A General and Highly Selective Palladium-Catalyzed Hydroamidation of 1,3-Diynes

Article abstract of DOI:10.1002/anie.202010768

A chemo-, regio-, and stereoselective mono-hydroamidation of (un)symmetrical 1,3-diynes is described. Key for the success of this novel transformation is the utilization of an advanced palladium catalyst system with the specific ligand Neolephos. The synthetic value of this general approach to synthetically useful α-alkynyl-α, β-unsaturated amides is showcased by diversification of several structurally complex molecules and marketed drugs. Control experiments and density-functional theory (M06L-SMD) computations also suggest the crucial role of the substrate in controlling the regioselectivity of unsymmetrical 1,3-diynes.

Full text of DOI:10.1002/anie.202010768

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: A General and Highly Selective Palladium-Catalyzed
Hydroamidation of 1,3-Diynes
Authors: Jiawang Liu, Carolin Schneider, Ji Yang, Zhihong Wei, Haijun
Jiao, Robert Franke, Ralf Jackstell, and Matthias Beller
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10.1002/anie.202010768
Angewandte Chemie International Edition
RESEARCH ARTICLE
A
General
and
Highly
Selective
Palladium-Catalyzed
Hydroamidation of 1,3-Diynes
Jiawang Liu,[a] Carolin Schneider,[a] Ji Yang,[a] Zhihong Wei,[a,b] Haijun Jiao,[a],* Robert Franke,[c] Ralf
Jackstell,[a] and Matthias Beller[a],*
[a]
[b]
[c]
[†]
Dr. J. Liu,† C. Schneider,† Dr. J. Yang, Dr. Z. Wei, Dr. H. Jiao, Dr. R. Jackstell, Prof. Dr. M. Beller
Leibniz-Institut für Katalyse e.V., Albert-Einstein-Str. 29a, Rostock, 18059, Germany
E-mail: Haijun.Jiao@catalysis.de; matthias.beller@catalysis.de
Dr. Z. Wei
Institute of Molecular Science, Key Laboratory of Materials for Energy Conversion and Storage of Shanxi Province, Shanxi University , Taiyuan 030006, P.
R. China
Prof. Dr. R. Franke
Evonik Performance Materials GmbH, Paul-Baumann-Str. 1, 45772 Marl, Germany and Lehrstuhl für Theoretische Chemie, Ruhr-Universität Bochum,
44780 Bochum, Germany
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
chemo-, regio- and stereoselective mono-
and the basicity of the amine reagent. Moreover, alkynes are
prone to side reactions such as hydroamination and
oligomerization/polymerization. Nevertheless, by selecting
appropriate catalysts and optimization of reaction conditions
notable progress was achieved in the past decades.[7]
hydroamidation of (un)symmetrical 1,3-diynes is described. Key for
the success of this novel transformation is the utilization of an
advanced palladium catalyst system with the specific ligand L6
(Neolephos). The synthetic value of this general approach to
synthetically useful α-alkynyl-α, β-unsaturated amides is showcased
by diversification of several structurally complex molecules and
marketed drugs. Control experiments and density functional theory
(M06L-SMD) computations also suggest the crucial role of the
substrate in controlling the regioselectivity of unsymmetrical 1,3-
diynes.
Introduction
Transition metal catalyzed carbonylation reactions belong to the
important examples of industrially applied homogeneous catalytic
reactions. Since their discovery, they became a powerful tool for
the synthesis of numerous value-added carbonyl containing
compounds.[1] Thus, carbonylation reactions are frequently
applied in organic synthesis due to the versatility of the carbonyl
groups and the possibility to easily expand carbon chains.[2]
Within this class of reactions, hydroamidations, also called
aminocarbonylations, represent a straightforward route for the
conversion of olefins or alkynes, carbon monoxide and amines
into the corresponding amides. Compared to the well-explored
aminocarbonylation of alkenes using catalytic systems based on
cobalt,[3a, 3b] nickel,[3c] iron,[3d] ruthenium,[3e] rhodium[3f] and mainly
palladium,[3g-3l] the related reactions of alkynes leading to α, β-
unsaturated amides have received much less attention.
Scheme 1. Selected catalytic hydroamidations of alkynes.
So far, almost all these reactions are restricted to terminal alkynes,
which can be easily controlled to afford branched
[7c-n,13]
α, β-Unsaturated amides are valuable intermediates and building
blocks in organic synthesis and are used as functional molecules
in material science.[4] In addition, they are occurring in natural
products and bio-active pharmaceuticals.[5] Traditionally, they are
prepared by nucleophilic condensation of carboxylic acid
derivatives with amines in the presence of stoichiometric amounts
of activating or coupling reagents.[6] Obviously, such processes
result in significant waste formation. In this context, the
aminocarbonylation of alkynes can be a more atom-economic and
benign methodology. However, aminocarbonylations of alkynes
(and olefins) are intrinsically challenging due to the problems
associated with the acidity of the active metal hydride catalysts
or
linear[7h,7m,7n-q] α,β-unsaturated amides (Scheme 1, a). In fact, only
few aminocarbonylations of “simple” unsymmetrical internal
alkynes were reported,[7o,7s] leading to unsatisfactory
regioselectivity (Scheme 1, b). Clearly, carbonylations of
unsymmetrical internal alkynes are more demanding because of
their low reactivity and the difficulty in achieving high
regioselectivity. Notable exceptions include the recent works on
hydroformylation and alkoxycarbonylation reported by the groups
of Breit,[8a] You[8b] and Ma,[9] respectively. In these studies,
regioselectivity could be controlled by hydrogen bonding
1
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interactions between substrates and catalysts, steric hinderance
and/or chelation.
chemoselectivity for mono-alkoxycarbonylation of 1,3-diynes, it
was not the most efficient ligand in Pd-catalyzed alkoxycarbony-
lation of dienes[15d] or diynes[15e]. Commercially available ligands
L7-L16, including mono and bidentate phosphine ligands, which
are commonly used in other carbonylations,[17] were examined,
too; however, in all cases no product was detected under the
standard conditions. Comparison of L6 with L1-L5 demonstrated
that the backbones of ligand, which may lead to different bite
angles in Pd complexes, are also crucial for this transformation.
