Mimicking transition metals in borrowing hydrogen from alcohols

Article abstract of DOI:10.1039/d1sc01681d

Borrowing hydrogen from alcohols, storing it on a catalyst and subsequent transfer of the hydrogen from the catalyst to anin situgenerated imine is the hallmark of a transition metal mediated catalyticN-alkylation of amines. However, such a borrowing hydrogen mechanism with a transition metal free catalytic system which stores hydrogen molecules in the catalyst backbone is yet to be established. Herein, we demonstrate that a phenalenyl ligand can imitate the role of transition metals in storing and transferring hydrogen molecules leading to borrowing hydrogen mediated alkylation of anilines by alcohols including a wide range of substrate scope. A close inspection of the mechanistic pathway by characterizing several intermediates through various spectroscopic techniques, deuterium labelling experiments, and DFT study concluded that the phenalenyl radical based backbone sequentially adds H⁺, H˙ and an electron through a dearomatization process which are subsequently used as reducing equivalents to the C-N double bond in a catalytic fashion.

Full text of DOI:10.1039/d1sc01681d

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Mimicking transition metals in borrowing hydrogen
from alcohols†‡
Cite this: Chem. Sci., 2021, 12, 8353
*
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have been paid for by the Royal Society
of Chemistry
Ananya Banik,
Jasimuddin Ahmed,
Swagata Sil
and Swadhin K. Mandal
Borrowing hydrogen from alcohols, storing it on a catalyst and subsequent transfer of the hydrogen from
the catalyst to an in situ generated imine is the hallmark of a transition metal mediated catalytic N-alkylation
of amines. However, such a borrowing hydrogen mechanism with a transition metal free catalytic system
which stores hydrogen molecules in the catalyst backbone is yet to be established. Herein, we
demonstrate that a phenalenyl ligand can imitate the role of transition metals in storing and transferring
hydrogen molecules leading to borrowing hydrogen mediated alkylation of anilines by alcohols including
a wide range of substrate scope. A close inspection of the mechanistic pathway by characterizing several
intermediates through various spectroscopic techniques, deuterium labelling experiments, and DFT study
concluded that the phenalenyl radical based backbone sequentially adds H+, Hc and an electron through
a dearomatization process which are subsequently used as reducing equivalents to the C–N double
bond in a catalytic fashion.
Received 24th March 2021
Accepted 7th May 2021
DOI: 10.1039/d1sc01681d
rsc.li/chemical-science
sustainable and environmentally safe process. In this regard,
Winans and Adkins14 have discovered this reaction and later
Grigg15 and Watanabe16 have reported the rst homogeneous
Introduction
Borrowing hydrogen from alcohols, and utilization of the har-
vested hydrogen for further reduction of in situ generated
imines is the hallmark of a transition metal mediated catalytic
process which leads to the synthesis of N-alkylated amines. It
may be noted that N-alkylated amines have widespread appli-
cations in chemistry and biology. These amines are extensively
utilized as universal building blocks for organic synthesis,
pharmaceuticals, agrochemicals, drugs, materials science, the
polymer industry, and various natural products.1–5 Traditional
methods for the preparation of substituted amines followed the
reductions of imines6 and amides,7,8 hydroamination,9,10
reductive amination11 and also, there are straight forward
methods such as the N-alkylation of amines.12,13 The conven-
tional methods for the alkylation of amines involve the use of
highly genotoxic alkylating agents such as alkyl halides or
sulfonate esters. However, these methods suffer from the
generation of stoichiometric amounts of halide waste, and the
chemoselectivity issue for the formation of over alkylated by-
products. In this regard, the use of an alcohol as a benign
alkylating agent has drawn considerable attention due to its
remarkable abundance in biomass as well as for the generation
of green waste (water as the sole by-product). Thus, the use of an
alcohol for N-alkylation of amines is considered as a green,
catalysis towards the alkylation of amines using an alcohol,
which has been termed ‘Borrowing Hydrogen or Hydrogen
Autotransfer (BH/HA)’. In this methodology, an alcohol is
dehydrogenated to a more reactive carbonyl compound, where
a proton and a hydride are transferred to the transition metal-
based catalyst and typically stored as the metal dihydride
(Scheme 1). Next, the carbonyl compound undergoes
a condensation reaction with an amine generating an imine
which subsequently undergoes reduction to an N-alkylated
Department of Chemical Sciences, Indian Institute of Science Education and
Research-Kolkata, Mohanpur, 741246, India. E-mail: swadhin.mandal@iiserkol.ac.in
† Dedicated to Professor Christian Bruneau.
