Nickel/Photoredox-Catalyzed Asymmetric Reductive Cross-Coupling of Racemic α-Chloro Esters with Aryl Iodides

Article abstract of DOI:10.1002/anie.201914175

A unique nickel/organic photoredox co-catalyzed asymmetric reductive cross-coupling between α-chloro esters and aryl iodides is developed. This cross-electrophile coupling reaction employs an organic reductant (Hantzsch ester), whereas most reductive cross-coupling reactions use stoichiometric metals. A diverse array of valuable α-aryl esters is formed under these conditions with high enantioselectivities (up to 94 %) and good yields (up to 88 %). α-Aryl esters represent an important family of nonsteroidal anti-inflammatory drugs. This novel synergistic strategy expands the scope of Ni-catalyzed reductive asymmetric cross-coupling reactions.

Full text of DOI:10.1002/anie.201914175

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Nickel/Photoredox-Catalyzed Asymmetric Reductive Cross-
Coupling of Racemic a-Chloro Esters with Aryl Iodides
Authors: Patrick Joseph Walsh, Haixing Guan, Qianwen Zhang, and
Jianyou Mao
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201914175
Angew. Chem. 10.1002/ange.201914175
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10.1002/anie.201914175
Angewandte Chemie International Edition
RESEARCH ARTICLE
Nickel/Photoredox-Catalyzed Asymmetric Reductive Cross-
a
Coupling of Racemic -Chloro Esters with Aryl Iodides
Haixing Guan, [a] Qianwen Zhang, [a] Patrick J. Walsh*[b] and Jianyou Mao*[a]
Dedicated to our colleague Prof. Gary A. Molander on the occasion
of his 67th birthday.
homo-coupling of aryl halides to make symmetrical biaryls
(Scheme 1C). Inspired by this advance, Weix’s team
demonstrated that TDAE could supply electrons for cross-
electrophile coupling reactions,[10] and Reisman’s group reported
an enantioselective coupling of N-hydroxyphthalimide esters
with vinyl bromides.[7f] Other organic reducing agents recently
used include amines, Hantzsch ester (HEH) and (Et3Si)3Si–H.[11]
Abstract:
A
unique nickel/organic photoredox co-catalyzed
asymmetric reductive cross-coupling between a-chloro esters and
aryl iodides is advanced. This cross-electrophile coupling reaction
employs an organic reductant (Hantzsch ester), whereas most
reductive cross-coupling reactions use stoichiometric metals. A
diverse array of valuable a-aryl esters is formed under these
conditions with high enantioselectivities (up to 94%) and good yields
(up to 88%). a-Aryl esters represent an important family of
nonsteroidal anti-inflammatory drugs. This novel synergistic strategy
expands the scope of Ni-catalyzed reductive asymmetric cross-
coupling reactions.
A. Traditional enantioselective cross-couplings
Ni, Co or Fe Cat.
Alkyl
FG
Alkyl
FG
M
Ar
+
X
Ar
X = Cl, Br
M = ZnX, MgX, B(OR)2, SiR3
FG = carbonyl, sulfonamide, aryl, alkyl, alkenyl, alkynyl etc.
B. Enantioselective reductive cross-coupling
Ni Cat.
Alkyl
FG
Alkyl
FG
+
R
X
+ M
Introduction
X
R
X = Cl, H
X = Br, I M = Mn, Zn
The catalytic enantioselective construction of C−C bonds
remains one of the foremost challenges in organic synthesis.[1]
FG = carbonyl, OR, NR2, CN, aryl etc.
Two
general
approaches
to
transition-metal-catalyzed
C. Homo-coupling with organic reductant, (Me2N)2C=C(NMe2)2 (Tanaka)
asymmetric C(sp2)−C(sp3) bond-forming reactions have been
developed. The first class is the conventional transition metal-
catalyzed enantioselective cross-coupling reactions, such as the
Kumada[2], Negishi[3], Suzuki−Miyaura[4], and Hiyama,[5] primarily
driven by Fu and co-workers (Scheme 1A).
Me2N
NMe2
Pd cat.
DMF
+
Ar–Br
Ar Ar
Me2N
NMe2
TDAE
D. Enantioselective coupling with an organic reductant
O
Ni cat.
O
Alkyl
Alkyl
The second class of enantioselective coupling reactions involves
reductive cross-couplings, which couple two electrophiles using
stoichiometric reductants to turn over the catalysts. The
advantage of this latter approach is that it avoids the synthesis
of reactive and air-sensitive organometallic cross-coupling
partners. To date, an array of reductive cross-coupling reactions
has been described, mostly using stoichiometric metal reducing
agents.[6] More recently, elegant asymmetric reductive cross-
coupling processes have been disclosed using manganese[7] or
zinc[8] as the terminal reductant (Scheme 1B). These reactions,
however, are complicated by the need to dispose of the
stoichiometric metal waste. A complementary approach to metal
promoted reductive coupling reactions employs organic reducing
agents. A pioneering study by Tanaka and coworkers[9] with
tetrakis(dimethylamino)ethylene (TDAE) as reductant led to the
+
I
HEH
+
Ar
OR
OR
Organic
photoredox
cat.
