Organocatalytic Atroposelective Arylation of 2-Naphthylamines as a Practical Approach to Axially Chiral Biaryl Amino Alcohols

Article abstract of DOI:10.1002/anie.201710537

The first phosphoric acid catalyzed direct arylation of 2-naphthylamines with iminoquinones for the atroposelective synthesis of axially chiral biaryl amino alcohols has been developed. This reaction constitutes a highly functional-group-tolerant route for the rapid construction of enantioenriched axially chiral biaryl amino alcohols, and is a rare example of 2-naphthylamines acting as nucleophiles in an organocatalytic enantioselective transformation. Furthermore, the products, which feature various halogen atoms, provide access to structurally diverse axially chiral amino alcohols through further transformations.

Full text of DOI:10.1002/anie.201710537

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Accepted Article
Title: Practical Approach to Axially Chiral Biaryl-amino-alcohols via
Organocatalytic Atroposelective Arylation of 2‑Naphthylamines
Authors: Bin Tan, Ye-Hui Chen, Liang-Wen Qi, and Fang Fang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201710537
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10.1002/anie.201710537
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Practical Approach to Axially Chiral Biaryl-amino-alcohols via
Organocatalytic Atroposelective Arylation of 2‑Naphthylamines
Ye-Hui Chen, Liang-Wen Qi, Fang Fang, and Bin Tan*
Dedicated to Professor Shizheng Zhu on the occasion of his 70th birthday
Abstract: The first phosphoric acid-catalyzed direct arylation of 2-
naphthylamines with iminoquinones for the atroposelective synthesis
of axially chiral biaryl-amino-alcohols has been developed. This
reaction features a highly functional group tolerant route to the rapid
construction of enantioenriched axially chiral biaryl-amino-alcohols
only been a few enantioselective attempts toward biaryl-amino-
alcohol derivatives, including metal-catalyzed enantioselective
oxidative cross-coupling reactions,[8] kinetic resolution of racemic
NOBIN (a kind of biaryl-amino-alcohol)
derivatives,[9] and
transformation of enantiopure binaphthyl derivatives.[10] In this
context, Kocovsky and co-workers pioneered the development
of an enantioselective version of the cross-coupling reaction of
2-naphthol and 2-naphthylamine using copper/chiral amines (10
equiv.) as mediator compounds to afford (R)-NOBIN in 42%
yield with 46% enantioselectivity excess (ee) (Scheme 2a).[8b]
After further crystallization, the ee could be improved to a very
high level. Obviously, there is a room for improvement of this
method, as it utilizes a large excess of chiral amine and
multistep crystallization. More recently, Zhao and co-workers
reported an efficient approach to synthesize enantioenriched
NOBIN derivatives with good results (selectivity factor is up to 42)
via NHC-catalyzed kinetic resolution.[9e] Although this elegant
approach has been one of the most powerful and reliable
strategies for the synthesis of enantiopure NOBIN derivatives,
the chemical yield is limited to no more than 50%. Thus, the
catalytic enantioselective synthesis of optically active NOBIN
derivatives via a more practical process remains challenging.
with good results. This represents
a rare example of 2-
naphthylamines acting as nucleophiles in organocatalytic
enantioselective transformation. Furthermore, the products which
have various halogen atoms offer access to structurally diverse
axially chiral amino alcohols through further transformation.
