Kinetic Resolution and Dynamic Kinetic Resolution of Chromene by Rhodium-Catalyzed Asymmetric Hydroarylation

Article abstract of DOI:10.1002/anie.201900721

A highly efficient kinetic resolution and dynamic kinetic resolution of chromene is reported for the first time and they procced by a rhodium-catalyzed asymmetric hydroarylation pathway. This new approach offers versatile access to various chiral 2,3-diaryl-chromanes containing vicinal stereogenic centers, as well as the recovered chiral flavenes, in high yields with excellent ee values (s factor up to 532). Particularly noteworthy is that this strategy can be further extended to the establishment of a dynamic version of the kinetic resolution of chromene acetals and allows complete access to chiral isoflavanes and α-aryl hydrocoumarins.

Full text of DOI:10.1002/anie.201900721

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Accepted Article
Title: Kinetic Resolution and Dynamic Kinetic Resolution of Chromene
via Rh-Catalyzed Asymmetric Hydroarylation
Authors: Qingjing Yang, Yanbo Wang, Shihui Luo, and Jun Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201900721
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10.1002/anie.201900721
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Kinetic Resolution and Dynamic Kinetic Resolution of Chromene
by Rh-Catalyzed Asymmetric Hydroarylation **
Qingjing Yang, Yanbo Wang, Shihui Luo and Jun (Joelle) Wang*
(Scheme 1b).7 Thus, we select 2H-chromene skeleton as
Abstract: A highly efficient kinetic resolution and dynamic kinetic
resolution of chromene is reported for the first time via a Rh-
catalyzed asymmetric hydroarylation pathway. This newly developed
approach offers a versatile access of various chiral 2,3-diaryl-
chromenes containing two vicinal stereogenic centers as well as the
recovered chiral flavenes in high yields with excellent ee (s factor is
up to 532). Particularly noteworthy is that this strategy can be further
extended to the establishment of a dynamic version of kinetic
resolution of chromene acetals, in which it allows complete access of
chiral isoflavanes and α-aryl hydrocoumarin successfully.
substrates, in which the arylrhodium intermediates do not have
syn β-hydrogens for β-hydrogen elimination, and they will
undergo protonation to give hydroarylation products.
Flavonoids are privileged structural motifs in numerous natural
products and pharmaceutical molecules, which show many
biological activities such as antitumor, antioxidant, antibacterial
and anti-inflammatory properties.1 Flavene, flavane and
isoflavane which feature a chiral center are subgroups of
flavonoid. Given the prevalence of this structural unit, there has
been considerable interest in developing methods for the
generation of flavene skeletons. Nevertheless, facile access of
their corresponding optically active variants via asymmetric
catalysis remains limited. 2
Scheme 1. Rh-catalyzed addition of arylboronic acids to alkenylarene
We embarked on this investigation using rac-flavene 1a as the
benchmark substrate and phenylboronic acid 2a as the arylating
agent (Table 1). To our delight, the arylation product 3aa with
vicinal chiral center was obtained as single diastereomer in 48%
isolated yield with 94% ee, and the recovered 1a was also
obtained in 31% yield with 95% ee, catalyzed by the chiral Rh
complex in-situ generated from 2.5 mol % [Rh(cod)Cl]2 and 6
mol % (R)-Binap (Table 1, entry 1). With the hopeful initial
results, other chiral bisphosphine ligands with different
backbones were then evaluated. Generally, all these ligands
provided hydroarylation product 3aa with trans-stereoselectivity
exclusively in 32-55% yields and 77-97% ee accompanied with
25-44% yields of enantio-enriched starting materials in 67-99%
ee (s-factor is 39-183). Among ligands being surveyed, (R)-
Difluorphos gave the best yield and enantioselectivity with
excellent selectivity factor (183) (Table 1, entry 4). Further
optimization of the solvents and reaction temperature revealed
that the optimal reaction condition was 2.5 mol % [Rh(cod)Cl]2
Figure 1. Structures of chiral flavonoids.
Rh-catalyzed asymmetric arylation have been intensively
investigated in recent years, however, the alkenes were limited
mainly to those activated by proximal electron-withdrawing
substituents (represented by carbonyl groups).3 In fact,
examples concerning the Rh-catalyzed asymmetric arylation of
alkene are rare. In 2008, Lautens reported an asymmetric
hydroarylation process in the reaction of bicyclo[2.2.1]heptane
system.4 Recently, Hayashi also reported several successful
examples of aymmetric hydroarylation of cycloalkene.5 To the
alkenylarene substrates, Lautens reported the Rh-catalyzed
asymmetric addition of arylboronic acid compounds to simple
styrenes that resulted in Heck-type products, owing to the
alkylrhodium intermediate often prefers β-H elimination rather
than protonation (Scheme 1a).6 The asymmetric hydroarylation
of styrene was realized by Lam where the strongly electron-
withdrawing group (-nitro) at the para-position of arene was
prerequisite to afford the desired hydroarylation product
o
combination with 6 mol % (R)-Difluorphos in toluene at 50 C,
using 2.5 equivalent KOH as base (see supporting information).
