Asymmetric Markovnikov Hydroaminocarbonylation of Alkenes Enabled by Palladium-Monodentate Phosphoramidite Catalysis

Article abstract of DOI:10.1021/jacs.0c11249

A palladium-catalyzed asymmetric Markovnikov hydroaminocarbonylation of alkenes with anilines has been developed for the atom-economical synthesis of 2-substituted propanamides bearing an α-stereocenter. A novel phosphoramidite ligand L16 was discovered which exhibited very high reactivity and selectivity in the reaction. This asymmetric Markovnikov hydroaminocarbonylation employs readily available starting materials and tolerates a wide range of functional groups, thus providing a facile and straightforward method for the regio- and enantioselective synthesis of 2-substituted propanamides under ambient conditions. Mechanistic studies revealed that the reaction proceeds through a palladium hydride pathway.

Full text of DOI:10.1021/jacs.0c11249

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Asymmetric Markovnikov Hydroaminocarbonylation of Alkenes
Enabled by Palladium-Monodentate Phosphoramidite Catalysis
Ya-Hong Yao, Hui-Yi Yang, Ming Chen, Fei Wu, Xing-Xing Xu, and Zheng-Hui Guan*
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ABSTRACT: A palladium-catalyzed asymmetric Markovnikov hydroaminocarbonylation of alkenes with anilines has been
developed for the atom-economical synthesis of 2-substituted propanamides bearing an α-stereocenter. A novel phosphoramidite
ligand L16 was discovered which exhibited very high reactivity and selectivity in the reaction. This asymmetric Markovnikov
hydroaminocarbonylation employs readily available starting materials and tolerates a wide range of functional groups, thus providing
a facile and straightforward method for the regio- and enantioselective synthesis of 2-substituted propanamides under ambient
conditions. Mechanistic studies revealed that the reaction proceeds through a palladium hydride pathway.
Scheme 1. Pd-Catalyzed Hydroaminocarbonylation of
Alkenes with Amines
ydrocarbonylation of alkenes is one of the most
fundamental and ideal reactions for the synthesis of
H
carbonyl compounds from readily available feedstocks.1
Whereas hydroalkoxycarbonylations2,3 and hydrothio-
carbonylations4 have been extensively developed over the
past decades and the state-of-the-art Pd-catalyzed methoxy-
carbonylation of ethylene has been conducted on a >300,000
ton per annum scale,5 hydroaminocarbonylation, a reaction
analogous with hydroalkoxycarbonylation and hydrothio-
carbonylation, has been far less well established. The original
catalytic systems for hydroaminocarbonylations based on Co,
Ni, Fe, and Ru complexes are operated at high temperatures
and often accompanied by aminoformylation side reactions,
thus resulting in limited substrate scope and fewer
applications.6 Recently, ligand-controlled regiodivergent Pd-
catalyzed hydroaminocarbonylations, which were promising
approaches to access either linear or branched amides, have
been developed by the groups of Beller,7 Cole-Hamilton,8 Liu,9
Huang,10 and Alper11 (Scheme 1 A,B).12 Despite these
advances, Pd-catalyzed asymmetric Markovnikov hydroamino-
carbonylations of alkenes with simultaneous control of the
regio- and enantioselectivity of the reaction, as well as a
straightforward and atom-economical approach to pharma-
ceutically interesting chiral amides with an α-stereocenter, have
not been realized so far.