‡ Electronic supplementary information (ESI) available: Detailed experimental
procedures, NMR and HRMS spectra, and coordinates of the computed
structures. See DOI: 10.1039/d1sc01681d
Scheme 1 Alkylation of amines by alcohols via hydrogen borrowing:
conventional approach and our strategy.
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amine through the transfer of the stored hydride and proton
In the current study, we have established that the PLY based
when the catalyst is regenerated. This method involves the use catalyst can store the borrowed hydrogen molecule by addition
of precious metals such as ruthenium,17,18 rhodium19 and of H+, Hc and an electron sequentially from the alcohol partner
iridium20-based catalysts and was extensively used in early and stores in the form of two C–H bonds through a dearomati-
studies. In more recent years, the alkylation of amines through zation process which are subsequently transferred to the in situ
the borrowing hydrogen strategy was dominated by inexpensive, generated imines to realize the corresponding alkylated
earth-abundant metal-based catalysts21–35 replacing the expen- aromatic amines (Scheme 1). This study presents an alternative
sive noble metal catalysts. In this regard, substantial progress strategy for replacing the transition metal based catalysts in the
has been demonstrated by the group of Feringa and Barta,21,22 alkylation of aromatic amines through the borrowing hydrogen
Beller,23 Milstein,24 Kempe,25–27 and others28–31 using early tran- methodology.
sition metals such as iron, manganese, cobalt, nickel and
chromium-based catalysts to make the processes more envi-
ronmentally benign. Towards the sustainable synthesis of
Results and discussion
At rst, several redox non-innocent PLY based molecules [(O,O)-
PLY, various (N,O)-PLY and (O,N,N,O)-PLY] were synthesized
according to literature methods.59–62 The preliminary investi-
gation of transition metal-free alkylation of amines started with
probing the reaction of aniline and benzyl alcohol in the pres-
ence of a catalytic amount of these PLY molecules with 1.2
equivalents of base, KOtBu, to realize the corresponding N-
benzylaniline (Table 1, also see ESI, Table S1‡). The reaction of
aniline, 1a (0.3 mmol), and benzyl alcohol, 2a (0.33 mmol), in
the presence of a catalytic amount of (N,O)-PLY (5.0 mol%) with
KOtBu (1.2 equivalents) in toluene at 130 ꢀC afforded 43% yield
of the N-alkylated amine, 3a (N-benzylaniline) within 18 hours
(entry 1, Table S1, ESI‡). Further increasing the loading of (N,O)-
PLY (10.0 mol%) and scrutinizing different PLY molecules
(Table 1), the maximum NMR yield (99%) of N-alkylated amine,
3a, was realized (entries 3–8, Table S1, ESI‡). Moreover, a dras-
tically reduced yield was observed when the temperature or
amount of KOtBu was lowered (entries 9–11, Table S1, ESI‡).
Notably, with the help of further trials using different bases,
solvents, and durations of the reaction, optimized conditions
were accomplished in the presence of 10.0 mol% (N,O)-PLY and
alkylated amines, the need for a transition metal-free catalyst is
inevitable. In this regard, a bioinspired catalytic combination
such as NADH-ADH36,37 or transition metal free combination
using pyridine/KOtBu38 evolved recently for the alkylation of
amines, but they differ conceptually from the borrowing
hydrogen mechanism followed typically by a transition metal
based catalyst. The transition metal based catalyst stores both
proton and hydride in its backbone (Scheme 1), which in turn
can deliver a hydrogen molecule for further reductions. On the
other hand, the existing metal-free catalysts are not capable of
mimicking such a role as they can store only hydride while
proton is stored in a different molecule. Although a few other
studies have been reported where a purely base mediated39–43 N-
alkylation by an alcohol is achieved using KOH, CsOH and
NaOH respectively, they do not follow the borrowing hydrogen
pathway as observed in transition metal based catalysis. Such
an observation in the existing literature prompted us to strate-
gize a transition metal-free catalyst, which can conceptually
mimic the role of a transition metal in borrowing hydrogen
mediated N-alkylation of amines involving the storage and
transfer of hydrogen molecules from the catalyst backbone.
Herein, we present the alkylation of anilines by various
alcohols using a redox non-innocent phenalenyl (PLY) based
ligand as a transition metal-free catalyst. It is well established
that PLY based molecules can access three redox active states,
namely a closed shell cation, an open shell radical, and a closed
shell anion using the non-bonding molecular orbital (NBMO).44
Over the past few decades, a remarkable advance has been
envisaged in the eld of quantum spin simulators,45–48 organic
molecular conductors,49–52 molecular batteries,53 and spin elec-
tronic devices54 by the group of Haddon, Nakasuzi, Takui,
Morita, and Kubo55 using the radical state of PLY molecules.
