Rh(II)-Catalyzed Alkynylcyclopropanation of Alkenes by Decarbenation of Alkynylcycloheptatrienes

Article abstract of DOI:10.1021/jacs.1c05422

Alkynylcyclopropanes have found promising applications in both organic synthesis and medicinal chemistry but remain rather underexplored due to the challenges associated with their preparation. We describe a convenient two-step methodology for the alkynyl

Full text of DOI:10.1021/jacs.1c05422

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Rh(II)-Catalyzed Alkynylcyclopropanation of Alkenes by
Decarbenation of Alkynylcycloheptatrienes
Mauro Mato, Marc Montesinos-Magraner, Arnau R. Sugranyes, and Antonio M. Echavarren*
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ABSTRACT: Alkynylcyclopropanes have found promising applica-
tions in both organic synthesis and medicinal chemistry but remain
rather underexplored due to the challenges associated with their
preparation. We describe a convenient two-step methodology for
the alkynylcyclopropanation of alkenes, based on the rhodium(II)-
catalyzed decarbenation of 7-alkynyl cycloheptatrienes. The catalytic
system employed circumvents a fundamental problem associated
with these substrates, which usually evolve via 6-endo-dig cyclization
or ring-contraction pathways under metal catalysis. This unique
performance unlocks a rapid access to a diverse library of
alkynylcyclopropanes (including derivatives of complex drug-like
molecules), versatile intermediates that previously required much
lengthier synthetic approaches. Combining experiments and DFT calculations, the complete mechanistic picture for the divergent
reactivity of alkynylcycloheptatrienes under metal catalysis has been unveiled, rationalizing the unique selectivity displayed by
rhodium(II) complexes.
corresponding aldehydes (mainly by Corey−Fuchs or Ohira−
Bestmann reactions) (Scheme 1B, left). For these reasons,
several groups have recently turned their attention to the
development of new methods for the synthesis of alkynylcy-
clopropanes, such as the hydroalkynylation of cyclopropenes12
or methylenecyclopropanes,13 the use of chromium Fischer
carbenes,14 and isolated examples based on the reactivity of
diazo compounds and other related substrates.15
Considering that all these strategies require an average of 4−
6 synthetic steps and often suffer from selectivity or generality
issues, the development of a direct alkynylcyclopropanation of
alkenes would be highly desirable (Scheme 1B, bottom). For
this purpose, we hypothesized that 7-alkynyl-1,3,5-cyclo-
heptatrienes 1 (prepared in one step from commercially
available terminal alkynes and tropylium tetrafluoroborate)
could be potentially used as alkynyl carbene equivalents under
metal catalysis (Scheme 1C). We have previously reported that
7-substituted cycloheptatrienes can undergo retro-Buchner
reactions generating metal carbenes catalytically.16 These
electrophilic intermediates can be trapped by alkenes to give
cyclopropanes or engage in insertion, cycloaddition, or
INTRODUCTION
■
Cyclopropanes are among the most studied functionalities in
organic synthesis1 and medicinal chemistry.2 Accordingly,
great efforts have been made to grant access to a wide variety
of three-membered rings in a straightforward manner.3 In
particular, alkyne-substituted cyclopropanes display very
diverse reactivity patterns and have been used by different
research groups as starting substrates for the development of
new synthetic methodologies through ring-expansion,4 ring-
opening,5 or cycloaddition processes,6 among others.7 The
versatility of these intermediates has been further illustrated by
their application in the total synthesis of natural products.8
Furthermore, the alkynylcyclopropane unit can be found in the
structure of commercial drugs such as efavirenz, an
antiretroviral medication used to treat and prevent HIV
(Scheme 1A).9 Remarkably, this structural motif was also
discovered in some naturally occurring compounds, such as the
callipeltoside family of highly bioactive products, which has
attracted considerable interest from the synthetic commun-
ity.10
Despite all this, the alkynylcyclopropane unit is a rather
underexplored functionality, arguably due to the lack of general
and short approaches for its assembly. A logical disconnection
for its synthesis involves the cyclopropanation of 1,3-enynes,11
which are not readily available substrates and can suffer from
selectivity issues (Scheme 1B, right). Because of this, the most
widespread method for the preparation of these compounds is
the cyclopropanation of alkenes with α-diazo esters, followed
by redox manipulation and subsequent homologation of the
Received: May 26, 2021
Published: July 8, 2021
© 2021 The Authors. Published by
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trienes 1. This resulted in the development of a convenient
two-step method for the assembly of alkynyl-substituted
cyclopropanes, using commercially available tropylium tetra-
fluoroborate, terminal alkynes, and alkenes (Scheme 1C). The
relevance of this strategy is illustrated by the rapid preparation
of a broad range of synthetically versatile compounds (which
could be easily derivatized), as well as the late-stage
derivatization of complex drug-like molecules. Experimental
and theoretical studies support the formation of rhodium(II)-
alkynylcarbene intermediates, which react smoothly with
alkenes to deliver cyclopropanes. On the basis of DFT
calculations, we have developed a full mechanistic picture
that explains the divergent reactivity of 7-alkynyl cyclo-
heptatrienes under Au(I) or Rh(II) catalysis. Furthermore,
we found that the cis-stereoselectivity of the cyclopropanation
can be rationalized in terms of attractive noncovalent
interactions.