With the optimized reaction conditions, we next examined the
scope of flavenes with various substituents on benzopyran or
C2-phenyl ring (Table 2). The substituents on both the
benzopyran core and C2-aryl group had limited effect on the
enantioselectivity. Generally, the reactions provided the trans-
arylated products 3aa-3oa as the single diastereomer with
excellent enantioselectivities (92-98% ee) accompanied with
recovered (R)-flavenes in 87->99% ee (s factor is 74-244). No
significant steric effects were observed as good yield and high
ee were maintained for flavene 1h with the ortho substituent on
the C2-phenyl ring, as well as product 3ha. The hydroarylation
of 2-aryl chromenes with electron-donating group at the 6- or 7-
[*]
Q. Yang, Y. Wang, S. Luo and Prof. J. Wang*
Department of Chemistry
Southern University of Science and Technology,
Shenzhen, Guangdong, 518055, China
E-mail: wang.j@sustc.edu.cn
[**]
We gratefully thank Shenzhen Basic Research Program
(JCYJ20170817112532779) for financial support.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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position (1l, 1m and 1n) were found sucessful, and furnished the
desired products 3la-3na in good yields (42-44% yield) with
excellent enantioselectivities (95-97% ee). The racemic flavenes
bearing -F or -Cl group (1k and 1o) were also tolerated. To our
delight, 2-alkyl-chromene 1p also worked well under this
reaction conditions, giving hydroarylation product 3pa in 40%
yields and 93% ee and recovering starting material in 30% yields
with 99% ee (s factor is 155). The enantioenriched chromenes
obtained by the kinetic resolution could be easily transform to
the chromane scaffold by hydrogenation without notable loss of
the enantiomeric purity.It should be noted that the hydrogenation
product of (R)-1q is an inhibitor of rhinovirus (BW683C).8
[a] Reaction conditions: [Rh(cod)Cl]2 (2.5 mol %) and (R)–Difluorphos (6
mol %) in solvent (1 mL) were stirred at rt for 30 min under argon. 1a-o (0.2
mmol), 2a (0.48 mmol), KOH (0.5 mmol) were then added. The mixture was
stirred at 50 C for indicate period of time. Isolated yields were shown; ees
were determined by HPLC analysis.
To further test the efficacy of the catalyst system in obtaining
the substituted chiral 2,3-diaryl-chromanes,
a
series of
arylboronic acids 2b-2o were examined (Table 3). Most of the
desired 2,3-diaryl-chromanes were obtained in good yields (28-
45% yields) with excellent enantioselectivities (95-99% ee, s
factor is 111-532). Arylboronic acids having electron-withdrawing
substituents (-CF3, -CO2Et) on the aromatic ring were
accommodated with excellent product enantioselectivities (3ag
and 3ah). The electron-donating methoxy group was also
compatible, albeit with lower conversion (3ad, 3aj). The chloro
and bromo groups remained intact under the present reaction
conditions (3ae and 3af), that allows further potential
functionalization. However, the reactions of ortho-substituted
arylboronic acids were sluggish, and only afforded trace
products. Finally, the configuration of recovered 1a was
assigned as R configuration by comparison with literature data
of the known compound,2c and this absolute configuration of 3af
was unambiguously confirmed as (2S, 3R) by X-ray
crytallographic analysis.9
Table 1. Initial screening of ligands. [a]
1a[b]
1a[d]
3aa[b,c]
3aa[d] conv[e]
S[f]
entry
ligand
yield %
ee %
yield %
ee %
94
77
85
96
97
93
97
97
92
(%)
50
56
54
50
41
51
45
48
50
1
2
3
4
5
6
7
8
9
(R)-Binap
(R)-Xyl-Binap
(R)-Synphos
(R)-Difluorphos
(R)-Biphep
31
28
25
44
36
26
38
40
28
95
99
99
95
67
97
80
84
92
48
32
55
43
42
44
44
33
48
121
39
64
183
132
116
162
175
79
(R)-Segphos
(R)-P-Phos
(R)-Xyl-P-Phos
(R)-Garphos
[a] Reaction conditions: [Rh(cod)Cl]2 (2.5 mol %) and ligand (6 mol %) in
solvent (1 mL) were stirred at rt for 30 min under argon. 1a (0.2 mmol), 2a
(0.48 mmol), KOH (0.5mmol) were then added. The result mixtures were
stirred at 50 C for 24 h. [b] Isolated yield. [c] Diastereomeric ratio (dr) > 99:1
(determined by 1H NMR). [d] Determined by chiral HPLC. [e] Calculated
conversion, C = ee1a/(ee1a + ee3a). [f] Selectivity factor (s) = ln[(1 –C) (1 –
ee1a)]/ ln[(1 –C) (1 + ee1a)]. cod = 1,5-cyclooctadiene.
