Highly economical and direct amination of sp3carbon using low-cost nickel pincer catalyst

Article abstract of DOI:10.1039/d0ra09639c

Developing more efficient routes to achieve C-N bond coupling is of great importance to industries ranging from products in pharmaceuticals and fertilizers to biomedical technologies and next-generation electroactive materials. Over the past decade, improvements in catalyst design have moved synthesis away from expensive metals to newer inexpensive C-N cross-coupling approaches via direct amine alkylation. For the first time, we report the use of an amide-based nickel pincer catalyst (1) for direct alkylation of amines via activation of sp3 C-H bonds. The reaction was accomplished using a 0.2 mol% catalyst and no additional activating agents other than the base. Upon optimization, it was determined that the ideal reaction conditions involved solvent dimethyl sulfoxide at 110 °C for 3 h. The catalyst demonstrated excellent reactivity in the formation of various imines, intramolecularly cyclized amines, and substituted amines with a turnover number (TON) as high as 183. Depending on the base used for the reaction and the starting amines, the catalyst demonstrated high selectivity towards the product formation. The exploration into the mechanism and kinetics of the reaction pathway suggested the C-H activation as the rate-limiting step, with the reaction second-order overall, holding first-order behavior towards the catalyst and toluene substrate.

Full text of DOI:10.1039/d0ra09639c

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Highly economical and direct amination of sp3
carbon using low-cost nickel pincer catalyst†
Cite this: RSC Adv., 2021, 11, 1862
Andrew Brandt,‡a Ambar B. RanguMagar,‡a Peter Szwedo,a Hunter A. Wayland,a
b
a
Charlette M. Parnell,a Pradip Munshi
and Anindya Ghosh
*
*
Developing more efficient routes to achieve C–N bond coupling is of great importance to industries ranging
from products in pharmaceuticals and fertilizers to biomedical technologies and next-generation
electroactive materials. Over the past decade, improvements in catalyst design have moved synthesis
away from expensive metals to newer inexpensive C–N cross-coupling approaches via direct amine
alkylation. For the first time, we report the use of an amide-based nickel pincer catalyst (1) for direct
alkylation of amines via activation of sp3 C–H bonds. The reaction was accomplished using a 0.2 mol%
catalyst and no additional activating agents other than the base. Upon optimization, it was determined
that the ideal reaction conditions involved solvent dimethyl sulfoxide at 110 ꢀC for 3 h. The catalyst
demonstrated excellent reactivity in the formation of various imines, intramolecularly cyclized amines,
and substituted amines with a turnover number (TON) as high as 183. Depending on the base used for
the reaction and the starting amines, the catalyst demonstrated high selectivity towards the product
formation. The exploration into the mechanism and kinetics of the reaction pathway suggested the C–H
activation as the rate-limiting step, with the reaction second-order overall, holding first-order behavior
towards the catalyst and toluene substrate.
Received 12th November 2020
Accepted 7th December 2020
DOI: 10.1039/d0ra09639c
rsc.li/rsc-advances
taken a particular interest to prodrug synthesis8–10 in order to
overcome blood–brain barriers or other transport challenges.
Introduction
Strong nucleophilic capabilities and efficient binding strengths
of heterogenic amines drive major biological processes and are
a part of synthetic organic, inorganic, and medicinal chem-
istry.11,12 Thus a high demand exists for amine derivatives, and
to uncover the hidden mysteries of the synthetic fallacies
involving trivalent nitrogen have recently directed remarkable
developments in the catalytic routes of preparation of amine
compounds.13,14 Still, the synthesis of amines leaves tremen-
dous opportunities to rejuvenate synthetic methodologies for
a more straightforward, environmentally, and economically
admirable approach for large-scale industrial preparation.
Commonly available methods are multistep and involve
ammoxidation, reduction, or the use of highly reactive and
costly reagents and large amounts of catalyst, making these
The great prevalence of carbon–nitrogen (C–N) frameworks in
biologically active natural products, pharmaceuticals, and
electroactive materials1–4 places a high value on streamlined
synthetic processes that can produce these compounds reliably
on a commercial scale with minimal wastage. The desire for
amine compounds as drug molecules and the versatility of
functionalization make it more attractive in synthetic chem-
istry.5–7 Amine compounds can also be made very exible to
adopt in polar, non-polar, or in aqueous media through qua-
ternization or by introducing structural features, which has
aDepartment of Chemistry, University of Arkansas at Little Rock, 2801 South University
Avenue, Little Rock, AR 72204, USA. E-mail: axghosh@ualr.edu; Fax: +1 501 569 8838;
Tel: +1 501 569 8827
processes highly uneconomic. Ullmann reported
a C–N
bResearch Center, Reliance Industries Limited, Vadodara, Gujarat 391346, India.