In general, the use of bidentate ligands favors Pd-catalyzed
anti-Markovnikov hydroaminocarbonylations for the formation
of linear amides,7a,b,8,10a while Pd-catalyzed Markovnikov
hydroaminocarbonylation prefers resorting to a monodentate
ligand.7c,9,10b,11,13 Nevertheless, as a result of there being no
“chelate effect”, enantioselective monodentate ligand-assisted
carbonylations with competitively coordinative CO are always
tough issues.14 In addition, the high temperatures and
pressures that are generally required in this type of reactions
would make enantiocontrol much more difficult.15 With the
goal of simultaneous control of regio- and enantioselectivities
of hydroaminocarbonylation, we present herein a novel Pd-
catalyzed asymmetric Markovnikov hydroaminocarbonylation
of alkenes with anilines (Scheme 1 C). By utilizing a new PdI2-
phosphoramidite ligand catalytic system, the features of the
reaction include the following: (i) Effectiveness. The
Received: October 26, 2020
Published: December 29, 2020
https://dx.doi.org/10.1021/jacs.0c11249
J. Am. Chem. Soc. 2021, 143, 85−91
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hydroaminocarbonylation was operated under mild ambient
conditions and achieved in a regio- and enantioselective
manner. (ii) Generality. The reaction was suitable for a range of
substrates including alkenylarenes and aliphatic alkenes, and
primary and secondary anilines, and exhibited good compat-
ibility with sensitive functional groups such as bromo, phenolic
hydroxyl, and nitro. (iii) Utility. The utility the reaction is
demonstrated in the synthesis of the anti-inflammatory new
chemical entity (NCE) 5t in one step and in the syntheses of
ibuprofen, naproxen, and flurbiprofen in two steps.
phosphoramidite ligands with a range of electronic variation
at the 3,3′-positions of the H8-BINOL framework were
prepared and screened (L11−L16). Encouragingly, the yield
and ee of 3a achieved important improvement in these cases,
with 4-iBuOPh and phenoxazinyl (POA) substituents L16
being the most optimal. Due to the high reactivity of the new
ligand L16 (98% yield), the optimal reaction conditions to
afford the corresponding 3a with 94% ee in 98% yield
(branched-to-linear (b/l) ratio >99:1) were obtained by
lowering the reaction temperature to ambient conditions.
Notably, further lowering the reaction temperature to 10 °C
and also the pressure of CO to 30 atm, or employing BINOL-
type L17 as the ligand, gave rise to inferior results.
We initiated our investigations with Pd-catalyzed Markovni-
kov hydroaminocarbonylation of styrene 1a and aniline 2a at
60 °C under CO atmosphere (50 atm) in THF (Table 1).
With the optimal reaction conditions in hand, we focused
our effort on the reaction scope (Table 2). First, the scope of
anilines was investigated (Table 2A). Anilines with electron-
donating substituents, such as alkyl and methoxy, underwent
the Pd-catalyzed Markovnikov hydroaminocarbonylation
smoothly to afford the desired products in high yields and
high ee values (3a−3k, 62−98% yield, 91−98% ee). Notably,
the sterically bulky 2,6-dimethylaniline and 2,6-diisopropyl-
aniline were compatible with the above conditions, implying
that the reaction is insensitive to the steric effect of anilines.16
Owing to the stronger nucleophilicity of anilines than that of
phenols,11,17 simultaneous chemo-, regio-, and enantioselective
reactions were observed to afford the corresponding single
isomers 3l−3n in 72−91% yields and 88−95% ee when
aminophenols were used as the substrates. Anilines with halide
substituents, such as F and Cl, and strong electron-with-
drawing groups, such as NO2, were tolerated in the reaction to
deliver the desired products 3o−3q in high yields and ee’s.
Additionally, naphthylamines and even coordinative 8-amino-
quinoline were also tolerated in the reactions (3r−3t).
a
Table 1. Optimization of the Reaction Conditions
Secondary anilines were tested in the reaction as well. As
depicted in Table 2B, various N-alkylanilines, including
indoline and tetrahydroquinoline, were compatible with the
conditions to give rise to the corresponding 2-phenylpropan-
amides 4a−4i in high yields and ee values. The substrate scope
with respect to alkenylarenes was also investigated (Table 2C).
