Copper-Catalyzed Carbonylative Hydroamidation of Styrenes to Branched Amides

Article abstract of DOI:10.1002/anie.202010509

Amides are one of the most ubiquitous functional groups in synthetic and medicinal chemistry. Novel and rapid synthesis of amides remains in high demand. In this communication, a general and efficient procedure for branch-selective hydroamidation of vinylarenes with hydroxyamine derivatives enabled by copper catalysis has been developed for the first time. The reaction proceeds under mild conditions and tolerates a broad range of functional groups. Applying a chiral phosphine ligand, an enantioselective variant of this transformation was achieved, affording a variety of chiral α-amides with excellent enantioselectivities (up to 99 % ee) and high yields.

Full text of DOI:10.1002/anie.202010509

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Accepted Article
Title: Copper-Catalyzed Carbonylative Hydroamidation of Styrenes to
Branched Amides
Authors: Xiao-Feng Wu, Yang Yuan, Fu-Peng Wu, Claas
Schünemann, Jens Holz, and Paul C.J. Kamer
This manuscript has been accepted after peer review and appears as an
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202010509
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Copper-Catalyzed Carbonylative Hydroamidation of Styrenes to
Branched Amides
Yang Yuan, Fu-Peng Wu, Claas Schünemann, Jens Holz, Paul C.J. Kamer, and Xiao-Feng Wu*
[
*]
Y. Yuan, F.-P. Wu, C. Schünemann, Dr. J. Holz, Prof. Dr. P. C.J. Kamer, Prof. Dr. X.-F. Wu, Leibniz-Institut fürKatalysee.V. an der UniversitätRostock,
Albert-Einstein-Straße 29a, 18059 Rostock, Germany; Prof. Dr. X.-F. Wu, Dal ia n National Laboratoryfor Clean Energy, Dalian Institute of Chemical
Physics, Chinese Academyof Sciences, 116023, Dalian, Liaoning, China, E-mail: Xiao-Feng.Wu@catalysis.de
Supporting information for this articleis given via a link at theend of the document.
[
14]
[15]
Abstract: Amides are one of the most ubiquitous functional groups in
synthetic and medicinal chemistry. Novel and rapid synthesis of
amides remains in high demand. In this communication, ageneral and
efficient procedure for branch-selective hydroamidationof vinylarenes
with hydroxyamine derivatives enabledby copper catalysis has been
developed for the first time. The reaction proceeds under mild
conditions and tolerates a broadrange of functional groups. Apply in g
a chiral phosphine ligand, an enantioselective variant of this
transformation was achieved, affording a variety of chiral α-amides
with excellent enantioselectivities (up to 99% ee) and highyields.
hydroesterification,
and
hydroxycarbonylation,
the
asymmetric hydroamidation of alkenes under CO atmosphere is
much more challenging.
Herein, we report for the first time the development of a
general and efficient copper catalyst for the hydroamidation of
vinylarenes with hydroxyamine derivatives, giving selectively
branched amides. The chiral α-amides were also obtained with
high ees by using a chiralphosphine ligand (Figure 1d).
Amides have been identified as one of the most important
structural motives since they are widely represented in natural
products, pharmaceuticals and agrochemicals, as well as
[
1]
chemical industry (Figure 1a). It is thus not surprising that
efficient construction of amide bonds has received considerable
interests from the synthetic community. Among numerous
[
2]
methods for the preparation of amides, transition-metal-
catalyzed hydroamidation represents a straightforward strategy
[
3]
[4]
[5]
[6]
for their synthesis from olefins. Although Fe, Co, Ni, and
[
7]
Ru were used as catalyst precursors in early studies for
hydroamidation, all these reactions required relatively severe
conditionsand resulted in fairlypoor chemoselectivity. Recently,
independent studies from several groups demonstrated that
palladium-based catalytic systems or rhodium-based catalytic
[
8]
systems, which involved palladium-hydride species or rhodium-
[
9]
hydride species as the key intermediate, could address the
problems of selectivity under relativelymild conditions and deliver
the corresponding amides in good yields (Figure 1b). Based on
the importance of amides, developing novel and efficient
strategiesforhydroamidation using earth-abundant catalystsand
readily available starting materials under mild conditions for the
synthesisof amidesis stillhighlydesirable.
Among the transition metal catalysts, copper catalysts are
attractive with severaladvantagesincluding abundant availability,
being non-expensive, lesstoxic, etc. However, compared with the
other metal catalysts, copper is much less explored in
[
10,11]
carbonylation chemistry.