The catalytic applications using in situ generated PLY based
radicals have only been recently developed.56 In this regard, we
earlier demonstrated that PLY can store and transfer redox
equivalents in the form of C–H bonds during multi-electron
reduction processes.57 Very recently, we reported that phena-
lenyl ligands can be reduced by two electrons and can subse-
quently trap two protons via dearomatization of one of the
phenyl rings of PLY.58 Such observations57,58 made us curious
whether the PLY moiety can store both hydride and proton
together thus imitating the role of a metal in a typical borrowing
hydrogen mechanism followed by its transfer for subsequent
reduction integrated in a catalytic fashion.
t
ꢀ
1.2 equivalents of KO Bu in toluene at 130 C within 18 hours,
providing 91% isolated yield of N-benzylaniline (entry 3, Table
S1, ESI‡). Control experiments unarguably validated that the
alkylation of amines could not materialize in the absence of
base, and only a trace (5%) amount of N-benzylaniline, 3a, was
realized in the absence of (N,O)-PLY.
Table 1 Optimization of ligands for the N-alkylation of aminesa
a
The reactions were carried out using aniline (0.3 mmol), benzyl
alcohol (0.33 mmol), different PLY based molecules (10 mol%), KOtBu
(1.2 equivalents), and toluene (1.5 mL). NMR yields.
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Having the optimized reaction conditions in hand (entry 3, anilines (Table 3). In this study, the effect of the various alcohols
Table S1, ESI‡), we investigated the efficacy of this methodology was evaluated using a series of substituted benzyl alcohols,
for the selective monoalkylation of various anilines (1a–1u) with naphthalen-1-ylmethanol, and substituted diphenylmethanol.
benzyl alcohol, 2a, and the derivatives of N-benzylaniline (3a– Preferably, we tested different para substituted benzyl alcohols
3u) were isolated through column chromatography (Table 2). containing halide functionality for the alkylation, affording 76–
Under the standard reaction conditions, aniline (1a) and para- 87% isolated yield of the corresponding products without any
substituted anilines (1b–1g) containing both electron donating functionalization of the halide moieties (4b–4e). Under the
or electron withdrawing groups such as methyl, ethyl, isopropyl, standard reaction conditions, electron donating methyl, iso-
methoxy, chloro, and bromo afforded good to excellent yield propyl and methoxy groups containing 4-substituted benzyl
(71–91%) of the corresponding N-benzylanilines (3a–3g). Next, alcohol provided moderate to good yield (55–70%) of alkylated
ortho-substituted anilines containing uoro, bromo, and amines (4f–4h). The more sterically encumbered 2-methyl, 3,5-
methoxy substituents were tested for the alkylation, and very dimethoxy, and 3,4,5-trimethoxy benzyl alcohol delivered good
good isolated yields (71–73%) of the corresponding N-alkylated yield (53–70%, 4i–4k) as well as strong electron withdrawing 3-
products (3h–3j) were obtained. Under similar reaction condi- triuoromethyl benzyl alcohol also afforded the desired alky-
tions, 3,5-disubstituted anilines (1k–1m) furnished good to lated product with 78% yield (4l). Under similar reaction
excellent isolated yields (63–82%) of the corresponding conditions, naphthalen-1-ylmethanol, 2m, reacts with aniline to
substituted amines (3k–3m). The standard catalytic reaction give 87% yield of N-(naphthalen-1-ylmethyl)aniline (4m). Next,
protocol was also well applicable for biarylated amine, i.e., [1,10- the versatility of this catalytic protocol was established by using
biphenyl]-2-amine, which yielded 72% of the N-benzyl-[1,10- various secondary alcohols in the reaction medium, whereas
biphenyl]-2-amine (3n). Given the importance of heterocyclic diphenylmethanol and di-para-tolylmethanol afforded 89% and
amines for the production of pharmaceuticals and natural 85% yield of the corresponding N-alkylated amines 4n and 4o,
products, we endeavoured several heteroaryl anilines such as 5- respectively.
substituted benzothiazole, quinoline, pyrazine, and pyrimidine
containing amines for the alkylation with benzyl alcohol. Under
the optimized reaction conditions, very good to excellent yields
(65–85%) of the corresponding N-alkylated products (3o–3s)
were realized. To our delight, when different diamines such as
benzene-1,4-diamine or benzene-1,2-diamine was subjected to
N-alkylation with benzyl alcohol, only the formation of mono-
alkylated products (3t and 3u) was observed with excellent
yield (86% and 87%, respectively).