All of the para-, meta-, and ortho-methyl-substituted styrenes
gave the corresponding 2-arylpropanamides 5a−5c in high
yields and ee values, thus indicating that the reaction is
insensitive to the sterics of the styrenes. Styrenes with electron-
donating groups on aryl rings displayed higher reactivity than
those with electron-withdrawing groups in the reaction, but all
of the MeO-, AcO-, F-, Cl-, Br-, and NO2-substituted styrenes
afforded the desired 2-arylpropanamides 5d−5m in high ee
values. The compatibility of aryl chloride (5i−5k) and aryl
bromide (5l) not only indicates that there was no reactive
Pd(0) species in the reaction but they could also facilitate
further functionalization reactions at the retained carbon−
halogen bond. In addition, enantioenriched 2-naphthylpropan-
amides 5n and 5o could be synthesized in high yields through
our reactions where alkenylnaphthalenes were employed as the
starting materials.
a
Conditions: unless otherwise noted, 1a (0.15 mmol), 2a (0.1 mmol),
PdI2 (10 mol%), ligand (11 mol%), CO (50 atm), THF (1.0 mL), 60
°C, 48 h. Isolated yields. The ratios of branched to linear isomers
shown within parentheses were determined by GC-MS analysis of the
crude products. Enantiomeric excess was determined by chiral HPLC
analysis. The reaction was performed at room temperature (rt) for
72 h. 10 °C, 72 h. CO (30 atm), rt, 72 h. L17 was based on BINOL
framework.
b
c
d
Owing to the unique advantages of monophosphine ligands in
this type of reactions, a variety of privileged monodentate
chiral ligands (L1−L5) were screened first. The reaction
occurred at low temperature (60 °C) with ferrocenylphosphine
L2 and phosphoramidite L4 or L5 as the ligand, albeit in low
yields and low enantiomeric excess (ee). These primary results
inspired us to further search for an effective monodentate
ligand for the reaction. In this context, various phosphor-
amidite ligands (L6−L10) with different amino substituents
were screened. It was found that phenoxazinyl (L10) was the
best choice in terms of the reactivity, regioselectivity, and
enantioselectivity of the reaction. Subsequently, various
To demonstrate the utility of this Pd-catalyzed asymmetric
Markovnikov hydroaminocarbonylation (Table 2D), ibupro-
fen, naproxen, flurbiprofen and ketoprofen-derived 2-
arylpropanamides 5p−5s were synthesized in high yields and
ee values with the respective alkenylarenes and aniline as the
starting materials. As a result, a series of enantioenriched non-
steroidal anti-inflammatory drugs (NSAIDs), including ibu-
profen 6, naproxen 7, flurbiprofen 8, and ketoprofen, were
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a
Table 2. Palladium-Catalyzed Asymmetric Markovnikov Hydroaminocarbonylation of Alkenylarenes with Anilines
a
Conditions: alkenylarene 1 (0.15 mmol), aniline 2 (0.10 mmol), PdI2 (10 mol%), L16 (11 mol%), CO (50 atm), THF (1.0 mL), rt, 72 h. Isolated
b
yields. The ratios of branched to linear isomers (b/l) were determined by GC-MS analysis of the crude products. Conditions: 1 M H2SO4 (aq, 1.0
mL), 1,4-dioxane (1.0 mL), 80 °C, 8 h.
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obtained in high yields by an additional hydrolysis step from
5p−5s. The p-amidophenol-derived NSAIDs, which were
recognized as NCEs, displayed reduced ulcerogenic potential
compared to their parent NSAIDs and enhanced anti-pyretic
activity compared to paracetamol.18 In this context, the anti-
inflammatory NCE 5t was synthesized in one step under our
conditions by employing 1-isobutyl-4-vinylbenzene and 4-
aminophenol as the starting materials.
hindered substrates. For example, the alkenes substituted with
more sterically demanding isopropyl or cyclohexanyl group
produced their desired amides 9h and 9i with moderate
regioselectivities in high yields and with 57−63% ee values.