To improve the benchmark reaction further, we evaluated the
influence of critical reaction parameters in the presence of L6 (for
more details, see Table S1-S6 in SI). It is worth pointing out that
there was no reaction without acid or in the presence of weak acid
(HOAc or PhCO2H, Table S2), indicating the importance of the
strong acid for the generation of catalytically active Pd hydride
species (Figure 1). As a result, the formation of the acid by-
product could be prevented using triflic acid instead of PTSA·H2O.
Based on our continuous interest in carbonylation reactions,
recently we started to investigate the selective carbonylation of
unsymmetrical 1,3-diynes, which can be conveniently generated
via alkyne coupling processes[10] and provide synthetically highly
useful intermediates. Obviously, the selective hydroamidation of
unsymmetrical 1,3-diynes compared to internal monoalkynes
implies further challenges: 1) due to their higher reactivity
competitive hydroamination also becomes potentially easier;[11] 2)
the two unbiased alkyne moieties of unsymmetrical diynes create
more complex selectivity problems, including chemo-, stereo-,
and regioselectivity.[12] Thus, it is not surprising that to the best of
our knowledge no such process has been reported, yet. In fact,
only in 2018 Huang[13] and co-workers reported the first
aminocarbonylations using symmetrical 1,3-diynes. The need of
a comparably high palladium catalyst loading (5 mol%), and
relative harsh conditions (140 ˚C) offers also potential for
improvements.
Herein, we present the first examples of regioselective Pd-
catalyzed hydroamidation of unsymmetrical 1,3-diynes. Notably,
the mild conditions can also be applied in various symmetrical
substrates and a wide range of α-alkynyl-α, β-unsaturated amides
are obtained in general in good yields with excellent selectivities
(Scheme 1, c).
In the past three years, inspired by the seminal work of Drent and
co-workers,[14] we prepared several novel bidentate pyridyl-
substituted phosphine ligands.[15] Some of these ligands showed
significantly
improved
performance
for
Pd-catalyzed
alkoxycarbonylations of olefins or alkynes. Mechanistic studies
revealed that the nitrogen atoms of the pyridyl groups act as
proton shuttle to accelerate the nucleophilic attack on the
intermediate Pd acyl complex and thereby increasing the rate of
the overall transformation.[16] We envisioned that these ligands
might also improve the reactivity in Pd-catalyzed
aminocarbonylations. Hence, in our initial studies we compared
the influence of these and related ligands for the hydroamidation
of
1-(5-(trimethylsilyl)penta-2,4-diyn-1-yl)pyrrolidine-2,5-dione
(1a) with aniline at room temperature.
Results and Discussion
Scheme 2. Pd-catalyzed aminocarbonylation of unsymmetrical 1,3-diyne 1a:
Influence of phosphine ligands. Reaction conditions: 1a (0.25 mmol), Pd(TFA)2
(1.0 mol%), ligand (4.0 mol% for L1-L12, and 8.0 mol% for L13-L16), PTSA·H2O
(16.0 mol%), PhNH2 (2a, 0.25 mmol), CO (40 atm), 23 °C and toluene (1.0 mL),
20 h. The ratio of 3aa/4aa and yield were determined by GC and GC-MS
analysis.
As shown in Scheme 2, applying 1,1'-ferrocenediyl-bis(tert-
butyl(pyridin-2-yl)phosphine) L1 a highly selective monocarbo-
nylation (regioselectivity: >99/1) occurred leading to product 3aa.
Unfortunately, the reactivity of this system is too low (15% yield).
In the presence of other pyridyl-substituted ligands such as 1,3-
bis(tert-butyl(pyridin-2-yl)phosphanyl)-propane L2, 1,4-bis(tert-
With optimized reaction conditions established, we set up to
explore the scope of different unsymmetrical 1,3-diynes using 2a
as the nucleophile. As shown in Table 1, the catalytic system can
be conveniently applied to various unsymmetrical 1,3-diynes
derivatized from propargylamine or alcohol. In general, good to
high yields (50-94%) were obtained with substrates based on
succinimide, glutarimide or phthalimide derivatives (3aa-3na).
While the corresponding free propargylic alcohol derivative gave
no clean conversion, the acetylated substrates 1o-1q reacted
smoothly and gave the corresponding amides in 50-76% yields.
Notably, in all these cases excellent regioselectivity (>99/1) was
observed and exclusive formation of the E-regioisomers took
butyl(pyridin-2-yl)phosphanyl)butane
L3,
1,2-bis((tert-butyl-
(pyridin-2-yl)phosphanyl)methyl)benzene L4 and 2,2'-((2,7-di-
tert-butyl-9,9-dimethyl-9H-xanthene-4,5-di-yl)bis-(tert-butylp-
hosphanediyl))dipyridine L5, under these mild conditions no
conversion is observed, although most of these ligands have been
proved to be active in Pd-catalyzed alkoxycarbonylations.