coupling reaction by carbon–hydrogen (C–H) activation for the
rst time in the early 1900s using stoichiometric amounts of
copper salt for coupling aryl halides with aryl amines in
reuxing aniline to give diarylamines.15 Later, Buchwald and
Hartwig led explorations for the full scope of C–N couplings
utilizing palladium, nickel, and copper catalysts.16–19 Over the
decade to follow, the teams succeeded in synthesizing even
previously difficult to produce arylamine using palladium-
based phosphine catalysts20,21 leading to research targeting
novel amination approaches ranging from microwave-assisted
E-mail: pradip.munshi@ril.com; Tel: +91 265 261 6066
† Electronic supplementary information (ESI) available: The study of the effect of
base and solvent (Table S1) and temperature and time (Fig. S1) on C–N coupling
reaction, GC/MS data of the products (Fig. S2–S44), effect of the base, toluene, 1,
and benzylamine concentrations on the rate of dibenzylamine product yield
(Fig. S45), the formation of product in increasing concentrations of the base,
benzylamine, toluene substrate and catalyst loads (Fig. S46), the plot of product
concentration versus time using toluene and toluene-d8 (Fig. S47), ESI-MS plot
of catalyst (Fig. S48) and GC/MS analysis of benzaldehyde and DMSO formed
during the reaction of toluene in the presence of 1 and base (Fig. S49). See DOI:
10.1039/d0ra09639c
‡ Equally contributing authors.
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methods to synergistic multi-ligand catalyst systems and also metals instead of expensive transition metals.39–43 Closely
the use of ammonia as a nitrogen substrate.22–24 N-Alkylation of resembling nickel and iron coordinated pincer catalysts have
alcohol in supercritical carbon dioxide (CO2) using Pd nano- been previously investigated for C–C coupling of Grignard
particles was also reported via cascade oxidation, condensation, reagents,44–46 but direct C–N coupling arising from activation of
and reduction steps.25
sp3 C–H hydrocarbon and primary amine has never been
We report here (Scheme 1), for the rst time, direct alkyl- investigated. Thus, the potential of the pincer catalyst is
ation of aliphatic amines via activation of sp3 C–H bond of pure furthered in the present work opening a new area of application
hydrocarbons, e.g., toluene, producing secondary, tertiary, in C–N bond formation.
cyclic and unsaturated amines using only 0.2 mol% of an
The C–H bonds are very stable by nature. While biological
amide-based nickel pincer type catalyst (1) in the presence of life has evolved processes for selective activation using moieties
base with quantitative yields reported. With 100% atom such as in cytochrome p450, it can be challenging to mimic this
economy and an 0.62 E factor,26,27 the present discovery brings activity synthetically without using high catalyst loads and
a paradigm change in amine synthesis, inviting huge promises accessory oxidants.47,48 In comparison to traditional
for large scale industrial preparation, the dream of industrial approaches, alkylation of nitrobenzene with toluene moieties
chemists.
has been reported using a heterogeneous cobalt catalyst in the
First-row transition metals such as manganese, cobalt, iron, presence of peroxide and hydrogen.49 Aziridine based amina-
and nickel have been investigated for catalyzing various C–N tion of toluene via activation of toluene sp3 carbon through H-
bond-forming reactions, and in many instances, have been atom transfer process using an iron(II) complex has been re-
found suitable;28–32 however, pincer catalysts have drawn special ported.50 Furthermore, investigations for a novel metal-free
interest due to their superiority of binding by satisfying the oxidative amination of benzylic C–H bonds using benzo-
metal electronic environment.33–38 Pincer-type catalysis pro- triazole and nBu4NI have been demonstrated.51 However, these
gressed from phosphine-based to nitrogen-incorporated struc- processes are mostly reagent assisted and thus differ from this
tures with less expensive and commercially viable transitional present work of direct amination. The present nding of
Scheme 1 Structures of ligand (A) and catalyst (1) and C–N functionalization reactions: (i) toluene with amines to form imine products. (ii)
toluene with amines to form amine products. (iii) intramolecular cyclization of amines to develop the cyclic products.
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alkylation of amines via C–H activation has been developed as 4, 6, 9, and 10, Table S1†). Toluene, which is the substrate used for
a direct coupling method that overcomes challenges such as all subsequent reactions, showed limited solubility for 1, and,
poor atom economy, the necessity of pre-functionalization, and therefore, was infeasible to use as a solvent (entry 2, Table S1†).
requisite of harsh conditions associated with the traditional Propylene carbonate, dimethylacetamide (DMA), and dime-
alkyl halide method.52–54
thylformamide (DMF) performed similarly to toluene and were
thus also deemed as unsuitable candidates (entries 5, 7, and 8,
Table S1†). Dimethyl sulfoxide (DMSO) produced the highest
turnover number (TON) of 46 among the solvents tested (entry 1,
Table S1†). Next, C–N coupling reactions were performed in the
presence of DMSO using various bases. In this study, all bases
showed capable of facilitating C–N cross-coupling to some extent,
although the range varied greatly. More alkaline bases generated
low yields, most likely due to the base strength of the reagents.
Stronger bases were able to deprotonate the amine hydrogen
readily to facilitate C–N cross-coupling more readily. However,
Results and discussions
Optimization of reaction conditions: solvent and base
To begin exploring C–N or C]N cross-coupling using 1, various
solvents and bases were tested to determine the optimal condi-
tions of which the results are displayed in Table S1.† As demon-
strated, several solvents were incompatible for the reaction due to
the insolubility of 1, including methyl tert-butyl ether (MTBE), iso-
butanol, triuorotoluene, cyclohexane and acetonitrile (entries 3,
Table 1 The reaction of different 1ꢀ amines with toluene in the presence of KOtBu catalyzed by 1 a
a
TONs and GC yields represent an average of two runs. TONs and percent GC yields were calculated by gas chromatography/mass spectrometry (GC/
MS) using decane as an internal standard. The GC/MS data of the products are given in the ESI.
