Ru-g-C3N4as a highly active heterogeneous catalyst for transfer hydrogenation of α-keto amide into β-aminol or α-hydroxyl amide

Article abstract of DOI:10.1039/d0nj01674h

This work reports a sustainable route for the catalytic transfer hydrogenation (CTH) of α-keto amide into β-aminol via an efficient heterogeneous catalyst wherein ruthenium is incorporated on an active graphite sheet of a carbon nitride support (Ru-g-C3N4). Other different metals like Ni or Pd were also screened with the same support but none of them showed efficient activity. Although, partial hydrogenation of ketone to alcohol has also been observed based on the optimization of the reaction parameters using all of the above catalysts. The catalyst has been characterized using field emission gun scanning electron microscopy (FEG-SEM), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), infra-red (IR) spectroscopy and thermogravimetric analysis (TGA). Furthermore, the catalyst has been recycled and further characterized and does not show any significant changes in its reactivity for the CTH process. Ru-g-C3N4 as a recyclable heterogenous catalyst has been used for the first time for the CTH of α-keto amide into β-aminol, making the process sustainable because economical and environmentally benign isopropyl alcohol is used as a solvent system. The proposed catalytic system shows a wide scope of substrates for α-hydroxyamide and β-aminol derivatives, which were confirmed from 1H and 13C-NMR. This journal is

Full text of DOI:10.1039/d0nj01674h

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Ru–g-C3N4 as highly active heterogeneous catalyst for transfer
hydrogenation of α–keto amide into β–aminol or α–hydroxyl
amide
Received 00th January 20xx,
Accepted 00th January 20xx
Ashish A. Mishra a, Shivkumar R. Chaurasia a and Prof. Bhalchandra M. Bhanage*a
DOI: 10.1039/x0xx00000x
This work reports a sustainable route for the catalytic transfer hydrogenation (CTH) of α–keto amide into β–aminol via an
efficient heterogeneous catalyst wherein ruthenium incorporated on active graphite sheet of carbon nitride support (Ru-g-
C3N4). Different other metal like Ni and Pd also has been screened with same support but none of them shows efficient
activity. Although partial hydrogenation of ketone to alcohol also have been observed based on optimization of reaction
parameter using all the above catalyst. Catalyst has been characterized using field emission gun scanning electron
microscopy (FEG-SEM), X-Ray diffraction (XRD), X-Ray Photoelectron Spectroscopy (XPS), Infra-Red (IR) Spectroscopy and
Thermogravimetric analysis (TGA). Furthermore, catalyst has been recycled and it is further characterized which doesn’t
show any significant changes in its reactivity for CTH process. Ru-g-C3N4 as a recyclable heterogenous catalyst has been used
first time for CTH of α–keto amide into β–aminol making the process sustainable because of economical and environmentally
benign isopropyl alcohol as a solvent system. Proposed catalytic system shows wide range of substrate scope for α-
hydroxyamide and β–aminol derivatives which are confirmed from 1H & 13C-NMR.
work-up issue. Recently Wu and co-workers showed some
interesting results for the synthesis of α–hydroxyl amide by the
use of NaOH, DMF (dimethyl formamide) in H2O under argon
Introduction
β–aminol and α–hydroxyl amide, are very important moieties
which are used in pharma industry, as it has reactive centre and
versatile intermediates for the synthesis of natural originated
biological active compounds.[1] β–aminol shows high activity as
β-blockers, chiral axillaries and also act as insecticidal agents. [2]
Similarly α–hydroxyl amide behaves as ligands and shows
several biological activities like anticonvulsant action,
antimycobacterial and in antibacterial drugs.[3] Synthesis of
both the products can be achieved by chemo-selective
reduction or hydrogenation of α–keto amide, but complete
reduction or hydrogenation of ketone as well as amide in α–
keto amide is quite difficult. Govindsamy and co-workers
reported the selective reduction of α–keto amide into α–
hydroxyl amide using Pd metals in presence of silane as
reducing agent, dissolved in THF solvent[4a]. Same group also
reported the use of K3PO4 as catalyst in silane dissolved in 1,4-
dioxane solvent[4b] even with Cs2CO3 as catalyst in presence of
