Recent progress in cobalt-mediated [2 + 2 + 2] cycloaddition reactions
Vincent Gandon, Corinne Aubert* and Max Malacria*
Received (in Cambridge, UK) 13th December 2005, Accepted 9th February 2006
First published as an Advance Article on the web 16th March 2006
For many years, our research group has been interested in the new developments of cobalt-
mediated cyclizations. In this article, our recent achievements in the field of inter- and
intramolecular [2 + 2 + 2] cyclizations are compiled.
Since the discovery of benzene formation by thermal cycliza-
tion of three molecules of acetylene by Berthelot1and the
pioneering work of Reppe in transition metal-mediated
cyclizations,2catalysts based on no less than seventeen early
to late transition metals have been developed for the
cyclotrimerization of acetylenic compounds. In addition to
alkynes, a large variety of other unsaturated partners such as
alkenes, nitriles, aldehydes, ketones, imines, isocyanates,
isothiocyanates, etc.3can take part in related cyclizations to
give products with four-, five-, six- or eight-membered rings.
Many of these cyclizations proceed with good chemo-, regio-
and stereoselectivities and have found applications in the
synthesis of complex polycyclic molecules. In the last three
decades, this reaction has been extensively investigated and the
topic has been thoroughly reviewed.4
Among all the available catalysts, cobalt complexes have
proved versatile reagents for the selective formation of
multiple carbon–carbon bonds in a single chemical step.5
Numerous applications of cobalt-catalyzed cyclizations have
been reported by Vollhardt and co-workers, who achieved very
elegant and efficient total syntheses of various natural
products and compounds of theoretical interest.6
For many years, our research group has also been interested
in the development of new cobalt-mediated transformations.
We anticipated that the potential of cobalt catalysis could be
spectacularly displayed by designing cascade reactions aimed
at the preparation of complex and highly functionalized
molecules starting from simple acyclic polyunsaturated pre-
cursors.7In this article, we wish to review our recent
achievements in the field of [2 + 2 + 2] cycloadditions involving
alkynes, alkenes and new unsaturated partners. We will focus
on the chemo- and regioselectivity of the cyclizations and their
applications in synthesis.
Cyclotrimerization of alkynes
Contribution to the chemo- and the regioselectivity
The selective synthesis of polysubstituted benzenes and
pyridines from intermolecular transition metal-catalyzed [2 +
2 + 2] cycloaddition reactions is a challenging problem. Indeed,
the cyclotrimerization of a single monosubstituted alkyne
Universite ´ Pierre et Marie Curie - Paris 6, Laboratoire de Chimie
Organique - UMR 7611, Institut de Chimie Mole ´culaire FR 2769, Tour
44–54, 2u e ´tage, CC. 229, 4 place Jussieu, 75252 Paris Cedex 05, France.
E-mail: firstname.lastname@example.org; email@example.com;
Fax: (+33) (0)144277360; Tel: (+33) (0)1442735876
Vincent Gandon was born in
Soissons, France. He obtained
his PhD in 2002 from the
University of Champagne-
Ardennes, Reims under the
supervision of Professor Jan
mediated organic transforma-
tions). After a one year post-
doctoral stay in the group of
Professor Guy Bertrand in
Riverside, California, he
joined the laboratory of
Professor Max Malacria in
Professor, working in colla-
boration with Dr C. Aubert. His main research interests are
the development of new synthetic methods using group 9
transition metals and boron chemistry.
Corinne Aubert was born in Les Ardennes, France. After having
studied chemistry at the University of Champagne-Ardennes,
Reims, she attended the Ecole
Nationale Supe ´rieure de
Chimie de Strasbourg. She
received her PhD in 1985
under the supervision of Drs
J. F. Biellmann and J. P.
Be ´gue ´ from the University of
Paris-Sud, Orsay. She was
appointed by the CNRS in
Recherches in the laboratory
of Dr J. P. Be ´gue ´ and worked
on fluorine chemistry. After
doing two years of postdoc-
University of California,
Berkeley with Professor K. P. C. Vollhardt, she joined the team
of Professor Max Malacria at the Universite ´ Pierre et Marie
Curie, Paris. In 2001, she was appointed Directeur de
Recherches. Her research interests concern new developments
in transition metal-mediated cyclizations and applications in
synthesis, asymmetric catalysis and boron chemistry.
Vincent GandonCorinne Aubert
FEATURE ARTICLEwww.rsc.org/chemcomm | ChemComm
This journal is ? The Royal Society of Chemistry 2006Chem. Commun., 2006, 2209–2217 | 2209
usually leads to regioisomeric 1,2,4- and 1,3,5-trisubstituted
benzenes. Moreover, the cyclization of two different mono-
substituted alkynes may give up to nine isomers, and that of
three monosubstituted alkynes up to 38 different ones. A few
methods have been proposed to overcome this crucial issue,
but despite their impressive efficiency, these strategies remain
restricted to specific cases.8–11For instance, a calixarene bound
titanium complex allowed the highly selective cyclization of
monosubstituted alkynes into 1,2,4-trisubstituted benzenes.9
Chemoselective assembly of terminal alkynes with DMAD via
iridium and ruthenium catalysis was also reported, yet with
moderate levels of regioselectivity.10Although limited to 1,2-
diynes, the palladium-catalyzed homodimerization of terminal
alkynes and subsequent [4 + 2] benzannulation gave tetra- and
pentasubstituted benzenes from three different alkynes with
excellent levels of regio- and chemoselectivity.11Stepwise
strategies involving stoichiometric amounts of zirconium and
titanium complexes were also proposed for the selective
formation of benzenes and pyridines.12In the cobalt series,
examples remain rare and specific. For instance, Sugihara et al.
