Mechanistic insight into the azo radical-promoted dehydrogenation of heteroarene towards N-heterocycles

Article abstract of DOI:10.1039/d0cy01008a

Borrowing hydrogenation-promoted annulations are considered to be important reactions to synthesize wide variety of N-heterocycles. In these processes, the dehydrogenation of saturated heteroarenes in the late stage is generally required to furnish the desired N-heterocycle. However, in a one-pot, multistep heterocycle synthesis, this step is not well elucidated, and the role of the catalyst is not thoroughly understood. Furthermore, the use of copious amount of base at elevated temperatures further complicates this matter and casts doubt on the involvement of the catalyst in heteroarene dehydrogenation. Herein, we report a molecularly defined nickel catalyst, which can perform two annulation reactions under mild conditions (80 °C, 8 h), towards the sustainable synthesis of triazine and pyrimidine. Mechanistically, we clearly describe the important role of the catalyst in promoting the dehydrogenation of heteroarenes. The binding of the saturated heterocycle to the metal catalyst undergoes a pre-equilibrium step (K = 238 at 80 °C), which is followed by a crucial hydrogen atom transfer. A series of kinetics experiments including Van't Hoff, Eyring analysis and interception of pyrimidinyl radical disclosed the details of the dehydrogenation process. This ligand-driven, base metal catalytic approach is significantly different from the considerably evaluated metal-ligand cooperative bond activation strategies, which may offer an alternative dehydrogenation pathway that demands less energy. This journal is

Full text of DOI:10.1039/d0cy01008a

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Mechanistic insight into the azo radical-promoted
dehydrogenation of heteroarene towards N-
heterocycles†
Cite this: DOI: 10.1039/d0cy01008a
*
Amreen K. Bains and Debashis Adhikari
Borrowing hydrogenation-promoted annulations are considered to be important reactions to synthesize
wide variety of N-heterocycles. In these processes, the dehydrogenation of saturated heteroarenes in the
late stage is generally required to furnish the desired N-heterocycle. However, in a one-pot, multistep
heterocycle synthesis, this step is not well elucidated, and the role of the catalyst is not thoroughly
understood. Furthermore, the use of copious amount of base at elevated temperatures further complicates
this matter and casts doubt on the involvement of the catalyst in heteroarene dehydrogenation. Herein, we
report a molecularly defined nickel catalyst, which can perform two annulation reactions under mild
conditions (80 °C, 8 h), towards the sustainable synthesis of triazine and pyrimidine. Mechanistically, we
clearly describe the important role of the catalyst in promoting the dehydrogenation of heteroarenes. The
binding of the saturated heterocycle to the metal catalyst undergoes a pre-equilibrium step (K = 238 at 80
°C), which is followed by a crucial hydrogen atom transfer. A series of kinetics experiments including Van't
Hoff, Eyring analysis and interception of pyrimidinyl radical disclosed the details of the dehydrogenation
process. This ligand-driven, base metal catalytic approach is significantly different from the considerably
evaluated metal–ligand cooperative bond activation strategies, which may offer an alternative
dehydrogenation pathway that demands less energy.
