Sustainable iron-catalyzed direct imine formation by acceptorless dehydrogenative coupling of alcohols with amines

Article abstract of DOI:10.1039/c6gc00565a

The Acceptorless Dehydrogenative Coupling (ADC) of alcohols with amines is reported using a heterogeneous Fe-catalyst. The reaction operates under mild conditions with the liberation of dihydrogen and water as the byproducts. The developed ADC strategy is simple, efficient, exhibits wide functional group tolerance and can be scaled up. The present catalytic approach possesses a dual role; acting as a catalyst as well as being magnetically separable. The sustainable reuse of a heterogeneous iron catalyst is also shown.

Full text of DOI:10.1039/c6gc00565a

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Sustainable iron-catalyzed direct imine formation
by acceptorless dehydrogenative coupling of
alcohols with amines†
Cite this: DOI: 10.1039/c6gc00565a
Received 27th February 2016,
Accepted 25th April 2016
Garima Jaiswal,a,c Vinod G. Landge,a,c Dinesh Jagadeesan*b,c and
DOI: 10.1039/c6gc00565a
Ekambaram Balaraman*a,c
www.rsc.org/greenchem
The Acceptorless Dehydrogenative Coupling (ADC) of alcohols dative dehydrogenative coupling accomplished with O2 might
with amines is reported using a heterogeneous Fe-catalyst. The be problematic at higher pressures (need for special high-
reaction operates under mild conditions with the liberation of di- pressure equipment) that are usually used on large scales to
hydrogen and water as the byproducts. The developed ADC strategy increase the effective concentration of the oxidant. Thus, the
is simple, efficient, exhibits wide functional group tolerance and can development of an efficient strategy for the selective construc-
be scaled up. The present catalytic approach possesses a dual role; tion of imine scaffolds under oxidant-free conditions is a key
acting as a catalyst as well as being magnetically separable. The sus- motivation in contemporary science.
tainable reuse of a heterogeneous iron catalyst is also shown.
Recently a direct coupling of alcohols with amines by the
acceptorless dehydrogenative strategy has been developed as
an efficient protocol to construct imine bonds (CvN) with the
liberation of molecular hydrogen and water as the byproducts,
which is a greener and more practical method. Despite several
Introduction
Imines are an exceptionally versatile functional group and are efficient homogeneous catalysts being well-developed for
ubiquitous in pharmaceuticals, biologically active heterocycles, acceptorless dehydrogenation reaction under oxidant-free con-
and natural products.1 Traditionally, imine formation was ditions,9 the major disadvantages such as the use of noble
achieved by the condensation reaction of amines with highly metals, extensive ligand synthesis, sensitivity, handling under
reactive carbonyl compounds and often required dehydrating practical conditions, poor recovery and competing hydrogen
agents as well as Lewis acid catalysts.2,3 However, the direct atom transfer reaction10 (leads to a mixture of amine and
formation of imines with easily accessible feedstock chemicals imine products) remain unaddressed. However, in a very
is very attractive and highly desirable in organic synthesis.4 In recent report by Feringa and co-workers, imine was reported as
this context, various methods for imine synthesis have been the potential intermediate in the homogeneous Fe-catalyzed
studied based on the oxidative dehydrogenation of amines,5,6 direct alkylation of amines with alcohols via hydrogen atom
and oxidative dehydrogenative coupling of alcohols with transfer reaction.11 Indeed, heterogeneous catalysts with such
amines using various oxidants such as dioxygen, TEMPO, activity for the straightforward synthesis of an imine by the
quinine, and iodosylbenzene.7,8 However, several drawbacks oxidant-free, acceptorless dehydrogenative coupling of alco-
remain, for example, the intrinsic self-coupling properties of hols with amines are rare and very limited. Very recently, Pt
the substrates, the formation of other side products such as nanoparticles loaded on TiO2 were shown to promote the
nitrile, amide, azo and a related compound, and the need for a direct synthesis of imines from alcohols and amines under UV
stoichiometric amount of oxidants.6 Although the use of mole- irradiation,12 and Pd(0)-immobilized recyclable hydrotalcite
cular oxygen as a mild oxidant is an attractive strategy, oxi- catalysts (HT4) for alcohol imination via acceptorless dehydro-
genation were also reported.13 Notably, catalysts (both homo-
geneous and heterogeneous) used for imine synthesis by the
ADC strategy are extensively based on precious metals. In this
regard, the development of novel highly active and selective
non-precious metal catalysts; in particular, base metal catalysts
is of pivotal importance and a focus point from the perspective
of cost, abundance, and sustainable chemistry.14,15 To the best
of our knowledge, there are no reusable heterogeneous cata-
lysts based on earth-abundant, economical ‘green’ metals for
aCatalysis Division, Dr. Homi Bhabha Road, CSIR-National Chemical Laboratory
(CSIR-NCL), Pune - 411008, India. E-mail: eb.raman@ncl.res.in,
balaramane2002@yahoo.com
bPhysical and Materials Chemistry Division, Dr. Homi Bhabha Road, CSIR-National
Chemical Laboratory (CSIR-NCL), Pune - 411008, India
cAcademy of Scientific and Innovative Research (AcSIR), New Delhi - 110 025, India
†Electronic supplementary information (ESI) available: Details of experimental
procedure, characterization of the catalyst, compounds and copy of NMR data.