reported that methylidynetricobalt nonacarbonyl is able to
catalyze the cyclotrimerization of phenylacetylene with total
In this context, we proposed an unusual approach to the [2 +
2 + 2] cycloaddition of alkynes based on the use of disposable
linkers.14The formal chemo- and regioselective intermolecular
[2 + 2 + 2] cyclizations of three different alkynes were achieved
via the judicious implementation of a temporary silylated
tether (TST).15The general concept is presented in Scheme 1.
Under refluxing conditions, visible light irradiation and in
the presence of 5 mol% of g5-cyclopentadienyldicarbonyl
cobalt [CpCo(CO)2], silicon-tethered triynes 1 and 3 led to the
corresponding cycloadducts 2 and 4 in good yields, regardless
of the steric hindrance induced by the iso-propyl groups at the
internal triple bond and of the substitution of the external
triple bonds (Scheme 2).16Displacement of the silylated
moieties was achieved using 4 equiv. of TBAF, giving diols 5
and 6 in ca. 60% yield. Similarly, cyclotrimerization of
unsymmetrical triyne 7 followed by protodesilylation afforded
diol 9 in 51% yield over the two steps.
This overall sequence led to di- or tetrasubstituted benzenes,
formally arising from the cyclotrimerization between two
molecules of propargyl alcohol and a third alkyne unit, which
in the case of 5, would be acetylene itself. In contrast, direct
reactions between propargyl alcohol and alkynes gave us
intractable mixtures of all feasible benzenic derivatives.
The reaction of silicon-tethered a,v-diynes and alkynes also
gave the corresponding cycloadducts in good yields (Scheme 3).
The opening of the silylated ether was achieved either with
TBAF or methyllithium to deliver quantitatively the bicyclic
benzenic derivatives 11 and 12, which formally originate from
the totally chemo- and regioselective bimolecular [2 + 2 + 2]
cyclizations between octa-2,7-diyne-1-ol and hex-1-yne or 1-
Max Malacria was born in
1949 in Marseille, France. He
obtained his PhD from the
University of Aix-Marseille
III with Professor Marcel
Bertrand in 1974. He was
appointed Assistant in 1974
at the University of Lyon I
with Professor J. Gore ´. After
almost two years as a post-
doctoral fellow with Professor
K. P. C.Vollhardt
Berkeley, he went back to the
University of Lyon as a
Maı ˆtre de Confe ´rences in
1983. In 1988, he was
appointed Full Professor at the UPMC. In 1991, he was elected
junior member of the Institut Universitaire de France and
promoted to senior member in 2001. His research interests
include the development of new domino processes in both
organometallic and radical chemistry, and applications in the
synthesis, asymmetric synthesis and new stereoselective reactions
involving heteroelements and platinum-catalyzed reactions.
Cyclization of silylated tethered triynes and displacement
2210 | Chem. Commun., 2006, 2209–2217This journal is ? The Royal Society of Chemistry 2006
Synthetic applications: access to the taxane framework by
sequential [2 + 2 + 2]/[4 + 2] cycloadditions
Our interest in the development of cobalt-mediated [2 + 2 + 2]
cyclizations for synthetic purposes brought us to develop
reaction cascades. We disclosed some years ago that cobalt(I)
complexes catalyze formal Alder ene reactions of allenynes and
enynes17, and also Conia ene type reactions of v-acetylenic
b-ketoesters to form functionalized methylenecyclopentanes in
a stereocontrolled manner.18After designing new polyunsatu-
rated substrates, we combined these reactions with cyclotri-
merizations, [4 + 2] cyclizations, or Pauson–Khand reactions,
and proposed different approaches to the basic skeletons of
natural tetracyclic diterpenes of the phyllocladane, kaurane
and triquinane families.19Recently, we investigated stereo-
selective routes to the ABC core of taxane, starting from
simple acyclic polyunsaturated precursors.
In the past ten years, taxane diterpenoids have been one of
the most challenging synthetic targets due to their unique
structural features as well as their considerable therapeutic
potential.20The taxane framework a, depicted in Scheme 4,
exhibits an aryl C-ring, an all-carbon D-ring and an additional
E-ring. We reasoned that this skeleton could be obtained from
an intramolecular [4 + 2] cycloaddition of triene b. The
benzocyclobutene unit of b could arise from the [2 + 2 + 2]
cyclization of the three alkyne units of enyne c. The link
between both unsaturated moieties d and e could be either
an alkylated or silylated tether, which might ensure the
chemo- and the regioselectivity (vide supra).