Scheme 1. Synthetic Approaches and Relevance of
Alkynylcyclopropanes
RESULTS AND DISCUSSION
■
At the outset of our investigation, we were aware of the rich
reactivity displayed by 7-alkynyl cycloheptatrienes under metal
catalysis.18,20 The presence of a 1,6-enyne system in 1
represents a fundamental challenge for the potential develop-
ment of a chemoselective metal-catalyzed retro-Buchner
reaction. These decarbenation processes have mostly been
studied using gold(I) complexes, which are also powerful
catalysts for the cycloisomerization of these enyne systems
(Scheme 2).21
Friedel−Crafts-type processes.17 However, whereas 7-aryl16a or
7-alkenyl16b cycloheptatrienes undergo this process smoothly
under Au(I) catalysis, 7-alkynyl cycloheptatrienes 1 undergo
different rearrangements under metal catalysis. In the presence
of gold complexes, they behave as 1,6-enynes and readily
evolve through 6-endo-dig cycloisomerization pathways,
leading to indenes 4a/4b18 or barbaralones 4d under oxidative
conditions (Scheme 2, top right).19 Similarly, Gandon and co-
workers have studied extensively the behavior of these
substrates in the presence of a wide variety of catalysts,
which promoted either cyclization or ring-contraction path-
ways to give products such as 4e or 4f (Scheme 2, left).20
We have now found that the use of rhodium(II) catalysis
allows the minimization (or even the suppression) of these
undesired pathways (Scheme 2, center right). This system
allowed us to promote, for the first time, a decarbenation−
alkynylcyclopropanation sequence using 7-alkynyl cyclohepta-
Accordingly, when the reaction of 1a with styrene in the
presence of a cationic gold(I) complex as catalyst was
attempted, the product of alkynylcyclopropanation 3a was
not detected. Rather, quantitative conversion of 1a to indenes
4a/4b (3.5:1) was observed (Table 1, entries 2, 3) through a
6-endo-dig cycloisomerization pathway.18 Then, we decided to
evaluate the activity of Rh(II) paddlewheel complexes, which
are also active in this type of carbene-transfer processes.17b
Gratifyingly, we found that the reaction of 1a with styrene in
the presence of 5 mol % of [Rh2(TFA)4] using PhMe/hexane
(1:1) as solvent afforded selectively the product of
decarbenation−alkynylcyclopropanation (3a) in 70% yield
and with good diastereoselectivity (10:1 cis/trans ratio), after
20 h at 80 °C (Table 1, entry 1).22 Under these optimized
conditions, only 7% and 8% yield of indenes 4b and 4c,
respectively, were observed as side products. The use of less
electrophilic Rh(II) complexes (Table 1, entries 4, 5) led to
Scheme 2. Diverse Reactivity Scenarios of 7-Alkynyl-1,3,5-cycloheptatrienes under Metal Catalysis
a
For 4a−d and 4g, [Au] = [(JohnPhos)Au(MeCN)]SbF6 (5 mol %). For more details about the known reactivity of 7-alkynyl cycloheptatrienes,
see previous publications by our group (4a−d)18,19 and by Gandon and co-workers (4e, 4f).20
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presumably due to a more efficient minimization of the 6-endo-
dig cyclization side pathway. Using a ferrocenyl group led to
the synthesis of crystalline derivative 3p, which allowed
confirming the cis configuration for the major product by X-
ray diffraction. A range of styrenes with a variety of
substituents were also tested (3r−aa), providing equally
good results in terms of both efficiency and stereoselectivity.
