CuH-Catalyzed Asymmetric 1,6-Conjugate Reduction of p-Quinone Methides: Enantioselective Synthesis of Triarylmethanes and 1,1,2-Triarylethanes

Article abstract of DOI:10.1021/acs.orglett.9b02308

The first copper hydride (CuH)-catalyzed asymmetric 1,6-conjugate reduction of p-quinone methides is reported. This protocol provides a new method to access a variety of triarylmethanes and 1,1,2-triarylethanes in good yields with excellent enantioselectivities and broad functional group tolerance.

Full text of DOI:10.1021/acs.orglett.9b02308

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
CuH-Catalyzed Asymmetric 1,6-Conjugate Reduction of p‑Quinone
Methides: Enantioselective Synthesis of Triarylmethanes and 1,1,2-
Triarylethanes
Ting Pan,†,§ Pan Shi,†,§ Bo Chen,† Da-Gang Zhou,† Ya-Li Zeng,† Wen-Dao Chu,*,† Long He,†
Quan-Zhong Liu,*,† and Chun-An Fan*,‡
†Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, College of Chemistry and Chemical Engineering,
China West Normal University, No. 1, Shida Road, Nanchong 637002, P.R. China
‡State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222
Tianshui Nanlu, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: The first copper hydride (CuH)-catalyzed
asymmetric 1,6-conjugate reduction of p-quinone methides
is reported. This protocol provides a new method to access a
variety of triarylmethanes and 1,1,2-triarylethanes in good
yields with excellent enantioselectivities and broad functional
group tolerance.
ecause of the use of inexpensive metals, the mild reaction
(Scheme 1a).15−17 Although these are big advances, there are
Bconditions and the operational simplicity, the application still limitations, for example, the requirement of multiple steps
of nonracemically ligated CuH in asymmetric hydrosilylation
reactions has drawn much attention during the last two
decades.1 In particular, CuH-catalyzed asymmetric reduction
of ketones,2 imines,3 and enantioselective 1,4-reduction of α,β-
unsaturated Michael acceptors4 has been well-developed.
However, CuH-catalyzed asymmetric 1,6-conjugate reduction,
to the best of our knowledge, has not been reported yet.
Triarylmethanes are important molecules owing to their
high utility in medicinal chemistry, materials science, and
organic synthesis.5 Although there are a number of methods
available for the synthesis of racemic triarylmethanes,6 the
preparation of optically active derivatives remains a distinct
challenge.7 The classic approach for the synthesis of chiral
triarylmethanes relies on stereospecific cross-coupling.8 There
are only a few approaches reported starting from racemic
compounds, including Friedel−Crafts alkylation of electron-
rich arenes,9 transition-metal-catalyzed aryl addition,10 desym-
metrization of achiral triarylmethanes,11 and enantioselective
functionalization of C(sp3)−H bonds.12 These successful
examples mostly focused on the C−C bond formation;
however, there has been no report on the C−H bond
formation.
Recently, as an important and readily available class of
synthetic intermediates, p-quinone methides (p-QMs) have
been extensively used to construct chiral diarylmethane
compounds through 1,6-conjugate addition.13 However, their
applications in the synthesis of chiral triarylmethanes have
been rarely investigated.14 Liao, Sun, and Weng’s groups
independently reported organo or metal-catalyzed asymmetric
1,6-conjugate addition of aryl compounds to p-QMs for the
preparation of chiral triarylmethanes directly or indirectly
Scheme 1. Synthesis of Chiral Triarylmethanes through 1,6-
Asymmetric Conjugate Addition of p-QMs
and limited scopes. We hypothesize that asymmetric reduction
of unsymmetrical diaryl-substituted p-QMs can potentially
serve as an attractive approach for the synthesis of
enantioenriched triarylmethanes. However, by now, no relative
experiment has reported. Because of the hardship in
distinguishing two enantiotopic faces in prochiral substrates,
this project is still an ultimate challenge. It occurred to us that
placement of the coordinated chloro group, which can undergo
further transformations such as cross-coupling reactions, at the
Received: July 4, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02308
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
ortho-position of one arene might result in sufficient
asymmetric bias in the transition state. Herein, we report the
first CuH-catalyzed asymmetric 1,6-conjugate reduction of p-
QMs as an approach to obtain enantiomerically enriched
triarylmethanes and 1,1,2-triarylethanes (Scheme 1b).