Ar
Cl
Scheme 1. Transition-Metal-Catalyzed Asymmetric Coupling Reaction
To develop cross-electrophile coupling reactions with organic
reducing agents we turned to photoredox methods.[12] Dual
photoredox/transition metal catalysis has gained traction in
enantioselective construction of C−C bonds,[13] however, we are
unaware of its use in enantioselective dual catalysis cross-
electrophile coupling reactions. Herein, we employ an organic
photoredox catalyst with Hantzsch ester (HEH) as the terminal
organic reductant to realize the nickel catalyzed asymmetric
reductive cross-coupling of a-chloro esters with aryl iodides to
furnish a-aryl esters (Scheme 1D). This method represents an
advance over prior methods that employed prefunctionalized
aryl coupling partners (organosilane, Grignard or organozinc
reagents),[14] or preformed enolates.[15] It is also an alternative
strategy for the enantioselective formation of C(sp2)−C(sp3)
bonds to the use of stoichiometric metal as reductant. The a-
aryl esters prepared herein belong to an important class of
nonsteroidal anti-inflammatory drugs (NSAIDs).[16]
[a]
[b]
H. Guan, Q. Zhang, Prof. Dr. J. Mao
Institute of Advanced Synthesis, School of Chemistry and Molecular
Engineering, Nanjing Tech University, 30 South Puzhu Road,
Nanjing 211816 (P.R. China)
E-mail: ias_jymao@njtech.edu.cn
Prof. Dr. P. J. Walsh
Roy and Diana Vagelos Laboratories, Department of Chemistry,
University of Pennsylvania, 231 South 34th Street, Philadelphia, PA
19104, USA
E-mail: pwalsh@sas.upenn.edu
Results and Discussion
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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10.1002/anie.201914175
Angewandte Chemie International Edition
RESEARCH ARTICLE
We began our investigation into the reductive coupling between
a-chloro ester (1a) and iodobenzene (2a) (for a systematic study
of reaction conditions screened see Table S1 in the Supporting
Information). Initially, the racemic reaction was optimized using
a-chloro ester (1a) with iodobenzene (2a), Ni(COD)2 (10 mol%,
COD = 1,5-cyclooctadiene), 4,4'-dimethoxy-2,2'-bipyridine (11
mol%), [Ir(ppy)2(dtb-bipy)]+[PF6]– (10 mol%), and Cy2NMe as the
reducing agent and irradiation with blue LEDs, giving 82% AY
(Table S1). These conditions, however, did not translate well
with enantioenriched ligands, so the system was reoptimized.
The reoptimized conditions for the racemic coupling of a-chloro
ester (1a) with iodobenzene (2a) involved irradiation with blue
LEDs of an N,N-dimethylacetamide (DMA) solution of Ni(COD)2
(10 mol%), bipyridine (Bipy, 11 mol%), Hantzsch ester (3 equiv),
Table 1. Optimization of reaction conditions.[a]
Entry
1a:2a
Ligand
R
AY (%)[b]
85
23
21
21
ee (%)[c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[e]
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:3
1:3
1:3
1:1
1:2
1:3
1:3
Bipy
L1
L2
L3
L4
L5
L6
L6
L6
L6
L6
L6
L6
L6
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
--
22
68
24
64
5
74
75
79
80
90
90
90
90
25
35
24
76[d]
82[d]
85[d]
50
photoredox
catalyst
(4CzIPN,
1,2,3,5-tetrakis(carbazol-9-yl)-4,6-
10 mol%) and N,N-
equiv) at room
Et
t-Bu
dicyanobenzene
dicyclohexylmethylamine (Cy2NMe,
3
2,3,3-trimethylbut-2-yl
2,3,3-trimethylbut-2-yl
2,3,3-trimethylbut-2-yl
2,3,3-trimethylbut-2-yl
65
temperature for 48 h. Under these conditions, the assay yield
(AY) for the racemic product 3a was 85% (Table 1, entry 1,
determined by GC using tetradecane as an internal standard).
We next initiated a search for an enantioselective catalyst.
