Catalytically Relevant Intermediates in the Ni-Catalyzed C(sp2)-H and C(sp3)-H Functionalization of Aminoquinoline Substrates

Article abstract of DOI:10.1021/jacs.9b09109

This Article describes the synthesis and characterization of cyclometalated aminoquinoline Ni^II σ-aryl and σ-alkyl complexes that have been proposed as key intermediates in Ni-catalyzed C-H functionalization reactions. These Ni^II complexes serve as competent catalysts for the C-H functionalization of aminoquinoline derivatives with I₂. They also react stoichiometrically with I₂ to form either aryl iodides or β-lactams within minutes at room temperature. Furthermore, they react with Ag^I salts at -30 °C to afford isolable five-coordinate Ni^III species. The Ni^III σ-aryl complexes proved inert toward C(sp²)-I bond-forming reductive elimination under all conditions examined (up to 140 °C in DMF). In contrast, a Ni^III σ-alkyl analogue underwent C(sp³)-N bond-forming reductive elimination at 140 °C in DMF to afford a β-lactam product. However, despite the ability of this latter Ni^III species to participate in stoichiometric product formation, the complex was not a competent catalyst for β-lactam formation. Overall, these results suggest against the intermediacy of Ni^III species in these C-H functionalization reactions.

Full text of DOI:10.1021/jacs.9b09109

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Catalytically Relevant Intermediates in the Ni-Catalyzed C(sp2)−H
and C(sp3)−H Functionalization of Aminoquinoline Substrates
Pronay Roy, James R. Bour, Jeff W. Kampf, and Melanie S. Sanford*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109, United States
S
* Supporting Information
ABSTRACT: This Article describes the synthesis and
characterization of cyclometalated aminoquinoline NiII σ-aryl
and σ-alkyl complexes that have been proposed as key
intermediates in Ni-catalyzed C−H functionalization reactions.
These NiII complexes serve as competent catalysts for the C−
H functionalization of aminoquinoline derivatives with I2.
They also react stoichiometrically with I2 to form either aryl
iodides or β-lactams within minutes at room temperature.
Furthermore, they react with AgI salts at −30 °C to afford
isolable five-coordinate NiIII species. The NiIII σ-aryl
complexes proved inert toward C(sp2)−I bond-forming reductive elimination under all conditions examined (up to 140 °C
in DMF). In contrast, a NiIII σ-alkyl analogue underwent C(sp3)−N bond-forming reductive elimination at 140 °C in DMF to
afford a β-lactam product. However, despite the ability of this latter NiIII species to participate in stoichiometric product
formation, the complex was not a competent catalyst for β-lactam formation. Overall, these results suggest against the
intermediacy of NiIII species in these C−H functionalization reactions.
Mechanistically, these aminoquinoline-directed C−H func-
tionalization reactions are proposed to involve initial C−H
activation at NiII to form nickelacycles of general structure 2.
To date, 2 has not been detected spectroscopically during
catalysis, but its intermediacy is supported by computational
investigations,5 experimental H/D exchange and kinetic
isotope effect studies,2−4 and model systems.6 In contrast,
considerable debate remains about the mechanism of the
oxidative functionalization step. Various pathways have been
proposed, including (i) direct electrophilic functionalization of
the Ni−C bond without a change in oxidation state at Ni
(Scheme 1, i);5b (ii) C−X bond-forming reductive elimination
from a NiIII intermediate of general structure 4 (Scheme 1,
ii);4,5 or (iii) C−X bond-forming reductive elimination from a
NiIV intermediate of general structure 5 (Scheme 1, iii).4,5
Notably, pathway ii, involving NiIII intermediates, is the most
common mechanistic proposal in the literature for C−X
coupling from Ni centers.3,4 However, to date, the direct
isolation or even observation of these putative high-valent Ni
intermediates or their cyclometalated NiII analogues has
proven elusive.
INTRODUCTION
■
Over the past 5 years there has been significant progress in the
development of Ni-catalyzed reactions for the oxidative
functionalization of unactivated C−H bonds.1 The vast
majority of these transformations involve the use of amino-
quinoline-based substrates of general structure 1 and result in
the formation of new carbon−carbon2 or carbon−heteroa-
tom3,4 bonds in products like 3 (Scheme 1).
