994,
35, 6677-6680.
(10) (a) Conia, J . M.; Le Perchec, P. Synthesis 1975, 1-19. (b)
Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978, 17, 476-
486. (c) Mandville, G.; Conia, J . M. Nouv. J . Chim. 1981, 5, 137-140.
(d) Boaventura, M. A.; Drouin, J . Bull. Soc. Chim. Fr. 1987, 1015-
1026. (e) J ackson, W. P.; Ley, S. V. J . Chem. Soc. Perkin Trans. 1 1981,
1516-1519.
(11) Snider, B. B. Acc. Chem. Res. 1980, 13, 426-432 and references
cited therein.
(12) (a) Fournet, G.; Balme, G.; Gore´, J . Tetrahedron Lett. 1989, 30,
69-70. (b) Bouyssi, D.; Balme, G.; Fournet, G.; Monteiro, N.; Gore´, J .
Tetrahedron Lett. 1991, 32, 1641-1644.
(13) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993,
32, 131-163.
(14) Cruciani, P.; Aubert, C.; Malacria, M. J . Org. Chem. 1995, 60,
2664-2665.
(15) Reynolds, R. C.; Trask, T. W.; Sedwick, W. D. J . Org. Chem.
1991, 56, 2391-2395.
0022-3263/96/1961-2699$12.00/0 © 1996 American Chemical Society

2700 J . Org. Chem., Vol. 61, No. 8, 1996
Cruciani et al.
Ni-Cr catalyst system16 or by the introduction of a
substituent on the alkene moiety able to coordinate to
the metal.1j
Sch em e 1
We, then, prepared γ-functionalized ω-acetylenic â-keto
esters 6, 11, and â-keto esters 12-14. The alkylation of
the dianion of methyl acetoacetate17 with 3-bromo-1-
propyne afforded 6 in 79% yield; 11 was made as
described in Scheme 2. Compounds 12-14 were synthe-
sized by using a basic modification of the Carroll method18
which consists of the opening of 2,2,6-trimethyl-1,3
dioxen-4-one by the propargylic alkoxides. Attempts to
execute the cobalt-catalyzed cycloisomerization of the
ω-acetylenic â-keto esters 6, 11-14 under our standard
conditions met with failure. No consumption of starting
material was observed after 5 h in refluxing benzene or
xylenes.
Sch em e 2
Thus, this new cobalt-catalyzed cyclization showed a
preference for formation of methylenecyclopentanes over
the six-membered analogs. Although some precursors
did not afford the corresponding cycloadducts, they
contribute to the understanding of the mechanism. First
of all, a thermal ene-reaction has to be rejected because
it usually requires usually high temperature (≈280 °C).10
Nevertheless, control experiments showed that 1 was
totally recovered after 5 h, in the absence of CpCo(CO)2
in boiling xylenes with or without irradiation, indicating
the crucial role of the catalyst. Moreover, it is unlikely
that CpCo(CO)2, could be considered as a Lewis acid19
catalyzing an ene-reaction. Free-radical cyclizations
could be also considered, but some elements allow us to
exclude such mechanisms: (i) the compounds 5-14 are
unreactive under our conditions whereas related com-
pounds are known to cyclize under oxidative free-radical
reactions20 and the very well-documented 5-exo and
6-endo dig radical chain processes;21 (ii) the cyclization
of ω-ethylenic â-keto ester 15 failed even with a stoichio-
metric amount of CpCo(CO)2 whereas in presence of Mn-
(III), Co(II), and Fe(II) complexes20c,22 related compounds
gave efficiently the corresponding cycloadducts; (iii)
moreover, 2 was the sole product of the cyclization of 1
in benzene, even in presence of radical inhibitor.
Finally, we checked the reactivity of a ꢀ-disubstituted
acetylenic â-keto ester 16 which was prepared by a Pd-
Cu coupling reaction between 1 and iodobenzene.23
Exposure of 16 to the standard conditions of the cycliza-
tion gave the methylenecyclopentane 17 as only one
diastereomer where the configuration of the double
bond24 is opposite to the one expected in a radical
process.20c,25
Ta ble 1. Cycloisom er iza tion of 1 in Differ en t Solven ts
in P r esen ce of 5 m ol % of Cp Co(CO)2
solvent (∆)
time (h)
yield (%)
2/3
3/1
100/0
100/0
xylenes
benzene
THF
0.5
1
3
92
93
76
tion was performed in lower boiling solvents (Table 1), 2
was the sole product of the reaction. Thus, in refluxing
benzene 2 was isolated in 93% yield; in THF, longer
reaction time was required but some decomposition was
observed.
(16) Trost, B. M.; Tour, J . M. J . Am. Chem. Soc. 1987, 109, 5268-
5270.
(17) Huckin, S. N.; Weiler, L. J . Am. Chem. Soc. 1974, 96, 1082-
1087.
(18) Bader, A. R.; Carroll, M. F. J . Am. Chem. Soc. 1953, 75, 5400.
(19) Fryzuk, M. D.; Lloyd, B. R.; Clentsmith, G. K. B.; Rettig, S. J .
J . Am. Chem. Soc. 1994, 116, 3804-3812.
(20) (a) Snider, B. B.; Merritt, J . E.; Dombroski, M. A.; Buckman,
B. O. J . Org. Chem. 1991, 56, 5544-5553. (b) Oumar-Mahamat, H.;
Moustrou, C.; Surzur, J .-M.; Bertrand M. J . Org. Chem. 1989, 30, 331.
(c) Iqbal, J .; Bhatia, B.; Nayyar N. K. Chem. Rev. 1994, 94, 519-564.
(21) (a) Curran D. P. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Semmelhack, M., Eds.; Pergamon Press: Oxford,
1991; Vol. 4, pp 785-831. (b) Curran, D. P.; Chang, C. T. J . Org. Chem.
1989, 54, 3140. (c) Curran, D. P. Synthesis 1988, 489-513.
(22) (a) Dombroski, M. A.; Kates, S. A.; Snider, B. B. J . Am. Chem.
Soc. 1990, 112, 2759-2767. (b) Curran, D. P.; Morgan, T. M.; Schwartz,
C. E.; Snider, B. B.; Dombroski, M. A. Ibid. 1991, 113, 6607-6617. (c)
Fristad, W. E.; Ernst, A. B. Tetrahedron Lett. 1985, 25, 3761.
(23) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467-4470. (b) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahe-
dron Lett. 1993, 34, 6403-6406.
To define the scope of the reaction, the behavior of
different substrates was examined (Scheme 2).
ω-Acetylenic â-keto esters 4 and 5, prepared following
the same procedure as 1,15 failed to cyclize under our
conditions and after a longer reaction time, decomposition
of the starting materials occurred. An important ring
strain during the formation of a three-membered ring
could be invoked to explain the lack of reactivity of 4; in
contrast, the behavior of the â-keto ester 5 was quite
surprising. The difficulty in forming six-membered rings
has been already reported1a in the palladium(0)-mediated
cycloisomerization and was ascribed to the poorer ability
of 1,7-enynes to function as bidentate ligands. This
difficulty was partially circumvented by the use of the

Cycloisomerization of ꢀ-Acetylenic â-Keto Esters
J . Org. Chem., Vol. 61, No. 8, 1996 2701
Sch em e 3
Sch em e 5
Sch em e 6
Sch em e 4
Thus, the most probable mechanism seems to be
similar to the palladium(0)-mediated cycloisomerizations1
or to the first step of the intramolecular Pauson-Khand
reaction.3a,26 Here, the â-keto ester through its enol
tautomer should be the reactive intermediate27 and could
form a complex with the triple bond (see Scheme 6).
Stu d ies on Dia ster eo- a n d Ch em oselectivities.
We next chose to investigate the cycloisomerization of
ꢀ-acetylenic â′-substituted â-keto esters for several pur-
poses, one would be the stereocontrol over two contiguous
stereogenic centers28 as well as the diastereoselective
entry into highly functionalized methylenecyclopentanes.
Indeed, the enol form of the â-keto ester and the presence
of substituents in the â′ position could control the
diastereoselective formation of a new stereogenic center.
The straightforward preparation9 of the precursors 21a -f
is outlined in Scheme 4.
Ta ble 2. Dia ster eoselectivity of th e Cycloisom er iza tion
of 21
entry
R
yield (%)a
22/23b
de (%)
21a
21b
21c
21d
21e
21f
Ph
Me
n-Bu
i-Pr
CH2-SiMe3
69
69
74
52
72
64
56/44
77/23
89/11
87/13
85/15
96/04
12
54
78
74
70
92
t-Bu
a
b
Isolated yield as a mixture of 22 and 23. Ratio calculated by
1H-NMR based on the integration of the CH3 of the ester group.
cobalt(I) complex which is the effective participant of the
cyclization. In fact, the process of the complexation
entails the coplanarity of the double bond of the enol and
the triple bond creating an allylic 1,3-strain between the
methyl group of the enol and the bulky substituent in â′
(rotamer B, Scheme 6).
Under the standard conditions of the cyclization, 21
furnished the cycloadducts 22 and 23 with moderate to
high level of diastereoselectivity (Scheme 5).29
The diastereoselectivities observed could be reasonably
explained by the conformational rigidity of the enol-yne
According to the increasing size of the â′ substituent,
the complex A will be favored, and thus the diastereo-
meric excess will increase. Nevertheless, a too bulky
substituent like CH2SiMe3 in 21e seems to generate an
antagonist 1,2 steric interaction with the ester group,
decreasing the diastereomeric excess.
The experiments with â-keto ester 16 (vide infra)
seemed to confirm this proposed mechanism (Scheme 7).
Indeed, 16 after oxidative addition would lead to the
cobaltacyclopentene 16D which establishes the configu-
ration of the double bond. Successive â- and reductive
eliminations allowed the formation of 17 with retention
of the E-configuration of the double bond. These obser-
vations have been already noticed in the transition metal-
(24) The E configuration of the double bond of 17 was deduced from
differential NOE experiments: irradiation of the aromatic hydrogens
caused a neat Overhauser effect on the allylic hydrogens H1 whereas
irradiation of the ethylenic proton H2 had no effect.
(25) J ournet, M.; Magnol, E.; Smadja, W.; Malacria, M. Synlett 1991,
58-60.
(26) (a) Khand, I. U.; Knox, G. R.; Pauson, P. L.; Watts, W. E.;
Foreman, M. I. J . Chem. Soc., Perkin Trans. 1 1973, 977-981. (b)
Khand, I. U.; Pauson, P. L.; J . Chem. Soc., Chem. Commun. 1974, 379.
(27) Skeean, R. W.; Trammell, G. L.; White, J . D. Tetrahedron Lett.
