Understanding Ni(II)-Mediated C(sp3)-H Activation: Tertiary Ureas as Model Substrates

Article abstract of DOI:10.1021/jacs.8b07708

We report a mechanistic study of C(sp³)-H bond activation mediated by nickel. Cyclometalated Ni(II) ureate [(PEt₃)Ni(?³-C,N,N-(CH₂)N(Cy)(CO)N((N)-quinolin-8-yl))] was synthesized and isolated from the urea precu

Full text of DOI:10.1021/jacs.8b07708

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Article
Understanding Ni(II) Mediated C(sp3)-H
Activation: Tertiary Ureas as Model Substrates
Douglas Dawson Beattie, Anna C. Grunwald, Thibaut Perse, Laurel L. Schafer, and Jennifer A. Love
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b07708 • Publication Date (Web): 06 Sep 2018
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Journal of the American Chemical Society
Understanding Ni(II) Mediated C(sp3)-H Activation:
Tertiary Ureas as Model Substrates
D. Dawson Beattie, Anna C. Grunwald, Thibaut Perse, Laurel L. Schafer,* and Jennifer A. Love*
ǂDepartment of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, British Columbia,
Canada V6T 1Z1
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Nickel ● C-H activation ● urea
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ABSTRACT: We report a mechanistic study of C(sp3)-H bond activation mediated by nickel. Cyclometalated Ni(II) ureate
[(PEt3)Ni(κ3-C,N,N-(CH2)N(Cy)(CO)N((N)-quinolin-8-yl))] (3a) was synthesized and isolated from urea precursor (2a),
(Me)(Cy)N(CO)N(H)(quinolin-8-yl), via C(sp3)-H activation. We investigated the effects of solvents and base additives on
the rate of C-H activation. Kinetic isotope effect experiments showed that C-H activation is rate determining. Through
deuterium labelling and protonation studies, we also showed that C-H activation can be reversible. We extended this reac-
tion to a range of ureas (2b,c,e-n) with primary and secondary C(sp3)-H bonds, which activate readily to form analogous
nickelated products (3b,c,e-n). Finally, we showed that carboxylate additives assist with both ligand dissociation and initial
N-H bond activation, consistent with a concerted metalation deprotonation mechanism.
Introduction
Scheme 1. (a) General scheme of nickel catalysis of am-
The selective activation of carbon-hydrogen (C-H) bonds
by transition metals has long been a major research goal in
the fields of organometallic chemistry and catalysis. Such
reactions would permit the construction of functionalized
molecules without prior activation of the coupling part-
ners, improving step economy and minimizing waste. De-
spite remarkable success in the coupling of unactivated
aryl C(sp2)-H bonds, the functionalization of unactivated
C(sp3)-H bonds remains difficult. The main challenges are
the low polarity (and thus low reactivity) of these bonds,
and the difficulty of distinguishing between different C-H
bonds. A number of strategies have been devised to over-
come the inherent low reactivity, including: activated
metal complexes,1–4 carefully selected base additives,5,6 and
photo-redox methods.7–11 The challenge in selecting one C-
H bond over another can be overcome by the use of direct-
ing groups,12–14 and in some cases judicious ligand selec-
tion.15,16
ides bearing 8-aminoquinoline (8AQ) directing
group;[28-58] (b) ureas as substrates for α-(C-H) function-
alization of nitrogenous compounds;66,67 (c) this work: A
study of nickel(II) mediated C(sp3)-H activation of ureas
as models for amides.
Transition metal-mediated C-H bond cleavage can occur
through multiple reaction mechanisms. Metals in low oxi-
dation states can activate C-H bonds by traditional oxida-
tive addition pathways,2,3 while other metals cleave C-H
bonds by radical pathways.17,18 Still others undergo redox
neutral reactions such as sigma bond metathesis,19,20 con-
certed metalation deprotonation (CMD),5,12,21–23 ambiphilic
metal ligand activation (AMLA),20,24 or ligand-to-ligand hy-
drogen transfer (LLHA).25 Even for a single transition metal
complex, several mechanisms may be accessible, which can
lead to competing processes and thus lower selectivity and
reaction yield. As such, it is imperative to develop a de-
tailed mechanistic understanding of these elementary re-
actions.
