Merging NiH Catalysis and Inner-Sphere Metal-Nitrenoid Transfer for Hydroamidation of Alkynes

Article abstract of DOI:10.1021/jacs.1c01138

The formal hydroamination/hydroamidation utilizing metal hydride is an appealing synthetic tool for the construction of valuable nitrogen-containing compounds from unsaturated hydrocarbons. While significant advances have been made for the functionalizations of alkenes in this realm, the direct hydroamidation of alkynes remains rather limited due to the high feasibility of the key metal-alkenyl intermediate to choose other reaction pathways. Herein, we report a NiH-catalyzed strategy for the hydroamidation of alkynes with dioxazolones, which allows convenient access to synthetically useful secondary enamides in (E)-anti-Markovnikov or Markovnikov selectivity. The reaction is viable for both terminal and internal alkynes and is also tolerant with a range of subtle functional groups. With H2O found as an essential component for high catalyst turnovers, the involvement of inner-sphere nitrenoid transfer is proposed that outcompetes an undesired semireduction process, thus representing the first example to show the competence of Ni catalysis for metal-nitrenoid formation from dioxazolones.

Full text of DOI:10.1021/jacs.1c01138

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Merging NiH Catalysis and Inner-Sphere Metal-Nitrenoid Transfer
for Hydroamidation of Alkynes
Xiang Lyu, Jianbo Zhang, Dongwook Kim, Sangwon Seo,* and Sukbok Chang*
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ABSTRACT: The formal hydroamination/hydroamidation utiliz-
ing metal hydride is an appealing synthetic tool for the
construction of valuable nitrogen-containing compounds from
unsaturated hydrocarbons. While significant advances have been
made for the functionalizations of alkenes in this realm, the direct
hydroamidation of alkynes remains rather limited due to the high
feasibility of the key metal-alkenyl intermediate to choose other
reaction pathways. Herein, we report a NiH-catalyzed strategy for
the hydroamidation of alkynes with dioxazolones, which allows
convenient access to synthetically useful secondary enamides in
(E)-anti-Markovnikov or Markovnikov selectivity. The reaction is
viable for both terminal and internal alkynes and is also tolerant with a range of subtle functional groups. With H2O found as an
essential component for high catalyst turnovers, the involvement of inner-sphere nitrenoid transfer is proposed that outcompetes an
undesired semireduction process, thus representing the first example to show the competence of Ni catalysis for metal-nitrenoid
formation from dioxazolones.
conditions required for the isomerization (110 °C) could be
detrimental for certain functional groups. Therefore, the
development of a mild alternative that could directly afford
(E)-anti-Markovnikov or Markovnikov addition, as well as that
applicable to internal alkynes, is highly sought after.
INTRODUCTION
■
Enamides are a versatile motif that play a significant role in
drug discovery, wherein they serve as a potent pharmacophore
in bioactive compounds1,2 or as an important intermediate for
the construction of more valuable nitrogen functionalities.3,4
Among the diverse range of synthetic strategies,5,6 the
transition-metal-catalyzed hydroamidation of alkynes, that is,
addition of an amide N−H bond across the C−C triple bond,
represents one of the most atom-economical methods to access
such a class of moieties.7−10 Processes that achieve high levels
of chemo-, regio-, and stereoselectivity have been developed
within this synthetic platform, especially for an anti-
Markovnikov addition of secondary amides. Despite these
advances, alkyne hydroamidation is generally limited to
terminal or activated internal alkynes,11−13 and to the best of
our knowledge, that leading to Markovnikov addition in
intermolecular reactions is yet to be achieved. Moreover,
primary amides remain as somewhat more challenging
reactants for this transformation, mainly due to their low
nucleophilicity as well as feasibility of the newly formed
secondary enamides for further reactions with alkynes. Only a
handful of examples of hydroamidation protocols have been
reported for the synthesis of secondary enamides (Scheme
1a),14,15 all of which are known to give (Z)-selective anti-
Markovnikov addition by either catalyst or substrate control.
Although the former example showed that (E) secondary
enamides can also be obtained via a one-pot isomerization (Z
to E),14 this sequential process is steric-dependent and often
results in low E/Z selectivities. In addition, the elevating
In this context, we envisaged to develop a new alkyne
hydroamidation strategy based on a polarity-reversed reaction
mode, utilizing metal hydride in combination with an
electrophilic amidating source. This concept of formal
hydrofunctionalization has emerged as a powerful synthetic
tool in recent years16−18 and offers thermodynamically differed
pathways for complementary reactivity and selectivity to the
traditional two-component methodologies. In particular, the
pioneering works by Buchwald19 and Miura20 established CuH
catalysis as a competent handle for a hydroamination or
hydroamidation of alkenes, and recent developments have
further engendered highly efficient, regio- and stereoselective
protocols with the exploitation of a variety of electrophilic
nitrogen sources.21−27 While much success has been achieved
with alkenes, the direct functionalization of alkynes in this
mechanistic approach is, however, limited. This is especially
Received: January 29, 2021
Published: April 9, 2021
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acids. The Bolm group elegantly showed that these reagents
serve as a robust acyl nitrene precursor in sulfur imida-
tions,32,33 and our group34−39 as well as others25,40−48 have
since demonstrated their versatility in various types of
transition-metal-catalyzed C−N-forming reactions. We visual-
ized to achieve the desired formal hydroamidation by engaging
our expertise in this chemistry with metal hydride catalysis
(Figure 1). Upon the selective hydrometalation of an alkyne to
Scheme 1. Synthesis of Secondary Enamides Via
Hydroamidation of Alkynes
Figure 1. Working hypothesis for formal hydroamidation of alkynes
via a merger of hydrometalation and inner-sphere metal-nitrenoid
transfer.