1976, 525-528.
(28) Mikami, K.; Takahashi, K.; Nakai, T. Tetrahedron Lett. 1989,
30, 357-360.
(29) The configuration of the cycloadducts was assigned by NOE
experiments: see reference 9.

2702 J . Org. Chem., Vol. 61, No. 8, 1996
Cruciani et al.
Sch em e 7
Sch em e 9
Sch em e 8
Sch em e 10
catalyzed cycloisomerizations involving disubstituted
triple bonds.1a,j,k
In addition, for synthetic purposes we had to examine
the reactivity of the â-keto ester 24.30 In presence of
CpCo(CO)2, 24 furnished the bicyclo[3.2.1]octane deriva-
tive 25 in 70% isolated yield, indicating the total chemose-
lectivity of this cycloisomerization (Scheme 8). When the
reaction was performed under the [2 + 2 + 2] cyclization
conditions (bis(trimethylsilyl)ethyne as solvent), no traces
of benzocyclobutene adduct were observed showing the
total selectivity of this new catalysis: cycloisomerization
versus [2 + 2 + 2]. The reaction of â-keto ester 26 with
a stoichiometric amount of CpCo(CO)2 demonstrated the
chemoselectivity as well, since the triple bond at γ-posi-
tion remained untouched.
Ap p lica tion in Syn th esis. Since cobalt(I) species
catalyze both cycloisomerization and [2 + 2 + 2] cocy-
clization, we could envisage to combine them in a one-
pot sequence. In this context, a new stereoselective
approach to the basic skeleton of tetracyclic diterpenes
of phyllocladane and kaurane families appears possible.
Our retrosynthesis depicted in Scheme 9 deserves some
comments: the cobalt(I)-ene type reaction of the ꢀ-acety-
lenic â-keto ester moiety and the cobalt(I)-mediated
cocyclization between the 1,5-diyne unit and bis(trimeth-
ylsilyl)ethyne will furnish the corresponding benzocy-
clobutene having a methylenecyclopentane unit. Then,
after the thermal rearrangement of this latter in ortho-
quinodimethane, an intramolecular [4 + 2] cyclization
will afford in the same pot the basic framework of the
diterpenes phyllocladane (R-H9) and/or kaurane (â-H9).
Although we have already accomplished a rapid access
to these diterpenes via three consecutive cyclization
reactions,4d the challenge still remains to achieve a
shorter and more efficient synthesis. The use of only one
transition-metal catalysis in a one-pot sequence of reac-
tions: cycloisomerization, [2 + 2 + 2], and [4 + 2], which
will create six carbon-carbon bonds and four rings,
would constitute an ultimate development.
Before performing this sequence in a one-pot operation,
we determined the optimal conditions for each synthetic
transformation. The preparation of the triyne 31 was
efficiently achieved in three steps from the known
aldehyde 284d in 66% overall yield according to the
Scheme 10. Exposure of the triyne 31 to 5 mol % CpCo-
(CO)2 in boiling benzene under irradiation for 8 h afforded
the ene cycloadducts 32a and 32b in 76% yield.
Compounds 32a and 32b were inseparable by flash
chromatography on silica gel. The diastereoselectivity
32a /32b ) 86/14 was determined on the crude mixture
by 1H-NMR and was consistent with our previous finding.
Cooligomerization of the diyne moiety 32a and 32b
with 20 equiv of bis(trimethylsilyl)ethyne catalyzed by 5
mol % CpCo(CO)2 in refluxing xylenes (necessary to the
solubilization of 32a +b ) provided after 30 min, under
irradiation, the benzocyclobutenes 33a /33b in 93% yield
(Scheme 11). However we observed 9% of benzocy-
clobutenes in which the double bond had migrated in the
thermodynamically more stable endocyclic position.
Thermolysis of 33a and 33b in refluxing decane for 12
h led to two tetracyclic compounds 35a and 35b in a ratio
86/14 in 92% yield, corrected from the 9% of endocyclic
double bond 33a +b. After separation by flash chroma-
tography, elucidation of the structures 35a and 35b
included a combination of spectroscopic and X-ray crys-
(30) 24 has been synthesized from an intermediate described in
Stammler, R.; Halvorsen, K.; Gotteland, J .-P.; Malacria, M. Tetrahe-
dron Lett. 1994, 35, 417-420; its full preparation will be given later.

Cycloisomerization of ꢀ-Acetylenic â-Keto Esters
J . Org. Chem., Vol. 61, No. 8, 1996 2703
Sch em e 11
Sch em e 13
Furthermore, treatment of triyne 31 with 5 mol %
CpCo(CO)2 under irradiation at 80 °C for 8 h produced
the ene cycloadducts 32a and 32b. Those underwent
cycloaddition to hot bis(trimethylsilyl)acetylene (btmse),
after its immediate addition, to provide the benzocy-
clobutenes 33a and 33b (each synthetic individual trans-
formation was evidenced by TLC). After 5 mol %
diphenyldiphosphinoethane (dppe) was added, the reac-
tion mixture was heated in refluxing decane for 12 h and
gratifyingly, we observed the formation of a 86:14 mix-
ture of tetracyclic compounds 35a and 35b in 42% overall
isolated yield. The Scheme 13 summarizes this remark-
able and powerful one-pot sequence of cyclizations cas-
cade: ene type, [2 + 2 + 2], and [4 + 2], which allowed
the formation of six carbon-carbon bonds and four rings
in total regio- and chemoselectivity and with a high level
of diastereoselectivity from an acyclic polyunsaturated
precursor bearing three uncontrolled centers.
Sch em e 12
tallographic techniques. The assigned stereochemistry
of 35a was unambiguously established by a X-ray analy-
sis,31 indicating the configuration of the phyllocladane
skeleton. The coupling pattern, doublet of doublet, for
the proton at the B/C ring junction corresponding to trans
diaxial (J ) 10.4 Hz) and axial-equatorial (J ) 5.5 Hz)
couplings characterizes the phyllocladane framework. In
addition, a NOE effect between H9 and CH3 of the ketone
in the minor compound 35b confirmed that 35a and 35b
are epimers at the â-keto ester position.
The ratio 86/14 of the tetracyclic compounds 35a and
35b resulted from the diastereoselectivity of the initial
ene type reaction and a total stereoselectivity during the
intramolecular Diels-Alder reaction through the transi-
tion state (34a /34b)-I versus (34a /34b)-II (Scheme 12).
Indeed, a severe H1-H12 nonbonding interaction, as we
reported earlier,4d with an additional destabilizing steric
hindrance between the bulky gem-dicarbonyl substituent
and the orthoquinodimethane were developed for the
latter.
Having secured the optimal conditions for each indi-
vidual synthetic transformation, we performed the reac-
tions cascade in a one-pot operation. However, our initial
attempts did not lead to the formation of the tetracyclic
compounds but gave untractable materials and trace
amount of benzocyclobutenes in which the double bond
had migrated in the thermodynamically more stable
endocyclic position. As mentioned above, this migration
results from a partial decomposition of the catalyst due
to a too long reaction time in refluxing decane. In order
to avoid this migration and to achieve the one-pot
sequence, we added a strong donor ligand such as
diphenylphosphinoethane (dppe) which is able to strongly
associate the cobalt species.32
Con clu sion
The catalytic cobalt-mediated ene type reaction of
ꢀ-acetylenic â-keto ester provides a useful new method
for the stereoselective preparation of highly functional-
ized methylenecyclopentanes. We investigated the mech-
anism of this new cyclization: the observed regio-,
chemo-, and stereoselectivities seem to support a process
of cycloisomerization: enol-yne complexation, oxidative
addition, â- and reductive eliminations. We demon-
strated that this cycloisomerization controlled the rela-
tive stereochemistry of two contiguous stereogenic cen-
ters.
Finally, we have described, in a one-pot sequence, a
rapid construction of tetracyclic systems belonging to the
phyllocladane family by using a cascade of cyclization
reactions: ene type, [2 + 2 + 2], [4 + 2]. This concise
strategy can be viewed as an illustration of the very high
performance of cobalt(I) tandem catalyses to the synthe-
sis of complex polycyclic molecules.
Exp er im en ta l Section
P r ep a r a t ion of ω-a cet ylen ic a n d ω-et h ylen ic â-k et o
ester s. I. Gen er a l P r oced u r e for th e P r ep a r a tion of 1,
4, 5, 15. To a cooled (-10 °C), stirred suspension of 80%
sodium hydride (0.19 g; 6.3 mmol) in THF (6 mL) was added
dropwise methyl acetoacetate (0.7 g; 6.0 mmol). After being
stirred at -10 °C for 10 min and at room temperature for 1h,
a solution of bromoalkyne (6.6 mmol) in THF (4 mL) and
hexamethylphosphoramide (HMPA; 1.1 mL; 6 mmol) was
(31) The authors have already deposited the atomic coordinates of
34 with the Cambridge Crystallographic Data Center: see reference
14.
(32) Butenscho¨n, H.; Kettenbach, R. T.; Kru¨ger, C. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 1066-1068.

2704 J . Org. Chem., Vol. 61, No. 8, 1996
Cruciani et al.
added. The resulting mixture was heated at 50 °C for 12 h,
cooled at room temperature, and diluted with ether (50 mL).
The organic layer was washed successively with a saturated
solution of NH4Cl (2 × 20 mL) and brine (20 mL), dried over
Na2SO4, filtered, and concentrated. The crude residue was
purified by flash chromatography33 (petroleum ether/ether )
80/20) or distillation to afford the ω-acetylenic â-keto esters
1, 4, 5 and the ω-ethylenic â-keto ester 15.
83.5, 69.1, 68.8, 58.4, 52.5, 41.3, 27.7, 27.2, 26.2, 22.5, 18.2,
18.1; IR (neat) 3300, 2960, 2120, 1750, 1710 cm-1. MS (m/ z)
249, 217, 201, 189, 171, 159, 145, 119, 109, 81, 61, 53. Anal.
Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.36; H,
8.25.
III. P r ep a r a t ion of Met h yl 3-Oxo-7-oct yn oa t e (11).
6-(Tr im eth ylsilyl)-5-h exyn -1-ol (7).34 To a cooled (-78 °C)
solution of 5-hexyn-1-ol (1.96 g; 20 mmol) in THF (40 mL) was
added n-butyllithium (1.5 M in hexane; 26.7 mL; 40 mmol).
After being stirred at -78 °C for 30 min, the reaction was
warmed to 0 °C over 2 h. The solution was then cooled to -78
°C, and trimethylsilyl chloride (4.5 g; 42 mmol) was added.
