Regio- And Enantioselective Allylic Alkylation of Terminal Alkynes by Synergistic Rh/Cu Catalysis

Article abstract of DOI:10.1021/jacs.0c08283

A highly branch- and enantioselective 1,4-enynes synthesis from readily available terminal alkynes and racemic allylic carbonates by Sonogashira type synergistic Rh and Cu catalysis under neutral conditions has been developed. Aliphatic and aromatic terminal alkynes with various functional groups could be used directly. An inner-sphere reductive elimination C(sp)-C(sp3) bond formation mechanism is supported by the stoichiometric reaction.

Full text of DOI:10.1021/jacs.0c08283

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Communication
Regio- and Enantioselective Allylic Alkylation of
Terminal Alkynes by Synergistic Rh/Cu Catalysis
Wen-Yu Huang, Chun-Hua Lu, Samir Ghorai, Bing Li, and Changkun Li
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Aug 2020
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Regio- and Enantioselective Allylic Alkylation of Terminal Alkynes
by Synergistic Rh/Cu Catalysis
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Wen-Yu Huang, Chun-Hua Lu, Samir Ghorai, Bing Li, Changkun Li*
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering,
Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai,
200240, China
Supporting Information Placeholder
the methoxide anion acts as the base to deprotonate the acidic
pronucleophiles. The less acidic C(sp)-H bond and the competing
Rh(I)-catalyzed terminal alkyne dimer- or trimerization are the
ABSTRACT: A highly branch- and enantioselective 1,4-enynes
synthesis from readily available terminal alkynes and racemic
allylic carbonates by Sonogashira type synergistic Rh and Cu
main obstacles to expand the scope of pronucleophiles to terminal
catalysis under neutral conditions has been developed. Aliphatic
alkynes. Inspired by the activation of terminal alkynes with Cu in
and aromatic terminal alkynes with various functional groups could
the Sonogashira coupling reaction, we envisioned that the addition
be used directly. An inner-sphere reductive elimination C(sp)-
of catalytic amount of copper salt is able to help enhance the acidity
C(sp3) bond formation mechanism is supported by the
of terminal alkynes. The Cu acetylide formation and subsequent
transmetalation to Rh may lead to the production of skipped
stoichiometric reaction.
enynes. Herein, we report a highly branch- and enantioselective
allylic alkylation of a variety of functionalized aryl, aliphatic and
silyl alkynes by synergistic Rh and Cu catalysis with challenging
Transition-metal-catalyzed asymmetric allylic substitutions
(AAS) provide powerful methods for enantioselective construction
racemic allylic carbonates under neutral conditions (Scheme 1, c).12
of carbon-carbon bonds.1 Various soft or hard carbon nucleophiles
Scheme 1. Transition-Metal-Catalyzed Asymmetric Allylic
have been successfully utilized. Terminal alkynes are also potential
Alkynylation to Chiral 1,4-Enynes
nucleophiles to prepare the 1,4-enynes products, which are
versatile building blocks in organic synthesis for the easy
a
) Hoveyda, Carreira and Breit's reports: applying of metal acetylides
functional group manipulation on the double and triple bonds.2
However, the AAS reaction from terminal alkynes is
underdeveloped probably due to the diverse reactivities of alkynes
in the presence of some commonly used AAS transition metals (Pd,
Ir and Rh).3 Hoveyda reported the first asymmetric allylic
alkynylation by using alkynylaluminum reagents in the presence of
Cu catalyst.4 Carreira5 and Breit6 successfully realized the synthesis
of highly enantio-enriched 1,4-enynes from alkynylboron and
alkynyl carboxylic acid respectively (Scheme 1, a).7 Direct
asymmetric allylation of readily available terminal alkynes under
mild condition is challenging and rewarding in terms of atom- and
step-economy. Only two examples have been reported. A
significant progress has been made by Sawamura and Ohmiya in
Cu-catalyzed asymmetric allylic alkylation of terminal alkynes
with (Z)-allylic phosphates (Scheme 1, b).8a High
enantioselectivities were observed for triisopropylsilylacetylene
and other bulky alkynes. The enantio-selectivities for the reactions
of aryl or aliphatic terminal alkynes are still moderate. Tan and Lee
R
R'
X
Cu, Ir, Rh
R'
M
+
or
M = Al, B, COOH
R
R
*
b
) Sawamura/Ohmiya's work: applying of terminal alkynes directly
R'
R
cat. Cu(I)
+
R'
H
OP(O)(OEt)2
Ph
Ph
R
R' = SiiPr3, high ees
Me
Z-allylic phosphates
N
N
Me
Me
OH
c
) This work:
Rh/Cu-catalyzed Sonogashira-Type Asymmetric Allylation of Terminal Alkynes
cat. Rh(cod)2BF4
R'
cat. Cu(CH3CN)4BF4
OCO2Me
racemic
+
NPNDTBM, Me
cat.