Surprisingly, using 2,2'-bis(tert-butyl(pyridin-2-yl)phosphaneyl)-
1,1'-binaphthalene L6 (Neolephos), the desired product 3aa was
afforded in 84% yield and with excellent regioselectivity (>99/1).
In addition, the corresponding acid, which is generated via
hydroxycarbonylation, was isolated as a side product in 16%. It
should be noted that although ligand L6 showed high
2
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10.1002/anie.202010768
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place. In addition, the reaction of 1,3-diyne bearing two different
aromatic substituents also proceeded well to afford the
corresponding product in 86% yield with low regioselectivity
(60/40) (Scheme S1). Apart from unsymmetrical 1,3-diynes, a
variety of symmetrical substrates provided the corresponding α-
alkynyl-α, β-unsaturated amides under very mild conditions, too
(Table 2). In fact, without further optimization products 6aa-6ma
were obtained in 68-96% with excellent stereoselectivity. More
specifically, aromatic 1,3-diynes 5a–5f with either electron-
donating (OMe, Me, tBu) or electron-withdrawing (F, CF3)
substituents on the phenyl ring provided 6aa–6fa in high yields
(70-96%) and excellent selectivity. Substituents in the ortho-
position of the phenyl ring have no significant influence on both
reactivity and selectivity of this reaction; thus, 6ia-6ja were
produced in 78-92% yield. In addition, the thiofuryl-substituted
substrate was well tolerated by the catalyst to afford 6ma. Next,
the reactivity of aliphatic 1,3-diynes was investigated. Gratifyingly,
also in these cases the palladium-catalyzed hydroamidation
proceeded selectively, affording carbonylative products 6na-6wa
in 60-96% yields. It should be noted that the obtained products
may undergo isomerization processes in the presence of
palladium hydride species; but no side-products were observed in
all cases. Furthermore, functional groups such as cyano, ester
and trimethylsilyl survived in products 6ra and 6ta-6wa.
Table 2. Pd-catalyzed aminocarbonylation of symmetrical 1,3-diynes a
[a] Reaction conditions: 5 (0.25 mmol), Pd(acac)2 (1.0 mol%), L6 (2.0 mol%)
HOTf (8.0 mol%), aniline (2a, 0.25 mmol), CO (40 atm), 40 °C in toluene (1.0
mL), 20 h. Yields of isolated products are shown. [b] 60 °C. [c] PTSA·H2O (16.0
mol%) was used instead of HOTf.
Table 1. Pd-catalyzed aminocarbonylation of unsymmetrical 1,3-diynes
Table 3. Pd-catalyzed aminocarbonylation of 1,3-diyne 1a or 5a with different
arylamines a
[a] Reaction conditions: 1a or 5a (0.25 mmol), Pd(acac)2 (1.0 mol%), L6 (2.0
mol%) HOTf (8.0 mol%), arylamines (2, 0.25 mmol), CO (40 atm), 40 °C in
toluene (1.0 mL), 20 h. Yields of isolated products are shown. [b] 60 °C. [c]
PTSA·H2O (16.0 mol%) was used instead of HOTf.
Reaction conditions: 1 (0.25 mmol), Pd(acac)2 (1.0 mol%), L6 (2.0 mol%) HOTf
(8.0 mol%), aniline (2a, 0.25 mmol), CO (40 atm),40 °C in toluene (1.0 mL), 20
h. Yields of isolated products are shown.
Next, we evaluated the scope of this novel hydroamidation
process with respect to the reactivity of amines using
unsymmetrical (1a) and symmetrical (5a) 1,3-diyne as a standard
coupling partner, respectively (Table 3). A variety of arylamines
with electron-neutral, electron-deficient, and electron-rich
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substituents led to the corresponding carbonylative products in
good yields (51-90%) and again with excellent regioselectivities
(>99/1). Apparently, the substituents on the arylamines have no
real impact on the catalysis. Specifically, the reactions of
arylamines bearing Me, F, Cl, Ac, CN, CO2Et, MeO and MeS
substituents proceeded smoothly, providing the corresponding
products 3ab-3ae, 3ah-3ak in good isolated yields.[19] Notably,
bromine- and even iodine-substituted arylamines, which are
known to be sensitive to palladium catalysis, also worked well and
afforded the corresponding products (3af-3ag). The position of
substituents on the phenyl ring has no influence on the reaction
outcome. Hence, arylamines 2n-2p afforded 3an-3ap in 81-89%
yields. Interestingly, the 2-aminophenol (2q) and 2-
aminobenzamide (2r), which contain two nucleophilic positions,
also reacted selectively to give the amides 3aq and 3ar in 84%
and 90% yield, respectively. Furthermore, the heterocycle-
substituted amine 2s proved to be a viable coupling partner and
gave 3as in 73% yield. While secondary aromatic amines (2t and
2u) gave the desired products in good yields (3at and 3au), in
case of benzyl amine or n-butylamine no product was detected
under these conditions. It should be noted that almost all these
tested amines have similar behaviour in the hydroamidation of
symmetrical 1,3-diynes 5a, providing products 6ab-6aq and 6at-
6au in 45-94% yield. Unfortunately, there was no conversion at all
when aliphatic amines such as benzylic amine or n-pentylamine
was used instead of aniline (Scheme S2), and this is probably due
to the higher basicity of aliphatic amines than aniline. [20]
was studied to prove functional group tolerance and compatibility
with bio-relevant derivatives (Table 4). We were particularly
delighted to find that this Pd-catalyzed regioselective
hydroamidation of 1,3-diynes progressed well with substrates 7a
and 7b derivatized from uracil, one of the nucleobases of RNA,
and furnished products 7aa and 7ba in high yields and excellent
regioselectivity. Compound 7c, containing dehydrocholic acid,
which is a drug for stimulation of biliary lipid secretion, could also
be applied to afford the amide product 7ca in decent yield.
