Chiral Ligand-Mediated Nucleophilic Aromatic Substitution of Naphthoic Acids: A Fast and Efficient Access to Axially Chiral Biaryls

Article abstract of DOI:10.1002/ejoc.202000317

A transition metal-free synthesis of enantioenriched biaryls from aryllithium species has been developed. This approach relies on atropoenantioselective nucleophilic aromatic substitution (S_NAr) reaction of unprotected naphthoic acids. The ability of a diverse set of chiral ligands to mediate this transformation has been investigated. 1,2-diether ligands outperform their diamine counterparts and the best enantiocontrol was obtained with readily accessible enantiopure trans-1,2-dimethoxycyclohexane. This S_NAr reaction offers an efficient and rapid access to enantioenriched binaphthalenes, phenylnaphthalene, and phenanthrylnaphthalenes (up to 94:6 er).

Full text of DOI:10.1002/ejoc.202000317

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Chiral Ligand-Mediated Nucleophilic Aromatic Substitution of
Naphthoic Acids: A Fast and Efficient Access to Axially Chiral
Biaryls
Authors: Thi Thanh Thuy Nguyen, Hélène Guyon, Kim Phi Phung
Nguyen, Anne Boussonnière, Jacques Mortier, and Anne-
Sophie Castanet
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000317
Link to VoR: https://doi.org/10.1002/ejoc.202000317
01/2020

10.1002/ejoc.202000317
European Journal of Organic Chemistry
COMMUNICATION
Chiral Ligand-Mediated Nucleophilic Aromatic Substitution of
Naphthoic Acids: A Fast and Efficient Access to Axially Chiral
Biaryls
Thi Thanh Thuy Nguyen ,[a] Hélène Guyon,[a] Kim Phi Phung Nguyen,[b] Anne Boussonnière,[a] Jacques
Mortier,[a] and Anne-Sophie Castanet*[a]
Abstract: A transition metal-free synthesis of enantioenriched biaryls
from aryllithiums has been developed. This approach relies on
atropoenantioselective nucleophilic aromatic substitution (SNAr)
reaction of unprotected naphthoic acids. The ability of a diverse set of
chiral ligands to mediate this transformation has been investigated.
1,2-diether ligands outperform their diamine counterparts and the best
enantiocontrol was obtained with readily accessible enantiopure
trans-1,2-dimethoxycyclohexane. This SNAr reaction offers an
efficient and rapid access to enantioenriched binaphthalenes,
phenylnaphthalene and phenanthrylnaphthalenes (up to 94:6 er).
Meyers reaction).11 Alternatively, stereocontrol can result from a
chiral alkoxide leaving group located ortho to an achiral oxazoline
or ester.12 A major limitation of these approaches relies in the
additional steps required for the prior introduction and later
removal of the covalently bound stereodirecting auxiliary. These
tedious protection-deprotection steps can in principle be
circumvented by the use of external chiral ligands chelating the
aryllithium nucleophiles. However, despite impressive progress in
enantioselective organolithium reactions, the chiral ligand-
controlled SNAr reaction has been scarcely investigated. This
strategy was pioneered in 1992 by Tomioka who reported on high
atroposelectivity (up to 95:5 er) in the reaction of 1-naphthyllithium
with hindered 1-fluoro-2-naphthimine in the presence of a chiral
1,2-diether ligand.13 However the tedious preparation of LiBr-free
naphthyllithium (crucial to attain high enantioselectivity), and the
harsh reaction conditions required to deprotect the bulky imino
group (stoichiometric amounts of TFA) greatly reduce the
attractiveness of this method and have hampered its further
application. To face this issue, hindered naphthoates were
investigated in chiral ligand-mediated SNAr reaction but led to
modest stereoselectivities (up to 76:24 e.r).14 As a consequence,
further developments on chiral-ligand mediated SNAr are still
needed.
