Rhodium-Catalysed Asymmetric Synthesis of 4-Alkyl-4H-Chromenes

Article abstract of DOI:10.1002/adsc.202000579

A general method for the catalytic asymmetric synthesis of 4-alkyl-4H-chromenes was developed. With readily available β-alkyl-substituted enones and 2-hydroxylated arylboronic acids, a rhodium-catalysed asymmetric conjugate addition/intramolecular hemi-acetalization/acid-promoted dehydration sequence leads to the formation of 4-alkyl-4H-chromenes in up to 99percent yield and with up to >99percent ee. The current study remedies the methodological deficiency in asymmetric synthesis of 4-alkyl-4H-chromenes. (Figure presented.).

Full text of DOI:10.1002/adsc.202000579

Title: Rhodium-Catalysed Asymmetric Synthesis of 4-Alkyl-4H-
Chromenes
Authors: Zhiqian Chang, Jian Yao, and Xiaowei Dou
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Advanced Synthesis & Catalysis
10.1002/adsc.202000579
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Rhodium-Catalysed Asymmetric Synthesis of 4-Alkyl-4H-
Chromenes
a
a
a,
Zhiqian Chang, Jian Yao, and Xiaowei Dou *
a
Department of Chemistry, School of Science, China Pharmaceutical University, Nanjing 211198, P. R. of China
Fax: (+86)-25-8618-5179; e-mail: dxw@cpu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A general method for the catalytic asymmetric
synthesis of 4-alkyl-4H-chromenes was developed. With which underwent intramolecular cyclodehydration to
hydroxyarylidene ketones to give -phenolic ketones,
[9]
readily available -alkyl-substituted enones and 2- give chiral 4H-chromenes (Scheme 1b). However,
hydroxylated arylboronic acids, rhodium-catalysed this reaction system only worked for the synthesis of
a
asymmetric conjugate addition/intramolecular hemi-
acetalization/acid-promoted dehydration sequence leads to
the formation of 4-alkyl-4H-chromenes in up to 99% yield
and with up to >99% ee. The current study remedies the
methodological deficiency in asymmetric synthesis of 4-
alkyl-4H-chromenes.
4
-aryl-4H-chromenes. To achieve the synthesis of 4-
alkyl-4H-chromenes, a different catalytic system that
could enable the efficient generation of chiral -
alkyl--phenolic ketones should be introduced.
Keywords: asymmetric synthesis; 4H-chromene;
arylboronic acid; catalysis; rhodium
Chromenes
(also
called
benzopyrans)
are
fundamental structures found in numerous natural
[1]
products and biologically active compounds. In
particular, chiral 4H-chromenes are highly useful in
[2]
medicinal and synthetic chemistry.
Given the
importance of this privileged chiral structure,
considerable efforts have been devoted to developing
[3]
versatile methods for their asymmetric synthesis.
Over the past decades, various approaches such as
asymmetric nucleophilic addition to benzopyrylium
[
4]
ion,
methide,
asymmetric trapping of ortho-quinone
[5]
and intermolecular cyclization under
[6]
asymmetric iminium-allenamine catalysis, among
[
7]
other, have been successfully developed to achieve
a series of chiral 4H-chromenes. Despite the merits of
these approaches, the existing strategies are generally
not applicable to the synthesis of 4-alkyl-4H-
chromenes. The 4-alkyl substitutions on 4H-
chromenes are essential for biologically active targets
Scheme 1. Importance and asymmetric synthesis of 4-
alkyl-4H-chromenes.
[
8]
(
Scheme 1a), thus development of a general method
for asymmetric synthesis of 4-alkyl-4H-chromenes
would be highly beneficial for applications in target-
oriented synthesis.