The resulting mixture was heated to reflux for 12 h, cooled to
room temperature, treated with 10% HCl (22.6 mL), and
stirred for 30 min. The reaction mixture was extracted with
ether (100 mL), washed with brine (2 × 40 mL), dried (Na2-
SO4), and concentrated. The residue was purified by flash
chromatography (petroleum ether/ether ) 50 /50) to yield 7
(2.40 g; 70%): 1H-NMR (400 MHz, CDCl3) δ 3.63 (t, J ) 6.0
Hz, 2H), 2.26 (t, J ) 6.6 Hz, 2H), 1.65, (m, 4H), 0.14 (s, 9H);
13C-NMR (100 MHz, CDCl3) δ 107.0, 84.7, 62.3, 31.7, 24.7, 19.5,
Meth yl 2-(1-oxoeth yl)-6-h ep tyn oa te (1): 1.0 g, 92%; 1H-
NMR (200 MHz, CDCl3) δ 3.71 (s, 3H), 3.43 (t, J ) 7.3 Hz,
1H), 2.20 (s, 3H), 2.19 (td, J ) 7.3, 2.6 Hz, 2H), 1.95 (m, 3H),
1.50 (m, 2H); 13C-NMR (50 MHz, CDCl3) δ 202.4, 172.6, 83.7,
68.9, 68.3, 59.1, 52.3, 27.1, 26.1, 18.1; IR (neat) 3300, 2960,
2120, 1730, 1710, 1640, 1610 cm-1. Anal. Calcd for C10H14
O3: C, 65.91; H, 7.74. Found: C, 65.95; H, 7.84.
-
Meth yl 2-(1-oxoeth yl)-4-p en tyn oa te (4): 0.80 g, 87%; bp
) 55 °C (15 mmHg); 1H-NMR (200 MHz, CDCl3) δ 3.71 (s, 3H),
3.67 (t, J ) 7.4 Hz, 1H), 2.65 (dd, J ) 7.4, 2.6 Hz, 2H), 2.25 (s,
3H), 1.96 (t, J ) 2.6 Hz, 1H); 13C-NMR (50 MHz, CDCl3) δ
200.7, 168.4, 80.3, 70.2, 58.0, 52.5, 29.3, 17.4; IR (neat) 3300,
2960, 2120, 1740, 1710, 1640, 1610 cm-1. MS (m/ z) 155, 137,
133, 127, 123, 111, 95, 83, 69, 43. Anal. Calcd for C8H10O3:
C, 62.33; H, 6.54. Found: C, 62.27; H, 6.67.
0.0; IR (neat) 3400, 2960, 2160, 1250, 840, 750 cm-1
.
6-(Tr im eth ylsilyl)-5-h exyn a l (8). A solution of dimethyl
sulfoxide (DMSO; 2.3 mL; 32.5 mmol) in CH2Cl2 (8 mL) was
added dropwise at -78 °C to a solution of oxalyl chloride (1.5
mL; 16.8 mmol) in CH2Cl2 (32 mL). After 5 min, a solution of
7 (2.4 g; 14.1 mmol) in CH2Cl2 (15 mL) was added dropwise.
After the solution was stirred at -78 °C for 15 min, triethyl-
amine (9.8 mL; 70.5 mmol) was added. The reaction mixture
was warmed to room temperature, diluted with ether (250 mL),
and washed with saturated solutions of NH4Cl (100 mL),
CuSO4 (2 × 100 mL), and brine (3 × 100 mL), dried over Na2-
SO4, filtered, and concentrated. Purification by flash chro-
matography (petroleum ether/ether ) 50/50) furnished 8 (2.20
g, 93%): 1H-NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 2.57 (t, J
) 6.7 Hz, 2H), 2.28 (t, J ) 6.7 Hz, 2H), 1.85 (quint, J ) 6.7
Hz, 2H), 0.12 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ 201.8,
105.8, 85.7, 42.6, 20.9, 19.2, 0.0; IR (neat) 3400, 2960, 2160,
1
Meth yl 2-(1-oxoeth yl)-7-octyn oa te (5): 1.07 g, 91%; H-
NMR (400 MHz, CDCl3) δ 3.77 (s, 3H), 3.47 (t, J ) 7.1 Hz,
1H), 2.26 (s, 3H), 2.23 (td, J ) 7.1, 2.7 Hz, 2H), 1.97 (t, J )
2.7 Hz, 1H), 1.90 (m, 2H), 1.58 (quint, 2H), 1.45 (m, 2H); 13C-
NMR (100 MHz, CDCl3) δ 203.2, 170.5, 84.3, 68.8, 59.7, 52.7,
29.1, 28.3, 27.9, 26.7, 18.4; IR (neat) 3300, 2960, 2120, 1740,
1710, 1640, 1610 cm-1. Anal. Calcd for C11H16O3: C, 67.33;
H, 8.22. Found: C, 67.22; H, 8.21.
Meth yl 2-(1-oxoeth yl)-6-h ep ten oa te (15): 0.64 g, 58%;
1H-NMR (400 MHz, CDCl3) δ 5.75 (m, 1H), 5.02-4.94 (m, 2H),
3.73 (s, 3H), 3.42 (t, J ) 7.1 Hz, 1H), 2.21 (s, 3H), 2.06 (dt, J
) 6.6, 7.1 Hz, 2H), 1.84 (m, 2H), 1.38 (m, 2H); 13C-NMR (100
MHz, CDCl3) δ 203.1, 170.3, 137.8, 115.1, 59.5, 52.4, 33.3, 28.8,
27.6, 26.6; IR (neat) 2940, 1740, 1710, 1640, 1430, 1240, 910
cm-1. MS (m/ z) 185, 167, 153, 142, 129, 109, 87, 81, 69, 55,
43. Anal. Calcd for C10H16O3: C, 65.19; H, 8.95. Found: C,
65.30; H, 8.95.
1250, 840, 750 cm-1
.
7-(Tr im eth ylsilyl)-6-h ep tyn -2-ol (9). To a cooled (-78 °C)
solution of the aldehyde 8 (2.0 g; 11.9 mmol) in THF (50 mL)
was added dropwise methyllithium (1.5 M in ether; 7.9 mL;
11.9 mmol). After the addition, the reaction mixture was
warmed to room temperature and diluted with ether (100 mL).
The organic layer was washed with a saturated solution of
NH4Cl (2 × 30 mL) and brine (30 mL), dried over Na2SO4, and
concentrated. The crude residue was purified by flash chro-
matography (petroleum ether/ether ) 50 /50) to give 9 (1.97
g, 90%): 1H-NMR (400 MHz, CDCl3) δ 3.81 (sextet, J ) 6.0
Hz, 1H), 2.22 (t, J ) 6.6 Hz, 2H), 1.58 (m, 4H), 1.17 (d, J )
6.0 Hz, 3H), 0.12 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ 107.1,
84.6, 67.4, 38.2, 24.7, 23.4, 19.7, 0.0; IR (neat) 3350, 2960, 2160,
II. P r ep a r a tion 16 of 6 a n d 26. Meth yl 3-Oxo-6-h ep -
tyn oa te (6). To a cooled (-10 °C), stirred suspension of 80%
sodium hydride (0.165 g; 5.5 mmol) in THF (10 mL) was added
dropwise methyl acetoacetate (0.57 g; 5.0 mmol). After being
stirred at -10 °C for 10 min and at room temperature for 1 h,
n-butyllithium (1.5 M in hexane; 3.5 mL; 5.25 mmol) was
added dropwise and the yellow to orange solution of dianion
was stirred for an additional 10 min before adding propargyl
bromide (80% in toluene; 0.61 mL; 5.5 mmol). After 15 min
of stirring, the reaction mixture was diluted with ether (20
mL) and washed successively with a saturated solution of NH4-
Cl (2 × 10 mL) and brine (10 mL), dried over Na2SO4, and
concentrated. The residue was purified by flash chromatog-
raphy (petroleum ether/ether ) 80/20) affording 6 (0.61 g,
79%): 1H-NMR (400 MHz, CDCl3) δ 3.70 (s, 3H), 3.46 (s, 3H),
2.78 (t, J ) 7.1 Hz, 2H), 2.42 (td, J ) 7.1, 2.7 Hz, 2H), 1.96 (t,
J ) 2.7 Hz, 1H); 13C-NMR (100 MHz, CDCl3) δ 200.3, 167.1,
82.3, 68.8, 52.1, 48.6, 41.3, 12.5; IR (neat) 3300, 2960, 2120,
1750, 1710 cm-1; MS (m/ z) 155, 147, 139, 133, 126, 123, 113,
101, 95, 89, 81, 65, 53, 43. Anal. Calcd for C8H10O3: C, 62.33;
H, 6.54. Found: C, 62.23; H, 6.65.
1250, 840, 750 cm-1
.
7-(Tr im eth ylsilyl)-6-h ep tyn -2-on e (10). 10 was prepared
using the procedure described for 8. Ketone 10 (1.75 g, 90%)
was purified by flash chromatography (petroleum ether/ether
) 50/50): 1H-NMR (200 MHz, CDCl3) δ 2.50 (t, J ) 7.2 Hz,
2H), 2.18 (t, J ) 6.9 Hz, 2H), 2.09 (s, 3H), 1.69 (quint, J ) 7.0
Hz, 2H), 0.07 (s, 9H); 13C-NMR (50 MHz, CDCl3) δ 207.8, 106.2,
85.3, 42.0, 29.8, 22.4, 19.1; IR (neat) 2960, 2160, 1720, 1250,
840, 750 cm-1
.
Meth yl 3-Oxo-2-(4-p en tyn yl)-8-n on yn oa te (26). A solu-
tion of dianion (4.3 mmol) in THF was prepared as above, and
a solution of 5-bromo-1-pentyne (1.4 g; 9.5 mmol) in THF (12
mL) and HMPA (1.5 mL; 8.6 mmol) was added dropwise. The
resulting mixture was heated at reflux for 12 h. After being
cooled and worked-up as above, the residue was flash chro-
matographed (petroleum ether/ether ) 70/30) to give 26 (0.65
g, 61%): 1H-NMR (400 MHz, CDCl3) δ 3.68 (s, 3H), 3.44 (t, J
) 7.4 Hz, 1H), 2.59-2.43 (m, 2H), 2.16 (td, J ) 7.6, 2.8 Hz,
4H), 1.94 (t, J ) 2.8 Hz, 1H), 1.92 (t, J ) 2.7 Hz, 1H), 1.90 (t,
J ) 7.6 Hz, 2H), 1.66 (quint, J ) 7.8 Hz, 2H), 1.47 (quint, J )
7.5 Hz, 4H); 13C-NMR (100 MHz, CDCl3) δ 204.6, 170.1, 83.9,
Meth yl 3-Oxo-7-octyn oa te (11). (a) At -78 °C, a solution
of ketone 10 (1.75 g; 9.63 mmol) in ether (60 mL) was added
dropwise to a solution of lithium diisopropylamide (10.6 mmol)
in ether (50 mL). After being stirred at -78 °C for 1 h, the
reaction mixture was cooled to -100 °C and a solution of
methyl cyanoformate (0.92 mL; 11.6 mmol) in ether (30 mL)
was added dropwise. After the mixture was stirred for 1 h at
-100 °C, it was allowed to warm to room temperature and
was diluted with ether (50 mL), washed with saturated
solution of NH4Cl (3 × 50 mL) and brine (2 × 40 mL), dried
over Na2SO4, and concentrated. The crude residue was
(34) Negishi, E.-I.; Boardman, L. D.; Sawada, H.; Baghen, V.; Stoll,
A. T.; Tour, J . M.; Rand, C. L. J . Am. Chem. Soc. 1988, 110, 5383-
5396.