R'
H
R
reported
alkynylation of cyclic allylic bromide under biphasic condition.8c
highly regio- and enantioselective direct coupling of
Cu/guanidine-catalyzed
enantioselective
allylic
possible competing
trimerization by Rh(I)
R1
R
P
A
R = alkyl, aryl R' = alkyl, aryl, silyl
exclusively branched
up to 99% yield
up to 98% ee
functionalized terminal alkynes and easily available unsymmetrical
N
N
O
O
allylic precursors under neutral conditions is still in demand.9
synergistic Rh/Cu catalysis
neutral reaction conditions
Me Me
R1 = 4-OMe-3,5-tBu2C6H2
high function group tolerance
alkyne trimerization retarding
NPNDTBM, Me
Rhodium has be reported to catalyze the highly branch-selective
allylic alkylation reactions from monosubstituted allylic
substrates.10 We recently developed the Rh(I)/bisoxazoline-
phosphine-catalyzed regio- and enantioselective allylic substitution
of different nitrogen, carbon, oxygen and sulfur pronucleophiles
under neutral conditions, in which challenging alkyl-group-bearing
branched racemic and linear (Z and E) allylic substrates were
converted to the same chiral products.11 The released carbonate or
Allylic carbonate rac-1a and phenylacetylene 2a were chosen as
the model substrates (Table 1). With L1 (10 mol%), skipped enyne
3aa was isolated in 63% yield and 91% ee in the presence 5 mol%
Rh(cod)2BF4 and 5 mol% Cu(CH3CN)4BF4 in acetonitrile at 60 oC
(entry 1), along with 7% benzene derivatives byproducts from Rh-
catalyzed alkyne trimerization.13 The use of coordinating
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Page 2 of 7
acetonitrile as solvent is essential for the high yields. Reactions in
DTBM and Me group leads to the full conversion (entry 13). The
reaction efficiency with L10 remains when reducing the catalyst
loading to 2 mol% and expanding the time to 24 h (entry 15), while
lower yield was obtained when L5 was used at lower catalyst
loading (entry 14). Various achiral ligands for Cu were examined
since chiral ligand is unnecessary for Cu. Nevertheless, no ligand
is superior than L10 in controlling both reactivity and
enantioselectivity, probably due to the ligand exchange between Rh
and Cu or the slow transmetalation (see SI).14
1
2
3
4
5
6
7
8
other solvents lead to the faster consumption of alkynes by
trimerization and low yields of 3aa (see SI). 36% yield and 72% ee
were obtained in the control experiment without Cu(CH3CN)4BF4
and the corresponding ligand, which indicates the important role of
Cu (entry 2). The yield dropped to 8% when 5 mol% Rh(cod)2BF4,
Cu(CH3CN)4BF4 and L1 were used respectively (entry 3). A
competition between Rh(I) and Cu(I) to coordinate with L1 may
exist. The reaction doesn’t proceed with only Cu catalyst (entry 4).
To accelerate the reaction rate of allylic substitutions, we then
modified the electronic and steric nature of the ligands. Catalysts
with electron-rich aromatic rings at R1 make the reaction more
reactive and 77% of 3aa was observed when ligands with 4-NMe2
and 4-MeO groups were used (entries 6, 7). Full conversion of 1a
was realized with the 3,5-di-t-butyl-4-MeOC6H2 (DTBM) group-
substituted ligand L5 (entry 8). The substituents on the oxazoline
rings have significant influence on the effect of the ligands.