Received 17th May 2020,
Accepted 20th July 2020
DOI: 10.1039/d0cy01008a
rsc.li/catalysis
H2 during desaturation. However, it is important to
understand the different pathways for this dehydrogenation
Introduction
The new discovery of reactions that can transform alcohols
to important value-added products greatly contributes
towards sustainability by preserving fossil fuel reserves. The
convenient and cheap sources of alcohol are indigestible
biomass, which makes this substrate an attractive chemical
feedstock.1 Accordingly, hydrogen borrowing (HB) from
alcohols,2–8 also known as hydrogen auto-transfer, has
since saturated heterocycles are regarded as organic liquid
hydrogen carriers, and thus attracts significant attention
from researchers.16
In the case of a one-pot, multi-component reaction towards
the synthesis of value-added N-heterocycle products,
dehydrogenation of the substrates is critical. The success of
multiple catalysts in homogeneous de/hydrogenation catalysis
is strongly governed by designer ligands, where the metal–
ligand scaffold activates a bond via a cooperative action.17,18
Noyori,19 Shvo,20 and Milstein21 showcased elegant examples
where the dehydrogenation reaction of an alcohol is
promoted by the tandem activation of two bonds by a metal
emerged as
a fascinating methodology to fabricate a
multitude of important organic molecules including N-
heterocycles.9–13 Aromatic N-heterocycles are ubiquitously
present in natural products, pharmaceutically important
molecules and organic functional materials.14 The
previously reported methods to assemble these heteroarenes
include dehydrogenation of the corresponding saturated
N-heterocycles using a stoichiometric oxidant.15 In contrast,
catalytic acceptorless dehydrogenations are much more
atom efficient and have the added advantage of extruding
and
a
heteroatom or aromatization–dearomatization
(Scheme 1). Using metal–ligand cooperativity, Fujita and
Yamaguchi developed an efficient Ir-catalyst that
dehydrogenated 1,2,3,4-tetrahydroquinolines and other cyclic
amines.22 Subsequently, Crabtree and Jones studied several
dehydrogenation reactions of N-heterocycles, which have a
similar underlying activation principle, but the active catalysts
are based on nickel,23 iron,24 and cobalt.2 Analogous to these
metal-catalyzed efforts, the recent approach of frustrated
Lewis pair-based dehydrogenation of heteroarenes has also
attracted significant attention.25–27
Department of Chemical Sciences, Indian Institute of Science Education and Research
(IISER) Mohali, SAS Nagar-140306, India. E-mail: adhikari@iisermohali.ac.in
† Electronic supplementary information (ESI) available: Experimental procedure,
spectroscopic and kinetic data. See DOI: 10.1039/d0cy01008a
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Scheme 1 Traditional M–L bifunctionality bond activation vs. azo radical-promoted dehydrogenation reactions.
However, despite the attempts to understand the
dehydrogenation of heteroarenes, there is still a lack of
precise knowledge, especially where an N-heterocycle is
isolated from a one-pot reaction. The seminal works reported
by the abovementioned groups examined dehydrogenations
on a pre-synthesized molecule. In contrast, when a one-pot,
multi-step reaction furnishes value-added heterocycles via a
series of oxidation, condensation, and dehydrogenation
reactions, clear mechanistic details of the late stage
dehydrogenation of heteroarenes are often lacking. In several
examples, the reaction is performed at high temperature for
an extended reaction time in the presence of a base. Thus,
whether the catalyst plays a critical role in bond activations
towards dehydrogenation or it is simply driven by gaining
study
the
dehydrogenation
pathway
of
saturated
heteroarenes. As will be delineated through further studies,
the reaction is completely radical mediated, and contrasts
heavily with the earlier examples of the dehydrogenation of
heterocycles via metal–ligand cooperative action.
Results and discussion
Recently, we established that the proximity of the two azo
functionalities to nickel in 1 is instrumental for alcohol
oxidation to occur via the radical pathway employing a
hydrogen atom transfer (HAT) event.29 During this process,
we further proved that the azo radical was generated by a very
mild reductant such as KOtBu, which was feasible due to the
low-lying π* of the nickel-bound azo moiety.
Encouraged by the dehydrogenating ability of 1, we
proposed a two-component coupling of alcohol with amidinate
salt, and subsequent dehydrogenation resulting in
triazines.31,32 It is well known that aryl-substituted 1,3,5-
triazine derivatives exhibit diverse biological activities.33 Thus,
to test the viability of the assumed synthetic protocol, a model
reaction was performed in the presence of benzyl alcohol and
amidinate salt. Gratifyingly, different triazine cores were readily
synthesized via the condensation of aldehydes with amidinates
at a mild reaction temperature of 80 °C. A series of control
experiments were performed, which clearly support the
aromaticity, is
Furthermore,
a
matter of considerable speculation.
