Enantioselective Construction of Quaternary All-Carbon Centers via Copper-Catalyzed Arylation of Tertiary Carbon-Centered Radicals

Article abstract of DOI:10.1021/jacs.8b13052

An enantioselective copper-catalyzed arylation of tertiary carbon-centered radicals, leading to quaternary all-carbon stereocenters, has been developed herein. The tertiary carbon-centered radicals, including both benzylic and nonbenzylic radicals, were produced by the addition of trifluoromethyl radical to α-substituted acrylamides, and subsequently captured by chiral aryl copper(II) species to give C-Ar bonds with excellent enantioselectivity. Importantly, an acylamidyl (CONHAr) group adjacent to the tertiary carbon radical is essential for the asymmetric radical coupling. The reaction itself features broad substrate scope, excellent functional group compatibility and mild conditions.

Full text of DOI:10.1021/jacs.8b13052

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Communication
Enantioselective Construction of Quaternary All-Carbon Centers via
Copper-Catalyzed Arylation of Tertiary Carbon-Centered Radicals
Lianqian Wu, Fei Wang, Pinhong Chen, and Guosheng Liu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 22 Jan 2019
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Enantioselective Construction of Quaternary All-Carbon Centers via
Copper-Catalyzed Arylation of Tertiary Carbon-Centered Radicals
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Lianqian Wu, Fei Wang, Pinhong Chen, and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry, Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, China,
2
00032.
Supporting Information
II
was enantioselectively captured by reactive chiral L*Cu -FG
ABSTRACT: An enantioselective copper-catalyzed arylation of
tertiary carbon-centered radicals, leading to quaternary all-carbon
stereocenters, has been developed herein. The tertiary carbon-
centered radicals, including both benzylic and non-benzylic
radicals, were produced by the addition of trifluoromethyl radical
to -substituted acrylamides, and subsequently captured by chiral
aryl copper(II) species to give C-Ar bonds with excellent
enantioselectivity. Importantly, an acylamidyl (CONHAr) group
adjacent to the tertiary carbon radical is essential for the
asymmetric radical coupling. The reaction itself features broad
substrate scope, excellent functional group compatibility and mild
conditions.
species (FG = CN, Ar and alkynyl) to forge enantiomerically
7
,8a,9
enriched C-C bonds (Scheme 1A, left).
Nevertheless, these
asymmetric transformations are limited to the reaction of
secondary benzylic radicals, the enantioselective trapping of non-
benzylic and tertiary carbon-centered radicals is still unsuccessful.
Herein, we communicate an asymmetric copper-catalyzed
trifluoromethyl-arylation of -substituted acrylamides, providing
a straightforward and efficient access to chiral quaternary all-
carbon centers, wherein both benzylic and non-benzylic tertiary
carbon-centered radicals can be enantioselectively trapped by
II
L*Cu Ar species (Scheme 1B).
Owing to the prevalence of optically pure quaternary all-
1
carbon centers in natural products and bioactive compounds, the
catalytic asymmetric synthesis of molecules bearing quaternary
all-carbon stereocenters has been considered as an important goal
2
in modern organic synthesis. Therefore, considerable effort has
been directed toward the straightforward and efficient
construction of the highly congested quaternary all-carbon
stereocenters, such as asymmetric cycloadditions, allylic
2
substitutions, Heck reactions and so on. In the last decades,
radical-based metal-catalyzed cross coupling has been regarded as
3
a powerful tool for the formation of C-C bonds, including
4
coupling reactions of tertiary carbon-centered radicals.
Although the asymmetric coupling of secondary carbon-
centered radicals has been successfully achieved by introducing
3
chiral ligands, the asymmetric coupling of tertiary carbon-
Scheme 1. Asymmetric radical transformations via Cu-catalyzed
radical relay. RA: radical addition, HAT: hydrogen atom transfer.
centered radicals still remains
a formidable challenge in
asymmetric radical transformations (ARTs). Very recently, Fu
and coworkers reported an elegant enantioconvergent coupling of
tertiary electrophiles with olefins for the formation of chiral
quaternary all-carbon centers, which involves the asymmetric
coupling of the tertiary carbon-centered radicals with chiral
Based on our previously reported asymmetric arylation of
7
d
styrenes, we turned our attention to investigating the arylation of
tertiary carbon-centered producing chiral quaternary all-carbon
centers. Unfortunately, the reactions of -methylstyrene failed to
deliver the arylation products (Scheme 1A, right). The reasons
might account for the tertiary benzylic radical (R = Me) as
following: (1) the increased steric repulsion between the bulky
II
5
(Box)Ni -alkyl species.