Compared to L1, L6 and L7 with smaller methyl and benzyl groups
at R2 are more effective (entries 9 and 10), while L8 and L9 with
bulkier phenyl and t-butyl groups give low conversions and
enantioselectivies (entries 11 and 12). As expected, L10 with
Scheme 2. Scope of Alkynesa
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2 mol% Rh(cod)2BF4
R
2 mol% Cu(MeCN)4BF4
OCO2Me
L10
4 mol%
R
+
Ph
MeCN, 60 °C, 24 h
Ph
1b
rac-
2
3bb-3b

3bb
3bc
3bd
3be
: p-OMeC6H4, 95%, 96% ee
: p-NMe2C6H4, 90%, 95% ee
: p-BrC6H4, 94%, 90% ee
: p-CF3C6H4, 92%, 93% ee
p-NO2C6H4, 85%, 88% eeb
R
3bf
:
b
3bg
3bh
: p-CHOC6H4, 91%, 91% ee
: p-CO2MeC6H4, 95%, 92% ee
: p-NHTsC6H4, 95%, 95% ee
: o-ClC6H4, 99%, 94% ee
c
Table 1. Optimization for Rh/Cu-Catalyzed Asymmetric
Allylic Alkylation of Terminal Alkynesa
3bi
3bj
Ph
3bm
Ph
: 88%, 93% ee
3bk
: m-FC6H4, 98%, 96% ee
Ph
3bl
: m-OHC6H4, 95%, 93% ee
5 mol% Rh(cod)2BF4
Ph
5 mol% Cu(MeCN)4BF4
10 mol% Ligand
OCO2Me
S
N
+
n-C5H11
rac-1a
TMS
MeCN, 60 °C, 12 h
n-C5H11
2a
3aa
Ph
Ph
Ph
Ph
, R1 = Ph, R2 = iPr
, R1 = 4-CF3C6H4, R2 = iPr
R1
P
, R1 = Ph, R2 = Me
, R1 = Ph, R2 = Bn
, R1 = Ph, R2 = Ph
, R1 = Ph, R2 = tBu
L1
L2
L3
L4
L6
L7
L8
L9
3bn
3bo
3bp
3bq
: 96%, 93% ee
: 92%, 94% ee
: 85%, 94% ee
: 92%, 98% ee
, R1 = 4-NMe2C6H4, R2 = iPr
, R1 = 4-OMeC6H4, R2 = iPr
CN
OTs
O
N
N
O
Me
OH
OH
Me
R2 R2
L10
, R1 = 4-OMe-3,5-tBu2C6H2, R2 = iPr
, R1 = 4-OMe-3,5-tBu2C6H2, R2 = Me
L5
Ph
Ph
Ph
Ph
yield (%)b
ee (%)c
91
: 93%, 95% ee
: 94%, 94% ee
: 96%, 95% ee
3br
3bs
3bt
3bu
: 89%, 95% ee
entry
ligand
L1
1
2d
3e
4f
5
63
36
8
NHR
Cl
S
EtO
OEt
L1
72
Me
L1
90
Ph
Ph
L1
< 5
62
77
77
99
97
88
29
11
99
80h
95h
--
Ph
Ph
3bz
3bv
3bx
: 98%, 95% ee
3by
, R = Boc: 92%, 93% ee
3bw
: 72%, 95% ee : 82%, 94% ee
L2
91
, R = Bz, 92%, 95% ee
6
L3
92
OH
Me
OH
7
L4
91
H
8
L5
92
Ph
H
H
Ph
Ph
3b
O
9
L6
91
3b
: 93%, 88% ee
3b
: 95%, dr > 20:1
: 94%, 95% ee
10
11
12
13
L7
92
aCondition: 1b (0.5 mmol, 1.0 equiv), 2 (0.75 mmol, 1.5 equiv) in 0.5
mL CH3CN. b48 h. c3 mol% Rh(I)/Cu(I) and 6 mol% L10 at 80 oC.
L8
85
L9
58
L10
L5
90
With the optimized condition in hand, we firstly evaluated the
scope of terminal alkynes (Scheme 2). With the rac-1b as the model
allylic carbonate, various alkynes successfully undergo the allylic
alkylation reactions. Electron-donating and moderately electron-
withdrawing groups in the aryl alkynes have neglectable effect on
yields and ees (3bb to 3be). However, strong electron-withdrawing
nitro group makes the reaction slow at the standard condition. The
yield was improved to 85% when the reaction was conducted at 80
oC with slightly lower ee (3bf). Aldehyde, ester, free sulfonamide
and hydroxyl groups can be tolerated (3bg to 3bi, 3bl). The ortho-
and meta-substituted aryl alkynes can also be transformed to
14g
15g
90
L10
90
aConditions: 1a (0.5 mmol), 2a (0.75 mmol) in CH3CN (0.5 mL).
bDetermined by 1H NMR integration relative to 1,3,5-
c
trimethylbenzene. The ee was determined by HPLC with a chiral
column.dCu(I) was not added and 5 mol% L1 was used. e5 mol% Rh(I),
5 mol% Cu(I) and 5 mol% L1 were used. fRh(I) was not added and 5
g
mol% L1 was used. Rh(cod)2BF4 (2 mol%), Cu(CH3CN)4BF4 (2
mol%) and 4 mol% L10 in 24 h. hIsolate yield.