(33) Still, W. C.; Kahn, M.; Mitra, A. J . Org.Chem. 1978, 43, 2923-
2925.

Cycloisomerization of ꢀ-Acetylenic â-Keto Esters
J . Org. Chem., Vol. 61, No. 8, 1996 2705
purified by flash chromatography (petroleum ether/ether ) 90/
10) to give the alkylated compound (1.06 g, 46%): 1H-NMR
(200 MHz, CDCl3) δ 3.61 (s, 3H), 3.36 (s, 2H), 2.57 (t, J ) 7.1
Hz, 2H), 2.15 (t, J ) 6.9 Hz, 2H), 1.67 (quint, J ) 7.0 Hz, 2H),
0.02 (s, 9H); 13C-NMR (50 MHz, CDCl3) δ 201.7, 167.3, 105.9,
85.4, 52.0, 48.9, 41.3, 22.1, 18.9, 0.0; IR (neat) 2960, 2160, 1750,
1710, 1250, 840, 750 cm-1. (b) To a DMSO (20 mL) solution
of potassium fluoride (0.59 g; 10.1 mmol) was added a solution
of the preceding compound (0.48 g; 2.0 mmol) in DMSO (10
mL). After being stirred at room temperature for 3 h, the
reaction mixture was filtered and diluted with ether (100 mL).
The organic layer was washed with brine (3 × 40 mL), dried
(Na2SO4), filtered, and concentrated. Purification of the crude
residue by flash chromatography (petroleum ether/ether ) 80/
20) furnished 11 (0.27 g, 80%): 1H-NMR (200 MHz, CDCl3) δ
3.69 (s, 3H), 3.43 (s, 2H), 2.66 (t, J ) 7.1 Hz, 2H), 2.19 (td, J
) 6.8, 2.5 Hz, 2H), 1.93 (t, J ) 2.5 Hz, 1H), 1.76 (tt, J ) 7.1,
6.9 Hz, 2H); 13C-NMR (50 MHz, CDCl3) δ 201.7, 167.4, 83.2,
69.1, 52.2, 49.0, 41.3, 22.0, 17.5; IR (neat) 3300, 2960, 2100,
1740, 1710 cm-1. MS (m/ z) 169, 160, 153, 137, 127, 109, 101,
95, 81, 65, 55, 43. Anal. Calcd for C9H12O3: C, 64.27; H, 7.19.
Found: C, 64.22; H, 7.28.
VI. P r ep a r a tion of th e E-a cetylen ic â-su bstitu ted
â-k et o E st er s 21a -f. 5-(Tr im et h ylsilyl)-4-p en t yn -1-ol
(18).34 18 (4.5 g, 96%) was prepared using the procedure
described for 7 and was purified by flash chromatography
(petroleum ether/ether ) 50/50): 1H-NMR (200 MHz, CDCl3)
δ 3.73 (t, J ) 6.1 Hz, 2H), 2.32 (t, J ) 6.9 Hz, 2H), 1.74 (quint,
J ) 6.5 Hz, 2H), 0.12 (s, 9H); 13C-NMR (50 MHz, CDCl3) δ
106.7, 85.3, 61.8, 31.2, 16.5, 0.1; IR (neat) 3350, 2960, 2180,
1430, 1250, 1070, 1050 cm-1
.
5-(Tr im eth ylsilyl)-4-p en tyn a l (19). Aldehyde 19 (4.3 g,
97%) was prepared using the procedure described for 8 and
was purified by flash chromatography (petroleum ether/ether
) 50/50): 1H-NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 2.56 (t, J
) 6.7 Hz, 2H), 2.48 (t, J ) 6.7 Hz, 2H), 0.10 (s, 9H); 13C-NMR
(100 MHz, CDCl3) δ 200.4, 104.7, 85.7, 42.5, 13.1, 0.0; IR (neat)
2960, 2900, 2720, 2180, 1730, 1380, 1250, 1050, 840 cm-1
.
Met h yl 7-(Tr im et h ylsilyl)-2-(1-oxoet h yl)-2-h ep t en -6-
yn oa te (20). Titanium tetrachloride (4.1 mL; 37 mmol) in
CCl4 (8 mL) was added dropwise at 0 °C to THF (68 mL) and
stirred for a few minutes during which time a yellow precipi-
tate appeared. Then, a THF (8 mL) solution of methyl
acetoacetate (2.15 g; 18.5 mmol) and a THF (8 mL) solution of
19 (2.85 g; 18.5 mmol) were added. After the mixture was
stirred for 75 min at 0 °C, a solution of pyridine (6 mL; 74
mmol) in THF (13 mL) was added by a syring pump over 90
min. The reaction mixture was stirred at 0 °C overnight and
then partitioned between ether (200 mL) and water (150 mL).
The aqueous phase was extracted with ether (200 mL) and
the combined organic layers were washed with brine (300 mL),
dried over MgSO4, and concentrated. The residue was purified
by flash chromatography (petroleum ether/ether ) 20/80) to
give 20 as a 1:1 mixture of E and Z isomers (3.64 g, 75%):
1H-NMR (200 MHz, CDCl3) δ 6.82 (t, J ) 7.0 Hz, 1H), 3.72 (s,
3H), 2.40 (td, J ) 7.3, 6.3 Hz, 2H), 2.29 (t, J ) 6.3 Hz, 2H),
2.21 (s, 3H), 0.02 (s, 9H); 13C-NMR (50 MHz, CDCl3) δ 195.1,
166.4, 146.6, 137.5, 104.9, 86.4, 52.1, 28.9, 26.9, 18.9, 0.0; IR
(neat) 2940, 2170, 1730, 1690, 1630, 1430, 1230, 840 cm-1; MS
(m/ z) 251, 237, 219, 205, 193, 177, 163, 149, 135, 109, 105,
89, 75, 59, 43. Anal. Calcd for C13H20SiO3: C, 61.90; H, 7.94.
Found: C, 61.64; H, 7.74.
IV. Gen er a l P r oced u r e for th e P r ep a r a tion of 12-14.
At room temperature, to a suspension of 80% sodium hydride
(0.214 g; 7.1 mmol) in THF (5 mL) was added dropwise the
alkynol (7.1 mmol) in THF (5 mL). After being stirred for 30
min, a solution of 2,2,6-trimethyl-1,3 dioxen-4-one (1.0 g; 7.1
mmol) in THF (10 mL) was added dropwise. After 2 h, the
solution was then partitioned between ether (50 mL) and
saturated solution of NH4Cl (30 mL). The organic layer was
separated, washed with brine (2 × 40 mL), dried (MgSO4), and
concentrated. The crude residue was purified by flash chro-
matography (petroleum ether/ether ) 50/50) to afford the keto
esters 12-14.
1
2-P r op yn yl-3-oxobu ta n oa te (12): 0.72 g, 73%; H-NMR
(200 MHz, CDCl3) δ 4.76 (d, J ) 2.6 Hz, 2H), 2.68 (s, 3H),
3.51 (s, 2H), 2.48 (t, J ) 2.4 Hz, 1H); 13C-NMR (100 MHz,
CDCl3) δ 207.2, 166.7, 76.7, 74.0, 52.7, 49.7, 30.9; IR (neat)
3280, 2920, 1750, 1710, 1150, 1030 cm-1
. Anal. Calcd for
C7H8O3: C, 59.99; H, 5.75. Found: C, 60.27; H, 5.85.
Gen er a l P r oced u r e for th e P r ep a r a tion of Com p ou n d s
21a -f. (a) To a cooled (-78 °C) THF (40 mL) solution of copper-
(I) cyanide (1.07 g; 12 mmol) and lithium chloride (1.02 g; 24
mmol) [dried overnight at 100 °C under vacuum 1 mmHg] was
added a solution of alkylmagnesium bromide (or chloride) or
alkyllithium (6 mmol) in THF (6 mL). After being stirred at
-78 °C for 15 min, a THF (6 mL) solution of 20 (3 mmol) and
TMSCl (0.76 mL; 6 mmol) was added dropwise. After stirring
for 2 h, the reaction mixture was hydrolyzed at -78 °C with
a solution of NH4Cl/NH4OH (2/1), warmed to room tempera-
ture, filtered on Celite, and diluted with ether (100 mL). The
organic layer was separated, washed with brine, dried over
MgSO4, and concentrated. The crude product was used in the
next step without purification. (b) The removal of the trimeth-
ylsilyl group followed the procedure b described for 11 except
for 21e whose triple bond is selectively deprotected by AgNO3/
KCN (1.2/6 equiv) in a cooled (0 °C) mixture of EtOH:H2O (3:
1).
Meth yl 2-(1-oxoeth yl)-3-p h en yl-6-h ep tyn oa te (21a ) (R
) Ph): 0.85 g, 67%; 1:1 mixture of two inseparable diastere-
omers; 1H-NMR (400 MHz, CDCl3) δ 7.28 (m, 5H), 7.16 (m,
5H), 3.86 (d, J ) 11.0 Hz, 1H), 3.80 (d, J ) 11.0 Hz, 1H), 3.76
(s, 3H), 3.53 (m, 2H), 3.39 (s, 3H), 2.31 (s, 3H), 1.98-1.68 (M,
8H), 1.96 (t, J ) 2.8 Hz, 2H), 1.90 (s, 3H); 13C-NMR (100 MHz,
CDCl3) δ 202.1, 201.9, 168.8, 168.2, 139.6, 139.4, 128.9, 128.8,
128.5, 128.1, 128.0, 127.7, 127.4, 127.2, 83.2, 69.1, 69.0, 68.9,
68.6, 52.8, 52.6, 44.5, 44.1, 32.9, 32.5, 29.9, 29.3, 16.2, 16.1;
IR (neat) 3300, 3050, 2940, 2100, 1740, 1710, 1430, 1350, 1230,
1150 cm-1; MS (m/ z) 258, 240, 226, 216, 198, 184, 156, 141,
128, 115, 91, 77, 59, 51. Anal. Calcd for C16H18O3: C, 74.41;
H, 6.98. Found: C, 74.11; H, 7.09.
3-Bu tyn yl-3-oxobu ta n oa te (13): 1.04 g, 96%; 1H-NMR
(200 MHz, CDCl3) δ 4.25 (t, J ) 6.8 Hz, 2H), 3.47 (s, 2H), 2.55
(td, J ) 6.8, 2.8 Hz, 2H), 2.27 (s, 3H), 2.00 (t, J ) 2.8 Hz, 1H);
13C-NMR (100 MHz, CDCl3) δ 200.0, 167.00, 80.2, 71.2, 62.9,
32.4, 49.9, 18.7; IR (neat) 3280, 2920, 1750, 1710, 1150, 1030
cm-1. Anal. Calcd for C8H10O3: C, 62.33; H, 6.54. Found: C,
62.55; H, 6.53.
1,1-Dim eth yl-2-p r op yn yl-3-oxobu ta n oa te (14): 1.1 g,
1
92%; H-NMR (200 MHz, CDCl3) δ 2.59 (s, 2H), 2.21 (s, 3H),
1.86 (s, 1H), 1.62 (s, 6H); 13C-NMR (50 MHz, CDCl3) δ 200.5,
165.4, 90.2, 84.0, 72.5, 50.8, 30.7, 28.7; IR (neat) 3280, 2920,
1750, 1710, 1150, 1030 cm-1
. Anal. Calcd for C9H12O3: C,
64.27; H, 7.19. Found: C, 64.15; H, 7.27.
V. P r ep a r a tion of Meth yl-2-(1-oxoeth yl)-7-p h en yl-6-
h ep tyn oa te (16). At room temperature, under argon, copper-
(I) iodide (0.016 g; 0.08 mmol; 15 mol%) and tetrakis-
(triphenylphosphine)palladium(0) (0.063 g; 0.05 mmol; 10 mol
%) were added at once to a solution of the ꢀ-acetylenic â-keto
ester 1 (0.1 g; 0.55 mmol) in benzene (2.5 mL) in the presence
of n-butylamine (0.27 mL; 2.7 mmol) and iodobenzene (0.23 g;
1.1 mmol). After being stirred for 6 h, the reaction mixture
was hydrolyzed with saturated solution of NH4Cl (8 mL) and
extracted with ether (10 mL). The organic layer was washed
with a saturated solution of CuSO4 (10 mL) and brine (2 × 10
mL), dried (MgSO4), and concentrated. Purification of the
residue by flash chromatography (petroleum ether/ether ) 85/
15) afforded 16 (0.127 g, 89%): 1H-NMR (400 MHz, CDCl3) δ
7.43-7.27 (m, 5H), 3.76 (s, 3H), 3.53 (t, J ) 7.4 Hz, 1H), 2.46
(t, J ) 6.9 Hz, 2H), 2.26 (s, 3H), 2.09-2.02 (m, 2H), 1.63 (br
quint, J ) 7.4 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ 202.9,
170.2, 131.6, 128.3, 127.8, 123.8, 89.1, 81.4, 59.3, 52.5, 28.9,
27.4, 26.5, 19.3; IR (neat) 3240, 2940, 2850, 2200, 1740, 1705,
1635, 1580, 1430 ,1145, 1070, 750, 690 cm-1. MS (m/ z) 240,
227, 216, 199, 184, 172, 155, 142, 128, 115, 105, 89, 69, 55,
43.
Meth yl 3-m eth yl-2-(1-oxoeth yl)-6-h ep tyn oa te (21b) (R
) Me): 0.18 g, 76%; 1:1 mixture of two inseparable diastere-
omers; 1H-NMR (400 MHz, CDCl3) δ 3.66 (s, 3H), 3.65 (s, 3H),
3.29 (d, J ) 8.2 Hz, 1H), 3.27 (d, J ) 8.2 Hz, 1H), 2.37-2.26
(m, 2H), 2.16 (s, 3H), 2.15 (s, 3H), 2.24-2.05 (m, 4H), 1.91 (t,

2706 J . Org. Chem., Vol. 61, No. 8, 1996
Cruciani et al.
J ) 2.2 Hz, 1H), 1.90 (t, J ) 2.2 Hz, 1H), 1.61-1.48 (m, 2H),
1.37-1.26 (m, 2H), 0.88 (d, J ) 10.4 Hz, 3H), 0.87 (d, J ) 9.9
Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 202.8, 202.7, 169.3,
77.0, 76.7, 68.9, 68.7, 65.6, 65.1, 52.2, 52.1, 32.7, 32.5, 32.2,
31.8, 29.3, 28.9, 16.4, 16.1, 15.9, 15.8; IR (neat) 3280, 2940,
2120, 1735, 1710, 1430, 1150 cm-1; MS (m/ z) 197, 181, 164,
149, 137, 125, 116, 107, 95, 79, 69, 59, 43, 41. Anal. Calcd
for C11H16O3: C, 67.35; H, 8.16. Found: C, 67.45; H, 8.21.
Meth yl 3-bu tyl-2-(1-oxoeth yl)-6-h ep tyn oa te (21c) (R )
n-Bu): 0.175 g, 62%; 1:1 mixture of two inseparable diaster-
eomers; 1H-NMR (200 MHz, CDCl3) δ 3.70 (s, 3H), 3.69 (s, 3H),
3.51 (d, J ) 7.7 Hz, 1H), 3.50 (d, J ) 9.3 Hz, 1H), 2.48-2.24
(m, 2H), 2.27-2.10 (m, 4H), 2.20 (s, 6H), 1.90 (t, J ) 1.9 Hz,
1H), 1.89 (t, J ) 1.8 Hz, 1H), 1.70-1.40 (m, 4H), 1.30-1.10
(m, 12H), 0.82 (t, J ) 10.9 Hz, 3H), 0.80 (t, J ) 9.8 Hz, 3H);
13C-NMR (50 MHz, CDCl3) δ 203.6, 169.6, 83.7, 83.5, 68.9, 68.7,
62.8, 52.1, 36.8, 36.7, 30.2, 30.0, 29.8, 29.6, 29.5, 29.2, 28.4,
22.8, 22.7, 15.9, 15.8, 13.9; IR (neat) 3290, 2930, 2850, 2225,
1735, 1710, 1430, 1350, 1150, 910, 730 cm-1; MS (m/ z) 223,
206, 196, 179, 167, 163, 149, 136, 117, 101, 85, 79, 59, 55, 43.
Anal. Calcd for C14H22O3: C, 70.59; H, 9.24. Found: C, 70.53;
H, 9.37.
Meth yl 3-isop r op yl-2-(1-oxoeth yl)-6-h ep tyn oa te (21d )
(R ) i-Pr): 0.29 g, 52%; 1:1 mixture of two inseparable
diastereomers. 1H-NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 3.71
(s, 3H), 3.54 (d, J ) 7.2 Hz, 1H), 3.50 (d, J ) 8.8 Hz, 1H),
2.26-2.10 (m, 4H), 2.25 (s, 3H), 2.23 (s, 3H), 1.94 (t, J ) 2.8
Hz, 1H), 1.92 (t, J ) 2.8 Hz, 1H), 1.77-1.61 (M, 4H), 1.61-
1.52 (m, 2H), 1.60-1.42 (m, 2H), 1.40-1.31 (m, 2H), 0.88-
0.76 (M, 12H); 13C-NMR (100 MHz, CDCl3) δ 203.1 (2C), 169.9,
169.8, 83.9, 83.6, 68.6, 68.5, 62.9, 62.0, 52.2, 52.1, 42.5 (2C),
29.5, 29.3, 29.1, 28.8, 27.4, 27.2, 21.7 (2C), 20.5, 19.7, 18.4,
17.8; IR (neat) 3280, 2940, 2110, 1730, 1630, 1600, 1430, 1240,
1140 cm-1; MS (m/ z) 193, 181, 149, 117, 116, 111, 101, 93,
79, 69, 59, 51. Anal. Calcd for C13H20O3: C, 69.61; H, 8.98.
Found: C, 69.31; H, 8.87.
Meth yl 3-[(tr im eth ylsilyl)m eth yl]-2-(1-oxoeth yl)-6-h ep -
tyn oa te (21e) (R ) CH2SiMe3): 0.18 g, 76%; 1:1 mixture of
two inseparable diastereomers; 1H-NMR (400 MHz, CDCl3) δ
3.68 (s, 3H), 3.67 (s, 3H), 3.52 (d, J ) 6.1 Hz, 1H), 3.45 (d, J
) 6.1 Hz, 1H), 2.50-2.41 (m, 2H), 2.18 (s, 3H), 2.17 (s, 3H),
2.12-2.11(m, 2H), 1.93 (t, J ) 2.6 Hz, 1H), 1.91 (t, J ) 2.6
Hz, 1H), 1.59 (m, 4H), 1.56-1.48 (m, 2H), 0.63-0.50 (m, 4H),
0.00 (s, 9H), 0.01 (s, 9H); 13C-NMR (100 MHz, CDCl3) δ 203.2
(2C), 169.7 (2C), 83.7, 83.4, 69.2, 68.9, 64.6, 63.4, 52.1 (2C),
33.7, 33.4, 32.1, 31.9, 29.7, 29.5, 19.1, 18.7, 15.5 (2C), -0.8,
-0.6; IR (neat) 3280, 2990, 2120, 1780, 1730, 1360, 1330, 1230,
1125, 960, 850 cm-1. Anal. Calcd for C14H24SiO3: C, 62.64;
H, 9.01. Found: C, 62.55; H, 8.96.
Meth yl 3-ter t-bu tyl-2-(1-oxoeth yl)-6-h ep tyn oa te (21f)
(R ) t-Bu): 0.18 g, 62%, 1:1 mixture of two inseparable
diastereomers; 1H-NMR (400 MHz, CDCl3) δ 3.72 (s, 3H), 3.70
(s, 3H), 3.68-3.66 (m, 2H), 2.27-2.26 (m, 2H), 2.24 (s, 3H),
2.23 (s, 3H), 2.13-2.11 (m, 4H), 1.93-1.91 (m, 2H), 1.75-1.65
(m, 4H), 0.90 (s, 9H), 0.89 (s, 9H); 13C-NMR (100 MHz, CDCl3)
δ 203.6, 170.8, 84.9, 68.7, 60.3, 52.4, 46.7, 34.7, 29.4, 29.3, 28.2,
27.1, 19.2; IR (neat) 3280, 2940, 2110, 1730, 1630, 1600, 1430,
1240, 1140 cm-1; MS (m/ z) 223, 206, 196, 181, 167, 163, 149,
135, 116, 107, 91, 79, 59, 57, 43. Anal. Calcd for C14H22O3:
C, 70.59; H, 9.24. Found: C, 70.58; H, 9.38.
