Synthesis of 1,2-Disubstituted Cyclopentadienes from Alkynes Using a Catalytic Haloallylation/Cross-Coupling/Metathesis Relay

Article abstract of DOI:10.1021/acs.orglett.6b01682

A three-step method based on Pd-catalyzed haloallylation of alkynes, Pd-catalyzed cross-coupling, and Ru-catalyzed ring-closing metathesis constitutes a new and short approach to variety of 1,2-substituted cyclopentadienes. The scope of the method is broad with respect to different substituents (alkyl, aryl, metallocenyl, and other substituents as well as their combinations are tolerated), and all steps proceeded with sensible yields. As a demonstration of product utility, several of the prepared cyclopentadienes were converted into the corresponding ferrocenes.

Full text of DOI:10.1021/acs.orglett.6b01682

Letter
pubs.acs.org/OrgLett
Synthesis of 1,2-Disubstituted Cyclopentadienes from Alkynes Using
a Catalytic Haloallylation/Cross-Coupling/Metathesis Relay
Nikola Topolovcan, Illia Panov,† and Martin Kotora*
̌
Department of Organic Chemistry, Faculty of Science, Charles University in Prague, Hlavova 8, 128 43 Praha 2, Czech Republic
S
* Supporting Information
ABSTRACT: A three-step method based on Pd-catalyzed
haloallylation of alkynes, Pd-catalyzed cross-coupling, and Ru-
catalyzed ring-closing metathesis constitutes a new and short
approach to variety of 1,2-substituted cyclopentadienes. The
scope of the method is broad with respect to different
substituents (alkyl, aryl, metallocenyl, and other substituents as well as their combinations are tolerated), and all steps
proceeded with sensible yields. As a demonstration of product utility, several of the prepared cyclopentadienes were converted
into the corresponding ferrocenes.
yclopentadienes are versatile organic compounds that
have found application in two major areas. First, they are
As far as the access to haloallylated alkynes is concerned, one
option is to carry out allylations of silylated alkynes10 or
allylstannylations of alkynes11 to furnish the corresponding
silylated or stannylated pentadienes, followed by halogenation.
Another one could rely on haloallylation as exemplified by
Pd(II)-catalyzed chloroallylation of alkynes giving rise to cis-1-
halo-1,4-dienes, as first described by Kaneda et al.12 Recently,
regioselective haloallylations of activated alkynes have been
reported as well.13 Also worth noting is the formation of trans-
or cis-1-halo-1,4-dienes by Pd(II)-catalyzed allylation of alkynes
with allylic alcohols in the presence of CuX2 salts or ionic
liquids.14 Haloallylation followed by further transformation of
the formed 1-halo-1,4-dienes was reported as well, and it
encompassed subsequent Suzuki cross-coupling,15 Wacker−
Tsuji oxidation, or Sonogashira reaction.16 The importance of
haloallylation is also demonstrated by its application in a
synthesis of the natural products (−)-haterumalide and
(−)-oocydin A.17
At the outset, bromoallylation of various alkynes using a
modified version of Kaneda’s protocol was performed. We
found that the best results were obtained when the reaction was
carried out in pure allyl bromide in the presence of
PdCl2(PhCN)2 (5 mol %) at 10 °C (Scheme 2). In the first
set, bromoallylation of variously substituted diphenylacetylenes
was carried out. In general, bromoallylation proceeded in a syn
manner to give the desired products having a cis configuration
with respect to the positions of the bromo and allyl groups.
Formation of the trans isomerthe product of anti
bromoallylationwas observed in minor amounts and never
exceeded 5% yield judging from 1H NMR spectra. Thus,
reactions with 1a−c proceeded uneventfully to give the desired
1-bromo-1,4-dienes 2a−c in high isolated yields of 89%, 98%,
and 95%. The reaction with bis(4-trifluoromethylphenyl)-
acetylene (1d) was sluggish and gave rise to two isomers,
C
convenient substrates in organic synthesis,1 and second, they
can be used as ligands in transition metal complexes.2 The
transition metal complexes bearing various cyclopentadienyl
ligands constitute an important class of compounds that have
found numerous applications in catalytic and stoichiometric
reactions.3 Although a number of processes enabling the
synthesis of variously substituted cyclopentadienes have been
developed, there is a lack of any general synthetic strategy
allowing the preparation of certain types. One class of such
compounds are 1,2-disubstituted cyclopentadienes and their
corresponding metallocenes, which have been shown to
catalyze various reactions such as polymerization of alkenes,4
cyclotrimerization of alkynes,5 C−H activation of arenes,6 and
cycloisomerization7 of enynes. Although methods for the
preparation of 1,2-disubstituted cyclopentadienes based on
Pauson−Khand8 or retro-Diels−Alder9 reactions (to name a
few) have been reported, the development of a more general
approach is of considerable interest because of their current and
potential applications in catalysis.
