Pyridine mediated transition-metal-free direct alkylation of anilines using alcohols: via borrowing hydrogen conditions

Article abstract of DOI:10.1039/d0cc05912a

Herein, we report pyridine and other similar azaaromatics as efficient biomimetic hydrogen shuttles for a transition-metal-free direct N-alkylation of aryl and heteroaryl amines using a variety of benzylic and straight chain alcohols. Mechanistic studies including deuterium labeling and the isolation of dihydro-intermediates of the benzannulated pyridine confirmed the role of pyridine and a borrowing hydrogen process operating in these reactions. In addition, we have extended this methodology for the development of dehydrogenative synthesis of quinolines and indoles, as well as the transfer hydrogenation of ketones. This journal is

Full text of DOI:10.1039/d0cc05912a

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Pyridine Mediated Transition-Metal-Free Direct Alkylation of Anilines
DOI: 10.1039/D0CC05912A
Using Alcohols via Borrowing Hydrogen Conditions
Rajagopal Pothikumar, Venugopal T Bhat* and Kayambu Namitharan*
Organic Synthesis and Catalysis Laboratory
SRM Research Institute and Department of Chemistry
SRM Institute of Science and Technology, Chennai (India)
E-mail: namithak@srmist.edu.in

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DOI: 10.1039/D0CC05912A
Communication
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Pyridine Mediated Transition-Metal-Free Direct Alkylation of
Anilines Using Alcohols via Borrowing Hydrogen Conditions
Herein, we report pyridine and other similar azaaromatics as asymmetric transfer hydrogenation reactions in the presence of
efficient biomimetic hydrogen shuttles for a transition-metal-free transition metal complexes or organocatalysts.12
direct N-alkylation of aryl and heteroaryl amines using a variety of
(a) Direct alkylation using alcohols
benzylic and straight chain alcohols. Mechanistic studies including
R1NH2
R1
R
OH
R
N
H
deuterium labeling and the isolation of dihydro-intermediates of
the benzannulated pyridine confirmed the role of pyridine and a
borrowing hydrogen process operating in these reactions. In
addition, we have extended this methodology for the development
of dehydrogenative synthesis of quinolines and indoles, as well as
the transfer hydrogenation of ketones.
[Cat.]
[Cat.]
Precious metals (Ru, Ir, Rh, Pd etc.,)
and base metals (Fe, Co, Ni, Mn etc.,)
[Cat. H2]
R1NH2
R1
R
O
R
N
(b) Transition-metal-free Direct alkylation using alcohols (This Work)
Borrowing Hydrogen (BH) catalysis utilizing alcohols has recently
gained prominence for the sustainable formation of carbon-carbon
and carbon-heteroatom bonds.1 In particular, the direct N-alkylation
of amines under BH conditions2 has been widely utilized for the
production of value added amines, which are used as intermediates
or additives for the synthesis of fine chemicals and pharmaceuticals.3
The borrowing hydrogen process generally relies on catalysts based
on precious transition metals like Ru, and Ir with privileged ligands as
catalysts.4 Recently, base metals like Mn, Fe, Co, and Ni have also
been utilized for these BH reactions (Figure 1, a).5 However,
sustainable organocatalytic approaches to borrowing hydrogen
catalysis have rarely been explored.6
A significant development in this field was the introduction of the
biocatalytic borrowing hydrogen concept by Turner et al., who used
a combination of two engineered enzymes.7,8 These oxidoreductases
generally function with the help of a catalytic dyad comprising of a
serine and a histidine at their active sites which together act as a
charge relay network to deprotonate the alcohol before the crucial
hydride transfer step to the NAD(P)+ cofactor.9 Although these
pyridine nucleotides are structurally quite complex, their hydride
transfer ability can be traced to the simple pyridine core which
oscillates between an aromatic pyridinium ion and a dearomatised
dihydropyridine (DHP) in enzyme catalyzed biological redox cycles.