the metal-alkenyl complex (I or I′), we envisioned that the
incorporation of metal-nitrenoid intermediacy (II) would
promote a low-energy C−N-forming pathway. This inner-
sphere nitrenoid transfer would outcompete the typically
favorable semireduction process, thus leading to the C−N
coupled species III and finally an enamide by selective
protonation. To successfully furnish this alkyne hydro-
amidation, the ability to attain a highly selective catalytic
cycle would be essential, as there are also a number of other
possible side pathways, such as the cyclopolymerization of
alkynes49 and decomposition of dioxazolones.50
With these challenges in mind, we started the optimization
with but-3-yn-1-ylbenzene 2 as a model alkyne in reaction with
methyl dioxazolone 1 (Table 1), given that the success with
the challenging aliphatic substrate would deliver a more
general strategy. We first tested the CuH28 and CoH29 systems
that were previously developed for semireduction/hydro-
amination cascade reactions, as to examine whether the use
of dioxazolones under these conditions could simply overturn
the reaction to favor the enamide formation (entries 1 and 2).
On the one hand, the Cu catalyst was completely ineffective to
make a full recovery of the starting materials (entry 1). On the
other hand, the alkyne hydrometalation was found to work to
some extent with a Co catalyst, but the subsequent protonation
was more favored to give a semireduced alkene 2-SP as the
major product (35%) along with a Markovnikov enamide 4 in
9% yield (entry 2). A modified procedure precluding H2O was
not beneficial either, indicating that the competing semi-
reduction process would be a critical hurdle to achieving the
desired reaction.
pertinent for aliphatic alkynes that lack an electronic bias for
both reactivity and selectivity, whereas the formal hydro-
amination of aromatic equivalents is known to some extent.28
Furthermore, the hydroamidation counterpart remains elusive,
regardless of the nature of alkynes (Scheme 1b). Alkynes have
been more frequently employed as a precursor of alkene
intermediates in cascade hydroamination reactions.28−30 For
instance, Buchwald26,28 and Lu29 reported Cu- and Co-
catalyzed processes, respectively, in which alkylamines are
afforded by a hydrometalation of alkynes, followed by
protonation (semireduction to alkenes) and then (anti)-
Markovnikov hydroamination (Scheme 1b). Although highly
appealing on its own right, avoiding this facile semireduction
pathway would be desirable for achieving the unexplored
formal hydroamidation of alkynes to enamides.
Herein, we show that NiH catalysis provides a unique
synthetic toolbox for a selective alkyne hydroamidation with
1,4,2-dioxazol-5-ones (dioxazolones) as an electrophilic
amidating reagent, which allows the incorporation of a wide
range of both terminal and internal alkynes with excellent
functional group tolerance (Scheme 1c). Tailoring the catalytic
system grants access to either (E)-selective anti-Markovnikov
or Markovnikov addition via hydrometalation and subsequent
amidation, thereby furnishing secondary enamides with
contrasting selectivities to that obtained by the conventional
alkyne hydroamidation with primary amides. This process
represents the first utilization of Ni catalyst for the activation of
dioxazolones by means of a metal-nitrenoid formation.
While this issue could probably be addressed by further
optimization with the aforementioned catalytic systems, we
turned our attention to NiH catalysis considering its rich
repertoire for the hydrofunctionalization of alkynes.51−57 In
addition, the compatibility of Ni for a metal-imido formation
has been well-recognized,58−60 although that with dioxazolones
remains unexplored. A series of bipyridine-based ligands (7.5
RESULTS AND DISCUSSION
■
Reaction Development. Dioxazolones are attractive
umpolung surrogates of primary amides in synthesis,31 as they
can be readily prepared from the corresponding carboxylic
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Figure 1), the steric increase could invert the selectivity by
directing the metal insertion into the less-hindered terminal
carbon (I in Figure 1).28 Indeed, the steric variation of 2,2′-
bipyridine ligand with dimethyl (L3) or di-sec-butyl (L4)
substituents at the 6,6′-positions gave altered selectivities
(entries 5 and 6). In particular, with ligand L4, the anti-
Markovnikov hydroamidation product 3 was afforded as the
major isomer in good regioselectivity (entry 6).