See DOI: 10.1039/c6gc00565a
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direct imine formation by the acceptorless dehydrogenative
coupling of alcohols with amines.
During the last decade, N-doped graphene materials have
been shown to be an interesting commodity for sustainable
catalysis.16 Inspired by these results, herein we report the
preparation of
a heterogeneous iron-based catalyst (Fe–
Phen@C) and describe for the first time the environmentally
benign dehydrogenative coupling of alcohols and amines to
form imines and H2 (Scheme 1).
Fig. 2 (a) Microstructural characterization of the Fe–Phen@C material
TEM image of Fe–Phen@C; scale bar, 50 nm. (b) FESEM image of Fe–
Phen@C; scale bar, 1 µm.
Scheme 1 Overview of the present work and the reusable Fe-based
heterogeneous catalyst used in this study.
one can observe the wrinkles on the thin layers of the RGO
support as dark lines and Fe-rich nanoparticles as dark
spots. It can be observed that the nanoparticles are located
only on the RGO sheets. The nanoparticles distributed
throughout the graphene sheets varied in size from 8 to
50 nm. However, the majority of particles were in the range
of 14–20 nm. The FESEM image in Fig. 2(b) shows the mor-
phology of the as-prepared Fe–Phen@C catalyst. In the dark
field, FE-SEM of Fe–Phen@C was taken using secondary elec-
trons in which the metal which has a high surface electron
density appears brighter than RGO. It can be observed
that Fe-rich particles are distributed spatially apart on the
graphene layers.
Results and discussion
The active heterogeneous iron catalyst was prepared by
the pyrolysis of an in situ generated Fe–Phen complex
(Fe(acac)3 : 1,10-phenanthroline
= 1 : 1) on an exfoliated
graphene oxide support at 800 °C for 4 h under an argon
atmosphere.17,18 The complete characterization of the active
material (Fe–Phen@C) has been carried out using PXRD, TEM
analysis, SEM analysis, XPS, ICP and Raman spectroscopy (see
the ESI† for characterization data).
A recent unprecedented report from our research group on
the heterogeneous iron-catalyzed acceptorless dehydrogena-
tion of fundamentally important feedstocks such as alcohols
to carbonyl compounds and cyclic amines to N-heterocycles17
prompted us to disclose our first report on a simple, efficient,
reusable heterogeneous iron-catalyzed direct imine formation
method by the acceptorless dehydrogenative coupling of alco-
hols with amines (Scheme 1, Table 1). The present ADC strat-
egy has a broad substrate scope as well as functional group
tolerance, and operates under mild conditions with the liber-
ation of hydrogen gas and water as the by-products, thus
making the protocol completely environmentally-benign. An
ease of separation and reusability of the heterogeneous iron
catalyst is also successfully demonstrated.
The XRD pattern of the Fe–Phen@C sample presented in
Fig. 1 shows diffraction peaks confirming the presence of
β″-Fe2O3 (JCPDS no 40-1139), Fe3O4 (JCPDS no 85-1436), Fe3N
(JCPDS no 01-1236), Fe3C (JCPDS no 85-1317) and Fe7C3
(JCPDS no 17-0333). The formation of Fe3N was probably due
to the decomposition of the N-containing Fe–phenanthroline
complex on exfoliated graphene oxide (EGO). A peak at 2θ =
26.6 degrees corresponding to the (002) lattice plane of
reduced graphite oxide (RGO) was also observed. The peak is
broad suggesting that the carbon support was composed of a
few layers of graphene sheets. In Fig. 2(a) the TEM image of
the Fe–Phen@C sample is shown. In the bright field image,
Optimization studies on iron-catalyzed direct imine for-
mation by the ADC of alcohols with amines are summarized in
Table 1. We began our investigation using (4-chlorophenyl)
methanol (1a) and m-toluidine (2a) as benchmark substrates
in the presence of a catalytic amount of Fe–Phen@C (8 mol%),
and t-BuOK (10 mol%) in n-octane heated at 120 °C (bath
temperature) under an open Ar atm for 24 h to yield 3aa in
93% isolated yield with the complete conversion of 1a
(Table 1, entry 1). Indeed, the formation of molecular hydro-
gen was qualitatively analyzed by gas chromatography (GC).