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some bases considered useful in cross-coupling (e.g. 1,8- reuxing effects in the system attenuated nal product forma-
diazabicyclo(5.4.0)undec-7-ene (DBU) and 1,4-diazabicyclo(2.2.2) tion. More so, shorter-chained aliphatic amines are less reactive
octane (DABCO)) were still inefficient in proton removal. Thus, due to lower electron releasing abilities.
a relatively bulky but strong base, potassium tertiary butoxide
(KOtBu), was used and revealed the highest TON of 46 recorded investigations began into the pathways resulting in C–N prod-
among the bases tested (entry 16, Table S1†). ucts. Further optimization reactions were performed to study
Once the initial imine formation studies were completed,
It is worthwhile to mention the low yields of products in the effects of solvent and base on the formation of products. As
some instances. The low yield is attributed to low concentra- shown in Table 2, lithium bis(trimethylsilyl)amide (LiHMDS)
tions (0.2 mol%) of catalyst used in the reactions. Though it is was quite efficient at not only forming the amine cross products
expected that yield will increase with higher catalyst loading, but also to maintain similar yields to those produced in the
the reaction was carried out in a vial where higher catalyst presence of KOtBu. Most notably, various new products were
loading was avoided due to safety concerns and the formation formed (3a, 3b, 3c, 3k, and 3l), although they were unable to be
of a viscous solution that leads to catalyst and product deposi- successfully produced to their imine counterparts in the pres-
tion on the sides of the vial wall. Therefore, in this case, more ence of KOtBu due to their chemical characteristics. Interest-
emphasis on being placed on TON to validate catalyst efficiency. ingly, several products were achieved in higher yields compared
to those in Table 1 when using LiHMDS (3i vs. 2h) while other
products (3g, 3h, 3l) exhibited attenuated yields. Products 3g
and 3h exhibited lower yields (TON ¼ 48 and 27, respectively),
most likely due to the increasingly long carbon chains present.
Longer chains spread out the charge of the entire molecule,
possibly contributing to decreased reactivity. Notably, 3l (TON
¼ 30) produced minimal amounts of product likely attributed to
the lower boiling point, difficulty in the deprotonating, and
possible steric hindrance of the amine. 3a and 3b showed the
largest TONs of 183 and 155, respectively. The highest and
lowest yields were demonstrated by aliphatic amines,
mentioned later, whereas the bulky, aromatic amines resulted
in more moderate yields. Quite remarkably, only LiHMDS
produced secondary amines while the rest of the bases
produced imines with a variation of yields. While the pKa of
bases in DMSO plays an essential role in controlling the product
yield, in the case of LiHMDS, the nature of the product reects
that nucleophilicity is likely more pronounced than basicity55
LiHMDS is primarily used as a strong nucleophile rather than
a base as the pKa of the conjugate base is ꢁ26 less basic than
lithium diisopropylamide (LDA, pKa 36).56,57 The pKa of LiHMDS
in DMSO is 30,58 and that of KtOBu is 32.2.59 This clearly dictates
that KOtBu acts as a stronger base, whereas LiHMDS may act as
more of a nucleophile.
Optimization of reaction conditions: temperature and time
Aer determining the optimal solvent and base for the reaction,
optimizations for time and temperature were performed. In
both reactions, DMSO and KOtBu were respectively used as
solvent and base for the reaction of benzylamine and toluene at
varying temperatures or times (Fig. S1†). As shown in Fig. S1a,†
the temperature played a crucial role in yields. As the temper-
ature increased, the TON values dramatically increased up to
ꢀ
ꢀ
110 C. However, when the temperature exceeded 120 C, TON
values decreased. This is potentially related to the boiling point
of toluene, which is around 111 ꢀC. Thus, upon reaching 120 ꢀC,
the toluene is under reux, and with no coolant in the system,
a reduced amount of accessible toluene is available to perform
C–N coupling. As a result, 110 ꢀC was chosen as the ideal
temperature to avoid any possible degradation of the substrate.
C–N cross-coupling was conducted at a range of reaction times
from 1 to 12 h (Fig. S1b†). Reaction yields at 1 h gave a TON of
approximately 31, while
3 h reaction time dramatically
increased over six times (TON ¼ 207). Increased reaction times
of up to 12 h exhibited a negligible effect on nal TON values. It
is apparent that aer 3 h, the catalyst became saturated, and
only a slight increase in TON was observed. Thus, 3 h was
determined to be the optimal reaction time.