We first tried the sequential [2 + 2 + 2] and then [4 + 2]
approach to the core of taxanes.21Compound 13, which
displays a tert-butyldimethylsilyl group, was submitted to
standard [2 + 2 + 2] cyclization conditions. The presence of a
sterically demanding substituent at the terminal position of the
1,3-butadiene moiety was revealed as necessary to avoid the
competitive formation of cyclohexadienes.
Benzocyclobutenes 14 and 15 were obtained in 50 and 37%
yield, respectively (Scheme 5). Compound 15 probably arose
from a 1,3-migration of the double bond leading to an enol,
which subsequently undergoes tautomerization to give the
corresponding ketone. Despite this unexpected side reaction,
both tautomers could be efficiently transformed into the same
compound. The oxidation of 14 was carried out using IBX,
and [4 + 2] cyclization was then promoted by Et2O?BF3,
leading to the formation of pentacycle 16 as a single
diastereomer of unidentified stereochemical configuration.
On the other hand, compound 15 was oxidized via selena-
tion–oxidation–elimination and converted in good yield into
16, as above.
The presence of the additional alkylated E-ring precludes
further functionalization of the aromatic C-ring. In order
to obtain an intermediate with latent functionalities, we
carried out the TST strategy. Besides, so as to avoid the 1,3-
migration, the monosubstituted double bond was removed.
a,v-diynes with alkyne.
Formal bimolecular [2 + 2 + 2] cyclotrimerization of
Scheme 4Retrosynthetic approach to the ABC core of taxoids.
Scheme 5 [2 + 2 + 2]/[4 + 2] approach to the ABC core of taxoids.
This journal is ? The Royal Society of Chemistry 2006Chem. Commun., 2006, 2209–2217 | 2211
Polyunsaturated precursor 17, which exhibits a di-iso-propyl-
silaketal linker, was submitted to the reaction sequence
depicted in Scheme 6.
[2 + 2 + 2] Cyclization followed by fluoride-mediated
desilylation furnished the corresponding diol 18 in 88% overall
yield. After the protection of the diol, deprotection of the
silylether, oxidation of the resulting alcohol into the ketone
and its transformation into enone 20, the Diels–Alder reaction
was carried out as above, affording cycloadduct 21, desilylated
at C13, in 65% yield. This unexpected protodesilylation should
not be troublesome because an allylic oxidation, leading to the
alcohol precursor of the lateral chain of the taxoid, could be
envisaged. Thus, the [2 + 2 + 2]/[4 + 2] approach to the core of
taxoids was validated successfully. The functionalization of the
aromatic C-ring of product 21 is now under investigation.
[2 + 2 + 2] cyclizations with new unsaturated partners
Allenediynes and their application to the synthesis of steroid
We previously reported that allenes are relevant partners for
intramolecular [2 + 2 + 2] cocyclizations leading to alkynes.
For instance, upon treatment with CpCo(CO)2, allenediynes of
yne–yne–allene type furnished the corresponding cycloadducts
in high yields and in a completely chemo-, regio- and
diastereoselective manner. Moreover, with optically-active
allenes, the process can be performed with a total transfer of
chirality (Scheme 7).22
Although still chemo- and regioselective, the cyclization of
yne–allene–yne compounds showed moderate to low diaster-
eoselectivities. g4-Complexed tricyclic (6,6,6) compounds were
obtained in moderate to good yield as mixtures of endo/exo
diastereomers that are independent of the substitution on
the allene. The cyclization is also compatible with an
oxy-functionality at C3 (Scheme 8).
Nevertheless, the resulting free ligands of the cyclizations
may be regarded as constituting the BCD and ABC moieties of
steroids, prompting us to explore the feasibility of building
steroid frameworks starting from a judiciously-substituted
In the past 20 years, a new class of antiprogestational
steroids that present an 11b-aryl unit have emerged due to
their relevant pharmacological properties. However, the
synthesis of such steroids still needs the development of new
The strategy depicted in Scheme 9 would allow the creation
in one step of the ABC ring system, and most interestingly, the
simultaneous introduction of substituents at both C11 and
C10. Indeed, tetracyclic complex b could be reached from the
intramolecular [2 + 2 + 2] cyclization of allenediyne c,
incorporating a pre-existing D-ring. Subsequent transforma-
tions of b might lead to 11b-aryl steroid a. At least for the time
being, no oxygenated function has been introduced at C3.
We observed that, depending on the stereochemical relation-
ship (cis or trans) between the ethynyl group on the five-
membered ring and the chain incorporating the allene,
two different trends occurred in the cobalt(I)-mediated
Access to the taxane framework via the use of the
[2 + 2 + 2] Cyclizations of allenediynes of yne–yne–allene
[2 + 2 + 2] Cyclizations of allenediynes of yne–allene–yne
2212 | Chem. Commun., 2006, 2209–2217 This journal is ? The Royal Society of Chemistry 2006
cyclizations.23If trans, the allenediyne 22 in the presence of a
stoichiometric amount of CpCo(CO)2in boiling xylenes under
irradiation gave the expected fused tetracyclic complex 23 in
60% yield as a single diastereomer. The structure of 23 was
established by a single crystal X-ray analysis which showed an
endo stereochemistry between CpCo and the vicinal methyl
group, and a trans relationship between the two angular
methyl groups (Scheme 10). The free ligand 24 could be readily
obtained in 90% yield upon treatment of complex 23 with silica
gel. The cyclization and decomplexation sequence could also
be carried out without purifying the complex and allowed the
formation of the 11b-aryl steroid skeleton in 48% overall yield.