Several chiral ligands such as bioxazolines[7a, 7f, 17] including L6
and phosphino-oxazoline ligands[7c], have emerged as generally
useful ligand for asymmetric cross electrophile coupling
reactions. Based on these prior studies, we tested several
classes of enantioenriched ligands (see Supporting Information
for details), and found that the bioxazoline (BiOX) framework
was also promising in our reaction. With R = n-Pr, the product
was obtained in 22% ee and 23% AY (entry 2). Bulkier ligands
with R = i-Pr (L2, 21% AY, 68% ee, entry 3) and i-Bu (L3, 21%
AY, 24% ee, entry 4) indicated that a secondary alkyl group was
better than a primary one. L4 and L5, containing sec-Bu and t-
Bu groups, provided product in 25% AY and 64% ee and 35%
AY with only 5% ee, respectively (entries 5–6). These results
inspired the synthesis of the known 4-heptyl substituted ligand
L6,[7e, 7g] which gave 74% ee (24% AY, entry 7).
Inspired by the work of Nakamura,[2c] we next opted to modify
the ester OR group. Continuing with L6, we examined OR =
OMe or OEt. The enantioselectivities were 75 and 79%,
respectively (entries 8 and 9). The t-Bu ester only resulted in a
small increase to 80% ee (entry 10). In contrast, increasing the
steric bulk of the ester OR substituent to 2,3,3-trimethylbut-2-yl,
the product was produced with 90% ee (entry 11), albeit in 50%
AY. We next turned our attention to improving the yield of 3a. By
increasing the ratio of 1a to 2a from 1:1 to 1:2 and 1:3, the AY
increased to 82% (entries 11–13). Ultimately the product 3a
was isolated by column chromatography in 77% yield. Control
experiments confirmed that little product was formed in the
absence of Ni precursor, L6, blue LEDs, Cy2NMe or 4CzIPN.
HEH was crucial for high yields, as only 21% yield of 3a was
detected without HEH (entry 14). In this control experiment,
however, the enantioselectivity remained 90%, suggesting that
the HEH is not involved in the enantiodetermining step, but is
essential for catalyst turnover.
82(77[d]
21
)
[a] Reactions conducted under Ar on 0.1 mmol scale for 48 h. [b] Determined
by GC using tetradecane as an internal standard. [c] Determined by chiral
HPLC on a CHIRALPAK IC−3 column. [d] Isolated yield. [e] No HEH.
With the optimized reaction conditions in hand, we next focused
on the scope of the aryl iodide coupling partners using a-chloro
ester 2a (Scheme 2). Aryl iodides with alkyl groups in the 4-
position (Me, t-Bu) and 3-position (Me) all exhibited 90% ee and
good yields (69–75%, 3b, 3c, 3n). The (S) configuration of 3a
was assigned by comparison of the optical rotation with the
literature value while the (S) configuration of 3c was confirmed
by reduction to the alcohol and comparison of its HPLC retention
time on the chiral column with the literature values (see
Supporting Information for details). Sterically hindered 2-iodo
toluene resulted in slightly diminished ee (86%, 58% yield).
Iodobenzenes substituted by electron-donating (4-NMe2, 4-OMe)
were formed in 84–86% ee with 52–72% yields (3d–3e). Aryl
iodides with electronegative or electron withdrawing groups (4-F,
4-CF3, 4-Cl, 3-Cl, 4-Ac, 4-CO2Et, 4-CN, 3-OPh) exhibited high
enantioselectivities (86–91%). It is noteworthy that the boronate
ester was also well-tolerated, affording the product 3m in 75%
yield with 90% ee. 4-Iodo biphenyl derivatives were fine
substrates, furnishing the products 3r and 3s with 88–89% ee
and 85–86% yield. Likewise, 1-(4-iodophenyl)-1H-pyrrole and 2-
iodo-9H-fluorene underwent coupling in 73–75% yield with
enantioselectivities of 88–89%. Aryl iodides with extended π-
systems,
such
as
those
derived
from
2-iodo-6-
methyoxynaphthylene and 1-iodonaphthylene provided products
3v (52% yield, 87% ee) and 3w (49% yield, 69% ee).
Heterocycles are important structural motifs in medicinal
chemistry. Several heteroaryl iodides were, therefore, examined.
5-Iodo-1-methyl indole, 2-fluoro-5-iodopyridine, 3-iodo thiophene
and 3-iodobenzofuran all exhibited good enantioselectivities
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10.1002/anie.201914175
Angewandte Chemie International Edition
RESEARCH ARTICLE
(84–89%), with yields ranging from 47–60%. For a method to be
useful, it must be practical and scalable. When the reaction was
conducted on 1.0 mmol, 3r was produced in 88% yield with 89%
ee. After isolation by column chromatography, 4CzIPN can be
reused without any change in activity (for at least two cycles).
bearing aryl substituents (4f–4i) were also tolerated and the
corresponding coupling products were isolated in 58–83% yield
with enantioselectivities of 87–89%. Although a β-OMe did not
impact the reaction yield (85%), diminished enantioselectivity
was observed (54%). When the methoxy group was located at
the δ-position, however, it did not negatively impact the
enantioselectivity (90% ee, 73% yield). It should be noted that
only traces of product 4l was obtained, with most of the starting
ester recovered as dechlorination byproduct 4l’ (65%, see
Supporting Information for details).