a
simple base-promoted dehydrogenation
under a high loading of base and elevated temperature, as
recently reported by Yu, complicates this issue further.28
Herein, we attempt to understand the dehydrogenation of
heteroarenes, where HB methods from alcohols are
employed. We recently discovered a nickel complex with a
redox-active azophenolate backbone that promotes facile
alcohol oxidation enroute to the N-alkylation of amines and
the formation of benzazoles.29,30 We aim to showcase that
the same catalyst can also furnish two N-heterocycles under
very mild reaction conditions and provide the opportunity to
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necessity of both catalyst and base for the success of this
reaction. Several functional groups with both electron donating
such as –OMe (2b) and –Me (2c) and withdrawing substituents
–Cl (2d), –Br (2e), and –F (2f) at the para-positions of the benzyl
alcohol gave the respective triazine products in good yield (66–
82%) (2a–2f, Table 1) within a reaction time of 8 h. Notably, the
reaction was performed under aerobic conditions by keeping
an oxygen-filled balloon on the reaction flask.
catalyst and base for the success of the reaction. Notably, in
our optimized reaction conditions, the temperature and
reaction time are significantly reduced compared to other
catalysts towards the synthesis of pyrimidine, which we
attribute to the low-energy reaction pathway.34–36 To
scrutinize the homogeneous nature of this catalyst, a mercury
test was performed, which did not have any adverse effect on
the reaction outcome (ESI,† section 2E). Furthermore, the
clear first order dependence of the reaction rate on catalyst
concentration also attests to the homogeneous nature of the
reaction. The generality of the synthetic method was further
tested with an array of primary alcohols. Primary alcohols
with different halides, such as –F and –Cl were well tolerated,
giving excellent yields of the corresponding pyrimidines
(Table 2, 3g–i). Furthermore, naphthyl-1-methanol afforded
the respective pyrimidine (3d) in 88% yield. Simple alkyl
substituents including –Me and –iPr at the p-position of the
benzyl alcohol, all assembled the respective pyrimidine (3b
and 3f) in good to excellent yield. Notably, this reaction was
also performed under neat oxygen conditions with an oxygen
balloon added to the neck of the reaction flask. The presence
of pure oxygen during the reaction had a strong influence on
the regeneration of the catalyst. We will further discuss the
effect of the catalyst and the reaction pathway to turn the
overall conditions to be a milder one.
Next, we anticipated that
a similar three-component
coupling by 1 including primary and secondary alcohols and
an amidine will result in pyrimidine. Pyrimidine is a very
important heterocycle, which is present in DNA base pairs
and exhibits notable biological activity. This type of three-
component coupling was first reported by Kempe and co-
workers using an iridium catalyst at high reaction
temperature.34 Further developments included many base
metals and modified conditions, but the details of
dehydrogenating saturated heteroarenes enroute to
pyrimidine was not explored thoroughly.35–38 We commenced
our synthesis of pyrimidine using benzyl alcohol, 1-phenyl
ethanol and benzamidinate salt as prototypical substrates.
Gratifyingly, the reaction mixture when heated at 80 °C for 8
h, conveniently resulted in the corresponding pyrimidine in
90% yield. The optimized conditions revealed that 5%
catalyst loading was required to obtain best yield, while the
optimum base loading was 0.5 equivalent (Table S1, ESI†). An
array of control experiments justified the requirement of both
To further expand the substrate scope of the reaction, a
diverse range of amidines was examined. Encouragingly, methyl
Table 1 Synthesis of 1,3,5-triazine
Reaction conditions: 1 (5 mol%), primary alcohols (0.5 mmol), 4-methyl benzamidine (1 mmol), KOtBu (0.5 mmol), toluene (2 mL), 80 °C, 8 h,
and O2 balloon (isolated yield).