Scheme 1. Proposed Pathways for Ni-Catalyzed Oxidative
Functionalization of C−H Bonds
This Article describes a detailed study of two related Ni-
catalyzed C−H functionalization reactions: (1) the C(sp2)−H
iodination of substrate 1a (eq 1)4 and (2) the intramolecular
C(sp3)−H amination of substrate 1b (eq 2).4 Toward this end,
we have developed a synthetic route analogues of two putative
nickelacycle intermediates of these transformations (2a and
Received: August 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b09109
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
Scheme 2. Decarbonylative Route to Complex 2a and
a
ORTEP Diagram (50% Probability)
2b) and conducted detailed investigations of their catalytic
competence and stoichiometric redox chemistry. These studies
reveal that NiIII complexes of general structure 4 (Scheme 1)
are isolable in these systems. Furthermore, they can, in some
cases, participate in C−heteroatom bond-forming reductive
elimination reactions. However, our studies show that these
isolated NiIII adducts are not competent for entering the catalytic
cycle. Overall, the data suggest that alternative mechanisms for
the functionalization step (involving either NiIV intermediates
or direct NiII−C bond cleavage) should be considered in these
systems.
a
Selected bond distances (Å): C(16)−Ni 1.889, N(1)−Ni 1.946,
N(2)−Ni 1.856, N(3)−Ni 1.888. Hydrogen atoms are omitted for
clarity.
with a more oxidatively stable picoline ligand to afford 2a in
71% overall yield.
Complex 2a is a diamagnetic NiII species that was
characterized by NMR spectroscopy as well as X-ray
crystallography. The X-ray crystal structure shows a slightly
distorted square planar nickel center, consistent with other
pincer NiII complexes.12 The structure of complex 2a is closely
analogous to its palladium analogue except that the M−C and
M−N bonds are ∼0.1 Å shorter than those in the
corresponding palladacycle.7b
RESULTS AND DISCUSSION
■
Studies of σ-Aryl Nickelacycle 2a. We first targeted the
cyclometalated σ-aryl NiII intermediate of the Ni-catalyzed
C(sp2)−H iodination of 1a-H with molecular iodine (eq 1).
Notably, analogous palladacycles have been prepared by Chen
and Maiti via C(sp2)−H activation, following similar
procedures to that reported by Daugulis for the C(sp3)
analogue.7 As such, we first examined this route to complex 2a.
As shown in eq 3, the reaction of 1a-H with Ni(OAc)2 and
Complex 2a is closely related to the putative catalytic
intermediate 2, but it contains a picoline ligand that is not
present under the standard catalytic conditions.13 Based on the
reaction conditions, the fourth ligand during catalysis is likely
triflate, carbonate, or solvent. To assess whether 2a can enter
the catalytic cycle, we examined this complex as a catalyst for
the C(sp2)−H iodination reaction in Table 1. The use of 10
Table 1. C(sp2)−H Iodination of 1a-Cl with Different Ni
Catalysts
NMe4OAc in DMSO-d6 at temperatures up to 160 °C resulted
1
in H NMR signals consistent with the formation of 2a in a
maximum of 12% yield.8 However, attempts to isolate 2a
resulted in decomposition, largely due to the challenges
associated with removing DMSO from the reaction mixture.
Furthermore, <5% of 2a was observed when this reaction was
conducted in other solvents (e.g., MeCN, dioxane).
We sought an alternative approach to 2a that would avoid
the use of DMSO as a solvent. We noted that anhydrides and
imides are known to undergo oxidative addition at Ni0
centers,9 and subsequent decarbonylation of the resulting
metal acyl intermediates can then afford NiII−alkyl/aryl
complexes.10 This sequence was leveraged by reacting 2
equiv of Ni(PEt3)4 with the cyclic imide 2-(quinolin-8-
yl)isoindoline-1,3-dione (6) (Scheme 2).11 The reaction
proceeded rapidly at 100 °C in benzene to afford 2a-PEt3 in
87% yield, presumably via decarbonylation from intermediate
7. The PEt3 ligand of 2a-PEt3 then underwent substitution
yield (%)
entry
[Ni]
3a-Cl
3a-H
1
2
3
4
Ni(OTf)2
2a
4a-OTf
4a-OTFA
56
48
<1
<1
−
7
<1
<1
mol% of 2a afforded 48% yield of product 3a-Cl along with 7%
of 3a-H (derived from the cyclometalated ligand on the pre-
catalyst). For comparison, in our hands the analogous reaction
with Ni(OTf)2 afforded 3a-Cl in 56% yield. These results
demonstrate that 2a is catalytically competent for this
transformation.14
B
DOI: 10.1021/jacs.9b09109
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We next examined the stoichiometric reaction of NiII
complex 2a with I2 (eq 4). The treatment of a toluene
Scheme 3. Synthesis of 4a-OTf and 4a-OTFA and ORTEP
Diagram of 4a-OTFA (50% Probability)
a
solution of 2a with 1 equiv of I2 at room temperature resulted
in an immediate color change from orange to yellow. Analysis
of the crude reaction mixture by 1H NMR spectroscopy
revealed that 2a was completely consumed within 30 min, with
concomitant formation of 3a-H in 72% yield.15 No
a
Selected bond distances (Å) and angles (degrees): C(16)−Ni 1.930,
N(1)−Ni 1.991, N(2)−Ni 1.888, N(3)−Ni 2.041, O(2)−Ni 1.954,
O(1)−Ni 2.628; N(1)−Ni−N(2) 102.65.