Meth yl 1-(1-oxoeth yl)-2-(ph en ylm eth ylid en e)cyclop en -
ta n eca r boxyla te (17): 0.191 g, 74 %; 1H-NMR (400 MHz,
CDCl3) δ 7.35-7.22 (m, 5H), 6.58 (t, J ) 2.5 Hz, 1H), 3.77 (s,
3H), 2.72 (td, J ) 7.0, 2.5 Hz, 2H), 2.49-2.16 (m, 2H), 2.25 (s,
3H), 1.82 (q, J ) 7.0 Hz, 2H); 13C-NMR (100 MHz, CDCl3) δ
204.2, 171.9, 141.6, 137.5, 131.6, 128.7, 128.4, 127.7, 127.1
(2C), 72.4, 52.8, 34.5, 32.2, 26.9, 24.9; IR (neat) 2950, 1735,
1710, 1480, 1430, 1350, 1230, 1120, 690 cm-1; MS (m/ z) 259,
240, 227, 216, 199, 184, 167, 155, 141, 129, 115, 102, 91, 77,
63, 43. Anal. Calcd for C16H18O3: C, 74.40; H, 7.02. Found:
C, 74.28; H, 7.19.
Met h yl 2-Met h ylid en e-1-(1-oxoet h yl)-5-p h en ylcyclo-
p en ta n eca r boxyla te (22+23)a (R) Ph): 0.095 g, 69%; 56:
44 mixture of inseparable diastereoisomers. 22a :
1H-NMR
(400 MHz, CDCl3) δ 7.29-7.23 (m, 5H), 5.40 (dd, J ) 2.7, 1.6
Hz, 1H), 5.36 (dd, J ) 2.7, 1.6 Hz, 1H), 4.30 (dd, J ) 9.3, 7.1
Hz, 1H), 3.21 (s, 3H), 2.57-2.40 (m, 2H), 2.29 (s, 3H), 2.19-
2.11 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 200.9, 170.4, 149.8,
140.9, 128.5, 128.3, 128.0, 127.4, 126.8, 113.0, 75.8, 51.9, 50.3,
33.4, 29.9, 26.8. 23a : 1H-NMR (400 MHz, CDCl3) δ 7.21-
7.14 (m, 5H), 5.26 (dd, J ) 2.7, 1.6 Hz, 1H), 5.18 (dd, J ) 2.7,
1.6 Hz, 1H), 4.20 (dd, J ) 6.6, 5.5 Hz, 1H), 3.81 (s, 3H), 2.76-
2.63 (m, 2H), 2.10-2.02 (m, 2H), 1.5 (s, 3H);
13C-NMR (100
MHz, CDCl3) δ 204.5, 171.5, 148.9, 138.8, 128.5, 128.3, 128.0,
127.4, 126.8, 111.7, 74.6, 52.7, 51.7, 32.4, 29.9, 28.8. 22a +23a :
IR (neat) 2940, 2220, 1710, 1645, 1430, 1345, 900 cm-1; MS
(m/ z) 240, 225, 215, 200, 181, 175, 155, 141, 131, 115, 103,
91, 77, 65, 51; Anal. Calcd for C16
Found: C, 74.64; H, 7.35.
H18O3: C, 74.40; H, 7.02.
Met h yl 5-m et h yl-2-m et h ylid en e-1-(1-oxoet h yl)cyclo-
p en ta n eca r boxyla te (22+23)b (R) Me): 0.135 g, 69%; 77:
23 mixture of inseparable diastereomers. 22b: 1H-NMR (400
MHz, CDCl3) δ 5.27 (t, J ) 1.6 Hz, 1H), 5.24 (t, J ) 2.2 Hz,
1H), 3.71 (s, 3H), 2.87-2.80 (m, 1H), 2.38-2.24 (m, 2H), 2.22
(s, 3H), 1.49-1.40 (m, 2H), 0.92 (d, J ) 6.6 Hz, 3H); 13C-NMR
(100 MHz, CDCl3) δ 202.0, 171.0, 148.7, 112.7, 73.9, 51.9, 40.7,
32.3, 31.5, 26.9, 16.1. 23b: 1H-NMR (400 MHz, CDCl3) δ 5.27
(t, J ) 1.6 Hz, 1H), 5.23 (t, J ) 2.2 Hz, 1H), 3.72 (s, 3H), 2.87-
2.80 (m, 1H), 2.53-2.46 (m, 2H), 2.23 (s, 3H), 1.97-1.86 (m,
2H), 0.93 (d, J ) 6.6 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ
202.0, 171.0, 148.7, 112.4, 73.9, 52.5, 42.2, 32.3, 31.7, 26.7, 15.6.
22b+23b: IR (neat) 2950, 2860, 2230, 1710, 1645, 1430, 1240,
910, 730 cm-1; MS (m/ z) 164, 154, 139, 137, 122, 111, 107,
95, 79, 67, 59, 43. Anal. Calcd for C11H16O3: C, 67.35; H, 8.16.
Found: C, 67.11; H, 8.18.
Meth yl 5-bu tyl-2-m eth ylid en e-1-(1-oxoeth yl)cyclop en -
ta n eca r boxyla te (22+23)c (R ) n-Bu): 0.176 g, 74%; 89:11
mixture of inseparable diastereomers. 22c: 1H-NMR (400
MHz, CDCl3) δ 5.23 (t, J ) 2.2 Hz, 1H), 5.17 (t, J ) 2.8 Hz,
1H), 3.71 (s, 3H), 2.48-2.46 (m, 1H), 2.25 (s, 3H), 1.96-1.89
(m, 1H), 1.52-1.41 (m, 1H), 1.40-1.10 (M, 6H), 0.86 (t, J )
6.6 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 202.4, 171.3, 149.6,
111.9, 73.6, 51.9, 46.4, 32.7, 30.4, 30.3, 28.9, 27.3, 22.7, 13.9.
23c: 1H-NMR (400 MHz, CDCl3) δ 5.18 (t, J ) 2.2 Hz, 1H),
5.17 (t, J ) 2.8 Hz, 1H), 3.75 (s, 3H), 2.71-2.67 (m, 1H), 2.35-
2.26 (m, 1H), 2.14 (s, 3H), 1.52-1.41 (m, 1H), 1.40-1.10 (M,
6H), 0.86 (t, J ) 6.6 Hz, 3H);
13C-NMR (100 MHz, CDCl3) δ
205.0, 171.8, 149.9, 111.8, 73.3, 52,4, 47.9, 32.4, 30.7, 30.0, 29.7,
29.3, 28.9, 13.9. 22c+23c: IR (neat) 2940, 2850, 1725, 1710,
1640, 1430, 1350, 1240, 900 cm-1
; MS (m/ z) 207, 206, 191,
179, 164, 149, 139, 135, 121, 107, 93, 79, 67, 59, 51; Anal. Calcd
for C14H22O3: C, 70.59; H, 9.24. Found: C, 70.56; H, 9.44.
Meth yl 5-isop r op yl-2-m eth ylid en e-1-(1-oxoeth yl)cyclo-
p en ta n eca r boxyla te (22+23)d (R ) i-Pr): 0.117 g, 52%; 87:
13 mixture of inseparable diastereomers. 22d : 1H-NMR (400
MHz, CDCl3) δ 5.01 (br s, 1H), 4.92 (br t, J ) 2.0 Hz, 1H),
3.59 (s, 3H), 2.60-2.53 (m, 1H), 2.40-2.34 (dd, J ) 6.5, 6.3
Hz, 1H), 2.25-2.16 (m, 1H), 2.19 (s, 3H), 1.85-1.77 (m, 1H),
1.43-1.34 (m, 1H), 1.36-1.29 (m, 1H), 0.74 (d, J ) 6.6 Hz,
3H), 0.72 (d, J ) 6.6 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ
203.8, 172.3, 152.0, 111.5, 74.0, 54.5, 52.7, 33.7, 30.9, 28.7, 28.6,
23.4, 21.8. 23d : 1H-NMR (400 MHz, CDCl3) δ 5.01 (br s, 1H),
4.92 (br t, J ) 2.0 Hz, 1H), 3.61 (s, 3H), 2.52-2.40 (m, 1H),
2.40-2.34 (dd, J ) 6.5, 6.3 Hz, 1H), 2.25-2.16 (m, 1H), 2.09
(s, 3H), 1.85-1.77 (m, 1H), 1.58-1.45 (m, 1H), 1.36-1.29 (m,
1H), 0.77 (d, J ) 4.0 Hz, 3H), 0.72 (d, J ) 6.6 Hz, 3H); 13C-
En e Typ e Rea ction s. Gen er a l P r oced u r e. CpCo(CO)2
(6 mL; 5 × 10-2 mmol) was added to a boiling solution of the
ω-acetylenic â-keto ester (1 mmol) in benzene or xylene (15
mL) degassed by three freeze-pump-thaw cycles and was
irradiated (light from a projector lamp; ELW, 300W, 50% of
its power). The reaction was monitored by TLC and after
completion the solvent was removed in vacuo. The residue
was purified by flash chromatography to afford the ene
cycloadduct.
Meth yl 2-m eth yliden e-1-(1-oxoeth yl) cyclopen tan e car -
boxyla te (2): 0.167 g, 92%. 1H-NMR (400 MHz, CDCl3) δ
5.23 (t, J ) 2.2 Hz, 1H), 5.16 (t, J ) 2.2 Hz, 1H), 3.68 (s, 3H),
2.39 (m, 2H), 2.33 (m, 1H), 2.15 (s, 3H), 2.12 (m, 1H), 1.66 (m,
2H); 13C-NMR (100 MHz, CDCl3) δ 203.5, 171.6, 148.6, 112.2,
70.4, 52.6, 35.0, 33.9, 26.6, 24.1; IR (neat) 3080, 2980, 1740,
1710, 1640, 890 cm-1
.

