Copper-catalyzed enantioselective carbonylation toward α-chiral secondary amides

Article abstract of DOI:10.1039/d1sc04210f

Secondary amides are omnipresent structural motifs in peptides, natural products, pharmaceuticals, and agrochemicals. The copper-catalyzed enantioselective hydroaminocarbonylation of alkenes described in this study provides a direct and practical approach for the construction of α-chiral secondary amides. An electrophilic amine transfer reagent possessing a 4-(dimethylamino)benzoate group was the key to the success. This method also features broad functional group tolerance and proceeds under very mild conditions, affording a set of α-chiral secondary amides in high yields (up to 96% yield) with unprecedented levels of enantioselectivity (up to >99% ee). α,β-Unsaturated secondary amides can also be produced though the method by using alkynes as the substrate.

Full text of DOI:10.1039/d1sc04210f

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DOI: 10.1039/D1SC04210F
ARTICLE
Copper-Catalyzed Enantioselective Carbonylation Toward α-Chiral
Secondary Amides
Yang Yuan,a Fengqian Zhao,a and Xiao-Feng Wu*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
Secondary amides are omnipresent structural motifs in peptides, natural products, pharmaceuticals, and agrochemicals. The
copper-catalyzed enantioselective hydroaminocarbonylation of alkenes described in this study provides a direct and
practical approach for the construction of α-chiral secondary amides. Electrophilic amine transfer reagent possesses a 4-
(dimethylamino)benzoate group was the key to the success. This method also features broad functional group tolerance
and proceeds under very mild conditions, affording a set of α-chiral secondary amides in high yields (up to 96% yield) with
unprecedented levels of enantioselectivity (up to >99 ee). α,β-Unsaturated secondary amides can also be produced though
the method by using alkynes as substrate.
DOI: 10.1039/x0xx00000x
carbonylations is the critical competitive coordination between CO
and chiral ligand-palladium species, resulting in no “chelate effect”,
especially under high temperatures and pressures.[15] To conquer
Introduction
Transition-metal-catalyzed hydrocarbonylations are one of the
most fundamental and ideal reactions for the synthesis of
numerous value-added carbonyl containing compounds from
readily available alkenes.[1] Within this class of reactions,
hydroaminocarbonylation, also called hydroamidation, represents
a straightforward route for the conversion of alkenes into amides.[2]
The original catalytic systems for hydroaminocarbonylations based
on cobalt,[3] nickel,[4] iron,[5] and ruthenium complexes[6] are
required severe conditions such as high temperatures and high
pressures and often accompanied by aminoformylation side
reactions, thus leading to poor chemoselectivity and limited
substrate scope. palladium-catalyzed hydroaminocarbonylation
reactions have been extensively developed over the past decades.
Recently, ligand-controlled regiodivergent palladium-catalyzed
hydroaminocarbonylations to access either linear or branched
amides under relatively mild conditions, which involved palladium-
hydride species, have been independently developed by the
groups of Beller,[7] Cole-Hamilton,[8] Liu,[9] Huang,[10] and Alper[11]
(Figure 1a).[12] Despite these advances, asymmetric Pd-catalyzed
hydroaminocarbonylations of alkenes with control of the regio- and
enantioselectivity are still less explored, and the substrate scope of
amines is limited to arylamines. The only elegant work was reported
from the Guan group, they presented a novel asymmetric
Markovnikov hydroaminocarbonylation of alkenes with anilines
enabled by Pd-monodentate phosphoramidite catalysis.[13]
this issue, an alternative way is to change palladium into a metal
with slightly weaker coordination ability to carbon monoxide and
copper might be a choice. Recent developments in copper hydride
chemistry enabled a new approach to the hydroamination of
alkenes based on the hydrocupration of the alkene and subsequent
amination of the reactive alkyl copper intermediate with
electrophilic amine reagents.[16] We proposed to carry out the
hydrocupration of alkenes with amine electrophiles under CO
atmosphere to achieve
reaction. Indeed, we
a
selective hydroaminocarbonylation
do realize this Cu-catalyzed
hydroaminocarbonylation reaction to prepare branched tertiary
amides (Figure 1b).[17] Nevertheless, this approach to
hydroaminocarbonylation has been limited to the synthesis of
tertiary amides with hydroxyamines (R2NOBz, R = alkyl) as the
dialkylamine transfer reagents.