silane as reducing agent in presence of solvent 2-MeTHF[4c] for
the synthesis of α–hydroxyl amide. However, all these systems
involve hazardous, non-recyclable inorganic bases and catalyst,
along with use of silane, all the mentioned protocol limits with
o
pressure at 120 C.[4d] However they are unable to prepare β–
aminol by the same protocol. Selective hydrogenation or
reduction of α–keto amide into α–hydroxyl amide has been
reported by our group by both reduction using NS-Ceria (Nano
Sphere) catalyst and by the use of UiO-66 catalyst wherein
catalytic transfer hydrogenation process has been achieved.[5]
Govindsamy and co-workers showed progress in β–aminol
synthesis from α–keto amide by the use of Ni metal with KOtBu
base[6a] or TBAF (Tetrabutylammonium fluoride)[6b] as catalyst
in silane as reducing agent dissolved in THF (Tetrahydrofuran)
solvent. However, protocol demands base additives or the use
of fluorinated hydro-silylation which limits it scope. The
reduction of secondary amides is quite difficult [7] and therefore
apart from less expensive, non-toxic metal based supported
catalyst which can be recycled, are current requirement for
industrial and academic research. Encouraged by our lab work
in the field of transfer hydrogenation reaction,[8] herein we
report the use of Ru-g-C3N4 as a heterogeneous catalyst for
complete transfer hydrogenation of α–keto amide into β–
aminol for the first time. The advantage of the catalyst is that it
can be modulated to show selective partial transfer
hydrogenation into α–hydroxyl amide in presence of
inexpensive and eco-friendly solvent IPA (isopropyl alcohol)
which also acts as supporting hydrogen source or for complete
transfer hydrogenation of α–keto amide wherein addition of
FA:TEA (5:4) [Formic acid: Tri-ethylamine; F/T] as hydrogen
donor along with above solvent IPA used, for synthesis of
desired compound β–aminol, within a short period of time at 80
a.
Ashish A. Mishra, Shivkumar R. Chaurasia, Prof. Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology,
Nathalal Parekh Marg, Matunga, Mumbai 400019, India;
Fax: (+91)-22-24145614; phone:(+91)-22-3361-1111/2222
E-mail: bm.bhanage@gmail.com ; bm.bhanage@ictmumbai.edu.in
†Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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oC. Although as per literature transfer hydrogenation of hydrogenation. Heterogenous Ru-g-C3N4 catalyst was
carbonyl require very high temperature or presence of base or synthesized by ultrasonic deposition method. In this method
View Article Online
DOI: 10.1039/D0NJ01674H
long duration however these problems can be overcome using 500 mg of yellow g-C3N4 (synthesized by pyrolytic method)
Ru-g-C3N4 as heterogeneous catalyst. Now in the mentioned dispersed in 60 ml of H2O which is then ultrasonicated for 2 h
catalyst, graphitic-C3N4 is chemically inert in nature both in after which, 12 mg of RuCl3 is further added, followed by
acidic and basic condition, and it is photo-catalytically highly ultrasonication for another 30 min. Then 10 ml of NaBH4
active for organic transformations [9] because of its visible light solution was added with continuous stirring which result into
storage energy along with band gap of ~ 2.7 eV which shows its grey-blue product which was then filtered and washed several
semiconductor properties with absorption wavelength at 460 times with water and ethanol. After washing it was dried at
nm. [10] Typically g-C3N4 is primarily used as support for catalytic 60oC. The weight of Ru-g-C3N4 obtained was 480 mg considering
hydrogenation and oxidation reaction. Many groups started the handling loss (†See ESI). Prepared Ru-g-C3N4 was well
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doping of different metal like Pd, Pt, Cu, Ni, etc. on the surface characterized by various characterization techniques.
[11]
g-C3N4 to enhances their catalytic activity.
Pt metal initially
a) Powder X-Ray Diffraction
used which enormously boost hydrogen evolution from g-C3N4. Typical X-Ray Diffraction (XRD) pattern of a) g-C3N4 and b) Ru-g-
[12a]
Similarly Ge et. al. reported Ag catalyst which increases C3N4 observed in Fig. 1 which clearly indicates peak (2θ value)
hydrogen evolution by twelve times over g-C3N4 due to the at 13.38o and 27.18o. These peaks are well recorded and are in
synergic effect of Ag metal with g-C3N4.