Scheme 2. Scope of aryl and (hetero)aryl iodides.[a]
Ni(COD)2 (10 mol%)
L6 (11 mol%)
4CzIPN (10 mol%)
O
O
Ar
I
+
OR
OR
HEH (3.0 equiv.)
Cy2NMe (3.0 equiv.)
DMA (0.2 M), RT
blue light, 48 h
Scheme 3. Scope of α-chloro esters.[a]
Cl
Ar
(rac)-1a
2
3
R = 2,3,3-trimethylbut-2-yl 3.0 equiv.
Ni(COD)2 (10 mol%)
L6 (11 mol%)
4CzIPN (10 mol%)
O
O
O
O
O
Alkyl
Alkyl
+
Ph I
OR
OR
HEH (3.0 equiv.)
Cy2NMe (3.0 equiv.)
DMA (0.2 M), RT
blue light, 48 h
OR
OR
OR
Ph
Cl
(rac)-1
2a
4
R = 2,3,3-trimethylbut-2-yl 3.0 equiv.
R'
R'
R' = Me, 3n[b], 70%, 90% ee
= OPh, 3o, 71%, 90% ee
= Cl, 3p, 73%, 90% ee
R' = H
= Me
3a, 77%, 90% ee
3q, 58%, 86% ee
O
O
O
3b, 75%, 90% ee
= t-Bu 3c, 69%, 90% ee
= NMe2 3d[b], 72%, 84% ee
= OMe 3e[b], 52%, 86% ee
= OCF3 3f[b], 72%, 86% ee
OR
Ph
OR
Ph
OR
O
O
Ph
OR
OR
4a, 82%, 93% ee
4b, 81%, 93% ee
4c, 79%, 94% ee
= F
3g, 72%, 90% ee
3h, 69%, 87% ee
3i[c], 70%, 86% ee
3j, 70%, 90% ee
= CF3
= Cl
= Ac
O
O
O
F
OR
Ph
OR
OR
Ph
= CO2Et 3k, 72%, 91% ee
= CN 3l, 73%, 89% ee
Ph
Ph
= Bpin 3m, 75%, 90% ee
4e, 77%, 91% ee
4f, 72%, 89% ee
4d, 80%, 93% ee
3r, 86%, 89% ee
88%, 89% ee[d]
3s, 85%, 88% ee
O
O
O
O
O
O
Bn
OR
OR
OR
OR
Ph
Ph
OR
Ph
4i, 71%, 87% ee
O
O
OR
F3C
F
OR
4g, 58%, 89% ee
4h, 83%, 87% ee
O
O
N
OR
O
OR
OR
O
OMe
Ph
Me Ph
Ph
Me
3w, 49%, 69% ee
3t, 73%, 88% ee
3v, 52%, 87% ee
3u, 75%, 89% ee
O
O
4l, trace
4j, 85%, 54% ee
4k, 73%, 90% ee
O
O
OR
OR
OR
[a] All reactions conducted under Ar on 0.1 mmol scale. Yield is that of the
OR
isolated product. The ee values were determined by chiral-phase HPLC.
N
F
O
S
N
To gain insight into the mechanism of this reductive cross-
coupling reaction, additional experiments were performed. Both
the HEH and tertiary amines are known to behave as sacrificial
reducing agents. Therefore, we set out to understand the role of
these reagents in the reductive arylation. Conducting the
reaction of 1a and 2a under the standard conditions with 3 equiv
HEH and 3 equiv Cy2NMe (Scheme 4A), the product 3a was
isolated in 77% yield with 90% ee. The fate of the HEH was the
expected pyridine (isolated in 100% yield relative to HEH),
derived from donation of 2 electrons and two protons. The
Cy2NMe largely acted as a base in the reaction, as determined
by the isolation of 55% of the total Cy2NMe as Cy2NMe•HX (6,
see supporting information for details).[17] Only about 5% of the
demethylated product, Cy2NH, was detected after workup. The
demethylated amine likely arises from oxidation of the amine by
Me
3x, 60%, 89% ee 3y, 60%, 88% ee 3z, 47%, 84% ee
3za, 52%, 89% ee
[a] All reactions conducted under Ar on 0.1 mmol scale. Yield is that of the
isolated product. The ee values were determined by chiral-phase HPLC. [b]
The reactions were run for 96 h. [c] The reactions were run for 72 h. [d]
Conducted on 1.0 mmol scale.