Our first investigations focused on the reaction of 1-fluoro-2-
naphthoic acid (1a) with 1-naphthyllithium (2) (Table 1). (1R,2R)-
1,2-dimethoxy-1,2-diphenylethane L1, which was the sole ligand
investigated so far in enantioselective SNAr reaction,13, 14 was
selected as chiral inducer. Initially, a solvent screening was
carried out at 20 °C with 1.1 equiv. of L1 against naphthyllithium
2. This aryllithium derivative was prepared by bromine-lithium
exchange from equimolar amount of t-BuLi and 1-
bromonaphthalene. No enantioenrichment was observed when
the SNAr reaction was carried out in THF, as the coordinating
ability of THF toward lithium presumably competes with that of
ligand L1 (Table 1, entry 1). We thus switched to less coordinating
solvents. Diethyl ether induced a modest stereoselectivity (70:30
er) (Table 1, entry 2). Reaction in n-hexane yielded only trace
quantities of the product, arguably due to the reduced solubility of
the lithium carboxylate arising from the deprotonation of 1a by
aryllithium 2 (Table 1, entry 3). Toluene was identified as the
most suitable solvent, demonstrating acceptable yield (60%) and
atroposelectivity (85:15 er) (Table 1, entry 4). To improve the
reaction, the effect of temperature on the enantiocontrol was
next studied (Table 1, entries 5–9). Increasing the temperature
over 20 °C resulted in side reactions, likely due to competitive
lithiation at the benzylic positions of toluene and L1,15 and led
to diminished yields and enantioselectivities. While decreasing
the temperature enhanced the stereoselectivity, the yield was
extremely low (7%) at 85 °C. Hence, we selected 65 °C as the
reaction temperature for further investigation on the influence of
Axially chiral biaryls are a family of privileged structural motifs that
are commonly found in natural products 1 pharmaceuticals,2
,
chiral ligands,3 and optically active organic materials.4 To satisfy
the continuously increasing demand for these valuable scaffolds,
considerable synthetic efforts have been devoted to their
atroposelective construction. The most widespread strategies rely
on transition-metal-catalyzed asymmetric reactions.5 However,
these reactions have major shortcomings for the pharmaceutical
industry, as removing transition-metal residues from active
pharmaceutical ingredients requires costly and time-consuming
purifications.6,7 On the other hand, biaryls can be efficiently
synthesized, under transition metal-free conditions, by
nucleophilic aromatic substitution (SNAr) reactions, using
organolithium or Grignard reagents as nucleophiles. We
previously
demonstrated
that
subjecting
o-fluoro
or
methoxynaphthoic acids to organolithiums results in fluoride or
methoxide displacement.8 This process, which doesn’t require
protection of the carboxyl group, provides a straightforward and
convenient access to racemic biaryls. In pursuit of our contribution
to the development of the CO2Li-mediated SNAr reaction,9 we
report herein an efficient atropo-enantioselective synthesis of
axially chiral biaryls through the chiral diether-mediated SNAr
reaction on naphthoic acids.
Various strategies to access enantioenriched chiral biaryls
through asymmetric SNAr have been documented.10 The most
investigated so far has been the use of chiral aryloxazolines (the
[a]
[b]
Institut des Molécules et Matériaux du Mans (IMMM) - UMR 6283
CNRS - Le Mans Université, Avenue Olivier Messiaen, 72085 Le
Mans, France
E-mail: anne-sophie.castanet@univ-lemans.fr
Department of Organic Chemistry, University of Science, Vietnam
National University – Ho Chi Minh City, 227 Nguyen Van Cu Street,
District 5, Ho Chi Minh City, 748355, Vietnam
Supporting information for this article is given via a link at the end of
the document. It contains experimental protocols, characterization
data and copies of 1H and 13C NMR spectra for all new compounds;
copies of HPLC spectra proving the enantiomeric purity of
compounds.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000317
European Journal of Organic Chemistry
COMMUNICATION
LiBr on the reaction course. It is well known that inorganic lithium
salts may have a dramatic effect on the aggregation state of
organolithiums,16 and thus affect the yield and/or
enantioselectivity of asymmetric reactions.17 However, in
contrast to the previously reported L1-mediated SNAr reaction on
naphthylimines,13 using LiBr-free naphthyllithium 2 (prepared by
tellurium-lithium exchange, see SI) or adding LiBr (2 equiv) to the
reaction mixture did not appreciably alter the atroposelectivity
(Table 1, entries 10 and 11). In addition, further optimization
showed that increasing reaction’s concentration positively
impacted the yield (70%) while not hampering the selectivity (91:9
er) (Table 1, entry 12). The influence of the chiral ligand
stoichiometry on the reaction outcome was then studied. When
the reaction was performed under ligand-free conditions in
toluene at –65 °C, less than 5% of racemic 3 was produced after
24 h (Table 1, entry 13). Thus the chiral ligand not only controls
the stereoselectivity of the SNAr reaction but also enhances the
reaction rate, presumably through deaggregation of the
organolithium.18 The catalytic use of diether L1 was therefore
evaluated. Employing substoichiometric amounts of L1 (0.25
equiv/ArLi) drastically slowed down the reaction whereas the
enantioselectivity diminished only slightly (80:20 er) (Table 1,
entry 14). Consequently, a stoichiometric amount of ligand L1 (1.1
equiv/ArLi) is required to achieve synthetically useful yields. It is
nevertheless worthy of note that the chiral ligand can be
recovered from the reaction mixture by column chromatography
and reused with maintained levels of yield and stereoselectivity.
