Elucidating the Mechanism of Aryl Aminations Mediated by NHC-Supported Nickel Complexes: Evidence for a Nonradical Ni(0)/Ni(II) Pathway

Article abstract of DOI:10.1021/acscatal.8b00856

Nickel catalysis is gaining in popularity in recent years, mostly within the area of cross-coupling. However, unlike Pd, the mechanisms of Ni-catalyzed C-C and C-heteroatom bond forming reactions have been much less studied, in particular when N-heterocyclic carbenes are used as ligands. Here, we present a thorough study of the mechanism of C-N cross-coupling reactions catalyzed by an NHC-Ni complex. Focusing on the coupling of 2-chloropyridines with indole catalyzed by [(IPrNi(styrene)₂] (IPr = N,N′-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), we have examined each of the elementary steps: i.e., oxidative addition, ligand substitution, and reductive elimination. All relevant catalytic intermediates have been isolated and structurally characterized by both spectroscopic and crystallographic methods. Kinetic studies have revealed that the reductive elimination is the rate-limiting step. Catalyst deactivation is related to the formation of unproductive dinuclear pyridyl-bridged NHC-Ni^II species, which can be prevented by increasing the size of the heteroaryl chloride. These investigations support a neutral Ni(0)/Ni(II) catalytic cycle. Calculations corroborate the experimental evidence and confirm the influence exerted by the ligands in each of the elementary steps.

Full text of DOI:10.1021/acscatal.8b00856

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Elucidating the Mechanism of Aryl Aminations Mediated by NHC-
Supported Nickel Complexes: Evidence for a Non-radical Ni(0)/Ni(II) Pathway
Silvia G Rull, Ignacio Funes-Ardoiz, Celia Maya, Feliu Maseras,
Manuel R. Fructos, Tomas R. Belderrain, and M. Carmen Nicasio
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00856 • Publication Date (Web): 07 Mar 2018
Downloaded from http://pubs.acs.org on March 7, 2018
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Page 1 of 13
ACS Catalysis
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Elucidating the Mechanism of Aryl Aminations Mediated by
NHC-Supported Nickel Complexes: Evidence for a Non-radical
Ni(0)/Ni(II) Pathway
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†
‡
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,‡,#
,†
Silvia G. Rull, Ignacio Funes-Ardoiz, Celia Maya, Feliu Maseras,* Manuel R. Fructos,*
,†
,§
Tomás R. Belderrain,* and M. Carmen Nicasio*
†
Laboratorio de Catálisis Homogénea, Unidad Asociada al CSIC, CIQSO-Centro de Investigación en Química
Sostenible and Departamento de Química, Universidad de Huelva, 21007 Huelva, Spain
‡
Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute of Science and Technology, Av. Països
#
Catalans 16, 43007 Tarragona, Spain and Departament de Química, Universitat Autonòma de Barcelona, 08193
Bellaterra, Catalonia, Spain
#
Departament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia, Spain
§
Departamento de Química Inorgánica, Universidad de Sevilla, Aptdo 1203, 41071 Sevilla, Spain
KEYWORDS. amination, C-N bond formation, mechanism, cross-coupling, nickel, NHC, indole
ABSTRACT: Nickel catalysis is gaining in popularity in recent years, mostly within the area of cross-coupling. However,
unlike Pd, the mechanisms of Ni-catalyzed C-C and C-heteroatom bond forming reactions have been much less
studied, in particular when N-heterocyclic carbenes are used as ligands. Here, we present a thorough study of the
mechanism of C-N cross-coupling reaction catalyzed by NHC-Ni complex. Focusing on the coupling of 2-
chloropyridines with indole catalyzed by [(IPrNi(styrene) ] (IPr = N,N’-bis-(2,6-diisopropylphenyl)imidazole-2-ylidene),
2
we have examined each of the elementary steps i.e., oxidative addition, ligand substitution and reductive elimination.
All relevant catalytic intermediates have been isolated and structurally characterized by both spectroscopic and
crystallographic methods. Kinetic studies have revealed that the reductive elimination is the rate-limiting step. Catalyst
deactivation is related to the formation of unproductive dinuclear pyridyl-bridged NHC-Ni(II) species, which can be
prevented by increasing the size of the heteroaryl chloride. These investigations support a neutral Ni(0)/Ni(II) catalytic
cycle. Calculations corroborate the experimental evidence and confirm the influence exerted by the ligands in each of
the
elementary
steps.
INTRODUCTION
Remarkably active Ni-based catalyst systems that
7
promote the monoarylation of primary amines and
The Buchwald-Hartwig amination (BHA) is a powerful
synthetic methodology for the construction of C-N
8
ammonia with aryl chlorides have been reported in
1
recent years. Additionally, since Ni is more
electropositive than Pd, it promotes the oxidative
bonds. It is particularly useful for the preparation of
arylamines, compounds that find important applications
in a variety of fields, such as medicinal chemistry,
synthesis of natural products, material chemistry and
addition of electrophiles that are lesser used under Pd
9
catalysis, such as aryl fluorides
and phenol
10
2
derivatives. However, although the number of catalytic
applications of Ni in cross-coupling chemistry has grown
significantly in the last few years, the study of the
mechanisms that govern these transformations has been
less addressed. The ease availability of odd oxidation
states, Ni(I) and Ni(III), introduces the possibility of
radical mechanism, uncommon in Pd-catalyzed cross-
catalysis. Extremely active Pd/phosphine catalysts,
which enable the coupling of (hetero)aryl chlorides with
primary amines or ammonia under mild conditions and
low catalyst loadings, have been reported in the last
5
,6
1
1
3
decade.