CMD has been found to be common in catalytic C-H ac-
tivation with group 10 metal complexes. In particular, the
mechanism has been studied in depth for palladium(II)
complexes.21–23,26,27 Computational reports by several re-
search groups point to concerted deprotonation of the C-
H bond during formation of the Pd-C bond.5,21,26 Bringing
the C-H bond to the correct geometry for a strong σ(C-H) or
C-H agostic interaction plays an important part in polariz-
ing the C-H bond. Carboxylate ligands on palladium have
been shown computationally to further polarize the C-H
bond by a hydrogen-bonding type interaction.20,21,26 In the
transition state, the carboxylate ligand is bound κ1-O to
palladium(II), and deprotonates the C-H bond to make a
new Pd-C bond and a new O-H bond (see ESI, Figure S1).
In principle, this process can be reversible, leading to pro-
tonation of the Pd-C bond.
Related work on CMD reactions with palladium suggests
that a combination of bases, usually carbonate and carbox-
ylate bases, increases the reaction rate and yield of catalytic
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C-H functionalization methodologies. Elegant work by
Rousseaux and Fagnou5 suggests that for Pd(II) C(sp3)-H
activation of amides, hemi-labile carboxylates are integral
to both lowering the CMD transition state energy, and fa-
cilitating dissociation of phosphine from palladium(II) in-
termediates. Other related work from Tsuji and Fujihara et
al. showed that bulky carboxylate bases can effect facile
Pd(II) C-H activation.28
Scheme 2. Computationally derived mechanism of
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nickel(II) mediated C(sp3)-H functionalization of 8AQ
substituted amides.[62,63]
Much less is known about the mechanism of Ni(II) me-
diated CMD reactions, despite the increasing focus on Ni-
based catalysis. The most well-studied examples use Dau-
gulis’s 8-aminoquinoline (8AQ) directing group29 (Scheme
1A, Scheme 2) to make new C-C,30-52 C-N,37,52,53 C-O,40 C-S,54–
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and even C-X59-61 cross coupling products. This strategy
has been applied to β-C(sp2)-H28–32,40,43,44,49,50,56–60 and β-
C(sp3)-H30,31,49–57,59,32,63,36,40–44,46 bonds in amides. Calcula-
tions by Liu64 and Sunoj65 on the 8AQ-amide system sug-
gest that the activation of secondary C(sp3)-H bonds
should be thermally accessible, however, the relative rates
are projected to be lower than for primary substrates. This
postulate is in contrast to the catalytic experimental obser-
vation that cyclic substrates with secondary C(sp3)-H
bonds are readily functionalized.31,42,56 In some rare cases,
substrates with acyclic secondary C(sp3)-H bond function-
alizations have been isolated.36,53,59 The regioselectivity of
primary C(sp3)-H bonds is therefore due to the reductive
elimination step, which is calculated to have higher barri-
ers for secondary substrates.64
There are some significant limitations in the above
methodologies for C(sp3)-H bond functionalization: (i)
substrates are generally limited to methyl, or cyclic alkyl
derivatives; and (ii) each report uses different acid addi-
tives; there is no consensus on which carboxylates are op-
timal for C-H activation with Ni. Surprisingly, there are no
experimental studies determining the factors which con-
tribute to the efficacy of C(sp3)-H activation at Ni(II).
Moreover, no intermediates in the C(sp3)-H functionaliza-
tion of 8AQ-amides have been isolated. Therefore, to push
the boundaries of C-H functionalization methodologies
using earth abundant nickel catalysts, we must aim to un-
derstand the mechanism of the C-H activation step itself.
Recently, Nishimura et al. showed that secondary and
tertiary ureas can be used as directing groups for iridium
catalyzed C(sp3)-H bond alkylation alpha to a nitrogen
atom (Scheme 1b).66,67 The authors suggest that iridium fa-
cilitates this reaction through an oxidative addition path-
way. Although the reaction has been extended to indoline
derivatives, the authors were not able to functionalize
other substrates with secondary C(sp3)-H bonds.67
Herein, we show that by using simple nickel salts we can
characterize, and in one case isolate, analogues of the pre-
viously proposed (but not observed) products of primary
and secondary δ-C(sp3)-H bond activation using 8AQ-
substituted ureas as model substrates (Scheme 1C).
Through a series of kinetic and mechanistic experiments
we show that C-H bond activation is rate determining and
reversible. We also probe the kinetic consequences of dif-
ferent solvents and additives. Additionally, a Hammett
analysis supports a transition state with an electrophilic
metal center, as expected for a CMD pathway.
Results and Discussion
(i) Reaction Discovery: We began by examining the C-
H
activation
conditions
of
urea
(2a);
(Me)(Cy)N(CO)N(H)(quinolin-8-yl). After screening a va-
riety of conditions, we found that heating (2a) in toluene
in the presence of NiCl2(PEt3)2 and K2CO3 led to the C(sp3)-
H
activation
product
[(PEt3)Ni(κ3-C,N,N-
(CH2)N(Cy)(CO)N((N)-quinolin-8-yl))] (3a) in moderate
yield (Scheme 3). Unfortunately, long reaction times are
required; however, we were able to scale this reaction up
to gram scales of (2a) to isolate (3a) in reasonable quanti-
ties. We characterized (3a) by multinuclear and multidi-
mensional NMR spectroscopy, X-ray diffraction (XRD),
and elemental analysis.
Our group has long been interested in the chemistry of
nickel and group 10 metals.68–70 Inspired by the aforemen-
tioned Nishimura contribution, we imagined using 8-ami-
noquinoline-substituted tertiary ureas (Scheme 1C) as
more reactive models for the 8AQ-amide catalysis pio-
neered by Daugulis. We hypothesized that by using ureas
instead of amides, that the C-H bond should have a higher
effective concentration at the metal center due to the con-
formation imposed by the πN-π*CO bonding interaction.
Additionally, we postulated that the increased acidity of C-
H bonds alpha to a urea nitrogen atom would allow for
trapping of the C-H activated intermediates by attenuating
the basicity of the resulting Ni-C bond.
Scheme 3. Synthesis of Ni(II) ureate (3a) by C(sp3)-H
activation of (2a).
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1
In the H NMR spectrum of (3a) (d8-toluene, 298 K), a
tonitrile (entry 4) did produce (3a), but were sluggish com-
pared to reactions in DMSO. Notably, reactions in acetoni-
trile have long induction periods.
These results show that coordinating polar aprotic sol-
vents such as DMSO and DMF increase the rate of nickel
mediated C(sp3)-H activation of (2a). We reason that coor-
dinating solvents may be beneficial for stabilizing an elec-
tropositive nickel center in the reaction coordinate, or the
solvent may assist with substitution of triethylphosphine
for the quinoline directing group.
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characteristic doublet assigned to the cyclometalated Ni-
CH2 [δ 2.67] displays phosphorus coupling through the
nickel center [3JH,P = 6.1 Hz]. Coupling is not observed when
phosphorus decoupling is employed. In the 31P{1H} NMR
spectrum, the triethylphosphine signal is observed at [δ
18.9] as a sharp singlet. Additionally, in the 13C NMR spec-
trum the urea (C=O) carbonyl resonance shifts downfield
by over 8 ppm relative to (2a). Notably, in the presence of
excess triethylphosphine the phosphine signal of (3a)
broadens significantly and the (PEt3)-Ni-CH2 [3JH,P] cou-
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pling disappears in the H NMR spectrum; this suggests
rapid phosphine exchange at room temperature.