Scheme 2. Scope of Triarylmethanes
We embarked on this study with ligand screening by using o-
Cl-substituted p-QM 1a as the model substrate, Ph2SiH2 as the
hydride source, K2CO3 as the base, and Cu(OAc)2 as the
catalyst (Table 1). Triarylmethane 3a was formed with poor
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
ligand
solvent
base
yield (%)
ee (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2f
2f
2f
2f
2f
2f
2f
2f
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
n-hexane
cyclohexane
n-pentane
CH2Cl2
EtOAc
THF
n-hexane
n-hexane
n-hexane
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
LiOtBu
Na2CO3
Na2CO3
16
13
42
48
95
98
86
88
15
84
trace
26
98
95
−10
−9
51
65
79
84
52
83
80
42
9
10
11
12
13
83
86
90
a
d
0.1 mmol scale. Yield of isolated product 3. ee determined by HPLC
14
analysis. See the SI for more details.
a
Conditions: p-QM 1a (0.1 mmol), copper(II) acetate (0.01 mmol),
ligand (0.011 mmol), diphenylsilane (0.4 mmol), base (0.4 mmol) in
b
c
solvent (4 mL). Isolated yields. Enantiomeric excess was
determined by HPLC analysis on commercial chiral columns. The
d
substituted p-QMs were reduced to the triarylmethanes 3e,f
with low enantioselectivities. In addition, disubstituted
substrates 1g−l, including 2,3-dichloro, 2,4-dichloro, 2,5-
dichloro, 2-chloro-4-methyl, 2-chloro-4-methoxyl, and 2-
chloro-4-fluoro units, were all readily converted at the present
conditions. Next, the substituent effect on the second benzene
core was examined. p-QMs that contained meta- or para-
substituted electron-rich or electron-deficient aryl groups all
underwent facile hydrosilylation, providing the corresponding
triarylmethanes 3m−y with similarly high levels of enantiose-
lectivity. The absolute configurations of 3a and 3w were
unambiguously established by X-ray crystallographic analysis.
Substrates with disubstituted aryl groups were also good
partners to generate 3z−ac in 90−91% ee. Interestingly, 2-
naphthyl and heterocyclic substituted p-QMs were also
amenable to this protocol to give the corresponding products
3ad−ae with 90% ee and 84% ee, respectively.
Furthermore, the hydrosilylation of benzyl-substituted p-
QMs was investigated to provide chiral 1,1,2-triarylethanes,
which are fundamental structural motifs present in numerous
bioactive compounds and drugs (Figure 1).18,19 In this case,
SEGPHOS 2a gave the best selectivities under similar
conditions (Scheme 3).20 A series of p-QMs 4a−l bearing
electron-rich, -deficient or -neutral aromatic substituents
readily proceeded to afford the corresponding 1,1,2-triaryl-
ethanes 5a−l in 90−96% ee and 80−98% yield. Substrates
containing heterocycles (4m,n) and multisubstituted aryl (4o)
reaction was carried out at 0 °C.
conversion and enantioselectivity with bisphosphine ligand 2a
or 2b (entries 1 and 2). The oxazoline ligand 2c resulted in
moderate enantioselectivity (entry 3). We found that the use of
ligands 2c−e, which bear more bulky substituents on the
oxazole ring, led to higher enantioselectivity (up to 79% ee and
95% yield, entries 3−5). When tetrahydroquinoline-based 2f
was used, 84% ee was obtained (entry 6). Next, solvent and
base effects were examined. n-Hexane and Na2CO3 were
identified as the best combination for this reaction (entries 6−
13). To our delight, the enantioselectivity was increased to
90% while the temperature was lowered to 0 °C (entry 14).