Table 1. Reaction Optimization
a
entry
1
2
1:2 (equiv)
catalysts
solvent
3:4 (%)
To obtain an improved set of orthogonal conditions for both
selectivities from these preliminary results, we performed
further optimization studies (entries 7−15, see also Supporting
Information, Tables S1−S3). Delightfully, modified conditions
utilizing dioxazolone 1 (1.5 equiv), alkyne 2 (1.0 equiv),
NiBr2·glyme (5 mol %), L2 (7.5 mol %), and N,N-
dimethylacetamide (DMA) or N,N′-dimethylpropyleneurea
(DMPU) solvent afforded the enamide products in higher
yields with good selectivities for the Markovnikov addition (4)
(entries 7 and 8). On the other hand, the catalyst system
consisting of NiCl2·glyme (5 mol %) and L4 (7.5 mol %) was
superior for the opposite selectivity, furnishing (E)-anti-
Markovnikov enamide 3 by a syn addition, in quantitative
yield and excellent regioselectivity (entry 9). The reaction was
found to be flexible in terms of the stoichiometries of starting
materials, as similar results could also be obtained with
reversed stoichiometries (entry 10) or with a reduced amount
of alkyne 2 (1.1 equiv, entry 11). 1,10-Phenanthroline-based
ligands with analogous substituents (L5−L6) were also
effective but resulted in slightly lower yields (entries 12 and
13, see Figure 4 for the crystal structure of isolated Ni-L6
complex). Notably, the formation of semireduction adducts
was barely observed in most of these conditions, which is in
stark contrast to the previously reported Cu or Co system that
typically undergoes the protonation pathway in the presence of
a protic source. In fact, H2O was identified as an essential
component for the present Ni strategy: the increased amount
of H2O had a negligible effect on the outcome (entry 14),
whereas the reaction was inefficient in its absence (entry 15).
Mechanistic Investigation: Intermediacy of Ni-Nitre-
noid. With H2O identified as an inevitable element for the
current transformation, we wondered how the typically favored
protonation pathway could be effectively suppressed under the
protic conditions. For this investigation, we first performed
density functional theory (DFT) calculations based on a
presupposed catalytic cycle involving Ni(I) as the active
species (Figure 2), in consideration of our experimental
evidence (vide infra) as well as the previously suggested
mechanism for the NiH-catalyzed alkene hydroamination67,68
and other hydrofunctionalization reactions utilizing silanes as a
hydridic source.69−74
1.5:1.0
1.5:1.0
2.0:1.0
2.0:1.0
2.0:1.0
2.0:1.0
1.5:1.0
1.5:1.0
1.5:1.0
1.0:1.5
1.0:1.1
1.0:1.5
1.0:1.5
1.0:1.5
1.0:1.5
CuH (ref 28)
CoH (ref 29)
THF
THF
nd
<1:9
nd
b
3
4
5
6
NiCl2·glyme, L1
NiCl2·glyme, L2
NiCl2·glyme, L3
NiCl2·glyme, L4
NiBr2·glyme, L2
NiBr2·glyme, L2
NiCl2·glyme, L4
NiCl2·glyme, L4
NiCl2·glyme, L4
NiCl2·glyme, L5
NiCl2·glyme, L6
NiCl2·glyme, L4
NiCl2·glyme, L4
acetone
acetone
acetone
acetone
DMA
DMPU
DMA
DMA
DMA
DMA
DMA
DMA
DMA
11:22
53:46
56:14
8:34
10:78
98:<1
99:<1
95:<1
85:<1
85:<1
89:<1
7:<1
c
7
c
8
9
10
11
12
13
d
14
e
15
a
Reactions performed on 0.5 mmol scale at 25 °C for 16 h; all
reagents were measured under argon atmosphere; nd, not detected;
DMMS, dimethoxymethylsilane; THF, tetrahydrofuran; DMA, N,N-
dimethylacetamide; DMPU, N,N′-dimethylpropyleneurea. Yields
determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal
b
standard. Semireduced alkene 2-SP was formed as the major product
c
d
e
(35%). 8 h. H2O (2.0 equiv). H2O not added.