The power of this methodology is illustrated by the two-step
preparation of cyclopropanes such as 3b, whose synthesis
required previously six steps starting from styrene and ethyl
diazoacetate.24 Similarly, indene was cyclopropanated with
excellent diastereoselectivity (3q). Less activated alkenes such
as simple cyclohexene also react to give 3k−l. Also, more
electron-rich alkenes such as N-vinylphthalimide proved to be
compatible with the reaction conditions, providing cyclo-
propylamine derivatives 3n−o in good yield and diastereose-
lectivity. Then, we examined other types of carbon substituents
in the alkyne terminus of 1. 1,3-Enynyl cycloheptatrienes were
prepared from terminal 1,3-enynes and were successfully
employed in the carbene-transfer process. This allowed the
synthesis of several 1,3-enynyl cyclopropanes, 3ab−af, with
high diastereoselectivity. The moderate yields obtained can be
attributed to oligomerization pathways. Analogously, extended
C(sp) systems were also tolerated, granting access to 1,3-diynyl
cyclopropanes 3aw and 3ax (Scheme 3, bottom right). To
cover the entire range of carbon substituents, we tested various
cycloheptatrienes 1 with alkyl groups in the alkyne terminus
(Scheme 4, top right). Tertiary C(sp3) groups performed very
well in the reaction, bearing either C- or O-substituents, giving
good to excellent yields and moderate to good diastereose-
lectivities. Styrenes with different substitution patterns (3ag−
ak), indene (3al), enamines (3ai), or cyclohexene (3ao) could
be employed, and an inverse relationship between steric bulk
of the R group in 1 and the diastereoselectivity could be
observed (3am vs 3an). Benzyloxy derivatives 3aq−av were
also prepared successfully. On the other hand, substrates with
primary and secondary alkyl groups were much more prone to
undergo cycloisomerization to indenes analogous to 4a−c,
giving cyclopropanes such as 3ap in lower yield.
In order to illustrate the potential of the reaction in late-
stage functionalization, we synthesized several alkynylcyclo-
propane derivatives of natural or drug-like molecules (Scheme
4, bottom left). Thus, new derivatives of indomethacin (anti-
inflammatory, 4ba), α-tocopherol (vitamin E, 3bb), and
estrone (steroid, 3bc) were accessed in a diastereoselective
manner. We proved the modularity of this approach by
introducing the complex molecular fragment as either the
alkene or the alkyne component of the reaction. For this
purpose, we prepared regioisomeric derivatives 3ay and 3az
from fenofibrate, a drug used to treat hypercholesterolemia,
which has recently been suggested for the treatment of life-
threatening symptoms of COVID-19.25 These examples
demonstrate the compatibility of the new method with
complex molecules containing diverse functional groups such
as esters, ketones, or indoles.
Table 1. Optimization and Control Experiments
1
Yields and cis/trans ratios determined by H NMR using Ph2CH2 as
a
internal standard. Standard conditions: 1 equiv of 1a with 4 equiv of
2a using [Rh2(TFA)4] (5 mol %) as catalyst in PhMe/hexane (1:1,
b
c
0.15 M) at 80 °C for 20 h. CHCl3 used as solvent. [(JohnPhos)-
d
Au(MeCN)]SbF6 used as catalyst. Hexane used as solvent.
23
much lower yields of 3a, and other Lewis acids such as ZnCl2
led only to trace amounts of indenes (Table 1, entry 7).
Reduced catalyst loading could be employed, leading to a small
drop in yield when using 1.7 mol % of [Rh2(TFA)4] (Table 1,
entry 6). Solvent choice proved to be critical for the success of
the reaction. Thus, no reaction was observed in polar or protic
solvents (Table 1, entry 11). Hexane was found to behave best
in terms of yield and diastereoselectivity (Table 1, entries 8−
10), only outperformed by a 1:1 mixture of hexane and
toluene, which was selected as a standard solvent system
considering both the efficiency and solubility of more polar
substrates. We found concentration to have little effect on the
reaction outcome (Table 1, entry 12). Performing the reaction
at 40 °C in either hexane or toluene led to lower yields and
conversions (Table 1, entries 13, 14), while a significant
erosion in both yield and diastereoselectivity was observed at
100 °C (Table 1, entry 15).