To the best of ourknowledge, there
is no report been published on successfully applying copper
catalysts in hydroamidation of alkenes under CO atmosphere.
Inspired by the recent work on copper-catalyzed hydroamination
[
12]
of alkenes, we hypothesized that Cu-Hcatalysis could serve as
a platform for synthesizing branched amides. Specifically, in the
presence of silane, [(L)Cu-X] could generate an active [(L)Cu-H]
species, which would subsequently insert olefins and produce
alkyl copper intermediates. After oxidative addition of
hydroxylamine derivative followed by CO insertion reductive
elimination deliversthe desired branched amides(Figure 1c). On
Figure 1. a) Relevant amide containing molecules. b) Catalytic hydroamidat io n
of olefins. c) Strategy of Cu-catalyzed hydroamidation of olefins. d) Cu-
catalyzed hydroamidat io n of olefins (this work).
To begin the investigation, we started by optimizing a model
reaction using styrene 1a (1.5 equiv) and hydroxylamine
[13]
the other hand, compared to asymmetric hydroformylation,
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derivative2a (1.0 equiv)as substrates, CuCl asthe metalcatalyst,
Xantphos(L1) asthe ligandand LiO Bu asthebase under CO(10
bar) atmosphere. As shown in Table 1 (entries 1-7), a survey of
representative silanes at 60 °C in DCE (1,2-dichloroethane)
4
Ph
2
SiH
SiH
SiH
2
L1
111
111
111
111
34
6
t
5
Et
2
2
L1
45
7
6
Ph
3
L1
27
trace
2
showed that MePhSiH as the hydride source could afford the
7
PMHS
L1
7
trace
desired product branched amide 3a in 56% GC yield, albeit the
direct C-N coupling product 4a was also generated in 10% yield
8
MePhSiH
MePhSiH
MePhSiH
MePhSiH
MePhSiH
MePhSiH
MePhSiH
MePhSiH
MePhSiH
MePhSiH
MePhSiH
MePhSiH
MePhSiH
2
2
2
2
2
2
2
2
2
2
2
2
2
L2
trace
0
9
L3
trace
0
(
entry 3). Then different Xantphos-type ligands were tested.
Xantphos with different substituents, such as L2, L3 (Cy-
Xantphos), onlygave3a in trace amount (entries 8-9). Meanwhile,
Xantphos-type ligands with different bite angles, such as
Sixantphos (L4, L5), Nixantphos (L6), Thixantphos (L7),
Benzoxantphos(L8) were applied in the reaction (entries10-14),
the results indicated that Nixantphoswith a largerbite angle was
the optimal ligand and provided the desired product 3a in 63%
10
L4
109
0
0
11
12
13
14
15
16
L5
0
0
L6
114
110
120
63
2
L7
37
6
L8
25
trace
L9
9
trace
[
16]
yield (entry 12; Figure 2). Nixantphos with phenoxaphosphine
substituents (L10, entry 16) could also deliver 3a in 44% yield.
Using other commonly used phosphorus ligands (L11-L15) did
not give the desired product (entries 17-21). From the relation
between yieldsand bite angle, it implies that tetrahedralcomplex
stabilization by the phosphine ligand was important here (Figure
L10
L11
L12
L13
L14
L15
L6
44
7
17
83
0
0
18
19
20
91
0
0
131
102
92
0
0
0
0
2
). Notably, the yield of 3a could be further improved to 72ꢀ% by
decreasing temperature to 50 °C, and only trace amount of 4a
was detected (entry 22). Notably, tert-
21
MePhSiH2
MePhSiH
0
0
c
b
22
2
114
72 (70)
trace
butoxy(methyl)(phenyl)silane can be detected as end reaction
product. Moreover, the catalyst system can be reused (See
Supporting information). After the original reaction, all reagents
except copperand ligand wereadded and 67% yield of 3a can be
obtained in the second round. To see if radical intermediatewas
involved during the process, 2 equivalentsof radicalscavengers
were added into ourmodel system under the optimal conditions,
the yield of 3a decreased (BHT =19%; α-phenylstyrene =56%).
This result impliesmight exist radical intermediate. More studies
are under progress to illustrate the reaction mechanism.
[
a] Standard conditions: 1a(0.3mmol, 1.5 equiv), 2a (0.2 mmol, 1.0 equiv), [S iH ]
t
(0.4 mmol, 2.0 equiv), CuCl (10 mol%), Ligand (10 mol%), LiOBu (0.6 mmol,
.0 equiv), CO (10 bar), DCE (1.0 mL), 60 ºC, 20 h; Yields are determined by
GC analysis using hexadecane asinternal standard. [b]Isolated yield. [c] Under
0 °C.
