General Olefin Synthesis by the Palladium-Catalyzed Heck Reaction of Amides: Sterically Controlled Chemoselective N-C Activation

Article abstract of DOI:10.1002/anie.201507776

Metal-catalyzed reactions of amides proceeding via metal insertion into the N-CO bond are severely underdeveloped due to resonance stabilization of the amide bond. Herein we report the first Heck reaction of amides proceeding via highly chemoselective N-CO cleavage catalyzed by Pd⁰ utilizing amide bond ground-state destabilization. Conceptually, this transformation provides access to a myriad of metal-catalyzed transformations of amides via metal insertion/decarbonylation.

Full text of DOI:10.1002/anie.201507776

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International Edition: DOI: 10.1002/anie.201507776
German Edition: DOI: 10.1002/ange.201507776
Heck Reaction
General Olefin Synthesis by the Palladium-Catalyzed Heck Reaction of
À
Amides: Sterically Controlled Chemoselective N C Activation
Guangrong Meng and Michal Szostak*
Abstract: Metal-catalyzed reactions of amides proceeding via
directly correlated with additive distortion parameters (St +
cN),[15] which allows to rationally design arrays of amides for
À
metal insertion into the N CO bond are severely under-
developed due to resonance stabilization of the amide bond.
N C scission via catalytic cross-coupling manifolds.[16]
À
À
Herein we report the first Heck reaction of amides proceeding
Expanding upon the N C amide bond activation concept,
0
via highly chemoselective N CO cleavage catalyzed by Pd
we hypothesized that the acyl-PdII intermediate[17] formed
after Pd insertion into the inert amide N CO bond might
À
0
À
utilizing amide bond ground-state destabilization. Conceptu-
ally, this transformation provides access to a myriad of metal-
catalyzed transformations of amides via metal insertion/
decarbonylation.
undergo selective decarbonylation[18] to give the aryl-PdII
electrophile, thereby providing access a wide variety of
valuable end-products by functionalization and/or elementary
reactions (Figure 1).[19]
T
he Heck reaction is one of the most powerful methods for
À
the catalytic construction of C C bonds under mild con-
ditions,[1,2] and has been widely utilized for the synthesis of
small molecules, natural products, polymers and pharmaceut-
icals on both the laboratory and industrial scale.[3,4] Over the
last four decades, a variety of aryl halides,[5a–d] aryl triflates,[5e]
aryl phosphates,[5f] aryl diazonium salts,[5g,h] arylsulfonyl
halides,[5i] aroyl halides,[5j,k] anhydrides[5l] and esters[5m] have
been shown to participate as aryl electrophiles in this
reaction.[6] Significant advances in the development of new
catalytic systems[7] and mechanistic studies have been
reported.[8] However, despite the reported advances, the use
of amides as electrophilic coupling partners in the Heck
reaction remains unknown.[1–8] There is little doubt that the
successful application of bench-stable amide building blocks
as olefination precursors would significantly broaden the
scope of electrophilic partners for the Heck reaction and
represent an attractive opportunity for the development of
[9]
À
new activation modes of inert N C bonds.
Metal-catalyzed reactions of amides proceeding via metal
À
insertion into the N CO bond are severely underdeveloped
due to nN!p*C stabilization.[10] We recently questioned
=
O
whether the use of amide ground-state distortion,[11] a well-
recognized property of non-planar amides,[12] can be exploited
À
to promote metal insertion into the amide N CO bond under
chemoselective conditions to deliver the acyl-metal inter-
mediate capable of participating in a myriad of catalytic cross-
coupling manifolds.[13] Recently, new methods for activation
of amides by electronic means have been reported.[14] Steric
activation of amides results in a general reactivity platform of
amide bonds.[9–14] Furthermore, we have recently demon-
strated that the N-/O-coordination aptitude in amides can be
Figure 1. A) Electrophiles in the Heck reaction. B) Transition-metal
catalyzed activation of amides. C) This work: the first Heck reaction of
amides via ground-state distortion.
Herein, we document the first Heck reaction of amides
À
proceeding via highly chemoselective N CO cleavage cata-
lyzed by Pd0, utilizing amide bond ground-state destabiliza-
tion as a new strategy for organic synthesis. The following
features are noteworthy: 1) The reaction proceeds with an
[*] G. Meng, Prof. Dr. M. Szostak
Department of Chemistry, Rutgers University
73 Warren Street, Newark, NJ 07102 (USA)
E-mail: michal.szostak@rutgers.edu
À
excellent N CO bond cleavage selectivity (> 95:5 in all cases
examined).[11c] 2) The protocol is characterized by a broad
substrate scope with respect to amide and alkene coupling
partners.[5j–m] 3) High yields and coupling selectivity are
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201507776.