The axially chiral 1,1'-bi-2-naphthol (BINOL) and its derivatives
are among the most successful chiral ligands/catalysts in
asymmetric catalysis, with extensive applications in various
catalytic enantioselective transformations.[1] Recently, axially
chiral biaryl-amino-alcohols have been extensively implemented
as chiral ligands/organocatalysts in the field of enantioselective
catalysis.[2] For example, ligand A has been successfully applied
in numerous Ti-catalyzed enantioselective aldol reactions.[3]
Ligand B, a NOBIN-derived N,P ligand, has shown high
efficiency in the Cu-catalyzed Michael addition with good
results.[4] The NOBIN-derived organocatalyst C proved to be
efficient in promoting the [2+2] photocycloaddition of 4-alkenyl-
substituted coumarins with high enantioselectivity.[5] In addition,
this motif has been found in natural products or biologically
active compounds (Scheme 1a).[6]
The electrophilic substitution of arenes represents one of the
most powerful and reliable strategies for the synthesis of
aromatic compounds. However, most of the examples reported
in the literature with respect to this reaction were concerned with
the use of indoles, pyrroles and naphthols as nucleophilic
partners, whilst other nucleophiles, such as naphthylamines,
have been less investigated as regarding to enantioselective
transformations.[11] Consequently, the expansion of the substrate
scope to include naphthylamines is of great importance in order
to construct more chiral naphthylamine derivatives. Motivated by
the recent developments in the synthesis of axially chiral
compounds,[12] we herein report the chiral phosphoric acids
(CPAs) catalyzed atroposelective arylation of 2-naphthylamine
derivatives with iminoquinones, which provides a practical
process to enantio-enriched axially chiral biaryl-amino-alcohols
with good enantioselectivities (Scheme 2b). To the best of our
knowledge, this transformation represents the first example of 2-
naphthylamines acting as nucleophiles in phosphoric acid-
catalyzed enantioselective reaction.
Scheme 1. a) Selected ligands/catalysts and natural products with axially
chiral biaryl-amino-alcohol moiety. b) Current status of enantioselective
synthesis of axially chiral BINOLs and biaryl-amino-alcohols.
The enantioselective construction of BINOL and its
derivatives has attracted considerable attention and relatively
practical approaches have already been accomplished.[7] In
contrast, enantioselective synthesis of axially chiral biaryl-amino-
alcohols remains largely unexplored (Scheme 1b). There have
Y.-H. Chen, L.-W. Qi, F. Fang, Prof. Dr. B. Tan
Department of Chemistry
South University of Science and Technology of China
Shenzhen, 518055, P. R. China
E-mail: tanb@sustc.edu.cn
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
Scheme 2. Enantioselective strategies for the synthesis of enantiopure
NOBINs or axially chiral biaryl-amino-alcohols.
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10.1002/anie.201710537
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As part of an ongoing effort in our group to construct axially
chiral compounds via organocatalysis,[7g,13] we recently
entry
catalyst
solvent
yield (%)[b]
ee (%)[c]
98
1
CPA1
CPA2
CPA3
CPA4
CPA5
CPA6
CPA7
CPA8
CPA9
CPA10
CPA1
CPA1
CPA1
CPA1
CPA1
CPA1
CPA1
CPA1
DCM
88
36
14
14
11
19
18
7
successfully
exploited
the
phosphoric
acid-catalyzed
98
2
DCM
enantioselective arylation of 2-naphthols with quinone
derivatives to access BINOLs in good yields with excellent
enantioselectivities.[7g] We envisioned that 2-naphthols could be
replaced by 2-naphthylamines, affording the possibility to
construct enantiomerically enriched axially chiral biaryl-amino-
alcohols via a similar process. The biggest challenge might be
the reactivity and chemoselectivity of the reaction and the
information is largely unknown due to the lack of published data
involving 2-naphthylamines as nucleophiles. We initiated our
studies by evaluating the reaction between quinone ester and 2-
naphthylamine in dichloromethane (DCM) at room temperature
in the presence of chiral phosphoric acid CPA1 (Scheme 3).
Unfortunately, the reaction afforded the unexpected product D in
80% yield without the formation of axially chiral amino alcohols
derivative E. Despite making great efforts toward optimization of
the reaction conditions, we could not obtain the desired product
by using the current model reaction.
99
3
DCM
98
4
DCM
93
5
DCM
93
6
DCM
95
7
DCM
93
8
DCM
97
9
DCM
7
96
10
11
12
13
14
15
16[d]
17[f]
18[g]
DCM
20
86
83
86
7
99
DCE
95
CHCl3
toluene
THF
99
93
ethyl acetate
DCM
93
98 (80)[e]
42
91
84
89
DCM
96
DCM
92
[a] Reaction was carried out with 1a (0.10 mmol), 2-naphthylamine (2a, 0.15
mmol), and CPA (10 mol%) in 2 mL of solvent for 12 h at room temperature
under Ar, unless noted otherwise. [b] Determined by 1H NMR analysis of the
crude reaction mixture with 1, 3, 5-triethylbenzene as an internal standard. [c]
Determined by HPLC analysis. [d] 4 mL of DCM; [e] Isolated yield. [f] 5.0 mol%
CPA1 in 4 mL of DCM. [g] At 0 oC in 4 mL of DCM.
