Cu/Chiral Phosphoric Acid-Catalyzed Asymmetric Three-Component Radical-Initiated 1,2-Dicarbofunctionalization of Alkenes

Article abstract of DOI:10.1021/jacs.8b11736

An asymmetric intermolecular, three-component radical-initiated dicarbofunctionalization of 1,1-diarylalkenes with diverse carbon-centered radical precursors and electron-rich heteroaromatics by a copper(I) and chiral phosphoric acid cooperative catalysis strategy has been developed, providing straightforward access to chiral triarylmethanes bearing quaternary all-carbon stereocenters with high efficiency as well as excellent chemo- and enantioselectivity. The key to success is not only the introduction of a sterically demanding chiral phosphoric acid to favor radical difunctionalization over the otherwise remarkable side reactions but also the in situ generation of carbocation intermediates from benzylic radical to realize asymmetric induction with the aid of a removable hydroxy directing group via cooperative interactions with chiral phosphate. Density functional theory calculations elucidated the critical chiral environment created by the hydrogen-bonding and ion-pair interactions between the chiral phosphoric acid catalyst and substrates, which leads to the enantioselective C-C bond formation.

Full text of DOI:10.1021/jacs.8b11736

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Article
Cu/Chiral Phosphoric Acid-Catalyzed Asymmetric Three-
Component Radical-Initiated 1,2-Dicarbofunctionalization of Alkenes
Jin-Shun Lin, Tao-Tao Li, Ji-Ren Liu, Guan-Yuan Jiao, Qiang-Shuai
Gu, Jiang-Tao Cheng, Yu-Long Guo, Xin Hong, and Xin-Yuan Liu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 18 Dec 2018
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Journal of the American Chemical Society
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Cu/Chiral Phosphoric Acid-Catalyzed Asymmetric Three-Component
Radical-Initiated 1,2-Dicarbofunctionalization of Alkenes
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0
†,§
†,§
II,§
†
‡
†
Jin-Shun Lin, Tao-Tao Li, Ji-Ren Liu, Guan-Yuan Jiao, Qiang-Shuai Gu, Jiang-Tao Cheng, Yu-Long
†
*,II
*,†
Guo, Xin Hong, Xin-Yuan Liu
†
Department of Chemistry and Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen 518055, China
SUSTech Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518055, Chi-
‡
na
II
Department of Chemistry, Zhejiang University, Hangzhou, 310027, China
ABSTRACT: An asymmetric intermolecular, three-component radical-initiated dicarbofunctionalization of 1,1-diarylalkenes with diverse
carbon-centered radical precursors and electron-rich heteroaromatics by a cop-
per(I) and chiral phosphoric acid cooperative catalysis strategy has been devel-
oped, providing straightforward access to chiral triarylmethanes bearing quater-
CPA
nary all-carbon stereocenters with high efficiency as well as excellent chemo- and
enantioselectivity. The key to success is not only the introduction of a sterically
demanding chiral phosphoric acid to favor radical difunctionalization over the
otherwise remarkable side reactions, but also the in-situ generation of carbo-
cation intermediates from benzylic radical to realize asymmetric induction with
the aid of a removable hydroxy directing group via cooperative interactions with
chiral phosphate. DFT calculations elucidated the critical chiral environment
created by the hydrogen-bonding and ion-pair interactions between chiral phosphoric acid catalyst and substrates, which leads to the enanti-
oselective C–C bond formation.