Secondary amides (-NH-CO-), including chiral secondary
amides, are omnipresent structural motifs in peptides, natural
products, pharmaceuticals, and agrochemicals (Figure 1c).[18] It is
therefore highly desired to develop an efficient and practical
methodology that can achieve secondary amides with high regio-
and enantioselectivity by using cheap catalysts under mild
conditions. Herein we report the development of a copper-
catalyzed hydroaminocarbonylation process to directly synthesize
α-chiral secondary amides from alkenes and modified amine
transfer reagents; The method can also be extended to the
synthesis of α,β-unsaturated secondary amides by using alkynes
as the substrate (Figure 1d).
In general, the use of monodentate ligands favors Markovnikov
selectivity in palladium-catalyzed hydroaminocarbonylations for the
formation of branched amides.[7c,9,10b,11,14] However, the challenge
of monodentate ligand-assisted Pd-catalyzed enantioselective
a. Leibniz-Institut für Katalyse e.V., Albert-Einstein-Straße 29a, 18059 Rostock,
Germany, E-mail: xiao-feng.wu@catalysis.de
b. Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, 116023, Dalian, Liaoning, China, E-mail:
xwu2020@dicp.ac.cn
Electronic Supplementary Information (ESI) available: [general comments, general
procedure, analytic data, and NMR spectra]. See DOI: 10.1039/x0xx00000x
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a)
Traditional hydroaminocarbonylation
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DOI: 10.1039/D1SC04210F
O
O
Table 2. Optimization of the Reaction Conditions.a
M
R
R1
R
R1
+
R1
N
R
N
R
or
+
CO
H NR2
CO (10 bar)
O
H
CuCl (10.0 mol %)
H


N
N
R
L
(10.0 mol%)
R
O
b)
Cu-catalyzed hydroaminocarbonylation: synthesis of branched tertiary amides
Ph
R
Ph
N
Ph
+
+
H
PhMeSiH2 (2.0 equiv)
LiOtBu (3.0 equiv)
DCE, 50 °C, 15 h
O
N
O
2d
2e
, R = Bn
, R = Cy
Cu
3
, R = Bn
4, R = Cy
3'
4'
, R = Bn
, R = Cy
R
R
R1
R
1a
R1
N
+
CO
+
N
R
OBz
c)
Selective molecules with a secondary amide motif
O
Entry
2
Ligand
L1-L3
L4
Yield (%)
ee (%)
1
2d
2d
2d
2d
2d
2d
2d
2d
2d
2e
2e
2e
trace (3/3’)
8/6 (3/3’)
/
H
H
N
N
N
N
O
2
n.d
O
O
S
O
O
HN
O
3
L5
10/7 (3/3’)
14/2 (3/3’)
trace (3/3’)
trace (3/3’)
trace (3/3’)
62/9 (3/3’)
trace (3/3’)
89/trace (4/4’)
91/trace (4/4’)
n.d
Glucokinase activator (GKA)
11b-HSD1 inhibitor
Ramelteon
4
L6
73 (3)
d) This work
: synthesis of -chiral secondary amides & ,-unsaturated secondary amides
R2
H
5
L7
/
R2
R1
O
N
R1
R2
R1
R3
H
N
Cu
R3
O
O
6
L8
/
or
+
CO
+
or
N
R1
R2
H
N
7
L9
/
R3
Cheap catalyst (copper)
Mild conditions (rt - 50 °C)
O
8
L10
L11
L10
L10
L10
99 (3)
/
Broad substrate scope (58 examples)
High enantioselectivity (up to >99 ee)
9
10b
11bc
12bcd
95 (4)
96 (4)
96 (4)
Figure 1. a) Traditional hydroaminocarbonylation. b) Cu-catalyzed
hydroaminocarbonylation: synthesis of branched tertiary amides. c) Selective
molecules with a secondary amide motif. d) Synthesis of α-chiral secondary
amides and α,β-unsaturated secondary amides (this work).
