Switchable Smiles Rearrangement for Enantioselective O-Aryl Amination

Article abstract of DOI:10.1021/acs.orglett.9b01848

Asymmetric assembly of atropisomeric anilines from abundant and readily available precursors is one of the most challenging but valuable processes in organic synthesis. The use of highly efficient Smiles rearrangement to accomplish switchable enantioselec

Full text of DOI:10.1021/acs.orglett.9b01848

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Switchable Smiles Rearrangement for Enantioselective O‑Aryl
Amination
Xihao Chang, Qinglin Zhang, and Chang Guo*
Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei 230026,
China
S
* Supporting Information
ABSTRACT: Asymmetric assembly of atropisomeric anilines
from abundant and readily available precursors is one of the
most challenging but valuable processes in organic synthesis.
The use of highly efficient Smiles rearrangement to
accomplish switchable enantioselective amination reactions
of O-arenes provides access to nonsymmetric 2′-amino[1,1′-binaphthalen]-2-ol (i.e., NOBIN-type) and [1,1′-binaphthalene]-
2,2′-diamine (i.e., BINAM-type) derivatives. This transition metal-free strategy provides a powerful way to access a wide range
of advanced highly functionalized enantioenriched anilines.
xially chiral biaryl compounds1 are versatile building
2
3
Ablocks for catalysts, functional materials, and natural
products.4 Atropisomeric anilines,5 as represented by 2′-
amino[1,1′-binaphthalen]-2-ol (NOBIN) and [1,1′-binaphtha-
lene]-2,2′-diamine (BINAM), are widely used as powerful
chiral ligands or auxiliaries in asymmetric synthesis.6−13
However, asymmetric synthetic methods for atropisomeric
anilines, especially nonsymmetric NOBIN derivatives, remain
elusive.14 Moreover, the development of more general
strategies for construction of enantioenriched axially chiral
aniline derivatives with functional diversity is highly
desirable.15
C−N bond formation has emerged as a powerful strategy for
generating anilines, which can be used to construct
enantioenriched organic frameworks.16 While great achieve-
ments have been realized, the development of regiodivergent
protocols for common precursors in a rational and predictable
manner remains a formidable challenge, offering a unique
opportunity to develop diversity-oriented synthesis.15 Fur-
thermore, given the great importance of atropisomeric anilines,
obtaining versatile reaction intermediates from readily available
starting materials is very appealing and of great synthetic value.
The development of transition metal-free protocols would offer
an eco-friendly alternative for chiral C−N bond construction.17
New methods and strategies for direct functionalization of
unactivated C−O bonds are beginning to reshape the field of
retrosynthetic analysis,18 which affects the synthesis of axially
chiral anilines (Figure 1). Early reports of racemic amination of
phenols by Smiles rearrangement reactions with amide-based
reagents indicate that this class of bromoacetamides might be a
suitable starting point for the development of highly selective
rearrangement of axially chiral O-arenes.19 However, general
and selective amination using more common unactivated
axially chiral phenols remains elusive, although methods for the
enantioselective synthesis of 1,1′-bi-2-naphthol (BINOL) are
well-established.20
Figure 1. New Smiles rearrangement approach for the enantiose-
lective synthesis of axially chiral anilines.
In this study, we aimed to develop an alternative strategy
using easily accessible axially chiral phenols as novel reaction
partners for aminating reagents in asymmetric Smiles
rearrangement reactions. There are several challenges
associated with the development of this reaction: (1) the
ability to match these bulky phenol derivatives with aminating
reagents in the rearrangement reaction, (2) control of the
selectivity of the axially chiral aniline products (NOBIN or
BINAM), and (3) determination of the reaction conditions
that give excellent regio- and enantioselectivity. Careful
selection of the reaction conditions can profoundly affect the
reaction outcome, leading to the formation of axially chiral
anilines with different regioisomers in a highly enantiomerically
enriched form. We suggest that the use of aminating reagents,
which are capable of effectively discerning the sensitive steric
bias between the mono- and dialkylation processes, would be
the key to the successful implementation of our proposed
Received: May 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01848
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
chemo- and enantioselective rearrangement. Herein, we report
the highly enantioselective and regiodivergent Smiles rear-
rangement reactions of BINOLs with aminating reagents,
providing NOBIN and BINAM derivatives with excellent
regio- and enantioselectivity.