Although Pd catalysts still largely dominate the field of
BHA, the search for more sustainable catalytic
processes based on the use of non-precious metals has
12
coupling reactions, adding complexity to the analysis of
the reaction pathways.
4
5,6
turned the attention to its first-row sibling, nickel.
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In the context of Ni-catalyzed BHA, the groups of
Page 2 of 13
amination of hetero(aryl) chlorides with indoles and
carbazoles in short reaction times (2 h), at 110 ºC
(Scheme 1).
7
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Hartwig and Stewart investigated, independently, the
mechanism of the amination of aryl chlorides and
bromides with primary aliphatic amines by different
1
7
Scheme 1. Amination of hetero(aryl)chlorides with
indoles and carbazoles catalyzed by 1.
(
BINAP)Ni(0) precursors. Both studies supported similar
non-radical Ni(0)/Ni(II) catalytic cycles but with different
rate-limiting steps. The formation of catalytically inactive
Ni(I) species, [(BINAP)Ni(ꢀ-Cl)], was identified by
Hartwig and co-workers as one of the major route of
7a
catalyst decomposition. However, in a recent report,
Stradiotto, Johnson and co-workers compared the
activity of (bisphosphine)Ni(I) and (bisphosphine)Ni(II)
precursors (bisphosphine = Pad-DalPhos, dppf), in the
amination of aryl chlorides with primary and secondary
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We were intrigued by the excellent activity displayed
by the (IPr)Ni(0) pre-catalyst in these transformations,
particularly when employing hereroaryl chlorides as
electrophiles, since the presence of a heteroatom in
these substrates could inhibit the catalysis. For that
reason, we focused our attention on the reaction of 2-
chloropyridine with the parent indole, which proceeded
with 80% yield at 10 mol% loading of 1. We postulated
that, instead of impeding the catalytic activity, the
presence of a nitrogen atom in the electrophile might
help to stabilize the catalytic intermediates by
coordination. Thus, we began by examining the oxidative
amines and ammonia.
Although the catalytic
performance of the former lagged behind that of the
Ni(II) pre-catalysts in most of C-N cross-coupling
studied, they proved to be superior in challenging
aminations when combined with dppf ligand.
Furthermore, DFT calculations acknowledge the
existence of competitive Ni(0)/Ni(II) and Ni(I)/Ni(III)
pathways for these aminations.
In addition to phosphines, N-heterocyclic carbenes
(
NHCs) have been widely employed as supporting
14
ligands in Ni-catalyzed BHA.
So far, a detailed
experimental and computational investigation on the
mechanism of the amination reactions catalyzed by
Ni/NHC systems has not yet been conducted. We are
aware of a single report: the DFT analysis of the nickel-
catalyzed BHA of carbamates with secondary amines
1
addition reaction of 2-chloropyridine to complex 1 by H
NMR in C D at room temperature (eq 1). After 90 min of
6
6
reaction, the distinct signals of the vinyl protons of free
styrene were clearly observed (ca. 6.53, 5.57 and 5.04
ppm). Integration of these signals revealed that the two
molecules of styrene present in 1 were released during
the reaction with the 2-chloropyridine. In addition to this,
a mixture of two (IPr)Ni compounds 2a and 2b in a 2:3
ratio was observed. The minor product 2a showed only
one resonance for the four methine protons (δ 3.21 ppm)
and two doublets for the eight methyl groups (ca. 1.06
and 1.44 ppm) of the four isopropyl substituents.
However, in the major product 2b all isopropyl groups of
the IPr ligand were in a different chemical environment,
giving rise to distinct signals for each of the methine and
methyl protons (see Supporting Information).
1
0c
conducted by Garg and co-workers.
This study
supported Ni(0)/Ni(II) pathway, with rate-limiting
a
reductive elimination. It is worth noting, however, that
monovalent (IPr)Ni(I) species have also proven active in
15
the amination of aryl bromides with diphenylamines.
We have been involved in studying the BHA catalyzed
by molecularly defined Ni(II) and Ni(0) complexes
16
bearing NHC ligands. Recently, we reported the first
amination of (hetero)aryl chlorides with indoles promoted
1
7
by the Ni(0) pre-catalyst [(IPr)Ni(styrene)2]. Given the
lack of detailed mechanistic information of C-N bond
1
8
formation catalyzed by NHC-Ni complexes,
we
accomplished a systematic experimental investigation of
the mechanism of the C-N coupling of 2-chloropyridine
with indole catalyzed by a NHC-Ni(0) complex, the
results of which are presented herein. We have isolated
and structurally characterized all relevant catalytic
intermediates and have provided evidence that support a
Ni(0)/Ni(II) catalytic cycle. The kinetic studies of the
catalytic reaction have revealed that the reductive
elimination is the rate-limiting step. The formation of
catalytically inactive dinuclear pyridyl-bridged NHC-Ni(II)
species has been found to be detrimental for the
outcome of the reaction. DFT analysis of the complete
catalytic cycle supports the experimentally proposed
non-radical pathway.