Moreover, nonsteroidal anti-inflammatory drugs such as
ibuprofen, indomethacin and isoxepac are viable components for
1,3-diynes substrates 7d-7f in this transformation. Finally, the
products 7at-7ct were prepared from the corresponding
secondary aniline.
To understand the observed regioselectivity and to gain more
mechanistic insights, several control experiments with
unsymmetrical 1,3-diynes were conducted. As shown in Scheme
3, the different substituents on the diyne unit control the
regioselectivity of the carbonylation reaction to a significant extent.
In general, the following selectivity order is observed: TMS ≤ prim.
alkyl < aryl << CH2OAc ≈ CH2NR2. Hence, testing 8 with our
catalyst under standard conditions, aminocarbonylation
proceeded preferentially at the phenyl-substituted alkyne group
(regioselectivity:
70/30)
(Eq.
1).
However,
applying
propargylamine/alcohol
derivatives,
hydroamidations
regioselectively took place at the triple bond substituted with these
functional groups. As an example, the protected propargyl alcohol
derivative 9 was synthesized and gave the amide product 9b in
56% yield with >99/1 regioselectivity (Eq. 2), which demonstrates
the crucial role of the oxygen atom for determining the
regioselectivity.
Table 4. Pd-catalyzed aminocarbonylation of 1,3-diynes containing biologically
or pharmaceutically relevant skeletons a
[a] Reaction conditions: diynes (0.25 mmol), arylamines (0.25 mmol), Pd(acac)2
(1.0 mol%), L6 (2.0 mol%), HOTf (8.0 mol%), CO (40 atm), 40 °C in toluene (1.0
mL), 20 h. Yields of isolated products are shown and in all cases the
regioselectivities are >99/1.
In general, our methodology vide supra allows to functionalize
aromatic amines to the corresponding enyne amides in a
straightforward manner under very mild conditions. We thought
that this unusual transformation, which also increases the
molecular complexity, can be of interest for many life science
applications including the diversification of natural products and
synthetic drugs. Notably, the resulting 1,3-enyne motif can be
additionally modified in several ways.[18] In this respect, the
hydroamidation of several structurally more complex molecules
Scheme 3. Pd-catalyzed hydroamidation of 1,3-diynes: Control experiments.
Standard condition: diynes (0.25 mmol), Pd(acac)2 (1.0 mol%), L6 (2.0 mol%)
HOTf (8.0 mol%), aniline (0.25 mmol), CO (40 atm), 40 °C in toluene (1.0 mL),
20 h. Yields of isolated products are shown and the ratio of regioisomers were
determined by GC and GC-MS analysis as well as 1H NMR analysis. [a] 70 °C.
Interestingly, the steric nature of the substituents on the alkyne
also plays a decisive role. Hence, the regioselectivity is increased
to 98/2 when trimethyl(phenylbuta-1,3-diyn-1-yl)silane 10 was
used (Eq. 3) instead of 8. In order to figure out, whether the
4
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carbonyl group plays
a decisive role in the control of
regioselectivity, the unsymmetrical 1,3-diyne 11 without nitrogen
atom but with carbonyl group was prepared and tested. Here,
product 11a was obtained with
a
completely different
regioselectivity (Eq. 4), which disproved the involvement of the
carbonyl group in the determination of the regioselectivity.
To understand the experimentally observed regioselectivity
further, density functional theory computations using different
methods in gas phase as well as in solution with and without
dispersion corrections were carried (see Supporting Information
for more details). If not otherwise mentioned, we used the
M06L/TZVP computed Gibbs free energies under the
consideration of solvation effect (toluene) on the basis of the
B3PW91/TZVP gas phase optimized geometries for discussion
and other results are given in the Supporting Information for
comparison. In our study we chose substrates 9 and 10 using the
complex of palladium and ligand L6 as active catalyst resulting in
totally opposite regioselectivity. These results are further
established with those of substrate 1a. Due to the chirality of the
ligand and the possible diastereomers of the formed complex, we
used the C2-symmetrical (R,R)-ligand for our computation with the
nitrogen atoms of the pyridyl groups in the Pd complex pointing
towards the Pd center. This enables a hemilabile coordination of
the ligand; and such complexation modes have been found in the
molecular structures of similar complexes.[16a]
Since the regioselectivity of metal-catalyzed carbonylation
reactions of non-symmetrical C=C or CC bonds comes from the
M-H insertion resulting in the formation of alkyl or alkenyl complex,
we computed this elementary step to elucidate the origin of the
regioselectivity. For the protonated active catalyst (Figure 1),
there are two stable isomers, and the one with proton on the Pd
center (LPd-H) is more stable than the one with proton on the N
atom of one 2-pyridyl ring (LPd-NH) by 2.4 kcal/mol. Such small
energy difference reveals the possibility of their mutual exchange
upon the change of the coordination sphere. It is noted that LPd-
NH is not stable und has been optimized directly to LPd-H at the
MN15/TZVP level. In both complexes, one 2-pyridyl nitrogen is
coordinated to the Pd center. With the coordination of substrate 9,
it shows that complexes with N-H functionality are more stable
than those with Pd-H group; and the most stable complex has the
CC coordination terminated with CH2OTBS substituent, and that
with Ph substituent is less stable by 3.7 kcal/mol. For the
coordination of substrate 10, the same energetic patterns have
been found and the most stable complex has the CC
coordination terminated with Ph substituent and that with TMS
substituent is less stable by 2.7 kcal/mol. This energetic order
reveals the increasing steric effect of CH2OTBS, Ph and TMS
substitutions.
