Chiral Bicyclo[2.2.2]octa-2,5-dienyltrifluoroborate Derivative as a Useful and Stable Precursor of C1-Symmetric Chiral Dienes

Article abstract of DOI:10.1021/acs.orglett.9b01609

A new approach has been developed to prepare monosubstituted C₁-symmetric chiral dienes Ar-MSBod from easily accessible chiral bicyclo[2.2.2]octa-2,5-dienyltrifluoroborate derivative. This alkenyl trifluoroborate was synthesized in five steps f

Full text of DOI:10.1021/acs.orglett.9b01609

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chiral Bicyclo[2.2.2]octa-2,5-dienyltrifluoroborate Derivative as a
Useful and Stable Precursor of C1‑Symmetric Chiral Dienes
Aymane Selmani, Fabien Serpier, and Sylvain Darses*
́
PSL Universite Paris, Chimie ParisTech - CNRS, Institute of Chemistry for Life and Health Sciences (i-CLeHS), 11 rue Pierre et
Marie Curie, 75005, Paris, France
S
* Supporting Information
ABSTRACT: A new approach has been developed to prepare
monosubstituted C1-symmetric chiral dienes Ar-MSBod from
easily accessible chiral bicyclo[2.2.2]octa-2,5-dienyltrifluorobo-
rate derivative. This alkenyl trifluoroborate was synthesized in
five steps from inexpensive (−)-carvone. This approach allows
the construction of large libraries of diversely substituted chiral
dienes via cross-coupling reactions with inexpensive and widely
available aryl halides.
ver the two past decades, the transition metal/chiral
diene catalytic systems have proved to be very powerful
rhodium-catalyzed asymmetric transformations.1,9 Among
these chiral dienes, the C1-symmetric Ar-MSBod ligands are
attractive not only because they have been shown to be
efficient in many rhodium-catalyzed reactions10 but also
because of their ease of synthesis starting from the cheap
and commercially available (+)- or (−)-carvone (Scheme 2).
O
for the formation of C−C bonds, thanks to their unique
reactivity and selectivity due to the strong π-accepting ability of
diene ligands.1 In 2003, Hayashi and co-workers described the
first use of chiral dienes for the Rh-catalyzed asymmetric 1,4-
addition on α,β-unsaturated ketones using disubstituted
bicyclo[2.2.1]heptadiene (nbd*) ligand (Scheme 1).2 Almost
Scheme 2. New Synthetic Route for the Preparation of R-
MSBod
Scheme 1. Some Representative Chiral Dienes
In 2004, Carreira’s group reported the first synthesis of Ar-
MSBod ligands using a Negishi-type coupling with the triflate
derived from ketone 211 and arylzinc reagents (Scheme 2).3
Inspired by this work, we described a more general preparation
of Ar-MSBod by introducing the aryl substituent through a
palladium-catalyzed Suzuki−Miyaura cross-coupling reaction
with readily available arylboron reagents.12 However, this
approach presented some drawbacks such as the cost of the
triflating reagents, the use of large excess of aryl derivative
reagents, and sometimes low yields, particularly for introducing
bulky aryl substituents and a moderate availability of
commercial organoboron compounds.
concomitantly, Carreira’s group developed another family of
chiral dienes, the C1-symmetric monosubstituted
bicyclo[2.2.2]octa-2,5-diene-type ligands (Ar-MSBod), in Ir-
catalyzed allylic substitution.3 Since then, other chiral dienes
have been developed bearing different structural backbones,
mainly C2-symmetric bicyclo[2.2.2]octadiene type ligands, like
bod*,4 tfb*,5 and another6 developed by Hayashi’s group or a
disubstituted diene, derived from carvone, described by
Carreira and co-workers.7 Laschat and Lin also reported the
development of C2-symmetric bicyclo[3.3.0]octadienes and
their use in asymmetric catalytic reactions.8
We envisioned a reverse approach for the synthesis of Ar-
MSBod ligands, involving the cross-coupling of potassium
All of those chiral dienes have been shown to be useful in
asymmetric transition-metal-catalyzed reactions, particularly in
Received: May 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01609
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
alkenyl trifluoroborate 1 with aryl halides (Scheme 2). Interest
in potassium organotrifluoroborates lies in their high stability,
easy purification, and good reactivity in palladium-catalyzed
cross-coupling reactions.13 Another advantage of this reverse
approach comes from the great diversity and availability of aryl
halides, allowing a fast access to larger libraries of
monosubstituted dienes.
Scheme 4. Preparation of Alkenylboronic Acid 7 and X-ray
Crystal Structure of 7·H2O
We report herein a facile and readily scalable synthesis of
enantiomerically pure Ar-MSBod relying on the alkenyl
trifluoroborate key derivative 1 as coupling partner with aryl
halide reagents through the Suzuki−Miyaura reaction.