Functionalization of either complex 23 or the free ligand 24 are
In contrast, allenediyne 25, which displays a cis relationship
between the ethynyl group on the five-membered ring and the
allenic chain, furnished the bicyclic yne-trienic compound 26 in
66% yield under the same experimental conditions (Scheme 11).
This compound results from a formal Alder ene reaction
between the ethynyl group and the double bond of the allene
bearing the methyl group. Such an Alder ene reaction, which
had already been observed by our group,17occurs competi-
tively with the [2 + 2 + 2] cyclization when the latter is
disfavored for geometrical reasons. In the present case,
molecular models show that, on the contrary to 22, both of
these unsaturated moieties can be easily brought closer
together, thus allowing a straightforward complexation to
cobalt. After oxidative coupling, b-elimination followed by
reductive elimination furnished compound 26.
Alkynyl boronic esters: synthesis of fused arylboronic esters and
Introduction of main group heteroelements to unsaturated
partners such as olefins, acetylenes, allenes and 1,3-dienes may
have a dramatic influence on the product distribution of the
cycloadditions.24For instance, they can control the chemo-
and regioselectivities. Besides, they can confer kinetic stabili-
zation and allow the preparation of structural moieties which
would be hardly accessible in the unsubstituted series. They
can be replaced under electrophilic substitution conditions and
thus be considered as latent functional groups. Of particular
interest are the substrates incorporating group 13 or 14
heteroatoms, such as boron, silicon, germanium or tin. These
elements can provide useful disposable tethers (vide supra)
or giverise totransition
Cycloadditions and cycloisomerizations of alkynylboranes
lead to compounds of synthetic value, in which the newly
formed Csp2–B bond can be subjected to coupling reactions25
or to the plethora of known functional group transforma-
tions.26We will now focus on our recent contribution in
The synthesis of arylboronic esters is usually accomplished
by metal–halogen exchange of haloarenes followed by the
addition of trialkoxyborates.27However, this strategy is not
compatible with many functional groups, and to address this
issue, new methods involving alkynylboronic esters have been
developed. In this respect, the Do ¨tz benzannulation with
Fischer carbenes allows the preparation of quinone boronic
esters.28Siebert et al. have shown that alkynyl catechol,
thiocatechol and dithiocatechol boronic esters undergo facile
catalytic cyclotrimerization with Co2(CO)8 or CpCo(CO)2,
giving 1,2,4- and 1,3,5-triborylbenzene derivatives, and up to
hexaborylbenzene when starting from diborylacetylenes.29On
the other hand, under the same experimental conditions, we
found that alkynyl pinacol boronic esters did not give
cyclotrimerization adducts. They instead proved to be much
better candidates for cocyclization reactions such as the
cobalt(0)-mediated [2 + 2 + 2] cycloaddition with a,v-diynes.30
Mixing the borylalkynes, such as 27, with a stoichiometric
amount of cobalt carbonyl in xylenes at room temperature led
Scheme 9Retrosynthetic approach to 11b-aryl steroid frameworks.
This journal is ? The Royal Society of Chemistry 2006Chem. Commun., 2006, 2209–2217 | 2213
to the corresponding dicobaltatetrahedrane derivatives 28 in
good yields after column chromatography (Scheme 12).
Treatment of complex 28 (1 equiv.) with 1,6-heptadiyne
(1 equiv.) in refluxing xylenes gave the cycloadduct 30 in an
isolated yield of 50%.
Because the dicobaltatetrahedrane complexes derived from
our substrates proved to be very light sensitive and therefore
hard to handle, we decided to avoid their isolation and to treat
them in situ with a,v-diynes, leading to the results compiled in
Scheme 13. Using this sequence, an excess of diyne is needed to
reach the same yields as those obtained in the stepwise
procedure. Unreacted cobalt–carbonyl might be responsible
for some depletion of diyne by oligomerization, affecting the
yields of the cycloaddition reaction. Alkyl-, aryl- and silyl-
substituted alkynylboronic esters were successfully converted
into arylboronates by following this one-pot procedure: A
xylenes solution of Co2(CO)8is added all at once to the alkyne
in the same solvent. The dark solution is stirred in the absence
of light until no more CO evolution is visible. The neat diyne is
then added and the mixture refluxed until the conversion is
complete. The product is then purified by column chromato-
graphy on silica gel. In this way, a variety of indan, tetralin
and benzocycloheptene derivatives become accessible starting
from 1,6-hepta-, 1,7-octa- and 1,8-nonadiyne.
To demonstrate the utility of the products, compound 30
was treated with phenyl iodide in the presence of 2 mol% of
Pd(PPh3)4 to furnish the cross-coupling product 31 in an
unoptimized 53% yield (Scheme 14).