Amination of toluene with different 1ꢀ amines
Cyclization of aliphatic amines
Following optimization studies, various 1ꢀ amine derivatives A variety of C–N and C]N products obtained in this study
were analyzed for C–N cross-coupling, and the results are indicated that aliphatic amines followed a different reaction
tabulated in Tables 1 and 2. Initially, C]N formation was pathway than the one initially recognized in optimization
observed for a variety of 1ꢀ amines when using KOtBu as a base studies. Table 3 lists long-chain amines that are found to be
(Table 1). Yields ranged from TON of 74 (2h) to 116 (2e), cyclized during the reaction in the absence of toluene. Mark-
showing relatively similar TON values, even with varying edly, cyclic products formed best for reactions involving
degrees of steric hindrance in the molecule. 2h had the lowest aliphatic amines four to seven carbons long. Generally, amines
TON value, most likely due to delocalization of the nitrogen lone capable of forming either 5 or 6-membered rings demonstrated
pair in the benzene ring via resonance, leading to less accessi- this effortlessly; however, several larger amines did not coop-
bility, preventing further reaction. The longer aliphatic amines erate in this fashion. Piperidine (4e) was the product of the
showed better yields due to the increased electron releasing highest yield (TON ¼ 131), and this can be attributed to the
ability in line with the amine's overall nucleophilicity trend. stability of 6-membered rings. Hexylamine produced the lowest
Smaller aliphatic amines such as 2a showed relative difficulty yield (TON ¼ 85) in the formation of 2-methylpiperdine (4f).
reacting under such conditions due to lower boiling points Octylamine, nonylamine, and decylamine all preferred C–N
below the optimized reaction conditions (Fig. S1†) as constant cross-coupling over intramolecular cyclization and were
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Table 2 The reaction of different 1ꢀ amines with toluene in the presence of LiHMDS catalyzed by 1 a
a
TONs and GC yields represent an average of two runs. TONs and percent GC yields were calculated by gas chromatography/mass spectrometry (GC/
MS) using decane as an internal standard. The GC/MS data of the products are given in the ESI.
unaccommodating for cyclic products likely due to steric products. Incorporating LiHMDS in the presence of KOtBu for
hindrance and other difficulties associated with cyclization previously attempted reactions accentuated the results. Aside
reactions. Several 2ꢀ amines were used to determine formations from toluene itself, substituted toluene had difficulty reacting
of target cyclized 3ꢀ amines. Several 3ꢀ amines (4b, 4c, 4d, 4g) in the presence of KOtBu, mostly when electron-donating
were produced, and these results are shown in Table 3. Yields groups were present in the para position. However, LiHMDS
were largely moderate to good (TON ¼ 85–131). The lowest TON facilitated cross-couplings for these derivatives, particularly in
of 85 (4f) is attributed to the varied products resulting from the the formation of single bonds for these derivatives. In general,
use of hexylamine, which reacts at multiple sites along its such derivatives (5I) still exhibited low yields (TON ¼ 17–51).
carbon chain. The highest TON of 131 occurred for piperidine The lowest TON is attributed to m-nitrotoluene (5Ib) directly
(4e), which enigmatically contains only one less carbon than 2- resulting from the utility of 1. In several situations, reactants
methylpiperdine (4f). Some 2ꢀ amines were unable to perform prone to reduction oen underwent such a process in the
cyclization successfully (i.e., dihexylamine).
presence of 1. Specically, for reactions containing m-nitro-
toluene and propylamine, reduction of m-nitrotoluene to m-
toluidine was experienced before the C–N cross-coupling
occurred with partner propylamine. While it is also possible
that further reduction of the nitro groups occurred aer the
cross-coupling occurred, ultimately, this still diminished target
product yields due to the propensity of reduced product
formation. Reactions involving toluene derivatives containing
Amination of toluene derivatives and other hydrocarbons with
different 1ꢀ amines
The results in Table 3 indicate the production of pyrrolidine,
piperidine, and their derivatives instead. Further investigation
revealed toluene was a nonfactor in formations of cyclized
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Table 3 Nickel pincer catalyzed cyclization of aliphatic primary and secondary aminesa
a
TONs and GC yields represent an average of two runs. TONs and percent GC yields were calculated by gas chromatography/mass spectrometry (GC/
MS) using decane as an internal standard. The GC/MS data of the products are given in the ESI.
para and ortho substitutions were also examined but were highest TON of 104, the product yield was similar to the original
unsuccessful in forming any C–N cross-coupled products.
reaction involving non-deuterated toluene (3d). Although 5IIIc
Next, investigations were performed for C–N cross-couplings showed the lowest TON of 77, this yield was also similar to what
using hydrocarbon sources other than toluene (5II). The hydro- was previously observed (3j). Further, GC/MS analysis of deuterated
carbons were selected based on low C–H bond energies. The versus non-deuterated dibenzylamine (Fig. S11 and S40†) was
yields for these reactions ranged in TON values from 79 to 136, of studied in order to determine whether the product was retaining
which the lowest was attributed to vinyl cyclohexane (5IId) due to the hydrogens or receiving them from another source (e.g., tetra-
the many side reactions inhibiting target product formation. On hydrofuran (THF)). Both the chromatograms and mass spectrum of
the other hand, p-xylene (5IIa) showed a better TON than its benzylamine (Fig. S11†) and labeled benzylamine (Fig. S40†)
toluene counterpart (3d, Table 2) under identical conditions. Due showed some variance. Most notably, the labeled dibenzylamine
to the promise it showed in earlier studies, and because it avoi- showed two distinct peaks that were attributed to a slight variation
ded cyclization, hexylamine was chosen as the ideal amine in molar mass (203 m/z, 204 m/z) of the compound due to the
coupling partner. In the reactions involving ethylbenzene and presence of both hydrogen and deuterium atoms. Additionally,
vinyl cyclohexane, the amine reacted at the 2ꢀ carbon of the ethyl using catalyst 1, pharmaceutically active molecules such as cycli-
group. Surprisingly, p-xylene (5IIe) and p-tert-butyltoluene (5IIf) zine – an anti-nausea drug that requires a multistep synthesis on
perform poorly with long-chain benzylic amine (3-phenylpropyl- the industrial scale60 – can be synthesized in one step by activating
amine). Electronic or steric effects may play a role in lowering the C–H bond and coupling to an amine. Cyclizine was synthesized
trend of yield from p-methyl to p-tert butyl.
