Synthesis of Medium-Sized Carbocycles by Gallium-Catalyzed Tandem Carbonyl-Olefin Metathesis/Transfer Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.9b03240

The first examples of a catalytic tandem process involving a ring-closing carbonyl-olefin metathesis and a transfer hydrogenation are described. 1,4-Cyclohexadiene has been used as an H₂ surrogate to reduce the cyclic alkenes formed after the m

Full text of DOI:10.1021/acs.orglett.9b03240

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Medium-Sized Carbocycles by Gallium-Catalyzed
Tandem Carbonyl−Olefin Metathesis/Transfer Hydrogenation
Alexandre Djurovic,† Marie Vayer,† Zhilong Li,† Regis Guillot,† Jean-Pierre Baltaze,†
Vincent Gandon,*,†,‡ and Christophe Bour*,†
†
́
́
́
́
Institut de Chimie Moleculaire et des Materiaux d’Orsay (ICMMO), CNRS UMR 8182, Universite Paris-Sud, Universite
̂
Paris-Saclay, Batiment 420, Orsay 91405 Cedex, France
‡
́
Laboratoire de Chimie Moleculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Institut Polytechnique de Paris, route de
Saclay, Palaiseau 91128 Cedex, France
S
* Supporting Information
ABSTRACT: The first examples of a catalytic tandem
process involving a ring-closing carbonyl-olefin metathesis
and a transfer hydrogenation are described. 1,4-Cyclo-
hexadiene has been used as an H2 surrogate to reduce the
cyclic alkenes formed after the metathesis step. The same
cationic gallium(III) complex, [IPr·GaCl2][SbF6], performs
the two steps with functional group tolerance. This stereo-
selective reaction leads to 1,2-cis-disubstituted cyclopentanes
and various cyclohexanes. DFT computations support an
unexpected mechanism involving activation of 1,4-cyclo-
hexadiene by superelectrophilic gallium(III) dimers.
the difficulty of reducing the RCM intermediate when the
he synthesis of substituted carbocycles from simple
Tsubstrates is a major objective in organic chemistry. endocyclic alkene is substituted (R ≠ H), all of the studies
directed toward this tandem process have been limited to the
synthesis of 1,1-disubstituted cycloalkanes (for instance, X =
(CO2R)2, no other substituents) or to a very few 1,1,3-
trisubstituted cycloalkanes (for instance, X = (CO2R)2 and R =
Me). In no report has the stereoselectivity of the reduction
step been addressed. Actually, only one paper describes the
synthesis of a 1,2-cis-disubstituted cyclopentane based on a Ru-
catalyzed RCM, but the hydrogenation step was achieved
independently by Pd/C-catalyzed hydrogenation.7
Among the medium-sized ones, 1,2-cis-disubstituted cyclo-
pentanes are a target of choice, notably because this particular
scaffold can be found in a variety of biologically active
compounds.1 A practical and chemoselective route to large-
and medium-sized carbocycles is the tandem ring-closing
metathesis (RCM)/hydrogenation (or transfer hydrogenation)
of dienes (Scheme 1A).2 So far, this strategy has always
involved ruthenium-based catalysts and H2,3 MeOH/borohy-
dride,4 silanes,5 or formic acid6 as reducing agents. Owing to
The carbonyl-olefin metathesis reaction is also an expedient
way to generate cyclic alkenes.8 In contrast with the diene
RCM, it is achieved from readily available ene−aryl ketones, or
more recently using aliphatic ketones,9h using simple Lewis
acids (particularly FeCl3 or GaCl3 by Schindler et al),9
Brønsted acids,10 tropylium cations,11 or organic reagents.12,13
Due to our interest in the development of gallium-catalyzed
transformations,14 and our recent work on the gallium-
catalyzed transfer hydrogenation of alkenes using 1,4-cyclo-
hexadiene as hydrogen donor,15,16 we decided to investigate a
tandem process combining a carbonyl-olefin metathesis and a
transfer hydrogenation to form cycloalkanes (Scheme 1B). We
kept in mind that the judicious installation of substituents (R1
and Ar) could allow the formation of two contiguous
stereocenters and possibly address the issue of the formation
of 1,2-cis-disubtituted cyclopentanes.