Performing the reaction under closed conditions yielded 3aa
in lower yield (40%) (Table 1, entry 2) clearly indicating that
the constant removal of H2 gas from the reaction medium
is crucial.9,10,19 Notably, the efficiency of the reaction was
Fig. 1 XRD spectra of the Fe–Phen@C material with indices of peaks
with the pattern of β’’-Fe2O3, Fe3O4, Fe7C3, Fe3N, Fe3C, and graphite.
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Table 1 Optimization of the reaction conditionsa
Conversion
Yield of
Entry
Cat.
Variation from the initial conditions
of 1a b (%)
3aa b (%)
1
2
3
4
5
6
7
8
Fe–Phen@C
Fe–Phen@C
Fe–Phen@C
Fe–Phen@C
Fe–Phen@C
Fe–Phen@C
Fe–Phen@C
Fe–Phen@C
Fe@C
None
Closed system
99
57
17
35
8
19
64
40
5
97(93)c
40c
8
Without t-BuOK
K2CO3instead of t-BuOK
KOH instead of t-BuOK
CH3CN instead of n-octane
Toluene instead of n-octane
At 80 °C
19
0
15
46
34c,d
0
9
None
10
11
12e
13e
14
15
16
Phen@C
—
None
0
0
8
0
0
Without Fe–Phen@C
Under homogeneous conditions
Under homogeneous conditions
None
None
None
Fe(acac)3/Phen
Fe(CO)5/Phen
Fe–Phen@SiO2
Fe–Phen@Al2O3
Fe–Phen@TiO2
Trace
0
Trace
31
17
46
18
8
31c
a Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), cat. Fe–Phen@C (8 mol%), t-BuOK (10 mol%), and n-octane (2 mL) heated at 120 °C (oil-
bath temperature) for 24 h under an open argon atm. b Conversion of 1a and yield of 3aa are based on GC using anisole as the internal reference.
c Isolated yields. d After 48 h. e Reaction under homogeneous conditions using the in situ generated Fe-catalyst by reacting a 1 : 1 mixture of Fe
salt and 1,10-phenanthroline (Phen) followed by treatment with t-BuOK (10 mol%).
significantly affected in the absence of t-BuOK (Table 1, entry 3). ingly, the reaction proceeded successfully with both cyclic and
Other bases like K2CO3 and KOH are ineffective under stan- acyclic secondary amines and gave the desired imines 3an
dard reaction conditions (Table 1, entries 4 and 5).20,21 The (81%), 3ao (74%), 3ap (73%), and 3aq (62%) in good yields. It
solvent dependency of the same reaction was carried out was noteworthy that benzylamine (2r) also afforded the corres-
(Table 1, entries 1, 6 and 7) and we found that the reaction pro- ponding imine in moderate yield (40%), along with the for-
ceeds efficiently in n-octane as compared to other solvents.22 mation of (E)-N-benzyl-1-phenylmethanimine (26% by GC) by
By lowering the temperature, we obtained the product in lower the dehydrogenative self-coupling of 2r. The reaction of
yield (Table 1, entry 8) and no reaction was observed in the benzene-1,3-diamine (2s) and 1a selectively gave the corres-
absence of the Fe–Phen@C catalyst (Table 1, entry 11). ponding diimine (3as) in 75% isolated yield under our catalytic
Notably, no imine formation or hydrogen gas was observed conditions.