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Table 2 Synthesis of pyrimidine with diverse alcohols and amidines
Reaction conditions: 1 (5 mol%), primary alcohols (1 mmol), 1-phenyl ethanol (1.25 mmol), amidines (1 mmol), KOtBu (0.5 mmol), toluene (2
mL), 80 °C, 8 h, O2 balloon (isolated yield).
amidinate smoothly furnished the 2-Me-4,6-phenyl pyrimidine
(3j, Table 2) in 74% yield under the optimized reaction
conditions. Additionally, p-substituted aryl amidines with a highly
electron withdrawing fluoro group offered the corresponding
pyrimidine (3l) in 65% yield. Similarly, p-tolyl amidine offered the
respective pyrimidine ring (3k) in very good yield.
component coupling. Hydrogen molecules are trapped in the
catalyst backbone during alcohol oxidation, and in the final
step, the dehydrogenative aromatization of the N-heterocycle
occurs. Our previous study clearly disclosed that alcohols can be
readily oxidized under fairly mild reaction conditions. Cross-
aldol condensation between benzaldehyde and acetophenone
followed by nucleophilic attack of the amidine results in
1,2-dihydropyrimidine, 4 (Scheme 3a, vide infra). We were very
intrigued by the dehydrogenation process of 4 in this study.
Thus, to prove that the dehydrogenation is an important step in
the formation of pyrimidine, we synthesized the methylated
analogue of 4 starting from 1-phenyl ethanol, and isolated the
intermediate in the final stage (Scheme 2b and Fig. S2, ESI†).
Conceivably, the oxidative dehydrogenation of 4 requires more
energy than the other steps involved in the synthesis of
Mechanistic study towards dehydrogenation of
dihydropyrimidine (4)
As described previously, the presence of the redox-active azo
functionality in the ligand backbone facilitates the oxidation
of
a
substrate via HAT.29 Towards the synthesis of
pyrimidine, a total of 2 molecules of H2O and 3 molecules of
H2 are eliminated (in the form of H2O2) during the three-
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Scheme 2 a) Dehydrogenative aromatization of 4 under the optimized reaction conditions. b) Arrested methylated analogue of 4. c) Pyrimidinyl-
TEMPO adduct formation.
pyrimidine. In fact, with the present catalyst system, both
primary and secondary alcohols can be oxidized at 50 °C within
2 h. In many previously reported pyrimidine syntheses, the
reaction temperature was usually maintained at 120–140 °C.34,36
However, the mechanism of the heterocycle dehydrogenation
reaction at elevated temperatures has thus far not been
thoroughly investigated. Whether the purported Mn, Ir, or Cu
catalyst has a specific role towards this dehydrogenation of
dihydropyrimidine or base promotes the dehydrogenation at
elevated temperature is not very clear.38 This is also indirectly
supported by the observation of Srimani, where
2,3-dihydroperimidine was isolated under Mn-catalyzed
conditions at 120 °C, whereas no dehydrogenated pyrimidine
was isolated.39 This observation is consistent with the difficulty
associated with producing pyrimidines from dihydropyrimidines
owing to the unfavorable change in enthalpy. As we discussed
earlier, our optimized temperature and reaction time were
reduced considerably, and we surmise that catalyst 1 has a
specific role in this dehydrogenation reaction. Previously, a
ruthenium and heterogeneous platinum-catalyzed pyrimidine
synthesis also alluded to the role of the catalyst in
2,3-dihydropyrimidine dehydrogenation, but did not present the
detailed steps.40,41
This observation corroborates well with the base-promoted
dehydrogenation of saturated heteroarenes reported recently.
Indolines and 1,2,3,4-tetrahydroqunolines were dehydrogenated
to indoles and quinolines, respectively, under severe conditions
of 2–3 equivalent of KOtBu and heating at 140 °C for 36 h when
no catalyst was present.28
To investigate the dehydrogenation of 4 in detail using our
catalyst system, we pre-synthesized the molecule and studied
the detailed kinetics of the dehydrogenation reaction. Initially,
to ensure that 4 requires binding to nickel during the
dehydrogenation step, we monitored the increase in the
observed rate constant (kobs) with a gradual increase in the
concentration of 4. The two rate constants used in this
discussion are kobs, which is the measured rate under pseudo-
first-order condition of substrate, and the derived first-order
rate constant k for the HAT step. This experiment clearly
displayed the saturation behavior of 4 at higher concentration
and unambiguously authenticated that the binding is
important (Fig. 2a). The saturation behavior was modeled via
the pre-equilibrium step following eqn (1), and non-linear
curve fitting provided the equilibrium constant of 238 M−1 at
80 °C.
k
K
½1·4ꢀ˙− Product
(1)
½1ꢀ˙− þ 4 ⇋
!