Scheme 1. Tandem Metathesis/Hydrogenation Routes to
Cyclic Compounds
Received: September 13, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03240
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Our catalyst of choice for the development of gallium-
catalyzed reactions is the cationic NHC-stabilized gallium
dichloride [IPr·GaCl2]+[SbF6]− A (IPr = 1,3-bis(2,6-diisopro-
pylphenyl)-imidazol-2-ylidene, see bottom of Table 1 for its
product, and the monitoring of the 2a/3a ratio over time,
confirmed its intermediacy toward 3a. The reaction could be
scaled up to 10 mmol without affecting the yield (68% on a 0.1
or 10 mmol scale). No conversion was observed without
AgSbF6 to activate IPr·GaCl3, nor with AgSbF6 alone (see
Table S1). Adding 1,4-CHD after 1 h drastically decreased the
proportion of 3a (entry 2). Lowering the catalytic amount of
gallium to 1 mol % (entry 3) or the temperature to 40 °C
(entry 4) also clearly disfavored the transfer hydrogenation
step. Running the reaction with GaCl3 gave good conversion
toward 2a and very little reduction (entry 5). Using a catalytic
amount of an equimolar mixture of GaCl3/GaBr3 (entry 6)
increased the proportion of 3a, suggesting the formation of a
heterobimetallic superelectrophile known to have a higher
Lewis acidity than the homobimetallic (GaCl3)2 super-
electrophilic dimer.9h The intervention of superelectrophilic
species in this chemistry will be further discussed below and in
the Supporting Information (IR and DFT studies). When
using a catalytic mixture of GaCl3 and AgSbF6, the desired
product 3a was observed as a major component of the mixture,
but significant decomposition lowered the isolated yield to
27% (entry 7). Among the other Lewis acids tested (entries 8−
13), BF3·OEt2 proved to be the only catalyst offering a
reactivity apparently similar to A, yet the isolated yield was
lower due to substantial degradation (entry 11). Importantly,
while B(C6F5)3 has been demonstrated to be a good transfer
hydrogenation catalyst,21 it failed at promoting the carbonyl-
olefin metathesis step (entry 9).
It is also striking that FeCl3, shown to be an excellent
carbonyl-olefin metathesis catalyst9a−e,h did not perform well
in the presence of 1,4-CHD and failed at promoting the
transfer hydrogenation step (entry 10). The softer Lewis acid
[IPr·InBr2][SbF6]22 formed the desired product in only 33%
yield (entry 12), while [Ph3PAu][SbF6] did not deliver 3a
(entry 13). Regarding the Brønsted acids, although TfOH led
to 2a, it proved ineffective for the transfer hydrogenation step
(entry 14). The desired product was observed when the
stronger acid Tf2NH was used, but it was admixed to many
other unidentified products (entry 15). With other H2
surrogates such as 2,4,6-Me3-1,4-CHD,21 Et3SiH, or Hantzsch
ester, no hydrogen transfer to the intermediate 2a was
observed (entries 16−18). The transfer hydrogenation step
did not proceed in toluene (entry 19), but the tandem process
worked very well in hexafluoroisopropanol (HFIP) (entry
20).23
Table 1. Catalyst Screening and Optimization
c
modifications from the above
yield of 3a
a
b
entry
conditions
1a/2a/3a ratio
(%)
d
1
2
3
4
5
6
none
0
0
0
0
7
0
16
64
96
91
92
50
84
36
4
9
1
68
1,4-CHD added after 1 h
1 mol % of A
40 °C
GaCl3 instead of A
GaCl3/GaBr3 (2.5/2.5 mol %)
instead of A
50
7
8
9
10
11
12
13
14
15
16
GaCl3/AgSbF6 instead of A
AlCl3 instead of A
B(C6F5)3 instead of A
FeCl3 instead of A
0
99
100
68
0
0
51
0
12
1
0
32
10
67
49
100
34
96
82
0
0
27
50
0
BF3·OEt2 instead of A
[IPr·InBr2][SbF6] instead of A
90
33
0
e
[Ph3PAu][SbF6] instead of A
HOTf instead of A
HNTf2 instead A
2,4,6-Me3-1,4-CHD instead of
1,4-CHD
0
f
0
0
66
4
17
18
Et3SiH instead of 1,4-CHD
Hantzsch ester instead of
1,4-CHD
0
0
94
100
6
0
19
20
toluene instead of 1,2-DCE
HFIP instead of 1,2-DCE
0
0
96
0
4
100
92
a
Generated in situ from IPr·GaCl3 (5 mol %) and AgSbF6 (7 mol %);
b
0.1 mmol of 1a, 0.2 M. Estimated by 1H NMR, diastereomeric ratio
c
d
cis/trans 4/1. Isolated yield. Same yield on a 10 mmol scale.
e
Generated in situ from Ph3PAuCl (5 mol %) and AgSbF6 (7 mol %).
f
Complex mixture.