The scope of the alkynylcyclopropanation reaction was
examined with a wide variety of 7-alkynyl cycloheptatrienes 1,
prepared in a straightforward manner by treating terminal
alkynes with nBuLi and subsequently with tropylium
tetrafluoroborate (Scheme 1C), giving exclusively the desired
products 1 in high yields.
First, we examined the transfer of carbon-substituted alkynyl
carbene fragments (Scheme 3). We selected styrene as model
alkene to evaluate the reactivity of a wide range of (aryl)alkynyl
cycloheptatrienes, obtaining disubstituted cyclopropanes 3a−j
in good to excellent yields and high selectivity for the cis
diastereoisomer. Electronically and sterically different sub-
stituents in any position of the ring are well tolerated, including
different halide groups. Interestingly, bulky aromatics such as
2-methylphenyl (3h) or 1-naphthyl (3m) give higher yields,
After observing that simple 7-ethynyl-1,3,5-cycloheptatriene
did not lead to any productive reactivity, we envisioned the
possibility of transferring silyl-protected alkynyl carbenes in
order to access terminal alkynyl cyclopropanes. First, we
explored the reactivity of different silyl-protected 7-alkynyl
cycloheptatrienes (Scheme 4). To our delight, we found that in
all cases these substrates afforded the product of decarbena-
tion−cyclopropanation of styrene in excellent yields. These
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Scheme 3. Scope of the Alkynylcyclopropanation Reaction and Late-Stage Functionalization
a
Standard conditions: 1 equiv of cycloheptatriene 1 (usually 0.3−0.5 mmol) with 4 equiv of alkene 2, using [Rh2(TFA)4] (5 mol %) as catalyst, in
b
c
d
PhMe/hexane (1:1, 0.15 M) at 80 °C until full consumption of 1 (usually 16−24 h). Isolated yield. 60 °C instead of 80 °C. CHCl3 as solvent. 2
equiv of 2 instead of 4. 1 equiv of alkene 2 and 1.5 equiv of 1. PhMe/CHCl3 (2:1) as solvent. Obtained as a 1:1 mixture of the two possible cis
products. NPhthal = N-phthalimide.
e
f
g
reactions proceeded smoothly, without detectable amounts of
side-products, and proved to be very robust.22 On the other
hand, when this reaction was attempted under Au(I) catalysis,
no cyclopropane was observed. Rather, 1b reacts to give allene
4g in 74% yield (Scheme 2). A clear correlation between the
bulkiness of the silyl group and the cis/trans ratio of products
5a−d was observed. We selected TMS as protecting group for
the assembly of terminal alkynylcyclopropanes on the basis of
giving the best diastereoselectivity, being easy to deprotect, and
affordability of TMS-acetylene. A simple one-pot addition of
TBAF after the cyclopropanation is completed leads cleanly to
the formation of the corresponding terminal alkynylcyclopro-
panes 6 in good to excellent yields and diastereoselectivities.
We extended the reaction to the cyclopropanation of mono-,
di-, tri-, and tetrasubstituted alkenes. 1,2-Dihydronaphthalene
(6h), indene (6i), and styrenes with diverse substitution
patterns (6a−g) were employed successfully. Less activated
alkenes such as cyclohexene (5e−f) or tetramethylethylene
(5g) behaved similarly, as well as more electron-rich N-
vinylphthalimide, giving almost exclusively the cis diaster-
eoisomer, as evidenced by the X-ray crystal structure of 6k.
The same type of alkynylcarbene could be trapped by a
dehydroalanine, giving cyclopropyl α-amino acid derivative 5i.
The alkynylcyclopropanation of a 1,3-enyne could also be
carried out,13 accessing interesting 1,2-dialkynylcyclopropanes
such as 5j/6j. Notably, among this library of compounds, we
obtained 6g, a gold(I)-carbene precursor recently developed
by our group,26 using only two reaction flasks, while the
original preparation required four steps from ethyl diazo-
acetate.