With the optimal reaction conditions in hand, we proceeded
to study the reaction scope. A range of ortho-substituted p-
QMs (1a−d) were transformed to the corresponding triaryl-
methanes in excellent yields with moderate to high ee values
(Scheme 2). The introduction of a more electron-withdrawing
o-chloro or o-bromo unit resulted in higher enantioselectivity
(3a,b versus 3d). However, as expected, meta- and para-
B
DOI: 10.1021/acs.orglett.9b02308
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Scale-up Experiments and Post-Functionalization
Reactions
Figure 1. 1,1,2-Triarylethanes target molecules.
a
Scheme 3. Scope of 1,1,2-Triarylethanes
a
0.1 mmol scale. Yield of isolated product 5. ee determined by HPLC
analysis. See the SI for more details.
were all smoothly reacted with CuH under the current
conditions. The absolute configuration of (S)-5k was
unambiguously established by X-ray crystallographic analysis.
In addition, the influence of substituents on the phenyl rings of
benzyls was investigated. The reactions with p-QMs 4p-v
bearing a variety of substituents on the aromatic rings all
readily converted to give the desired 1,1,2-triarylethanes 5p−v
in 92−96% ee. Finally, the reaction could also be extended to
methyl and butyl substituents, and the corresponding products
could be obtained in 90% ee (5w) and 93% ee (5x),
respectively.
Figure 2. Rationale for enantioselection.
The synthetic potential of this strategy could be established
by performing scale-up experiments and postfunctionalization
reactions (Scheme 4). When starting from 1a or 4k (2.0
mmol), the gram-scale preparation of 3a or 5k could be
performed without a major impact on either reaction yield or
enantioselectivity. By treating 3a or 5k with a mixture of Tf2O
and TfOH in toluene, the de-tert-butylation products 3a′ and
5k′ were obtained in excellent yields without a loss of
stereoselectivity. Additionally, when undergoing further
palladium-catalyzed reactions, the chloro group could trans-
form to the desired dechlorinated, phenylated, and boronated
products in moderate to excellent yields.
1a. Thus, (S)-configured triarylmethane was afforded in a large
excess.
In conclusion, we have developed the first CuH-catalyzed
asymmetric 1,6-conjugate reduction of p-QMs. It provided
chiral triarylmethanes and 1,1,2-triarylethanes in good yields
(up to 99%) with excellent enantioselectivities (up to 96% ee).
A unique o-chloride effect was viewed in the synthesis of
triarylmethanes, which led to high enantioselectivity. This
approach afforded a potential alternative to prepare a variety of
chiral triarylmethanes due to its easy removal and further
transformations of the chloro group.
A plausible stereocontrol model is shown in Figure 2. Two
transition structures I and II, in which the π-stacking
interactions between the tetrahydroquinoline moiety and
phenyl group might be involved, are respectively shown to
result in the triarylmethane with (S) and (R) configurations.
Structure I is energetically more favored than II owing to the
steric repulsion existed in II between the tertiary butyl group of
the oxazoline ligand 2f and the o-Cl phenyl group of the p-QM
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02308.
■
S
Detailed experimental procedures, spectral data, and
analytical data (PDF)
C
DOI: 10.1021/acs.orglett.9b02308
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
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CCDC 1915124, 1915126, and 1943869 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: chuwendaonpo@126.com.
*E-mail: quanzhongliu@cwnu.edu.cn.
*E-mail: fanchunan@lzu.edu.cn.
ORCID
Wen-Dao Chu: 0000-0003-0058-2461
Chun-An Fan: 0000-0003-4837-3394
Author Contributions
§T.P. and P.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Science & Technology Department of Sichuan
Province (2019YJ0339) and NSFC (21572083, 21572183,
21772158, 21801208, 21825104) for financial support.
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