3
5
7
6
5
4
3
2
1
0
0
0
0
0
0
0
0
a
Table 1. Optimization ofthe Reaction Conditions.
7
0
90
110
130
150
BiteAngle
Figure 2. Relation between bite angle and yie ld of 3a.
With the optimalconditions in hand, we initially investigated
the scope of vinylarenes in the reactions with 2a (Scheme 1).
Styrene bearing different electron-donating or electron-
withdrawing group at the para position were successfully
converted into the branched amides 3a-3h in moderate to good
yields (51-83%). The ortho-substituted (o-OBn) and meta-
substituted (m-Me, m-F) styrenes were also converted well (3i-
3
k). Functionalizable styrenes bearing
a
butene or
Entry
Silane
Ligand
Bite Angle
Yield 3a
%)
Yield 4a
(%)
(
bis(pinacolato)boron at the meta- position reacted effectively to
give 3i and 3m in 71% and 63% yields, respectively. Moreover,
di- and tri-substituted styrenes also reacted smoothly to furnish
the desired products (3n, 3o). 1-vinylnaphthalene, 2-
1
2
3
Et
(EtO)
MePhSiH
3
SiH
L1
L1
L1
111
111
111
0
0
2
MeSiH
39
56
6
vinylnaphthalene,
5-vinylbenzo[d][1,3]dioxole
and
5-
2
10
vinylbenzo[b]thiophene
and 2-vinylthiophene were also
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Angewandte Chemie International Edition
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COMMUNICATION
converted efficiently in the reaction (3p-3t). Surprisingly, the
bicyclic strained alkene could also provide 3u in 57% yield.
However, only trace of the desired products could be detected
when using α-substituted styrene and -substituted styrene as the
substrates.
Cholestan-3β-ol derived styrenes as the reactants afforded the
desired products 3ak and 3al in good yields. Furthermore,
Duloxetine and Paroxetine-based hydroxylamine derivative
electrophiles participated in this transformation efficiently to
provide the modified pharmaceutical products 3am and 3an ꢀi n
high yields with 1:1 dr. Ethene gas can applied as well and
moderate yields of the corresponding products (3ao, 3ap) were
isolated under standard conditions.
Scheme 2. Substratescopeof hydroxyamine derivatives. Reaction condit io ns:
1
2
(0.3 mmol, 1.5 equiv), 2a (0.2 mmol, 1.0 equiv), MePhSiH (0.4 mmo l, 2.0
t
equiv), CuCl (10 mol%), Nixantphos (10 mol%), LiOBu (0.6 mmol, 3.0 equ iv ),
CO (10 atm), DCE(1.0 mL), 50 ºC, 20 h, isolated yie ld s.
Scheme 1. Substrate scope of vinylarenes. Reaction conditions: 1 (0.3 mmol,
1
.5 equiv), 2a (0.2 mmol, 1.0 equ iv ), MePhSiH
2
(0.4 mmol, 2.0equiv), CuCl (10
t
mol%), Nixantphos (10 mol%), LiO Bu (0.6 mmol, 3.0 equiv), CO(10 bar), DCE
(
1.0 mL), 50 ºC, 20 h, isolated yields.
The compatibility of this catalytic system with a variety of
hydroxylamine derivative electrophiles was then examined
Scheme 2). Cyclic dialkyl (3v-3z), acyclic dialkyl (3aa-3ac),
(
dibenzyl (3ad) and alkylbenzylamine-based electrophiles (3ae)
were all suitable partners, deliveringthe correspondingbranched
amides in good yields. Moreover, N, N-diallylamine provided the
desired product 3af in 67% isolated yield. Additionally, substrates
bearing heterocyclicmotifs, including furan (3ag) and piperazine
(
3ah), could also be accommodated, providing the hydroamidated
products in good yields.
To demonstrate the potential applications, late-stage
modification of pharmaceutical derivatives and natural products
were investigated (Scheme 3).More specifically, styrenesbearing
carbon-carbon double bonds, such as Nerol and (R)-Myrtenol,
gave the corresponding products 3ai and 3aj in 57% and 66%
yields, respectively. Applying α-D-galactopyranose and 5α-
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Scheme 3. Substrate scope of complex molecules and ethene. React io n
conditions: 1 (0.3 mmol, 1.5 equiv), 2 (0.2 mmol, 1.0 equiv), MePhSiH
2
(0.4
mmol, 2.0 equiv), CuCl (10 mol%), Nixantphos (10 mol%), LiO Bu (0.6 mmol,
.0 equiv), CO (10 bar), DCE (1.0 mL), 50 ºC, 20 h, isolated yie ld s, ees are
t
3
determined by chiral-phaseHPLC. [a] ethene gas (2 bar) was used instead of
styrenes.