The understanding of the detailed mechanism for
dehydrogenative aromatization has been often overlooked to
date. Sometimes pure aerial oxidation of the dihydropyrimidine
has been assumed as a possible route to its unsaturated
analogue, which is clearly not a facile process.38 In good
agreement with our proposed hypothesis, the conversion of 4 to
the aromatic pyrimidine is a background reaction when the
reaction was conducted at 80 °C without any catalyst (Fig. 1).
kK½4ꢀ
kobs
¼
1 þ K½4ꢀ
The fitting also gave the first-order rate constant, k = 9.1 × 10−4
s−1 for the subsequent process, which is HAT to the azo radical.
We studied the pre-equilibrium behavior of
4 under
dehydrogenation at three different temperatures, which
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Scheme 3 a) Schematic representation for the formation of 4 via the oxidation of alcohols and subsequent Claisen–Schmidt condensation. b)
Plausible mechanism for the azo radical mediated dehydrogenation of 4 via a critical hydrogen atom transfer step.
followed the expected trend of a decrease in the equilibrium
constant at higher temperature (Table 3). The calculated
equilibrium constants at different temperatures and their plots
of natural logarithm with respect to inverse temperature
disclosed ΔH° and ΔS° to be −5.74 kcal mol−1 and −3.34 cal
mol−1 K−1 respectively (Fig. 2b) based on the Van't Hoff
equation. The moderate value of the enthalpy change can be
ascribed to the simultaneous protonation of the phenolate arm
Fig. 1 Kinetic analysis for the dehydrogenation of 4 in the presence and absence of catalyst. a) Product growth with time, reaction temperature
80 °C. b) Calculation of pseudo-first-order rate constant.
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Fig. 2 a) Saturation kinetics profile for the binding of 4 to 1, at three different temperatures, b) Van't Hoff plot from equilibrium constant data.
and its detachment to nickel during the binding of 4 to the
complex (Scheme 3b). The overall ΔS° for the formation of the
complex is also the sum of several entropy changes with
different signs. The loss of entropy accompanies the restriction
due to binding of 4, while an increase in entropy occurs when
the phenol arm detaches from the metal center.
broken. It can be anticipated that the C–H bond in the
present case is benzylic in nature, and hence weak. Likewise,
HAT from 4 will generate a transient carbene radical, which
upon reducing the second unreduced azo arm, will generate
pyrimidine. The proton transfer from phenol to nitrogen
completes the reduction of the azo and leaves it with a
hydrazo form (Scheme 3b). The hydrazo form of the catalyst
was isolated and authenticated by NMR spectroscopy. Overall,
the two-electron azo/hydrazo redox couple that can
Interestingly,
the
pseudo-first-order
rate
of
dehydrogenation for 4 at 80 °C under oxygenated conditions
is 9.1 × 10−4 s−1, while that at the same temperature without
any catalyst is only 1.6
×
10−6 s−1. Thus, the rate
interconvert in
dehydrogenation step required in this reaction.42
Further, to unambiguously ascertain
a
reversible fashion facilitates the
enhancement for the dehydrogenation of 4 in the presence
of the catalyst is at least 550 times. However, in the absence
of catalyst 1 (but in the presence of 0.5 equiv. of base) the
rate of dehydrogenation reached the observed rate only when
the temperature was elevated to 140–150 °C (Fig. S5, ESI†).