Table 3 Substrate scope for (N,O)-PLY catalyzed N-alkylation using
benzylic and aliphatic alcoholsa
Furthermore, the catalytic alkylation of aniline was investi-
gated using different alcohols to realize substituted N-benzyl
Table 2 Substrate scope for (N,O)-PLY catalyzed N-alkylation using
anilinesa
a
The reactions were carried out using anilines (0.3 mmol), alcohols
The reactions were carried out using anilines (0.3 mmol), alcohols (0.33 mmol), (N,O)-PLY (0.03 mmol), KOtBu (0.36 mmol), and toluene
(0.33 mmol), (N,O)-PLY (0.03 mmol), KOtBu (0.36 mmol), and toluene (1.5 mL) at 130 ꢀC for 18 h. Average isolated yields from two catalytic
a
(1.5 mL) at 130 ꢀC for 18 h. Average isolated yields from two catalytic runs are presented. Characterized by 1H and 13C NMR spectroscopy.
runs are presented. Characterized by H and 13C NMR spectroscopy.
Parentheses indicate the GC yield.
1
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Next, to realize the general applicability of the catalytic followed the process of alcohol dehydrogenation, condensation,
protocol, more inert aliphatic alcohols were explored. To our and imine hydrogenation, where a transition metal catalyst can
delight, cyclohexylmethanol, 2p, reacted with 4-ethylaniline store hydrogen via borrowing it from alcohols and further
under the standard reaction conditions to accomplish 71% transfers to in situ generated imines for the production of N-
isolated yield of the corresponding product (4p). Moreover, alkylated amines. However, the transition metal-free borrowing
other cyclic alcohols such as cyclopentanol, cyclohexanol and of hydrogen from alcohols which mimics transition metals by
cycloheptanol provided 42–90% yield of 4q–4s, respectively. storing it in a catalyst has not been realized although such
Isobutanol, 2t, delivered moderate isolated yield (64%) of 4- attempts have been reported in the literature in which the
ethyl-N-isobutylaniline (4t), whereas 1-butanol and 1-hexanol hydride was stored in the transition metal free catalyst back-
displayed lower yields of corresponding N-alkylated aromatic bone while the proton was stored separately.36–38 Nevertheless,
amines, 4u–4v (35–38%). Biologically active long chain alcohols the signature of the borrowing hydrogen mechanism considers
were also tested successfully for N-alkylation of aromatic the formation of aldehyde and imine as intermediates in the
amines, when 1-octanol or 1-decanol or 1-dodecanol was reaction medium. Interestingly, we noticed the formation of
charged with 4-ethylaniline to achieve excellent isolated yields aldehyde and imine intermediates during time dependent NMR
(65–87%) of the corresponding products (4w–4y). Similarly, 1- studies (supported by 1H NMR peaks at d 10.02 ppm and
tetradecanol (myristyl alcohol) and 1-hexadecanol (cetyl d 8.46 ppm, Fig. S110, ESI‡) rather than the generation of car-
alcohol) furnished 84% and 83% isolated yield of the corre- bocations or ethers as reported for other metal-free N-alkylation
sponding products 4z and 4aa, respectively when reacted with mechanisms.63,64 Such an observation indicates that the
aniline. Under the standard reaction conditions, 4-ethyl-N-(2- borrowing hydrogen mechanism is operative. Furthermore, to
ethylhexyl)aniline (4ab) was obtained in 79% yield with 2-ethyl- understand the role of KOtBu, we have treated benzyl alcohol,
1-hexanol, whereas oleyl alcohol delivered 80% yield of (Z)-N- 2a, with 1 equivalent N-benzylideneaniline, 5a, along with
(octadec-9-en-1-yl)aniline (4ac).
10 mol% (N,O)-PLY and only 20 mol% KOtBu resulting in 88%
The broad substrate scope of this reaction prompted us to N-benzylaniline, 3a, aer isolation (Scheme 3a). This
further study the applicability of this transition metal free
borrowing hydrogen methodology for the preparation of phar-
maceutical molecules or natural products without discomfort-
ing any other functionality. We could successfully functionalize
the derivative of (ꢁ)-a-tocopherol, i.e., vitamin E, by introducing
a benzyl group as an N-benzylated amine with the help of our
standard catalytic protocol, where 69% yield of the corre-
sponding amine was achieved (3v, Scheme 2). Moreover, gram
scale synthesis of the product, 3v, was accomplished, where
65% yield of 3v was obtained. Another commercially available
drug, adapalene, which is a third-generation topical retinoid
and used for the treatment of acne, could be functionalized
aer reduction in carboxylic acid functionality. The corre-
sponding reduced alcohol (2ad) when charged with aniline (1a)
under the standard catalytic protocol provides 72% mono-
alkylated amine (4ad, Scheme 2).