A retrosynthetic analysis of the 1,2-disubstituted cyclo-
pentadiene framework is depicted in Scheme 1. The cyclo-
Scheme 1. Retrosynthetic Analysis of 1,2-Disubstituted
Cyclopentadienes
pentadiene should be available via ring-closing metathesis of a
1,3,6-triene. The triene should be accessible through cross-
coupling of a cis-1-halo-1,4-diene with a vinylmetal, and finally,
the halodiene should be obtainable by Pd-catalyzed haloally-
lation of an alkyne. In such a manner, cyclopentadienes should
be accessible in just three steps.
Received: June 10, 2016
© XXXX American Chemical Society
A
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the other hand, in the case of 2j and 2k only one regioisomer
was formed.
Scheme 2. Bromoallylation of Alkynes 1: Formation of 1-
Halo-1,4-dienes 2
With bromodienes 2 in hand, cross-coupling with vinylmetals
ensued (Scheme 3). Initially, cross-coupling under Suzuki
Scheme 3. Cross-Coupling Reactions of 1-Bromo-1,4-dienes
a
2 with Vinylmetals To Give 1,3,6-Trienes 3
a
Conditions: A (Suzuki coupling): PEPPSI-i-Pr (5 mol %),
Cs2CO3,THF/H2O (9/1), 50 °C; B (Stille coupling): PEPPSI-i-Pr
(5 mol %), CsF, THF, 4 Å MS, 50 °C. Isolated yields are shown.
(Z)-2d and (E)-2d, that were isolated in 29% and 27% yield,
respectively. Bromoallylation of 5-decyne (1e), a representative
of bisalkylated alkynes, again proceeded smoothly to give 2e in
a very nice isolated yield of 85%.
conditions with potassium vinyltrifluoroborate in the presence
of a catalytic amount of PdCl2 (5 mol %) and PPh3 (10 mol %)
at 100 °C was attempted with 2a−c, 2f, and 2h. Although 80−
85% conversion of the starting materials to the corresponding
trienes was observed, the trienes could not be separated from
the unreacted starting materials by using chromatography or
distillation techniques. In order to find reaction conditions
enabling 100% conversion of the bromodienes, a catalytic
system composed of PdCl2 (5 mol %) and dppf (5 mol %) was
examined for 2a−c, 2f, and 2h. In this instance, conversions in
the range of 90−95% were observed. Finally, cross-coupling of
vinylboronic acid pinacol ester with various bromodienes in the
presence of a catalytic amount of PEPPSI-i-Pr (5 mol %) was
undertaken (Scheme 3). Gratifyingly, the reactions with
bromodienes 2a−c, 2f, and 2h proceeded with full conversion
of the starting materials already at 50 °C, giving the
corresponding products 3a−c, 3f, and 3h in nice isolated
yields. It should be mentioned that during the cross-coupling
reactions of phenyl-substituted substrates isomerization to the
trans isomer (with respect to the relative positions of the vinyl
and allyl groups) of up to 5% was noticed.