mol %) were first investigated for the reaction between
dioxazolone 1 (2.0 equiv) and terminal alkyne 2 (1.0 equiv), in
combination with NiCl2·glyme (5.0 mol %), dimethoxyme-
thylsilane (DMMS, 2.0 equiv), H2O (1.0 equiv), and acetone
solvent at 25 °C for 16 h (entries 3−6). Unsubstituted 2,2′-
bipyridine ligand L1 was found to be completely inefficient
(entry 3), and an electronic variation of the ligand by
introducing electron-donating or -withdrawing groups at the
4,4′- or 5,5′-positions (L12−L15, see Supporting Information,
Tables S1 and S2) did not promote the desired reactivity
either. In sharp contrast, the ligand modulation by installation
of a methyl group at the 6-position (L2) intriguingly provoked
the reactivity to give Markovnikov hydroamidation product 4
as the major isomer albeit in low yield and moderate selectivity
(entry 4). This vivid improvement in catalytic activity
presumably stems from the introduced steric hindrance,
which may facilitate the dissociative formation of an active
NiH monomeric species and also stabilize other involved
three-coordinate Ni intermediates.61−63 Similar steric effects
have previously been observed in a number of Ni-catalyzed
hydrofunctionalization reactions.54,56,64−66
Taking the anti-Markovnikov hydroamidation of substrate 2
as a model reaction, the initial hydrometalation process with
Ni(I)−H would lead to Ni-alkenyl complex int1 (see
Supporting Information, Figure S1 for energy profiles of the
whole process). While the oxidative N−X insertion mechanism
was mostly proposed for the subsequent activation of
electrophilic nitrogen sources in the previously reported formal
hydroamination procedures,18 we hypothesized that the
participation of Ni-nitrenoid might be liable for empowering
the ability to intercept int1 selectively. Coordination of the
dioxazolone is a prerequisite for this pathway, which affords
tetrahedral Ni complex int2 with increase in energy by 6.7
kcal/mol. It was revealed that Ni is indeed highly viable for
promoting the subsequent oxidative decarboxylation of
It was found that the steric ligand also plays a crucial role for
the regioselectivity, which would be governed during the initial
hydrometalation step. While the methyl substituent in L2
might not provide sufficient steric hindrance, thereby favoring
the inherently preferred Markovnikov hydrometalation (I′ in
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Figure 2. Potential energy surfaces for the formation of Ni-nitrenoid and subsequent C−N formation.
dioxazolone to furnish Ni-nitrenoid int3, traversing the
transition state int2-TS that lies only 4.1 kcal/mol higher in
energy than the Ni-dioxazolone adduct int2. On the other
hand, protodemetalation of int1 to semireduced alkene 2-SP
was found to be substantially less favorable with the activation
barrier of 21.8 kcal/mol (int1-TS).
In addition, the C−N formation leading to the Ni-enamido
complex int4 via inner-sphere nitrenoid transfer of int3 was
energetically highly feasible, with the transition state int3-TS
being located only at 3.5 kcal/mol higher in energy. This low
activation barrier clarifies the observations that other known
transformations of metal-nitrenoid are precluded in the current
reaction system. Adversely, the direct experimental validation
of such an intermediacy was proven highly challenging.
Nevertheless, the reaction between dioxazolone 1 and
PPh3(2.0 equiv) in the presence of NiBr2·glyme (5 mol %)
gave an imidophosphorane 5 in 80% yield (Scheme 2), which
actions,54,57,75−78 and therefore, we wondered whether our
reaction also proceeds via this pathway. Although DMMS was
identified to be the most efficient silane source for the current
system (see Supporting Information, Table S1), control
experiments were performed by alternatively using diphenylsi-
lane (Ph2SiH2 and Ph2SiD2), due to the commercial availability
of the deuterated reagent (Scheme 3). Once again, we took our
Scheme 3. Deuterium Experiments to Investigate the
Feasibility of H2O as a Formal Hydride Source
Scheme 2. Capture of Nitrenoid Intermediate by Formation
of Imidophosphorane with PPh3
anti-Markovnikov-selective hydroamidation as a model reac-
tion for this investigation, and it was soon found that H2O is
not likely the source of hydrogen that is inserted into the
unsaturated carbon. The reaction was completely ineffective in
the absence of a silane reagent, indicating that a hydridic
source is certainly required for productive outcomes.
Furthermore, deuterium experiments using either Ph2SiD2/
H2O or Ph2SiH2/D2O also showed that the incorporation of D
or H takes place exclusively from the silane source.
Further to the above scenario, the addition of protic reagents
is often required in silane-based hydrofunctionalization
reactions.18 Their role in those processes is not entirely
understood, but such a requisite was generally attributed to the
need for a protonation source to enhance the product release
that could bypass the slow transmetalation.79 In our system,
the transmetalation between Ni-enamido complex (III in
Figure 1) and hydrosilane (DMMS) might also be kinetically
or thermodynamically unfavorable otherwise, and H2O would
provide an alternative route to facilitate the product liberation
and catalyst regeneration. Indeed, the reactions employing
higher catalyst loadings (20−100 mol %) consistently showed
catalyst turnover numbers of ∼1 (0.8−1.4) when H2O was not
added (Figure 3a, entries 1−4), indicating that there may exist
a catalyst inhibition presumably by the hydroamidated species.
is a well-known adduct derived from a nitrene transfer to
phosphines.43 Although this nitrenoid capture does not
provide direct evidence for the existence of Ni-nitrenoid
int3, it somehow proves the competence of Ni to activate
dioxazolone by means of a metal-nitrenoid formation. In
combination with the DFT calculations, this experimental
result should therefore give a good indication that the
proposed nitrenoid transfer would be viable in the current
hydroamidation reaction.
Mechanistic Investigation: Role of H2O. With the Ni-
nitrenoid intermediate pinpointed as an essential mechanistic
piece that enables surpassing the conventional semireduction
pathway, in a process seemingly necessitating H2O as an
imperative additive, we next wished to scrutinize the role of
H2O. It is well-established that protic reagents, such as H2O or
alcohols, could often act as a formal hydride source in
alternative types of Ni-catalyzed hydrofunctionalization re-
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nickel hydroxide Ni2 and DMMS (Figure 3b, right) were
energetically downhill by ΔG = −17.3 kcal/mol and ΔG =
−14.1 kcal/mol, respectively, and we believe that this
thermodynamic driving force would be responsible for the
improved transmetalation in either case.