Unsurprisingly, synthetic analogues and mimics of these redox
cofactors have mostly utilized the pyridine structure decorated with
suitable substituents tuned for optimal hydride donor ability.10,11
These DHPs and other related organohydride donors (OHDs) are now
well entrenched in transfer hydrogenation protocols for the
reduction of a variety of carbon-carbon and carbon-heteroatom
double bonds. An ideal example is the Hantsch ester which is widely
Pyridine (0.4 equiv)
t-BuOK (0.4 equiv)
R1NH2
NHR1
+
R
OH
R
Toluene, 135 ºC
Ar, 12 h
1
2
3
Figure 1. Direct N-alkylation reactions using alcohols
Inspired by the elegant enzymatic recycling of catalytic amounts of
NADH in a biocatalytic borrowing hydrogen process and literature
proceedings, we envisaged the direct use of pyridine/benzannulated
pyridines and the corresponding dihydropyridines (DHPs) as catalytic
hydrogen shuttles in organocatalytic borrowing hydrogen reactions
(Figure 1, b). We were also prompted to undertake this challenge by
the remarkable discovery by Bocarsly, Musgrave and others on the
utility of pyridine as an efficient organocatalyst for the
photoelectrochemical reduction of carbon dioxide to
methanol.10c,13,14 This interesting catalytic behavior of pyridine is
attributed to the aromatization-dearomatization cycle of the 1,2-
dihydropyridine/pyridine in which the 1,2-DHP reduces carbon
dioxide to methanol via a series of hydride and proton transfer steps.
The instability of the dearomatized DHPs is the key driving force for
the direct hydride transfer in the reduction of C=C, C=N, and C=O
bonds. However, to attain a complete redox-neutral catalytic cycle
for utilizing DHPs in BH reactions, the conditions required for the in-
situ generation of the DHP should be congruous with the final
hydrogenation step. Therefore, the key challenge in utilizing
organohydride donors like the DHPs in these BH reactions lies in the
development of efficient methods for regenerating the DHPs.
Traditionally, the regeneration of bio-mimetic DHPs like the Hantsch
esters requires stoichiometric amounts of reducing agents, and very
often transition metals.15 Based on very early reports on the
oxidation of lithium alkoxides using stoichiometric amounts of
nicotinamides,16 we reasoned that with suitable thermal activation,
utilized as
a stoichiometric hydrogen source in biomimetic
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a combination of a base and an alcohol could easily generate the Notably, when t-BuONa was used instead of t-BuOK, a significant loss
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DHPs under inert conditions. If the alcohol utilized as the hydrogen in the product yield was observed (entries 1DaOnId: 160).1.0T3h9e/Ds0aCmCe0t5r9e1n2dA
source to generate the DHP gets incorporated into the final alkylated was observed when KOH and NaOH were employed (entries 7 and
product via a transfer hydrogenation step, the BH cycle would be 8). Therefore, to understand the role of alkali metal ions in the
catalytic with respect to the DHP (Figure 2).
reaction mechanism, metal-ion- sequestering experiments with 18-
Herein, we discuss our studies on the use of pyridine and crown-6 were performed. When we have 18-crown-6 in the reaction
benzannulated pyridines like quinoline, phenanthridine, and acridine medium, N-alkylation did not proceed well and the starting alcohol
mediated borrowing hydrogen-based N-alkylation of amines using was almost completely recovered (ESI, 2a Scheme S1) these results
alcohols. We also extend the concept to a direct pyridine-mediated indicate that alkali-metal ion plays a key role in the reaction
transition-metal-free transfer hydrogenation of ketones using mechanism (Figure 2). Subsequently, a solvent screen was also
isopropyl alcohol as the sacrificial hydrogen donor. The undertaken; besides toluene, other solvents such as m-xylene, 1,4-
dehydrogenation ability of pyridines/benzannulated pyridines were dioxane, DMF, and DMSO were also tested. The reaction proceeded
also utilized for a modified Friedländer synthesis of quinolines. best in apolar aprotic solvents, while polar aprotic solvents led to
Finally, we report a new role for N, N-dimethylaminopyridine, trace amounts of products (Supporting Information (ESI, Table S1).