Scheme 1. Asymmetric Three-Component Radical-Initiated 1,2-
Dicarbofunctionalization of Alkenes
■
INTRODUCTION
Dicarbofunctionalization of alkenes has recently attracted increasing
attention given the rapid generation of molecular complexity from
1
readily available alkene starting materials. In regard to the booming
radical chemistry, impressive advances have been achieved in the de-
velopment of catalytic radical alkene difunctionalization initiated by
intermolecular addition of carbon-centered radicals to alkenes cata-
lyzed by transition-metal redox systems2 owing to the high innate
,3
4
reactivity and unique selectivity of radical intermediates. In contrast,
catalytic radical asymmetric dicarbofunctionalization of olefins, espe-
cially for the intermolecular three-component version, is much less
developed given the number of side reactions that highly reactive alkyl
radical intermediates can undergo. In this aspect, Liu and co-workers
recently adopted chiral metal species to trap reactive alkyl radical, a
5
strategy pioneered by Fu and others (Scheme 1a), to elegantly devel-
op state-of-the-art enantioselective intermolecular trifluoromethylary-
6
lation and cyanotrifluoromethylation (Scheme 1b). Although impres-
sive results have been achieved with this approach, pre-
functionalization of the carbon nucleophiles as boronic acid or trime-
thylsilane was mechanistically indispensable. On the other hand, there
have been no general and practical solutions to allow for the efficient
7
construction of chiral all-carbon quaternary stereocenters, presumably
5
due to the inherently unfavorable steric hindrance. From the view-
point of high step-economy as well as versatility, a mechanistically
distinct and alternative approach for reactions capable of not only gen-
erating all-carbon quaternary stereocenters but also accommodating
direct intermolecular C–H functionalization is highly desirable.
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To this end, we wondered if our recently developed Cu(I)/chiral
lation of a possibly removable hydroxy or amino directing group on
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
phosphoric acid (CPA) dual-catalysis for radical asymmetric intramo-
lecular transformations could be translated into a general and practical
solution toward this issue. It has been assumed that the in situ-
one of the two aryl groups might impart effective stereocontrol, con-
sidering the fact that a chiral phosphate anion is able to interact with
8
1
7
such groups via hydrogen bonding. Subsequently, we chose the sub-
strates 1ba, 1a, and 1ca bearing OH or NH groups at different posi-
generated electronically activated benzylic radical might readily under-
2
II
go a single-electron oxidation process in the presence of Cu species to
tions (para or meta) of one aryl ring based on our initial hypothesis
(Table 1, entries 2–4), and we were pleased to observe a significant
increase in enantioselectivity with the hydroxy directing group, albeit
with low product yield and along with other side reactions including
perfluoroalkylation and direct hydroarylation with indole.
afford a carbocation intermediate. This carbocation might associate
with chiral phosphate through electrostatic interactions, thereby result-
ing in a good chiral environment (Scheme 1c) for subsequent direct
2
intermolecular C(sp )–H functionalization on electron-rich het-
eroarene (E-R). Accordingly, it would provide the desired optically
active dicarbofunctionalization product in a mode that is mechanisti-
This proof-of-principle result encouraged us to carry out further sys-
tematic optimizations of different reaction parameters with use of 1a as
the model substrate (Table 2). To suppress the more common hy-
droarylation or perfluoroalkylation clearly observed in this reaction and
improve the enantioselectivity, we screened different copper salts and
various organic solvents as well as reaction temperature. Unfortunately,
either enantioselectivity or chemoselectivity could not be significantly
improved under these reaction conditions (Table 2, entries 1–6). Con-
sidering the reported significant steric effect of CPAs in the direct C-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
II
cally distinct from those in previous works invoking chiral Cu species
to trap alkyl radical as a key step.6 If achieved, this type of radical re-
dox-relay cooperative catalytic strategy would be synthetically signifi-
cant because the resulting chiral triarylmethanes bearing quaternary all-
carbon stereocenters represent key structural elements of a large of
molecules in dye industry, medicinal chemistry, and material science as
,8
9
well as organic synthesis (Figure 1), but their asymmetric construction
10
remains a significant challenge and scare. At the outset, we recognized
10e
alkylation reaction, we then screened various BINOL- and SPINOL-
that several challenges would need to be overcome to reduce this idea
to practice, including securing good discrimination between the enan-
tiotopic faces of this carbocation11 via electrostatic interactions that
lack rigidity in their association and selectively controlling promiscu-
ous reactivity, such as competitive β-elimination from the carbocation,
derived CPAs (Table 2, entries 7–12) and found that the use of a steri-
cally bulky 6,6′-bis(2,4,6-triisopropylphenyl)-4,4′-dimethyl SPINOL-
18
derived chiral phosphoric acid (S)-A4 dramatically inhibited the
hydroarylation process, presumably due to its significant steric bulki-
ness hindering nucleophilic indole from approaching toward the alkene.