Finally, the impact of the leaving group on the reaction course was
investigated. Although the reaction of 1-methoxy-2-naphthoic acid
(1b) with 2 proceeded smoothly in THF under ligand-free
conditions,8a poor yield (46%) and modest enantioselectivity
(67:33 er) were obtained when 1b was reacted with 2 in toluene
in presence of diether L1, (Table 1, entry 15).
Table 1. Optimization of atropo-enantioselective L1-mediated SNAr reaction
Entrya
1
Substrate
1a
Preparation of 2b
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method A
Method B
Method A
Method A
Method A
Method A
Method A
Temperature (°C)
Ratio L1/2
1.1
1.1
1.1
1
Solvent
THF
Additive
Yield (%)c
(Ra-3 : Sa-3) erd
49.5 : 50.5
70:30
86:14
85:15
74:26
83:17
87:13
91:9
20
20
20
20
20
_
_
55
60
2
1a
Et2O
3
1a
hexane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
_
< 5
41
4
1a
_
5
1a
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
_
_
38
6
1a
0
_
35
7
1a
45
65
85
65
65
65
65
65
65
_
57
8
1a
_
61
9
1a
_
7
92:8
10
11e
12f
13g
14
15
1a
_
48
90:10
91:9
1a
LiBr
_
59
1a
70
91:9
1a
_
< 5
27
n.d
1a
0.25
1.1
_
80:20
67:33
1b
_
46 (25*)
b
a Unless otherwise noted, reactions were carried out under the following conditions : 1 (1.0 mmol ), 2 (2.2 mmol.), ligand L1 (2.4 mmol), solvent (48 mL), 24 h.
Method A: 2 is prepared by Br-Li exchange; Method B : 2 is prepared by Te-Li exchange. Yield estimated by 1H NMR spectroscopy on fractions from silica-gel
chromatography containing a mixture of 1 and 3. Isolated yields of pure 3 are followed by an asterisk d er measured by HPLC analysis (Chiralcel OD column). The
absolute configuration of 3 was determined on the basis of []D comparison with previously reported data. e 2 equiv. of LiBr was used. f 1 (1.0 mmol ), 2 (2.2 mmol.),
ligand L1 (2.4 mmol), toluene (23 mL), 24 h. g reaction run without L1.
c
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10.1002/ejoc.202000317
European Journal of Organic Chemistry
COMMUNICATION
The absolute configuration of 3 was assigned by comparing its
specific rotation ([]D) with that reported in the literature.19 The
sense of enantioselection is consistent with the model proposed
by Tomioka for the L1-promoted SNAr reaction of
fluoronaphthylimines.13 It is assumed that the SNAr reaction
proceeds by an addition-elimination mechanism, with the overall
stereoselectivity determined by the two steps (Scheme 1). Initial
complexation of naphthyllithium 2 with diether L1 would result in
the formation of chelate A, in which the two Me groups on the
ether oxygens are in a locked trans relationship to avoid steric
repulsion with the phenyl groups.20 This chelation creates a chiral
environment around the lithium that would govern the facial
selectivity of the subsequent addition step. Thus, complex A
would add stereoselectively to the lithium 1-fluoro-2-naphthoate
B to give the Meisenheimer intermediate C.21 Of the two possible
resulting conformers C’ and C”, C’ would be disfavored owing to
the steric interactions between the peri hydrogen atom and the
naphthalene ring undergoing the substitution. Subsequent
elimination of LiF with central-to-axial chirality conversion would
afford the Ra-3 lithium salt.
(84%) and enantioselectivity (94 :6 er). This level of
atroposelectivity equals or exceeds the stereoselectivities
previously reported for enantio- or diastereoselective SNAr
reactions using 1-naphthyllithium or 1-naphthyl Grignard reagent.