Recently, and complementary to our investigations, the [2 +
2 + 2] cocyclotrimerization of tethered alkynylboronic esters
with alkynes catalyzed by Ru(II) was reported by Yamamoto
and co-workers.31In this work, the product arylboronates
could not be isolated but were converted directly by Suzuki–
Miyaura coupling reactions. The synthesis of bi- and tricyclic
arylboronates via Ru(II)-catalyzed cycloaddition of a,v-diynes
to alkynylboronates was also accomplished by the same
team. Because internal alkynes proved to be inefficient
substrates for such cyclizations, this reaction was limited to
In addition to this novel one-pot method for the preparation
of arylboronic esters via the Co(0)-mediated cycloaddition of
alkynylboronates to a,v-diynes, we also performed Co(I)-
mediated [2 + 2 + 2] cycloadditions of alkynyl boronates to
alkenes.33This strategy, which proved compatible with various
substrates, allowed the rapid and efficient construction of
highly functionalized 1,3-cyclohexadienes and arenes after
oxidative demetallation (Scheme 15). Extensive chemo-, regio-
and diastereoselective assembly of mono-, bi- and tricyclic 1,3-
and 1,4-diboryl-1,3-cyclohexadienes was accomplished by
means of the CpCo-mediated cycloaddition of alkynyl
pinacolboronates to alkenes. The method produces a rapid
entry route to highly functionalized 1,3-cyclohexadiene syn-
thons of potential use in complex molecule synthesis.
Alkenylboranes are useful intermediates for the preparation
of a wide range of important organic molecules. Specifically,
mono- and diborylated 1,3-dienes have found various applica-
tions as dienylation reagents,34Diels–Alder partners35and
in the synthesis of a,b- or c,d-unsaturated ketones.36Their
cyclic counterparts, namely boryl-1,3-cyclohexadienes, were
plex and its cocyclization with a,v-diyne.
Preparation of pinacolboryldicobaltatetrahedrane com-
One-pot procedure for the preparation of fused arylboro-
2214 | Chem. Commun., 2006, 2209–2217This journal is ? The Royal Society of Chemistry 2006
unreported. Considering that the 1,3-cyclohexadiene nucleus
is a key sub-unit of many natural and/or biologically
active compounds, including those of the didehydroretinol
and -carotene families,37borylated 1,3-cyclohexadienes con-
stitute valuable reagents by which to introduce this synthon
directly. The latter task had been accomplished in the
past by using 1,3-cyclohexadienyl–metals,38–triflates,39or
–phosphates,40but these reagents had to be generated in
several steps from enolizable cyclohexenone derivatives, and
the methodology has not been applied to dimetallated 1,3-
cyclohexadienes. Our strategy allowed us to prepare 1,3- and
1,4-diboryl-1,3-cyclohexadienes regioselectively. The success of
the present study was predicated by the employment of g5-
been exploited as an active source of CpCo for the cool-
igomerization of alkynes with alkenes.6With 2,5-dihydro-
furan, cyclopentene and cyclohexene, the reactions proceeded
completely regioselectively in very good overall yields, with
moderate to excellent stereoselectivity (Scheme 16). In all
cases, the endo diastereomer was favored (33, 35 and 37). The
free dienes could be liberated through rapid oxidative
demetallation using iron(III) chloride in acetonitrile. For
instance, both complexes 32 and 33 furnished the same
Aromatization was accomplished, albeit in only moderate
yields so far, using ceric ammonium nitrate, either starting
from the free ligand or directly from the complex. In that
respect, 32 and 33 were converted into arene 39 in 45% yield.
Terminal alkenes revealed interesting stereo- and regioselec-
tivities (Scheme 17). For instance, a preference for placing the
was found with vinyltrimethylsilane and vinyl(tributyl)tin,
respectively. The stereochemistry of addition was exclusively
exo, an outcome that is most likely to be of steric origin.
The scope of the reaction was expanded to the cycloaddition
of various a,v-diboryldiynes to alkenes (Scheme 18). These
substrates enforced the 1,4-orientation of the boryl substitu-
ents in the resulting diene and granted access to the first
which has previously
reactions proceeded in good yield and, in the case of 44, with
high stereoselectivity, boding well for its synthetic application
to more complex structures.
Thus, the cyclization of alkynyl pinacolboronates to alkenes
produces a rapid entry into highly functionalized 1,3-cyclo-
hexadiene synthons of potential use in complex molecule
synthesis. Applications of such syntheses and the mechanistic
rationale for the selective outcome of these cyclizations are
Over the last few years, we have made continuous contribu-
tions to the development of cobalt-mediated [2 + 2 + 2]
cyclizations and have tried to solve the chemo- and regio-
selective problems of the cyclotrimerization reactions of alkynes.
By using temporary silylated tethers, we could efficiently
produce di- or tetrasubstituted benzenic derivatives starting
from up to three different unsymmetrical alkynes. This TST
strategy allowed us to propose a rapid entry route to the core of
taxanes starting from acyclic polyunsaturated precursors by
combining a cobalt(I)-catalyzed cyclotrimerization and a Diels–
Alder reaction. The resulting pentacyclic compounds exhibit
latent functionalities for further transformations.