Then conversion of the prepared dienes to the correspond-
ing cyclopentadienes was undertaken. In general, ring-closing
metathesis of trienes 3 with Grubbs I catalyst (2.5 mol %) in
dichloromethane (∼0.05 M) proceeded, according to 1H NMR,
within ∼30 min to provide the corresponding cyclopentadienes
4 (Scheme 4).20 The use of Grubbs II catalyst (5 mol %) in
dichloromethane (∼0.05 M) provided the same results;
however, usually 6−12 h of reaction time was required to
achieve full conversion. Although the metathesis reactions
Then our attention turned to unsymmetrically substituted
alkynes such as 1-(4-trifluoromethylphenyl)-2-(4-
methoxyphenyl)acetylene (1f), 4-(TBSO)-pent-2-yne (1g)
propynylbenzene (1h), propynylferrocene (1i), ethyl butynoate
(1j), and methyl 3-phenylpropynoate (2k). Bromoallylation of
1f proceeded with full conversion and furnished only one
regioisomer 2f in a high isolated yield of 86%. The formation of
the opposite regioisomer was not detected. The observed
regioselectivity is in agreement with the generally accepted
reaction mechanism of halopalladation outlined by Kaneda et
al.12 and supported by observations of Backvall et al.18 On the
̈
basis of haloallylation reactions with differently substituted allyl
halides, halopalladation of the triple bond is assumed to be the
first step. In this respect it not surprising that the halide anion
should attack the carbon atom with a lower electron density (an
electrophilic carbon atom) whereas the palladium cation should
attack the carbon atom with a higher electron density (a
nucleophilic carbon atom). (The electron density is also in
agreement with resonance structures of the corresponding
alkynes.) The observed regioselectivity is in accordance with
the data observed for carbometalation or hydrostannation19 of
disubstituted alkynes. A similar trend was observed also with
1g, bromoallylation of which gave rise to 2g in 62% yield. A
somewhat different course of the reaction was observed during
bromoallylations of 1h and 1i. Bromoallylation of the former
yielded a mixture of 3 products: (Z)-2h, (E)-2h′, and (E)-2h in
a 20:1:2.5 ratio and 89% yield. Bromoallylation of the latter
furnished (E)-2i and (Z)-2i′ in a 1:10 ratio and 84% yield. On
B
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Scheme 4. Ring-Closing Metathesis of 3 To Form
Cyclopentadienes 4
Scheme 5. Formation of Ferrocenes 5a−c and meso- and rac-
5f
a
Full conversion of the starting material was observed, but 4j could
b
not be detected in the reaction mixture. Full conversion of the
starting material to afford 4k was observed, and its structure was
confirmed by spectroscopic data.
proceeded quantitatively, the stumbling block became isolation
of the formed cyclopentadienes as analytically pure substances.
In general, column chromatography of the crude reaction
mixtures on silica gel resulted in the formation of intractable
products. Only 4a was isolated as an analytically pure
compound in 68% yield. In all other cases, column
chromatography on Brockmann 4 alumina had to be performed
to harvest pure products in the 58−83% yield range. Although
full conversion of the starting material 3j was observed under
metathesis conditions, the isolated substance did not have
structural features required for 4j. Since the low stability of 4j
was noticed previously,21 we assume that after its formation it
rapidly undergoes further reactions. In a similar manner,
cyclopentadiene 4k was also unstable upon standing and
underwent decomposition upon isolation. Nonetheless, NMR
measurements and other analytical techniques applied to the
crude product provided data that unequivocally confirmed its
structure (see comments in the Supporting Information).
Finally, metalation of the isolated cyclopentadienes 4a, 4b,
and 4c with n-BuLi followed by reaction with anhydrous FeCl2
provided the corresponding new ferrocenes 5a, 5b, and 5c in
42%, 65%, and 64% isolated yield, respectively, as orange-
colored solids (Scheme 5). X-ray structure analysis of 5b
unambiguously confirmed its structure (Figure 1). Analogously,
the transformation of cyclopentadiene 4f was carried out, giving
rise an inseparable mixture of meso- and rac-5f in 66% isolated
yield.
Figure 1. X-ray structure of ferrocene 5b.
corresponding metallocenes, as demonstrated by the syntheses
of several ferrocenes. There is no doubt that this new protocol
could also be used to prepare other 1,2-disubstituted
cyclopentadienes and their corresponding metallocenes.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01682.
Experimental procedures, analytical data for all new
compounds, and crystallographic data for 5b (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kotora@natur.cuni.cz.
Present Address
In conclusion, we have described a hitherto-unexplored
approach to the class of 1,2-substituted cyclopentadienes based
on transition-metal-catalyzed methodologies composed of
haloallylation of internal alkynes, cross-coupling, and ring-
closing metathesis. The reaction proceeded under mild
conditions with a rather broad tolerance to pendant functional
groups and was high-yielding. The formed cyclopentadienes
were in general stable enough to be converted into the
†I.P.: Enamine Ltd., 23 Alexandra Matrosova Street, Kiev
01103, Ukraine. E-mail: Illia.panov@gmail.com.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the Czech Science Foundation (Project 13-15915S)
and the Charles University Grant Agency (Project 1132/2015)
for generous financial support. We also thank Dr. Ivana
́
̌ ́
Cısarova (Department of Inorganic Chemistry, Faculty of
Science, Charles University in Prague) for X-ray structure
determinations.
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