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achieved under base-free and ligand-free conditions, leading
to an operationally simple protocol, reduction of waste and
cost of the process.[5l] 4) Stoichiometric corrosive halide waste
is not formed in the reaction.[4a] 5) This reaction constitutes
the first general method for the synthesis of aryl electrophiles
from amides under catalytic conditions.[9–14] Notably, this
transformation represents a significant advance in the con-
metal intermediate;[18c] 3) the leaving group should regener-
ate Pd0,[1,2] thus obviating the need for a stoichiometric
amount of external base.[9]
The optimization results in Table 1 revealed that no
reaction or low yields were observed with Weinreb amides
(entry 1),[22a] tmp amides (entry 2),[22b] acylpyrroles
(entry 3),[22c] and five-membered imide derivatives
(entry 4).[22d] However, we were delighted to find that by
using the six-membered imide derivative 1 f (entry 5),[22d] the
proposed Heck reaction was indeed feasible delivering the
desired olefin in excellent 95% yield (2,1/1,2 > 98:2; E/Z >
98:2). Pyramidalized aziridinyl (entry 6) and azetidinyl
(entry 7) amides[22e] resulted in no product formation. Fur-
À
À
struction of C C bonds directly from amides via N C
activation[20] with potential applications ranging from func-
tionalization of biomolecules (amino acids, peptides, pro-
teins)[21] to large scale industrial olefinations for the produc-
tion of specialty and bulk chemicals.[4b]
The following gram scale procedure is representative:
a mixture of 1a (1.49 g, 5 mmol), olefin (0.77 g, 6 mmol), and
PdCl2 (26.6 mg, 0.15 mmol) was stirred in the presence of
LiBr (39.1 mg, 0.45 mmol) in NMP at 1608C to afford 1.14 g
of 3a (80% yield) [Eq. (1)].
À
thermore, it is worth noting that N C bond activation was not
observed using electronically-activated amide substrates
(entry 8),[14] which presents an attractive opportunity for
chemoselective transformations using complementary amide
bond activation modes. Overall, the results in Table 1 validate
À
the feasibility of the N C activation/decarbonylation plat-
form of sterically-activated amides. The results show a unique
behavior of twisted imide 1 f, and suggest that the ground-
state destabilization may not be the only factor contributing
to the observed reactivity.[13] Importantly, under these con-
ditions reductive elimination from the acyl-Pd intermediate
was not observed, suggesting that decarbonylation is facile.
Table 1-SI (SI = Supporting Information) presents
selected results obtained during optimization of the reaction
using 1 f and styrene. Palladium chloride was identified as the
most active precatalyst. NMP was found to be the optimum
solvent. Phosphane ligands and base were not required for the
efficient coupling. Catalytic halide salts[7a] exerted small but
beneficial effect on the reaction selectivity, consistent with the
ligand effect on the olefin insertion step during the catalytic
cycle (see below).[8a] Optimization of the temperature
revealed that catalytic turnover of Pd ensues at lower
temperatures, but the process is less efficient. Other products
resulting from the acyl-PdII intermediate were not detected in
the reaction. As for related cross-couplings,[5j–m] the addition
to styrene is not completely regioselective; however, the
observed selectivity compares very favorably with other
reported olefinations.[1,2] Notably, olefin overaddition prod-
ucts were not detected in the reaction.
Our initial efforts focused on screening a range of
electronically and sterically distorted amides in the reactions
with n-butyl acrylate as a coupling partner in the presence of
palladium catalytic systems under various conditions
(Table 1). We hypothesized that 1) metal insertion into the
À
N C bond in amides in which the sum of distortion
parameters (Æt + cN) is close to 508 should be thermodynami-
cally favorable;[15] 2) less coordinating ligands and high
temperatures should favor decarbonylation of the acyl-
Table 1: Optimization of the amide bond geometry.[a]
With the optimized conditions in hand, we explored the
scope of the reaction using styrene as a standard olefin
(Table 2). The reaction exhibits an excellent chemoselectivity
profile, tolerating a wide range of functional groups. The
observed coupling selectivity (2,1/1,2 see SI) is good to
excellent in all cases examined. In all cases, single olefin
isomers were obtained (E/Z > 98:2). Electron-donating (3d,
3e) and electron-withdrawing (3 f–3h) substituents are well-
tolerated. Amides containing sensitive functional groups at
the para position of the aromatic ring such as cyano (3g), nitro
(3h), fluoro (3i), chloro (3j), and bromo (3k) were all
successfully coupled in high yields, providing a synthetic
handle for further functionalization. Steric hindrance in the
ortho-position was well-tolerated (3l–3m). Naphthyl (3n)
and heteroaromatic amides (3o) underwent olefination in
high yields. Remarkably, the reaction was fully chemoselec-
Entry
NR’R’’
t
cN
[deg]
Conv.
[%]
Yield
[%]
[deg]
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1h
1i
1.2
34.1
39.7
45.9
87.8
14.3
5.1
16.3
17.0
8.4
10.7
6.8
69.6
33.1
33.1
<5
<5
<5
<5
>98
<5
<5
<5
<5
<5
<5
<5
95
<5
<5
<5
5.1
[a] Conditions: R=CO2nBu (1.2 equiv), PdCl2 (3 mol%), LiBr (9 mol%),
NMP (0.25m), 1608C. See Supporting Information for full details.