(DMAP), a nucleophilic catalyst of renown and utility, as an efficient Next, we explored the potential of other azaaromatic heterocycles in
organocatalytic hydrogen shuttle in these borrowing hydrogen borrowing hydrogen N-alkylation of amines using alcohols. As
reactions.
expected, quinoline (Cat-2) and phenanthridine (Cat-4) gave near
quantitative yields of the N-alkylated amine product 3a similar to
pyridine (Cat-1) (Table 1, entries 10 and 12). Conversely, acridine
(Cat-3) gave moderately lower GC yields of the benzylidineaniline
product 3a under similar conditions (Table 1, entry 11). Also, when
acridine and phenanthridine were employed, we detected the
corresponding DHPs (DHP-1 and DHP-2), as well as the aldehyde and
imine intermediates in the reaction mixture by GC and crude 1H NMR
(ESI, 2c). To confirm the role of azaaromatics in the present BH
reaction, a control experiment was undertaken with the absence of
azaaromatics. As expected, under our reaction conditions (catalytic
amount of base, 0.4 equiv), only 2% of product was observed (Table
1, entry 14). Also, reaction performed under oxygen atmosphere,
gave only trace amounts of 3a. It is important to note that the
present report is strictly different from the earlier reports regarding
transition-metal-free dehydrative N-alkylation of anilines with
alcohols where either super stoichiometric base or much higher
temperature was employed.17, 18, 19
Table 1. Optimization Conditionsa
Entry
Catalyst
pyridine
Base
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuONa
KOH
NaOH
K2CO3
Cs2CO3
t-BuOK
t-BuOK
GC Yield (%)
GC Yield (%)
3a
99
3a’
0
0
0
4
18
26
18
39
3
2
3
0
2
2
69
1
2b
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
quinoline
acridine
99
99 (95)
83
71
56
80
56
0
3c
4d
5e
6c
7c
8c
9c
10c
11c
12c
13c
14
15c,f
0
96
81
97
2
phenanthridine t-BuOK
-
t-BuOK
t-BuOK
pyridine
1
To verify if a true BH mechanism operates in our pyridine mediated
Reaction Conditions: Benzyl alcohol (1 equiv, 0.92 mmol), Aniline (1.5 equiv 1.38 mmol),
Base (0.4 equiv, 0.37 mmol), Mediator (1 equiv, 0.92 mmol), Toluene 1 ml, 135 °C,
Argon, 12 h. (b) 0.5 equiv of mediator was used. (c) 0.4 equiv of mediator was used. (d)
0.3 equiv of mediator was used. (e) 0.3 equiv of base was used. (f) under oxygen
atmosphere.
N-alkylation reactions, we performed
a deuterium crossover
experiment of benzyl alcohol 1a, deuterated benzyl alcohol [D2]-1a
and aniline 2a under our optimized conditions. The crossover D/H
exchange product [D1]-3a was obtained in 40% yield as determined
Initially, we attempted a pyridine/benzannulated pyridine mediated
BH N-alkylation reaction of amines with alcohols. When
stoichiometric pyridine (Cat-1) was employed for the N-alkylation of
aniline 2a (1.5 equiv) with benzyl alcohol 1a (1 equiv) in the presence
of t-BuOK (0.4 equiv) as a base under argon atmosphere, the N-
alkylated amine product 3a was observed in >99% GC yield (Table 1,
entry 1). With this promising result, we proceeded to optimize the
amount of pyridine and t-BuOK required to catalyze this
transformation. The reaction was found to proceed with the same
efficiency with just 0.4 equiv of pyridine and 0.4 equiv of t-BuOK in
12 h under inert conditions (Table 1, entry 3). Reducing the
equivalents of either pyridine or base lowers the product 3a yields.
Both the pyridine and base were found to be essential in catalyzing
the reaction (Electronic Supporting Information (ESI), Table S2).