The assumption that the transmetalation of hydride is
accelerated by H2O was further evaluated by X-band electron
paramagnetic resonance (EPR) spectroscopy, using a Ni(II)
complex 6 prepared from NiBr2·glyme and ligand L6 (Figure
4). It is known that the Ni(I) species can be generated from
Figure 4. Experimental X-band EPR spectra of 6 + DMMS in DMA
(gray) and 6 + DMMS + H2O in DMA (red); measured at 100 K, and
simulated EPR spectrum (blue); simulation parameters: g =
[2.094 81, 2.126 59, 2.475 39].
Figure 3. (a) Effects of H2O additive on catalyst turnovers. (b)
Thermodynamics of the product release and catalyst regeneration
from int4 via a transmetalation/hydrolysis or protonation/trans-
metalation pathway.
Ni(II) precursors in combination with silanes,67−74,80 likely via
a transmetalation of hydride followed by a reductive
elimination/comproportionation,62 and we hypothesized that
the access to such an active catalyst in our system should also
be facilitated in a similar manner. As expected, the X-band EPR
spectrum of Ni(II) complex 6 was EPR-silent and so was its
mixture with H2O. Interestingly, a mixture of 6 and DMMS
gave only negligible signals (gray), indicating that the
formation of a Ni(I) species might not be so efficient for
this combination. On the other hand, an addition of H2O to
the mixture of 6 and DMMS gave significantly intensified
signals (red) that show almost an identical shape to those
observed for previously reported Ni(I) complexes.63,81,82
Moreover, the corresponding mass of the anticipated Ni(I)
hydride monomer was detected by MS (see Supporting
Information). Although more comprehensive studies are
required for the full mechanistic descriptions, the above EPR
and MS analyses implicate that the presence of H2O might
indeed enhance the transmetalation between Ni and DMMS
by Si−O bond formation as the driving force,80 thereby leading
to the effectual production of Ni(I) species. The formation of a
Si−O bond may occur via a stepwise process as shown in
Figure 3b or in a concerted manner during transmetalation.83
Furthermore, it was also found that H2O could be replaced by
alcohols (e.g., MeOH or EtOH, see Supporting Information,
Table S2), which are expected to play a similar role in the
current transformation.
Consistent with this hypothesis, Ni-enamido int4 could be
observed by mass spectroscopy (MS) under the above H2O-
free conditions (see Supporting Information). These results are
in stark contrast to the procedure with 1.0 equiv of H2O
additive, in which high catalyst turnover numbers of up to 170
could be achieved using 0.5 mol % of NiCl2·glyme (Figure 3a,
entry 5).
To understand this explicit effect of H2O on the
substantially enhanced catalyst turnovers, DFT calculations
were performed. First, the transmetalation between Ni-
enamido int4 and hydrosilane (DMMS) leading to nickel
hydride Ni1 and silyl-enamidate 3-Si was computed to be
highly endergonic (ΔG = 16.7 kcal/mol, Figure 3b, left). This
thermodynamic reluctance may indeed lead to the catalyst
inhibition in the absence of any additional mechanistic
handles, which conforms to the case of H2O-free reactions
giving poor catalyst turnovers. For the H2O additive system,
we alternatively considered a stepwise process in which the
product is released by the protonation of int4 with the catalyst
being regenerated by a subsequent transmetalation (as
depicted in Figure 1, X = OH). However, the initial
protonation of int4 was also found to be thermodynamically
uphill (ΔG = 13.6 kcal/mol, Figure 3b, right), which indicates
a strong affinity of the enamidate moiety to the Ni complex.
This outcome suggested that the major role of H2O for the
improved catalyst turnovers is not as a proton source. Although
the protonation might indeed provide a kinetically more
favored pathway, we tentatively attribute the beneficial effects
of H2O mainly to the ease of thermodynamic disfavor by an
irreversible Si−O bond formation. Both the hydrolysis of silyl-
enamidate 3-Si (Figure 3b, left) and transmetalation between
Reaction Scope. With a better understanding of the
mechanistic aspects, we next investigated the reaction scope of
the current NiH-catalyzed hydroamidation. We first explored
the anti-Markovnikov selective process by utilizing optimized
conditions consisting of NiCl2·glyme (5 mol %) and L4
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a
Scheme 4. Reaction Scope of the NiH-Catalyzed Hydroamidation of Alkynes with Dioxazolones
a
Conditions A: Dioxazolone (0.5 mmol), alkyne (1.5 equiv), NiCl2·glyme (5 mol %), L4 (7.5 mol %), DMMS (2.0 equiv), H2O (1.0 equiv), and
DMA (1.0 mL), 25 °C, 16 h. Conditions B: Alkyne (0.5 mmol), dioxazolone (1.5 equiv), NiBr2·glyme (5 mol %), L2 (7.5 mol %), DMMS (2.0
equiv), H2O (0.6 equiv), and DMPU (1.0 mL), 25 °C, 8 h. Unless otherwise stated, greater than 20:1 regioselectivity was obtained, and isolated
yields of the major isomers are reported. Regioisomeric ratios given in parentheses were determined by crude 1H NMR. All reagents were measured
b
c
d
under an argon atmosphere. No H2O additive. NMR yields using 1,1,2,2-tetrachloroethane as an internal standard. The corresponding
Markovnikov enamides were found to be extremely unstable, giving inconsistent and diminished yields after purification on silica or alumina.