1
intermediates were observed via H NMR spectroscopy or
relatively weak, particularly compared to that of Ni−O(2) =
1.954 Å.
EPR spectroscopy during this transformation. Overall, these
results demonstrate that C(sp2)−I bond formation is extremely
fast at room temperature and suggest that the functionalization
step is unlikely to be turnover-limiting during catalysis.
To gain further insights into the redox chemistry of 2a, the
electrochemical oxidation of this complex was interrogated via
cyclic voltammetry (CV). As shown in Figure 1, the CV of 2a
We next explored the reactivity of the isolated NiIII
complexes toward C(sp2)−I bond formation under both
stoichiometric and catalytic conditions. Importantly, a number
of reports have shown the feasibility of C(sp2)−halogen
coupling at NiIII centers.18 However, as shown in Table 1,
entries 3 and 4, 4a-OTf and 4a-OTFA are not competent
catalysts for the conversion of 1a-Cl to 3a-Cl. Furthermore,
heating these NiIII complexes in the presence of either NBu4I
or I2 did not afford traces of the C(sp2)−I coupled product 3a-
H (eq 5), even after 16 h at temperatures as high as 140 °C.
Figure 1. CV of complex 2a in MeCN/NBu4PF6 at a scan rate of 50
mV/s. The CV in red was recorded from −0.5 to +0.5 V to isolate the
first oxidation wave.
Overall, these results provide evidence that NiIII complexes are
accessible from 2a with mild AgI oxidants. However, at least in
the case of 4a-OTf and 4a-OTFA, these NiIII species are dead
ends rather than intermediates that lead to productive catalysis.
Studies of σ-Alkyl Nickelacycle 2b. We conducted
analogous investigations of the σ-alkyl nickelacycle 2b, the
putative intermediate in Ni-catalyzed β-lactam formation (eq
2).4 Attempts to prepare this complex by stoichiometric
C(sp3)−H activation yielded no detectable product.19
However, 2b was readily accessed via a synthetic route
analogous to that used to synthesize 2a. The decarbonylative
reaction of Ni(PEt3)4 with 3,3-dimethyl-1-(quinolin-8-yl)-
pyrrolidine-2,5-dione (8) followed by ligand exchange with
picoline afforded 2b in 81% overall yield (Scheme 4).
in MeCN/NBu4PF6 shows a quasi-reversible one-electron
redox event at approximately +0.2 V versus Ag/Ag+, which we
assign as the NiII/III couple. A second, irreversible oxidation
wave is observed at approximately +1.1 V versus Ag/Ag+ and is
assigned as the NiIII/IV couple.