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products smoothly (3bj to 3bl). Other aromatic rings, such as 2-
this reaction to generate 3jb in 85% yield and 97% ee. The absolute
configuration of 3jb was assigned to be R by comparing with
literature.5 3kb and 3lb with free or protected hydroxyl groups were
obtained with high ees. Tertiary allylic carbonates can also be
applied in this transformation to build 1,4-enynes with quaternary
carbon centers in moderate yields (3mb to 3pb) and ees (3ob and
3pb) under the standard condition.
1
2
3
4
5
6
7
8
naphthyl, 3-thiophenyl and 3-pyridyl groups, can also be
introduced to give 1,4-enynes 3bm to 3bo. Silyl-containing 3bp
was prepared in high yield and ee from trimethylsilylacetylene 2p,
which allows further deprotection to prepare chiral terminal alkyne.
Aliphatic alkynes with different functional groups were also
utilized in this transformation. Free propargyl alcohols react
selectively at the C-H bond and no allylic ethers were detected (3br
and 3bs). Cyano, p-toluenesulfonate, amides, chloride and sulfide
were all tolerated under this mild condition (3bt to 3by). Acetal-
containing 3bz was synthesized in high yield, which could be
converted to the aldehyde. 1,3-Enynes readily react to afford the
dienynes 3b and 3b. The highly diastereoselective formation of
3b from ethisterone indicates this method can be used in late-stage
functionalization of complex molecules. The absolute
configurations of 3bp and 3b were assigned to be S by comparing
with literature.8a
As predicted, Z- and E-linear allylic methyl carbonates (Z-4a and
E-4a) underwent this asymmetric allylic alkylation of terminal
alkyne 2b to afford 3db (eq 1, Scheme 4). However, these reactions
were slower than the reaction of branched substrate 1d. 3 mol%
catalysts and longer time (48 h) are necessary to get high yields.
The same level of enantioselectivities were observed from three
different allylic precursors. The asymmetric allylic alkylation of
terminal alkynes can be conducted in 10 mmol scale. 3kd can be
prepared in 52% yield and 88% ee in the presence of 1 mol%
catalyst after 48 hours (eq 2). After protection with 3,5-
dinitrobenzoic acid, a solid 5 was isolated and the S absolute
configuration was further confirmed by single crystal X-ray
diffraction analysis.
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Scheme 3. Scope of Allylic Carbonatesa
2 mol% Rh(cod)2BF4
Ar
2 mol% Cu(MeCN)4BF4
OCO2Me
L10
4 mol%
Scheme 4. Reactions of Linear Allylic Carbonates and
Absolute Configuration Assignment
Ar
Ar = 4-MeOC6H4
2b
+
R
MeCN, 60 °C, 24 h
R
1
rac-
3cb-3pb
3 mol% Rh(cod)2BF4
Ar
n-C3H7
OCO2Me
E
-4a
(1.0 eq)
3 mol% Cu(MeCN)4BF4
Ar
Ar
Ar
Ar
L10 or L1
6 mol%
MeCN, 60 °C, 48 h
Ar
eq 1
+
or
n-C3H7
Ar = 4-MeOC6H4
n-C3H7
Me
Me
OCO2Me
3db
Me
n-Pr
4a
79%, 91% ee, from E- , with
75%, 90% ee, from Z , with
L10
L1
Z-4a (1.0 eq)
2b
(1.5 eq)
Br
-4a
3cb
3db
3eb
3fb
, 86%, 93% ee
, 90%, 92% ee
, 91%, 96% ee
, 95%, 96% ee
Br
Ar
Ar
Ar
Ar
O
1 mol% Rh(cod)2BF4
1 mol% Cu(MeCN)4BF4
L10
O
+
Me
O
eq 2
2 mol%
Me
t-Bu
Ph
HO
3kd
MeCN, 60 °C, 48 h
b,c
3gb
3hb
3ib
3jb
, 71%, 93% ee
, 88%, 94% ee
, 82%, 83% ee
, 85%, 97% ee
1k
2d,
10 mmol, 1.0 eq.