We scaled up the reaction in an attempt to isolate 2a
and 2b, but free styrene hampered the workup and the
purification of the products. To circumvent this problem,
6
the complex [(IPr)Ni(η -toluene)], described by Ogoshi
19
and co-workers, was used instead of 1 (eq 2). Since
toluene is a more labile ligand than styrene, the oxidative
addition reaction occurred upon mixing the two reagents
in hexane at room temperature. The yellow precipitate
obtained, constituted by 2a and 2b with a composition
identical to that previously observed, was recrystallized
from toluene. A mixture of yellow and orange crystals
RESULTS AND DISCUSSION
Synthesis and structures of relevant nickel
intermediates. In 2015, we described that the pre-
catalyst [(IPr)Ni(styrene) ], 1, efficiently catalyzed the
2
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1
was obtained. The former were suitable for X-ray
monitored by H NMR. The mixture was heated at 70 ºC
for 90 min, since no reaction occurred at room
temperature. The formation of a single product 3
together with free styrene was then observed. The NMR
features of 3 resembled those displayed by complex 2a:
the four isopropyl groups of the IPr ligand were
equivalent resulting in only one resonance for the
methine protons (δ 3.24) and two doublets for the methyl
protons (ca. 1.07 and 1.45 ppm). In addition, resonances
due to the tert-butylpyridyl ligand were observed at δ
1.01, 6.03, 6.49 and 6.65. Complex 3 was prepared in a
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diffraction studies and its molecular structure is shown in
Figure 1. This consists of a dimeric Ni(II) complex in
which the two square planar nickel units are bridged by
2
the two pyridyl groups in a ꢀ -(C,N) fashion. The chlorine
atoms are in trans position to the α-carbon atom of the
pyridyl groups, whereas the positions trans to the N
atoms of the pyridyl moiety are occupied by the IPr
ligands. The long distance of 3.2496(7) Å between the
two Ni(II) centers indicates the absence of a metal-metal
interaction. This structure is very similar to those
described for other pyridyl-bridged containing Ni(II)
0
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62% yield from [(IPr)Ni(η -toluene)] following the
procedure shown in eq 3.
20
species.
IPr
Ni
Cl
+
N
Cl
hexane
IPr Ni
(3)
rt
N
3
62% (isolated yield)
Single-crystal analyses of 3 revealed that it is a
mononuclear complex (Figure 2). The Ni(II) ion is
coordinated in
a
highly distorted square planar
environment by the chloride, the IPr carbene ligand and
2
the pyridyl ligand in a η -(N,C) manner. The Ni-Cl and
Ni-IPr bond distances are comparable to those found for
2
2
other (IPr)Ni(II) complexes. The Ni-C(pyridyl) bond of
1
.821(3) Å is shorter than the distances in trans-[NiF(2-
23a
C NF H)(PEt ) ]
C F N)(PEt ) ]
(1.869(4) Å) and trans-[NiX(2-
5
3
3 2
2
3b
(X = OTf, 1.851(3) Å; X = OPh,
5
4
3 2
1
.861(6) Å). The angle Ni-C28-N4 of 41.08(14)º is higher
2
than those reported for other η -(C,N)-pyridyl metal
Figure 1. Molecular structure of the dimer complex 2b.
Hydrogen atoms are omitted for clarity. Selected bond
distances (Å) and angles (º) for 2b: Ni1-Cl1, 1.892(4); Ni1-
C6, 1.890(4); Ni-N1, 1.926(3); Ni1-Cl1, 2.2143(13), Ni2-
C38, 1.888(4); Ni2-C1, 1.878(4);Ni2-N2, 1.938(3); Ni2-Cl2,
2
4
complexes. The IPr ligand is almost perpendicular to
the Ni-C28-N4 plane (dihedrical angle = 84.3(3)º). To the
best of our knowledge this is the first example of a group
2
10 metal complex bearing a η -(C,N)-pyridyl ligand.
2
.2234(11); Cl2-Ni2-N2, 89.16(9); Cl2-Ni2-C1, 170.60(11);
N2-Ni2-C1, 86.10(14); Cl1-Ni1-C6, 86.63(14); N1-Ni1-C6,
86.63(14); N1-Ni1-Cl1, 89.37(10); N1-Ni1-C11, 162.47(13);
C6-N1-C11, 93.21(15); N2-Ni2-C38, 165.36(14), C1-Ni2-
C38, 92.81(15).
At this point, we were unable to assign the obtained
structure to one of the two compounds 2a or 2b, since
re-dissolution of the yellow crystals in C D furnished
6
6
again the mixture of 2a and 2b in a 2:3 ratio. In this
sense, DOSY NMR experiments confirmed the presence
of two species with different diffusion coefficients (see
Supporting Information). It was clear, however, that the
pyridyl-bridged Ni(II) dimer was formed in the oxidative
addition reaction. On the other hand, the identity of the
second product could not be established, albeit we
suspected that it could be the mononuclear [(IPr)Ni(2-
2
1
pyridyl)Cl] complex, in equilibrium with the dimer.