Noteworthy is that CPA (S)-A5 bearing sterically more bulky tricyclo-
hexylphenyl groups at the 6,6′-positions totally abolished the per-
fluoroalkylation side reaction while significant inhibiting hydroaryla-
tion and efficiently providing 4A in superior yield (88%) and enanti-
oselectivity (95% ee) with a reaction temperature at 3 °C (Table 2,
entry 13).
1
0b-
a direct hydroarylation of alkene with electron-rich heteroaromatics,
e,12
8d,13
Kharasch addition type reaction of alkene,
and direct radical
1
4
fluoroalkylation of electron-rich heteroaromatics. Herein we describe
our efforts toward the development of the first general and efficient
asymmetric intermolecular three-component radical-initiated dicarbo-
functionalization of 1,1-diarylalkenes with electron-rich heteroaromat-
ics and a diverse array of carbon-centered radical precursors enabled by
Cu(I)/CPA cooperative catalysis (Scheme 1d).15
With the optimal reaction conditions established, we next investi-
gated the substrate scope of the asymmetric intermolecular perfluoro-
alkylarylation of alkenes (Table 3). Various diversely functionalized
1
,1-diarylethylenes, including those having aryl groups with electron-
withdrawing (CF , F, Cl, NO , CO Me) or electron-donating groups
3
2
2
(OMe, Me) at different positions (ortho, meta, or para) as well as a
polyarene naphthalene ring were found to be suitable substrates to
afford the expected products 4A–4P in 56–97% yields with 91–98% ee.
It is noteworthy that substrate containing the other reactive and useful
ethynyl group also afforded the corresponding product 4I with the
additional triple bond intact. In addition, thiophene-substituted olefin
was tolerated to give 4L in 95% yield and 97% ee. Furthermore, a range
of substituted indoles all underwent the current perfluoroalkylarylation
reaction smoothly to deliver the corresponding products 4Q–4V in
excellent yields with excellent enantioselectivity. Encouraged by the
above success, we thus switched our synthetic target to chiral difluoro-
Figure 1. Representative biologically active indole-containing triaryl-
methanes bearing a quaternary carbon center.
acetyl-triarylmethane, as the difluoromethyl group (CF R) routinely
2
16
serves as a core pharmacophore in drug discovery in recent years. To
our delight, the reaction of 1,1-diarylethylene substrate 1a with
■ RESULTS AND DISCUSSION
MeO
2
CCF
2
SO Cl (3b) under the otherwise identical reaction condi-
2
Given the increasing importance of fluoroalkyl-containing mole-
cules in the development of pharmaceuticals and agrochemicals as well
as materials,16 we began our investigation using fluorine-containing
carbon-centered radical precursors. To this end, we selected 1,1-
diarylalkene 1aa bearing one OMe-substituted electron-rich arene as
the pilot alkene substrate, indole derivative 2a as the carbon nucleo-
phile, and perfluorobutanyl sulfonyl chloride 3a as the oxidative radical
precursor (Table 1, entry 1). However, the three-component reaction
tions delivered difluoroacetyl-containing product 5A in moderate yield
with 80% ee.