Figure 1. Relative energy of the active catalysts as well as corresponding
alkyne complexes of substrates 9 and 10
OTBSCH2-C-H/C2Ph,
−7.5 kcal/mol and
LPd-9-Ph-C-
H/C2CH2OTBS, −4.7 kcal/mol). It is interesting to note that the
presence of the hemilabile 2-pyridyl ligand results in the more
stable alkenyl intermediates ((LPd-9-OTBSCH2-CH/C2Ph and
LPd-9-R1-CH/C2R2); and the former is also more stable than the
latter by 2.5 kcal/mol, which indicates
a thermodynamic
performance. These energy differences rationalize the observed
regioselectivity of substrate 9, which is favored both kinetically
and thermodynamically. For substrate 10, different results have
been found (Figure 2). For example, the transition state with
sterically less hindered Ph group at the coordinated C-C bond is
higher in energy than that with the sterically more hindered TMS
group by 2.1 kcal/mol (LPd-NH-10-Ph/C2TMS-TS vs. (LPd-NH-
10-TMS/C2Ph-TS). Such reversed energetic difference is indeed
understandable, since the C atom bonded to Ph is less negatively
charged than that bonded to TMS (−0.241 vs. −0.725 ) in the
transition states due to the difference in electronegativity of
carbon and silicon atoms. Consequently, the former will have
weaker attractive interaction than the latter. Next, it is not possible
to locate the C-H agostic intermediate following LPd-NH-10-
Ph/C2TMS-TS, and all attempts resulted in the direct formation of
the corresponding alkenyl complex LPd-10-PhCH/C2TMS. In
contrast, the corresponding C-H agostic intermediate (LPd-10-
Based on these complexes, we computed this elementary step
and the simplified potential energy surface for the regioselective
formation of the alkenyl complexes is shown in Figure 2. For
substrate 9, two transition states for the N-H insertion into the CC
bond have been located, which differs from the traditional Pd-H
insertion. The transition state with the sterically less hindered
CH2OTBS group at the CC bond (LPd-NH-9-OTBSCH2/C2Ph-
TS) is more stable than that one with Ph group (LPd-NH-9-
Ph/C2CH2OTBS-TS) at the CC bond by 3.0 kcal/mol, and this
reveals a kinetic preference.
Following these transition states, the corresponding intermediates
with C-H agostic interaction have been located (LPd-9-
5
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Figure 2. Potential energy surface for the regioselective formation of alkenyl complexes of 9 (top) and 10 (bottom).
TMS-C-H/C2Ph) following LPd-NH-10-TMS/C2Ph-TS was
located (−5.0 kcal/mol). Subsequently, the more stable alkenyl
intermediate (LPd-10-TMSCH/C2Ph) was located. On the
potential energy surface, the alkenyl intermediate LPd-10-
PhCH/C2TMS is more stable than LPd-10-TMSCH/C2Ph (−17.8
vs. −12.5 kcal/mol) due to the enhanced steric difference between
Ph and TMS, although the formation of the former is less favored
kinetically than the latter formation. Consequently, the observed
regioselectivity of substrate 10 should be governed
thermodynamically by considering the reversibility between (LPd-
NH-10-TMS/C2Ph-TS) and (LPd-10-TMS-C-H/C2Ph).
A similar potential energy surface for substrate 1a has been found
(Figure S3). For the CH2R terminated CC bond, the reaction has
an insertion free energy barrier of 9.9 kcal/mol and goes directly
to the corresponding alkenyl intermediate with exergonic reaction
free energy of 20.4 kcal/mol. For the TMS terminated CC bond,
the reaction has an insertion free energy barrier of 9.6 kcal/mol
followed by an C-H agostic intermediate (−4.6 kcal/mol) and the
6
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[1]
a) P. W. N. M. van Leeuwen, C. Claver, Rhodium Catalyzed
Hydroformylation, Vol. 22, Springer, Netherlands, 2002; b) Catalytic
Carbonylation Reactions (Ed.: M. Beller), Springer, Berlin
Heidelberg, 2006; c) B. Breit, in Metal Catalyzed Reductive C@C
reaction goes to the corresponding alkenyl intermediate with
exergonic reaction free energy of 13.5 kcal/mol. This indicates
once again the thermodynamic origin of the observed
regioselectivity.
Bond Formation:
A
Departure from Preformed Organometallic
Reagents (Ed.: M. J. Krische), Springer, Berlin, Heidelberg,
2007, pp. 139-172; d) Modern Carbonylation Methods, Wiley-VCH,
Weinheim, 2008; e) Transition Metals for Organic Synthesis: Building
To analyze the steric effect of different substituents, we computed
the relative energies of the products (Figure 3). For example, 9a
is more stable than 9b by 1.7 kcal/mol, while 10a is more stable
than 10b by 10.6 kcal/mol. Furthermore, 3aa is more stable than
4aa by 10.0 kcal/mol (Figure S3). To confirm this thermodynamic
trend, we computed the relative energy of isomers with H
substitution as reference and the substitution of CH2OTBS, Ph
and SiMe3 is less favored by 1.7, 2,4 and 11.1 kcal/mol,
respectively, indicating the increasing steric interaction. This
energetic order is in line with the observed regioselectivity.