The chromene structure can be readily generated
by an intramolecular cyclodehydration reaction from
the -phenolic ketones (Scheme 1c), so the key is
how to efficiently construct such a chiral phenolic
intermediate. As a pioneering work, Miyaura and co-
workers reported the palladium-catalysed asymmetric
conjugate addition of arylboronic acids to 2-
The rhodium-catalysed asymmetric conjugate
addition of arylboronic acids to enones has emerged
as a reliable method for synthesizing chiral
[
10]
molecules.
deactivated
hydroxylated arylboronic acids have been rarely
Early studies showed that phenol
[11]
the
rhodium
catalyst,
thus
[12]
employed under rhodium catalysis. Recently, we
proved the compatibility of hydroxylated arylboronic
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000579
[
13]
acids with rhodium catalyst in ethanol.
In this
2a and -alkyl enone 1a. The synthesis involves a
two-step sequence: chiral rhodium catalyst was used
to control the formation of the new stereogenic center,
and the hemiacetal intermediate 3a was dehydrated to
give the desired 4-alkyl-4H-chromene 4a. As
summarized in Table 1, chiral diene-ligated rhodium
catalysts showed high reactivity for the reaction
context,
we
considered
addressing the
aforementioned issue using the combination of 2-
hydroxylated arylboronic acids and -alkyl enones
under rhodium catalysis. As part of our ongoing
efforts on the synthesis of important structures under
[
14]
rhodium catalysis,
we herein report that the
[
15]
rhodium catalyst efficiently promoted the asymmetric
conjugate addition of 2-hydroxylated arylboronic
acids to -alkyl enones, and a general method for the
synthesis of chiral 4-alkyl-4H-chromenes via a
(entries 14), and easily prepared chiral diene L1
proved to be the best to give 4a in a high yield with
96% ee. In contrast, the bisphosphine (R)-binap-
ligated rhodium catalyst showed a much lower
reactivity (entry 5), validating the importance of the
rhodium-catalysed
asymmetric
conjugate
[
16]
addition/intramolecular hemiacetalization/ acid-
promoted dehydration process was successfully
developed.
diene ligand.
In addition to ethanol, the reaction
also proceeded well in other solvents like THF and
toluene (entries 67), although the enantioselectivity
was slightly lower.
Table 1. Optimization for the asymmetric synthesis of
chiral chromene from -alkyl enone 1a and 2-hydroxylated
[
a]
phenylboronic acid 2a.
Entry
Reaction conditions
Yield
ee
[%]
[
b]
[c]
[%]
1
2
3
4
5
6
7
L1 as ligand
L2 as ligand
L3 as ligand
95
86
90
85
14
95
96
96
93
81
71
87
95
95
(R,R)-Ph-bod as ligand
(R)-binap as ligand
L1, THF instead of EtOH
L1, toluene instead of EtOH
[
a]
Conditions for Rh-catalysed addition: 1a (0.20 mmol),
a (0.40 mmol), [RhCl(L)]2 (1 mol% Rh ), and KOH (5
mol%) in EtOH/H2O (1.0 mL/0.1 mL) at 60 C for 12 h.
Conditions for dehydration: crude 3a, TsOH·H2O (20
mol%), and 4 Å MS (200 mg) in toluene (3.0 mL) at
10 C for 4 h.
Isolated yield of 4a.
2
o
Scheme 2. Substrate scope of -alkyl enones. [a] 2 mol%
Rh and 3 equiv. of 2a were used in EtOH at the conjugate
addition step. [b] Conducted on 1.0 mmol scale.
o
1
[
b]
c]
[
The ee value of 4a was determined by HPLC analysis
on a chiral stationary phase.
With the conditions in entry 1 of Table 1 as the
optimal conditions, the scope of the asymmetric
synthesis of chiral 4-alkyl-4H-chromene was then
studied. The generality of -alkyl enones was first
We embarked on the investigation from the model
reaction between 2-hydroxylated phenylboronic acid
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000579
investigated, and the results were summarized in
Scheme 2. The established method worked well to
give chiral 4H-chromenes bearing a variety of 4-alkyl
substitutions in high yields and with good to excellent
enantioselectivities (87%99% yield, 90%99% ee).