The trihalomethyl unit has emerged as a key moiety presented in
numerous bioactive natural products and pharmaceutical drugs,19 and
thus, its preparation has spurred the development of many new rea-
20
gents and strategies. To this end, we successfully prepared trichloro-
methyl-containing products 6A–6D in good to excellent yields with
9
0–94% ee (Table 4) via reaction of 1,1-diarylethylene substrate 1 with
trichloromethanesulfonyl chloride 3c under the almost identical condi-
tions. As for chiral CF -containing triarylmethanes, we identified the
well-known Togni’s reagent (3d) but not trifluoromethanesulfonyl
in the presence of CuI and CPA (S)-A1 (10 mol%) with Ag
2
CO as an
3
additive provided the desired product 4Aa in poor yield and enantiose-
lectivity, along with side monofunctionalization product 5Aa in good
yield through a β-hydride elimination process and direct hydroaryla-
tion product 6Aa, respectively. Given this, we surmised that the instal-
3
2
d
8
b
chloride (CF
3
SO
2
Cl) as the appropriate CF source to obtain 7A–
3
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a
Table 1. Initial Exploration of Reaction Conditions
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Entry
1
R1
R2
4
y (%)b
20
ee (%)c
5
y (%)
53
6
y (%)
24
0
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
a
1aa
1ba
1a
4-H
OMe
OMe
Me
H
4Aa
4Ba
4A
7
5Aa
5Ba
5Ca
5Da
6Aa
6Ba
6Ca
6Da
3-OH
4-OH
54
43
68
--
44
10
44
43
0
1ca
4-NH
2
4Ca
0
68
Reaction conditions: 1 (0.1 mmol), 2a (0.12 mmol), n-C
4
F
9
SO
2
Cl (0.12 mmol), CuI (10 mol%), Ag
2
CO (0.06 mmol), CPA (10 mol%), DCM
3
b
c
(
1.0 mL) under argon. Isolated yield. Ee value on HPLC.
a
Table 2. Screening of Reaction Conditions
Yield (%)
6Cab
ee(%)c
Entry
[Cu]
CPA
Solvent
4
Ab
5Cab
45
15
86
0
1d
2
CuI
(S)-A1
(S)-A1
(S)-A1
(S)-A1
(S)-A1
(S)-A1
(S)-A2
(R)-A3
(S)-A4
(S)-A5
(R)-A6
(R)-A7
(S)-A5
DCM
DCM
EtOAc
6
47
60
13
79
80
76
33
54
19
28
62
20
11
73
69
--
CuI
22
0
3
CuI
4
CuI
PhCF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
3
20
8
62
71
75
38
-72
-75
-95
43
48
-95
5
CuBr
CuOAc
CuI
10
11
34
12
11
0
6
9
7
28
31
68
70
20
44
88
8
CuI
9
CuI
10
CuI
1
1
2
CuI
18
36
0
1
CuI
1 e
3
CuI
a
Reaction conditions: 1a (0.05 mmol), 2a (0.06 mmol), n-C
4
F
9
SO
2
Cl (0.06 mmol), [Cu] (10 mol%), Ag
2
CO
Br
3
(0.03 mmol), CPA (10 mol%), dry
as an internal standard. Ee value on
b
1
c
solvent (0.5 mL), 0 °C, 60 h under argon. Yield based on H NMR analysis of the crude product using CH
HPLC. 20 °C. (S)-A5 (7.5 mol%) was used at 3 °C.
2
2
d
e
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a,b,c
Table 3. Substrate Scope for Perfluoroalkylarylation or Difluoroacetylarylation of 1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
b
c
d
e
Reactions were conducted on 0.1 mmol scale. Isolated yield based on 1 were given. Ee was determined by HPLC analysis. Run at 3 °C. Run at
f
g
h
0
3
°C for 72 h, then 29 °C for 42 h. 15 mol% CuI. 20 mol% CuI. The reaction was conducted on 0.025 mmol scale with Ag
,3′-(3,5-(Ph) -8H-BINOL-derived CPA at 30 °C for 72 h.