We envisioned the formation of potassium alkenyl
trifluoroborate 1 via lithium−halogen exchange from the
corresponding vinyl iodine 4 (Scheme 3), which could be
Scheme 3. Preparation of Potassium Alkenyltrifluoroborate
1
a
Table 1. Optimization of the Suzuki−Miyaura Reaction with
a
1
a
Key: (a) NH2NH2·H2O (2.5 equiv), AcOH cat., EtOH, rt, 91%; (b)
I2 (2 equiv), DABCO (5 equiv), Et2O, rt, 63%; (c) n-BuLi (1.1
equiv), B(OMe)3 (1.5 equiv), THF, −78 °C to rt, then aq KHF2 (8
equiv), 75%.
b
b
entry
[Pd] cat.
PdCl2
Pd(OAc)2
Pd2dba3
Pd2dba3
Pd2dba3
ligand
PPh3
PPh3
PPh3
dppf
conv of 5a (%) 6a/6b ratio
1
2
3
48
32
52
48
30
43
25
17
16
100
50:50
78:22
67:33
86:14
100:0
100:0
100:0
100:0
100:0
100:0
prepared from readily available ketone 2. Among the few
approaches described for transforming a ketone to vinyl iodide,
the Barton iodination reaction14 is predominantly used,
although it requires the prior conversion of the ketone to
hydrazone. In the presence of iodine and a strong non-
nucleophilic base, the hydrazone is generally converted to vinyl
iodide with good yields.15
c
4
c
5
c
RuPhos
HPCy3BF4
6
Pd2dba3
7
8
RuPhos Pd G4
Pd(OAc)2
PCy3 Pd G4
Pd2dba3
c
HPCy3BF4
9
10
To avoid the reduction of the double bond, mild conditions
were used to convert ketone 2 to hydrazone 3, that is,
hydrazine monohydrate, in the presence of a catalytic amount
of acetic acid, which provided the expected hydrazone 3 in
72% yield after recrystallization. Hydrazone 3 was converted to
the vinyl iodide 4 by oxidation using iodine and DABCO at
room temperature in 63% yield. Vinyl iodide 4, which provides
a cheap alternative to the corresponding triflate derivative, was
successfully cross-coupled with arylboronic acids to prepare
Ar-MSBod via Suzuki−Miyaura cross-coupling.16 However,
vinyl iodide 4 proved to be quite unstable at room
temperature. which motivated the formation of potassium
organotrifluoroborate 1, affording an attractive alternative for
the formation of Ar-MSBod ligands. The potassium trifluor-
oborate derivative 1 was obtained from the vinyl iodide 4 in
75% yield via lithium−halogen exchange, transmetalation, and
fluorination. To the best of our knowledge, this is the first
example of formation of a chiral diene−BF3K. Starting from
(+)-carvone, it is possible to synthesize the other enantiomer
of this chiral alkenyl trifluoroborate.
At this stage, no single crystals suitable for X-ray analysis
could be obtained from alkenyl trifluoroborate 1, but the
structure of the corresponding boronic acid 7, obtained by
defluorination of 1 over wet silica gel,17 was unambiguously
confirmed (Scheme 4).
Formation of Ar-MSBod via Suzuki−Miyaura reaction was
then studied using the Pd-catalyzed cross-coupling between
the alkenyl trifluoroborate 1 and 4-bromoanisole (5a) as
model substrates (Table 1).
d
HPCy3BF4
a
The reaction was conducted with 1 (0.3 mmol), 5a (0.25 mmol),
[Pd] cat. (4 mol % Pd), ligand (12 mol %) and K3PO4 (0.9 mmol) in
degassed THF/H2O 10:1 at 85 °C. Determined by GC using
naphthalene as internal standard. 8 mol % of ligand. Pd2dba3 (8 mol
% Pd) and HPCy3BF4 (16 mol %).