Moreover, to authenticate the feasibility of the
dehydrogenation at the reaction temperature (80 °C), we
performed an Eyring analysis with the first-order rate
constants. The Eyring plot conveyed ΔH‡ of 20.23 1.83 kcal
mol−1, while ΔS‡ to be −24.98 0.94 cal mol−1 K−1 (Fig. 3).
The negative ΔS‡ value indicates the bimolecular nature of
the dehydrogenation step, where 4 binds to reduced 1. The
overall reaction barrier, ΔG‡ of 29.05 2.81 kcal mol−1, for
the process calculated at 80 °C is consistent with the
that
the
dehydrogenation is radical mediated, we tried to quench the
reaction in the presence of a well-known radical quencher,
TEMPO (TEMPO = 2,2,6,6-tetramethylpiperidinyloxy), and
observed significant quenching of the reaction (section 2B
and C, ESI†). Moreover, the pyrimidinyl radical generated
upon HAT can be intercepted as a TEMPO-adduct. The
adduct was easily traced at 464.2616 amu in high-resolution
mass-spectrometry, further providing compelling evidence for
dehydrogenation of
conditions.
4 proceeding under our reaction
Considering the reduced azo functionality as a ligand
arm, we proved earlier that HAT is a facile process.29 In the
case of the oxidative dehydrogenation processes, the utility of
the redox process is dependent on the C–H bond being
Table 3 First-order rate constants and equilibrium constants at different
temperatures for the aromatic dehydrogenation of 4 by 1
Temperature
(°C)
S. No
k (s−1
)
K (M−1
)
1.
2.
3.
70
80
90
1.1 × 10−4
9.1 × 10−4
5.4 × 10−3
253
238
217
Fig.
3 Plot of ln(k/T) against 1/T to determine the activation
parameters for the dehydrogenation of 4.
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the generation of the pyrimidinyl radical upon HAT (Fig. S3,
requirement for HB-based methods poses a significant
ESI†).
This
type
of
radical-mediated
aromatic
challenge to control the stereoselection.9 Thus, the
considerably milder reaction conditions achieved using the
present method can ideally help in further controlling the
stereoselectivity.
dehydrogenation is extremely rare and only has few
precedence in photocatalyzed reactions.43,44 Furthermore, the
dehydrogenation reactions totally circumventing the
formation of metal hydride may possibly make this protocol
tolerant to diversely functionalized N-heterocycles. It is
known that the stability of 3d transition metal-based
hydrides is poor, which affects the reaction conditions in an
adverse way, and thus becomes problematic for sensitive
functionalities.45 Another advantage of our catalyst is the easy
conversion of the hydrazo form to the catalytic resting state,
the azo form, by simple oxidation with O2. During the
catalyst regeneration, H2O2 is formed as a by-product, which
was detected via iodometry. The moderate energy demand for
the crucial HAT step during the dehydrogenation and the
ease of catalyst regeneration via oxidation by O2 make the
reaction conditions milder compared to that in many prior
reports on the transition metal-catalyzed formation of
heterocycles. It is also noteworthy that the dehydrogenation
of the dihydropyrimidine adopting a radical pathway is
completely different from the typical metal–ligand
cooperative bond activation and offers an alternative
desaturation pathway.46–53 Although we did not describe the
mechanistic details for the formation of triazine, a similar
late-stage dehydrogenative aromatization of N-heterocycle is
required (Scheme S1, ESI†), and thus it is anticipated that
the catalyst functions in a similar manner.
Experimental
General information
All reactants employed in this study were procured from
commercial suppliers. Potassium tert-butoxide and potassium
hydroxide were purchased from Sigma Aldrich. Primary
alcohols, secondary alcohols, and amidines were purchased
from Tokyo Chemical Industry (TCI). Glassware was dried
overnight at 160 °C in an oven prior to use for the reactions.