using diphenylmethane and 1-methylpiperizine in the presence of
Next, several additional amines were reacted in the presence of catalyst 1, and this was conrmed using GC/MS analysis (Fig. S44†).
toluene-d8. These reactions allowed us to establish toluene's role in
the formation of imines and amines. Slightly decreased yields were
observed during isotope labeling as exhibited (5III) for all partici-
Kinetic studies
pating amines. 5IIIa and 5IIId showed TON values almost half of
the original non-deuterated toluene counterparts (3a and 3i,
respectively). For product 5IIIb, however, which exhibited the
To determine whether the mechanism consisted of radical
intermediates, (2,2,6,6,-tetramethylpiperidin-1-yl)oxyl (TEMPO)
and galvionxyl, radical quenchers, were introduced into the
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reaction of propylamine with toluene in the presence of strengthening the idea that toluene was donating its hydrogens
LiHMDS at 110 ꢀC for 3 h in two separate reactions. It was noted, during the reduction process. The reduction of benzophenone
however, that the reactions proceeded with similar yields to to phenylbenzene methanol was also attempted; however,
those observed in 3a (Table 2). The rate of the reactions was benzophenone reduced directly to diphenylmethane,
determined under identical conditions to the previously con- completely removing the oxygen group present.
ducted C–N cross-coupling reactions by using various concen-
trations of the base, toluene, 1, and amine during the amination
of toluene with benzylamine to determine the order of each
Proposed mechanism
component with respect to the overall reaction (Fig. S45†). The A mechanism is proposed for respective amine and imine
variation on the concentration of a particular reagent simulta- products. By changing the base affected product formation.
neously retaining other parameters unchanged was achieved by KOtBu promoted iminations (C]N) with no formation of amine
modifying the reagents stoichiometrically. The base was rst (C–N) products. On the other hand, LiHMDS promoted ami-
investigated by varying concentrations from 0.16–0.47 M while nations with no imine products. This occurs because the cata-
maintaining all other reaction conditions identically. As shown lyst exhibits high specicity in the presence of different bases.
in Fig. S45a,† the changes in base concentration had small Therefore, base selection plays a signicant role in each case.
overall effects on the nal TON, as demonstrated by the hori- Evaluations of several control reactions along with kinetic
zontal slope of the plot. This is indicative the base played only isotopic studies were conducted to elucidate mechanistic
a slight role in the actual formation of the C–N coupled product pathways. Based on controls, our ndings indicate that when
that the kinetic behavior of the base was likely zero order with two different bases were used, the system responded along two
respect to the overall reaction.
distinct pathways. Both processes are summarized below in
Next, the reactions were repeated by changing toluene Fig. 1.
concentrations from 0.45–1.80 M. In Fig. S45b,† the
In one of the cycles, we believe that KOtBu triggers the action.
pronounced increase in the rates shows a relatively linear rela- The substrate activated catalyst (2ab) easily deprotonates in the
tionship with respect to the toluene concentration, indicating presence of KOtBu (2ad) to release the imine product (2af). It
that toluene was rst order with respect to the overall reaction. has been reported that DMSO can hold roles in chemical reac-
Next, in Fig. S45c,† changing the concentration of the catalyst tions aside from solvent only.61,62 An aldehyde is formed and
was examined for its effect on the reaction. The pronounced combines with the amine, ultimately producing the imine. The
increased rates ranging from concentrations of 1.2–4.0 mol% base will choose either the proton or carbon required for
also showed a linear relationship with respect to product yield bonding. In the case of KOtBu, this is simply accomplished
leading to the conclusion that 1 was rst order with respect to through proton abstraction, ultimately paving the way to
the overall reaction. Lastly, upon examination of amine produce the imine (2af). DMSO's high polarizability potential
concentration from 0.16–0.49 M, Fig. S45d† exhibits a similar creates a negative charge around the oxygen, enabling it to
effect to that of the base indicative of a likely zero-order process coordinate to electron-decient centers. The substrate activated
with respect to the overall reaction. Further, the effects of carbon enters the reaction cycle upon oxidative addition, and
varying the concentrations of the base, benzylamine, toluene, DMSO's sacricial oxygen facilitates reductive elimination. The
and 1 on the formation of the dibenzylamine product can be reaction cycle is then recommenced as DMSO is reduced to
seen in Fig. S46.† As the plots exhibit, the effects are almost the dimethyl sulde (DMS), replanting 2aa from 2ac.