22
F
Li
1) ligand L1–L8
CO2H
CO2H
toluene, –65 °C
+
2) H3O+
1a
3
2
Diethers
Ph
Ph
Me
Me
Cy
Cy
OMe
MeO
OMe
MeO
OMe
MeO
MeO
OMe
(R,R)-L1
(R,R)-L2
31%
(S,S)-L3
59%
17:83 er
(R,R)-L4
84% (75%*)
94:6 er
70%
91:9 er
65:35 er
Diamines
H
N
N
H
Ph
Ph
N
N
tBu
tBu
NMe2
Me
Me2N
Me
Me2N
NMe2
(
–
)-L8
22%
50:50 er
(S,S)-L5
(R,R)-L6
74%
(R,R)-L7
10%
68%
60:40 er
32:68 er
48:52 er
Ph
Ph
*
Five-membered chelate formation
Scheme 2. Survey of ligand effects in atropoenantioselective SNAr reaction. 1a
(1 equiv.), 2 (2.2 equiv., prepared by Br-Li exchange), ligand L1-L8 (2.4 equiv.),
toluene, –65 °C. Yields estimated by 1H NMR spectroscopy on fractions from
silica-gel chromatography containing a mixture of 1a and 3. Isolated yields of
pure 3 are followed by an asterisk (*). (Ra-3 : Sa-3) er measured by HPLC
analysis (Chiralcel OD column).
Li
O
O
O
O
Ph
Ph
Me
Me
Me
Me
Me
Li
Li
+
OMe
MeO
Ar
Ar
L1
2
A
(Ar = 1-naphthyl)
Me
Ar
L1-mediated addition
O
O
Li
Me
O
O
Li
F
O
F
CO2Li
O
O
Li
+
Me
F
A
OLi
We then switched to chiral tertiary diamine ligands as these
compounds have been frequently used as chiral inducers in
organolithium chemistry.23 To gain insight about the influence of
the chelating function of the ligand on the stereoselectivity of the
SNAr reaction, 1,2-diamines featuring the same carbon skeleton
as diether ligands L1 and L4 were first investigated. Results
displayed in scheme 2 reveal that none of the evaluated diamines
surpasses the stereocontrol imparted by L1 and L4. N,N,N’,N’-
tetramethyldiamines L5 and L6 afforded biaryl 3 in correct yields
but in modest stereoselectivities. Remarkably, switching from
diether (R,R)-L4 to diamine (R,R)-L6 led to an unexpected
reversal of the enantioselectivity. Results obtained with 1,2-
diphenylethane-based ligands L1 and L5 suggest that this
enantioreversal would be rather general for this enantioselective
SNAr reaction. Although it has been demonstrated that tertiary
diamines in which the nitrogen atoms bear two different
substituents impart better stereoselectivities than their
Ar
B
control of
Meisenheimer
complex C
central chirality
Elimination
large
Me
O
large
F
Li
O
H
small
small
Me
H
OLi
O
OLi
CO2Li
O
Me
Me
F
Li
F
Li
O
O
central-to-axial
C''
C'
chirality conversion
O
O
Me
Me
Scheme 1. Postulated mechanism for the chiral diether L1-mediated atropo-
enantioselective SNAr reaction.
Prior to the present work, the effect of ligand structure on the
atropoenantioselective SNAr reaction had not been studied in the
literature. In an attempt to further increase the enantiocontrol of
this reaction, we then investigated the efficiency of a diverse set
of chiral ligands in the reaction of naphthoic acid 1a with
naphthyllithium 2 (scheme 2). These exploratory reactions were
conducted under the optimized conditions (Toluene, –65°C, 2.2
equiv. of 2, 2.4 equiv. of L). Diether ligands were first investigated.