[12b]
[14a]
Similarly Mo also proper pattern as per reported procedure
which
evolve hydrogen eleven times higher than g-C3N4 because of corresponds to (100) and (002) diffraction planes of graphitic g-
[12c]
matching energy.
However Yu et. al. reported hydrogen C3N4 materials, respectively. In both the XRD-pattern, (002)
evolution with 0.5 mol% Ni metal [12d] as Ni(OH)2 at a rate of 7.6 plane which corresponds to 2θ value 27.18o is more intense as
μmol/h which can be equal to hydrogen evolved with 1.0 wt% compare to other reflection. This peak corresponds to stacking
[12e]
Pt-g-C3N4.
Based on the previous work on the use of Ru- of conjugated aromatic system. [14] The absence of peak related
metal for hydrogenation of carbonyl group, [5c, 8] Ru, Pd and Ni to Ru is due to lower loading of Ru with uniform distribution of
metal doped on the g-C3N4 were prepared for catalytic transfer
hydrogenation of α–ketoamide. From the above data even,
addition of metal enhances activity of catalyst which boost the
hydrogen production. Catalytic screening study shows that
metal doped C3N4 shows the higher rate of hydrogen evolution
than undoped C3N4. In same context we focused to establish a
network on the catalytic performance of Ru-g-C3N4 for the
parallel synthesis of β–aminol and α–hydroxyl amide at
different conditions based on thermal activity of catalyst.
Herein we report Ru-g-C3N4 as thermally most stable and active
catalyst as compared to Ni and Pd supported on g-C3N4 for
complete transfer hydrogenation of α–ketoamide into β–
aminol and partial transfer hydrogenation into α–hydroxyl
amide in presence of economical and environmentally benign
isopropyl alcohol as a solvent.
Previous Work:
Homogeneous Catalytic hydrosilylation, Fluorinated hydrosilylation
OH
O
H
Ni(OAc)2, TMEDA, THF
Ph2SiH2, KOtBu, RT, 12h
Figure 1: XRD pattern of a) g-C3N4 and b) Ru-g-C3N4
H
N
N
the surface of C3N4. Similarly, for Pd-g-C3N4 and for Ni-g-C3N4
material, XRD pattern has been recorded (†Fig. S4 in ESI) which
resembles g-C3N4 indicating retention of conjugated aromatic
system.
O
TBAF, THF, Ph2SiH2
RT, (4-7) h
Sekar et al.
This Work:
Heterogenous Catalytic transfer hydrogenation
OH
H
N
g-C3N
4 , IPA
Ru
b) FEG-SEM and Elemental Mapping using EDX
O
80oC, 8 h
FA:TEA,
(5:4)
H
N
OH
O
H
N
g-C3N
4 , IPA
Ru
50 oC, 3 h
O
Scheme 1: Catalytic Transfer Hydrogenation of α–keto amide into β–aminol & α–
hydroxyl amide
Results and discussion
Graphitic support C3N4 is prepared by known procedure
reported somewhere else.[13] Different metals like Ru, Cu, Ni
and Pd are doped into it to study their effect for transfer
Figure 2: SEM images of catalyst A) and B) Ru-g-C3N4
2 | J. Name., 2012, 00, 1-3
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Synthesized ruthenium loaded g-C3N4 materials i.e.; Ru-g-C3N4
ARTICLE
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oxide species which can also be confirmed by peakVoiebwsAertricvleeOdnflioner
are characterized by FEG-SEM analysis. Visualization of SEM O 1s spectrum at 531.9 eV. (†Fig. S2) [15b]
DOI: 10.1039/D0NJ01674H
analysis shows sheet like aggregation morphology of C3N4 with
d) AT-IR Spectroscopy and TGA of Catalyst
5
aggregation of sheets of g-C3N4 at several places as visualized in Characterization of synthesized material g-C3N4 and Ru-g-C3N4
(†Fig. S1 in ESI) whereas Fig. 2 and †Fig S1 (D, E, F) clearly has also been done by AT-IR spectroscopy to affirm the
represent images for Ru-g-C3N4 material, shows smaller unit of functional groups. As visualized in Fig. 5A, broad bands at
agglomeration of g-C3N4 where several very small Ru-NP’s around 3165 cm-1 indicates presence of N–H stretching
dispersed on the surface of g-C3N4. Enlarge portion of figure vibrations. Some intense band are also observed at around 1610
shows a uniform distribution of Ru nanoparticle over the cm-1 which confirm the presence of C=N stretching vibration,
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surface of g-C3N4 layer. Moreover, elemental mapping (Fig. 3)
whereas absorption at 1240 cm-1 confirm presence of C–N
stretching vibrations. Apart from it, in addition sharp band also
observed at 810 cm-1 which reflects characteristic breathing
mode of triazine units which is related to s-triazine ring
absorption band vibration. Intense band at 1560 cm-1 and 1409
cm-1 are also observed which signifies typical stretching
vibration modes of triazine derived repeating units. Fig. 5A
clearly reflects parallel bands for both synthesized material g-
C3N4 and Ru-g-C3N4 which indicates preservation of all modes of
vibration after doping of ruthenium metal on g-C3N4 without
changing its molecular structure. Apart from it AT-IR for Ni-g-
C3N4 and Pd-g-C3N4 has also been recorded which shows same
peak in comparison to Ru-g-C3N4 material as observed in †Fig.