To gain mechanistic insight into the reaction, control
experiments were performed (Table 4). First, it was found that
Table 4. Control Experiments
Furthermore, the scope and limitations of aliphatic alkenes
were explored (Table 3). Ethylene was well compatible with
Table 3. Palladium-Catalyzed Hydroaminocarbonylation of
a
Aliphatic Alkenes with Aniline
yield of 3a
a
entry
variation from standard conditions
(%)
1
2
3
4
5
6
none
98
<10
95
81
0
anhydrous THF as the solvent
anhydrous THF as the solvent + H2O (1.0 equiv)
Pd/C (10 mol%) and HI (10 mol%) instead of PdI2
Na2CO3 (1.0 equiv) was added as a base
K2CO3 (1.0 equiv) was added as a base
0
a
Conditions: styrene 1a (0.15 mmol), aniline 2a (0.10 mmol), PdI2
(10 mol%), L16 (11 mol%), CO (50 atm), THF (1.0 mL), rt, 72 h.
Isolated yields.
the trace amount of H2O played a vital role in the reaction.
The reaction was significantly suppressed when anhydrous
THF was used as the solvent, while a 95% yield of 3a was
obtained when 1.0 equiv of H2O was employed as the additive
(entries 2 and 3). The replacement of PdI2 by Pd/C and HI
resulted in 3a in 81% yield (entry 4). And the reaction was
completely suppressed by a base, such as Na2CO3 or K2CO3
(entries 5 and 6). These experimental results suggest that the
Pd-catalyzed hydroaminocarbonylation reaction proceeded
most likely through a palladium hydride pathway.
a
Conditions: alkene 1 (0.30 mmol), aniline 2a (0.20 mmol), PdI2 (10
mol%), L16 (11 mol%), CO (50 atm), THF (2.0 mL), rt, 72 h.
Isolated yields. The ratios of branched to linear isomers (b/l) were
determined by GC-MS analysis of the crude products. Alkene
(ethylene, propene, 1-butene) (1 atm). 60 °C.
On the basis of the above preliminary observations and the
known reports on Pd-catalyzed hydrocarbonylations,7−11,20
a
b
c
tentative mechanism is proposed in Scheme 2. Initially, a
Scheme 2. Tentative Reaction Mechanism
the conditions to afford the desired propionanilide 9a in 93%
yield, although the regio- and enantioselectivities were not
involved in the reaction. In general, the transition-metal-
catalyzed Markovnikov hydrocarbonylations (hydro-
formylation, hydroalkoxycarbonylation, and hydroamino-
carbonylation) of aliphatic alkenes toward branched carbonyl
compounds are particularly not favored because of the
increasing steric effects for both the step of alkene insertion
into the [M−H] to form the secondary carbon−metal species
and the step of CO insertion into the secondary carbon−metal
species.3a,15a,19 Meanwhile, the Pd-catalyzed Markovnikov
hydroaminocarbonylation of propene for the formation of
isobutyrylanilide 9b with b/l = 91:9 was achieved in 90% yield
under our conditions. Encouraged by this result, we then
evaluated various alkenes. Non-functionalized bulk aliphatic
alkenes, such as 1-butene, 1-hexene, 1-octene, 1-decene, and
methyl 10-undecenoate were tolerated under the conditions to
afford the corresponding branched amides 9c−9g with b/l =
83:17 to 91:9 in high yields. Presumably due to the lack of
functional groups that can provide binding or affinity
interaction with the catalyst as well as the very small
differentiation of the two prochiral faces of aliphatic alkenes,
low ee values were obtained in these cases. However, the
situation can be partially improved by utilizing sterically
palladium hydride species A is generated from the reaction of
PdI2, H2O, and CO. Coordination and insertion of alkene 1
into palladium hydride A afford the alkyl-Pd intermediate B.