Replacing the phenyl substituents of L1 with cyclohexyl or methyl
moieties (ligands L2 and L3) resulted in decreased yield and
enantioselectivity. Gratifyingly, diether L4, which exhibits a rigid
trans-cyclohexane backbone, proved to be an excellent chiral
promoter as it delivered the binaphthyl 3 with improved yield
tetramethylated
analogs
in
diverse
organolithium
transformations,24 disappointing results were obtained with
ligand L7. Indeed, this sterically hindered diamine produced an
aryllithium complex that was unreactive (low yield with significant
amounts of recovered starting materials) and gave almost a
racemic product. The widely used (–)-sparteine L8 similarly
proved ineffective at promoting the SNAr reaction. Noteworthy,
none of the chiral controllers evaluated in our ligand survey led to
the formation of detectable amounts of the ketone resulting from
the nucleophilic 1,2-addition of the 1-naphthyllithium to the
carboxylate.25
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10.1002/ejoc.202000317
European Journal of Organic Chemistry
COMMUNICATION
Ar
F
1) ligand L1 or L4
toluene, –65 °C
As previous studies on enantioselective SNAr reactions were
restricted to the use of 1-naphthyllithium, it was also of interest to
briefly probe the scope of the aryllithiums (Scheme 3). Both
diethers L1 and L4 were investigated in this study. Phenanthren-
9-yllithium successfully participated in the SNAr reaction and
afforded phenanthrylnaphthalene 4 in good yields (up to 77%)
with high enantiocontrol (91:9 er). 2-naphthyllithium also proved
CO2H
CO2H
+
ArLi
2) H3O+
4–7
1a
Me
suitable and the corresponding 1,2’-binaphthalene
obtained with acceptable yields (63%) and
5
was
good
CO2H
CO2H
Ph
Ph
enantioselectivities (up to 91:9). Additionally, the enantiocontrol
was efficient in the benzene series as 2-methylphenyllithium
smoothly displaced the fluoride leaving group of 1a, delivering the
phenylnaphthalene 6 with up to 88:12 er. Increasing the steric
hindrance further, using 2-isopropylphenyllithium as nucleophile,
had a slight impact on the enantioselectivity (85:15 er) but
drastically decreased the conversion (38%). Importantly, in all
these transformations, cyclohexyl-based diether L4 compares
favorably with the Tomioka’s diether L1. To the best of our
knowledge, the use of L4 as stereocontroller in asymmetric
reactions is unprecedented. This compound can be synthesized
from the corresponding enantiopure diol, which is commercially
available or can be readily obtained by chemical resolution.26
In conclusion, we have successfully developed an
atropoenantioselective nucleophilic aromatic substitution on
naphthoic acids. Enantioenriched biaryls are thus available from
unprotected precursors without recourse to tedious chemical
manipulations of chiral auxiliaries or protecting groups. The
enantiocontrol relied on the use of a chiral bidentate ligand
chelating the aryllithium nucleophile. A ligand survey revealed the
superiority of the diether ligands over their diamine counterparts
and the best enantiocontrol was obtained with the previously
unknown (1R,2R)-dimethoxycyclohexane. This enantioselective
SNAr reaction provides an efficient and direct approach to highly
valuable axially chiral carboxylic acids. These compounds have
found useful applications as chiral ligands in their own right.28
Alternatively, the carboxyl group can serve as a versatile handle
for further transformation into various functional groups and
4
5
MeO
OMe
(R,R)-L1
L1 : 66% (42%*), 91:9 er
L4 : 77% (59%*), 91:9 er
L1 : 59% (42%*), 91:9 er
L4 : 63% (51%*), 90:10 er
MeO
OMe
Me
iPr
(R,R)-L4
CO2H
CO2H
6
7
L1 : 38% (30%
L4 : 38% (36%
*
*
), 66:34 er
), 85:15 er
L1 : 59% (50%*), 83:17 er
L4 : 79% (69%*), 88:12 er
Scheme 3. Atropoenantioselective SNAr reaction of 1a with various
aryllithiums. 1a (1 equiv.), ArLi (2.2 equiv., prepared by Br-Li exchange),
ligand L1 or L4 (2.4 equiv.), toluene, –65 °C. Yields estimated by 1H NMR
spectroscopy on fractions from silica-gel chromatography containing a
mixture of 1a and 4-7. Isolated yields of pure 4-7 are followed by an asterisk
(*). Enantiomeric ratios were determined by chiral HPLC.27
Acknowledgments
This research was supported by CNRS, Le Mans Université and
Région Pays-de-la-Loire (SEBAC project). T.T.T.N. and H.G.
would like to thank the Ministry of Education and Training of the
Socialist Republic of Viêt Nam and the French Ministry of
Research and Technologies for PhD grants. We also express
appreciation to A. Durand, P. Gagnery, E. Mebold and F. Legros
for technical assistance
heterocyclic
compounds.
Evaluation
of
(1R,2R)-
dimethoxycyclohexane in other stereoselective organolithium
reactions as well as extension of the atropoenantioselective SNAr
reaction to Grignard reagents are currently ongoing in our
laboratory.
Keywords: organolithium • chiral ligand • biaryl • axial chirality •
nucleophilic aromatic substitution
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10.1002/ejoc.202000317
European Journal of Organic Chemistry
COMMUNICATION
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[27] The absolute configuration of 4 was assigned by []D comparison with
reported data. The absolute configuration of 6 was determined by
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optical rotation to reported data. The absolute configuration of biaryls 5
and 7 are tentatively assigned as shown in scheme 3 on the assumption
that the SNAr reaction with (1-methylnaphthalen-2-yl)lithium and (2-
isopropylphenyl)lithium proceeds with the same sense of stereoinduction
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