83/trace (4/4’)
O
O
O
Results and discussion
O
O
PPh2
PPh2
MeO
MeO
PAr2
PAr2
PPh2
PPh2
PAr2
PAr2
We began our work by studying the reaction between styrene
1a (1.2 equiv) and O-benzoyl-N-benzylhydroxylamine 2a
[BnN(H)OBz, 1.0 equiv] utilizing our previously reported conditions
(Table 1). Unfortunately, only trace of the desired secondary amide
3 can be detected. We reasoned that this result might be caused
by the poor stability of amine transfer reagent 2a, the rapid
nonproductive consumption of 2a by LCuH diminished the yield.
Thus, we tested different amine transfer reagents for this
hydroaminocarbonylation under the same conditions. The results
were summarized in Scheme 1, we found that the use of 2d, an
amine transfer reagent bearing a 4-(dimethylamino)benzoate group,
delivered the desired secondary amide 3 in the highest yield, albeit
the direct C-N coupling product 3’ was also generated in 18% yield.
O
O
O
L1
L3
L2
Ar=3,5-(tBu)2-4-MeO-C6H2
L4
Ar=3,5-(tBu)2-4-MeO-C6H2
P
N
N
P
P
P
P
Ph2P
PPh2
P
L5
L6
Ph
L7
L8
P
P
Ph
O
H
N
O
P
P
P
P
N
Ph
Ph
2e
L9
L10
L11
Table 1. Screening of amine transfer reagents.a
[a] Standard conditions: 1a (0.12 mmol, 1.2 equiv), 2d (0.1 mmol, 1.0 equiv), [SiH]
(0.2 mmol, 2.0 equiv), CuCl (10 mol%), Ligand (10 mol%), LiOtBu (0.3 mmol, 3.0
equiv), CO (10 bar), DCE (0.5 mL), 50 ºC, 15 h; Yields are determined by GC
analysis using hexadecane as internal standard. Ee values are determined by
chiral-phase HPLC. n.d. = not determined. [b] Using 2e as substrate, isolated yield.
[c] CuCl (5 mol%), Ligand (5 mol%). [d] rt (room temperature, 26 ºC).
CO (10 bar)
CuCl (10 mol %)
Xantphos
H


O
N
Bn
(10 mol%)
H
Bn
N
H
N
+
+
Ph
PhMeSiH2 (2.0 equiv)
LiOtBu (3.0 equiv)
DCE, 50 °C, 16 h
Bn
O
R
O
1a
2
3
3'
O
After determined the best amine transfer reagent 2d, we
started to investigate the reaction by using chiral ligands for
constructing α-chiral secondary amides. As shown in Table 2, chiral
ligands L1-L3 only gave a trace amount of product 3. Bulky (S)-
DTBM-Segphos (L4) and (S,S)-BDPP (L5) delivered the desired
product in very low yields. The use of (S,S)-QuinoxP* L6 leads to
14% yield of the desired product 3 with moderate enantioselectivity
(Table 2, entry 4, 73 ee). (S,S)-BenzP* (L7), L8, (R,R)-Me-DuPhos
(L9), and (S,S)-Me-BPE (L11) were ineffective for this reaction.
H
O
O
N
H
H
O
Bn
O
N
H
N
Bn
O
Bn
O
N
Bn
O
N
2a
2b
2c
2d
, 45%/18%
, trace
, 12%/24%
, 15%/22%
[a] Standard conditions: 1a (0.12 mmol, 1.5 equiv), 2 (0.1 mmol, 1.0 equiv), [SiH]
(0.2 mmol, 2.0 equiv), CuCl (10 mol%), Ligand (10 mol%), LiOtBu (0.3 mmol, 3.0
equiv), CO (10 bar), DCE (0.5 mL), 50 ºC, 16 h; Yields are determined by GC
analysis using hexadecane as internal standard.