The CV of 2a suggests that AgI salts should promote the
single electron oxidation of this NiII complex.16 Indeed, the
treatment of 2a with 1 equiv of AgOTf or AgOTFA afforded
the NiIII triflate and trifluoroacetate complexes 4a-OTf and 4a-
OTFA in 65% and 80% yield, respectively (Scheme 3). Both
4a-OTf and 4a-OTFA are paramagnetic NiIII complexes that
were characterized by elemental analysis as well as EPR
spectroscopy. Both EPR spectra (Figures S1 and S2) are
consistent with S = 1/2 NiIII centers. Complex 4a-OTFA was
further characterized by X-ray crystallography, and the solid
state structure (Scheme 3) shows a slightly distorted square
pyramidal geometry with a τ value of 0.03. Similar geometries
have been reported for related organometallic NiIII PCP and
NCN pincer complexes.17 Notably, the carbonyl oxygen of the
carboxylate ligand is also in the proximity of the NiIII center
and could potentially act as a sixth ligand. However, the bond
distance (Ni−O(1) = 2.628 Å) suggests that this interaction is
The diamagnetic square planar NiII complex 2b was
characterized by NMR spectroscopy, elemental analysis, X-
ray crystallography (Scheme 4), and cyclic voltammetry (CV,
Figure 2). The X-ray crystal structure shows a slightly distorted
square planar nickel center, very similar to 2a as well as a Pd
analogue.12,20 Again, the M−C and M−N bonds are ∼0.1 Å
shorter in 2b versus the corresponding palladacycle. The CV of
2b in MeCN/NBu4PF6 shows a quasi-reversible single electron
oxidation at approximately −0.15 V versus Ag/Ag+ along with
a second, irreversible oxidation wave at approximately +1.15 V
versus Ag/Ag+. Notably, the first oxidation occurs at ∼350 mV
C
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Scheme 4. Synthesis of 2b and ORTEP Diagram (50%
Probability)
Scheme 5. Oxidation of 2b with (a) I2 and (b) AgOTf and
ORTEP Diagram of 4b (50% Probability)
a
a
a
Selected bond distances (Å): C(12)−Ni 1.915(5), N(1)−Ni
1.960(5), N(2)−Ni 1.846(5), N(3)−Ni 1.895(5). Hydrogen atoms
are omitted for clarity.
a
Selected bond distances (Å), angles (degrees): C(12)−Ni 1.988,
N(1)−Ni 2.009, N(2)−Ni 1.861, N(3)−Ni 1.960, O(2)−Ni 2.087;
N(3)−Ni−N(2) 152.27. Hydrogen atoms are omitted for clarity.
NiIII product 4b, which was isolated in 91% yield (Scheme 5b).
1
The EPR spectrum of 4b is consistent with an S = /2 NiIII
center (see Figure S3). The X-ray structure confirms that this
is a 5-coordinate NiIII center with a slightly distorted square
pyramidal geometry (Scheme 5b). The NiIII−C bond distance
of 1.988 Å is similar to that observed for complex 4a-OTFA.
The τ value of 4b (0.25) is higher than that of 4a-OTFA
(0.03) but is still in line with those reported for other
structurally characterized organometallic NiIII PCP and NCN
pincer complexes.17
Figure 2. CV of complex 2b in MeCN/NBu4PF6 at scan rate of 50
mV/s. The CV in red was recorded from −1.0 V to +0.5 V to isolate
the first oxidation wave.
Finally, we interrogated the reactivity of NiIII complex 4b.
Notably, Chatani proposed two possible routes to β-lactam
product 3b-H. The first involves direct C(sp3)−N bond-
forming reductive elimination from a high-valent Ni center.
The second involves the generation of a C(sp3)−I bond and
subsequent intramolecular SN2 cyclization to generate the
lactam. Complex 4b showed no reactivity toward C(sp3)−X
coupling at room temperature either in the presence or
absence of added NBu4I. However, heating 4b for 16 h at 140
°C in DMF resulted in C(sp3)−N coupling to afford β-lactam
3b-H in 60% yield (eq 6). Although C(sp3)−heteroatom
lower potential than that for 2a, consistent with the stronger
donor ability of the σ-alkyl versus σ-aryl ligand.16c,21
As summarized in Table 2, complex 2b serves as an effective
catalyst for intramolecular C(sp3)−H amidation of 1b-Cl. 2b
Table 2. Intramolecular C(sp3)−H Amination of 1b-Cl with
Different Ni Catalysts
yield (%)
entry
[Ni]
3b-Cl
3b-H
reductive elimination has been demonstrated from NiIV model
complexes,22 to our knowledge, this represents the first directly
observable example of C(sp3)−N coupling from an isolated
NiIII center.23 This transformation establishes the viability of
NiIII intermediates for forming C(sp3)−N bonds. However, the
elevated temperature required for this reaction (particularly
compared to the room temperature reaction between 2b and
I2, Scheme 5a) suggests that this reaction is unlikely to be
catalytically relevant. Indeed, the use of 4b as a catalyst for the
C−H amination of 1b-Cl showed no formation of the product
3b-Cl (Table 2, entry 3).