The successful catalytic N-alkylation of aromatic amines
using redox active PLY molecules encouraged us to delve the
mechanistic details based on a series of control experiments
and DFT study. Transition metal catalyzed N-alkylation of
amines has been well documented in the literature and typically
Scheme 3 Control experiments. (a) Reduction of imine by an alcohol
with a catalytic amount of base. (b) Quenching of the catalytic reaction
in the presence of radical inhibitors. (c) Storing of borrowed hydrogen
from the alcohol on the PLY backbone via dearomatization (inset
Scheme 2 Applications of (N,O)-PLY catalyzed N-alkylation towards indicates deuterium incorporation from the deuterium enriched
the diversification of biologically important molecules.
alcohol).
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experiment suggests that only 0.2 equivalent base suffices the dearomatized products as conrmed by NMR analysis, which
imine hydrogenation step while the additional equivalent of suggests that the two new C–H bonds in 80aMes/80bMes result
base (total 1.2 equivalent base is used in the catalytic reaction) is from the borrowed hydrogen molecule from the alcohol which
required in the imine generation step. Next, we have performed is stored in the PLY molecule. Furthermore, two peaks at
deuterium labelling experiments using deuterium enriched 4- d 15.90 ppm and 13.29 ppm in the 1H NMR spectrum were
chloro benzyl alcohol (4-Cl-C6H4-CD2-OH, 2c-d2) and aniline to observed for the puried product of such a reaction which can
afford a mixture of deuterium labelled isotopomers of N-alky- be assigned to –OH and –NH functional groups, respectively, as
lated anilines (Scheme S5, ESI‡). Such an observation indicates shown in 80aMes and 80bMes (Scheme 3c). Such ndings suggest
that the source of hydrogen in this reaction is benzyl alcohol.
the formation of two isomers (80aMes and 80bMes) in a 1.8 : 1 ratio
As discussed earlier, phenalenyl (PLY) based moieties can (from 1H NMR) as shown in Scheme 3c. Further 13C NMR
store and transfer a redox equivalent through its backbone.57 (Fig. S118, ESI‡) and DEPT-135 (Fig. S119, ESI‡) NMR spec-
The efficacious catalytic alkylation of amines supported by PLY troscopy support our assumption of proposed dearomatized
based ligands, encouraged us to demonstrate how a borrowed products as depicted in Scheme 3c. In the high resolution mass
hydrogen molecule from the alcohol partner is stored in the PLY spectrometry spectra of the isolated products, only one peak at
backbone and transferred to the in situ generated imine. m/z 316.1697 amu (Fig. S122, ESI‡) refers to the presence of two
Accordingly, we planned a series of stoichiometric reactions. At isomers when correlated with the NMR spectroscopic results.
rst, to establish whether the alkylation of amines followed Moreover, when (MesN,O)-PLY was charged with two equivalents
a radical pathway or not, we examined the effect of 2,2,6,6-tet- of KOtBu and one equivalent of deuterium analogue of 4-
ramethylpiperidinoxyl (TEMPO) as well as galvinoxyl radical for chlorobenzylalcohol (4-Cl-C6H4-CD2-OD, 2c-d3) in another set of
the alkylation of aniline (1a) using benzyl alcohol (2a) under reactions, aer leaching with aqueous HCl, to our delight, we
standard reaction conditions (Scheme 3b). The reduced yield observed the formation of dideuterated dearomatized PLY
(56%) of N-benzylaniline was realized upon charging of 1 molecules such as 80aMes-d2 and 80bMes-d2 (Scheme 3c, inset)
equivalent TEMPO, whereas a trace amount of N-benzylaniline along with other isotopomers (Fig. S128, ESI‡). The formation of
was observed when 2 equivalents of TEMPO or 1 equivalent of such dideuterated dearomatized isotopomers was conrmed by
galvinoxyl free radical was used. These experiments suggest that high-resolution mass spectrometry when a peak at 318.1861 was
the catalytic alkylation of amine proceeds through a radical observed (see Fig. S128, ESI‡). Such an observation unarguably
pathway. Keeping this information in mind, we proceeded to establishes the source of the harvested D2 originating from the
react the bidentate (MesN,O)-PLY based ligand with one equiv. deuterated benzyl alcohol. Furthermore, we have performed
KOtBu which produces a K-(MesN,O)-PLY complex 6Mes. The deuterium labelling experiments with 4-chlorobenzylalcohol (4-
formation of such a complex was earlier established and was Cl-C6H4-CD2-OH), (2c-d2) when the relative concentration of
characterized by single crystal X-ray crystallography.58 Next, the dideuterated dearomatized isotopomers (80aMes-d2 and 80bMes
addition of another equivalent of KOtBu to K-coordinated d2) decreased as expected (HRMS, Fig. S131, ESI‡), while the use
MesN,O)-PLY (6Mes) produces the radical anion species (7Mes
of DCl in place of HCl did not alter the relative intensity of such
-
(
)
upon acceptance of an electron from KOtBu and such a radical a dideuterated dearomatized isotopomer (Table S2, ESI‡) as
anion species was also recently characterized by single crystal X- observed from HRMS (Fig. S129, ESI‡). All these control exper-
ray and spectroscopic measurements.58 Interestingly, the iments further strengthen the proposal that the borrowed
radical anion species 7Mes can next accept the alcoholic proton hydrogen molecule from the alcohol is stored on the PLY moiety
from benzyl alcohols which was supported by DFT calculation in the form of two C–H bonds via a dearomatization process.