2 | J. Name., 2012, 00, 1-3
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Fortunately, using (R,R)-Ph-BPE (L10) as the ligand provided 3 in reagent 2d to 2e, the desired product 4 can be affVoiredweAdrticilne O8n9li%ne
DOI: 10.1039/D1SC04210F
62% yield with excellent enantioselectivity (Table 2, entry 8, 99 ee). yield with 95 ee (Table 2, entry 10). Notably, the yield of 4 would
From these results, especially compare with result between L9-L11, not be diminished by decreasing the catalyst loading to 5.0 mol%,
we believe the bite angle and the basicity of the ligand applied are and trace of 4’ was detected (Table 2, entry 11, 91% yield, 96 ee).
crucial for the success of this transformation. Then different kinds Surprisingly, lowering the temperature to room temperature (26 ºC),
of silanes were tested, low or no yield of product 3 was formed the reaction still could proceed well, giving product 4 in 83% yield
when Et3SiH, PMHS, or (EtO)2MeSiH was applied. Excellent ee of (Table 2, entry 12, 96 ee).
the carbonylated product can be obtained when Ph2SiH2 was used,
but the yield of 3 decreased to 47%. Changing the amine transfer
CO (10 bar)
Ph
Ph
O
CuCl (5.0 mol %)
L10
R2
O
H
N
(5.0 mol%)
R2
R3
P
O
H
P
R1
+
N
PhMeSiH2 (2.0 equiv)
LiOtBu (3.0 equiv)
DCE, rt-50 °C, 15 h
R1
R3
N
Ph
Ph
2
1
L10: (R,R)-Ph-BPE
Styrenes
H
H
N
H
N
H
H
N
N
N
O
O
, 78%, 99 ee
O
O
O
tBu
Ph
a
b
4
9
5
6
, 84%, 96 ee
, 91%, 96 ee
7
8
, 85%,85 ee
, 85%, 96 ee
H
N
H
H
N
H
N
H
N
N
O
O
O
O
O
MeO
PhO
BnO
F
Cl
b
10
11
12
13
, 73%, 84 ee
, 77%, 94 ee
, 76%, 92 ee
, 83%, 96 ee
, 77%, 94 ee
OBn
F
H
N
H
N
H
N
H
N
H
N
MeO
MeO
MeO
BnO
O
O
O
O
O
b
14
15
16
17
18
, 72%, 90 ee
, 93%, 94 ee
, 83%, 98 ee
, 64%, 96 ee
, 74%, 93 ee
H
N
H
N
H
N
H
N
H
N
MeO
MeO
O
O
O
O
O
O
MeO
O
OMe
b
b
b
19
20
21
22
23
, 77%, 90 ee
, 75%, 99 ee
, 76%, 80 ee
, 64%, 85 ee
, 73%, 90 ee
H
H
N
H
N
H
N
N
O
O
O
O
O
S
N
O
b
b
24
25
26
27
, 81%, 95 ee
, 70%, 88 ee
, 95%, 94 ee
, 70%, 92 ee
H
N
H
N
H
H
N
N
BnO
O
N
O
O
O
a
O
O
O
S
b
a
a
28
29
30
31
, 88%, 85 ee
, 72%, 93 ee
, 81%, 85 ee
, 62%, 85 ee
H
H
H
N
N
N
O
O
O
O
O
O
O
O
O
O
O
b
33
, 71%, 94 ee
b
32
, 51%, 90 ee
from Nerol
34
, 71%, 99 ee
from (-)-Borneol
from Diacetonefructode
Internal alkenes
Ethene
OBn
H
N
H
H
N
O
N
H
H
N
N
O
N
H
O
O
40
35
O
O
59%, 97 ee (from trans)
50%, > 99 ee (from cis)
c
c
36
37
38
39
, 60%, 98 ee
, 62%, 85 ee
, 63%, 57 ee
, 81%
, 86%
Scheme 1. Substrate scope of alkenes. Standard conditions: 1 (0.12 mmol, 1.2 equiv), 2 (0.1 mmol, 1.0 equiv), MePhSiH2 (0.2 mmol, 2.0 equiv), CuCl
(5.0 mol%), L10 (5.0 mol%), LiOtBu (0.3 mmol, 3.0 equiv), CO (10 bar), DCE (0.5 mL), 50 ºC, 15 h, isolated yields. ee values are determined by chiral-
phase HPLC. [a] 40 ºC. [b] rt (room temperature, 26 ºC). [c] Ethene gas (2 bar) was used instead of styrenes.
electron-donating or electron-withdrawing groups at the para
position were successfully converted into the α-chiral secondary
amides 4-13 in high yields and excellent enantiomeric ratios (73-
91% yield, 85-99 ee). Meta-F, meta-Me, and ortho-OBn-substituted
styrenes gave the corresponding products 14-16 in 64-93% yields
and 94-98 ee values, thus indicating that the reaction is insensitive
After identification of the optimal conditions, we next
investigated the generality of this asymmetric Cu-catalyzed
hydroaminocarbonylation reaction. The reaction efficiency was first
evaluated under the optimal reaction conditions with the scope of
alkenes. As shown in Scheme 1, styrenes bearing different
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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CO (10 bar)
CuCl (5.0 mol %)
to the steric of the styrenes. Di- and tri-substituted styrenes were
also proceeded smoothly to generate the desired products 17-20
with high enantioselectivities (72-75% yield, 90-99 ee). To our
delight, 1-vinylnaphthalene, 2-vinylnaphthalene, 2-methoxy-6-
O
View Article Online
H
N
H
L10
(5.0 mol%)
DOI: 10.1039/D1SC04210F
N
R3
R3
O
+
PhMeSiH2 (2.0 equiv)
LiOtBu (3.0 equiv)
O
N
2
1
DCE, rt or 50 °C, 15 h
vinylnaphthalene,
5-vinylbenzo[d][1,3]dioxole,
and
5-
H
H
N
H
N
vinylbenzo[b]thiophene converted efficiently in the reaction even at
room temperature (20-24, 64-77% yield, 80-90 ee). Gratifyingly,
excellent enantiomeric ratios were observed even by using
functionalized styrenes as the coupling partners (25-31, 62-95%
yield, 85-95 ee). Moreover, the late-stage functionalization of
bioactive molecules has been investigated. Nerol, (-)-Borneol, and
Diacetonefructose derived styrenes were all reacted well,
generating the corresponding secondary amides in good yields and
high er values (32-34, 51-71% yield, 90-99 ee). Furthermore,
internal styrenes were also proved to be compatible under the
catalytic system; trans-β-methylstyrene afforded product 35 in 59%
yield with 97 ee, cis-β-methylstyrene gave 35 in 50% yield with >99
ee, product 36 can be delivered in good yield and excellent
N
Ph
O
O
O
a
a
3
, 62%, 99 ee
41
42
, 74%, 88 ee
, 83%, -90 ee
L10
with (S,S)-
H
N
H
N
O
O
CCDC:2084474
Displacement ellipsoid plot of
(30% probability level, without H)
43
44
, 92%, 93 ee
, 70%, 90 ee
44
H
N
H
N
H
N
O
O
O
S
a
a
46
47
50
, 90%, 87 ee
, 62%, 83 ee
45
, 96%, 98 ee
enantioselectivity
(60%
yield,
97
ee).
When
1,2-
dihydronaphthalene was employed, the desired product 37 was
isolated in 62% yield with 93:7 er. The bicyclic strained alkene could
also provide 38 in 63% yield but with moderate enantioselectivity
(57 ee). Meanwhile, ethene gas can be applied as well and high
yields of the corresponding products (39, 40) were isolated under
standard conditions，which further demonstrated the generality of
the reaction. However, no desired product could be detected when
the other aliphatic alkenes were tested, but the decomposition of
the hydroxylamine starting material.
H
N
H
N
H
N
O
O
O
a
49
, 74%, 1.5:1 dr
, 76%,1:1 dr
48
, 76%, 91 ee
H
N
H
N
H
Ph
N
Ph
H
O
O
O
O
O
0%
trace
Ph
H
H
N
N
H
Ph
51
, 84%, 1:1 dr
from Cholestan-3-ol
Ph
H
0%
O
0%
We then turned our attention to the compatibility of
hydroxylamine electrophiles and were pleased to find a broad
substrate scope. The reactivities of various mono alkyl-substituted
amine transfer reagents were investigated for the synthesis of α-
chiral secondary amides (Scheme 2). We observed that cyclic
amine sources were tolerated with five-, seven-, and even twelve-
membered rings, affording the desired products 41, 43, and 44 with
high yields and excellent enantioselectivities (70-92% yield, 88-93
ee). The absolute configuration of 44 was confirmed by X-ray
crystallographic analysis,[19] and the configuration of the other
compounds described in this work was assigned in analogy to 44.
The (S)-configuration product 42 can be obtained in 83% yield (-90
ee) by using (S,S)-Ph-BPE. In the current system, amine transfer
reagents were well tolerated regardless of the bulky adamantyl
group (45), heterocyclic group (46), and indanyl group (47). Amine
transfer reagent with a tertiary alkyl group substituent was a
competent substrate, delivering product 48 in good yield and
enantioselectivity (76% yield, 91 ee). Additionally, desired products
49-51 can be also isolated in 74%-84% yields with indicated
diastereomeric ratio (dr) values. In these cases, there are ee values,
but we been not able to measure the value. Additionally, several
other examples of substrates were prepared and tested as well, but
very low or no desired product could be detected. This might be
due to the decreased stability of the corresponding amine
substrates. The attempting to prepare substrate related with aniline
derivate failed.
O
Scheme 2. Substrate scope of hydroxylamines. Reaction conditions: 1 (0.12
mmol, 1.2 equiv), 2 (0.1 mmol, 1.0 equiv), MePhSiH2 (0.2 mmol, 2.0 equiv), CuCl
(5.0 mol%), L10 (5.0 mol%), LiOtBu (0.3 mmol, 3.0 equiv), CO (10 bar), DCE (0.5
mL), 50 ºC, 15 h, isolated yields; ee values are determined by chiral-phase HPLC,
diastereoselectivities determined by 1H NMR analysis. [a] rt (room temperature,
26 ºC).
Table 3. Scale-up reaction and the synthesis of 52a
CO (10 bar)
O
H
CuCl (2.5 mol %)
H
N
N
L10
(2.5 mol%)
O
+
+
PhMeSiH2 (2.0 equiv)
LiOtBu (3.0 equiv)
DCE, 50 °C, 15 h
O
N
44
1a
2h
1 mmo
87%, 92 ee
l
(1.2 equiv)
CO (10 bar)
CuCl (5.0 mol %)
O
O
H
N
H
N
L10
(5.0 mol%)
O
PhMeSiH2 (2.0 equiv)
LiOtBu (3.0 equiv)
DCE, 40 °C, 15 h
N
2i
(R)-52
, 69%, 96 ee
11b-HSD1 inhibitor
[a] Isolated yield, ee values are determined by chiral-phase HPLC.
As a demonstration of the robustness and practicality of this
method, the hydroaminocarbonylation process could be easily
conducted on 1.0 mmol scale with styrene and hydroxylamine
electrophiles 2h (Table 3, eq 1). Using reduced catalyst loading,
2.5 mol% CuCl and (R,R)-Ph-BPE-phos, 44 could be synthesized
in 87% isolated yield with high stereoselectivity (92 ee).
Furthermore, the (R)-52 product (52 is a 11b-HSD1 inhibitor)[18b]
can also be obtained easily in 69% yield and 96 ee by using trans-
β-methylstyrene and 2i under standard conditions (Table 3, eq 2).
4 | J. Name., 2012, 00, 1-3
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CuCl
anticipated and, as shown in Scheme 4, the pVroiedwuAcrtticsle Ownelirnee
L
DOI: 10.1039/D1SC04210F
produced as single geometric isomers.
LiOtBu
R3SiH
LiX
t
L
(
)Cu-O Bu
R3Si-OtBu
LiOtBu
Conclusions
L
L
(
)Cu-H
(
)Cu-
X
O
NHR
R2
In conclusion, we have developed a copper-catalyzed
regioselective
hydroaminocarbonylation
D
R1
R2
R1
and
enantioselective
of alkenes
intermolecular
electrophilic
H
with
X
NHR
hydroxylamines. Electrophilic amine transfer reagent possesses a
4-(dimethylamino)benzoate group was the key to this process. The
use of these reagents enabled the development of a general
method to directly convert styrenes and even challenging β-
substituted styrenes to α-chiral secondary amides. The method
displays broad functional group tolerance and proceeds under very
mild conditions, producing the desired α-chiral secondary amides
in high yields with excellent enantioselectivities (up to >99 ee). We
believe this Cu-catalyzed enantioselective synthesis of α-chiral
secondary amides provided a new idea in the study of asymmetric
hydroaminocarbonylation. Furthermore, alkynes were also
compatible substrates bearing in this catalytic system, giving the
corresponding α,β-unsaturated secondary amide products.
O
L
Cu(
)
L
Cu(
)
R2
R2
R1
R1
H
H
A
X
C
NHR
L
(
)Cu
R2
R1
CO
R-NH-X
H
B
Scheme 3. Proposed catalytic cycle.
The reaction mechanism is proposed according to previous
literature (Scheme 3).[16, 20] Initial formation of (L)CuOtBu from Cu(I),
ligand, and LiOtBu, followed by reaction with [Si]H, generates an
active copper hydride species (L)Cu-H. Subsequently, (L)Cu-H
insertion into alkene provides alkylcopper intermediates A. After
oxidative addition with electrophile hydroxylamine, the
intermediates B formed, which underwent CO insertion to give the
intermediates C. Then, reductive elimination occurs to deliver the
desired product, together with a (L)Cu-X complex D. Finally, ligand
exchange with LiOtBu regenerates the (L)CuOtBu species for the
next catalytic cycle.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank the Chinese Scholarship Council (CSC) for financial
support. We thank the analytical team of LIKAT for their very
kind support. We also thank Dr. Anke Spannenberg for the X-ray
crystal analysis.
CO (10 bar)
O
H
CuCl (5.0 mol %)
O
N
L10
(5.0 mol%)
R3
R3
O
R1
R2
+
R2
N
PhMeSiH2 (2.0 equiv)
LiOtBu (3.0 equiv)
DCE, 40 °C, 15 h
H
N
R1
2
O
O
O
S
S
N
N
N
H
H
H
Notes and references
R
R
1
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54
, R= H, 41%
, R= Me, 43%
55
56
, 48%
O
, 41%
O
O
N
Cl
N
N
H
H
H
57
58
59
, 45% (1.5:1)
, 46%
, 38%
Scheme 4. Substrate scope of alkynes. Reaction conditions: alkynes (0.1 mmol,
1.0 equiv), 2 (0.12 mmol, 1.2 equiv), MePhSiH2 (0.2 mmol, 2.0 equiv), CuCl (5.0
mol%), L10 (5.0 mol%), LiOtBu (0.3 mmol, 3.0 equiv), CO (10 bar), DCE (0.5 mL),
40 ºC, 15 h, isolated yields.
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