We expanded the scope of this reaction to the transfer of
germanylalkynyl carbenes (Scheme 5). Thus, cycloheptatriene
1z was used to obtain cyclopropanes 5k and 5l in good yield
and diastereoselectivity. This grants access to new types of
organogermanes, reagents that have recently arisen as relevant
orthogonal cross-coupling partners.27
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The Au(III)-catalyzed hydration of 6a delivers cyclopropyl
ketone 7c,28 resulting in an overall formal transfer of an
acceptor carbene, a process often carried out using diazo
compounds. Conveniently, the obtained cis product is the
opposite diastereoisomer to the one usually accessible by
classical approaches that involve cyclopropanations with these
classical carbene-transfer reagents. Submitting 6a to a
lithiation/borylation/oxidation sequence gave homologous
carbonyl cyclopropane 7d in 56% overall yield. In the presence
of a cationic gold(I) complex, the same intermediate 6a
undergoes a smooth hydroarylation to afford bicyclic cyclo-
propane 7e, in 1 h at room temperature. On the other hand,
when a disubstituted alkynyl cyclopropane such as 3f is
submitted to the same gold catalysis, the product of
hydroarylation is not observed. Instead, methylnaphthalene
7f was obtained in 93% yield. This compound can be described
as the product of formal (3 + 3) cycloaddition between the
corresponding alkynyl carbene and styrene.
Scheme 4. Scope of the Silylalkynylcyclopropanation and
One-Pot Assembly of Terminal Alkynylcyclopropanes
Finally, we found that benzyloxy-substituted products 3aq−
av can be transformed cleanly into allenyl cyclopropanes 8a−f,
using a modified version of a reported protocol based on a
gold(I)-catalyzed retro-ene reaction, which releases benzalde-
hyde as byproduct.29 This results in a two-step formal transfer
of an allenyl carbene unit, a challenging transformation that has
not been explored thus far (Scheme 7). A range of
allenylcyclopropanes were assembled while keeping the
diastereomeric ratio intact after the isomerization process.
This grants easy access to another type of versatile synthetic
intermediates,30 avoiding the use of synthetically challenging 7-
allenyl-1,3,5-cycloheptatrienes, which have not been described
so far. All these new reactions, together with previous reports
on the use of alkynylcyclopropanes in the discovery of novel
methodologies,4−7 highlight the versatility and potential of
these now readily accessible compounds.
a
Standard conditions: 1 equiv of 1 (usually 0.3−0.5 mmol) with 4
equiv of alkene 2, using [Rh2(TFA)4] (5 mol %) as catalyst, in CHCl3
(0.15 M) at 80 °C until full consumption of 1 (usually 16−24 h).
Isolated yield. For the synthesis of terminal alkynes, [Si] = TMS was
b
The progress of the reaction and the side-pathways leading
1
used in all cases. NPhthal = N-phthalimide.
to indenes 4a−c can be easily followed by H NMR (Scheme
8). When the reaction was attempted under gold(I) catalysis,
quantitative cycloisomerization of 1a to 4a and 4b was
observed (Table 1, entry 2).22 On the other hand, under
rhodium(II) catalysis, the formation of alkynylcyclopropane 3a
was clearly observed over time (Scheme 8A). The formation of
small amounts of 4a and 4b was also detected. Interestingly,
indene 4a slowly undergoes double-bond isomerization to
more stable indene 4c under rhodium(II) catalysis, a process
that was not observed with gold(I). Furthermore, we found
that, under similar reaction conditions, cycloheptatrienes 1p
and 1w react with triisopropylsilane to afford propargyl silanes
9a and 9b, respectively (Scheme 8B).31 This further supports
the intermediacy of an alkynylcarbene species that can also be
trapped through intermolecular Si−H insertion processes.17b,32
In order to rationalize the observed differences in chemo-
selectivity while using either rhodium(II) or gold(I) catalysis
in the reaction of 7-alkynyl-1,3,5-cycloheptatrienes, we
modeled both pathways theoretically: the decarbenation/
cyclopropanation sequence and the cycloisomerization to
give indenes. We used cycloheptatriene 1a and styrene (2a)
as model substrates, and [Rh2(TFA)4] or [(PMe3)Au]+ as
model catalyst, with DFT at the B3LYP-D3/6-31G(d,p)(H, C,
O, F, P) + LANL2DZ(Rh, Au)//6-311G(2d,2p)(H, C, O, F,
P) + LANL2TZ(Rh, Au) level of theory (Schemes 9 and 10).