We have also expanded the arsenal of unsaturated partners
which can be involved in these cyclizations. Allenes are
relevant partners for intramolecular cycloadditions to alkynes.
Depending on the position in the chain and the substitution of
the allene, different patterns can be prepared. By carefully
designing an allenediyne having a pre-existing D-ring, we
succeeded in building skeletons of steroids in one step, with the
simultaneous introduction of an angular methyl group at C10
and an aryl substituent at C11.
Finally, pinacol alkynylboronates have been revealed as
exciting unsaturated partners in such cyclizations. We have
developed a novel one-pot method for the synthesis of fused
arylboronic esters via the Co(0)-mediated cycloadditions of
alkynylboronates to a,v-diynes. We have also described
extensively the chemo-, regio- and diastereoselective assembly
This journal is ? The Royal Society of Chemistry 2006Chem. Commun., 2006, 2209–2217 | 2215
of mono-, bi- and tricyclic 1,3- and 1,4-diboryl-1,3-cyclohex-
adienes by means of the CpCo-mediated cycloaddition of
alkynyl pinacolboronates to alkenes. We believe that the
synthetic applications of this newly developed cyclization will
be very fruitful.
C. A. and M. M. are grateful for the excellent contributions of
our talented co-workers, whose names are listed in our
publications, including: Olivier Buisine, Gae ¨lle Chouraqui,
Phannarath Phansavath, Marc Petit and Franck Slowinski.
The authors thank the group of Professor K. P. C. Vollhardt at
the University of California, Berkeley for fruitful collabora-
tions on boron chemistry. Funding for the research was
provided by CNRS, MRES, IUF and the companies Sanofi-
Aventis and Glaxo Wellcome.
Notes and references
1 M. Berthelot and C. R. Hebd, C. R. Hebd. Seances Acad. Sci.,
1866, 62, 905.
2 W. Reppe and W. J. Schweckendiek, Justus Liebigs Ann. Chem.,
1948, 560, 104.
3 N. E. Schore, Chem. Rev., 1988, 88, 1081; N. E. Schore, in
Comprehensive Organic Synthesis, ed. B. M. Trost, I. Fleming and
L. A. Paquette, Pergamon Press, Oxford, 1991, vol. 5, pp. 1129;
D. B. Grotjahn, in Comprehensive Organometallic Chemistry II, ed.
E. W. Abel, F. G. A. Stone, G. Wilkinson and L. Hegedus,
Pergamon Press, Oxford, 1995, vol. 12, pp. 741; D. F. Harvey,
B. M. Johnson, C. S. Ung and K. P. C. Vollhardt, Synlett, 1989,
15; J. A. Varela and C. Saa ´, Chem. Rev., 2003, 103, 3787;
H. A. Duong, M. J. Cross and J. Louie, J. Am. Chem. Soc., 2004,
126, 11438; Y. Yamamoto, H. Takagishi and K. Itoh, J. Am.
Chem. Soc., 2002, 124, 28.
4 M. Lautens, W. Klute and W. Tam, Chem. Rev., 1996, 96, 49;
I. Ojima, M. Tzamarioudaki, Z. Li and R. J. Donovan, Chem.
Rev., 1996, 96, 635; S. Saito and Y. Yamamoto, Chem. Rev., 2000,
100, 2901; Y. Yamamoto, Curr. Org. Chem., 2005, 9, 503; S. Kotha,
E. Brahmachary and K. Lahiri, Eur. J. Org. Chem., 2005, 4741.
5 K. P. C. Vollhardt, Acc. Chem. Res., 1977, 10, 1; K. P. C. Vollhardt,
Angew. Chem., Int. Ed. Engl., 1984, 23, 536; M. Malacria,
C. Aubert and J. L. Renaud, in Science of Synthesis: Houben-
Weyl Methods of Molecular Transformations, ed. M. Lautens
and B. M. Trost, Georg Thieme Verlag, Stuttgart, 2001, vol. 1,
6 K. P. C. Vollhardt, Pure Appl. Chem., 1985, 57, 1819; E. J. Johnson
and K. P. C. Vollhardt, J. Am. Chem. Soc., 1991, 113, 381;
J. Germanas, C. Aubert and K. P. C. Vollhardt, J. Am. Chem. Soc.,
1991, 113, 4006; M. J. Eichberg, R. L. Dorta, D. B. Grotjahn,
K. Lamottke, M. Schmidt and K. P. C. Vollhardt, J. Am. Chem.
Soc., 2001, 123, 9324; D. L. Mohler and K. P. C. Vollhardt, in
Advances in Strain in Organic Chemistry, ed. B. Halton, JAI Press,
London, 1996, pp. 121; S. Han, A. D. Bond, R. L. Disch,
D. Holmes, J. M. Schulman, S. J. Teat, K. P. C. Vollhardt and
G. D. Whitener, Angew. Chem., Int. Ed., 2002, 41, 3223;
S. Kumaraswamy, S. S. Jalisatgi, A. J. Matzger, O. S. Miljanic
and K. P. C. Vollhardt, Angew. Chem., Int. Ed., 2004, 43, 3711 and
pertinent references cited therein.