To test our hypothesis, we focused on the bulkier 2-
chloro-6-tert-butylpyridine, substrate that might
Figure 2. Molecular structure of complex 3. Hydrogen
atoms are omitted for clarity. Selected bond distances (Å)
and angles (º) for 3: Ni-C1, 1.873(3); Ni1Cl1, 2.2115(9);
Ni1-C28, 1.821(3); Ni1-N4, 1.928(3); C28-Ni1-N4,
a
disfavor the formation of the dimer. First, the suitability of
this substrate was examined under catalytic conditions.
The amination of 2-chloro-6-tert-butylpyridine with indole
4
1.08(14); N4-Ni1-C1, 141.79(13).
1
As mentioned above, 2a displayed a H NMR signal
catalyzed by [(IPr)Ni(styrene) ] afforded the coupling
pattern fairly similar to that observed for the
mononuclear Ni complex 3. Therefore, it is reasonable to
propose that 2a, the minor product obtained in the
2
product in 64% isolated yield. Next, the stoichiometric
reaction of
1 with 2-chloro-6-tert-butylpyridine was
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Page 4 of 13
oxidative addition reaction of 1 with 2-chloropyridine, is a are similar to those described for 3 and do not deserve
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mononuclear species with a structure similar to that
shown in Fig 2. Consequently, we assign the dimer
structure to the major product 2b. Both complexes form
an equilibrium mixture that favors the dinuclear species.
further comments.
It is interesting to note that the oxidative addition
reactions of 2-chloropyridines to the (IPr)Ni(0) complex 1
affords only Ni(II) products. These results contrast to
those observed by Louie and co-workers in the reactions
of homoleptic Ni(0) complexes (NHC) Ni with aryl
2
2
5
halides. Paramagnetic Ni(I) species [(IMes) NiX] were
2
0
1
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formed with the bulky IMes (IMes = N,N’-bis-(2,4,6-
trimethylphenyl)imidazole-2-ylidene) ligand, whereas
with the less hindered carbene ligand tmiy (tmiy =
tetramethylimidazol-2-ylidene)
Ni(II)
products
[Ni(tmiy) ArX] were isolated. It becomes clear that the N
2
atom in the pyridyl ligand favors the formation of the 16-
electron Ni(II) species by coordination. The preference of
Ni(II) species with respect to hypothetical Ni(I)
alternatives was confirmed by calculations detailed in
Figure S24. The Ni(II) intermediate 2a is more stable
than the [IPrNi(I)Cl] alternative complex by 23.6 kcal/mol.
Figure 3. Molecular structure of complex 4. Hydrogen
atoms are omitted for clarity. Selected bond distances (Å)
and angles (º) for 4: Ni1A-C1A, 1.856(4); Ni1A-N3A,
1.884(3); Ni1A-N4A, 1.901(3); Ni1A-C28A, 1.823(4); C28-
Ni1A-N3A, 41.39(16); C1A-Ni1A-N4, 109.56(15); C1A-Ni1A-
N3A, 146.14(17).
To rule out that radical Ni(I) species formed in the
reaction being the key players for these amination
reactions,
the
coupling
reaction
between
2-
chloropyridine and indole catalyzed by 1 was performed
in the presence of the radical scavenger 2,6-di-tert-butyl-
4
-methylphenol, BHT,. No adverse effect on the yield of
Evaluating the catalytic competence of isolated
intermediates in the amination of indole. The mixture
of monomer and dimer Ni(II) complexes 2a,b was tested
in the reaction of 2-chloropyridine with indole in the
presence of LiOtBu, using 10 mol% of 2a,b at 110 ºC
(Scheme 2a). The reaction afforded the coupling product
in 80% isolated yield in 2 h. This result is almost identical
product was observed in the presence of this additive.
Thus, this experiment suggests that Ni(I) species,
althought they may be formed, do not play a central role
in the catalytic formation of the product.
to that obtained when [(IPr)Ni(styrene) ] is employed as
2
1
7
K+
N
N
pre-catalyst.
These experiments may show the
Cl
Ni
C
6
D
6
catalytic competence of the mixture of 2a,b but, it raises
the question about which of these two complexes is
more effective in the amination reaction
IPr
N
IPr Ni
N
+
(4)
rt
4
3
quantitative by 1H NMR
Scheme 2. Amination of (a) 2-chloropyridine and (b)
2-chloro-6-tert-butylpyridine with indole catalyzed by
the mixture of monomer and dimer complexes, 2a,b
With the oxidative addition product 3 in our hands, we
moved to the next step of the catalytic cycle, the
nucleophilic attack of the indolate. We examined the
reaction of 3 with potassium indolate in C D at room
2
and
respectively.
by
[(IPr)Ni(η -(C,N)6-tBu-pyridyl)Cl],
3,
6
6
1
temperature by H NMR (eq 4). The immediate and
clean formation of compound 4 was observed (see SI).
In addition to the signals due to the IPr ligand, the
spectrum displayed a new group of resonances at δ
(a)
2
a,b (10 mol%)
Cl
N
+
N
N
H
dioxane, LiOtBu
N
6
.80, 6.94, 7.22, 7.76 and 7.92 that were assigned to the
110 ºC, 2 h
indolate group. When the reaction was performed on a
preparative scale, 4 was isolated in 76% yield as orange
crystals suitable for X-ray crystallography. The molecular
structure of 4 is depicted in Figure 3. The complex
possesses a distorted square planar geometry, in which
80% (isolated yield)
(b)
Cl
N
tBu
3 (10 mol%)
+
N
H
N
N
2
dioxane, LiOtBu
the tert-butylpyridyl ligand still maintains the η -(C,N)
110 ºC, 2 h
tBu
coordination mode. The Ni-indolate bond distance of
1.901(3) Å is significantly shorter than those reported for
70% (isolated yield)
2
6
[(dippe)Ni(indolate) ] (1.9307(16) Å and (1.9339(15) Å).