(vide infra).
To gain more insight into the reaction mechanism, the
Next, to corroborate whether the borrowed hydrogen from alkylation of aniline (1a) with benzyl alcohol (2a) was investi-
the alcohol is stored in the PLY backbone or not, we performed gated by density functional theory (DFT) for a full mechanistic
a control reaction between (MesN,O)-PLY radical anion species cycle by the m062x method employing the 6-31+g(d) basis set
(7Mes) and benzyl alcohol in toluene (Scheme 3c). On treatment with the SMD solvent model for toluene, as elucidated in Fig. 1.
of (MesN,O)-PLY with two equivalents of KOtBu and one equiv- The catalytic alkylation was studied with the N-Me substituted
alent of 4-chlorobenzyl alcohol (2c) in toluene at 130 ꢀC, a color phenalenyl [(N,O)-PLY] radical anion, 7. The radical anion 7
change from orange to wine red was observed. The resulting upon reaction with benzyl alcohol accepts the alcoholic –OH
reaction mixture was subsequently charged with aqueous HCl proton at one of the spin-bearing positions of PLY via a transi-
to leach the coordinated K affording a deep green reaction tion state TS1 with an activation energy barrier, DG1‡
¼
mixture when hydrogen gas evolution was noted and conrmed 12.4 kcal molꢂ1, to form the intermediate 7Int where one
by GC-MS analysis (Fig. S131, ESI‡) as well as 1H NMR spec- unpaired electron is situated on the adjacent carbon atom of the
troscopy (Fig. S130, ESI‡) (d 4.46 ppm in toluene-d8).57 On phenalenyl moiety. Notably, the interaction of the alkoxide
scrutiny of the 1H NMR spectrum of the isolated products aer anion with the potassium ion in 7Int favors the benzylic
HCl treatment (by column chromatography), two triplets in the hydrogen atom transfer (HAT) from alkoxide to the radical
region d 2.63 ppm and 3.12 ppm (Fig. S117, ESI‡) along with carbon center of PLY through the transition state TS2. Such
a multiplate at d 4.19–4.28 ppm (Fig. S117, ESI‡) were observed, a hydrogen atom transfer mechanism was further supported by
suggesting the dearomatization of the PLY ring.57,58 The treat- a series of control experiments which enabled us to trap the
ment of DCl in place of HCl also resulted in similar ketyl radical intermediates by TEMPO and characterize them.
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(DG‡4). This nal step regenerates the active radical anionic
phenalenyl catalyst 7 along with the product formation.
Accounting all these trapped and in situ generated interme-
diates based on several control experiments and DFT calcula-
tions, we depicted the plausible mechanism as a borrowing
hydrogen methodology in Scheme 4 where sequentially, H+, a H-
atom and an electron are stored in the PLY backbone via
dearomatization and subsequently transferred to the in situ
generated imine functionality thus mimicking the metal based
borrowing hydrogen mechanism. At rst, the active radical
catalyst 7 is formed by addition of two equivalents of KOtBu to
(N,O)-PLY. Next, upon interacting with benzyl alcohol, the –OH
proton and the benzylic hydrogen atom are transferred to the
PLY backbone followed by an electron transfer process, which
results in the dearomatization of the PLY backbone and the
hydrogen molecule is stored in the form of two C–H bonds as
shown in 8 (consists of 8a and 8b). It may be noted that in the
rst step, the resulting alkoxide aer proton transfer can bind
with the K ion as shown in 7Int for its stabilization. Subse-
quently, the benzylic hydrogen atom can be transferred to the
dearomatized PLY through a HAT process, which generates
a radical on the benzylic carbon. The benzylic radical species
recombines with the anionic oxygen to release aldehyde and an
electron is transferred to the PLY species generating 8. Next, the
in situ generated aldehyde, 20, reacts with aniline to produce the
corresponding imine. Finally, the dearomatized intermediate 8
transfers the stored hydrogens sequentially to the imine. Upon
Fig. 1 Energy profile diagram along the reaction coordinate for the
catalytic N-alkylation, obtained from DFT calculation. Only one isomer
is represented for the sake of simplicity.