We next examined the scope of the a-alkyl group of the a-chloro
esters (Scheme 3). We were please to find that not only primary
alkyl groups, such as Et (4a), n-Bu (4b) and i-Bu (4c), but also
secondary alkyl groups, including isopropyl (4d) and cyclopentyl
(4e), exhibited good yields (77–82%) and excellent
enantioselectivities (91–94%). In prior publications, secondary
alkyl esters either gave low enantioselectivities or were not
included among the reported substrates.[2b,
2c, 5a]
Alkyl groups
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10.1002/anie.201914175
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RESEARCH ARTICLE
*4CzIPN to the amine radical cation, loss of H• to generate the
iminium ion, and hydrolysis by advantageous water during the
reaction or upon workup.[18] These results indicate that HEH is
the terminal reductant for the reaction.
asymmetric reductive cross-coupling appears reasonable
(Figure 1). The (BiOX)Ni(0) species oxidatively adds the aryl
iodide (2) to give the (BiOX)Ni(Ar)I complex.[6c] Next, the a-
chloro ester (1) is reduced by SET to the a-carbonyl radical.
There are three possibilities for this reduction. Based on
Scheme 4B reduction could take place from Ni(0) (Figure 1) or
Ni(I) (Figure S1A in the Supporting Information). Alternatively,
the reduced photocatalyst 4CzIPN•− may be responsible for the
reduction (as described above[20]). The a-carbonyl radical
species is quickly trapped by (BiOX)Ni(Ar)I to generate the
reactive Ni(III) species. The resulting Ni(III) complex[22] then
undergoes rapid reductive elimination to form the C(sp2)−C(sp3)
bond of 3a. After excitation of 4CzIPN by blue light, the long
lived photoexcited state *4CzIPN (τ = 5.1 ± 0.5 μs) can be
reduced by HEH to give 4CzIPN•− (E1/2red = −1.21 V vs SCE).[23]
The LnNi(0) species could be regenerated by SET [E1/2red
(NiII/Ni0) = −1.2 V vs SCE] from 4CzIPN•−.[21a]
In addition to the role of the Ni catalyst in cleavage of the Ar–I
bond through oxidative addition, we considered the possibility
that Ni could act as a catalytic reductant[19] toward the a-chloro
ester. Stoichiometric studies with 1.0 equiv Ni(COD)2 and 1.1
equiv L6 under blue light irradiation and in the absence of HEH
and Cy2NMe, established that 1a reacted with 2a to form cross-
coupled product 3a (68% yield, 90% ee) (Scheme 4B). Likewise,
when this reaction was conducted without irradiation, cross-
coupled product 3a (66% yield, 90% ee) (Scheme 4B). It is
noteworthy that the ee of these stoichiometric reactions are
identical to that observed under the standard catalytic conditions
(Table 1, entry 13). This observation suggests that the
enantiodetermining step in the catalytic and stoichiometric
reactions (Scheme 4B) are identical, and do not involve the HEH
or Cy2NMe.
It is interesting to note that organic photoredox catalysts are also
reported to reduce a-halo esters to dehalogenated esters in the
presence of HEH as the hydrogen atom donor.[20] We performed
the model reaction without Ni/L6 and iodobenzene (Scheme 4C).
The dehalogenated product (8) can be obtained in 84% AY. In
this experiment it is proposed that the photoredox catalyst
undergoes SET to the a-halo carbonyl compounds to generate
a-carbonyl radicals. Abstraction of H• from HEH by a-carbonyl
radicals generates the dehalogenated products. Given that our
system also proceeds via an a-carbonyl radical, it must be that
the a-carbonyl radicals undergo addition to L*Ni(Ar)I faster than
HAT from HEH.
II
EtOOC
1/2
COOEt
4CzIPN
I
LnNi
Ar-I
Ar
N
O
– e–, H
SET
LnNi0
OR
1/2 HEH
4CzIPN
_ Cl
SET
4CzIPN*
hv
O
SET
OR
III Ar
1a
LnNi
I
4CzIPN
4CzIPN
I
LnNi I
Ln = BiOX
3a
EtO2C
CO2Et
A.
Figure 1. Plausible catalytic reaction pathway.
3.0 equiv
EtO2C
CO2Et
O
N
H
N
O
O
10 mol% 4CzIPN
10 mol% Ni(COD)2
Ph
+
Ph–I
Conclusion
O
3a
77%, 90% ee
5
100%
11 mol% L6
Cy2NMe (3 equiv)
Cl
+
+
Cy2NMeH
–
Cy2NH
1a
2a
X
In summary, we have developed the first enantioselective dual
nickel and organic photoredox catalyzed reductive cross-
coupling between a-chloro esters and aryl iodides to afford α-
aryl esters. Enantioenriched a-aryl ester derivatives are
important precursors to nonsteroidal anti-inflammatory
medications. Key features and advantages of this method
include broad scope in both coupling partners, avoidance of
preformed organometallic reagents, and circumvention of
stoichiometric metal reductants used in most cross-electrophile
coupling reactions. Future directions include the use of
6
conv. 55%
7
GC yield: 5%
B.