Blocks
and
Fine
Chemicals
(Eds.:
M.
Beller,
C.
Bolm), Wiley-VCH, Weinheim, 2008; f) R. Franke, D. Selent, A.
Bçrner, Chem. Rev. 2012, 112, 5675-5732.
[2]
[3]
a) X.-F. Wu, H. Neumann, M. Beller, Chem. Soc. Rev. 2011, 40, 4986-
5009; b) X.-F. Wu, X. Fang, L. Wu, R. Jackstell, H. Neumann, M. Beller,
Acc. Chem. Res. 2014, 47, 1041-1053; c) B. Sam, B. Breit, M. J. Krische,
Angew. Chem. Int. Ed. 2015, 54, 3267-3274; d) S. D. Friis, A. T.
Lindhardt, T. Skrydstrup, Acc. Chem. Res. 2016, 49, 594-605; e) J.-B.
Peng, F.-P. Wu, X.-F. Wu, Chem. Rev. 2019, 119, 2090−2127.
a) P. Pino, P. Paleari, Gazz. Chim. Ital. 1951, 81, 64; b) S. I. Lee, S. U.
Son, Y. K. Chung, Chem. Commun. 2002, 1310-1311; c) W. Reppe, H.
Main, Chem. Abstr. 1953, 47, 5428; d) A. Striegler, J. Weber, J. Prakt.
Chem. 1965, 29, 281-295; e) Y. Tsuji, T. Ohsumi, T. Kondo, Y. Watanabe,
J. Organomet. Chem. 1986, 309, 333-344; f) K. Dong, X. Fang, R.
Jackstell, G. Laurenczy, Y. Li, M. Beller, J. Am. Chem. Soc. 2015, 137,
6053-6058; g) C. Jim8nez-Rodriguez, A. A. NfflÇez-Magro, T.
Seidensticker, G. R. Eastham, M. R. L. Furst, D. J. Cole-Hamilton, Catal.
Sci. Technol. 2014, 4, 2332-2339; h) H. Liu, N. Yan, P. J. Dyson, Chem.
Commun. 2014, 50, 7848-7851; i) X. Fang, R. Jackstell, M. Beller, Angew.
Chem. Int. Ed. 2013, 52, 14089-14093; j) G. Zhang, B. Gao, H. Huang,
Angew. Chem. Int. Ed. 2015, 54, 7657-7661; k) T. Xu, F. Sha, H. Alper,
J. Am. Chem. Soc. 2016, 138, 6629-6635; l) J. Liu, H. Li, A. Spannenberg,
R. Franke, R. Jackstell, M. Beller, Angew. Chem. Int. Ed. 2016, 55,
13544-13548.
Figure 3. Relative energy (kcal/mol) of the regioisomers as well as the simplified
reference molecules.
[4]
a) T. K. Hyster, T. Rovis, Chem. Sci. 2011, 2, 1606-1610; b) J.-H. Fan,
W.-T. Wei, M.-B. Zhou, R.-J. Song, J.-H. Li, Angew. Chem., Int. Ed. 2014,
53, 6650-6654; c) X. Mu, T. Wu, H.-Y. Wang, Y.-L. Guo, G. Liu, J. Am.
Chem. Soc. 2012, 134, 878-881; d) The Amide Linkage: Selected
Structural Aspects in Chemistry, Biochemistry and Materials Science; A.
Greenberg, C. M. Breneman, J. F. Liebman, Eds.; Wiley-VCH: New York,
2000; e) M. J. Caulfield, G. G. Qiao, D. H. Solomon, Chem. Rev. 2002,
102, 3067-3084.
Conclusion
In summary, we have developed a general and convenient Pd-
catalyzed hydroamidation of (un)symmetrical 1,3-diynes. For the
first time differently substituted 1,3-diynes undergo highly chemo-,
regio-, and stereoselective transformation to the corresponding
α,β-unsaturated amides. This novel catalytic transformation was
enabled by the “built-in-base” ligand (L6, Neolephos) under mild
conditions and provided a general approach to a variety of
interesting functionalized synthetic building blocks in good to high
yields. The utility of the catalytic system is showcased in versatile
modifications of several structurally complex molecules and
marketed drugs. Mechanistic studies and M06L-SMD density
functional theory computations revealed the key role of the
intrinsic substituents of substrates and the ligand in determining
the selectivity. We believe these findings will provide new impetus
for other selectivity-controlled carbonylation reactions using
unsymmetrical substrates.
[5]
[6]
a) C. Marrano, P. de Macedo, J. W. Keillor, Bioorg. Med. Chem. 2001, 9,
1923-1928; b) C.-C. Hung, W.-J. Tsai, L.-M. Yang Kuo, Y.-H. Kuo, Bioorg.
Med. Chem. 2005, 13, 1791-1797; c) S. Chaudhury, T. R. Welch, B. S.
J. Blagg, ChemMedChem 2006, 1, 1331-1340.
a) E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606-631; b) V. J.
Pattabiraman, J. W. Bode, Nature, 2011, 480, 471-479; c) J. M.
Concellón, J.A. Pérez-Andrés, H. Rodríguez-Solla, Angew. Chem., Int.