, 1.5 eq.
, 52%, 88% ee
NO2
Ar
Ar
Ar
Br
O2N
COOH
HO
TBSO
Me
NO2
DCC, DMAP
DCM, 0 o
Me
, 52%
Ar
3kd
C
d
d,e
3kb
3lb
, 50%, 87% ee
, 97%, 93% ee
3mb
O
O2N
Ar
Ar
O
5
, 90%, 89% ee
Me
Me
Ph
Me
Me
N-Benzyl-2-ethynylaniline 2 reacted at the terminal alkyne site
selectively and chiral N-benzyl-2-allylindole15 3a was isolated in
82% yield and 91% ee after the gold-catalyzed cyclization (eq 3,
Scheme 5). This method was also utilized to synthesize 3pp in the
presence of ent-L10, which could be transformed to compound 6
as the key fragment in the synthesis of (+)-Breynolide.16
d,e
b,d,e,f
d,e
3nb
3ob
, 70%, 44% ee
3pb
, 63%, 40% ee
, 60%
aConditions: 1 (0.5 mmol, 1.0 equiv) and 2b (0.75 mmol, 1.5 equiv) in
CH3CN (0.5 mL). b48 h.c3 mol% Rh(I)/Cu and 6 mol% L10 were used.
d1 (0.75 mmol, 1.5 equiv) and 2b (0.5 mmol, 1.0 equiv). 5 mol%
e
f
Rh(I)/Cu and 10 mol% L10. t-Butyl carbonate was used instead of
methyl carbonate.
To gain mechanistic insight of the Rh/Cu-catalyzed asymmetric
allylic alkylation of terminal alkynes, control and stoichiometric
reactions were conducted (Scheme 6). 3ca was isolated in 60%
yield and 90% ee under the catalysis of Rh/Cu and L1 (eq 4). The
stoichiometric reaction of previously reported [L1-
RhCl(MeC3H4)]OTf with Cu-acetylide in the presence of K2CO3
gives no trace of 3ca. The addition of 1.5 eq of L1 leads to the
isolation of 3ca in 83% yield and 95% ee (eq 5). This result is
consistent with the fact that extra ligand for Cu is mandatory for
high conversions. The addition L1 may break the Cu acetylide
oligomers and generate the key Cu-L1 acetylide. Complex L1-CuI
The scope of allylic carbonates was then examined with alkyne
2b as model substrate (Scheme 3). Simple methyl and n-propyl
substituted chiral 1,4-enynes 3cb and 3db were synthesized
routinely under the standard condition. Sterically more hindered -
and -branched allylic carbonates with isopropyl, cyclopropyl,
cyclohexyl and isobutyl groups reacted smoothly to afford the
corresponding skipped enynes in high yields and
enantioselectivities (3eb to 3hb). The challenging t-butyl group
was also introduced to 1,4-enynes, although the ee is slightly lower
(3ib). Phenyl substituted allylic carbonate 1j also participated in
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Scheme 5. The Synthesis of Chiral 2-Allylindole and the
Fragment of (+)-Breynolide
inner-sphere reductive elimination C-C bond formation process,
which encourages us to explore the Rh/bisoxazolinephosphine-
catalyzed asymmetric allylation of other hard nucleophiles in the
future.19
1
2
OCO2Me
3
4
5
6
n-C5H11
3 mol% Rh(cod)2BF4
3 mol% Cu(MeCN)4BF4
1a
, 1 eq.
+
5 mol% PPh3AuCl
5 mol% AgOTf
ASSOCIATED CONTENT
BnN
L10
6 mol%
eq 3
MeCN,60 °C, 36 h
MeCN, 90 °C 12 h
Supporting Information. Detailed experimental procedures,
characterization data, copies of 1H, 13C NMR spectra, HPLC
spectra and X-ray crystal structures of compound 5 and L1-CuI.
This material is available free of charge via the Internet at
http://pubs.acs.org.
n-C5H11
7
3a

NHBn
82%, 91% ee
8
2
, 1.5 eq.
9
OCO2Me
TMS
3 mol% Rh(cod)2BF4
3 mol% Cu(MeCN)4BF4
L10
10
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60
TBDPSO
6 mol% ent-
1p
AUTHOR INFORMATION
, 1.0 eq
+
TMS
MeCN,60 °C, 36 h
TBDPSO
Corresponding Author
3pp
, 89%
94% ee
2p
, 1.5 eq
*E-mail: chkli@sjtu.edu.cn
1) m-CPBA
2) K2CO3, MeOH
OH
OH
O
Notes
Me
O
H
ref. 16
The authors declare no competing financial interests.