1.0 equiv Ni(COD)2
1.1 equiv L6
O
O
+
Ph–I
2a
O
O
DMA (0.2 M), RT
Ph
Cl
3a
under blue light: 68%, 90% ee
In the dark: 66%, 90% ee
1a
C.
10 mol% 4CzIPN
3.0 equiv HEH
3.0 equiv Cy2NMe
O
O
O
H
O
DMA (0.2 M), RT
blue light
electrochemical methods as
a
source of electrons for
Cl
8
GC yield: 84%
1a
enantioselective reductive coupling reactions.[24]
Scheme 4. Mechanistic experiments.
Acknowledgements
Based on the mechanistic experiments above, and related
studies in the literature,[21] a dual catalytic process for the
The authors acknowledge the National Natural Science
Foundation of China (21801128 to J.M.), Natural Science
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10.1002/anie.201914175
Angewandte Chemie International Edition
RESEARCH ARTICLE
Angew. Chem., Int. Ed. 2017, 56, 13426-13430; c) T. Q. Chen, D.
W. C. MacMillan, Angew. Chem., Int. Ed. 2019, 58, 14584–14588;
d) J. Yi, S. O. Badir, L. M. Kammer, M. Ribagorda, G. A. Molander,
Org. Lett. 2019, 21, 3346-3351.
a) K. L. Skubi, T. R. Blum, T. P. Yoon, Chem. Rev. 2016, 116,
10035-10074; b) J. C. Tellis, C. B. Kelly, D. N. Primer, M. Jouffroy,
N. R. Patel, G. A. Molander, Acc. Chem. Res. 2016, 49, 1429-
1439; c) J. Twilton, C. Le, P. Zhang, M. H. Shaw, R. W. Evans, D.
W. C. MacMillan, Nat. Rev. Chem. 2017, 1, 0052.
a) J. C. Tellis, D. N. Primer, G. A. Molander, Science 2014, 345,
433-436; b) O. Gutierrez, J. C. Tellis, D. N. Primer, G. A. Molander,
M. C. Kozlowski, J. Am. Chem. Soc. 2015, 137, 4896-4899; c) Z.
Zuo, H. Cong, W. Li, J. Choi, G. C. Fu, D. W. C. MacMillan, J. Am.
Chem. Soc. 2016, 138, 1832-1835; d) N. A. Romero, D. A.
Nicewicz, Chem. Rev. 2016, 116, 10075-10166; e) W. Ding, L.-Q.
Lu, Q.-Q. Zhou, Y. Wei, J.-R. Chen, W.-J. Xiao, J. Am. Chem. Soc.
2017, 139, 63-66; f) H.-H. Zhang, J.-J. Zhao, S. Yu, J. Am. Chem.
Soc. 2018, 140, 16914-16919; g) F.-D. Lu, D. Liu, L. Zhu, L.-Q. Lu,
Q. Yang, Q.-Q. Zhou, Y. Wei, Y. Lan, W.-J. Xiao, J. Am. Chem.
Soc. 2019, 141, 6167-6172.
a) J. Mao, F. Liu, M. Wang, L. Wu, B. Zheng, S. Liu, J. Zhong, Q.
Bian, P. J. Walsh, J. Am. Chem. Soc. 2014, 136, 17662-17668; b)
F. Liu, J. Zhong, Y. Zhou, Z. Gao, P. J. Walsh, X. Wang, S. Ma, S.
Hou, S. Liu, M. Wang, M. Wang, Q. Bian, Chem. Eur. J. 2018, 24,
2059 – 2064; c) X. Dai, N. A. Strotman, G. C. Fu, J. Am. Chem.
Soc. 2008, 130, 3302-3303.
Foundation of Jiangsu Province, China (BK20170965 to J.M)
and Nanjing Tech University (3980001601 and 39837112) for
financial support. PJW thanks the Petroleum Research Fund
(59570-ND1) and US National Science Foundation (CHE-
1902509).
[12]
[13]
Keywords: asymmetric reductive a-arylation
• cooperative
catalysis • nickel • organic photosensitizer • carboxylic acids
[1]
[2]
a) E. C. Swift, E. R. Jarvo, Tetrahedron 2013, 69, 5799-5817; b) A.