For example, we have been able to trap the ketyl radical
generated from 4-uoro benzyl alcohol (2b) upon reaction with
2 equivalents of TEMPO and was characterized by high resolu-
tion mass spectroscopy (m/z 282.1870, Fig. S107, ESI‡). The
trapped ketyl radicals with 4-nitrobenzyl alcohol (2r) and 4-tri-
uoromethylbenzyl alcohol (2s) were also characterized
through GC-MS (Fig. S108 and S109, ESI‡).
The transition state energy barrier for this HAT process is
only 0.3 kcal molꢂ1 (DG2‡), which results in the formation of
dearomatized phenalenyl radical intermediate 8 (consists of 8a
and 8b), where both alcoholic O–H and benzylic C–H hydrogens
were stored as two C–H bonds via dearomatization. Interest-
ingly, the formation of intermediate 8 through the transition
state, TS2, involves two concerted steps. At the rst step, the
HAT from the benzylic position of alkoxide to the catalyst
produced a new C–H bond and results in the formation of
a benzylic radical. In the very next step, this newly generated
ketyl radical anionic species transfers an electron to the dear-
omatized phenalenyl catalyst backbone to release the aldehyde.
The aldehyde and aniline undergo KOtBu mediated imine
formation, and the TS calculation shows that this process
involves two transition states TS1i (DG‡1i ¼ 1.5 kcal molꢂ1) and
TS2i (DG‡2i ¼ 21.4 kcal molꢂ1), and both the transition states
consider interaction with K counter ions (Fig. S133, ESI‡). This
calculation excludes the possibility of catalyst's involvement in
the imine formation step. Next, the stored hydrogens in the
form of C–H bonds get transferred to the imine intermediate to
yield the corresponding amines. The transfer of stored hydro-
gens follows a two-step process, where a hydride is transferred
from intermediate 8 to the imine to generate an anion over the
nitrogen centre of the imine, which is stabilized by delocaliza-
tion over the aromatic ring (9) through the transition state TS3
with an activation energy barrier of 14.8 kcal molꢂ1. Next, the
nal step is accomplished by abstracting a proton from the
phenalenyl catalyst backbone by the nitrogen center of anilido
to produce the desired alkylated product through transition
state TS4 with a transition state energy barrier of 3.2 kcal molꢂ1
Scheme 4 Plausible mechanism for the transition metal free catalytic
N-alkylation of amines.
8358 | Chem. Sci., 2021, 12, 8353–8361
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transfer of one hydride from 8 to the imine, it generates an glovebox and sealed prior to bring out from the glovebox.
anionic K-coordinated complex, 9, where anionic charge is Next, the reaction mixture was allowed to stir at 130 ꢀC for 18 h.
distributed over the aryl ring and is coordinated with K. Further Aer completion of the reaction, the crude reaction mixture was
acceptance of another proton from the dearomatized PLY passed through Celite using 25 mL ethyl acetate (EtOAc) and
backbone produces the desired alkylated product 3a along with dried over anhydrous sodium sulphate. The solvent was
the regeneration of the active catalyst, 7.
removed under reduced pressure and the crude product was
puried by column chromatography using a neutral alumina
and hexane/EtOAc mixture as an eluent to yield the pure desired
product which was further characterized by NMR spectroscopy.
Conclusions
In conclusion, we have demonstrated an efficient method for
the storage of a hydrogen molecule harvested from an alcohol in
a redox non-innocent organic molecule and transferred it to an
in situ generated imine for its reduction in a catalytic fashion.
This catalytic protocol for the alkylation of aromatic amines
affords good to excellent yield of N-alkylated amines and it is
applicable for the diversication of natural products such as the
derivatives of vitamin E in gram scale and adapalene derivative.
Based on several control experiments, deuterium labelling
experiments, time dependent NMR experiments, DFT study and
isolation/trapping of several intermediates along the catalytic
cycle, we infer that the borrowed hydrogen from the alcohol is
stored in the redox active PLY backbone in the form of two C–H
bonds upon its dearomatization. Such a hydrogen molecule
stored as C–H bonds was further transferred to the in situ
generated imine resulting in its reduction and regenerates the
active catalyst. Thus, this mechanism conceptually resembles
the transition metal catalyzed borrowing hydrogen mediated
reactions. This study opens up the possibility of exploring
various other transition metal free catalytic Borrowing
Hydrogen/Hydrogen Autotransfer (BH/HA) mediated reactions.