2
CO (0.5 equiv.), (R)-
3
2
C
6 3 2
H )
7
G in good to excellent yields with excellent ee. Meanwhile, it was
(Scheme 3, eq. 3) and carboxylic acid 8B in good yields (Scheme 3, eq.
4). An important aspect of the transformations discussed above is that
no significant enantiopurity erosion has ever occurred, establishing the
utility of this method in practical synthetic chemistry. It is interesting
to note that the chiral dichloroolefin-containing product 9A was ob-
tained in excellent yield and enantioselectivity through direct elimina-
tion of hydrogen chloride from corresponding trichloromethylated
products in cases of electron-rich indole reactant (Scheme 3, eq. 5).
Such resultant dichloroolefin can not only serve as a potential synthetic
platform for facile access to other valuable chiral triarylmethanes, but
also as a key structural element for potent activity in numerous bioac-
striking to note that 2-methyl-1H-pyrrole as a nucleophile also under-
went the current reaction to deliver 7H in 78% yield with promising
enantioselectivity, which is currently under further optimization in our
laboratory. The absolute configuration of 7G has been determined to
be S by X-ray crystallographic analysis (Figure S2 in SI for experi-
ments), and those of other perfluoroalkyl-, trichloromethyl-, difluoroa-
cetyl-, and trifluoromethyl-containing triarylmethanes were inferred
accordingly.
To further demonstrate the practicality of the current methodology
in preparative organic synthesis, we carried out gram-scale synthesis of
products 4C, 6E, and 7E. As displayed in Scheme 2, the asymmetric
21
tive compounds.
1
,2-dicarbofunctionalization of 1c with different radical precursors was
To gain some insight into the reaction mechanism, a series of con-
trol experiments were conducted. First, the present reaction was com-
pletely inhibited by the addition of 2,2,6,6-tetramethyl-1-
performed on a 1.008 g scale under the standard reaction conditions,
and high efficiency and enantioselectivity were still maintained all the
time.
piperidinyloxy (TEMPO), and the radical trapping product n-C
4
9
F –
1
9
TEMPO was observed in F NMR and detected by GC-MS, suggest-
ing that the n-C radical was likely generated in situ in the presence
of Cu catalyst through a single electron transfer process (Scheme 4, eq.
). In addition, no desired product 4A was obtained in the absence of
any copper catalysts. Furthermore, rac-4A was obtained in lower yield
in the absence of phosphoric acid. These observations, together with
the above-mentioned significant effects of different CPAs in the reac-
tion condition optimization study (Table 2) indicate that both the
An apparent drawback of our current transformation is the require-
ment for a hydroxy directing group. In fact, this hydroxy group was
readily removed by straightforward triflation and subsequent reduction
to afford 7Bb with an unsubstituted phenyl ring (Scheme 3, eq. 1). In
addition, the triflated intermediate 7Ba also provided extra synthetic
potentials for further derivatization by cross-coupling reaction, as
demonstrated by synthesizing 7Bc with excellent efficiency (Scheme 3,
eq. 2). Besides, simple reduction or hydrolysis of the ester group in 5A
smoothly generated the corresponding difluoro-containing alcohol 8A
F
4 9
1
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Table 4. Substrate Scope for Trichloromethylarylation and Trifluo-
romethylarylation of 1
cases, but its participation in our desired reaction via either protonation
with CPA (path b in Figure 2b) or any other pathways was unlikely
a,b
10b
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
given that no reaction of 5Ca was observed either under standard con-
ditions or in presence of CPA only, respectively (Scheme 4, eq. 3).
Thus, the in situ-generated carbocation intermediate from benzylic
radical might directly undergo attack by nucleophile (path a in Figure
2
b), which would be mechanistically distinct from the previous work
1
0b
via the direct protonation of alkenes by CPA, i.e., path b. Owing to
not only the facile oxidation of electronically activated radical to a car-
bocation intermediate but also the straightforward installation of a
diverse array of carbon-centered radicals to alkenes, the current syn-
thetic protocol exhibits a number of clear advantages over the direct
alkene protonation approach in terms of high reactivity, a broader
substrate scope as well as versatile functionalization of the products,
thus constituting a more appealing alternative to the previous ap-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
0,12
proach.