7 M. Malacria, Chem. Rev., 1996, 96, 289.
8 K. Tanaka, K. Toyoka, A. Wada, K. Shirasaka and M. Hirano,
Chem.–Eur. J., 2005, 11, 1145; S. Saito, T. Kawasaki, N. Tsuboya
and Y. Yamamoto, J. Org. Chem., 2001, 66, 796; N. Mori,
S.-i. Ikeda and K. Odashima, Chem. Commun., 2001, 181;
Y. Yamamoto, T. Arakawa, R. Ogawa and K. Itoh, J. Am.
Chem. Soc., 2003, 125, 12143.
9 O. V. Ozerov, B. O. Patrick and F. T. Ladipo, J. Am. Chem. Soc.,
2000, 122, 6423.
10 R. Takeuchi and Y. Nakaya, Org. Lett., 2003, 5, 3659; Y. Ura,
Y. Sato, M. Shiotsuki, T. Kondo and T.-a. Mitsudo, J. Mol. Catal.
A: Chem., 2004, 209, 35.
11 V. Gevorgyan, U. Radhakrishnan, A. Takeda, M. Rubina,
M. Rubin and Y. Yamamoto, J. Org. Chem., 2001, 66,
2835; M. Rubin, A. W. Sromek and V. Gevorgyan, Synlett,
12 T. Takahashi, Pure Appl. Chem., 2001, 73, 271; T. Takahashi, Y. Li,
T. Ito, F. Xu, K. Nakajima and Y. Liu, J. Am. Chem. Soc., 2002,
124, 1144; D. Suzuki, H. Urabe and F. Sato, J. Am. Chem. Soc.,
2001, 123, 7925; D. Suzuki, K. Tanaka, H. Urabe and F. Sato,
J. Am. Chem. Soc., 2002, 124, 3518.
13 T. Sugihara, A. Wakabayashi, Y. Nagai, H. Takao, H. Imagawa
and M. Nishizawza, Chem. Commun., 2002, 576.
14 Several reviews have compiled different aspects of the chemistry of
silicon linkers, see: M. Bols and T. Skrydstrup, Chem. Rev., 1995,
95, 1253; L. Fensterbank, M. Malacria and S. M. Sieburth,
Synthesis, 1997, 813; D. R. J. Gauthier, K. S. Zandi and K. J. Shea,
Tetrahedron, 1998, 54, 2289; T. Skrydstrup, in Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations, ed.
I. Fleming, Georg Thieme Verlag, Stuttgart, 2001, vol. 4, pp. 439;
J. D. White and R. G. Carter, in Science of Synthesis: Houben-
Weyl Methods of Molecular Transformations, ed. I. Fleming, Georg
Thieme Verlag, Stuttgart, 2001, vol. 4, pp. 371. Concerning the [2 +
2 + 2] cyclization, Eckenberg and Groth described the preparation
of 1,9,10-trihydroxyoctahydroanthracene, which represents the
ABC core of many anthracyclin antibiotics. Prior to the cobalt-
mediated [2 + 2 + 2] cyclization, a diyne and an alkene were
connected through a TST, which was cleaved afterwards either by
oxidation or hydrolysis, see: P. Eckenberg and U. Groth, Synlett,
15 G. Chouraqui, M. Petit, C. Aubert and M. Malacria, Org. Lett.,
2004, 6, 1519.
16 M. Petit, G. Chouraqui, C. Aubert and M. Malacria, Org. Lett.,
2003, 5, 2037.
17 D. Llerena, C. Aubert and M. Malacria, Tetrahedron Lett., 1996,
37, 7027; D. Llerena, C. Aubert and M. Malacria, Tetrahedron
Lett., 1996, 37, 7353.
18 R. Stammler and M. Malacria, Synlett, 1994, 92; P. Cruciani,
R. Stammler, C. Aubert and M. Malacria, J. Org. Chem., 1996, 61,
19 P. Cruciani, C. Aubert and M. Malacria, J. Org. Chem., 1995, 60,
2664; P. Cruciani, C. Aubert and M. Malacria, Synlett, 1996, 105;
J. L. Renaud, C. Aubert and M. Malacria, Tetrahedron, 1999, 55,
20 D. G. I. Kingston, Chem. Commun., 2001, 867 and references
21 M. Petit, G. Chouraqui, P. Phansavath, C. Aubert and
M. Malacria, Org. Lett., 2002, 4, 1027.
22 D. Llerena, O. Buisine, C. Aubert and M. Malacria, Tetrahedron,
1998, 54, 9373; O. Buisine, C. Aubert and M. Malacria, Synthesis,
23 M. Petit, C. Aubert and M. Malacria, Org. Lett., 2004, 6, 3937.
24 V. Gandon, C. Aubert and M. Malacria, Curr. Org. Chem., 2005,
25 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;
N. Miyaura, Top. Curr. Chem., 2002, 219, 11; N. Miyaura in
Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and
F. Diederich, Wiley-VCH, Weinheim, 2004, vol. 1, pp. 41.
26 For representative examples, see: C. Thiebes, G. K. Surya Prakash,
N. A. Petasis and G. A. Olah, Synlett, 1998, 141; K. S. Webb and
D. Levy, Tetrahedron Lett., 1995, 36, 5117; T. D. Quach and
R. A. Batey, Org. Lett., 2003, 5, 4397.
27 M. Vaultier and B. Carboni, in Comprehensive Organometallic
Chemistry II, ed. E. W. Abel, F. G. A. Stone and G. Wilkinson,
Pergamon Press, Oxford, 1995, vol. 11, pp. 191.