2
The Ni-C(pyridyl) bond (1.823(4)) is almost equal to that
found for 3. The remaining structural features found for 4
Next, we gauged the catalytic activity of the
mononuclear complex 3 in the amination reaction of 2-
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chloro-6-tert-butylpyridine with indole, using same
reaction conditions as those applied in the reaction
catalyzed by 1 (Scheme 2b). The yield of the amination
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
product was practically the same as that found in the
previous experiment with
1
(see above). Thus,
2
[
(IPr)Ni(η -(C,N)6-tBu-pyridyl)Cl] 3 demonstrates to be a
competent intermediate in this catalytic reaction.
We could not measure the catalytic capability of the
dimer 2b, since the monomer/dimer equilibration
occurred rapidly in solution. But, we prepared a Ni(II)-
2
pyridyl complex in which the η -(C,N) coordination mode
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
of the pyridyl ligand was impeded. This material was
6
obtained by the reaction of [(IPr)Ni(η -toluene)] with 1
equiv of 3-chloropyridine under the conditions depicted
in eq 5. Compound 5 was isolated as a yellow crystalline
1
solid in 82% yield. Its H NMR spectrum in C D
6
6
exhibited the characteristic lack of symmetry previously
observed for the dimer 2b, i.e. single resonances for
Figure 4. Molecular structure of complex 5. Hydrogen
atoms are omitted for clarity. Selected bond distances (Å)
and angles (º) for 5: Ni1-N3, 1.944(2); Ni2-N6, 1.935(3);
Ni3-N9, 1.930(3); Ni1-C1, 1.898, Ni2-C33, 1.896(3); Ni3-
C65, 1.886(3); Ni1-C95, 1.905, Ni2-C29, 1.907(3), Ni3-C63,
1.901(3); C1-Ni1-N3, 177.92(12); C95-Ni1-N3, 96.93(12);
C29-Ni2-N6, 84.23(12); C33-Ni2-N6, 178.01(13); C65-Ni3-
N9, 178.98(13); C63-Ni3-N9, 84.23(12).
each of the CH (δ 1.39, 3.37, 3.67 and 4.94) and CH (δ
3
0.06, 0.63, 0.84, 1.05, 1.13, 1.63, 1.79 and 1.89) groups
of the isopropyl substituents of the IPr ligand.
Cl
IPr
IPr
Ni
Ni IPr
Cl
N
N
Ni
+
hexane
rt
N
(5)
Cl
N
Ni
IPr Cl
Complex 5 (10 mol%) was used as pre-catalyst in the
coupling of 2-chloropyridine and indole at 110 ºC
5
82% (isolated yield)
(Scheme 3). No coupling product was detected, which
provided evidence of the lack of catalytic activity of the
trimer compound 5 in this reaction. It is interesting to
note that the reaction of 3-chloropyridine with indole
does not proceed in the presence of [(IPr)Ni(styrene)2]
as the catalyst either.
Compound 5 was identified by X-ray diffraction studies
as the trinuclear Ni(II) macrocycle depicted in Figure 4.
The three Ni atoms present a slightly distorted square-
planar geometry. Like in the case of 2b the carbon
atoms of the pyridyl groups are in trans position to the
chlorine atoms, and the NHCs ligands are trans to the
pyridyl nitrogen atoms. In contrast to 2a and 3, the meta-
position of the nitrogen atom with respect to the pyridyl
carbon bonded to the nickel center in 5 prevents the
formation of a mononuclear species and, consequently a
twelve membered-ring macrocyclic compound by the
coordination of bridging pyridyl ligands is formed instead.
The three Ni—carbene carbon bond distances for 5 are
Scheme 3. Amination of 2-chloropyridine with indole
catalyzed by the trinuclear complex 5.
5 (10 mol%)
Cl
N
X
no reaction
+
N
H
dioxane, LiOtBu
110 ºC, 2 h
To further progress on this point, we focused on the
amination of 2-chloroquinoline with indole. This reaction
proceeded with quantitative yield using 10 mol%
2
2
similar to those reported for other (IPr)Ni(II) complexes
and to those described above for 2b and 4. Matsubara
and coworkers have recently described the formation of
a tetranuclear species with similar bridging pyridyl
moieties, by the reaction the [Ni(IPr)] (μ-Cl) with 3,5-
[
2
(IPr)Ni(styrene) ] as the precatalyst. We suspected that
-chloroquinoline could not favor the formation of
2
2
2
dinuclear species due to its larger size. So, we checked
the nature of the Ni(II) product resulting from the
2
7
dichloropyridine. The Ni—pyridyl carbon, 1.901-1.907
Å, Ni—N, 1.930-1940 Å, lengths are similar to those
reported by Matsubara for the mentioned tetranuclear
6
oxidative addition of 2-chloroquinoline to [(IPr)Ni(η -
1
27
toluene)] by H NMR. A single species 6, which exhibited
species (1.886 and 1.939 Å, respectively).
the characteristic pattern of resonances for the isopropyl
2
substituents indicative of the η -(N,C)-coordination mode
of the 2-quinolyl moiety, was obtained. Complex 6 was
isolated in 80% yield following the procedure described
in eq 2 and it was characterized by NMR spectroscopy
(
see SI). Since only the mononuclear Ni(II)-quinolyl
species was formed, we re-examined the effect of the
catalyst loading in the reaction of 2-chloroquinoline with
indole catalyzed by [(IPr)Ni(styrene) ], 1 (Scheme 4).