S6. This confirm presence of all functional group stretching
characteristic vibration in characterized catalyst. In fact, mostly
all the metal loaded peak shows similarity to g-C3N4. However
little shifting for characteristic peak of triazine units has been
observed around (790-820) cm-1 which may be because of
different metal loaded into it. After understanding comparative
AT-IR spectra for the synthesized catalyst, stability of prepared
heterogenous catalyst with g-C3N4 support has been checked.
The stability of synthesized materials was measured by using
TGA technique. Samples were heated from room temperature
to 900 °C at a rate of 10 °C min−1 under nitrogen atmosphere,
and the TGA curves are shown in Fig. 5B which shows the
fluctuation for Ru-g-C3N4. From graph it is cleared that catalyst
Figure 3: Elemental mapping of catalyst Ru-g-C3N4: A) Carbon B) Ruthenium C) Oxygen
and D) Nitrogen
Using Energy-Dispersive X-ray spectroscopy (EDX) (†Fig. S3 in
ESI) also confirms uniform loading of ruthenium metal on g-C3N4
materials by showing uniform distribution of carbon, nitrogen
and ruthenium nanoparticle in the material.
c) X-Ray Photoelectron Spectroscopy
Furthermore, to determine the electronic state of the Ru
element in Ru-g-C3N4 material, XPS spectroscopy technique has
been employed (†Fig. S2 in ESI). XPS analysis was done with a
PHI 5500 multi-technique system using a standard Al X- ray
o
decomposition starts at 348 C and it completely ends near to
o
435 C with residual weight fraction of ~ 5.65% which may be
because of formation of oxides of ruthenium metal. Similarly,
other catalyst like Ni-g-C3N4 and Pd-g-C3N4 has been prepared
and are characterized. It makes clear that Ru-g-C3N4 starts
decomposition at lower temperature than other metal on the
Figure 4: XPS spectra: a) Ru 3d region of Ru-g-C3N4; b) Ru 3p region of Ru-g-C3N4
source. XPS analysis makes easy way to determine the chemical
environment and formal oxidation state of all elements like
incorporation of ruthenium metal over g-C3N4 material has
been studied. From †Fig S2, it is easily visible that C 1s spectrum
shows two characteristic peak components at 284.8 eV
(represent C-C) and 287.9 eV (represent N=C–N). [9d] In Fig. 4, Ru
3d spectra peak observed at 278.7 eV and 282.6 eV represents
metallic Ru phase, which is overlapping with the characteristic
peak of C 1s spectrum (as observed in †Fig. S2 full scan of Ru-g-
C3N4 catalyst). Apart from this, peak at 398.9 eV indicates
presence of sp2 hybridized nitrogen (C=N–C) present in
pyridine-N species which is observed in N 1s spectrum
respectively. Along with that one major peak also observed at
Figure 5: A) AT-IR spectra of g-C3N4 and Ru-g-C3N4; b) TGA Graph of catalyst Ru-g-C3N4
same support. Ni on g-C3N4 shows decomposition at 398 oC and
ends at 525 oC apart from it Pd on g-C3N4 shows decomposition
o
o
at 496 C and ends at 640 C. However, when TGA for plain g-
C3N4 has been processed, it shows decomposition at 525 oC and
464.5 eV in Ru 3p XPS spectra with another peak observed at
[15a]
485.3 eV.
(Fig. 4) These peaks correspond to ruthenium
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o
ends at 685 C reflecting that when metal loaded on g-C3N4 it
Table 1: Optimisation of Ru-catalysed transfer hydrogenation of α-ketoamide into β-
aminol and α-hydroxyl amide
View Article Online
DOI: 10.1039/D0NJ01674H
enhances its reactivity. (†Fig. S7)
With all characterized data in hand,
OH
OH
O
H
H
H
N
N
N
catalyst has been used for
application process in synthetic
chemistry. Based on the literature
study of catalyst for the use in
hydrogenation process, we tried to
implement the same process on our
previous model substrate 2-oxo-N-2-
diphenylacetamide to understand
catalyst effect as compare to other
catalyst used so far. Our initial step
commenced with the use of series of
same family of heterogenous catalyst
g-C3N4, with different metal loading
such as Ru, Ni and Pd. From the Table
1 it is quite clear that Ru metal shows
better activity for hydrogenation
over other metal for conversion of α-
ketoamide into β-aminol, whereas Ni
shows predominantly synthesis of
55% of α-hydroxyl amide along with
35% of β-aminol similarly, Pd shows
65% of α-hydroxyl amide and 20% of
β-aminol respectively (Table 1, Entry
1-4). However, RuCl3 and Cu(OAc)2
shows only formation of α-hydroxyl
amide about 30% and 57% yield
(Table 1, Entry 5-6). Although
absence of catalyst doesn’t favour
progress of reaction which confirms
the importance of catalyst for
g-C3N4
Ru
+
O
O
Conditions
2a
2aa
Yieldd in %
1a
Entry Catalyst
No.
Catalyst
loading
Hydrogen
source
Solvent
Time
in h
Temp
in oC
Conv
in %
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
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48
49
50
51
52
53
54
55
56
57
58
59
60
2a
-
2aa
-
1
g-C3N4
20 mg
FA: TEAa (5:2)
FA: TEAa (5:2)
FA: TEAa (5:2)
FA: TEAa (5:2)
FA: TEAa (5:2)
FA: TEAa (5:2)
FA: TEAa (5:2)
FA: TEAa (5:2)
FA: TEAa (5:2)
FA: TEAa (5:2)
IPA
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
12
8
80
80
80
80
80
80
80
50
80
80
80
80
80
80
80
80
80
80
80
80
80
60
RT
100
80
80
50
80
50
-
2
Ru-g-C3N4 50 mg
Ni-g-C3N4 50 mg
Pd-g-C3N4 50 mg
RuCl3 40 mg
Cu (OAc)2 36 mg
IPA
-
86
35
20
-
100
100
100
40
3
IPA
55
65
30
57
-
4
IPA
5
IPA
6
IPA
-
80
7
-
-
IPA
-
20
8
Ru-g-C3N4 50 mg
Ru-g-C3N4 50 mg
Ru-g-C3N4 50 mg
Ru-g-C3N4 50 mg
Ru-g-C3N4 50 mg
Ru-g-C3N4 50 mg
Ru-g-C3N4 50 mg
Ru-g-C3N4 50 mg
Ru-g-C3N4 40 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 20 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
Ru-g-C3N4 30 mg
DCM
EtOH
MeOH
55
25
45
97
59
82
63
-
18
-
100
30
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
-
80
IPA
-
100
75
HCOONaa
IPA
-
b
NaBH4
MeOH
-
95
IPA: H2O (1:1)
-
90
FA: TEAa (5:4)
FA: TEAa (5:4)
FA: TEAa (5:4)
FA: TEAa (5:4)
FA: TEAa (5:4)
FA: TEAa (5:4)
FA: TEAa (5:4)
FA: TEAa (5:4)
FA: TEAa (5:4)
FA: TEAa (5:4)
IPA
IPA
IPA
IPA
IPA
IPA
IPA
IPA
IPA
IPA
98
98
98
82
97
97
68
62
15
98
-
100
100
100
100
100
100
100
100
100
100
100
100
100
100
90
-
hydrogenation process. (Table
1
-
entry 7) From these data it can be
predicted that Ru in (+3) oxidation
state can’t satisfy for complete
hydrogenation rather only allow CTH
of α-ketoamide into α-hydroxyl
amide to some extent whereas when
it is loaded in (0) oxidation state on g-
C3N4 support, it can show complete
hydrogenation reaction into β-
aminol. It indicates Ru in 0 oxidation
state shows better activity for
hydrogenation as compared to Ru in
its +3-oxidation state. Henceforth
solvent study was screened where
DCM solvent shows 55% yield of α-