To further elaborate the mechanistic details, we studied the relation-
ship between product enantiopurity and catalyst enantiopurity. The
observed linear relationship indicates the involvement of one CPA
catalyst in the enantioselectivity-determining transition states (Figure
6,8
2
a). On the basis of above observations and previous reports, we have
proposed a working mechanism, as shown in Figure 2b. Cu(I) first
8d
reacts with CPA-activated RSO Cl by hydrogen bonding via single-
2
electron transfer, giving the crucial chiral Cu(II) phosphate complex A
accompanied by the generation of carbon-centered radical and a stoi-
chiometric amount of sulfur dioxide and hydrogen chloride (HCl).
a
b
All the reactions were conducted on 0.1 mmol scale. Ee was de-
The additive Ag
2
CO acts as a HCl scavenger via the formation of in-
3
c
d
termined by HPLC analysis. Ag
mol% CuI. Run at 2 °C. Run at 0 °C for 12 h, then 28 °C for 48 h.
S)-3,3′-(3,5-(t-Bu)
2
CO
3
(0.6 equiv.), 35 °C, DCM. 20
soluble AgCl in organic solution. Subsequently, the addition of carbon-
centered radical to alkene 1 gives alkyl radical B, which subsequently
undergoes single-electron oxidation with the Cu(II) complex A to form
the corresponding carbocation intermediate. This carbocation inter-
mediate is next attacked by electron-rich heteroaromatics through
e
f
g
(
2
C
6
H ) -SPINOL-derived CPA, 15 °C for 72 h.
3
2
Scheme 2. Gram-Scale Reaction with Diverse Radical Precursors
10,12
intermediate C or its p-quinone methide resonance structure C′
1
5
invoking both hydrogen-bonding interactions and ion-pair interac-
tions in C or only hydrogen bonding interactions in C′ to realize excel-
1
1
lent stereocontrol. In the case of the meta-phenol substrate 1ba (4Ba
up to 53% ee, Scheme S1), only intermediate C is reasonably involved
since no quinone methide resonance structure can be invoked.
Our hypothesized enantioselective C–C bond formation through in-
termediate C is supported by density functional theory (DFT) calcula-
22
tions. Using (S)-A5 as the model CPA catalyst and 1a and indole 2b
as the model substrates, we were able to locate the C–C bond for-
mation transition states TS10-S and TS10-R that lead to enantiomeric
product formation (Figure 3). Various complexation types between
CPA catalyst and substrates, as well as careful conformational searches,
are considered to ensure that the most favorable transition states are
located (Figure S1–S4 in SI for Computations). Both transition states
involve the proposed hydrogen bonding and ion-pair interactions be-
tween the CPA catalyst and substrates, which create the chiral envi-
2
3
ronment for enantiodiscrimination. TS10-S is 5.0 kcal/mol more
favorable than TS10-R in terms of free energy (Figure 3), which is
consistent with the observed enantioselectivity (Table 4). Calculations
with additional functionals were performed to further validate the en-
ergy difference between the two transition states (Table S1 in SI for
Computations). The leading factor that differentiates the two compet-
ing transition states is the CH-π interaction between the cyclohexyl
group of CPA catalyst and the para-methylphenyl group of alkene.24
This favorable CH-π interaction stabilizes TS10-S by 3.9 kcal/mol
based on the calculations of interacting fragments (Figure S5 in SI for
Computations), while TS10-R does not possess this interaction due to
the stereogenic configuration of forming C–C bond. The proposed
Cu(I) salt and CPA are essential for this reaction, and CPA might have
played an important role in the activation of sulfonyl chloride.