28 M. W. Davies, C. N. Johnson and J. P. A. Harrity, J. Org. Chem.,
2001, 66, 3525.
29 A. Maderna, H. Pritzkow and W. Siebert, Angew. Chem., Int. Ed.
Engl., 1996, 35, 1501; C. Ester, A. Maderna, H. Pritzkow and
W. Siebert, Eur. J. Inorg. Chem., 2000, 1177; Y. Gu, H. Pritzkow
and W. Siebert, Eur. J. Inorg. Chem., 2001, 373; A. Goswami,
C.-J. Maier, H. Pritzkow and W. Siebert, Eur. J. Inorg. Chem.,
2216 | Chem. Commun., 2006, 2209–2217This journal is ? The Royal Society of Chemistry 2006
30 V. Gandon, D. Leca, T. Aechtner, K. P. C. Vollhardt, M. Malacria Download full-text
and C. Aubert, Org. Lett., 2004, 6, 3405.
31 Y. Yamamoto, J.-i. Ishii, H. Nishiyama and K. Itoh, J. Am. Chem.
Soc., 2004, 126, 3712; Y. Yamamoto, J.-i. Ishii, H. Nishiyama and
K. Itoh, J. Am. Chem. Soc., 2005, 127, 9625; Y. Yamamoto,
J.-i. Ishii, H. Nishiyama and K. Itoh, Tetrahedron, 2005, 61, 11501.
32 Y. Yamamoto, K. Hattori, J.-i. Ishii, H. Nishiyama and K. Itoh,
Chem. Commun., 2005, 4438.
33 V. Gandon, D. Leboeuf, S. Amslinger, K. P. C. Vollhardt,
M. Malacria and C. Aubert, Angew. Chem., Int. Ed., 2005, 44,
34 A. B. Smith, G. K. Friestad, J. Barbosa, E. Bertunesque,
J. J.-W. Duan, K. G. Hull, M. Iwashima, Y. Qiu, P. G. Spoors
and B. A. Salvatore, J. Am. Chem. Soc., 1999, 121, 10478;
S. A. Frank and W. R. Roush, J. Org. Chem., 2002, 67, 4316;
G. N. Maw, C. Thirsk, J.-L. Toujas, M. Vaultier and A. Whiting,
Synlett, 2004, 1183.
35 G. Hilt and P. Bolze, Synthesis, 2005, 2091 and references cited
36 A. Hassner and J. A. Soderquist, J. Organomet. Chem., 1977, 131,
C1; G. Zweifel, M. R. Najafi and S. Rajagopalan, Tetrahedron
Lett., 1988, 29, 1895; G. Desurmont, S. Dalton, D. M. Giolando
and M. Srebnik, J. Org. Chem., 1996, 61, 7943 and references
37 For representative examples, see: M. B. Ksebati and F. J. Schmitz,
J. Org. Chem., 1985, 50, 5637; R. D. Dawe and J. L. C. Wright,
Tetrahedron Lett., 1986, 23, 2559; X. Fu, E. P. Hong and
F. J. Schmitz, Tetrahedron, 2000, 56, 8989.
38 E. Piers and H. E. Morton, J. Org. Chem., 1979, 44, 3437;
E. J. Corey and H. Kigoshi, Tetrahedron Lett., 1991, 32, 5025;
K. Morihira, T. Nishimori, H. Kusama, Y. Horiguchi, I. Kuwajima
and T. Tsuruo, Bioorg. Med. Chem. Lett., 1998, 8, 2977;
K. Morihira, R. Hara, S. Kawahara, T. Nishimori,
N. Nakamura, H. Kusama and I. Kuwajima, J. Am. Chem. Soc.,
1998, 120, 12980; S. Aoyagi, R. Tanaka, M. Naruse and
C. Kibayashi, J. Org. Chem., 1998, 63, 8397.
39 A. S. E. Karlstro ¨m, M. Ro ¨nn, A. Thorarensen and J.-E. Ba ¨ckvall,
J. Org. Chem., 1998, 63, 2517.
40 A. S. E. Karlstro ¨m, K. Itami and J.-E. Ba ¨ckvall, J. Org. Chem.,
1999, 64, 1745.
41 K. Jonas, E. Deffense and D. Habermann, Angew. Chem., Int.
Ed. Engl., 1983, 22, 716; J. K. Cammack, S. Jalisatgi, A. J.
Matzger, A. Negron and K. P. C. Vollhardt, J. Org. Chem., 1996,
This journal is ? The Royal Society of Chemistry 2006 Chem. Commun., 2006, 2209–2217 | 2217