OH
O
HO
TBDPSO
H
O
S
6
, 51%,
93% ee (2 steps)
ACKNOWLEDGMENT
(+)-Breynolide
This work is supported National Natural Science Foundation of
China (NSFC) (21602130) and the starting fund of Shanghai Jiao
Tong University.
with distorted tetrahedral geometry was synthesized in high yield
when CuI and L1 were mixed in DCM (eq 6). A linear relationship
between the ee values of the product and ligand indicates that no
metal complex with two chiral ligands is involved in the catalysis
(see SI). The C-C bond formation step is different from the
previously proposed outer-sphere addition of nitrogen and other
nucleophiles.11a A mechanism involving the transmetalation of Cu-
acetylide to rhodium complex and subsequent reductive
elimination is more likely based on the observed absolute
configuration of product 3bp, 3b, 3jb, 3ca and crystalized 5.17,18
The high exo/endo selectivity in [L1-RhCl(MeC3H4)]OTf complex
leads to the excellent enantioselectivity.
REFERENCES
(1) For selected reviews, see: (a) Trost, B. M.; Van Vranken, D. L.
Asymmetric Transition Metal-Catalyzed Allylic Alkylations. Chem.
Rev. 1996, 96, 395-422. (b) Trost, B. M.; Crawley, M. L. Asymmetric
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Synthesis. Chem. Rev. 2003, 103, 2921-2943. (c) Lu, Z.; Ma, S. Metal-
Catalyzed Enantioselective Allylation in Asymmetric Synthesis.
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(e) Qu, J.; Helmchen, G. Applications of Iridium-Catalyzed
Asymmetric Allylic Substitution Reactions in Target-Oriented
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Zheng, C.; Qu, J.-P.; Helmchen, G.; You, S.-L. Chem. Rev. 2019, 119,
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Scheme 6. Mechanism Studies
Ph
5 mol% Rh(cod)2BF4
5 mol% Cu(MeCN)4BF4
OCO2Me
L1
10 mol%
+
Ph
eq 4
Me
MeCN, 60 °C, 12 h
Me
1c
rac- , 1.0 eq
2a
, 1.5 eq
3ca
, 60%, 90% ee
OTf-
Ph
O
P
K2CO3 (1.5 eq.)
Ph
N
i-Pr
+ Cu
O
N
Rh
eq 5
MeCN, 60 °C, 12 h
Me
i-Pr
Me
1.5 eq.
Cl
RhCl(MeC3H4)]OTf
L1 3ca
not detected
L1 3ca
, 83%, 95% ee
without
,
L1-
[
with 1.5 eq
,
O
L1
+
CuI
P
N
i-Pr
DCM, rt, 12 h
eq 6
O
N
Cu
I
i-Pr
L1
-CuI, 85% yield
In summary, we developed a highly branch- and enantioselective
allylic alkylation of terminal alkynes by synergistic Rh and Cu
catalysis. Chiral 1,4-enynes were synthesized from a variety of
readily available terminal alkynes with different functional groups
and racemic allylic carbonates under neutral conditions. The
challenging alkyne trimerization by Rh(I) could be retarded by the
applying of acetonitrile solvent. Mechanism studies support the
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Fürstner, A.
Protecting-Group-Free and Catalysis-Based Total
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Lett. 2020, 22, 1599-1604.
1
2
3
4
5
6
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8
(10) For recent reviews on rhodium-catalyzed asymmetric allylations,
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and Enantioselective Allylic Substitutions. ACS Catal. 2020, 10, 4491-
4496. For a cobalt-catalyzed asymmetric allylic amination, see: (b)
Ghorai, S.; Chirke, S. S.; Xu, W.-B.; Chen, J.-F.; Li, C. Cobalt-
Catalyzed Regio- and Enantioselective Allylic Amination. J. Am.
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(12) For selected reviews on synergistic bimetallic catalysis, see:
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C
a
t
a
l
y
s
i
s
in Asymmetric Allylic Substitution. Org. Biomol. Chem. 2017, 15,
9747-9759. (b) Pye, D. R.; Mankad, N. P. Bimetallic Catalysis for C-
C and C-X Coupling Reactions. Chem. Sci. 2017, 8, 1705-1718. (c)
Wu, Y.; Huo, X.; Zhang, W. Synergistic Pd/Cu Catalysis in Organic
Synthesis. Chem. Eur. J. 2020, 26, 4895-4916. For recent
examples on Pd/Cu-Catalyzed asymmetric Sonogashira type
reaction of terminal alkynes, see: d) Bai, X.; Wu, C.; Ge, S.; Lu, Y.