For rhodium, we established [Rh2(TFA)4] coordinated to
two cycloheptatrienes 1a (through each of the metal centers of
the dimeric complex) as the resting state of the catalytic cycle,
Scheme 5. Transfer of a Germanylalkynylcarbene Unit
a
1 equiv of 1z with 4 equiv of 2, using [Rh2(TFA)4] (5 mol %) as
catalyst, in CHCl3 (0.15 M) at 80 °C for 20 h. Isolated yield. NPhthal
= N-phthalimide.
We demonstrated the scalability of the protocol by preparing
more than one gram of terminal alkynylcyclopropane 6a, which
could be obtained in excellent yield as a single diastereoisomer
after flash column chromatography. This versatile intermediate
could be easily diversified to access a variety of structures
(Scheme 6). While exploring the general scope of the reaction,
we found acceptor R groups and several heteroatoms (such as
halogens) in 1 to be incompatible with the reaction
conditions.22 However, these derivatives can often be directly
accessed from the corresponding terminal alkynes 6. For
example, treatment of 6a with NBS and catalytic Ag2CO3
affords bromoalkynyl cyclopropane 7a in 86% yield.
Alkynylcyclopropane 6a underwent Pd-catalyzed Sonogashira
coupling to afford heterocyclic derivative 7b quantitatively.
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Scheme 6. Gram-Scale Alkynylcyclopropanation: Reactivity and Diversification of Versatile Intermediates
a
[Au] = [(JohnPhos)Au(MeCN)]SbF6.
be the productive species in the cycloisomerization pathway. A
6-endo-dig cyclization leads to metal-stabilized barbaralyl
cations VIII,33 which can rearrange through rate-limiting
transition states TSVIII−IX to give indene-like intermediates IX.
Once this point has been reached, intermediates IX evolve
irreversibly to give indene side-products 4a−c through a series
of low-energy transition states.20b On the other hand, alkynyl
norcaradiene intermediates II can undergo decarbenation or
retro-Buchner reaction34 by cleavage of the first C−C bond of
the three-membered ring through rate-limiting transition states
TSII−III. In accordance with our experimental observations, for
gold(I), we found the transition state of the cycloisomerization
reaction to be more favored than that for the retro-Buchner
reaction. Contrastingly, the rhodium(II)-catalyzed cycloisome-
rization of 1a is much less favorable (ΔG⧧ = 24.4 kcal·mol−1),
allowing the more energetically feasible decarbenation process
(ΔG⧧ = 21.9 kcal·mol−1) to proceed. This leads to Wheland-
type carbenoid intermediate III-[Rh], a shallow minimum that
evolves smoothly into rhodium(II) alkynylcarbene IV upon
release of a molecule of benzene. After benzene−styrene
exchange, the alkynyl carbene unit in V undergoes nucleophilic
attack by styrene to afford carbocationic intermediate VI,
which readily closes up to give alkynylcyclopropane complex
VII irreversibly, in an overall stepwise cyclopropanation
process (Scheme 10).35
Scheme 7. Gold(I)-Catalyzed Synthesis of
Allenylcyclopropanes
a
[Au] = [(JohnPhos)Au(MeCN)]SbF6. Isolated yield.
Scheme 8. Reaction Kinetics and Mechanistic Experiments
In order to rationalize the diastereoselectivity observed
experimentally, we compared TSV−VI_cis and TSV−VI_trans,
obtaining a significantly lower activation barrier for the cis-
cyclopropanation (ΔΔG⧧ = 2.6 kcal·mol−1). NCI plot analysis
of these structures clearly shows the stabilizing noncovalent
interactions between the two organic fragments (Scheme 10,
green surfaces) present in TSV−VI_cis, but absent in TSV−VI_trans
,
responsible for the observed selectivity. This rationale also
correlates with the fact that in some cases bulkier substituents
can lower the cis/trans ratio (Scheme 4, 5a−d), as a
consequence of hampering these attractive interactions. All in
all, the complete mechanistic picture for the reactivity of 7-
alkynylcycloheptatrienes in the presence of metals has been
fully unveiled, accounting for the unique chemoselectivity
observed under rhodium(II) catalysis. All these findings are
consistent with the cleanness of the diastereoselective carbene-
transfer process observed experimentally.
whereas for gold, [(PMe3)Au]+ coordinated to one molecule of
1a was identified as the most stable adduct. Alkynylcyclohepta-
triene−metal η2-coordinated complexes I were considered to
CONCLUSIONS
■
In conclusion, we have developed the first general, two-step
alkynylcarbene transfer reaction for the assembly of alkynylcy-
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Scheme 9. Free-Energy Profile Calculated by DFT for the Divergent Reactivity of 7-Alkynylcycloheptatrienes under Metal
Catalysis (kcal·mol−1 at 25 °C)
clopropanes from alkenes and terminal alkynes, through
decarbenation of readily available 7-alkynyl cycloheptatrienes.