À
tive for the C N bond activation in the presence of other
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Table 3: Olefin scope in the Pd-catalyzed Heck reaction of amides.[a,b]
Table 2: Amide scope in the Pd-catalyzed Heck reaction of amides.[a,b]
Entry
1
2
Olefin
Yield
[%]
Regio-
selectivity
1
2
1 f
1 f
2b
2c
86
84
15:1
>20:1
3
4
5
6
1 f
1 f
1 f
1 f
2a
2d
2e
2 f
81
86
93
85
>20:1
>20:1
13:1
[c]
–
7
8
1 f
1 f
2g
2h
94
80
4:1
13:1
9
1 f
1 f
2i
2j
89
91
10:1
9:1
10
[a,b] See Table 2. [c] Olefin isomers (1:0.4:1:1). See SI for full details.
[a] See Table 1. [b] Yields of isolated products. See SI for full details.
typically more reactive carboxylic acid derivatives such as
esters (3p), ketones (3q) and aldehydes (3r); these moieties
are poised for further functional group manipulation. The
chemoselective coupling of amides nicely illustrates the
synthetic potential of the amide bond activation platform
via distortion.[12] Finally, the decarbonylative Heck reaction
could be readily extended to the a,b-unsaturated amide
substrate to yield the diene product with excellent selectivity
(E/Z > 98:2) (3s).
The scope of olefin coupling partners is also very broad
(Table 3). Styrenes and electron deficient olefins provide the
products in high yields and with excellent regioselectivity.[23]
Acrylic esters (entries 2 and 3), amides (entry 4) and nitriles
(entry 5) are well-tolerated.[23a] Terminal olefins can be used
as substrates (entry 6);[23b] however, olefin isomerization
results in a mixture of isomers, in agreement with previous
studies.[5l] Cyclooctane, the only cyclic olefin examined, gave
isomeric arylcyclooctenes (entry 7).[5l] Notably, sterically
demanding n-butyl methacrylate and a-methylstyrene were
arylated in high yields (entries 8 and 9);[23c] double bond
isomerization constituted a minor reaction pathway. Finally,
the synthetically valuable E-stilbenes are accessible in high
yields by using trimethylvinylsilane as an ethylene equivalent
(entry 10).[23d] Formation of styrenes was not observed under
these conditions.
Extensive studies on the Heck reaction of aryl anhydrides
demonstrated that the reaction involves a cationic palladium
complex with decarbonylation as the rate limiting step.[24] The
presence of halide accelerates the reaction and increases the
selectivity by acid to halide exchange. We conducted several
studies to gain preliminary insight into the mechanism of the
Heck reaction of amides (see SI). 1) Intermolecular competi-
tion experiments with differently substituted amides revealed
that electron-deficient arenes are more reactive substrates;
however, the relative reactivity suggests that oxidative
addition is not the rate-determining step in the reaction.[25]
2) Competition experiments with sterically-demanding ortho
aryl substrates revealed that steric effects may play an
important role in accelerating the reaction.[18c] 3) Intermolec-
=
ular competition experiments with different olefins (H2C
CHR) established the following order of reactivity:
CO2nBu > Ph > n-C8H17, which follows the reactivity in
Heck reactions of aryl halides.[1,2] 4) Competition experi-
ments established the following reactivity order: Ar-I > Ar-
C(O)NR2 @ Ar-Br. Moreover, we established the following
reactivity order of carboxylic acid electrophiles: Ar-C-
(O)NR2 ꢀ (Ar-CO)2O @ Ar-CO2R. 5) Electrospray ioniza-
tion mass spectrometry (ESI/MS) analysis using stoichiomet-
ric palladium was performed.[26] Intermediates corresponding
to the aryl-PdII species containing halide and amine ligands
were detected. 6) The role of halide was probed by prelimi-
nary kinetic studies using styrene and acrylate nucleophile.[5k]
The effect of halide salt on the cross-coupling rate was found
We demonstrated the synthetic utility of this new protocol
in the gram scale synthesis of 3aa, which is a common UV-B
sunscreen produced on an industrial scale [Eq. (2)].[4a]
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Overall, the preliminary mechanistic studies are consis-
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À
particularly noteworthy that activation of the inert N C bond
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Decarbonylation of the acyl-Pd intermediate is favored by the
coordination of sterically-demanding anionic amine ligand.
Reductive elimination appears to be a kinetically relevant
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Scheme 1. Proposed mechanism. B=base (glutarimide); X=halide,
glutarimide (ESI-MS experiments).
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elucidate the mechanism are ongoing.
In conclusion, we have documented the first Heck
À
reaction of amides via chemoselective N C bond activation
using amide ground-state destabilization. The ability of
amides to engage in catalytic manifolds as aryl electrophiles
sets the stage for the design of new catalytic reactions via
metal insertion/decarbonylation beyond the coupling de-
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Acknowledgements
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We acknowledge Rutgers University for financial support.
The Bruker 500 MHz spectrometer used in this study was
supported by the NSF-MRI grant (CHE-1229030)
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Keywords: amide bonds · base-free Heck reaction ·
À
Heck reaction · N C activation · twisted amides
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Received: August 19, 2015
Revised: September 1, 2015
Published online: October 12, 2015
14522 www.angewandte.org
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