same validating the previous results. Therefore, changing the
As conrmed by electrospray ionization mass spectrometer
concentrations of toluene and 1 affected overall reaction rates, (ESI-MS) analysis of 1 (Fig. S48†), a chloride ion attachment
yet, doing so for the concentrations of base and amine did not exists on the Ni(II) complex. In the presence of a base, the amine
affect the overall rate of product yield.
is likely to reduce 1 to 2aa, removing the labile Clꢂ.63 Upon
Next, the reactions were repeated in the presence of toluene- oxidative addition, toluene is substituted, producing 2ab. We
d8 as the evaluation of kH/kD can help to determine the rate- hypothesize that the toluene is then oxidized to the aldehyde in
determining step (RDS) of the reaction. Intuitively, C–H acti- the presence of DMSO. Catalyst 1 was treated with DMSO &
vation was studied as the possible RDS in the reaction since toluene to demonstrate the formation of benzaldehyde, and the
toluene was being examined. The reaction was repeated and product benzaldehyde was detected via GC/MS analysis
monitored at 20 min intervals to establish the rate of the reac- (Fig. S49†). Here, we believe that DMSO is acting as the primary
tion (Fig. S47†), which upon comparison revealed a kH/kD value oxidant. Furthermore, GC/MS analysis also revealed the
of approximately 2.7 indicative that the C–H bond activation in formation of DMS (Fig. S49†).
toluene was indeed the RDS. Furthermore, the reduction reac-
The second cycle, also demonstrated in Fig. 1 is primed by
tions were also performed to trace the isotopic hydrogens in the the base as in the rst cycle, but this time LiHMDS initiates the
reaction. As previously established, with the reduction of m- action. Again, oxidative addition is facilitated by ligand substi-
nitrotoluene to m-toluidine in the presence of 1 before C–N tution as toluene enters the reaction cycle (2ab). The cycle then
cross-coupling with the amine (5Ia, Table 4), we introduced propagates differently, as previously illustrated. LiHMDS
toluene-d8 into the system to observe if the reduction was deprotonates the amine directing the reaction cycle to 2ag.
explicitly related to toluene or another source. Isotopic versions Before reductive elimination, another amine molecule further
of m-toluidine were observed using GC/MS, further drives the reaction forward as the amine product is expelled in
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Table 4 Nickel pincer catalyzed (I) amination of substituted toluene derivatives with a primary amine, (II) amination of hexylamine with carbon
substrates, (III) amination of toluene-d8 with primary aminesa
a
TONs and GC yields represent an average of two runs. TONs and percent GC yields were calculated by gas chromatography/mass spectrometry (GC/
MS) using decane as an internal standard. The GC/MS data of the products are given in the ESI.
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Fig. 1 Schematic representation of amine and imine formation by means of C–N cross of toluene and an amine catalyzed by 1.
a concerted rearrangement leading to 2ac. Again, the catalyst coordinate with oxygen donor atoms. Therefore, it is likely that
returns from 2ac to 2aa as DMSO is reduced to DMS. Unlike the Li+ coordinated to the amide oxygen of 1, forcing it to conform
reactions involving KOtBu, no benzaldehyde formation was to the imine-like functionality. NMR evidence showed asym-
detected via GC/MS analysis.
metry in the ligand structure, and, therefore, we believe such
While it is possible that a high-valent Ni species, as two a structure manifested.44
deprotonated s-donating amides, make up 1, in the presence of
Single-electron transfer (SET) has been proposed in nickel-
DMSO, which may be responsible for the oxidation of toluene, it catalyzed organic transformations, and we believe such reac-
is unlikely that such a high-valent Ni species64–68 is stabilized. tions were also occurring in our case.70,71 So, a low-valent Ni
Dibenzylamine was treated with KOtBu and 1 to prove imine species (2aa) is formed aer the addition of amine or LiHMDS
formation occurred before the amine (Fig. 1). Yet, no change in through SET. When amination reactions were conducted using
amine formation was observed via GC/MS analysis. However, toluene and benzylamine in the presence of radical quenchers
catalyst 1 facilitates the reaction in the presence of LiHMDS. such as TEMPO and galvinoxyl, the isolated product indicated
The catalyst was synthesized using lithium salt, and additional this possibility. The imine bond in the structure of the catalyst
Li+ was added in the form of LiHMDS. It is assumed that (1), along with the pyridinic ligand, may be suitable for stabi-
LiHMDS may play a dual role. Due to excess lithium, 1 is more lizing Ni in a low-valent state such as Ni(I).72 Once reduced
likely to sustain the imine type bonding coordinated to Ni(II). through SET, toluene was oxidatively added to the Ni catalyst
Thus, it may be possible that both amide bonds in 1 are in the leading to 2ab. As indicated by kH/kD studies, this may be the
imine form, and such structures have been previously rate-limiting step. Some control reactions involving toluene and
reported.69
amines were attempted and characterized via ESI-MS. Upon the
Due to its small size, Li+ has a higher ionic potential (charge/ introduction of the amine, a new species resembling 2ag was
radius) compared to other alkali metal ions and is known to observed. Upon reductive elimination, the nal product was
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furnished. Furthermore, it is believed that 2ac was oxidized by under mild reaction conditions. Depending on the base used
DMSO to its original structure, which further reacted with for the reaction and the starting amines, the catalyst demon-
toluene completing the catalytic cycle. When the reaction was strated high selectivity towards the product formation. The
performed in the presence of either air or oxygen, no product catalyst also showed great potential for product formation using
was observed. It can also be possible that an imine product aromatic and non-benzylic substrates. 1 was noted to have
underwent further reduction to the amine product.