Ed. 2000, 39, 2773-2775; d) S. Kim, C. J. Lim, Angew. Chem., Int. Ed.
2004, 43, 5378-5380; e) M. K. Hadden, B. S. J. Blagg, J. Org. Chem.
2009, 74, 46974704.
[7]
For reviews, see: a) A. Brennführer, H. Neumann, M. Beller,
ChemCatChem, 2009, 1, 28-41; b) S. Quintero-Duque, K. M. Dyballa, I.
Fleischer, Tetrahedron Lett. 2015, 56, 2634-2650; For selected
examples, see: c) S. Torii, H. Okumoto, M. Sadakane, L. H. Xu, Chem.
Lett. 1991, 20, 1673-1676; d) E. Drent, P. Arnoldy, P. H. M. Budzelaar,
J. Organomet. Chem. 1993, 455, 247-253; e) B. El Ali, A. M. ElGhanam,
M. Fettouhi, J. Tijani, Tetrahedron Lett. 2000, 41, 5761-5764; f) B. El Ali,
J. Tijani, A. M. El-Ghanam, Appl. Organomet. Chem. 2002, 16, 369-376;
g) B. El Ali, J. Tijani, A. M. El-Ghanam, J. Mol. Catal. A: Chem. 2002,
187, 17-33; h) B. El Ali, J. Tijani, Appl. Organomet. Chem. 2003, 17, 921-
931; i) Y. Li, H. Alper, Z. Yu, Org. Lett. 2006, 8, 5199-5201; j) S.-M. Lu,
H. Alper, J. Am. Chem. Soc. 2008, 130, 6451-6455; k) R. Suleiman, J.
Tijani, B. El Ali, Appl. Organomet. Chem. 2010, 24, 38-46; l) H. Liu, G. P.
S. Lau, P. J. Dyson, J. Org. Chem. 2015, 80, 386-391; m) F. Sha, H.
Alper, ACS Catal. 2017, 7, 2220-2229; n) D.-L. Wang, W.-D. Guo, L. Liu,
Q. Zhou, W.-Y. Liang, Y. Lu, Y. Liu, Catal. Sci. Technol., 2019, 9, 1334-
1337; o) K. M. Driller, S. Prateeptongkum, R. Jackstell, M. Beller, Angew.
Chem. Int. Ed. 2011, 50, 537-541; p) M. Pizzetti, A. Russo, E. Petricci,
Chem. Eur. J. 2011, 17, 4523-4528; q) Z. Huang, Y. Dong, Y. Li, M.
Acknowledgements
This work is supported by Evonik Performance Materials GmbH,
the BMBF (Bundesministerium für Bildung und Forschung), and
the State of Mecklenburg-Vorpommern. We thank the analytical
team of LIKAT for their kind support. J. Y. thanks the Chinese
Scholarship Council (CSC) for financial support.
Keywords: catalysis • regioselectivity • hydroamidation • P ligand
• amides
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RESEARCH ARTICLE
Makha, Y. Li, ChemCatChem, 2019, 11, 5236-5240; r) T. Sugihara, Y.
Okada, M. Yamaguchi, M Nishizawa, Synlett, 1999, 6, 768-770; s) J. H.
Park, S. Y. Kim, S. M. Kim, Y. K. Chung, Org. Lett. 2007, 9, 2465-2468.
[19] CCDC 1998320 (3ah) and 2001174 (3ai) contain the supplementary
crystallographic data for this paper. These data are provided free of
charge by the joint Cambridge Crystallographic Data Centre and
Fachinformationszentrum Karlsruhe Access Structures service
www.ccdc.cam.ac.uk/structures.
[8]
a) W. Fang, B. Breit, Angew. Chem. Int. Ed., 2018, 57, 14817-14821; b)
G. Tan, Y. Wu, Y. Shi, J. You, Angew. Chem. Int. Ed. 2019, 58, 7440-
7444. For other regioselective hydroformylation of internal alkynes, see:
c) B. G. Van den Hoven, H. Alper, J. Org. Chem.1999, 64, 9640-9646; d)
B. G.Van den Hoven, H. Alper, J. Org. Chem. 1999, 64, 3964-3968; e) J.
R. Johnson, G. D. Cuny, S. L. Buchwald, Angew. Chem. Int. Ed. Engl.
1995, 34, 1760-1761.
[20] P. L. H. Edward, G. L. Sharon, J. Phys. Chem. Ref. Data, 1998, 27, 413-
686.
[9]
C. Huang, H. Qian, W. Zhang, S. Ma, Chem. Sci., 2019, 10, 5505-5512.
a) C. Glaser, Ber. Dtsch. Chem. Ges. 1869, 2, 422-424; b) C. Glaser,
Ann. Chem. Pharm. 1870, 154, 137-171; c) A. S. Hay, J. Org. Chem.
1960, 25, 1275-1276; d) A. Lei, M. Srivastava, X. Zhang, J. Org. Chem.
2002, 67, 1969-1971; e) Y. Nishihara, K. Ikegashira, K. Hirabayashi, J. -
i. Ando, A. Mori, T. Hiyama, J. Org. Chem. 2000, 65, 1780-1787; f) W.
Yin, C. He, M. Chen, H. Zhang, A. Lei, Org. Lett., 2009, 11, 709-712.
a) T. Shimada, Y. Yamamoto, J. Am. Chem. Soc., 2002, 124, 12670-
12671; b) D. H. Camacho, S. Saito, Y. Yamamoto, Tetrahedron Lett.,
2002, 1085-1088.