As part of our continuous research program to develop
6
asymmetric radical transformations (ARTs),
a
series of
II
7
tertiary benzylic radical and chiral (L*)Cu Ar species impedes
enantioselective functionalizations of alkenes and benzylic C-H
8
7a-b,8a
7d-e
7f
their interaction; or (2) the weaker oxidative ability of the tertiary
bonds, such as cyanation,
arylation
and alkynylation ,
II
10
benzylic radical makes the oxidation of (L*)Cu Ar unfavorable.
have been developed via a copper-catalyzed radical relay process.
In these reactions, a benzylic radical (R = H) as a key intermediate
1
1
Inspired by the pioneering study of Peters and Fu, we envisaged
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that introducing a carbonyl group instead of the methyl group in
the tertiary benzylic radical would increase its oxidative ability;
methanol at
0
C was conducted, both the yield and
enantioselectivity were increased (up to 85% yield and 90% ee).
Further copper catalyst screening showed that Cu(OTf)2 could
efficiently catalyze the reaction to afford the product 3d in 93%
yield with 90% ee.
After having established the optimal reaction conditions, the
scope of this asymmetric arylation of the tertiary carbon-centered
radicals was then investigated. As highlighted in Table 2A,
electron-rich aryl boronic acids could be employed as coupling
partners to yield the corresponding products 4-11 with excellent
enantioselectivities (88-95% ee). Notably, compared to p-
CH C H B(OH) (4), the reaction of the o-CH C H B(OH) gave
the product 5 in a lower yield (80% vs 42%) but with a slightly
higher enantioselectivity (90% vs 94% ee), because of a steric
effect. In addition, aryl boronic acids bearing various halides also
worked nicely to deliver the desired products 12-14 in good yields
with excellent enantioselectivities (76-89% yield and 93-97% ee).
Furthermore, aryl boronic acids bearing strong electron-
withdrawing groups on the aromatic ring, which exhibited poor
meanwhile, the carbonyl group potentially coordinates to
II
(
L*)Cu Ar, which could facilitate their interaction. Therefore, the
carbonyl-substituted tertiary carbon-centered radical might be a
good candidate to survey the possibility of the asymmetric
1
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arylation of the tertiary carbon-centered radicals.
On the basis of this hypothesis, several alkenes bearing
various carbonyl groups were chosen to generate tertiary carbon-
centered radicals via CF radical addition, which were tested for
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t
the asymmetric coupling with (L1)Cu Ar (Ar = p- BuC H , from
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4
2
a). As shown in Table 1A, the reaction of ketone 1a or ester 1b
didn't give the desired arylation products; pleasingly, the amides
c and 1d yielded the corresponding arylated products 3c and 3d
3
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2
1
in 40% and 48% yields, respectively, indicating that the
acylamidyl groups did have a remarkable effect on the coupling of
II
the tertiary carbon-centered radical with (L1)Cu Ar species.
Notably, the reaction of 1c gave the product 3c without
enantioselectivity, while the enantioselective control was
observed in the reaction of 1d, albeit giving the product 3d with
7d-e
reactivities in our previous studies, also performed very well to
2
3% ee. Encouraged by these results, a series of bisoxazoline
give the desired products 15-23 in good yields (53-87%) with
excellent enantioselectivities (90-96% ee). Importantly, heteroaryl
boronic acids, such as benzothiophene, pyridine and pyrimidine,
were also suitable for the reaction to deliver the arylation products
24-26 with excellent enantioselectivities (88-96% ee). It is
noteworthy that a wide array of functional groups, such as halide,
ether, thioether, CF , OCF , ketone, cyano, ester, nitro, acetal, and
(Box) ligands were then examined for the reaction of 1d (see
Table 1B and SI). Interestingly, the gem-disubstituted ligands
have a significant effect on the reactivity and enantioselectivity.