Besides, either the N-protected indole 2i (Scheme 4, eq. 2) or me-
thyl-protected 1,1-diarylalkene 1aa (Table 1) is not an effective sub-
strate to provide satisfactory enantioselectivity under similar reaction
conditions. These facts indicate the important roles of the N–H and
the O–H moieties in these substrates, presumably via formation of
cooperative multiple hydrogen bonding with chiral phosphate. Note-
worthy is that Sun and co-workers have elegantly developed direct C-
alkylation reaction of indoles via formation of a tertiary carbocation
intermediate by protonation of electron-rich terminal 1,1-diarylalkene
2
5
with CPA.10b In our reactions, a small amount of internal alkene prod-
uct 5Ca was formed via radical alkylation of 1,1-diarylethylene in some
CH-π interaction is also proved by IGM analysis; the green oval rep-
resents the favorable interaction between the highlighted fragments
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Scheme 3. Representative Product Transformations
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
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2
2
2
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3
3
3
3
3
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3
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4
4
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4
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5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Mechanistic Study
(
Figure 3). Therefore, our calculations indicate the importance of
ters with high efficiency as well as excellent chemo- and enantioselec-
hydrogen bonding and ion-pair interactions in the chiral induction, as
well as the non-covalent CH-π interaction that differentiates the enan-
tiomeric C–C bond formations.
tivity. Incorporating a removable/convertible hydroxy group as the
directing group and introducing a sterically demanding chiral phos-
phoric acid jointly favor the desired radical difunctionalization over the
otherwise remarkable side reactions. This method represents a mecha-
nistically distinct approach to enable the rapid asymmetric difunction-
alization of olefins via the intermediacy of a carbocation species
through single-electron oxidation. The obtained products can serve as
practical synthons toward valuable chiral molecular entities in the fields
of pharmaceuticals, agrochemicals and materials. Mechanistic investi-
gations by combined experiments and computations elucidated the
reaction mechanism and origins of enantioselectivity. The key enanti-
■
CONCLUSION
In summary, we have utilized copper(I) and chiral phosphoric acid
cooperative catalysis to develop an asymmetric intermolecular three-
component radical-initiated dicarbofunctionalization of 1,1-
diarylalkenes with a diverse array of carbon-centered radical precursors
and electron-rich heteroaromatics, encompassing a direct intermolecu-
2
lar arene C(sp )–H functionalization. It provides straightforward ac-
cess to chiral triarylmethanes bearing quaternary all-carbon stereocen-
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ASSOCIATED CONTENT
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Supporting Information.
Experimental procedures, characterization, and spectra data.
The Supporting Information is available free of charge via the Internet
at http://pubs.acs.org.
Figure S1, S2 and, experimental procedures and theory (DFT) calcula-
tions, characterization data (PDF)
Crystallographic data for 7G (CIF)
AUTHOR INFORMATION
Corresponding Author
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*
*
liuxy3@sustc.edu.cn (X.-Y.L.)
hxchem@zju.edu.cn (X.H.)
ORCID
Xin-Yuan Liu: 0000-0002-6978-6465
Xin Hong: 0000-0003-4717-2814
Author Contributions
§J.S.L., T.T.L., and J.R.L. contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support from the National Natural Science Foundation of
China (nos 21722203, 21831002, 21602098, 21572096 and
2
1702182), Shenzhen special funds for the development of biomedi-
cine, Internet, new energy, and new material industries
JCYJ20170412152435366, and JCYJ20170307105638498), Shen-
(
zhen Nobel Prize Scientists Laboratory Project (C17213101), the
Chinese “Thousand Youth Talents Plan” (X. H.), “Fundamental Re-
search Funds for the Central Universities” (X. H.), and Zhejiang Uni-
versity (X. H.) is greatly appreciated. Calculations were performed on
the high-performance computing system at the Department of Chem-
istry, Zhejiang University.
Figure 2. Absence of nonlinear effects and mechanistic proposal.
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