We subsequently set out to develop an enantioselective
variant of this Cu-catalyzed hydroamidation by using chiral
ligands (Table 2). Unfortunately, P‑chirogenic Xantphos ligands
[
17]
(
L1’-L5’) were ineffective here. (S)-Segphos (L6’) only gave
trace of 3a’, bulky (S)-DTBM-Segphos (L7’) gave the desired
product in 27% yield, albeit with an excellent enantioselectivity.
Then we identified a combination of CuCl and (R,R)-Ph-BPE (L8’)
to be optimal in view of the yield and enantioselectivity, and the
desired 3a’ was isolated in 83% yield with 93% ee.
Table 2. Optimization Studies for Cu-Catalyzed Enantioselect iv e
a
Hydroamidation of 1a with 2a.
Scheme 4. Substrate scope of enantioselective Cu-catalyzed hydroamidat io n.
Reaction conditions: 1 (0.3 mmol, 1.5 equiv), 2 (0.2mmol, 1.0 equiv), MePhSiH
2
t
(
0.4 mmol, 2.0 equiv), CuCl (10 mol%), (R,R)-Ph-BPE (10 mol%), LiOBu (0.6
mmol, 3.0 equiv), CO (10 bar), DCE (1.0 mL), 50 ºC, 20 h, isolated yields, ees
are determined by chiral-phase HPLC.
In summary, we have developed the first Cu-catalyzed
hydroamidation of vinylarenes with hydroxyamine derivatives to
produce a variety of amides with excellent regioselectivities. The
method displays broad functional group tolerance and proceeds
under mild conditions. An enantioselective Cu-catalyzed
hydroamidation of vinylarenes has been also developed
successfully by using (R,R)-Ph-BPE as the chiral phosphine
ligand. The asymmetric variant of this transformation allows for
the synthesis of α-chiral amides in good yields with excellent
enantioselectivities(up to 99% ee). We believe thishighlybranch-
selective hydroamidation presented in the study provides a new
strategy to enantioselectivelyforged amide bonds.
[
a] Standard conditions: 1a (0.3 mmol, 1.5 equiv), 2a (0.2 mmol, 1.0 equ iv ),
MePhSiH (0.4 mmol, 2.0 equiv), CuCl (10 mol%), Ligand (10 mol%), L iO tBu
0.6 mmol, 3.0 equiv), CO (10 bar), DCE (1.0 mL), 50 ºC, 20 h; Yields are
2
(
determined by GC analysis using hexadecane as internal standard; Ees are
determined by chiral-phase HPLC. n.d. = not determined. [b]Isolated yie ld . [c]
Cu(OAc) instead of CuCl.
2
Acknowledgements
The scope of the enantioselective Cu-catalyzed
hydroamidation of vinylarenes wastested subsequently(Scheme
We thank the Chinese Scholarship Council (CSC) for financial
support. We thanktheanalytical team of LIKAT fortheir verykind
support.
4
). Overall, both styrenes and hydroxyamine derivatives worked
well under the asymmetric catalytic system, leading to the
corresponding α-chiral amides in high yields with excellent
enantioselectivities. The absolute configuration of 3a’ was
[18]
determined to be R by comparingitsopticalrotation with (R)-3a,
and the configuration of the other compounds described in this Conflict of interest
work are assigned in analogy to 3a’.
The authors declareno conflict of interest.
Keywords: hydroamidation • copper • amides• carbonylation •
enantioselectivity
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[18] a) The absolute configuration of 3a’ [α]
D
3
= -59.1 (c = 0.7, CHCl ) was
determined to be R by the comparison ofthe signof optical rotation (R)-
2
4
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D
3
3a [α] = -75.5 (c = 0.84, CHCl ), which was prepared from (R)-(-)-2-
Phenylpropionic acid;b) T. Slagbrand, A. Volkov, P. Trillo, F. Tinn is , H.
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COMMUNICATION
The first Cu-catalyzed hydroamidation of vinylareneswith hydroxyamine derivativeshas been developed. The method displaysbroad
functionalgroup tolerance and proceedsunder mild conditions, allowing for the synthesis of branched amides. The asymmetricvariant
of this transformation was also achieved by applying (R,R)-Ph-BPE as the ligand, delivering the α-chiral amides in good yields with
excellent enantioselectivities(up to 99% ee).
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