Table 1. Effect of solvent on initial rates of formation
of complex (3a)
We isolated XRD quality single crystals of (3a) from tol-
uene-hexamethyldisiloxane mixtures cooled to -35 °C. The
solid-state molecular structure (Figure 1) reveals a square
planar nickel center [ΣθNi = 360.25(25)]. The carbon-nickel
bond [C(1)-Ni(1) = 1.923(2)] is shorter than other Ni(II)-
C(sp3) bonds (see SI for list of other Ni(II)-C(sp3) bond
lengths),71–74 likely due to the weak trans-influence of the
quinoline nitrogen donor. Of note is the strain induced by
the five-membered cyclometalated ring, where the angles
made by (i) C(1)-N(1)-C(2) and (ii) N(1)-C(2)-N(2) are each
reduced by five degrees compared to the solid-state struc-
ture of the proteoligand, (2a) [∆(°) = (i) 5.1(2); (ii) 4.9(2)]
(see ESI Figure S183 for solid-state structure of (2a)).
Rate75
(M/min)
Temperature
Solvent
Entry
(°C)
145
145
90
90
decompositiona
d2-TCE
d6-DMSO
d6-DMSO
CD3CN
1
t1/2 ~ 5 hours
(3.3 ± 0.1) x 10-5
2
3
4
5
6
7
complex (Fig. S105)
(6.9 ± 0.4) x 10-6
negligibleb
decompositiona
d6-DMSO
d8-THF
70
70
CDCl3
70
aNo product is observed, and myriad paramagnetic peaks
are detected instead; bOver 36h, < 1% product formation by 1H
NMR spectroscopy.
Solution
of (3a) in
d6-DMSO
(iii) Additive Effects: Using DMSO as our reaction sol-
vent going forward, we screened different additives for
their effects on the described C-H activation reaction
(Scheme 4). In catalytic C-H functionalization methodolo-
gies, many research groups have found it advantageous to
add bulky carboxylic acids or external bases. Thus, we
screened a variety of carboxylate bases in the reaction of
(2a) to (3a).76
We first conducted a series of reactions to establish base-
line reactivity (Scheme 4). In the absence of carbonate base
or additive, the reaction proceeds to ~2% yield after 150
minutes at 110 °C. The observation of product suggests that
another component of the reaction (e.g. urea or phos-
phine) may facilitate C-H activation to some degree. It is
likely that the acid which is produced is neutralized by sub-
strate quinoline or PEt3. When carbonate is present, the re-
action proceeds slowly and levels off at low conversions.
We postulate that this poor conversion is due to competi-
tive substrate-phosphine binding as the reaction proceeds.
Addition of the bulky 1-admantyl carboxylic acid (Ad-
COOH) somewhat increased the rate of C-H activation
compared to the control reactions without additives. How-
ever, the addition of the slightly smaller potassium pivalate
(KOPiv) resulted in a more significant rate increase. Nota-
bly, these conditions at 110 °C in the presence of KOPiv ex-
hibit reaction half lives of approximately thirty minutes at
110 °C; t1/2 ~ 0.5 h (c.f. Table 1, no additive, t1/2 ~ 5 h, 145 °C).
Figure 1. ORTEP depiction of the solid-state structure of com-
plex (3a) (ellipsoids at 50% probability, hydrogens and solvent
omitted). Selected bond lengths (Å) and angles (°): C1-Ni1
1.923(2), N2-Ni1 1.855(2), N3-Ni1 1,972(2), C2-O1 1.238(3), C1-
Ni1-N3 166.5(1), N1-C1-Ni1 109.8(2).
(ii) Solvent Effects: Having characterized (3a), we
sought to examine how solvent choice may affect the rate
of C(sp3)-H activation. Six solvents, in three distinct tem-
perature regimes ranging from 70-145 °C were chosen (Ta-
ble 1). Reactions in d6-DMSO (DMSO = dimethyl sulfox-
ide) heated to 145 °C converted nearly half of (2a) to (3a) in
five hours (entry 2). Moreover, we found that (3a) is pro-
duced appreciably even at 70 °C in DMSO (entry 5). Reac-
tions in d7-DMF (DMF = N,N-dimethylformamide) pro-
duced (3a) at comparable rates to d6-DMSO reactions,
however, in our hands reactions in d7-DMF suffered from
a lack of reproducibility (see SI).
Reactions prepared in chlorinated solvents d2-tetrachlo-
roethane (entry 1) and CDCl3 (entry 7) resulted in decom-
position to myriad paramagnetic products. In contrast, re-
actions in deuterated tetrahydrofuran (entry 6), and ace-
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