For instance, the ligand L2 bearing a gem-cyclopropyl group gave
the product 3d in 35% yield with 8% ee; while the ligand L3 with
gem-dibenzyl groups yielded the product 3d with better
enantioselectivity (45% ee). Further variation of substituents in
the oxazoline moiety revealed that the ligand L4 with benzyl
groups remarkably increased the enantioselectivity of the product
3
3
sulfonyl groups, could be well tolerated under our current reaction
conditions. In addition, our reaction could be performed on a
gram scale, yielding 1.28g of the desired product 12 in 67% yield
without loss of enantioselectivity (93% ee). The absolute
configuration of (S)-12 was unambiguously determined by X-ray
crystallography.
Next, we examined the scope of the alkenes. As revealed in
Table 2B, acrylamides with various aryl groups at the -carbon
position reacted smoothly with aryl boronic acids to provide the
coupling products 27-32 bearing a quaternary all-carbon center
with excellent enantioselectivities (89-98% ee). Moreover, aryl
substituents at the nitrogen atom in acrylamides could also be
variable to provide the corresponding products 33-36 in good
yields with excellent enantioselectivities (87-94% ee). Notably,
similar to the N-arylacryamides, the reaction of N-methyl
acrylamide also proceeded smoothly to give product 37 in good
result (75% yield, 86% ee).
3
d (68% yield and 76% ee). Notably, the gem-dibenzyl groups are
very crucial to the enantioselective induction of the radical
coupling, switching the benzylic groups to an alkyl group
diminished the ee value (e.g., L5 and L6), which might be
12
attributed to a side-arm effect. Interestingly, when the reaction in
As
a challenging issue in our previous studies, the
enantioselectively trapping of non-benzylic radicals by L*Cu(II)-
FG species is not realized. Given that carbon-centered radicals
can be stabilized by the adjoining acylamidyl groups, asymmetric
II
trapping of the non-benzylic radicals by the L*Cu Ar species was
further examined (Table 2C). Excitingly, the reaction of N-
phenyl--methylacryamide with ortho-fluorophenyl boronic acid
under the optimized conditions proceeded smoothly to afford the
arylated product 38 in 71% yield with 92% ee; in addition,
various aryl boronic acids bearing electron-withdrawing
substituents, such as halides and carboxylic esters, proved to be
good coupling partners to give the products 39-43 in satisfied
yields with excellent enantioselectivities (86-93% ee). In
comparison, the reaction of electron-rich aryl boronic acid, such
t
as p- BuC H B(OH) , exhibited moderate reactivity to provide the
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desired product 44 in 49% yield, but with a slightly lower
enantioselectivity (81% ee). Moreover, reactions of acrylamides
bearing different alkyl groups at the α-position proceeded
smoothly to yield the corresponding products 45-49 in moderate
to good yields with excellent enantioselectivities (83-93% ee).
Notably, acrylamides bearing the alcohol moiety were suitable for
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the reaction to give the desired product 47 with 93% ee, albeit in a
activation of the amidyl group and LiAlH4 reduction of 4
delivered the chiral β,β-diaryl alcohol 52 in 59% yield. In addition,
the direct reduction of 12 by BH •Me S yielded the -CF -β,β-
diaryl propylamine 53 in 80% yield. Moreover, nucleophilic
aromatic amination of 14 furnished the optically pure CF -
3
modest yield (44%). It was worthy noting that, the reactions were
limited to the terminal alkenes, and -substituted internal alkene
exhibited low efficiency. Moreover, when substrate without
3
2
3
i
substituent or bearing a steric bulky alkyl group (e.g. Pr) at the -
position, the reaction also exhibited poor or no reactivity to yield
the desired products (50 or 51).
To showcase the utility of our method, further transformations
of the arylation products were investigated (Scheme 2). Sequential
containing oxindole 54 in 59% yield. Finally, removing the p-
methoxyphenyl group in amide 33 by CAN afforded the free
amide 55 in 51% yield. Notably, no obvious erosion of
enantiomeric excess was observed in these transformations.
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To gain more insight into the plausible radical mechanism, a
radical scavenger CBr was subjected to the standard reaction of
4
1
d; the arylation was completely inhibited, but the bromination
product 56 was obtained in 80% yield (Scheme 3A), indicating
the involvement of benzylic radicals. In addition, the reaction of
ketone 1a or ester 1b didn't provide any arylation products
(Scheme 3B). For the case 1a, although the benzylic radical int-I
II
couldn't be trapped by (L4)Cu Ar, its mesomer int-II reacted
100
80
60
40
20
0
3
d from 1d
II
3c from 1c
with (L4)Cu Ar smoothly to yield the coupling product 3a' in
8
7% yield via the reductive elimination of Cu(III) species int-III
1
3a-b
(Scheme 3B and 3C).