The scope of the reaction was then studied. With a p-
methoxyphenyl group, 3b was obtained in 53% and 70% yield
in 1,2-DCE and HFIP, respectively (Scheme 2).
structure),17 which can be employed as such or prepared in
situ from the air-stable IPr·GaCl3 complex18 and AgSbF6.19
This protocol is much more practical than the use of GaCl3,
which is very sensitive toward moisture and usually less
efficient than A. After screening several experimental
parameters (see Table S1), we found that the reductive
cyclization of β-ketoester 1a, bearing a dimethyl substitution at
the olefin terminus, could be efficiently carried out in the
presence of a catalytic amount of in situ generated [IPr·
GaCl2][SbF6] A (5 mol %) and 1,4-cyclohexadiene (1,4-CHD,
10 equiv) in 1,2-dichloroethane at 80 °C for 5 h (Table 1,
entry 1). Ethyl 2-phenylcyclopentane-carboxylate 3a was
obtained in 68% isolated yield with a cis/trans diastereomeric
ratio of 4:1. The relative cis configuration was ascertained by
NOE experiments and is consistent with the data available in
the literature.20 The presence of the cycloalkene 2a as side
The electron-withdrawing p-fluoro and -chloro substituents
were also well-tolerated, giving 3c and 3d in up to 81% yield in
HFIP. The tricyclic compound 3f was also isolated in good
yield from α-tetralone 1f in HFIP.24 In contrast, the desired
products were not formed when α-indanone 1e or α-
benzosuberone 1g was subjected to the reactions conditions.
For the latter, only the metathesis product 2g was isolated in
quantitative yield when 1,2-DCE was employed. In HFIP, only
the reduction of the alkene function of 1e and 1g was
observed. According to the work of Schindler,9a in the absence
of a substituent in the β position of the ketone (R2 = CO2R for
instance), the carbonyl-olefin metathesis tends to be less
efficient. However, under our conditions, 1h transformed into
the cis-1,2-diphenylcyclopentane product 3h in 61% yield with
an excellent cis/trans selectivity in 1,2-DCE (20:1).25 The
B
DOI: 10.1021/acs.orglett.9b03240
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reluctant to undergo the transfer hydrogenation step. This was
yet not an issue with one less carbon in the tether (4e) or with
a p-fluoro substituent (4m).
Scheme 2. Substrate Scope: Part 1
The mechanism of the tandem process can be hypothesized
as follows (Scheme 4). With FeCl3 as catalyst, the formation of
Scheme 4. Discarded Mechanistic Hypotheses
a
cis/trans dr: 3b−d, 4:1; 3h−n, > 20:1.
the metathesis product E from A was shown to be a
noncationic process through just B and the [2 + 2]
cycloadduct C.9h The formation of C and its scission were
described as concerted. Two catalytic cycles can be envisaged
for the reduction of E into the final product K. According to
our previous proposal in the case of gallium catalysis,15 it could
be the result of a hydride transfer from 1,4-CHD to
carbocation F, followed by protodegallation of G. Alternatively,
as suggested in the case of boron catalysis,21d 1,4-CHD could
react with the catalyst to form species I. Its cationic part could
be used to protonate E, and its metal hydride moiety could
then react with J to give K.
To gain a deeper insight into the mechanism of this novel
hydrogenative carbonyl-olefin metathesis by a gallium
catalyst,27 we performed DFT calculations at the ωB97-XD/
6-31G(d) level of theory using 1a as a model substrate and 1,3-
dimethylimidazol-2-ylidene as the model NHC (noted IMD,
see the SI for details). However, with [(IMD)GaCl2]+ as active
species, none of the above hypotheses proved energetically
favorable.
structure of cis-3h was ascertained by X-ray crystallography
analysis.26 In HFIP, only the reduction of the alkene moiety of
the starting material was observed. Other 1,2-diarylpropan-2-
ones bearing different substituents at the arene moiety were
converted into the corresponding 1,2-cis-diarylcyclopentanes
(3i−n), which were isolated in moderate to good yields. The
best yield was actually obtained with two electron-rich p-
methoxyphenyl groups (3n, 87%).