hydroxyl amide along with 18% of β-
aminol (Table 1 entry 8) whereas
increasing the polarity of solvent to
EtOH and MeOH doesn’t favour β-
aminol synthesis but it shows only
-
-
-
6
20
11
56
-
8
8
8
IPA
5
98
98
97
97
25
IPA
IPA
3
-
3
-
IPA (10 ml)
FA: TEAc (5:4)
8
-
DCM
8
54
Conditions: 1 mmol of compound 1a dissolved in 5 ml solvent, along with
a
b
mentioned catalyst. 0.2 ml of FA: TEA (5:2) / (5:4) in IPA solvent; 1 mmol of
formation of α-hydroxyl amide (Table 1 entry 9-10). After that,
hydrogen source has been screened out and it has been
observed that solvent IPA alone which can show dual role both
c
NaBH4 in 5 ml of MeOH solvent and 1 ml of FA: TEA (5:4) taken in 5 ml of DCM
solvent; d Isolated yield based on GC-MS analysis.
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as solvent and hydrogen source deliver 97% yield of α-hydroxyl of β-aminol to 62% which further decreased to 35% when
View Article Online
amide (Table 1 entry 11) whereas using HCOONa decreased the temperature reduced to RT (29 oC). HoweDvOerI:s1a0m.10e39te/Dm0pNeJ0ra16t7u4rHe
yield of α-hydroxyl amide to 59% (Table 1 entry 12). increases the yield of α-hydroxyl amide to 56% and when
Nonetheless, using NaBH4 in MeOH solvent increased the yield temperature increased to 100 oC it shows 98% of β-aminol but
to 82% (Table 1 entry 13). Further to make the process more no α-hydroxyl amide. From observed data it can be confirmed
sustainable IPA: H2O were used in ration of (1:1) however 63% that at higher temperature and at moderate basic condition β-
yield of α-hydroxyl amide was observed (Table 1 entry 14). aminol is favoured and lower temperature favours α-hydroxyl
Further FA: TEA in ration of (5:4) were used which shows amide synthesis. Henceforth encouraged with result observed
surprisingly dominancy for the desired product β-aminol as in entry 11, synthesis of α-hydroxyl amide also has been
compare to other the hydrogen source. Comparing with FA: TEA screened, where solvent IPA shows dual role (also as hydrogen
in ratio of (5:2) (which shows 86% yield of β-aminol) (Table 1 source) producing 97% yield of above said product. Further
entry 2), (5:4) ratio of FA: TEA, increased the yield to 98% (Table optimisation study shows that lowering temperature to 50 oC
1 entry 15) which may be because with lower F/T molar ratio doesn’t affect the yield significantly, nearly similar results
from 2.5 to 1.25 increases pH of the medium which initiates obtained while decreasing the time to 3 h from 5 h (Table 1,
complete CTH of α-keto amide, this confirms that CTH is pH Entry 25-27). To understand the effect of IPA in hydrogenation
dependent. With product in hand catalyst loading is screened process it is even increased to 10 ml so that it may yield β-
which shows 30 mg is sufficient for complete transfer aminol but it favours only α-hydroxyl amide (Table 1, Entry 28).
hydrogenation reaction for the synthesis of desired product. Further entry 8 insist us to optimise DCM as solvent so it has
Yield remain same by increasing the catalyst loading to 40 mg been used in presence of hydrogen donor FA: TEA (5:4) in excess
whereas decreasing catalyst loading to 20 mg reduced the yield amount but it shows decrease in yield of β-aminol to 54% (Table
to 82% (Table 1, Entry 16-18). Furthermore, time scale and 1 entry 29). Thus, from entry (8-11), 25,29 clearly indicates IPA
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o
temperature has been optimized where 8 h and 80 C shows and FA: TEA (5:4) tandemly work for synthesis of β-aminol.