The benzylic radical generated from 1b
II
couldn't react with (L4)Cu Ar either, but only the self-coupling
product 3b' was detected (Scheme 3B). In comparison, the
benzylic radicals adjacent to an amidyl group (e.g., generated
from 1c or 1d) could be trapped by (L4)Cu Ar to give the
arylation products 3c or 3d,
II
0
10 20 30 40 50 60 70
13b-d
and the reaction rate of 1d was
faster than that of 1c (Scheme 3D, left). We reasoned that, owing
Scheme 3. Mechanistic studies, and all the reactions in part B
were conducted at room temperature with Cu(OTf) /L4 as catalyst.
1
4
to the preferred geometry of cis-1c and trans-1d, the resultant
benzylic radical int-IV produced from cis-1c is more sterically
bulky than int-V generated from trans-1d (Scheme 3D, right). On
the other hand, the slow reaction of the benzylic radical int-IV
2
Supporting Information
Synthetic procedures, characterization, mechanistic study data,
and additional data. This material is available free of charge via
the Internet at http://pubs.acs.org.
II
with (L4)Cu Ar species could allow 5-exo-trig cyclization of int-
1
5
IV to give a small amount of the side product 3c'; while the 5-
exo-trig cyclization did not occur in the reaction of 1d, because of
the trans configuration of int-V. The product 3d was generated
with higher enantioselectivity than 3c (80% ee vs 50% ee),
revealing that the CONH moiety played a key role in the
enantioselective trapping step, but the detailed mechanism is still
Corresponding Author
gliu@mail.sioc.ac.cn
ACKNOWLEDGMENT
1
6
unclear at the moment.
In summary,
We are grateful for financial support from the National Basic
Research Program of China (973-2015CB856600), the National
Nature Science Foundation of China (NFSC, Nos. 21532009,
21761142010, 21790330 and 21821002), the Science and
Technology Commission of Shanghai Municipality (Nos.
the
first
asymmetric
Cu-catalyzed
trifluoromethylarylation of α-substituted acrylamides has been
developed, where an enantioselective coupling of tertiary carbon-
II
centered radicals with (L4)Cu Ar acts as a key step to construct a
quaternary all-carbon stereocenter. Further exploration of the
mechanistic details and new asymmetric radical transformations
based on the acylamide-substituted tertiary carbon-centered
radicals are in progress in our laboratory.
1
7QA1405200, 17XD1404500 and 17JC1401200), and the
strategic Priority Research Program (No. XDB20000000) and the
Key Research Program of Frontier Science (QYZDJSSWSLH055)
of the Chinese Academy of Sciences.
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3
species to generate quaternary C-N bond, see: (b) Kainz, Q. M.; Matier, C.
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. Wang, F.; Chen, P.; Liu, G. Copper-Catalyzed Radical Relay for
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3 4 6
15. When Cu(CH CN) PF was used as catalyst, the reaction of 1c
provided the arylation product 3c in 13% yield (49% ee) and the radical
cyclization product 3c' in 28% yield. For details, see the SI.
8
. For the asymmetric benzylic C-H cyanation, see: (a) Zhang, W.; Wang,
F.; McCann, S. D.; Wang, D.; Chen, P.; Stahl, S. S.; Liu, G.
Enantioselective Cyanation of Benzylic C-H Bonds via Copper-Catalyzed
Radical Relay. Science 2016, 353, 1014. For the benzylic C-H arylation,
see: (b) Zhang, W.; Chen, P.; Liu, G. Copper-Catalyzed Arylation of
Benzylic C-H bonds with Alkylarenes as the Limiting Reagents. J. Am.
Chem. Soc. 2017, 139, 7709. (c) Vasilopoulos, A.; Zultanski, S. L.; Stahl,
S. S. Feedstocks to Pharmacophores: Cu-Catalyzed Oxidative Arylation of
16. We assumed that the CONH moiety in acrylamides would facilitate
II
the interaction of the tertiary carbon-centered radicals with (L4)Cu Ar
and enhance the enantioselectivity, which might involve the bonding of an
oxygen of carbonyl or a nitrogen atom of amides to copper, but the
detailed mechanism is unknown.
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