Scheme 1. Scope of the NOBIN Derivatives in the C−N
a
Coupling Reaction
We began our study by investigating the enantioselective
Smiles rearrangement of unprotected enantiopure 1a using
aminating reagent 2 as the model substrate (Table 1). We
Table 1. Optimization of the Switchable Smiles
a
Rearrangement Reaction
4a
b
entry
2
3a:4a
3a (%)
ee of 3a
(%) ee of 4a (%)
1
2
3
4
2a
2b
2c
2d
2e
2e
<1:20 not detected not detected
<1:20 not detected not detected
12
82
65
35
4
99
99
99
99
1:6
1:4
11
8
not detected
not detected
c
5
d
9:1
12:1
35
72
99
99
not detected
not detected
6
6
a
Unless otherwise specified, all of the reactions were performed using
(R)-BINOL 1a (0.2 mmol) and 2 (0.6 mmol) with K2CO3 (0.6
mmol), KI (0.02 mmol), and DMSO (2 mL) at 50 °C for 24 h. After
the disappearance of 1a from the reaction mixture, KOH (2.5 mmol)
was added to the reaction mixture and the temperature was increased
b
c
1
to 150 °C. Determined by crude H NMR spectroscopy. The first
d
step was performed at 110 °C. Acetone was used as the solvent for
the first step under the refluxing condition.
found that using KOH as the base at 150 °C gave desired
product 4a in 12% yield with a 99% enantiomeric excess (ee),
demonstrating that there was no decrease in the ee during the
rearrangement process (entry 1). We then evaluated aminating
reagents 2. Of the aminating reagents tested, desired product
4a was obtained in 82% yield with a 99% ee when racemic 2-
bromopropanamide 2b was used (entry 2). Further attempts
were made to switch the chemoselectivity to give 3a using
various other aminating reagents (entries 2−5). Significantly,
using sterically hindered 2-bromo-2-methylpropanamide 2e,
we achieved regiochemical switching of the monorearrange-
ment, leading to formation of 3a in 72% yield with a 99% ee
(entry 6). From the results, it is clear that this aminating
reagent scaffold is multifunctional because it can be easily
modified to control the selectivity.
NOBIN is a structural unit of natural products and the
architectures of chiral transition metal catalysts and organo-
catalysts.14 Most currently used methods for the preparation of
NOBIN are by oxidative coupling21 or the Bucherer reaction22
in the racemic form. New and powerful synthetic strategies are
needed to complement existing methods.23 We envision the
direct Smiles rearrangement of BINOL is an alternative route
for preparing a diverse range of NOBIN derivatives.24 With the
optimized conditions established (Table 1, entries 2 and 6),
the scope of the reaction for the synthesis of NOBIN
derivatives was explored (Scheme 1). A number of BINOLs
a
Unless otherwise specified, all of the reactions were performed using
1 (0.2 mmol, 1.0 equiv) and 2 (0.4 mmol, 2.0 equiv) with K2CO3 (0.4
mmol, 2.0 equiv) and KI (0.02 mmol, 0.1 equiv) at 50 °C for 24 h.
KOH (2.5 mmol) was then added to the reaction mixture, and it was
stirred at 150 °C for 4 h. The ee was determined by chiral high-
performance liquid chromatography (HPLC) analysis. The yields are
for the isolated materials. See the Supporting Information for the
experimental details.
with diverse substituents at different ring positions gave the
desired products, typically in good yields with complete
enantiospecificity. Initial screening showed that the process
extends the range of functional groups that are compatible with
the new protocol (3a−3m). The utility of this chemistry was
further evaluated by stereospecific rearrangement of BINOL-
based diaryl- and arylalkylamines. Direct amination of 1 gave
the desired rearrangement process without the need for
protection of the hydroxyl group (3n−3r), which shows that
the methodology tolerates steric hindrance of the amines and is
compatible with amine functionalities. Furthermore, a set of
substituted amides 2 also effectively coupled with 2′-methyl-
[1,1′-binaphthalen]-2-ol in good yields with complete
enantiospecificity (3s−3ab). To demonstrate the practicality
of the method, the asymmetric C−N coupling reaction was
performed on a gram scale, and a high yield with complete
B
DOI: 10.1021/acs.orglett.9b01848
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
diastereospecificity was achieved (Scheme 1, 3ad). Remark-
ably, the reaction was effective even for a set of spiro-phenols,
giving the corresponding products 3ae and 3af in good yields
and optical purities. Furthermore, using readily available (S)-2-
(4-isopropyl-4,5-dihydrooxazol-2-yl)phenol as the starting
material gave the corresponding products (3ag−3ak),
demonstrating the power of the new methodology.
Given the abundance of axially chiral biaryl compounds in
nature and their importance in asymmetric catalysis and
materials science, it is surprising that relatively few methods are
Importantly, a variety of aminating reagents (2) were also
investigated for amination of spiro-phenol, and they gave the
designed chiral adducts with complete enantioselectivity (4q−
4s).