Cycloisomerization of ꢀ-Acetylenic â-Keto Esters
J . Org. Chem., Vol. 61, No. 8, 1996 2707
NMR (100 MHz, CDCl3) δ 205.9, 173.4, 152.8, 111.8, 73.3, 56.2,
53.2, 33.0, 31.3, 30.2, 29.2, 23.2, 22.6. (22+23)d : IR (neat)
2940, 2845, 1730, 1710, 1640, 1430, 1350, 1230, 900 cm-1. MS
(m/ z) 225, 207, 192, 183, 165, 149, 139, 121, 107, 91, 79, 65,
53, 43. Anal. Calcd for C13H20O3: C, 69.61; H, 8.99. Found:
C, 69.99; H, 9.18.
Meth yl 2-m eth ylid en e-1-(1-oxoeth yl)-5-[(tr im eth ylsi-
lyl)m eth yl]cyclop en ta n e ca r boxyla te (22+23)e (R ) CH2-
SiMe3): 0.193 g, 72%; 85:15 mixture of inseparable diastereo-
isomers. (22+23)e: 1H-NMR (400 MHz, CDCl3) δ 5.23-5.16
(m, 4H), 3.74 (s, 3H), 3.71 (s, 3H), 2.85-2.77 (m, 2H), 2.58-
2.26 (m, 4H), 2.24 (s, 3H), 2.13 (s, 3H), 1.94-1.87 (m, 2H),
1.48-1.41 (m, 2H), 0.36-0.17 (m, ABX, 4H), 0.01 (s, 9H), 0.00
(s, 9H); IR (neat) 2950, 1730, 1710, 1640,1385, 1250, 1080, 890
cm-1. Anal. Calcd for C14H24SiO3: C, 62.6; H, 9.01. Found:
C, 62.69; H, 8.97. 22e: 13C-NMR (100 MHz, CDCl3) δ 206.2,
172.2, 150.2, 112.8, 76.1, 52.8, 44.0, 34.0, 32.2, 28.5, 18.9, 0.0.
23e: 13C-NMR (100 MHz, CDCl3) δ 203.5, 172.7, 150.3, 112.9,
75.6, 53.3, 45.5, 33.7, 30.6, 28.6, 19.0, -0.01.
Meth yl 5-ter t-bu tyl-2-m eth ylid en e-1-(1-oxoeth yl)cyclo-
p en ta n eca r boxyla te (22+23)f (R ) t-Bu): 0.152 g, 64%; 96:4
mixture of inseparable diastereomers. 1H-NMR (200 MHz,
CDCl3) δ 5.03 (t, J ) 2.3 Hz, 2H), 4.92 (t, J ) 2.7 Hz, 2H),
3.68 (s, 3H), 3.67 (s, 3H), 3.00 (dd, J ) 7.1, 6.9 Hz, 2H), 2.61-
2.30 (m, 4H), 2.39 (s, 3H), 2.38 (s, 3H), 1.89-1.70 (m, 4H), 0.85
(s, 18H); 13C-NMR (50 MHz, CDCl3) δ 203.2, 172.8, 153.0,
109.5, 70.3, 57.6, 51.6, 32.7, 32.5, 28.9, 28.4, 25.6; IR (neat)
2940, 1730, 1710, 1640, 1430, 1350, 1230, 885 cm-1; MS (m/
z) 223, 206, 196, 182, 178, 163, 150, 135, 121, 107, 91, 79, 59,
51, 43. Anal. Calcd for C14H22O3: C, 70.59; H, 9.24. Found:
C, 70.82; H, 9.34.
matography (petroleum ether/ether ) 90/10), 30 (1.57 g; 94%)
was obtained as a mixture of three inseparable diastereomers
in equilibrium with the enol forms.1H-NMR (400 MHz, CDCl3)
δ 3.70 (s, 3H), 3.69 (s, 3H), 3.68 (s, 3H), 3.54-3.48 (m, 3 ×
1H), 2.44-2.39 (m, 3x1H), 2.44-2.31 (M, 3 × 4H), 2.22 (s, 3H),
2.21 (s, 3H), 1.70-1.39 (M, 3 × 7H), 0.11-0.10 (2xs, 3 × 27H);
13C-NMR (100 MHz, CDCl3) δ 202.8 (3C), 174.1, 173.7, 169.4,
107.9, 107.8, 107.7, 106.4, 106.0, 103.8 (2C), 86.5, 86.4 (2C),
86.0, 85.2, 84.9, 63.1, 63.0, 62.9, 52.1, 51.0, 36.5, 36.1, 32.0,
31.9, 31.8, 30.0, 29.9, 29.8, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0,
27.3 (2C), 27.2, 25.8, 25.7, 18.1, 17.1, 17.0, 0.0; IR (neat) 2950,
2165, 1740, 1710, 1430, 1245, 840 cm-1; MS (m/ z) 487, 391,
313, 275, 243, 239, 225, 209, 201, 187, 173, 155, 147, 89. Anal.
Calcd for C27H46Si3O3: C, 64.48; H, 9.22. Found: C, 64.54; H,
9.21.
Meth yl 3-(3-Bu tyn yl)-6-eth yn yl-2-(1-oxoeth yl)-8-n on -
yoa te (31). To a cooled (-10 °C) solution of 30 (1.0 g; 2 mmol)
in THF (15 mL) was added a THF solution of n-Bu4NF (1 M
in THF; 6.4 mL; 3.2 equiv) dropwise. After being stirred for
30 min at -10 °C and an additionnal 3 h at room temperature,
the reaction mixture was extracted with ether (50 mL), washed
with brine (2 × 20 mL), dried (MgSO4), filtered, and concen-
trated. The residue was flash chromatographed (petroleum
ether-ether ) 80/20) affording 31 (0.54 g; 94%) as a mixture
of three inseparable diastereomers in equilibrium with the enol
forms: 1H-NMR (200 MHz, CDCl3) δ 3.74 (s, 3H), 3.73 (s, 3H),
3.55-3.51 (m, 3 × 1H), 2.51 (m, 3 × 1H), 2.42-2.34 (m, 3 ×
4H), 2.24 (s, 3 × 3H), 2.12 (b s, 3 × 1H), 2.05 (t, J ) 2.2 Hz,
3 × 1H), 1.96 (m, 3 × 1H), 1.80-1.40 (M, 3 × 7H); 13C-NMR
(50 MHz, CDCl3) δ 202.8 (3C), 169.5 (3C), 85.4 (3C), 83.4 (3C),
81.4, 81.2, 81.1, 70.6, 70.5, 70.4, 70.3, 70.2, 70.1, 69.1, 68.9,
68.5, 62.8, 62.7, 62.7, 52.3 (3C), 36.5, 36.4, 36.3, 30.9 (3C), 30.8,
30.7, 30.3, 29.6 (3C), 29.4 (3C), 27.8, 27.6, 27.5, 24.5, 24.4, 24.3,
15.9, 15.8, 15.7; IR (neat) 2950, 2850, 2230, 1710, 1640, 1430,
1235, 900 cm-1; MS (m/ z) 243, 215, 211, 187, 183, 173, 169,
149, 129, 116, 101, 91. Anal. Calcd for C18H22O3: C, 75.50;
H, 7.74. Found: C, 75.44; H, 7.66.
Met h yl 2-(3-E t h yn yl-5-h exyn yl)-5-m et h ylid en e-1-(1-
oxoet h yl)cyclop en t a n e ca r boxyla t e (32). Following the
general procedure described above for the ene reaction, 32 was
obtained as a mixture of three inseparable diastereomers
(0.218 g; 76%): 1H-NMR (400 MHz, CDCl3) δ 5.26 (t, J ) 2.2
Hz, 3 × 1H), 5.20 (t, J ) 2.2 Hz, 3 × 1H), 3.79 and 3.73 [(s,
32b: 14%) and (s, 32a : 86%), 9H], 2.79-2.72 (m, 3 × 2H),
2.55-2.51 (m, 3 × 1H), 2.46-2.33 (m, 3 × 2H), 2.27 and 2.17
[(s, 32a : 86%) and (s, 32b: 14%), 9H], 2.11 (t, J ) 2.2 Hz, 3
× 1H), 2.04 (m, 3 × 1H), 1.96-1.92 (m, 3 × 1H), 1.74-1.63
(m, 3 × 1H), 1.60-1.40 (M, 3 × 4H), 1.30-1.20 (m, 3 × 1H);
13C-NMR (100 MHz, CDCl3) δ 202.1 (3C), 171.1 (3C), 149.3
112.1 (3C), 85.6 (3C), 81.3 (3C), 76.7 (3C), 70.3 (3C), 70.1 (3C),
52.0 (3C), 46.0 (3C), 32.6 (3C), 32.2 (3C), 30.8(3C), 29.2 (3C),
28.7 (3C), 27.2 (3C), 24.4 (3C); IR (neat) 3280, 2940, 2110, 1720,
1640, 1430, 1160 cm-1; MS (m/ z) 287, 255, 245, 227, 211, 197,
183, 169, 153, 145, 128, 117, 107, 91, 79, 65, 51. Anal. Calcd
for C18H22O3: C, 75.50; H, 7.74. Found: C, 75.34; H, 7.80.
Ben zocyclobu ten es (33). The reaction was carried out
under argon in a flame-dried flask, and all the solutions were
degassed by three freeze-pump-thaw cycles. A solution of 32
(0.20 g; 0.7 mmol) and CpCo(CO)2 (17 mL; 0.14 mmol) in
degassed bis(trimethylsilyl)ethyne (3.4 mL) and xylenes (1 mL)
was added dropwise over 20 min to a boiling degassed solution
of btmse (7 mL) and CpCo(CO)2 (8.5 mL; 0.07 mmol). Light
from a projector lamp (ELW, 300W, 50% of its power) was
directed at the reaction mixture during the addition. After
the mixture was boiled and irradiated for an additional 15 min,
the solvents were removed by vacuum transfer. The crude
residue was purified by flash chromatography (petroleum
ether/ether ) 95/5) to give an inseparable diastereomeric
mixture of benzocyclobutenes 33. 33a +b: 0.27 g; 84%. 1H-
NMR (400 MHz, CDCl3) δ 7.41 (br s, 3 × 1H), 7.38 (br s, 3 ×
1H), 5.29-5.20 (m, 3 × 2H), 3.77 and 3.75 [(s, 33b: 14%) and
(s, 33a : 86%), 9H], 3.47-3.46 (m, 3 × 1H), 3.37-3.33 (m, 3 ×
1H), 2.52-2.49 (m, 3 × 1H), 2.37-2.35 (m, 3 × 2H), 2.29 and
2.25 [(s, 33a : 86%) and (s, 33b: 14%), 9H], 2.08-1.97 (m, 3 ×
1H), 1.80-1.20 (M, 3 × 6H), 0.36 (s, 3 × 9H), 0.35 (s, 3 × 9H);
13C-NMR (100 MHz, C6D6) δ 204.7, 204.5, 202.9, 202.7, 171.9
Meth yl 5-eth yn yl-7-m eth ylen e-2-oxobicyclo[3.2.1]oc-
ta n e-1-ca r boxyla te (25): 0.153 g, 70%; white solid; mp 92
°C; 1H-NMR (400 MHz, C6D6) δ 5.85 (dd, J ) 2.7, 2.2 Hz, 1H),
4.84 (br s, 1H), 3.39 (s, 3H), 2.66 (ddd, J ) 17.0, 4.4, 2.7 Hz,
1H), 2.50 (dd, J ) 12.6, 3.0 Hz, 1H), 2.29 (ddd, J ) 17.0, 4.4,
2.2 Hz, 1H), 2.18 (dd, J ) 12.6, 2.2 Hz, 1H), 2.14 (ddd, J )
15.9, 12.1, 9.3 Hz, 1H), 1.85 (s, 1H), 1.84 (ddd, J ) 15.9, 6.6,
2.2 Hz, 1H), 1.58 (m, 2H); 13C-NMR (100 MHz, C6D6) δ 202.4,
169.5, 145.1, 112.8, 87.9, 70.8, 68.9, 52.7, 48.3, 45.4, 38.3, 35.7,
35.6; IR (CHCl3) 3300, 3010, 2100, 1740, 1640, 750 cm-1
;
HRMS calcd 218.0943, found 218.0948. Anal. Calcd for C13
H14O3: C, 71.53; H, 6.46. Found: C, 71.43; H, 6.42.