several competing functionalities ranging from C–H activation
Multiple control reactions were performed to elucidate the to direct C–N cross-coupling as well as intramolecular C–N
mechanism involving LiHMDS. Since LiHMDS is stabilized in coupling. Various bases produced vastly different results in the
THF, it is hypothesized that perhaps the reduction of imines to reactions studied, and notable product formations were
amines occurred in the presence of THF. Initially, an imine was observed. Kinetics insight demonstrated that C–H activation in
synthesized by reacting benzaldehyde and benzylamine in toluene was the RDS in the overall reaction; however, the
equivalent amounts in methanol. Then, the imine was used to hydrogens removed from toluene were possibly not used for
perform a few control reactions in the presence of 1. Two reduction as indicated in the several examined cases. Further-
reactions were carried out to test the potential roles of THF and more, both oxidation and reduction reactions meeting specic
Li+. Firstly, the imine was reacted in a reaction vessel in the criteria were performed. This included base and oxygen-based
presence of lithium chloride (LiCl) without THF, and secondly, substituent requirements. The nickel(II) pincer complex (1)
in the presence of both LiCl and THF. Both reactions were run exhibited tremendous versatility, and many other facets were
for 3 h at 110 ꢀC in the presence of KOtBu. GC/MS analysis discovered in the course of this study. As a result, other inter-
conrmed that in both cases, no reduction of the imine to esting pathways have been uncovered and are currently being
amine occurred. Furthermore, toluene's role was scrutinized as further investigated. We believe the methodology opens up an
it can act as the hydrogen source necessary for the reduction of avenue for direct synthesis of amine-based drugs eliminating
imine to the amine. In one set of reactions, toluene was present, multistep organic synthesis that is environmentally
and in the other, no toluene was used. GC/MS analysis responsible.
conrmed the system lacking toluene did not reduce the imine
to the amine. Whereas, the reaction in the presence of toluene
reduced the imine to the amine. This suggests that toluene
Materials and methods
General
likely donated hydrogens in the reduction of the imine inter-
mediate rather than THF within LiHMDS. When the reaction
was done without LiHMDS while keeping all other reagents
intact, no product was obtained. Therefore, LiHMDS is essential
for our reactions and is presumably the source of SET.
All chemicals were purchased from Aldrich Chemical Company,
Fischer Scientic Company, and VWR International and were
used without further purication unless stated otherwise.
Solvents were puried according to literature procedures73 and
purged under argon gas (Ar) prior to use. Amines were passed
through neutral alumina and purged with Ar prior to use.
Reaction products were analyzed by GC/MS using the Shimadzu
model QP2010, equipped with a DB-5 column. Samples were
run at an iꢂn1itial ramp temperature of 70 ꢀC with a ramp climb of
15 ꢀC min ꢂu1 ntil 200 ꢀC was reached and then a ramp increase
of 5 ꢀC min until 300 ꢀC was reached where the temperatures
were held for 5 minutes. The injection temperature was 250 ꢀC,
with an ionization temperature of 300 ꢀC, and samples were
injected 3 times. Catalyst characterization was performed using
a JEOL 400 NMR and an Agilent 100 series MSD VL ESI-MS.
Lastly, for coupling reactions involving m-nitrotoluene, reduc-
tion of the nitro group was observed; however, it is unclear what
the hydrogen source may be. Therefore, the reaction was repeated
in the presence of equivalent amounts of toluene-d8 for 3 h at
110 ꢀC with LiHMDS. Aer purication, GC/MS analysis revealed
a m-toluidine product with a heavy mass spectrum (Fig. S41†). This
indicates that the hydrogen is responsible for the nitro group
reduction originated from toluene or some sort of hydride species
consequential of the toluene substrate rather than from any other
hydrogen source. Thus, it is surmised that the imine is formed
before the amine, and further reduction occurs due to possible
hydride intermediate production within the reaction.
Repeated experiments and careful GC/MS analyses conrm
the absence of any byproducts and impurities. The reaction
Synthesis of A and 1
seems to stop aer the rst substitution of N–H functionality for Both A and 1 were synthesized according to the literature
amine production. Calculations of thermodynamic parameters procedure with slight modications.44–46 A was synthesized in
indicate that the reaction is thermodynamically controlled with the following manner: acid chloride of 2,6-dicarboxylic acid
Gibbs free energy change (DG) of the stoichiometric reaction pyridine was reacted with 2,6-diisopropylaniline in the presence
under experimental conditions is nearly zero (Table S2†). of triethylamine and puried via crystallization. To produce 1, A
Therefore, such an inherent limitation of yield can only be (0.297 g, 0.612 mmol) was dissolved in THF (15 mL) under
overcome by higher catalyst loading.