Table 3. Scope of arylboronic acids.[a]
Table 2. Scope of flavenes[a] and transformation of flavene (R)-1q.
[a] Reaction conditions: [Rh(cod)Cl]2 (2.5 mol %) and (R)–Difluorphos (6
mol %) in solvent (1 mL) were stirred at rt for 30 min under argon. 1a (0.2
mmol), 2b-o (0.48 mmol), KOH (0.5 mmol) were then added. The mixture was
stirred at 50 C for indicate period of time. Isolated yields; ees were
determined by HPLC analysis. [b] Tris(4-carbo methoxyphenyl)boroxine was
used. [c] [Rh(cod)Cl]2 (5 mol %) and (R)-Difluorphos (12 mol %) were used.
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To better understand the mechanism, a deuterium labeling
experiment was performed (see supporting information for
detail). The hydroarylation of 1e under the optimized conditions
using D5-phenylboronic acid 2a’ gave the product 3ea’ labelled
with deuterium at the C4-position (90% D) (Scheme 2). A small
amount of deuterium (10% D) was reserved at the ortho-position
of phenyl group derived from the D5-phenylboronic acid. On the
basis of the deuterium incorporation studies, the hydroarylation
mechanism is proposed and is shown in Scheme 2.
is that the two substrate enantiomers can undergo rapid in situ
interconversion under the same reaction conditions.10 Based on
Metz’s kinetic resolution of flavanones11, a dynamic kinetic
resolution version was developed through
a
conjugate
elimination/conjugate addition pathway in concert with
asymmetric ketone transfer hydrogenation step.12 Therefore, we
surveyed the chromene acetal 4a in our preliminary trial. In
previous report, the addition of the aryl-rhodium to chromene
acetals occured at the C2-position to give 2-aryl chromene
under base-free conditions.13 Herein, the hydroarylation product
5aa was obtained in 43% yield with 90% ee, accompanied with
several decomposition byproducts catalyzed by 2.5 mol %
[Rh(cod)Cl]2 combination with 6 mol % (R)-Difluorphos, using 2.5
equivalent KOH as base. As expected, the recovered substrate
was found to be a racemate. Encouraged by these preliminary
results, we further optimize the reaction parameters for the
possible dynamic kinetic resolution process (see supporting
information Table S3). The use of (R)-Xyl-P-Phos ligand
provided relatively good product yield and enantioselectivity.
Further investigation of Rh precursor disclosed that
[Rh(cod)OH]2 showed higher reactivity. The product yield was
further improved by using phenyl boroxine instead of PhB(OH)2.
Both the product yields and ee values were sensitive to the
additive base. After extensive and elaborative optimization, we
identified that the addition of 0.5 equivalent K3PO4 and 0.5
equivalent triethylamine rendered the full consuming of substrate
and less byproducts, while maintaining high enantioselectivity.
Under this condition, the interconversion of enantiomers is very
rapid, and full racemization of optically pure ethoxy-chromene 4a
finished in 3 h (Table 4, Eq. a).
Phenylrhodium
species
B,
generated
from
chiral
hydroxorhodium species A by transmetalation, adds to flavene
1e to generate alkylrhodium intermediate C. With the
conformationally rigid structure of intermediate C, cis hydrogens
for β-elimination are not available, and hence 1,4-Rh shift from
alkyl carbon to ortho position of phenyl ring4a, 5c takes place to
generate intermediate D because Rh-Csp2 intermediate was
thermodynamically more stable than Rh-Csp3 intermediate. Thus,
intermediate D leads to the main product of 3ea’ after
protonolysis. The (2S, 3R) configuration of the product 2,3-diaryl
chromene 3ae which was obtained with (R)-Difluorphos is
rationalized by the coordination of flavene (S)-1e to chiral
phenylrhodium species with its α-re face. The coordination of
chiral Rh-Ph complex with flavene (R)-1e is much less favorable
due to the high steric repulsions between arene moiety of
flavene and the phenyl group at the phenylrhodium species. In
such a situation, (S)-flavene is competitively consumed allowing
isolation of (2S, 3R) 2,3-diaryl chromene together with a
remaining optically pure substrate (R)-flavene.