The alkyl-Pd B undergoes CO coordination and insertion to
give the acyl-Pd intermediate C. Finally, aminolysis of acyl-Pd
C results in the desired amide and regenerates the active
palladium hydride catalyst A.
To gain further insight into the catalytic cycle, deuterium-
labeling experiments were conducted under the standard
conditions. First, when the deuterium-labeled 1a-D2 was used
as the substrate and 1.0 equiv of H2O was used as the additive,
88
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Scheme 3. Deuterium-Labeling Studies
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11249.
■
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Experimental procedure and characterization data for all
the products (PDF)
Crystallographic data for 3p (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Zheng-Hui Guan − Key Laboratory of Synthetic and Nature
Molecule of Ministry of Education, Department of Chemistry
& Materials Science, Northwest University, Xi’an 710127,
P.R. China; orcid.org/0000-0003-4901-5951;
Email: guanzhh@nwu.edu.cn
Authors
Ya-Hong Yao − Key Laboratory of Synthetic and Nature
Molecule of Ministry of Education, Department of Chemistry
& Materials Science, Northwest University, Xi’an 710127,
P.R. China
Hui-Yi Yang − Key Laboratory of Synthetic and Nature
Molecule of Ministry of Education, Department of Chemistry
& Materials Science, Northwest University, Xi’an 710127,
P.R. China
Ming Chen − Key Laboratory of Synthetic and Nature
Molecule of Ministry of Education, Department of Chemistry
& Materials Science, Northwest University, Xi’an 710127,
P.R. China
Fei Wu − Key Laboratory of Synthetic and Nature Molecule of
Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710127, P.R.
China
Xing-Xing Xu − Key Laboratory of Synthetic and Nature
Molecule of Ministry of Education, Department of Chemistry
& Materials Science, Northwest University, Xi’an 710127,
P.R. China
H/D scrambling was not observed (Scheme 3a). This result
suggested that the hydropalladation process from palladium
hydride A to intermediate B is irreversible and should be the
regio- and enantiodetermining step of the reaction. However,
when the deuterium-labeled 2a-D7 (>98% D on nitrogen) was
used as the substrate, an important deuterium loss was
observed, even in the presence of 1.0 equiv of D2O (Scheme
3b). This result indicated that a trace amount of active H
(maybe in the form water) is still contained in the reaction. For
comparison, the control experiments were carried out by using
either 2a-D7/H2O (1:1) or 2a/D2O (1:1) as the substrates
(Scheme 3c,d). In both cases, similar results (20% D in 3a-D1)
were obtained. These two experiments indicated that H/D
exchange on aniline and water is fast under the conditions.
Since these experiments were operated under identical
conditions (Scheme 3b−d), we then concluded that the
kinetic isotope effect (KIE) on the hydrogen of aniline was
3.33, thus indicating that aminolysis is probably the rate-
limiting step of the reaction.
In summary, we have developed the first Pd-catalyzed
asymmetric Markovnikov hydroaminocarbonylation of alkenes
with anilines. A new catalytic system of PdI2-phosphoramidite
ligand L16 was discovered. The reaction proceeded under mild
ambient conditions and exhibited good functional group
compatibility. A diverse array of 2-substituted propanamides
was obtained straightforwardly in high yields and enantio-
selectivities, several of which could be easily converted to non-
steroidal anti-inflammatory drugs. Mechanistic investigations
revealed that the reaction proceeds through a palladium-
hydride mechanism, and the hydropalladation is irreversible
and is the regio- and enantiodetermining step, while aminolysis
is probably the rate-limiting step. Further scope and
mechanistic studies of such reactions are underway and will
be reported in due course.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11249
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by generous grants from the National
Natural Science Foundation of China (NSFC-21971204,
21622203, 21702161) and the Innovation Capability Support
Program of Shaanxi Province (No. 2020TD-022). We thank
Prof. Xi Chen for her helpful polishing of the paper. This paper
is dedicated to Prof. Xumu Zhang on the occasion of his 60th
birthday.
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