under homogeneous conditions (Table 1, entries 12 and 13).23
Next, the impact of varying the substituents on the alcohol
It is worth noting that under similar experimental conditions, coupling partner was also assessed (Table 3). The straight-
catalysts (Fe–Phen) prepared on other conventional supports forward imine formation reaction proceeded in excellent yields
such as SiO2, Al2O3 and TiO2 showed lesser activity in the with either electron donating (4-methyl, 4-methoxy) or electron
imine formation (Table 1, entries 14–16).18,24 These studies withdrawing (4-fluoro, 4-nitro) substituents on the benzyl
show that the special structure of reduced graphene oxide alcohol. Notably, ortho-substituted alcohols yielded the imines
(RGO) may affect the reactivity in the environmentally-benign (3bi and 3bj) in lower yields, which could be explained by
dehydrogenative coupling of alcohols and amines to form steric effects.25 To our delight, biomass-derived furfuryl
imines and H2.
alcohol also gave the corresponding imine in good yield (3bk
With an optimized catalytic system in hand (Table 1), we in 76% yield). The less reactive cinnamyl alcohol was also
set out to probe its versatility in the direct imine synthesis of tested for the direct imine formation reaction and efficiently
various alcohols and amines by the ADC strategy. Using gave the corresponding imine in 45% isolated yield with 66%
(4-chlorophenyl)methanol 1a as the benchmark substrate, a selectivity. However, 1-hexanol failed to convert into the corres-
number of different anilines were tested using the Fe–Phen@C ponding aliphatic imine (3bm) under optimized conditions.
catalyst under standard conditions. As shown in Table 2, the
Gram-scale synthesis
present heterogeneous Fe-catalysis is compatible with various
anilines containing electron-rich and electron-deficient substi- We have successfully shown the scalability and particle viabi-
tuents, affording the desired imines in good to excellent yields lity of this catalytic protocol under standard conditions. In this
(up to 95%) under very mild, eco-benign conditions. Interest- regard, the present iron-catalyzed direct imine synthesis was
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Table 2 Iron-catalyzed direct imine synthesis: scope of aminesa,b
Table 3 Iron-catalyzed direct imine synthesis: scope of alcoholsa,b
a Reaction conditions: 1 (0.5 mmol), 2a (0.55 mmol), cat. Fe–Phen@C
(8 mol%), t-BuOK (10 mol%), and n-octane (2 mL) heated at 120 °C
(oil-bath temperature) for 24 h under an open argon atm. b Yields in
parentheses are based on the conversion of alcohol and selectivity of
3 respectively and are based on GC using anisole as the internal
reference. c Isolated yields. d Based on 1H NMR of the crude reaction
mixture.
a Reaction conditions: 1a (0.5 mmol), 2a (0.55 mmol), cat. Fe–Phen@C
(8 mol%), t-BuOK (10 mol%), and n-octane (2 mL) heated at 120 °C
(oil-bath temperature) for 24 h under an open argon atm. b Yields in
parentheses are based on the conversion of 1a and selectivity of
imines (3) respectively and are based on GC using anisole as the
internal reference. c Isolated yields. d Self-dehydrogenative coupling of
benzylamine to (E)-N-benzyl-1-phenylmethanimine was observed as
the side reaction. e 2 equiv. of 1a.
Scheme 2 Gram-scale synthesis of imine (3aa).
tested for the gram-scale synthesis of 3aa, and it worked excel-
lently with the expected imine obtained in 78% isolated yield
after 36 h (Scheme 2). The result implies that the hetero-
geneous Fe-based catalytic system has a potential in the large-
scale production of imines under operationally simple, environ-
mentally benign conditions.
Time-dependent experiments on direct imine formation by
the ADC of alcohols with amines were conducted using a
heterogeneous iron-catalyst to study the reaction kinetics
(Fig. 3). Continuous sampling was undertaken with different
time intervals, and the conversion of alcohol (1a) and yield of
imine (3aa) were determined by gas chromatography. The for-
mation of an aldehyde intermediate was observed during the
reaction pathway, along with the desired imine as the major
product.
Fig. 3 Reaction profile for the iron-catalyzed formation of 3aa. Reac-
tion conditions: 1a (0.5 mmol), 2a (0.55 mmol), cat. Fe–Phen@C (8 mol%),
t-BuOK (10 mol%), and n-octane (2 mL) heated at 120 °C (oil-bath
temperature) under an open argon atm.
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Reusability and heterogeneity
The significant advantage of heterogeneous catalysts over
soluble homogeneous catalysts is their capability for easy sep-
aration and recycling. The iron catalyst was easily separated
from the reaction medium under a strong magnetic field,
as shown in Fig. 4a & b. The recovered heterogeneous
Fe–Phen@C was reused for direct imine synthesis in at least
six cycles without a considerable loss in the yield (Fig. 4c).18
The results were within the error limits, and indeed, no de-
activation of the catalyst was observed. The hot filtration test
was carried out, and it was observed that no further imine for-
mation (3aa) took place after the catalyst was filtered off at the
conversion of 1a in 67% yield. Inductively coupled plasma
(ICP) analysis confirmed that the iron concentration in the fil-
trate was less than 0.22 ppm. Notably, no imine formation was
observed in the reaction under complete homogeneous con-
ditions (Table 1, entries 12 and 13).23 All these results clearly
demonstrate that the present Fe-catalysis is truly hetero-
geneous in nature.