For instance, linear alkyl substitutions with different
chain length, including those bearing aryl and
halogen groups, all worked well (4a4e). The
sterically hindered alkyl substitutions (4f4g) and
cycloalkyl substitutions (4h4i) were all well
tolerated. Furthermore, substitutions on the 2-position
of 4H-chromene products were amendable to both
aryl and alkyl groups (4j4n).
addition step showed very low reactivity for ,-
disubstituted enones.
Scheme 4. Synthetic transformations of chromene 4a. a)
o
o
Pd/C, H2, rt. b) BH3, THF, 0 C. c) H2O2, NaOH, 60 C.
The synthetic transformation of the 4-alkyl-4H-
chromene product was illustrated in Scheme 4.
Chromene 4a was readily hydrogenated to the
corresponding chromane 5a, and chroman-3-ol 6a
was easily obtained quantitatively by the standard
hydroboration/oxidation procedure. It is noteworthy
that high diastereoselectivity was observed for both
transformations.
In summary, we have developed the first general
method for the asymmetric synthesis of 4-alkyl-4H-
chromenes. The key to success is the asymmetric
addition of 2-hydroxylated arylboronic acids to
enones enabled by rhodium catalysis. The developed
method features low catalyst loading, excellent
enantiocontrol, and broad substrate scope, and it shall
find broad applications in target-oriented synthesis of
chiral chromene derivatives.
Experimental Section
General Procedure for the Asymmetric Synthesis of 4-
Alkyl-4H-Chromenes
[
Rh Cl(L1)]2 (0.9 mg, 1 mol, 1 mol% Rh), enone 1 (0.20
mmol), and 2-hydroxylated arylboronic acid 2 (0.40 mmol)
were placed in a Schlenk tube under nitrogen. EtOH (1.0
mL) and aqueous KOH (0.1 mL, 0.1 M, 5 mol%) were
o
added and the resulting solution was stirred at 60 C for 12
h. Upon completion, the reaction solution was diluted with
water (5 mL) and extracted with EtOAc (5 mL*3). The
combined organic layer was passed through a short pad of
silica gel, and the solvent was removed under vacuum to
give the crude intermediate. The intermediate was directly
dissolved in toluene (3.0 mL), and TsOH·H2O (20 mol%)
and 4 Å MS (200 mg) were then added. The resulting
Scheme 3. Scope of hydroxylated arylboronic acids and
enones. [a] 10 mol% acid was used at the dehydration step.
[b] Conducted on 1.0 mmol scale.
o
mixture was stirred at 110 C for 4 h. Upon completion,
As shown in Scheme 3, 2-hydroxylated
arylboronic acids bearing different substitutions can
be used to generate substituted chiral 4-alkyl-4H-
chromenes (4o4r), without affecting the yields and
the mixture was subjected to silica gel chromatography
with petroleum ether to petroleum ether/EtOAc (v/v =
10/1) to give the chromene product 4.
enantioselectivities. In addition, the feasibility of the Acknowledgements
current method for the synthesis of chiral 4-aryl-4H-
We thank the financial support from the “Double First-Class”
University project (CPU2018GY35) of China Pharmaceutical
University and the Six Talent Peaks Plan of Jiangsu Province.
chromenes was tested, and we were delighted to see
that 4-aryl-4H-chromenes (4s4w) were attainable in
high yields and with excellent enantioselectivities by
using -aryl enones under the established reaction
[
17]
conditions.
However, the current method is not
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3
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4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000579
COMMUNICATION
Rhodium-Catalysed Asymmetric Synthesis of 4-
Alkyl-4H-Chromenes
Adv. Synth. Catal. Year, Volume, Page – Page
Zhiqian Chang, Jian Yao, and Xiaowei Dou*
5
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