H. Cherney, N. T. Kadunce, S. E. Reisman, Chem. Rev. 2015, 115,
9587-9652; c) F. Wang, P. Chen, G. Liu, Acc. Chem. Res. 2018,
51, 2036-2046.
a) S. Lou, G. C. Fu, J. Am. Chem. Soc. 2010, 132, 1264-1266; b) J.
Mao, F. Liu, M. Wang, L. Wu, B. Zheng, S. Liu, J. Zhong, Q. Bian,
P. J. Walsh, J. Am. Chem. Soc. 2014, 136, 17662-17668; c) M. Jin,
L. Adak, M. Nakamura, J. Am. Chem. Soc. 2015, 137, 7128-7134;
d) M. S. Eno, A. Lu, J. P. Morken, J. Am. Chem. Soc. 2016, 138,
7824-7827.
[14]
[3]
[4]
a) C. Fischer, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 4594-4595;
b) J. T. Binder, C. J. Cordier, G. C. Fu, J. Am. Chem. Soc. 2012,
134, 17003-17006; c) H.-Q. Do, E. R. R. Chandrashekar, G. C. Fu,
J. Am. Chem. Soc. 2013, 135, 16288-16291; d) Y. Liang, G. C. Fu,
J. Am. Chem. Soc. 2014, 136, 5520-5524; e) Y. Liang, G. C. Fu, J.
Am. Chem. Soc. 2015, 137, 9523-9526; f) J. Schmidt, J. Choi, A. T.
Liu, M. Slusarczyk, G. C. Fu, Science 2016, 354, 1265-1269.
a) M. C. Willis, L. H. W. Powell, C. K. Claverie, S. J. Watson,
Angew. Chem., Int. Ed. 2004, 43, 1249-1251; b) B. Saito, G. C. Fu,
J. Am. Chem. Soc. 2008, 130, 6694-6695; c) P. M. Lundin, G. C.
Fu, J. Am. Chem. Soc. 2010, 132, 11027-11029; d) A. S. Dudnik,
G. C. Fu, J. Am. Chem. Soc. 2012, 134, 10693-10697; e) H. Cong,
G. C. Fu, J. Am. Chem. Soc. 2014, 136, 3788-3791; f) G. Xu, W.
Fu, G. Liu, C. H. Senanayake, W. Tang, J. Am. Chem. Soc. 2014,
136, 570-573; g) X. Jiang, M. Gandelman, J. Am. Chem. Soc.
2015, 137, 2542-2547; h) P. Schafer, T. Palacin, M. Sidera, S. P.
Fletcher, Nat. Commun. 2017, 8, 15762pp.
[15]
[16]
Z. Huang, Z. Liu, J. Zhou, J. Am. Chem. Soc. 2011, 133, 15882-
15885.
a) M. F. Landoni, A. Soraci, Curr. Drug Metab. 2001, 2, 37-51; b) H.
Dhall, A. Kumar, A. K. Mishra, Curr. Bioact. Compds. 2018, 14, 26-
32.
R. Wang, M. Ma, X. Gong, G. B. Panetti, X. Fan, P. J. Walsh, Org.
Lett. 2018, 20, 2433-2436.
a) L.-L. Liao, G.-M. Cao, J.-H. Ye, G.-Q. Sun, W.-J. Zhou, Y.-Y.
Gui, S.-S. Yan, G. Shen, D.-G. Yu, J. Am. Chem. Soc. 2018, 140,
17338-17342; b) X. Fan, X. Gong, M. Ma, R. Wang, P. Walsh, J.,
Nat. Commun. 2018, 9, 4936.
a) S. Biswas, D. J. Weix, J. Am. Chem. Soc. 2013, 135, 16192-
16197; b) A. C. Wotal, R. D. Ribson, D. J. Weix, Organometallics
2014, 33, 5874-5881.
M. Neumann, S. Fueldner, B. Koenig, K. Zeitler, Angew. Chem.,
Int. Ed. 2011, 50, 951-954.
a) Q.-Y. Meng, S. Wang, G. S. Huff, B. Koenig, J. Am. Chem. Soc.
2018, 140, 3198-3201; b) J. Luo, J. Zhang, ACS Catal. 2016, 6,
873-877.
G. C. Fu, ACS Cent. Sci. 2017, 3, 692-700.
H. Uoyama, K. Goushi, K. Shizu, H. Nomura, C. Adachi, Nature
2012, 492, 234-238.
[17]
[18]
[19]
[20]
[21]
[5]
[6]
a) X. Dai, N. A. Strotman, G. C. Fu, J. Am. Chem. Soc. 2008, 130,
3302-3303; b) J. Gonzalez, P. Schafer, S. P. Fletcher, ChemRxiv,
Catal. 2018, 1-4; c) A. Varenikov, M. Gandelman, Nat. Commun.