After the optimization of the reaction conditions, we set out
to explore various substituted 2-naphthylamines substrates 2
(Table 2). All of the tested 2-naphthylamines reacted completely
within 12 h to afford the corresponding products 3a-3p in
moderate to good yields (45−85%) with high enantioselectivities
(86−99% ee). The position and the electronic properties of the
substituents of 2-naphthylamines had a negligible impact on the
enantioselectivity of the reaction. However, the electronic
properties of the substituents on the aromatic ring appeared to
have significant effects on chemical yields. Relatively, electron-
withdrawing groups (CN, CO2Me) gave low yields (3e, 3f),
whereas the electron-donating groups such as Me or OMe
Scheme 3. Initial investigation involving 2-naphthylamine as nucleophile.
Inspired by the pioneering works of Akiyama[14a] and
Terada[14b] on the use of chiral phosphoric acids as
organocatalysts in the activation of imine for enantioselective
transformations, we postulated iminoquinones might have
additional interactions with the catalyst to construct axially chiral
compounds. Additionally, we aimed to inhibit the formation of the
cyclization product; therefore a substituent was introduced into
the ortho position. We decided to select readily available N-
sulfonyl iminoquinone 1a as a substrate to take the place of
quinone ester for the above-mentioned model reaction. As
expected, the desired product 3a was obtained in 71% isolated
yield with 88% ee (Table 1, entry 1). Then various chiral
phosphoric acid catalysts were screened but insufficient results
were obtained (Table 1, entries 2-10). CPA1 proved to be the
best catalyst with respect to enantioselectivity for the model
reaction. Of the solvents investigated for the reaction catalyzed
by CPA1 (Table 1, entries 11−15), DCM proved optimal. Having
identified CPA1 as the best catalyst and DCM as the best
solvent, we turned our attention to other reaction variables.
Lower concentration had a positive effect on enantioselectivity.
When 4 mL of DCM was employed, the ee of product increased
to 91% (Table 1, entry 16).
Table 2. Substrates scope with respect to variation of 2-naphthylamines.[a],[b],[c]
Table 1. Screening results of reaction conditions.[a]
[a] Reaction was carried out with 1a (0.10 mmol), 2-naphthylamines 2 (0.15
mmol), and catalyst CPA1 (5 mol%) in 4 mL of DCM at room temperature for
12 h under Ar, unless noted otherwise. [b] Isolated yields based on 1a. [c] ee
values were determined by HPLC analysis. [d] Reaction was carried out with
1a (1.65 g, 5 mmol), 2n (1.40 g, 6 mmol).
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10.1002/anie.201710537
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transferred the central chirality information to the axial chirality,
affording the final axially chiral biaryl-amino-alcohols via
aromatization.[7g,i] Another pathway via a cascade process that
involves sequential aminal formation, sigmatropic rearrangement,
and aromatization cannot be ruled out at the present stage.[7h]
afforded higher yields (3d, 3k). Notably, when N-substituted 2-
naphthylamines were employed to react with 1a, the desired
products (3m-3p) were afforded in moderate yields (65-85%)
with excellent enantioselectivities (>98% ee). To show the
practicality of this transformation, a gram-scale reaction of 1a
(1.65 g) and 2n was carried out in the presence of 5 mol%
CPA1 to afford 3n in 67% yield with 99% ee. The results
indicate that this direct arylation reaction for construction of
axially chiral biaryl-amino-alcohols could easily be scaled up
without decreasing the chemical yield or enantioselectivity. The
absolute configuration of 3a was determined as (aS) by X-ray
diffraction analysis (see Supporting Information), and those of
other products were assigned by analogy.
Scheme 4. Proposed reaction mechanism.