b
c
d
Inspired by the work of Molander’s group18 dealing with the
Suzuki−Miyaura reaction of alkenyl trifluoroborates and aryl
halides, catalytic systems, using Pd(II) sources and PPh3 as
ligand, were tried (Table 1, entries 1 and 2), using THF/water
as solvent mixture and K3PO4 as a base. However, these
conditions showed low conversions of 4-bromoanisole. More
surprisingly, a side product 6b was observed which resulted
from the exchange of one of the phenyl group of PPh3,
indicating that the reduction elimination is the rate-
determining step.19 The use of a Pd(0) precursor, Pd2dba3,
offered a better reactivity than PdCl2 favoring the formation of
the desired diene 6a (Table 1, entries 3 and 4). To avoid aryl
scrambling on the palladium center, some nonphenyl-
containing phosphine ligands were evaluated in the presence
of Pd2dba3 (Table 1, entries 5 and 6). Despite lower activity
compared to [Pd/PPh3] catalytic systems, the formation of
side product 6b was totally suppressed. Other sources of
Pd(II), such as Pd(OAc)2 and Buchwald’s precatalysts, known
for their readily activation in mild conditions,20 did not offer
better reactivity (Table 1, entries 7−9). It seems that the in
situ reduction of Pd(II) to Pd(0) is a limiting process which, in
B
DOI: 10.1021/acs.orglett.9b01609
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
this case, forces the use of Pd(0) directly. Finally, a full
conversion of 4-bromoanisole had been obtained by increasing
the catalyst loading to 8 mol % Pd in the presence of
HPCy3BF4 as ligand (Table 1, entry 10). These reaction
conditions allowed us to isolate the desired diene 6a in 67%
yield, without any formation of other side products.
These conditions proved to be quite general, and the
reaction of diversely substituted aryl bromide reagents 5 with 1
afforded the expected Ar-MSBod 6 with moderate to good
yields (Scheme 5).
under identical conditions, furnished the chiral diene 6a in
71% yield. Chiral dienes 6f and 6n were also obtained from the
corresponding aryl iodide with good yields. However, cross-
coupling reaction with more interesting aryl chlorides failed.
Moreover, cross-coupling reaction with 2- and 3-substituted
electron-rich aryl bromides does afford the expected chiral Ar-
MSBod with equally good yields, while the cross-coupling of
the corresponding diene triflate with the corresponding
boronic acids was generally low yielding.3,10e−g,12 Indeed, the
yields were increased by 10 to 30% in the formation of chiral
dienes 6a, 6g, and 6j−m, and compound 6o was produced
with 77% yield, while the coupling of the corresponding diene
triflate was low yielding (11%). This represents an interesting
feature of this approach as those 2- and 3-substituted chiral
diene are generally the most effective in asymmetric rhodium-
catalyzed reactions.10 Diversely substituted heteroaryl bro-
mides were also successfully cross-coupled with 1 to afford
chiral dienes bearing dibenzo[b,d]furan (6s), quinoxaline (6t),
pyridine (6u), or quinoline (6v) substituents with good yields.
The efficiency of this approach to monosubstituted chiral
dienes was supported by a scale-up experiment. Under
standard conditions, a gram-scale reaction of 1 with 1-
bromo-4-methoxy-2-methylbenzene delivered the desired
diene 6j in 71% yield.
These optimized conditions are also adapted for the
coupling of aryl iodides as the reaction of 4-iodoanisole,
Scheme 5. Chiral Ar-MSBod from Potassium
a
Alkenyltrifluoroborate 1
In conclusion, we have developed an efficient and easily
scalable method for the synthesis of Ar-MSBod chiral diene
ligands using the Suzuki−Miyaura cross-coupling reaction of
stable potassium bicyclo[2.2.2]octa-2,5-dienyltrifluoroborate
derivative 1 as key intermediate and inexpensive and widely
available aryl halides. This synthetic approach allows the
formation of a large variety of Ar-MSBod, notably the ones
substituted in the ortho positions, which could further lead to
better activity and selectivity in transition-metal/chiral diene
catalytic systems.
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.9b01609.
Experimental procedures, description of the compounds,
and X-ray diffraction of 7 (PDF)
Accession Codes
CCDC 1903322 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 Author
*E-mail: sylvain.darses@chimie-paristech.fr.
ORCID
a
The reaction was conducted with 1 (0.3 mmol), aryl bromide 5
(0.25 mmol), K3PO4 (0.9 mmol), Pd2dba3 (4 mol %), and HPCy3BF4
(16 mol %) in degassed THF/H2O 10:1 at 85 °C. Isolated yields are
b
Sylvain Darses: 0000-0003-3350-1736
Notes
indicated. 71% yield using 4-iodoanisole instead of 4-bromoanisole
and no reaction observed using 4-chloroanisole instead of 4-
c
bromoanisole. Reaction from the corresponding aryl iodide.
d
Reaction conducted with 4 mmol of 1.
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.9b01609
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ACKNOWLEDGMENTS
■
We thank the CNRS (Centre National de la Recherche
Scientifique) and MENESR (Ministere de l’Education
Nationale et de l’Enseignement Superieur et de la Recherche)
for finanical support. A.S. thanks the Ministere de l’Education
Nationale et de l’Enseignement Superieur et de la Recherche
for a grant. We gratefully acknowledge Geoffrey Gontard and
Lise-Marie Chamoreau for the X-ray analyses (Sorbonne
́
̀
́
́
̀
́
́
Universite, Paris).
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DOI: 10.1021/acs.orglett.9b01609
Org. Lett. XXXX, XXX, XXX−XXX