Pd/Cu-Catalyzed Enantioselective Sequential Heck/Sonogashira
Coupling: Asymmetric Synthesis of Oxindoles Containing
Trifluoromethylated Quaternary Stereogenic Centers. Angew.
Chem. Int. Ed. 2020, 59, 2764-2768. e) Sun, F.-N.; Yang, W.-C.;
Chen, X.-B.; Sun, Y.-L.; Cao, J.; Xu, Z.; Xu, L.-W. Enantioselective
Palladium/Copper-Catalyzed C-C -Bond Activation Synergized
with Sonogashira-Type C(sp3)-C(sp) Cross-Coupling Alkynylation.
Chem. Sci., 2019, 10, 7579-7583.
(13) Phenylacetylene 2a was converted to mixture of 1,3,5-
triphenylbenzene and 1,2,4-triphenylbenzene in 86% yield and 4.2 : 1
ratio in the presence of 5 mol% Rh(cod)2BF4 and L1 at 60 oC in CH3CN
when no allylic carbonate was added. Significant amount of
trimerization products was formed when other solvents were used. For
details, see Table S1 in the supporting information.
(14) For examples on asymmetric allylation catalyzed by one chiral
metal complex and one achiral metal complex, see: a) Sawamura,
M.; Sudoh, M.; Ito, Y. An Enantioselective Two-Component Catalyst
System: Rh-Pd-Catalyzed Allylic Alkylation of Activated Nitriles. J.
Am. Chem. Soc. 1996, 118, 3309-3310. b) Wei, L.; Xu, S.-M.; Zhu, Q.;
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-Amino Acids. Angew. Chem. Int. Ed. 2017, 56, 12316-12316.
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J. K.; Unsworth, W. P.; You, S.-L. Angew. Chem. Int. Ed. 2020, 59,
7598 –7604.
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Decarboxylative Alkynylation of Allenes with Arylpropiolic Acids.
Org. Lett. 2018, 20, 1066-1069.
(7) For other methods on asymmetric synthesis of 1,4-enynes, see: (a)
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Molybdenum-Catalyzed Alkylations of Polyenyl Esters. J. Am. Chem.
Soc. 1999, 121, 10416-10417. (b) Shirakura, M.; Suginome, M. Nickel-
Catalyzed Asymmetric Addition of Alkyne C-H Bonds across 1,3-
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Chem. Int. Ed. 2010, 49, 3827-3829. (c) Li, H.; Alexakis, A. Enyne
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Organocatalytic Enantioselective Nucleophilic Alkynylation of Allyl
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K. Asymmetric Synthesis of Chiral 1,4-Enynes through
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(8) (a) Harada, A.; Makida, Y.; Sato, T.; Ohmiya, H.; Sawamura, M.
Copper-Catalyzed Enantioselective Allylic Alkylation of Terminal
Alkyne Pronucleophiles. J. Am. Chem. Soc. 2014, 136, 13932-13939.
(b) Makida, Y.; Takayama, Y.; Ohmiya, H.; Sawamura, M. Copper-
Catalyzed -Selective and Stereospecific Direct Allylic Alkylation of
Terminal Alkynes: Synthesis of Skipped Enynes. Angew. Chem. Int. Ed.
2013, 52, 5350-5354. For an elegant Cu-catalyzed asymmetric allylic
alkynylation of cyclic substrates, see: (c) Cui, X.-Y.; Ge, Y.; Tan, S.
M.; Jiang, H.; Tan, D.; Lu, Y.; Lee, R.; Tan, C.-H. (Guanidine)copper
Complex-Catalyzed Enantioselective Dynamic Kinetic Allylic
Alkynylation under Biphasic Condition. J. Am. Chem. Soc. 2018, 140,
8448-8455.
(16) Williams, D. R.; Jass, P. A.; Tse, H.-L. A.; Gaston, R. D. J. Am.
Chem. Soc. 1990, 112, 4552-4554.
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2005, 127, 13510-13511. (b) Mendis, S. N.; Tunge, J. A. Palladium-
Catalyzed Stereospecific Decarboxylative Benzylation of Alkynes.