2
Complete conversion to the coupling product was
achieved in 2 h using only 5 mol% of 6. Even with a
lower catalyst loading of 2.5 mol%, the amination
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Page 6 of 13
product was obtained in 87% isolated yield in same
Kinetics experiments. We decided to examine the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction time. However, on lowering the catalyst loading
of 1 from 10 mol% to 5 mol% in the coupling of 2-
chloropyridine with indole, the yield dropped from 80 to
influence of the concentration of all the substrates in the
rate of the amination of heteroaryl chlorides with indole
catalyzed by the Ni(0) complex 1. The studies were
6
7%.
conducted
on
the
reaction
of
2-chloro-4-
(
trifluoromethyl)pyridine with indole in the presence of
LiOtBu catalyzed by 1 in toluene-d as the solvent, since
8
Scheme 4. Amination of 2-chloropyridine with indole
in the presence of 6 lowering the catalyst loading.
no significant difference was observed when using
toluene or dioxane. The reaction was conveniently
19
monitored by F NMR spectroscopy.
Plots of the kobs of the reaction vs the concentrations of
each of the substrates (i.e. catalyst, indole,
chloropyridine, base and styrene) are provided in the
Supporting Information. The kinetic studies show that
this amination reaction is first order in the catalyst
concentration and inverse order in styrene. Additionally,
the base, the chloropyridine and the indole
concentrations do not have influence in the reaction rate,
which implies that none of these substrates is involved in
the rate-limiting step.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
These observations clearly indicate that mononuclear
2
Ni(II)-[η -(C,N)-pyridyl] complexes are chemically and
kinetically competent catalytic intermediates in these
amination reactions. Furthermore, the formation of
catalytically inactive polynuclear Ni(II)-pyridyl complexes
are clearly detrimental for the reaction yield, as it
removes active species out of the catalytic cycle.
To verify that reductive elimination was rate
determining, we studied the formation of the amination
product from complex 4 (Scheme 6). No reaction was
detected at 90 ºC but on heating at 110 ºC in dioxane, a
brown precipitated was observed. After purification, the
coupling product was isolated in 61% yield. It has been
demonstrated that olefins facilitate the reductive
Finally, we examined the stability of the pyridyl
complexes 2a,b and 3. These compounds are stable in
the solid state. However, the mixture 2a,b slowly
decomposed at room temperature in THF-hexane
solution yielding crystals of the complex trans-
[
(IPr) NiCl ], that was identified by comparing its X-ray
2 2
7c,28
30
elimination reaction in Pd-catalyzed C-C couplings,
structure with the previously reported data.
On
therefore we conducted the reductive elimination
process in the presence of 2 equiv of styrene. However,
no improvement in the reaction yield was observed
under these conditions.
heating a mixture of 2a,b under the conditions of the
catalytic reaction (i.e. dioxane at 110 º for 2 h) the
degradation process was accelerated producing trans-
[
(IPr) NiCl ] and 2,2-bipyridine (observed and quantified
2 2
by GC), both in 50% yield, together with unidentified Ni
species (Scheme 5). The product resulting from the
decomposition of 2b, trans-[(IPr) NiCl ], showed to be
Scheme 6. Study of the reductive elimination
reaction from complex 4.
2
2
catalytically inactive in the amination of 2-chloropyridine
with indole. By contrast, when performing the same
reaction with mononuclear complex
3 no thermal
decomposition was observed, probably due to the steric
protection conferred by the tert-butyl group on the pyridyl
ligand
Finally, we questioned about the nature of the catalyst
resting state. To address this point, we examined the
coupling of 2-chloro-6-tert-butylpyridine with potassium
Scheme 5. Thermal decomposition of 2a,b.
indolate in the presence of 10 mol% [(IPr)Ni(styrene) ] at
2
1
9
0 ºC, by H NMR (toluene-d /THF-d mixture). The
8
8
unique nickel species observed in solution after 3 h was
the indolate 4. We believe this should be interpreted as
evidence of the role of such species as the feasible
resting state of the catalyst during the catalytic
transformation.
Mechanistic proposal. On the basis of stoichiometric
reactions and kinetic studies discussed above, we
propose the non-radical Ni(0)/Ni(II) catalytic cycle
outlined in Figure 5 for the amination of heteroaryl
chlorides with indole promoted by the [(IPr)Ni(styrene)2],
The formation of trans-[(IPr) NiCl ] and 2,2-bipyridine
2
2
could be the result of dispropotionation of 2b to
di(pyridyl)-Ni(II) and Ni(II)-halides complexes, the former
of which undergoes facile reductive elimination of
1
.
2
9
bipyridine with concomitant generation of Ni(0) species.