e
Combined NMR yields of the two isomers are reported, with M/anti-M ratios given in parentheses. Dioxazolone (1.0 equiv) and alkyne (1.5
f
g
h
equiv). NiCl2·glyme instead of NiBr2·glyme. L3 instead of L4. NiBr2·glyme (10 mol %), L2 (15 mol %) and alkyne (3 equiv).
(Scheme 4). A wide range of alkynes could be efficiently
hydroamidated in high yields and excellent selectivities (3, 7−
21) with exceptional functional group tolerance: alkyl chloride
(9), nitrile (10), epoxide (11), acetal (12), ester (13),
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cyclopropyl (14), aldehyde (15), ketone (16), alkene (17),
amides (18−20), and hydroxyl group (21) could all be well-
tolerated.
instance, by utilizing it in sequential derivatizations (vide
infra).
In contrast, (hetero)aromatic derivatives were found to be
relatively more stable than the aforementioned aliphatic
terminal enamides. Significantly, (hetero)aromatic terminal
alkynes favored a Markonikov hydroamidation irrespective of
the ligand used, but the complete selectivities were obtained
with the use of a less bulky ligand L2 (39−45). Phenyl-
acetylene (39) and analogous substrates installed with fluoro
(40), trifluoromethyl (41), aldehyde (42), and methoxy (43)
groups were effectively transformed to the Markovnikov
enamide products in good yields and complete regioselectivity.
Likewise, 2- and 3-ethynylthiophenes were viable substrates to
afford enamides 44 and 45, respectively.
The reaction was not limited to terminal alkynes but could
also be applied to internal substrates to furnish α,β-
disubstituted (E)-enamides by a syn addition (46−50).
Symmetric alkynes bearing alkyl (46) or phenyl (47)
substituents could be successfully converted to the correspond-
ing enamides with (E)-selectivity. For unsymmetrical internal
alkynes, the regioselectivity could be controlled by either
sterics (48) or electronics (49 and 50), with the amide
functionality being inserted into the sterically less-demanding
site or that bearing aromatic rings. With these promising
results, it is worthwhile mentioning that the obtained (E)-
configured α,β-disubstituted secondary enamides are challeng-
ing to synthesize in a selective fashion by other means,87,88 as
they are thermodynamically less stable than the (Z)-counter-
parts. Therefore, the ability to incorporate internal alkynes to
access these challenging enamides is one of the appealing
features of our protocol.
Some of the examined functional groups are noteworthy, as
they would often suffer in other types of reactions for enamide
synthesis. For example, carbonyl moieties, such as aldehydes
(15) or ketones (16), might encounter issues in the classical
condensation-type strategies whereby those functional groups
are transformed in reaction with amides.84 The tolerance of a
secondary amide also deserves a special mention (20), as this
kind of functional group within the alkyne motif could prompt
an undesired intramolecular reaction if the traditional hydro-
amidation protocols were utilized.85,86 The compatibility with
the hydroxyl group is another interesting feature, albeit isolated
in reduced yield due to the instability of enamide 21. Despite
the superior functional group tolerance, a few alkynes were
found to be unsuited, including those containing propiolate,
enyne, or unprotected aniline moiety (see Supporting
Information, Figure S4).
A range of dioxazolones could also be employed, giving anti-
Markovnikov enamides in similar efficiencies to the standard
substrate. Dioxazolones with simple aliphatic functionality (22
and 23), alkene functionality (24), alkyl benzene (25), alkyl
thiophene (26), and benzylic (27) groups were compatible,
furnishing the corresponding (E)-enamides in good to
excellent selectivities. Hydroamidation with styryl (28) and
aryl (29−31) dioxazolone reactants were also feasible,
however, giving somewhat diminished yields and lower
regioselectivities. The attenuated efficiency in these cases is
attributed to the relative instability of conjugated dioxazolones
under the current Ni conditions, in which their decomposition
may also disturb the selectivity-determining hydrometalation
step by altering the active catalyst.