To demonstrate the synthetic utility of the current method,
the products were subjected to further transformations. 3a
reacted with bis(trifluoromethyl)phenyl isothiocyanate to produce
axially chiral thiourea which is a potential organocatalyst with
complete retention of enantiomeric purity (91% ee). After
recrystallization from petroleum ether/DCM, the ee of thiourea
was enriched to 99% (Scheme 5a). To expand the diversely
functionalized axially chiral amino alcohols (Scheme 5b), the
resultant product 3w can be further transformed into aryl
substituted axially chiral biaryl-amino-alcohols (5a-5d) without
erosion of enantioselectivities via palladium-catalyzed-Suzuki
Encouraged by these results, we next expanded the
generality of the reaction with regard to the variation of the
iminoquinone derivative 1. As shown in Table 3, the nature of
the sulfonyl group had limited influence on chemical yields and
enantioselectivities of the products 3q-3u. When the N-benzoyl-
protected iminoquinone was used as substrate, the reaction
proceeded very well under the optimized conditions, producing
the desired axially chiral biaryl-amino-alcohols in 85% yield with
88% ee. By replacing the Cl group with Br or Me at the
iminoquinone moiety, the corresponding products 3w-3z were
also obtained with good results. To our delight, the iminoquinone
ester 1j was a suitable substrate to react with N-substituted 2-
naphthylamines 2m and 2n in the presence of 5 mol% of CPA2,
giving the expected axially chiral amino alcohols 3aa and 3bb
with excellent enantioselectivities.
cross-coupling reaction
Information).[17]
(for
details,
see Supporting
Table 3. Substrates scope in terms of variation of iminoquinones.[a],[b],[c]
Scheme 5. Further transformations to expand the diversity.
In conclusion, we have successfully developed the first
phosphoric acid-catalyzed direct arylation approach for the
atroposelective synthesis of axially chiral biaryl-amino-alcohols
in moderate to good yields (up to 85% yield) with high
enantioselectivities (up to 99% ee). Moreover, the reaction
utilizes starting from readily available 2-naphthylamines and
iminoquinones. This reaction features a rare example of 2-
naphthylamines acting as nucleophiles in organocatalytic
enantioselective transformation. Furthermore, the resultant
products which contain various halogen atoms provide the
possibility of transformation into structurally diverse axially chiral
biaryl-amino-alcohols through further functionalization. Studies
are ongoing in our group to apply these compounds as ligands
and catalysts for asymmetric catalysis.
[a] Reaction was carried out with standard condition. [b] Isolated yields based
on 1. [c] ee values were determined by HPLC analysis. [d] Reacted at room
temperature for 24 h. [e] 5 mol% of CPA2 was used.
Based on the experimental results and the elegant work of
Rodriguez and Bonne involving central-to-axial chirality
conversion strategy,[15]
a
possible reaction process was
proposed (Scheme 4). The reaction process involves
regioselective conjugate addition followed by aromatization with
central-to-axial chirality First, the
conversion.[16]
a
Acknowledgements
We are thankful for the financial support from the National
Natural Science Foundation of China (Nos. 21572095,
21772081), Shenzhen special funds for the development of
a
enantioselective conjugative addition of 2-naphthylamines to
iminoquinones catalyzed by chiral phosphoric acid CPA1 is
proceeded to form intermediate M. The following step
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10.1002/anie.201710537
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biomedicine, internet, new energy, and new material industries
(JCYJ20170412151701379).
Keywords:
biaryl-amino-alcohols
•
atroposelective
•
iminoquinones • arylation • 2-naphthylamines
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10.1002/anie.201710537
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
The first phosphoric acid-catalyzed
Y.-H. Chen, L.-W. Qi, F. Fang, B. Tan*
direct arylation of 2-naphthylamines
Page No. – Page No.
with
iminoquinones
for
the
atroposelective synthesis of axially
chiral biaryl-amino-alcohols has been
developed. This reaction features a
highly functional group tolerant route
to the rapid construction of enantio-
enriched axially chiral amino alcohols
with good results. This represents a
rare example of 2-naphthylamines
Practical Approach to Axially Chiral
Biaryl-amino-alcohols via
Organocatalytic Atroposelective
Arylation of 2‑Naphthylamines
acting
as
nucleophiles
in
organocatalytic
transformation.
enantioselective
This article is protected by copyright. All rights reserved.