The observation that styrene has a negative effect on
the reaction rate is consistent with a pre-equilibrium step,
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whereby the pre-catalyst 1 reversibly dissociates one
styrene ligand to form the low-coordinate Ni(0) species
(Figure 6). The dissociation of the second molecule of
styrene required a higher activation energy (46.2 kcal
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-
1
A. The oxidative addition of the heteroaryl chlorides to A
mol ), consequently it remained coordinated to the Ni
center. In the following step, 2-chloropyridine was
coordinated to c1 via the nitrogen atom leading to
intermediate c2. From this intermediate, the activation of
the C-Cl bond was not feasible and required the change
2
leads to the formation of the Ni(II)-η -(C,N)-heteroaryl
species B, in equilibrium with dinuclear species
depending upon the steric hindrance of the heteroaryl
chloride. The observed first order rate-dependence in
catalyst concentration together with studies of the role of
such intermediates in the catalytic reaction (see above)
strongly suggest that mononuclear Ni(II) complex B is
the catalytically active species. The substitution of the
chloride ligand by the indolate anion in B affords C from
which reductive elimination takes place. The
coordination of styrene regenerates the low-coordinate
species A.
2
in the coordination mode of the pyridine ring to η -(C,N)
fashion to give intermediate c3. The oxidative addition
proceeded via a S 2 type transition state TS c3-c4,
N
-1
which lied 4.4 kcal mol higher than c3. Concerted
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
transition states are more common for aromatic systems,
1
2e
but the S 2 arrangement is not without precedent. The
N
connectivity for the reported TS was moreover confirmed
by IRC calculations (Figure S20). The reaction is quite
-
1
exergonic, releasing 29.0 kcal mol from c3 and forming
irreversibly c4. Intermediate c4 evolved to the
experimentally observed 2a by styrene dissociation,
which was in equilibrium with the slightly more stable (by
-
1
2
.8 kcal mol ) dinuclear species 2b.
Figure 5. Mechanistic proposal for the amination of
heteroaryl
chlorides
with
indole
catalyzed
by
[
(IPr)Ni(styrene)
2
], 1.
DFT/MM analysis of the mechanism. As a final
investigation of the mechanism of this aryl amination
reaction, we carried out QM/MM computational
using the long-range corrected ωB97X-D
a
3
1,32
study,
3
3
34
functional for the QM part and the UFF force field for
the MM part (which consisted of the isopropyl groups of
the IPr ligand). All the calculations were performed in
Figure 6. Free energy profile for the oxidative addition of 2-
-
1
chloropyridine to 1. Energies in kcal mol . 1,4-dioxane used
3
5
as solvent through SMD model.
solution using the SMD method (see the Computational
Details in the Supporting Information for a full description
of the methods). The singlet spin state has been found
to be most stable in all calculations, and all reported
energies correspond to this state. The triplet alternative
was evaluated in a number of intermediates, and found
to be always higher in energy. Further details on spin
states are provided in the Supporting Information. A
collection of data set of the computed structures is
The next steps of the catalytic cycle, i.e. the ligand
substitution and the reductive elimination, were
computed and the free energy profile is shown in Figure
7
. The indole reactant is introduced as indolate because
its formation must be quantitative in the presence of
LiOtBu (see Figure S22 for details). The reaction of 2a
with the indolate reagent produced intermediate c5,
3
6
available in the ioChem-BD repository.
-1
which lied 4.8 kcal mol lower in energy than 2a. From
The first step of the catalytic cycle i.e., the oxidative
this point, we explored three different pathways for the
reductive elimination step. The most favored one (in
black in Figure 7) started with the loss of chloride into the
solvent medium and formation of intermediate c6
(experimentally observed and isolated when using tert-
butyl-chloropyridine as reactant). This step is exergonic
by 5.9 kcal/mol. The formation of the C-N bond of the
addition of 2-chloropyridine (PyCl) to [(IPr)Ni(styrene) ] 1
2
was computed (the experimentally unidentified species
are labelled with a prefix c). The reaction started with the
dissociation of one molecule of styrene from the initial
complex [(IPr)Ni(styrene) ] 1 to form the 14-electron
2
-
1
intermediate c1, which was 10.2 kcal mol above 1
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product occurred via transition state TS c6-c7 and
Page 8 of 13
-
1
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
required free activation energy of 29.8 kcal mol .
Consistent with the experimental observations, this step
was the rate limiting transition state. Finally, the C-N
coupling product was released from c7, regenerating 1
by styrene coordination. The overall reaction was found
-
1
to be exergonic by 36.2 kcal mol .
N
N
N
N
R
R
N
N
N
R
R
N
R
R
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cl Ni
Ni
Ni
Figure 8. 3D structure of the reductive elimination transition
state (TS c6-c7). Bond lengths in Å. Ball and sticks for QM
part and tubes for MM part.