Substrates exhibiting a gem-dimethyl ester tether located at
the β-position of the ketone were also well-tolerated (Scheme
3). Most products (cyclopentanes or cyclohexanes) were
obtained in good to excellent yields (up to 98%) with electron-
donating or -withdrawing substituents. Surprisingly, enone 4l,
displaying a p-bromo substituent, transformed quantitatively
into the corresponding metathesis product, which proved
Scheme 3. Substrate Scope: Part 2
Instead of [(IMD)GaCl2]+ as the active species, we then
u s e d t h e h o m o d i m e r { [ ( I M D ) G a C l ] ( μ - C l ) -
[GaCl2(IMD)]2}2+.28 Schindler et al. have recently shown
that in the case of the FeCl3-catalyzed carbonyl-olefin
metathesis reaction the superelectrophilic homodimer [Cl2Fe-
(μ-Cl)FeCl3] was more active than FeCl3.9h The mechanism
remained concerted in their case, i.e., no carbocationic
intermediate involved. With the Ga(III) homodimer, the
carbonyl-olefin metathesis became much more favorable
indeed, but it was found to involve carbocationic intermediates
(Scheme 5). In particular, the presence of a second
[(IMD)GaCl2]+ unit allowed the formation of pentacoordi-
nated gallium species (Figure 1) and the formation of
carbocations D2 and D4.
However, even using the gallium(III) homodimer, the two
transfer hydrogenation hypotheses presented in Scheme 4
remained unfavorable (see D6−D9 in the SI). The main issue
with one or two gallium atoms is the high free energy of
activation associated with the protonolysis of the strong Csp3−
a
Metathesis product obtained quantitatively.
C
DOI: 10.1021/acs.orglett.9b03240
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
+
+
Scheme 5. Free Energies Profile of the {[(IMD)GaCl2]2}2 -
Catalyzed Carbonyl-Olefin Metathesis (ΔG, kcal/mol)
Scheme 6. Free Energies Profile of the {[(IMD)GaCl2]2}2 -
Catalyzed Transfer Hydrogenation (ΔG, kcal/mol)
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03240.
Figure 1. Geometries of selected transition states.
Experimental procedures and characterization data
(PDF)
1H and 13C NMR spectra (PDF)
Coordinates and energy of the computed species (XYZ)
Ga bond in G displayed in Scheme 4 or the unfavorable
formation of the gallium hydride I. We thus visited a new
mechanistic hypothesis that involves the activation of cyclo-
hexadiene by coordination (Scheme 6). The pathway leading
to the cis product D12 from D10 starts with a thermoneutral
step giving D11, which contains a σ-dienyl gallium complex. It
easily transfers a hydride to the carbocationic counterpart
through TSD11‑D12. The formation of the trans product D14 is
thermodynamically more favorable but involves highest lying
transition states since it takes place on the more bulky side of
the carbonyl-olefin metathesis product. This mechanism,
which does not involve any proto-degallation, rationalizes the
cis selectivity observed and also explains why the more
sterically congested 2,4,6-Me3-CHD was not efficient, as it
would be more difficult to activate by the gallium(III)
homodimer (Table 1, entry 16).
In summary, we have devised an efficient gallium-catalyzed
tandem carbonyl-olefin metathesis/transfer hydrogenation
protocol. It represents a main group metal catalyzed version
of the Ru-catalyzed diene RCM/transfer hydrogenation. It
allows the synthesis of medium-sized carbocycles, notably 1,2-
cis-disubstituted cyclopentanes. Computations support the role
of gallium(III) homodimers in the two steps and reveal an
unexpected activation of 1,4-cyclohexadiene.
Accession Codes
CCDC 1920340 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: vincent.gandon@u-psud.fr.
*E-mail: christophe.bour@u-psud.fr.
ORCID
Vincent Gandon: 0000-0003-1108-9410
Christophe Bour: 0000-0001-6733-5284
Notes
The authors declare no competing financial interest.
An early preprint of this work appeared on ChemRxiv.29
ACKNOWLEDGMENTS
We are grateful to the China Scholarship Council (CSC),
■
́
CNRS, MESRI, Universite Paris-Sud, ANR ANR-18-CE07-
0033-01 (HICAT), and Ecole Polytechnique for their support
of this work.
D
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Schindler, C. S. Catalytic Carbonyl-Olefin Metathesis of Aliphatic
Ketones: Iron(III) Homo-Dimers as Lewis Acidic Superelectrophiles.
J. Am. Chem. Soc. 2019, 141, 1690−1700.
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Letter
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(26) See the Supporting Information.
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