2018, 9, 3566.
a) D. A. Everson, R. Shrestha, D. J. Weix, J. Am. Chem. Soc. 2010,
132, 920-921; b) X. Wang, S. Wang, W. Xue, H. Gong, J. Am.
Chem. Soc. 2015, 137, 11562-11565; c) D. J. Weix, Acc. Chem.
Res. 2015, 48, 1767-1775; d) M. Borjesson, T. Moragas, D.
Gallego, R. Martin, ACS Catal. 2016, 6, 6739-6749; e) X. Wang, Y.
Dai, H. Gong, Top. Curr. Chem. 2016, 374, 1-29; f) T. Lin, J. Mi, L.
Song, J. Gan, P. Luo, J. Mao, P. J. Walsh, Org. Lett. 2018, 20,
1191-1194; g) X. Wang, G. Ma, Y. Peng, C. E. Pitsch, B. J. Moll, T.
D. Ly, X. Wang, H. Gong, J. Am. Chem. Soc. 2018, 140, 14490-
14497.
[22]
[23]
[24]
M. Durandetti, J. Périchon, J.-Y. Nédélec, J. Org. Chem. 1997, 62,
7914-7915.
[7]
a) A. H. Cherney, N. T. Kadunce, S. E. Reisman, J. Am. Chem.
Soc. 2013, 135, 7442-7445; b) A. H. Cherney, S. E. Reisman, J.
Am. Chem. Soc. 2014, 136, 14365-14368; c) N. T. Kadunce, S. E.
Reisman, J. Am. Chem. Soc. 2015, 137, 10480-10483; d) Y. Zhao,
D. J. Weix, J. Am. Chem. Soc. 2015, 137, 3237-3240; e) K. E.
Poremba, N. T. Kadunce, N. Suzuki, A. H. Cherney, S. E. Reisman,
J. Am. Chem. Soc. 2017, 139, 5684-5687; f) N. Suzuki, J. L.
Hofstra, K. E. Poremba, S. E. Reisman, Org. Lett. 2017, 19, 2150-
2153; g) B. P. Woods, M. Orlandi, C.-Y. Huang, M. S. Sigman, A.
G. Doyle, J. Am. Chem. Soc. 2017, 139, 5688-5691; h) Z.-X. Tian,
J.-B. Qiao, G.-L. Xu, X. Pang, L. Qi, W.-Y. Ma, Z.-Z. Zhao, J. Duan,
Y.-F. Du, P. Su, X.-Y. Liu, X.-Z. Shu, J. Am. Chem. Soc. 2019, 141,
7637-7643; i) J. L. Hofstra, A. H. Cherney, C. M. Ordner, S. E.
Reisman, J. Am. Chem. Soc. 2018, 140, 139-142.
[8]
a) K. Wang, Z. Ding, Z. Zhou, W. Kong, J. Am. Chem. Soc. 2018,
140, 12364-12368; b) Y. Jin, C. Wang, Angew. Chem., Int. Ed.
2019, 58, 6722-6726; c) D. Anthony, Q. Lin, J. Baudet, T. Diao,
Angew. Chem., Int. Ed. 2019, 58, 3198-3202.
[9]
a) M. Kuroboshi, Y. Waki, H. Tanaka, Synlett 2002, 2002, 0637-
0639; b) M. Kuroboshi, Y. Waki, H. Tanaka, J. Org. Chem. 2003,
68, 3938-3942.
[10]
a) D. A. Everson, B. A. Jones, D. J. Weix, J. Am. Chem. Soc. 2012,
134, 6146-6159; b) D. A. Everson, R. Shrestha, D. J. Weix, J. Am.
Chem. Soc. 2010, 132, 920-921; c) L. L. Anka-Lufford, K. M. M.
Huihui, N. J. Gower, L. K. G. Ackerman, D. J. Weix, Chem. Eur. J.
2016, 22, 11564-11567.
[11]
a) K. Shimomaki, K. Murata, R. Martin, N. Iwasawa, J. Am. Chem.
Soc. 2017, 139, 9467-9470; b) Q.-Y. Meng, S. Wang, B. König,
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10.1002/anie.201914175
Angewandte Chemie International Edition
RESEARCH ARTICLE
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RESEARCH ARTICLE
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RESEARCH ARTICLE
Haixing Guan, Qianwen Zhang, Patrick
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Nickel/Photoredox-Catalyzed
Asymmetric
Reductive
Cross-
Coupling of Racemic
with Aryl Iodides
a
-Chloro Esters
Text for Table of Contents
The first dual nickel/photoredox catalyzed asymmetric reductive cross-coupling was developed. Three
advantages of this reaction include: 1) no preformed nucleophiles; 2) no metal reductant; and 3)
excellent scope.
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