On the basis of our initial results that the regioselectivity of
the current Ni-catalyzed alkyne hydroamidation can be
switched by the choice of ligands (Table 1), we next explored
the generality of the Markovnikov hydroamidation using
NiBr2·glyme (5 mol %) and L2 (7.5 mol %) in DMPU. This
part of the investigation was highly challenging, as α-alkyl-
substituted terminal enamides expected from the Markovnikov
selectivity are extremely unstable, which may affect the
reaction efficiency and selectivity. Indeed, to our knowledge,
there are no general methods to access such a class of
enamides, thus explicating the lack of their presence in
synthetic applications contrarily to their aromatic counter-
parts.3
Despite this challenge, we could take advantage of the mild
conditions applied in our NiH catalytic system, affording the
aliphatic enamides in good yields and decent selectivities (4,
32−38). Alkyl (4 and 32), cyclopropyl (33), alkyl chloride
(34), acetal (35), imide (36), and benzaldehyde (37) on the
alkyne substrate were tolerated, as well as phenyl dioxazolone
giving rise to N-benzoyl enamide 38 in good yield. However,
the isolation of these enamide products was found to be
difficult because of their instability. In addition, the
regioselectivity was generally lower in comparison to those
achieved for an anti-Markovnikov addition, which could be
partly ascribed to some decomposition of the Markovnikov
products. Nonetheless, the obtained efficiency and selectivity
were gratifying in our case, especially considering the
aforementioned issues with α-alkyl-substituted terminal
enamides. The current strategy for Markovnikov selectivity
is, thus, expected to find useful synthetic applications, for
Synthetic Utility. The practicality of the current NiH-
catalyzed strategy was next demonstrated by a gram-scale
hydroamidation of alkyne 2, which furnished enamide 3 in
good yield (Scheme 5a). With this practical procedure in hand,
the synthetic utility was subsequently explored by derivatiza-
tions of enamide 3. The direct alkyne functionalization by
means of hydroamidation certainly offers a synthetic diversity
in comparison to the semireduction sequential processes, as
enamides represent common access points for the synthesis of
value-added nitrogen-containing compounds.3 In particular,
secondary enamides have been utilized as a versatile
intermediate in various organic transformations. For example,
the acid-catalyzed reaction with indole nucleophile and rac-
1,1′-binaphthyl-2,2′-diyl hydrogen phosphate PA1 as a catalyst
(5 mol %) gave the arylation product 51 in 86% yield (Scheme
5a). The functionalization of the β-carbon of enamides by a
treatment with a suitable electrophile is also a well-known
strategy, and indeed, the Cu-catalyzed oxy-trifluoromethylation
89
+
using Togni’s reagent (CF3 ) and MeOH, followed by a
reduction with hydrosilane, successfully afforded the β-
trifluoromethylated product 52. The acid-catalyzed Povarov
reaction of enamide 3 was also investigated with a range of in
situ generated imines, which resulted in the tetrahydroquino-
line products as single diastereomers (53−55).90
We next examined the hydrogenation of α-alkyl-substituted
terminal enamides obtained from the Markovnikov hydro-
amidation of aliphatic alkynes. We considered this worthy of
investigation given that such a class of enamides is under-
presented in the related chemistry.3 As aforementioned, this is
ascribed to the lack of methods for their syntheses, presumably
due to the issues encountered by the instability. Therefore, we
conceived to prove the viability of our NiH approach for the
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a
subjected to the reduction conditions using hydrogen
phosphate PA1 as a catalyst (10 mol %). A range of aliphatic
terminal alkynes could be efficiently converted to the
corresponding alkylamides albeit in moderate yields over two
steps (56−60). The successful result with an aromatic-based
internal alkyne further demonstrated the generality of this
sequential transformation (61).
Scheme 5. Synthetic Utility
Furthermore, we briefly investigated an asymmetric version
by using chiral phosphoric acids possessing bulky substituents.
The conditions previously established for aryl-substituted
enamides91 were effectively combined with our strategy to
convert 1-phenyl-1-propyne to enamide (R)-61 in good yield
and excellent enantioselectivity (54%, e.r. = 97:3), by using an
(S)-phosphoric acid PA2 (3.5 mol %, 50 °C). However, the
standard aliphatic alkyne 2 was found to be ineffective under
the same conditions; hence, slightly modified procedures with
PA3 or PA4 (2.0 mol %, 25 °C) were consequently employed.
Notably, differing enantioselectivities were obtained in
comparison to the aromatic substrate: the use of an (S)-
phosphoric acid (PA3) resulted in (S)-56 as the major
enantiomer (31%, e.r. = 35:65), whereas the opposite
atropisomeric catalyst (PA4) furnished (R)-56 in good
enantioselectivity (22%, e.r. = 85:15). Although the reaction
efficiency and stereoselectivity of this aliphatic example are not
at satisfactory levels at this stage, the proven viability should
stimulate further developments for tandem asymmetric
transformations of prochiral alkynes by utilizing the current
system, especially considering the importance and challenges
in constructing chiral alkylamides of such type.
CONCLUSION
■
We have developed a NiH-catalyzed strategy for a formal
hydroamidation of alkynes, which surpasses the highly
susceptible semireduction pathway through the involvement
of low-energy inner-sphere nitrenoid transfer. A ligand-
controlled hydrometalation granted access to both (E)-anti-
Markovnikov and Markovnikov hydroamidations in good to
excellent regioselectivities, with a wide range of functional
groups well-tolerated under mild and convenient conditions.