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Palladium-Catalyzed Synthesis of Conjugated Allenynes via
Decarboxylative Coupling. Org. Lett. 2017, 19, 5497-5500.
(18) Deuterium labelling method was utilized to explore the inner- or
outer-sphere mechanism. The results and explanation could be found
in SI. For recent examples, see: a) Kim, S. W.; Schwartz, L. A.; Zbieg,
J. R.; Stivala, C. E.; Krische, M. J. Regio- and Enantioselective
(9) For selected non-asymmetric examples, see: (a) Grushin, V. V.;
Alper, H. Copper(I) and Phase Transfer Catalyzed Allylation of
Alkynes. J. Org. Chem. 1992, 57, 2188-2192. (b) Li, Y.-X.; Xuan, Q.
Q.; Liu, L.; Wang, D.; Chen, Y.-J.; Li, C.-J. A Pd(0)-Catalyzed Direct
Dehydrative Coupling of Terminal Alkynes with Allylic Alcohols To
Access 1,4-Enynes. J. Am. Chem. Soc. 2013, 135, 12536-12539. (c)
Yang, Q.; Zhou, Y.; Chen, J.; He, X.; Xu, J.; Kwong, F. Y.; Fan, B. Pd-
Catalyzed Allylic Alkynylation of Allylic Acetates with Terminal
Alkynes. Eur. J. Org. Chem. 2015, 5330-5333. (d) Xie, P.; Sun, Z.; Li,
S.; Zhang, L.; Cai, X.; Fu, W.; Yang, X.; Liu, Y.; Wo, X.; Loh, T.-P.
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Iridium-Catalyzed Amination of Racemic Branched Alkyl-Substituted
Regio- and Enantiospecific Rhodium-Catalyzed Arylation of
Unsymmetrical Fluorinated Acyclic Allylic Carbonates:ꢀ Inversion of
Absolute Configuration. J. Am. Chem. Soc. 2003, 125, 7158-7159. (b)
Menard, F.; Chapman, T. M.; Dockendorff, C.; Lautens, M. Rhodium-
Catalyzed Asymmetric Allylic Substitution with Boronic Acid
Nucleophiles. Org. Lett. 2006, 8, 4569-4572. (c) Menard, F.; Perez, D.;
Roman, D. S.; Chapman, T. M.; Lautens, M. Ligand-Controlled
Selectivity in the Desymmetrization of meso Cyclopenten-1,4-diols via
Rhodium(I)-Catalyzed Addition of Arylboronic Acids. J. Org. Chem.
2010, 75, 4056-4068. (d) Sidera, M.; Fletcher, S. P. Rhodium-
Catalysed Asymmetric Allylic Arylation of Racemic Halides with
Arylboronic Acids. Nat. Chem. 2015, 7, 935-939.
Allylic Acetates with Primary and Secondary Aromatic and
Heteroaromatic Amines. J. Am. Chem. Soc. 2019, 141, 671-676. (b)
Kim, S. W.; Schempp, T. T.; Zbieg, J. R.; Stivala, C. E.; Krische, M. J.
Regio- and Enantioselective Iridium-Catalyzed N-Allylation of Indoles
and Related Azoles with Racemic Branched Alkyl-Substituted Allylic
Acetates. Angew. Chem. Int. Ed. 2019, 58, 7792-7766. c) Sorlin, A. M.;
Mixdorf, J. C.; Rotella, M. E.; Martin, R. T.; Gutierrez, O.; Nguyen, H.
M. The Role of Trichloroacetimidate To Enable Iridium-Catalyzed
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Regioand Enantioselective Allylic Fluorination:
A Combined
Experimental and Computational Study. J. Am. Chem. Soc. 2019, 141,
14843-14852.
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(19) For selected examples on rhodium-catalyzed asymmetric allylic
substitution of hard nucleophiles, see: (a) Evans, P. A.; Uraguchi, D.
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2 mol% Rh(cod)2BF4
R1
R'
2 mol% Cu(CH3CN)4BF4
P
OCO2Me
NPNDTBM, Me
4 mol%
+
R'
H
CH3CN, 60 oC, 24 h
N
N
R
O
O
R
R' = alkyl, aryl, silyl
R = alkyl, aryl
racemic
Me Me
R1 = 4-OMe-3,5-tBu2C6H2
up to 99% yield
up to 98% ee
NPNDTBM, Me
exclusively branch-selective
high function group tolerance
synergistic catalysis
neutral condition
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