The use of Rh(II) catalysis was key to this discovery, which
circumvents the fundamental problem associated with the
common incompatibility of these 1,6-enyne-contaning sub-
strates with Lewis acids, due to side reactivity. This led to a
straightforward synthesis of a wide library of cis-alkynylcyclo-
propanes, bearing C(sp3)-, C(sp2)-, C(sp)-, H-, Si-, or Ge-
substituents in the alkyne terminus, streamlining the access to
these synthetically complex targets. The versatility of these
now readily available intermediates was illustrated by their
further diversification to give not only different types of
alkynylcyclopropanes but also other types of three-membered
carbocycles, such as allenyl-, alkyl-, or acceptor cyclopropanes.
The robustness and modularity of the new synthetic approach
was demonstrated by the diastereoselective preparation of
alkynylcyclopropane derivatives of several biologically relevant
complex molecules. Furthermore, by means of DFT calcu-
lations, we developed a divergent mechanistic model that
explains the unique chemoselectivity of Rh(II) complexes
toward the retro-Buchner reaction of 7-alkynyl cyclopropanes,
whereas the 6-endo-dig cycloisomerization pathway is favored
under Au(I) catalysis. A rate-limiting Rh(II)-catalyzed
decarbenation generates alkynylcyclopropane intermediates,
which can be trapped efficiently by an ample variety of alkenes.
The cis-diastereoselectivity of this cyclopropanation can be
rationalized in terms of noncovalent interactions that arise
between the two organic fragments.
Scheme 10. DFT Model of the Alkynylcyclopropanation of
Styrene to Rationalize the cis-Diastereoselectivity (kcal·
a
mol−1 at 25 °C)
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c05422.
a
■
In the NCI representations, strong attractive interactions are blue
sı
(C−C bond formation), weak attractive interactions are green
(noncovalent interactions), and strong repulsive interactions are
red. Color code: Rh, violet; O, red; F, cyan; C, gray; H, white.
Experimental procedures and characterization data for
compounds (PDF)
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Article
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Accession Codes
CCDC 2085762−2085763 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Antonio M. Echavarren − Institute of Chemical Research of
Catalonia (ICIQ), Barcelona Institute of Science and
Technology, 43007 Tarragona, Spain; Departament de
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Chromium- and Tungsten-Triggered Valence Isomerism of cis-1-
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̀
Química Analítica i Química Organica, Universitat Rovira i
Virgili, 43007 Tarragona, Spain; orcid.org/0000-0001-
6808-3007; Email: aechavarren@iciq.es
Authors
Mauro Mato − Institute of Chemical Research of Catalonia
(ICIQ), Barcelona Institute of Science and Technology,
43007 Tarragona, Spain; Departament de Química Analítica
̀
i Química Organica, Universitat Rovira i Virgili, 43007
Tarragona, Spain; orcid.org/0000-0002-2931-5060
Marc Montesinos-Magraner − Institute of Chemical Research
of Catalonia (ICIQ), Barcelona Institute of Science and
Technology, 43007 Tarragona, Spain; orcid.org/0000-
0003-1713-6257
Arnau R. Sugranyes − Institute of Chemical Research of
Catalonia (ICIQ), Barcelona Institute of Science and
Technology, 43007 Tarragona, Spain; Departament de
̀
Química Analítica i Química Organica, Universitat Rovira i
Virgili, 43007 Tarragona, Spain; orcid.org/0000-0001-
5481-0154
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c05422
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Ministerio de Ciencia e Innovación (PID2019-
104815GB-I00, FPI predoctoral fellowship to M.M., IJC2019-
040181-I Juan de la Cierva contract to M.M.-M.), Severo
Ochoa Excellence Accreditation 2020−2023 (CEX2019-
000925-S), the European Research Council (Advanced Grant
No. 835080), the AGAUR (2017 SGR 1257), and CERCA
Program/Generalitat de Catalunya for financial support. We
also thank the ICIQ X-ray diffraction unit.
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