A series of experiments were performed to elucidate the
asymmetric amination mechanism. To determine whether
aminating reagent equilibration occurs under the reaction
conditions, 15N-aminating reagent 2b′, which is typically
prepared from [15N]ammonia and 2-bromopropanoyl bro-
mide, was substituted for 2b in the rearrangement reaction
(Scheme 3a). BINAM with the 15N isotope 4a″ formed, which
available for atroposelective amine synthesis. Recently, Kurti
̈
and co-workers25 and List and co-workers26 independently
reported benzidine rearrangement of hydrazine catalyzed by
chiral phosphoric acid for the synthesis of BINAMs.
Encouraged by the results described above (Table 1 and
Scheme 1), we turned our attention to more challenging
processes that make use of double rearrangement using
aminating reagent 2 (Scheme 2). Under the optimized
Scheme 3. Mechanistic Studies
a
Scheme 2. Synthesis of BINAM Derivatives
was confirmed by mass spectrometry. Importantly, selective
introduction of 15N can now be accomplished using axially
chiral phenols as starting materials, and this process provides
access to 15N-labeled compounds that cannot be accessed by
conventional chemistry. In addition, reaction of a mixture of
15N2-etherified 1a and N2-etherified 1o produced only the
expected isotopologues, [15N2]-4a and 4d, without any
crossover products (Scheme 3b). C−N coupling was then
performed in the presence of the radical quencher TEMPO or
BHT, and coupling product 4a was isolated without a decrease
in the yield, suggesting no involvement of a radical
intermediate in the rearrangement amination process (see
the Supporting Information for details).28 Combined with the
optical purity of the products, these factors suggest ionic
intramolecular rearrangement is favored in the reaction.
In summary, we have developed a general method for
coupling axially chiral phenolic compounds with achiral
aminating reagents to give NOBIN and BINAM derivatives,
which are of great importance in synthetic chemistry. Using
this methodology, structurally diverse axially chiral anilines can
be produced in good yields with a broad scope, allowing the
straightforward preparation of anilines from the corresponding
aryl phenols. The reaction involves the initial formation of an
alkylation complex leading to the synthesis of functionalized
axially chiral anilines with complete stereospecificity. The
process is a convenient, safe, transition metal-free, and user-
friendly method for large-scale preparation. We anticipate that
this strategy will have extensive applications in the synthesis of
complex target molecules and provide new enthusiasm for
asymmetric aryl functionalization.
a
Unless otherwise specified, all of the reactions were performed using
1 (0.2 mmol, 1.0 equiv) and 2 (0.6 mmol, 3.0 equiv) with K2CO3 (0.6
mmol, 3.0 equiv) and KI (0.02 mmol, 0.1 equiv) at 50 °C for 24 h.
KOH (2.5 mmol) was then added to the reaction mixture, and it was
stirred at 150 °C for 4 h. The ee was determined by chiral HPLC
analysis. The yields are for the isolated materials. See the Supporting
Information for the experimental details.
rearrangement reaction conditions (Table 1, entry 2), a wide
range of 1 and aminating reagents 2 were investigated (Scheme
2). In general, 3,3′- or 6,6′-diaryl substituted aromatic rings
smoothly underwent this rearrangement transformation with
excellent chemoselectivities and optically pure enantioselectiv-
ities (4b−4d). In addition, a variety of aminating reagents were
well tolerated to give the corresponding products (4e−4o)
with complete enantiospecificity and without a distinct steric
effect. Importantly, the reaction with methyl aminating reagent
2ba proceeded without any difficulty to give methyl-BINAM
4e in a gram scale (97% yield, 99% ee), which is highly
desirable but has previously been achieved only by resolution
of racemic biaryls.27 3,3′-Disubstituted binaphthalene also gave
the corresponding adduct with a good yield with 99% ee (4p).
C
DOI: 10.1021/acs.orglett.9b01848
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
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Behnke, N. E.; Ess, D. H.; Ku
(17) Sun, C. L.; Shi, Z. J. Chem. Rev. 2014, 114, 9219.
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rti, L. Nat. Chem. 2017, 9, 681.
Corresponding Author
*E-mail: guochang@ustc.edu.cn.
ORCID
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Chang Guo: 0000-0003-4022-9582
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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The authors acknowledge financial support from the National
Natural Science Foundation of China (Grant 21702198), the
Anhui Provincial Natural Science Foundation (Grant
1808085MB30), the “1000-Youth Talents Plan”, and the
Fundamental Research Funds for the Central Universities
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DOI: 10.1021/acs.orglett.9b01848
Org. Lett. XXXX, XXX, XXX−XXX