[10]
[11]
[12] a) Z. Yan, X.-A. Yuan, Y. Zhao, C. Zhu, J. Xie, Angew. Chem. Int. Ed.
2018, 57, 12906-12910; b) J. Liu, J. Yang, W. Baumann, R. Jackstell, M.
Beller, Angew. Chem. Int. Ed. 2019, 58, 10683-10687; c) S. Cembellín,
T. Dalton, T. Pinkert, F. Schäfers, F. Glorius, ACS Catal. 2020, 10, 197-
202; d) H. L. Sang, C. Wu, G. G. D. Phua, S. Ge, ACS Catal., 2019, 9,
10109-10114.
[13] X. Ji, B. Gao, X. Zhou, Z. Liu, H. Huang, J. Org. Chem., 2018, 83, 10134-
10141.
[14] a) E. Drent, P. Arnoldy, H. M. Budzelaar, J. Organomet. Chem., 1993,
455, 247-253; b) E. Drent, P. Arnoldy, P. H. M. Budzelaar, J. Organomet.
Chem. 1994, 475, 57-63.
[15] Several ligands were developed for different reactions, L4: a) K. Dong, X.
Fang, S. Gülak, R. Franke, A. Spannenberg, H. Neumann, R. Jackstell,
M. Beller, Nat. Commun. 2017, 8, 14117; L1: b) K. Dong, R. Sang, X.
Fang, R. Franke, A. Spannenberg, H. Neumann, R. Jackstell, M. Beller,
Angew. Chem. Int. Ed. 2017, 56, 5267-5271; L2 and L3: c) J. Liu, K.
Dong, R. Franke, H. Neumann, R. Jackstell, M. Beller, J. Am. Chem. Soc.
2018, 140, 10282-10288; HeMaRaphos: d) J. Yang, J. Liu, H. Neumann,
R. Franke, R. Jackstell, M. Beller, Science, 2019, 366, 1514-1517; L6: e)
J. Liu, J. Yang, C. Schneider, R. Frank, R. Jackstell, M. Beller, Angew.
Chem. Int. Ed. 2020, 59, 9032-9040.
[16] a) K. Dong, R. Sang, Z. Wei, J. Liu, R. Dühren, A. Spannenberg, H. Jiao,
H. Neumann, R. Jackstell, R. Franke, M. Beller, Chem. Sci. 2018, 9,
2510-2516; b) L. Crawford, D. J. Cole-Hamilton, E. Drent, M. Bühl, Chem.
-Eur. J., 2014, 20, 13923-13926; c) L. Crawford, D. J. Cole-Hamilton, M.
Bühl, Organometallics, 2015, 34, 438-449.
[17] a) G. Vasapollo, A. Scarpa, G. Mele, L. Ronzini, B. El Ali, Appl. Organomet.
Chem. 2000, 14, 739-743; b) C. J. Rodriguez, D. F. Foster, G. R.
Eastham, D. J. Cole-Hamilton, Chem. Commun., 2004, 1720-1721; c) T.
Xu, H. Alper, J. Am. Chem. Soc. 2014, 136, 16970-16973; d) P. Roesle,
L. Caporaso, M. Schnitte, V. Goldbach, L. Cavallo, S. Mecking, J. Am.
Chem. Soc., 2014, 136, 16871-16881; e) P. W. van Leeuwen, P. C.
Kamer, Catal. Sci. Technol. 2018, 8, 26-113; f) J. Y. Wang, A. E. Strom,
J. F. Hartwig, J. Am. Chem. Soc. 2018, 140, 7979-7993; g) S. J. Byrne,
A. J. Fletcher, P. Hebeisen, M. C. Willis, Org. Biomol. Chem. 2010, 8,
758-760; h) J. K. Stille, P. K. Wong, J. Org. Chem. 1975, 40, 532-534; i)
S. Klaus, H. Neumann, A. Zapf, D. Strübing, S. Hübner, J. Almena, T.
Riermeier, P. Groß, M. Sarich, W.-R. Krahnert, K. Rossen, M. Beller,
Angew. Chem. Int. Ed. 2006, 45, 154-158.
[18] a) D. Kang, J. Kim, S. Oh, P. H. Lee, Org. Lett. 2012, 14, 5636-5639; b)
H. Qian, X. Yu, J. Zhang, J. Sun, J. Am. Chem. Soc. 2013, 135,18020-
18023; c) Q. Yao, Y. Liao, L. Lin, X. Lin, J. Ji, X. Liu, X. Feng, Angew.
Chem., Int. Ed. 2016, 55, 1859-1863; d) P. H. Poulsen, Y. Li, V. H.
Lauridsen, D. K. B. Jørgensen, T. A. Palazzo, M. Meazza, K. A.
Jørgensen, Angew. Chem., Int. Ed. 2018, 57, 10661-10665; e) Z.-G. Ma,
J.-L. Wei, J.-B. Lin, G.-J. Wang, J. Zhou, K. Chen, C.-A. Fan, S.-Y. Zhang,
Org. Lett. 2019, 21, 2468-2472; see also reference 15e and the
references therein.
8
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10.1002/anie.202010768
Angewandte Chemie International Edition
RESEARCH ARTICLE
Select one of the twins: The advanced Pd catalyst system with L6 (Neolephos) as ligand enables highly selective hydroamidation of
unbiased (un)symmetrical 1,3-diynes. In this way, a wide range of synthetically useful α-alkynyl-α,β-unsaturated amides are afforded
in good to high yields with excellent chemo-, regio-, and stereoselectivities.
9
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