1
by H NMR and HRMS analysis. (ESI, 2e). This observation confirms
that our methodology is consistent with the proposed
dehydrogenative borrowing hydrogen mechanism. Importantly, to
confirm the role of pyridine as a hydrogen shuttle, fully deuterated
[D5]-pyridine was employed in an N-alkylation reaction of aniline 2a
and benzyl alcohol 1a under standard reaction conditions. As
expected, deuterium incorporated final product [D1]-3a was isolated
20% (ESI, 2f). This confirms the proposed mechanism that pyridine
undergoes dehydrogenation-hydrogenation cycle during the
process. Next, we set out to ensure that the present process is truly
transition-metal-free because literature reports indicate that the
trace amounts of metal impurities present in reagents/laboratory
equipment can catalyze reactions. A control reaction was performed
2 | J. Name., 2012, 00, 1-3
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in a new flask using a new stirrer bar with freshly distilled 1a, 2a,
pyridine and toluene, as well as the sublimed grade t-BuOK (99.99%
trace metal basis, bought from Sigma Aldrich). The reaction was
found to proceed with the same efficiency as entry 3 in Table 1. Also,
to understand the role of carbonyl as a catalyst in our conditions,
experiments with varied pyridine and benzaldehyde equivalents
were performed (ESI, Table S3). Increasing the equivalents of
benzaldehyde has no positive impact on the reaction yields. In fact,
when more than 0.2 equiv was used, it reduces the product yield (ESI,
Table S3, entries 6 and 7). This is strictly in contrast to the carbonyl-
catalysed transition-metal-free N-alkylations, where carbonyl
equivalents play a major role in the reaction outcome.20 whereas
reducing the pyridine equivalents drastically decreased the product
yield in our conditions (ESI, Table S3, entries 8, 9 and 10). The above
results clearly reflected the significant role of pyridine in our
reactions. Based on the above findings, the possibilities of carbonyl-
catalyzed processes can be eliminated.
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DOI: 10.1039/D0CC05912A
(a) Alcohol oxidation and generation of semi-hydrogenated pyridine intermediate
K
O
K
N
O
N
H
O
N
H
K
+
+
R
H
H
R
H
R
H
H
H
H
I
II
TS1
Transition State
(b) Imine reduction and regeneration hydrogen-shuttle pyridine
R1
K
R1
R1
K
N
N
H
N
N
N
H
K
N
+
+
H
H
H
R
H
H
H
R
R
H
IV
III
TS2
Transition State
Figure 2. Plausible mechanism
We then, studied the
scope of the pyridine
Figure 3. Scope of N-alkylation reaction
The isolation of stable DHPs in the case of acridine and
phenanthridine together with the important role of the alkali metal
ion in the process points towards the role of a semi hydro-
pyridine/benzannulated pyridine in the reaction mechanism. The
alkali metal ion could play a crucial role in the TS for the alcohol
dehydrogenation resulting in the formation of the semi
mediated N-alkylation reaction of aryl/heteroaryl amines with
alcohols (Figure 3). Substrates with electron-rich aryl groups
provided excellent yields of product amines (3a−e, 81%− 95%), while
lower yields were observed with electron-deficient groups (3f−l,
63%−95%). Interestingly, anilines bearing reducible groups such as
Cl, Br, and I were also well tolerated under our reaction conditions
(3f−l, 63%−95%). Also, heteroaromatic amines such as
aminopyridines and aminopyrazines, important structural motifs
found in many pharmaceuticals, could be efficiently transformed
into the corresponding alkylated products (3m-o, 65-94%). When a
substrate containing a reducible double bond, like 4-amino styrene
was tested under our reaction conditions, a mixture of products was
obtained with the major product retaining the unreduced double
bond (3p, 85%). The scope of the reaction with respect to various
alcohols was also examined (3q-3u). A heterocyclic alcohol was also
found to yield the corresponding N-alkylated product under our
standard conditions (3v, 72%). Significantly, aliphatic straight chain
alcohols also worked well in these pyridine mediated BH reactions
affording the N-alkylated products 3w-z’ in good yields (57% - 88%)