Scheme 3 Mechanistic studies.
Mechanistic study
effect of the catalyst in the consequent condensation step. It
was clearly observed that the rate of condensation of aldehydes
and amines was accelerated in the presence of the Fe–Phen@C
catalyst, which implies the presence of Lewis acid sites on the
catalyst.
To determine if any radical intermediates (e.g. superoxide
radical anion, O•−2; due to the presence of residual oxygen/air
or use of t-BuOK) were involved in the reaction, we performed
the reaction in the presence of a radical scavenger (2,6-di-tert-
butyl-4-methylphenol). The scavenger had no effect on the
reaction rate in the formation of 3aa, and thus the effect of
residual oxygen or air as an oxidant, and the involvement of
a radical mechanism can be completely ruled out.26 Indeed,
t-BuOK is required to activate alcohols for the initial dehydro-
The high activity and selectivity of the Fe-catalyst in the direct
imine formation by the acceptorless dehydrogenative coupling
of alcohols with amines motivated us to gain an insight into
the mechanistic details (Scheme 3). In this regard, we per-
formed the acceptorless dehydrogenation of alcohol, 1a (in the
absence of amine) under identical conditions, and a quantitat-
ive yield of the corresponding aldehyde was obtained after
24 h with the liberation of hydrogen gas.17 The formation of
H2 gas in the Fe–Phen@C catalyzed direct synthesis of imines
from alcohols and amines was qualitatively observed on gas
chromatography. We have also endeavored to investigate the
genation reaction.
A deuterium labeling experiment un-
ambiguously illustrated that the initial alcohol dehydrogenation
step is irreversible. Thus, upon treatment of a 1 : 1 mixture of
4-methylbenzyl alcohol and α,α-d2-(4-chlorophenyl)methanol
with m-toluidine 2a (1.1 equiv.) at 120 °C in n-octane for 22 h
with a catalytic amount of Fe–Phen@C catalyst (8 mol%) and
t-BuOK (10 mol%), 69% of (E)-1-(4-chlorophenyl)-N-(m-tolyl)
methanimine-d (3aa-d) and 37% of (E)-N-m-tolyl-1-(p-tolyl)
methanimine (3bd) were obtained as reaction products
(Scheme 3d). H/D scrambling was not detected in both of the
imine products, suggesting that the initial alcohol dehydro-
genation step is irreversible.
Conclusions
In summary, a more sustainable iron-catalyzed direct imine
formation by the acceptorless dehydrogenative coupling of
alcohols with amines under oxidant-free conditions is reported
for the first time. The reaction operates under very mild and
environmentally benign conditions with the liberation of
Fig. 4 Separation of the catalyst under a strong magnetic field ((a):
reaction mixture; (b): under magnetic field). (c) Recovery and reuse of
the Fe–Phen@C catalyst.
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dihydrogen and water as the byproducts. The present catalytic
approach possesses a dual role; acting as a catalyst as well as
being magnetically separable. The recyclability experiments
showed that the catalytic activity for imination can be retained
for at least six cycles. The present strategy has great potential
for the straightforward synthesis of imines from feedstock
chemicals because it tolerates a wide range of substrates with
high yields. Mechanistic studies showed that the reaction pro-
ceeds in a tandem manner (via aldehyde formation), and deu-
terium labeling experiments unambiguously illustrated that
the initial alcohol dehydrogenation step is irreversible.
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Acknowledgements
This research is supported by the SERB (SB/FT/CS-065/2013)
and EMR/2015/30 (under Green Chemistry program) and
CSIR-NCL. GJ thanks UGC and VGL thanks CSIR for fellow-
ships and DJ acknowledges the financial support of
DST-Ramanujan Fellowship (RJN-112/2012) and BRNS (37(2)
14/21/2015/BRNS). We thank Dr P. R. Rajamohanan for the
NMR facility and Dr S. P. Borikar for GC-MS analysis. EB
thanks Dr Abhishek Dey, IACS, Kolkata for providing Fe(CO)5.
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