Radical quenching with radical inhibitors
An oven dried 15 mL tube was charged with aniline, 1a (27.4 mL,
0.3 mmol), benzyl alcohol, 2a (34.3 mL, 0.33 mmol), (N,O)-PLY
(6.3 mg, 0.03 mmol, 10 mol%), KOtBu (40.4 mg, 0.36 mmol,
1.2 equivalents), and TEMPO (93.6 mg, 0.6 mmol) or galvinoxyl,
free radical (126.5 mg, 0.3 mmol) along with 1.5 mL toluene
inside a nitrogen-lled glovebox and sealed prior to bring out
from the glovebox. Subsequently, the reaction mixture was
allowed to stir at 130 ꢀC for 18 h. Next, the reaction mixture was
cooled down and the crude reaction mixture was passed
through Celite using 25 mL ethyl acetate (EtOAc) and dried over
anhydrous sodium sulphate. The solvent was removed under
1
reduced pressure and the NMR yields were determined by H
NMR spectroscopy using 1,4-dimethoxybenzene as the internal
standard.
Leaching experiment with HCl
An oven dried 15 mL tube was charged with (MesN,O)-PLY
(31.4 mg, 0.1 mmol) and KOtBu (22.4 mg, 0.2 mmol, and
20 mol%) along with 1.5 mL toluene inside a nitrogen-lled
glovebox and sealed prior to bring out from the glovebox.
Subsequently, the reaction mixture was allowed to stir at 130 ꢀC
for 6 h and a sharp color change from orange to wine red was
observed. Aer 6 hours, the reaction mixture was cooled down
and 4-chloro benzyl alcohol, 2c (14.2 mg, 0.1 mmol), was added
inside a nitrogen lled glovebox. Again, the reaction mixture
Experimental section
General considerations
Different phenalenyl (PLY) ligands were prepared following re-
ported literature procedures.59–62 All solvents were distilled from
Na/benzophenone or calcium hydride prior to use. All chem-
icals were purchased and used as received unless otherwise
mentioned. Liquid anilines were distilled under vacuum before
ꢀ
was stirred at 130 C for another 8 h. Aer completion of the
reaction, 1.0 mL of 12 (M) aqueous HCl was added dropwise to
the reaction mixture and stirred at room temperature for 1 h
and the crude organic product was extracted in Et2O. The
solvent was removed under reduced pressure and the dearom-
atized PLY (80aMes and 80bMes) was isolated through column
chromatography using a hexane : ethyl acetate mixture as the
eluent (10 : 1). Upon successful isolation, the oily product was
characterized through NMR spectroscopy and mass spectrom-
etry (HRMS).
1
using in catalytic reactions. The H and 13C{1H} NMR spectra
were recorded on 400 and 500 MHz spectrometers in CDCl3 with
residual undeuterated solvent (CDCl3, 7.26/77.0) as an internal
standard using tetramethylsilane as a reference. Chemical
shis (d) are given in ppm, and J values are given in Hz.
Chemical shis (d) downeld from the reference standard were
assigned positive values. Column chromatography and thin
layer chromatography (TLC) were performed on silica gel
(Merck silica gel 100–200 mesh). Potassium tert-butoxide was
purchased from Sigma Aldrich. High-resolution mass spec-
trometry (HRMS) was performed on a Bruker maXis impact.
Computational details
Theoretical calculations were performed with the Gaussian16
program suite.65 All theoretical calculations were carried out
using the density functional theory (DFT) method with the
m062x method66 employing the 6-31+g(d) basis set67 for all
General procedure for the N-alkylation of amines
An oven dried 15 mL tube was charged with amines, 1a–v (0.3 atoms for the geometry optimization for all molecules including
mmol), alcohols, 2a-ad (0.33 mmol), (N,O)-PLY (6.3 mg, transition states and intermediates. Single point energy calcu-
0.03 mmol, 10 mol%), and KOtBu (40.4 mg, 0.36 mmol, 1.2 lations were used for carrying out the m062x method66 with the
equivalents) along with 1.5 mL toluene inside a nitrogen-lled 6-31+g(d) basis set considering SMD solvent model in toluene.68
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18 P. A. Slatford, M. K. Whittlesey and J. M. J. Williams,
Tetrahedron Lett., 2006, 47, 6787–6789.
Author contributions
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SKM originated the idea of the work. AB and SKM planned the
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experiments. JA conducted all the theoretical calculations. SS
carried out the optimization reactions. SKM supervised the
work. AB and SKM analyzed the data and prepared the
manuscript.
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and M. Beller, Nat. Commun., 2016, 7, 12641.
24 A. Mukherjee, A. Nerush, G. Leitus, L. J. W. Shimon,
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There is no conict to declare.
Acknowledgements
We thank SERB (DST), India (Grant No. EMR/2017/000772) for
nancial support. A. B. and J. A. thank IISER Kolkata and S. S.
thanks CSIR India for research fellowships.
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