Methanol was used as received. Toluene was dried by heating
over sodium with benzophenone. For thin layer
chromatography (TLC), aluminum foil coated with silica and
fluorescent indicator (from Merck) were used. Column
chromatography was performed using silica gel 60–120 mesh
using ethyl acetate and hexane as the mobile phase. High-
resolution mass spectra were recorded on a Waters QTOF
mass spectrometer. 1H NMR and 13C NMR spectra were
recorded on a 400 MHz Bruker Biospin Advance III FT-NMR
spectrometer. Proton chemical shifts were internally
referenced to the residual proton signal in CDCl3 (δ 7.26
ppm). Carbon chemical shifts were internally referenced to
the deuterated solvent signals in CDCl3 (δ 77.1 ppm).
1,4-Dihyro-2,4,6-triphenyl-pyrimidine (4) was synthesized
according to the reported procedure.55
Conclusion
In summary, the nickel catalyst presented herein can be
employed to easily synthesize triazine and pyrimidine via
dehydrogenative annulation reactions. The reaction
conditions for the synthesis of pyrimidine are fairly mild and
can truly rival the precious metal catalysts employed for this
process. The azo motif in the ligand backbone has a vital role
in the HAT-based oxidation and trapping the borrowed
hydrogen, which obviates the need for a sacrificial acceptor
molecule. Specifically, the easy oxidation of both primary and
secondary alcohols and regeneration of the catalyst by
Synthesis of 1
A methanolic solution of L (0.1 mmol) was placed in a 50 mL
round-bottom flask, KOH (0.1 mmol) was added and the
mixture was stirred for 30 min. Ni(OAc)2 (0.05 mmol) was
added to the reaction mixture and refluxed for another 30
min. The precipitate was filtered. A dark brown product was
obtained in 82% yield.
oxidizing the trapped hydrogen in the form of H2O2 are the General procedure for N-heterocycle
key factors for reducing the reaction time and temperature
formation
1. General procedure for the synthesis of 1,3,5-triazines
considerably.
Furthermore,
the
dehydrogenative
aromatization step, which is often required during the last
phase in the formation of heterocycles, is assisted by the
generation of a radical due to HAT. This study sheds light on
the dehydrogenation of saturated heteroarenes and proves
that the catalyst plays an important role in this specific step
compared to base-promoted dehydrogenation at high
A
5
mL vial was charged with alcohols (0.5 mmol),
4-methylbenzamidine hydrochloride (1 mmol), KOtBu (0.5
mmol), and 1 (5 mol%) in 2 mL toluene. The resulting
solution was kept under a balloon filled with O2. The reaction
mixture was stirred at 80 °C for 8 h. Upon completion, the
reaction mixture was cooled to room temperature and
concentrated in vacuo. The crude mixture was purified by
column chromatography using ethyl acetate/petroleum ether
(15–20%) as the eluent to afford pure products. The desired
product was characterized by 1H and 13C NMR
spectroscopies.
temperature. Our synthetic protocol can also be
a
complementary route to the well-investigated metal–ligand
cooperative bond activation towards dehydrogenation
reactions.2,54 Moreover, there is a strong current interest to
accomplish asymmetric transformations utilizing the HB
methodology. However, the usual high temperature
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2. General procedure for the synthesis of pyrimidine
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A
5 mL vial was charged with alcohols (1 mmol),
1-phenylethanol (1.25 mmol), amidine hydrochloride (1
mmol), KOtBu (0.5 mmol), and 1 (5 mol%) in 2 mL toluene.
The resulting solution was kept under a balloon filled with
O2. The reaction mixture was stirred at 80 °C for 8 h. The
reaction mixture was cooled to room temperature and
concentrated in vacuo. The crude mixture was purified by
column chromatography using ethyl acetate/petroleum ether
(15–20%) as the eluent to afford pure products. The desired
product was characterized by 1H and 13C NMR
spectroscopies.
Conflicts of interest
The authors declare no competing financial interests.
Acknowledgements
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We thank SERB (DST), India (Grant No. ECR/2017/001764) for
financial support and IISER Mohali for start-up funding. The
central facility in IISER Mohali is acknowledged for NMR and
HRMS measurements. AKB thanks IISER Mohali for
a
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