albeit at slightly higher temperatures (145 °C). Next, we decided to
check whether 4-dimethylaminopyridine (DMAP), a well-known
hydropyridine and again in
a second TS for the transfer
hydrogenation of the imine intermediate leading to the final amine
product (Scheme 2. These proposed TS are similar to the six
membered TS of carbonyl catalyzed Oppenauer /MPV reactions as
well as the base catalyzed acceptorless dehydrogenation of N-
heterocycles reported recently.20 Hence, the reaction likely proceeds
via an initial formation of alkoxide intermediate I from a base and
alcohol. This will then undergo dehydrogenation with the assistance
of pyridine/benzannulated pyridine to form a carbonyl and a semi-
hydrogenated pyridine/benzannulated pyridine intermediate II via a
six membered transition state TS1 (Figure 2a). The in situ generated
carbonyl intermediate reacts with amine present in the reaction
medium and gives the imine intermediate. Finally, semi-hydro-
pyridine/benzannulated pyridine transfers the borrowed hydrogen
back to the imine with the help of alkali-metal ion to give the
intermediate IV via TS2 (Figure 2b). This intermediate IV would then
yield the final product 3.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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nucleophilic catalyst with a pyridine core, can catalyze these BH
reactions. Under our standard reaction conditions, in the presence
of 0.4 equiv of DMAP as the catalyst, the N-alkylated product 3a was
obtained in 75% isolated yield (ESI, 2g). A heterogeneous version of
a pyridine-based mediator for N-alkylation reactions was also
explored using a commercially available polystyrene supported
DMAP (PS-DMAP) (ESI, 2h). Extending our pyridine mediated BH
methodology for the synthesis of heterocycles, we performed an
intramolecular N-alkylation of 2-aminophenethyl alcohol. The
reaction was very facile and the desired indole product was obtained
Notes and references
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(a) Transition-metal-free dehydrogenative synthesis of quinolines
R3
Pyridine (0.1 equiv)
KOH (0.2 equiv)
O
OH
R3
+
1,4-dioxane, 135 o
C
R2
N
R2
NH2
Argon atmosphere, 1 h
4
, R3 = H (or) Me
5
6a-k
, 11 examples
6. Heterogenous functionalized carbon has been utilized in transition metal-
free BH reactions and transfer hydrogenation of ketones and
nitrocompounds. The carbonyl moieties in these heterogenous carbons
have been suggested as active sites for these reactions. H. Yang, X. Cui, X.
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(b) Transition-metal-free reduction of ketones
OH
O
OH
Pyridine (0.4 equiv)
t-BuOK (0.4 equiv)
135 oC, Ar, 12 h
R3
R2
+
, R3 = H (or) Me
5
7a-k
, 11 examples
Figure 4. Transition-metal-free dehydrogenative quinoline synthesis
and transfer hydrogenation of ketones.
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Friedlander synthesis of quinolines from aminobenzyl alcohols and
ketones.21a In a similar approach using 0.1 equiv of pyridine as a
catalyst and 0.2 equiv of KOH as a base, we synthesized various
quinolines from 2-amino benzyl alcohols and aryl alkyl ketones in
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source.22 Pleasingly, various acetophenones and propiophenone
were smoothly reduced under our pyridine mediated N-alkylation
conditions (Figure 4b, 7a-k) (ESI, 2k).
In conclusion, we have developed a pyridine/benzannulated pyridine
mediated transition-metal-free borrowing hydrogen N-alkylation
reaction for the synthesis of a variety of substituted amines. These
azaaromatics have also been explored for the catalytic transfer
hydrogenation of ketones and dehydrogenative quinoline synthesis.
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provides a readily accessible alternative to the traditional approach
of using transition metal systems for the activation of alcohols in
borrowing hydrogen reactions. We believe that these results would
help in the design and understanding of new modes of
organocatalysis based on pyridine and its analogues.
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