N
Ph
N
N
TS c5-Cl
TS c7'-sty
TS c6-c7
Finally, we studied the thermodynamics for the
decomposition pathway displayed in Scheme 5. The
formation of bipyridine product from the dinuclear
species 2b and the transfer of one NHC ligand to the
Ni(II) to form trans-[(IPr) NiCl ] was found to be
TS c7'-sty
19.6
iPr
TS c5-Cl
3.4
c7'
8.5
1
2
2
R =
Styrene
exergonic by 2.2 kcal/mol. The resulting Ni(0)-bpy
complex evolved then to form Ni(0) aggregates.
iPr
Indolate
2
a
TS c6-c7
3.7
Cl-
c7
-18.5
-
15.4
c5
20.2
2 Styrene
Product
-
c6
26.1
-
CONCLUSIONS
1
-36.2
A detailed experimental mechanistic analysis of the
amination of heteroaryl chlorides with indoles catalyzed
N
N
N
N
N
N
N
R
R
R
R
R
R
Cl Ni
N
Ni
Ni
N
by [(IPr)Ni(styrene) ] has allowed, for the first time, the
2
N
N
N
isolation and characterization of all relevant Ni-based
catalytic intermediates proposed for a C-N coupling
reaction, demonstrating the involvement of a Ni(0)/Ni(II)
catalytic pathway in this amination process. We have
found that the oxidative addition of 2-chloropyridine to
IPr-Ni(0) species proceeds at room temperature with
formation of mononuclear and dinuclear pyridyl-Ni(II)
species (2a and 2b, respectively); The coordination of
the N atom of the the pyridyl group fashion is key to
stabilized the Ni(II) species. The catalytic studies reveal
the competence of the mononuclear complex 2a as
intermediate in the C-N coupling, but also the
unproductive nature of the dinuclear complex 2b. The
formation of latter withdraws catalytically active species
out of the cycle; The suppression of the dinuclear Ni(II)
species formation i.e. by increasing the steric hindrance
around the metal center using a bulkier NHC ligand
might improve the pre-catalyst performance. Kinetic and
experimental studies show that the reductive elimination
is the rate-limiting step. The calculations provide a
complete mechanistic picture, which is consistent with
experiment, and confirm the specific role played by the
different ligands.
c5
c6
c7
Figure 7. Free energy profile from 2a to the product.
Energies in kcal mol . 1,4-dioxane used as solvent through
SMD model.
-1
We envisaged two other alternative pathways (in blue
and red in Figure 7) for the reductive elimination step, in
which either the chloride or the styrene ligands remained
coordinated, but both pathways were higher in energy.
The structure of the key transition state TS c6-c7 is
depicted in Figure 8. The indolate ligand is trans to the
NHC ligand and the Ni-N and Ni-C bond distances are
almost identical, 1.88 and 1.87 Å, respectively. The C-N
distance in the transition state is only 1.70 Å, close to the
product bond length (1.40 Å). We also studied an
alternative structure with the pyridine ring trans to the
NHC ligand, but the transition state optimization always
leads to TS c6-c7.
At this stage, we have not experimental evidence to
conclude that the Ni(0)/Ni(II) catalytic cycle found in this
study is also operative in the amination of simple aryl
chlorides with indoles. As others have noted, the
mechanism of Ni-catalyzed cross-coupling reactions
does not seem to be general and minor changes in the
ligand or in the substrates can have a significant effect
1
3,18
on the reaction mechanism.
ASSOCIATED CONTENT
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Supporting Information
ACS Catalysis
Am. Chem. Soc. 2009, 131, 11049. (d) Lundgren, R. J.; Peters,
B. D.; Alsabeh, P. G.; Stradiotto, M. P,N-Ligand for
Palladium-Catalyzed Ammonia Arylation: Coupling of
Deactivated Aryl Chlorides, Chemoselective Arylations, and
Room Temperature Reactions. Angew. Chem. Int. Ed. 2010,
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
A
The Supporting Information is available free of charge on
the ACS Publications website.
Data for 2b (CIF)
Data for 3 (CIF)
4
9, 4071. (e) Ruiz-Castillo, P-; Blackmond, D. G.; Buchwald, S.
Data for 4 (CIF)
Data for 5 (CIF)
Additional experimental details, procedures, and NMR
spectra for all new compounds (PDF)
L. Rational Ligand Design for the Arylation of Hindered Primary
Amines Guided by Reaction Progress Kinetic Analysis. J. Am.
Chem. Soc. 2015, 137, 3085. (f) Sharif, S.; Rucker, R. P.;
Chandrasoma, N.; Mitchell, D.; Rodriguez, M. J.; Froese, R. D.
J.; Organ, M. G. Selective Monoarylation of Primary Amines
Using the Pd-PEPPSI-IPent Precatalyst. Angew. Chem. Int.
Ed. 2015, 54, 9507.
Cl
AUTHOR INFORMATION
Corresponding Authors
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0
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Renaissance of Catalysis with Abundant Metals. Acc. Chem.
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H.-J. Spotlight on Non-Precious Metal Catalysis. Org. Process
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E-mail: fmaseras@iciq.es
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Garg, N. K.; Percec, V. Nickel-Catalyzed Cross-Couplings
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Tasker, S. Z.; Standley, E. A.; Jamieson, T. F. Recent
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F.; Poblet, J. M.; Bo, C. Managing the Computational Chemistry
Big Data Problem: The ioChem-BD Platform. J. Chem. Inf.
Model. 2015, 55, 95.
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ACS Catalysis
SYNOPSIS TOC. A detailed investigation on the mechanism of aryl amination promoted by [(IPr)Ni(styrene) ] (IPr
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=
N,N’-bis-(2,6-diisopropylphenyl)imidazole-2-ylidene) has been conducted, where all relevant intermediates have
been isolated and characterized. Experimental, kinetic and computational studies support a neutral Ni(0)/Ni(II)
catalytic cycle.
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