Scheme 2. Deuterium labeling experiment, proposed mechanism and
stereochemical pathway for the Rh-catalyzed hydroarylation of flavene.
With these modified reaction conditions, the scope of the
chromene acetals and arylboroxines was then tested. Both
methyl acetal 4b and isopropyl acetal 4c were suitable
substrates. Different substituent groups (such as -Me, -MeO, -F,
-Br, -NO2, -CF3) at the 5-, 6- or 7-position of chromene acetal all
worked well, and gave the desired products in 55-80% yields
and 71-97% ees. The absolute configuration of the product 5ea
was determined to be (2S, 3R) by single crystal X-ray
crystallographic analysis.9 The scope of organoboron reagents
appeared to be broad, and both electron-withdrawing (e.g.,
product 5af, 5ag) and electron-donating group (e.g., product 5ad,
5ak) were found compatible under these conditions, while
arylboronic acids with electron-withdrawing groups gave better
results than corresponding arylboroxines. When D2O was used
as the co-solvent, the product 5ag’ was labelled with 90%
deuterium at the ortho-position of phenyl group derived from
phenylboroxine where the 1,4-Rh shift was happened. Reductive
removal of the ethoxy group from acetal 5aa was accomplished
using BF3•OEt2 and triethylsilane to give (R)-isoflavane 7 with 70%
yield and 94% ee (Table 4, Eq. b).14 The hydrolysis and
oxidation of acetal moiety 5aa were also presented in a single
procedure to give α-aryl hydrocoumarin 8 with 62% yield in a
slightly decreased ee (87%) (Table 4, Eq. b).15 In fact, both
isoflavane and α-aryl hydrocoumarin are biologically active
compounds, and relevant catalytic approaches for accessing
This developed kinetic resolution of flavenes via Rh-catalyzed
asymmetric hydroarylation of 2-aryl chromene is highly efficient
(s factor is up to 532). Additional attempt of dynamic kinetic
resolution process in which the maximum theoretical yield is 100%
would be highly desirable. The fundamental requirement of DKR
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enantiomerically pure form of isoflavane16 and α-aryl
hydrocoumarin successfully. We believe the study would have
versatile application in the synthesis of natural products and
bioactive compounds which contain chromene core.
hydrocoumarin17 are very limited.
Table 4. Scope of chromene acetals and arylboroxines,[a] racemization of
ethoxy-chromene 4a, and transformation of product 5aa.
Keywords: Asymmetric catalysis
• Kinetic Resolution •
Dynamic Kinetic Resolution • Hydroarylation • Flavonoids
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[a] Reaction conditions: [Rh(cod)OH]2 (2.5 mol %) and (R)-Xylyl-P-Phos (6
mol %), and H2O (0.2mmol) in toluene (1 mL) were stirred at rt for 30 min
under argon. 4a-k (0.2 mmol), (ArBO)3 (0.16 mmol), and K3PO4 (0.1 mmol)
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In summary, a novel kinetic resolution and dynamic kinetic
resolution of chromene via Rh-catalyzed asymmetric
hydroarylation is well-developed. Under the mild conditions, a
variety of chiral 2,3-diaryl-chromanes containing two vicinal
stereogenic centers as well as the recovered flavenes were
afforded in good yields with excellent ees. The deuterium
labeling experiment and proposed mechanism revealed why
hydroarylation product was resulted here instead of Heck-type
products (s factor is up to 532). In addition, the strategy was
further applied to the development of dynamic kinetic resolution
of chromene acetals. The products obtained could be easily
converted into either chiral isoflavanes (3-aryl chromanes) or
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COMMUNICATION
Q. Yang, Y. Wang, S. Luo, J. (Joelle)
Wang*
Page No. – Page No.
Kinetic Resolution and Dynamic
Kinetic Resolution of Chromene via
Rh-Catalyzed
Asymmetric
Kinetic Resolution and Dynamic Kinetic Resolution: A highly efficient kinetic
resolution of flavenes is reported for the first time via a Rh-catalyzed asymmetric
hydroarylation pathway. This newly developed approach offers a versatile access of
various chiral 2,3-diaryl-chromenes containing two vicinal stereogenic centers as
well as the recovered chiral flavenes in high yields with excellent ee (s factor is up to
532). Particularly noteworthy is that this strategy can be further extended to the
establishment of a dynamic version of kinetic resolution of chromene acetals, in
which it allows complete access of chiral isoflavanes and α-aryl hydrocoumarin
successfully.
Hydroarylation
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