nitrogen atmosphere in a Schlenk ask, and the temperature
was adjusted to 0 C in an ice bath. N-butyllithium (0.80 mL,
ꢀ
1.26 mmol, 1.6 M in hexanes) was added to the solution and
stirred for 30 min. Nickel(II) chloride glyme (0.137 g, 0.612
Conclusion
In summary, 1 was used successfully to activate C–H bonds and mmol) was added to the reaction. The reaction was slowly
directly form C–N and C]N bonds, as well as cyclic amines, brought back to room temperature and allowed to stir
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overnight. THF was removed by a liquid nitrogen trap to yield 1 with Ar for 10 min) and purged under Ar atmosphere for an
(345 mg). It is believed that chlorometallated form (1) may get additional 30 min. DMSO (1.0 mL) was added to the system via
converted to hydroxymetallated catalyst in the presence of a gas-tight syringe to prevent any further exposure to the
moisture, which may also show catalytic activity.74,75
external environment. Aer 10 min of purging, amine (1.71
mmol) and toluene derivatives or other hydrocarbons (1.71
mmol) were added using gas-tight syringes. The system was
then sealed and vigorously mixed to dissolve any catalyst and
base. The temperature was brought to 110 ꢀC in an oil bath, and
the reaction was allowed to react for 3 h. Aer the allotted time,
the system was removed from the heat source and allowed to
cool to room temperature for 1 h. The reaction mixture was
passed through a small ltration column to remove any
precipitate followed by dilution with ethanol in preparation for
GC-MS analysis. The TON ranged from 16–137.
Synthesis of amine and imine coupled products
All reactions were performed under similar conditions unless
stated otherwise. 0.2 mol% of 1 (2.0 mg, 3.46 mmol) and KOtBu
(55.0 mg, 0.49 mmol) were added to a 10 mL screw-top vial
(previously purged with Ar for 10 min) and purged under Ar
atmosphere for an additional 30 min. DMSO (1.0 mL) was
added to the system via a gas-tight syringe to prevent any
additional exposure to the external environment. Aer 10 min
of purging, amine (1.71 mmol) and toluene (1.71 mmol) were
added using gas-tight syringes. The system was then sealed and
vigorously mixed to dissolve any catalyst and base. The
temperature was brought to 110 ꢀC in an oil bath, and the
reaction was allowed to react for 3 h. Aer the allotted time, the
system was removed from the heat source and allowed to cool to
room temperature for 1 h. The reaction mixture was passed
through a small ltration column to remove any precipitate
followed by dilution with ethanol in preparation for GC-MS
analysis. Various amines and imines were analyzed in the
presence of a base (KOtBu or LiHMDS) depending on desired
products. Yields ranged from 74–184 TON, where TON ¼
(concentration of standard/AUC of standard) ꢃ (AUC of
product) ꢃ (dilution factors) ꢃ (1/moles of catalyst) and AUC is
the area under the curve. Dilution factors included GC/MS vial
dilution plus any additional dilution done during purication
before GC/MS preparation. An internal standard of 3.00 mL
decane in 10.00 mL of ethanol was used to quantify the product
formation.
Kinetic studies
In order to determine the roles of 1, base, and each substrate in
the reaction, kinetic studies were conducted in duplicates. The
effect of each reaction parameter was checked by varying it
within a specic range keeping other conditions remains
constant. Firstly, the base was investigated by varying its
concentration (0.16–0.47 M). Next, 1 was varied from 1.2–
4.0 mol%. Then, the effect of each substrate was explored.
Toluene concentration was varied from 0.45–1.80 M. Lastly, the
concentration of amine was varied from 0.16–0.49 M.
Author contributions
A. B., A. B. R., P. S., H. A. W., and C. M. P. contributed to writing
the manuscript, performing the experiments and interpreting
the data. A. B. and A. B. R. contributed to catalyst synthesis. A.
G. conceived the research idea, designed the experiments,
interpreted the data, and wrote the manuscript. P. M. contrib-
uted to writing the manuscript, designing the experiments,
interpreting the data, and establishing the reaction mecha-
nism. All authors reviewed and approved the nal version of the
manuscript.
Synthesis of cyclic products
All reactions were performed under similar conditions unless
stated otherwise. 0.2 mol% of 1 (2.0 mg, 3.46 mmol) and KOtBu
(55.0 mg, 0.49 mmol) were added to a 10 mL screw-top vial
(previously purged with Ar for 10 min) and purged under Ar
atmosphere for an additional 30 min. DMSO (1.0 mL) was
added to the system via a gas-tight syringe to prevent any
additional exposure to the external environment. Aer 10 min
of purging, amine (1.71 mmol) was added using gas-tight
syringes. The system was then sealed and vigorously mixed to
dissolve any catalyst and base. The temperature was brought to
110 ꢀC in an oil bath, and the reaction was allowed to react for
3 h. Aer the allotted time, the system was removed from the
heat source and allowed to cool to room temperature for 1 h.
The reaction mixture was passed through a small ltration
column to remove any precipitate followed by dilution with
ethanol in preparation for GC-MS analysis. TON ranged from
85–131.
Conflicts of interest
There are no conicts to declare.
Acknowledgements
This research was nancially supported by the National Science
Foundation (grant no. IIA-1457888) and the Arkansas EPSCoR
Program, ASSET III (CASE).
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