-
1-(Met h oxyca r b on yl)-2-m et h ylid en e-1-(1-oxo-6-h ep -
tyn yl)cyclop en ta n eca r boxyla te (27): 0.208 g, 81%; 1H-
NMR (400 MHz, CDCl3) δ 5.22 (t, J ) 2.1 Hz, 1H), 5.14 (t, J
) 2.1 Hz, 2H), 3.67 (s, 3H), 2.58-2.41 (m, 2H), 2.48 (dt, J )
7.1, 2.1 Hz, 2H), 2.32 (t, J ) 7.1 Hz, 2H), 2.12 (td, J ) 7.1, 2.6
Hz, 2H), 1.87 (t, J ) 2.6 Hz, 1H), 1.70-1.48 (M, 4H), 1.49-
1.41 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 205.8, 172.1, 148.9,
112.6, 84.5, 70.7, 68.9, 53.0, 38.7, 35.5, 34.3, 28.2, 24.5, 23.6,
18.7; IR (neat) 3300, 2940, 2850, 2250, 1735, 1710, 1640, 1430,
1230, 910, 730 cm-1; MS (m/ z) 249, 217, 199, 189, 171, 161,
147, 139, 131, 122, 109, 95, 81, 65, 53. Anal. Calcd for
C15H20O3: C, 72.55; H, 8.12. Found: C, 72.85; H, 8.52.
Ap p lica tion in Syn th esis. Meth yl 6-[2-(Tr im eth ylsi-
lyl)eth yn yl]-2-(1-oxoeth yl)-2-n on en -9-(tr im eth ylsilyl)-8-
yn oa te (29). 29 was prepared using the procedure described
for 20. Compound 29 (4.06 g; 75%) was purified by flash
chromatography (petroleum ether/ether ) 80/20) and was
obtained as a 1:1 mixture of E and Z isomers: 1H-NMR (400
MHz, CDCl3) δ 6.93 (t, J )8.2 Hz, 1H), 6.88 (t, J ) 7.7 Hz,
1H), 3.83 (s, 3H), 3.78 (s, 3H), 2.54 (m, 2H), 2.45 (m, 2H), 2.40
(m, 2H), 2.39 (m, 2H), 2.38 (s, 3H), 2.37 (dt, J ) 7.7, 6.5 Hz,
2H), 2.31 (s, 3H), 1.79-1.68 (m, 4H), 0.14 (s, 18H), 0.13 (s,
18H); 13C-NMR (100 MHz, CDCl3) δ 200.7, 194.9, 166.7, 164.8,
148.0, 147.9, 137.1, 135.8, 107.2 (2C), 103.6 (2C), 87.3, 87.2,
86.8 (2C), 52.1(2C), 32.5, 32.3, 31.8, 31.7, 27.8 (2C), 27.1, 25.9
(2C), 22.6, 0.04, 0.00; IR (neat) 2950, 2170, 1710, 1690, 1630,
1250, 840 cm-1; MS (m/ z) 361, 303, 264, 249, 231, 199, 159,
131, 96, 89. Anal. Calcd for C20H32Si2O3: C, 63.78; H, 8.56.
Found: C, 63.58; H, 8.76.
Meth yl 3-[4-(tr im eth ylsilyl)-3-bu tyn yl]-6-[2-(tr im eth -
ylsilyl)et h yn yl]-2-(1-oxoet h yl)-9-(t r im et h ylsilyl)-8-n on -
yoa te (30). Compound 30 was prepared following the general
procedure (a) for the preparation of 21a -f. After flash chro-

2708 J . Org. Chem., Vol. 61, No. 8, 1996
Cruciani et al.
(2C), 171.8 (2C), 150.2, 150.1, 149.9, 149.8, 145.4, 144.7, 144.3
(2C), 137.9, 137.4, 136.6, 132.4 (2C), 132.3, 131.5, 130.1, 129.4,
129.1 (3C), 128.9 (2C), 128.8 (2C), 112.8, 112.7, 112.6, 112.5,
74.4, 74.2, 74.0, 73.9, 52.6, 52.5, 52.4, 53.1, 46.9 (2C), 46.8 (2C),
44.8 (2C), 44.7, 44.6, 37.3 (2C), 37.2 (2C), 33.4, 33.3, 33.1, 30.9,
30.8, 29.9 (2C), 29.7, 29.6 (2C), 28.1 (2C), 27.8 (2C), 2.9 (4C);
IR (neat) 3010, 2940, 2395, 1730, 1700, 1430, 1250, 1210, 850,
830 cm-1; MS (m/ z) 456, 353, 301, 281, 265, 251, 219, 207,
187, 167. Anal. Calcd for C26H40Si2O3: C, 68.37; H, 8.83.
Found: C, 68.33; H, 8.86.
Tetr a cyclic Com p ou n d s 35. A degassed solution of
benzocyclobutenes 33 (0.24 g; 0.52 mmol) in decane (15 mL)
was heated at reflux until TLC indicated that starting material
had been consumed (12 h). The solvent was removed by
vacuum transfer, and the crude residue was purified by flash
chromatography (petroleum ether/ether ) 90/10) to afford two
compounds 35a (0.19 g; 79%) and 35b (0.03 g; 13%). 35a : 1H-
NMR (400 MHz, C6D6) δ 7.74 (s, 1H), 7.54 (s, 1H), 3.46 (dd, J
) 10.4, 5.5 Hz, 1H), 3.27 (s, 3H), 2.76 (ddd, J ) 12.6, 5.5, 4.9
Hz, 1H), 2.71-2.67 (m, 1H), 2.43 (dt, J ) 12.6, 5.5 Hz, 1H),
2.29 (ddd, J ) 12.1, 6.0, 5.5 Hz, 1H), 2.27 (m, 1H), 2.22 (m,
1H), 2.20 (m, 1H), 2.16 (ddd, J ) 12.6, 5.5, 2.2 Hz, 1H), 1.96
(s, 3H), 1.82 (dt, J ) 12.1, 4.9 Hz, 1H), 1.60 (ddd, J ) 9.3, 4.4,
4.4 Hz, 1H), 1.47 (m, 1H), 1.46 (m, 1H), 1.22 (ddd, J ) 9.9,
4.9, 4.9 Hz, 1H), 0.47 (s, 9H), 0.46 (s, 9H); 13C-NMR (100 MHz,
C6D6) δ 202.9, 172.2, 142.6, 142.1, 139.5, 136.5, 135.8, 134.7,
74.8, 51.2, 48.9, 42.0, 40.9, 29.4, 29.3, 29.2, 28.1, 27.8, 27.0,
25.1, 2.2, 2.1. 35b: 1H-NMR (400 MHz, C6D6) δ 7.73 (s, 1H),
7.54 (s, 1H), 4.10 (dd, J ) 11.5, 5.7 Hz, 1H), 3.25 (s, 3H), 2.74-
2.66 (m, 1H), 2.72-2.55 (m, 1H), 2.63-2.60 (m, 2H), 2.35-
2.23 (m, 1H), 1.93 (s, 3H), 1.68-1.60 (m, 3H), 1.55-1.48 (m,
1H), 1.48-1.38 (m, 1H), 1.38-1.29 (m, 1H), 1.31-1.24 (m, 2H),
0.5 (s, 9H), 0.48 (s, 9H); 13C-NMR (100 MHz, C6D6) δ 202.8,
171.1, 142.8, 141.8, 139.9, 136.5, 135.4, 134.5, 73.7, 51.3, 49.0,
42.0, 38.3, 30.6, 30.2, 30.1, 28.9, 27.7, 26.7, 24.8, 2.3, 2.1.
35a +35b: IR (neat) 3010, 2940, 2395, 1730, 1700, 1430, 1250,
1210, 850, 830 cm-1; MS (m/ z) 456, 441, 409, 381, 353, 340,
309, 301, 265, 237, 213, 197, 161, 147, 131. Anal. Calcd for
C26H40Si2O3: C, 68.37; H, 8.83. Found: C, 68.72; H, 9.08.
On e-P ot Sequ en ce P r oced u r e. CpCo(CO)2 (7 mL; 5.8 ×
10-2 mmol) was added in boiling solution of 31 (0.23 g; 0.5
mmol) in benzene (4 mL) and was irradiated. After 8h, warm
btmse (8.5 mL) was quickly added. After being refluxed and
irradiated for an additional 30 min, a solution of diphen-
ylphosphinoethane (dppe; 0.06 g; 0.15 mmol) in decane (50 mL)
was added. After being heated at reflux for 12h, the solvents
were removed in vacuo and the crude residue was purified as
above to furnish 35a +35b in 42% yield.
Ack n ow led gm en t. Financial support was provided
by the CNRS, MRES, and Centre de Recherche des
Carrie`res Rhoˆne-Poulenc. R.S. and P.C. were supported
by fellowships from Rhoˆne-Poulenc. The authors are
indebted to Dr. O. Convert and Dr. F. Robert, Universite´
1
P. et M. Curie, respectively, for running H-NMR NOE
experiments and for carrying out the X-ray structural
determination of 35.
J O9600619