The addition of H2O was found to be essential for achieving
high catalyst turnovers, and the combined experimental and
theoretical investigations suggested that H2O is engaged in
facilitating the transmetalation step. With the improved
catalytic efficiency, not only aliphatic- and aromatic-terminal
alkynes but also internal alkynes could be employed. The
virtue of the present synthetic approach was demonstrated by a
number of postmodifications, which led to the construction of
synthetically valuable alkylamide moieties, even in an
asymmetric fashion. This development offers a complementary
reactivity and selectivity that allows the synthesis of underex-
plored classes of enamides and, thus, should find broad
synthetic applications. Moreover, the unique mechanistic
platform acquired by the Ni-nitrenoid intermediacy should
engender new methodology developments for other types of
C−N bond-forming processes.
a
Isolated yields are reported; d.r., diastereomeric ratio; e.r.,
enantiomeric ratio (see Supporting Information for details of the
reaction conditions). The hydrogenation step was performed at 50
°C. NMR yields using dibromomethane as an internal standard.
b
c
incorporation in a sequential reduction transformation, with-
out the isolation of the unstable species.
While transition-metal-based procedures employing hydro-
gen gas have been most broadly investigated for the
hydrogenation of aromatic- or sterically encumbered enam-
ides,3 we envisioned that an organocatalysis offering milder
conditions would be more suited for the subtle aliphatic
enamides.91 Pleasingly, the use of a Hantzsch ester as a
reducing reagent and phosphoric acid as a catalyst was effective
for achieving the desired sequential transformation (Scheme
5b). Aliphatic enamides were first obtained using our standard
procedure and, after a simple workup, were subsequently
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c01138.
Experimental procedures, characterization of new
compounds, information about computational studies,
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X-ray crystallographic data for compounds 6, 47, 50, and
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Accession Codes
CCDC 2059010−2059012 and 2071245 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Authors
Sangwon Seo − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science, Daejeon
34141, South Korea; Department of Chemistry, Korea
Advanced Institute of Science and Technology, Daejeon
34141, South Korea; orcid.org/0000-0003-2281-9167;
Email: s.seo@kaist.ac.kr
Sukbok Chang − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science, Daejeon
34141, South Korea; Department of Chemistry, Korea
Advanced Institute of Science and Technology, Daejeon
34141, South Korea; orcid.org/0000-0001-9069-0946;
Email: sbchang@kaist.ac.kr
Authors
Xiang Lyu − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science, Daejeon
34141, South Korea; Department of Chemistry, Korea
Advanced Institute of Science and Technology, Daejeon
34141, South Korea; orcid.org/0000-0003-1227-8563
Jianbo Zhang − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science, Daejeon
34141, South Korea; Department of Chemistry, Korea
Advanced Institute of Science and Technology, Daejeon
34141, South Korea
Dongwook Kim − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science, Daejeon
34141, South Korea; Department of Chemistry, Korea
Advanced Institute of Science and Technology, Daejeon
34141, South Korea; orcid.org/0000-0003-4432-371X
(14) Gooßen, L. J.; Salih, K. S. M.; Blanchot, M. Synthesis of
Secondary Enamides by Ruthenium-Catalyzed Selective Addition of
Amides to Terminal Alkynes. Angew. Chem., Int. Ed. 2008, 47, 8492−
8495.
(15) Panda, N.; Mothkuri, R. Stereoselective Synthesis of Enamides
by Pd-Catalyzed Hydroamidation of Electron Deficient Terminal
Alkynes. J. Org. Chem. 2012, 77, 9407−9412.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c01138
(16) Jordan, A. J.; Lalic, G.; Sadighi, J. P. Coinage Metal Hydrides:
Synthesis, Characterization, and Reactivity. Chem. Rev. 2016, 116,
8318−8372.
(17) Chen, J.; Guo, J.; Lu, Z. Recent Advances in Hydrometallation
of Alkenes and Alkynes via the First Row Transition Metal Catalysis.
Chin. J. Chem. 2018, 36, 1075−1109.
Author Contributions
The manuscript was written by S.S. and S.C., and all authors
have given approval to the final version of the manuscript.
(18) Liu, R. Y.; Buchwald, S. L. CuH-Catalyzed Olefin
Functionalization: From Hydroamination to Carbonyl Addition.
Acc. Chem. Res. 2020, 53, 1229−1243.
Notes
The authors declare no competing financial interest.
(19) Zhu, S.; Niljianskul, N.; Buchwald, S. L. Enantio- and
Regioselective CuH-Catalyzed Hydroamination of Alkenes. J. Am.
Chem. Soc. 2013, 135, 15746−15749.
ACKNOWLEDGMENTS
■
This research was supported by the Institute for Basic Science
(IBS-R010-Y2 and IBS-R010-D1) in South Korea. The authors
thank Mr. J. Heo (KAIST) for helpful discussion. This article is
dedicated to Professor Christian Bruneau for his outstanding
contribution to catalysis.
(20) Miki, Y.; Hirano, K.; Satoh, T.; Miura, M. Copper-Catalyzed
Intermolecular Regioselective Hydroamination of Styrenes with
Polymethylhydrosiloxane and Hydroxylamines. Angew. Chem., Int.
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