1
2
3
Ni(OTf)2
2b
4b
48
17
<1
−
8
7
affords a modest (17%) yield of 3b-Cl along with 8% of the
pre-catalyst-derived β-lactam 3b-H. For comparison, in our
hands the analogous reaction with Ni(OTf)2 resulted in 48%
yield of 3b-Cl.
Similar to 2a, complex 2b reacts stoichiometrically with I2 at
room temperature to afford the C−H functionalization
product 3b-H in 85% yield (Scheme 5a). This σ−alkyl NiII
complex also reacts rapidly with AgOTf at −30 °C to afford
D
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SUMMARY AND CONCLUSIONS
■
This Article describes the synthesis of NiII pincer complexes
relevant to catalytic C(sp2)−H and C(sp3)−H functionaliza-
tion reactions of aminoquinoline substrates. These NiII
complexes are readily oxidized with AgI oxidants to afford
isolable NiIII species. Although C(sp2)−halogen coupling has
been demonstrated from a variety of isolated NiIII model
complexes,18 the σ-aryl complex 4a proved completely inert to
C(sp2)−I bond formation under both stoichiometric and
catalytic conditions. In contrast, the NiIII σ-alkyl species 4b did
undergo slow intramolecular C(sp3)−N bond-forming reduc-
tive elimination at 140 °C to form a β-lactam. This represents
the first direct observation of C(sp3)−N coupling from an
isolable NiIII intermediate. However, despite the fact that this
NiIII species reacts stoichiometrically to form a β-lactam, it is
not a competent catalyst for the C−H functionalization
reaction that generates this product.
Overall, these experiments do not definitively rule out a role
for all possible NiIII intermediates in this transformation.
However, they strongly suggest that other pathways, such as
direct electrophilic cleavage of the NiII−C bond and/or the
formation of more reactive, higher valent Ni intermediates,
should be closely considered/examined as alternatives. More
broadly, this study opens the door for further detailed
interrogations of organometallic intermediates in Ni-catalyzed
C−H functionalization reactions. Ongoing work in our group
is leveraging the readily accessible nickelacycles 2a and 2b to
investigate other elementary transformations relevant to Ni
catalysis.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b09109.
■
S
Experimental details and complete characterization data
for all new compounds (PDF)
X-ray crystallographic data for 2a, 2b, 4a-OTFA, and 4b
(CIF)
(5) (a) Omer, H. M.; Liu, P. Computational study of Ni-catalyzed
C−H functionalization: Factors that control the competition of
oxidative addition and radical pathways. J. Am. Chem. Soc. 2017, 139,
9909−9920. (b) Haines, B. E.; Yu, J.-Q.; Musaev, D. G. The
mechanism of directed Ni(II)-catalyzed C−H iodination with
molecular iodine. Chem. Sci. 2018, 9, 1144−1154. (c) Li, Y.; Zou,
L.; Bai, R.; Lan, Y. Ni(I)-Ni(III) vs. Ni(II)-Ni(IV): Mechanistic study
of Ni-catalyzed alkylation of benzamides with alkyl halides. Org. Chem.
Front. 2018, 5, 615−622. (d) Zhang, S.-K.; Samanta, R. C.;
Sauermann, N.; Ackermann, L. Nickel-catalyzed electro-oxidative
C−H amination: Support for nickel(IV). Chem. - Eur. J. 2018, 24,
19166−19170.
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Love, J. A. Understanding Ni(II)-mediated C(sp3)−H activation:
Tertiary ureas as model substrates. J. Am. Chem. Soc. 2018, 140,
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AUTHOR INFORMATION
Corresponding Author
*mssanfor@umich.edu
ORCID
Pronay Roy: 0000-0002-5649-8747
James R. Bour: 0000-0002-0372-7323
Jeff W. Kampf: 0000-0003-1314-8541
Melanie S. Sanford: 0000-0001-9342-9436
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the U.S. National Science
Foundation (CHE 1664961 to M.S.S. and CHE 0840456 for
X-ray instrumentation).
(7) (a) Zaitsev, G. V.; Shabashov, D.; Daugulis, O. Highly
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ortho-C−H alkylation of N-quinolyl benzamides: evidence for
stereoretentive coupling of secondary alkyl halides. J. Am. Chem.
Soc. 2015, 137, 531−539. (c) Deb, A.; Hazra, A.; Peng, Q.; Paton, R.;
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F
DOI: 10.1021/jacs.9b09109
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX