Ruthenium Metathesis: A Key Step to Access a New Cyclic Tetrasubstituted Olefin Platform

Article abstract of DOI:10.1021/acs.orglett.0c01344

An rapid and mild synthetic route for the preparation of cyclic tetrasubstituted platforms via ruthenium-catalyzed ring-closing metathesis (RCM) has been developed. This process tolerates a wide range of functionalities such as nitrogen, oxygen, sulfur, silicon, and carbon tethered groups, as well as very challenging fluorine and boron atoms (36 derivatives, up to 96%). This diversity-oriented method was further demonstrated by the postfunctionalization reactions, such as Pd-couplings, N-substitution, and reductive amination introducing a morpholine moiety.

Full text of DOI:10.1021/acs.orglett.0c01344

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Letter
Ruthenium Metathesis: A Key Step To Access a New Cyclic
Tetrasubstituted Olefin Platform
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Clement F. Heinrich, Didier Durand, Jerome Starck,* and Veronique Michelet*
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ABSTRACT: An rapid and mild synthetic route for the preparation of cyclic tetrasubstituted platforms via ruthenium-catalyzed
ring-closing metathesis (RCM) has been developed. This process tolerates a wide range of functionalities such as nitrogen, oxygen,
sulfur, silicon, and carbon tethered groups, as well as very challenging fluorine and boron atoms (36 derivatives, up to 96%). This
diversity-oriented method was further demonstrated by the postfunctionalization reactions, such as Pd-couplings, N-substitution, and
reductive amination introducing a morpholine moiety.
hrough the past decades, ruthenium catalysis has
emerged as a powerful tool to construct complex
T
structures.1 Among them, Ring Closing Metathesis (RCM)
has been recognized as a versatile and powerful tool in organic
chemistry to synthesize small, medium, or large rings.2 The
synthesis of cyclic polysubstituted olefins can be achieved using
Grubbs, Hoveyda−Grubbs, or tailormade catalysts, depending
on the substitution pattern of the alkene.3 Whereas several
studies have been published on di- and trisubstituted alkenes,
relatively few studies have been done on cyclic tetrasubstituted
olefins.1e,4,5 Considering our interest for diversity-oriented
synthesis (DOS)6 and atom-economical metal-catalyzed
reactions7 as well as tetrahydropyridine cores as key building
blocks for medicinal chemistry8 (Figure 1), we anticipated that
readily available and functionalized diene derivatives may be
suitable substrates for Ru-catalyzed metathesis. We wish,
therefore, to report therein our preliminary results on the
general, rapid, and unprecedented synthesis of an original and
functionalized tetrasubstituted cyclic olefin platform bearing
other substituents than the vic-dimethyl moiety. Some
preliminary postfunctionalization transformations are also
presented.
Figure 1. Tetrahydropyridine and cyclohexene cores in bioactive
compounds.
Supporting Information).9 For phenyl- and methyl-substituted
derivatives in the R1 position of 1, an alkylation of sulfones,
readily accessible from the corresponding aldehydes, by
methylallyl magnesium chloride yielded the corresponding
carbamates,10 which were submitted in an N-alkylation
To examine the possibilities of access to tetrahydropyridine
and other oxygen, carbon, sulfur, and silicon cores via-Ru-
catalyzed metathesis, a wide range of dienes 1 (36 derivatives)
were prepared as summarized in Figure 2. A simple two-step
synthesis of substrates 1 bearing R1 = CO2Me has been
developed, starting from commercially available methyl N-
(diphenylmethylene)glycinate and methylallyl bromide (see
Received: April 17, 2020
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Scheme 2. Synthesis of Heteroatomic-Core Tetrasubstituted
Cyclic Olefins
Figure 2. General structures of dienes.
reaction.11 We gained interest to functionalize the olefin by
introducing several heteroatoms. Over the years, it has become
clear that fluorine substituents could display a positive effect on
pharmacokinetic and pharmacodynamic properties of potential
drugs due to their specific chemical, biological, and physical
properties.12 In spite of their interesting features, to date, only
scarce examples have been disclosed on metathesis reactions
on fluoroalkene derivatives limited mainly to the synthesis of
trisubstituted fluoro-olefins.3u,13 We therefore prepared 1k−
1o, bearing a fluoride or trifluoromethyl group, according to
nucleophilic substitution with the corresponding allylic bro-
mide derivatives. We also turned our attention to the reactivity
of a wide series of heteroatom-tethered dienes 2−5, which
were synthesized according to known methodologies (see
Supporting Information).11 Methylmalonate derivatives 6 were
also easily prepared, as well as sulfonamide derivatives 7.
Having in hand a wide range of functionalized dienes (36
congeners), we further utilized them in ring closing metathesis
cyclizations (Schemes 1, 2, and 3). Nitrogen-tethered dienes
Scheme 3. RCM of Compounds 7a−c and Pinacol Boranes
Derived from 7a and 6e
The use of vinyl bromide derivative 1i led to no observable
conversion with either Grubbs II and Hoveyda−Grubbs
catalysts, in accordance to Dorta and co-workers.14 To our
delight, fluorinated olefins 1j−l underwent a cyclization
process with the Hoveyda−Grubbs II catalyst (2 × 5 mol %)
affording the fluorinated cyclic olefin 8j−l with good yields
(72−88%). Trifluoromethylated tetrahydropyridines 8m−o
could be obtained as well (56−84%) using the same
conditions, but with longer reaction times (24 h). A significant
decrease in yield has been observed with the ester derivative
8m (56% yield).15 High yields were also observed for
tetrahydropyridines 8p−q (75 and 79%).16
Scheme 1. Synthesis of Tetrahydropyridines 8a−q
We then turned our attention to oxygen-, silicon-, sulfur-,
and carbon-tethered dienes and were pleased to see that the
Ru-catalyzed metathesis reactions of these derivatives were also
feasible (Scheme 2). The vic-dimethyl cyclic olefin arising from
ethers 2a, sulfones 5a, silyl 4a, and malonate derivatives 6a
could be obtained with excellent yields (93−95%), comparable
to those obtained with NBoc protected tetrahydropyridines
1a−c (86−92%). Sulfide 3 did not cyclize under these
conditions.17 Interestingly, the TBS-hydroxymethyl group was
still tolerated, giving access to heterocycles 9b16 and 12b−13b
with good yield (93−96%), comparably to those obtained for
tetrahydropyridines 1e−g (80−92%).
1a−g have been successfully cyclized in toluene (0.04 M)
using 2 × 5 mol % of Grubbs II catalyst, which allowed the
formation of new tetrahydropyridines with good to excellent
yields (Scheme 1). A bulky group, such as a TBS-
hydroxymethyl group, was tolerated (8e−g). The RCM
reaction was also feasible starting from an acrylate 1h with
65% even if this reaction took a longer time (24 h).
When the olefin was functionalized by a fluorine or a
trifluoromethyl group, malonate-tethered dienes were tolerated
and the cyclohexenes 13c and 13d were isolated in 71% and
63% yields, respectively. Sulfone 5c and ethers 2c−d were
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found unreactive under these conditions (Scheme 2).
Considering the nonreactivity of 1i, we turned our attention
to the reaction of chloro and bromo sulfonamides 7a−b
(Scheme 3, eq 1).18 Pleasingly, whereas the bromo derivative
7a was unreactive, the chloro derivative 7b reacted nicely,
leading to the cyclic derivative 14b in moderate 55% yield.19a
Vinyl enol ether 7c was also subsequently engaged in an RCM
reaction,20 leading remarkably to the corresponding tetrahy-
dropyridine 14c with 43% yield.19b In the pursuit of our effort
to gain more diversity, a pinacol borane derivative was
considered.21 We chose to start from vinyl bromide 7a or 6e
by a classical Miyaura borylation reaction.22 But all our
attempts to isolate pinacol boranes were found to be
unsuccessful. So we decided to perform a tandem boryla-
tion/RCM reaction, which was able to afford the desired stable
pinacol borane 15a with a fair yield of 68% over two steps.
This methodology was also applied to the malonate derivative
6e forming the pinacol borane 15b in 75% yield (Scheme 3, eq
2).
We have also carried out various preliminary postfunctionaliza-
tion reactions over the tetrahydropyridine scaffolds, leading to
interesting building blocks. Further studies will focus on
practical and industrial applications of this straightforward and
diversity-oriented process.
ASSOCIATED CONTENT
* Supporting Information
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sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01344.
Experimental procedure and analytical data (PDF)
1H and 13C spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
́
̂
Jerome Starck − Institut de Recherches Servier, 78290 Croissy-
Seine, France; Email: jerome.starck@servier.com
́
Veronique Michelet − Institut de Recherche de Chimie Paris,
Finally, to further illustrate the synthetic utility of such a
platform, we chose to perform some post-transformations of
the corresponding cyclic aminocyclohexene derivatives
(Scheme 4). Palladium-catalyzed Suzuki cross-couplings have
75005 Paris, France; Institut de Chimie de Nice, 06100 Nice,
France; orcid.org/0000-0002-2217-9115;
Email: veronique.michelet@univ-cotedazur.fr
Authors
Scheme 4. Postfunctionalization Reactions
́
Clement F. Heinrich − Institut de Recherche de Chimie Paris,
75005 Paris, France
Didier Durand − Institut de Recherches Servier, 78290 Croissy-
Seine, France
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01344
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the Ministere de l’Education et de
la Recherche and the Centre National de la Recherche
Scientifique (CNRS). C.F.H. is grateful to the Institut de
Recherches Servier for a grant. The authors thanks Pr. F.
Goutenoire (Le Mans, France) for residual ruthenium
quantification.
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been achieved, starting from vinyl chloride 14b22 or pinacol
borane 15a,23 giving access to product 16a−b. We illustrated
the complementarity of having the halogen- or boron-
functionalized derivative, giving rise to similar isolated yields
for both methods employed (Scheme 4, eq 1). An acidic
deprotection on 8c could be followed by a classical peptidic
coupling, leading to amide 17 in 72% isolated yield (Scheme 4,
eq 2). A tandem DIBAL reduction/reductive amination could
afford pharmacophores 18a−b in 40−42% yields for the two-
step synthesis (Scheme 4, eq 3).
In conclusion, we have therefore extended the methodology
of the ruthenium-catalyzed metathesis reactions by studying its
applications and opportunities to prepare tetrasubstituted
dienes. A practical route for the preparation of cyclic
tetrasubstituted olefins was proposed in the presence of
Grubbs II or Hoveyda−Grubbs II catalysts giving rise to a
rapid access to functionalized platforms. Various carbon- and
heteroatom-tethered dienes were tolerated such as oxygen,
sulfone, silane, or malonate derivatives, and this protocol also
allowed the formation of fluoro- or trifluoromethyl derivatives.
■
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D
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