excellent yield of β-aminol. Yield remain same by decreasing the Hence entry 20 reports selectivity, for β-aminol synthesis when
time from 24 h to 8 h but further decrease to 6h decreases the azeotropic mixture FA:TEA ratio of 1.25 used along with IPA
yield of desired β-aminol whereas simultaneously also shows which behaves like supportive hydrogen donor and solvent
presence of α-hydroxyl amide, which reflects that α-hydroxyl both, at 80 oC whereas entry 27 reports selective synthesis of α-
amide may be intermediate during the synthesis of β-aminol hydroxyl amide when only IPA used both as hydrogen donor as
o
(Table 1, Entry 19-21). During temperature scale study it seems well as solvent at 50 C (†see ESI, Fig. 9). Both the condition
requires Ru-g-C3N4 as a heterogenous catalyst.
Table 2: Substrate scope of 1a for partial transfer hydrogenation of α-ketoamide into α-
hydroxyl amide
Table 3: Substrate scope of 1a for complete transfer hydrogenation of α-ketoamide into
β-aminol
O
OH
H
H
N
N
g-C3N
4 , IPA
Ru
O
OH
H
H
N
N
O
O
g-C3N
Conditions
Ru
4 , FA:TEA (5:4)
O
2a
Br OH
IPA
, Conditions
1a
2aa
Br OH
1a
F
OH
Cl OH
H
H
H
N
N
N
F
OH
Cl OH
H
H
H
N
N
N
O
O
O
2b (98%)
2c (95%)
2d (94%)
2ac (92%)
2ad (90%)
2ab (93%)
Me OH
Me OH
O
OH
H
O
OH
H
H
N
N
O
N
O
OH
H
O
OH
H
H
N
N
O
N
O
O
O
2e (89%)
2f (90%)
2g (93%)
2ae (85%)
2af (87%)
2ag (89%)
O
O
OH
H
OH
H
OH
I
H
N
N
N
OH
H
OH
H
OH
H
I
O
N
N
N
O
O
O
O
2h (91%)
2i (93%)
2j (87%)
2ah (88%)
2ai (87%)
2aj (87%)
iPr OH
O
OH
H
H
OH
H
N
OH
H
OH
H
N
N
N
N
O
O
iPr
iPr
O
Br
F
Cl
2ak (93%)
2al (92%)
2am (91%)
2k (90%)
2l (89%)
Conditions: 1 mmol of substrate compound (1a) and its derivatives dissolved in 5
ml IPA solvent, along with 30 mg of mentioned catalyst. Isolated yield based on GC-
MS analysis.
OH
H
OH
H
OH
H
N
N
N
Br
O
2an (86%)
2ao (80%)
2ap (82%)
that lower temperature more prone to α-hydroxyl amide as
compared to β-aminol. From Table 1 entry (22-24) it is clear that
Conditions: 1 mmol of substrate compound (1a) and its derivatives in presence of
0.2 ml of FA: TEA (5:4) dissolved in 5 ml IPA solvent, along with 30 mg of mentioned
catalyst. Isolated yield based on GC-MS analysis.
o
reducing the temperature to 60 C further decreases the yield
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With optimization table in hand, substrate scope also has been position it shows 80% yield which increase to 87% when -Me
studied for the derivative synthesis of α–hydroxyl amide and β– present solely at para position in 2ai. After this -OMe at ortho
View Article Online
DOI: 10.1039/D0NJ01674H
aminol. Initiation for substrate study done from purification of position and -Me at meta position shows its dual effect in 2ap
α-hydroxyl amide and its derivatives where both electron for its yield to 85% respectively. Here, it can be clear that (+I
withdrawing and electron donating tendency has been effect) shows favours in β-aminol synthesis in lesser yield as
measured for CTH reaction. According to the observation from compare to EWG which shows (-I effect).
the Table 2 it is quite clear that with respect to model substrate
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electron withdrawing group shows better yield as compare to
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electron donating group. When at ortho position, -F (2b) group
present on aromatic part of ketone, 98% yield is obtained which
remains nearly same by substitution with -Cl (95%) or -Br (94%),
whereas when ortho position is occupied by electron donating
group like -Me yield reduced to 89% or by -OMe (90%).
However, when 2nd and 3rd position (ortho and meta position)
are occupied by -OMe then yield remains 93% which even
remains same when 2nd and 5th position is occupied by same
moiety. However small loss in yield to 90% is observed when -
OMe substituted at both ortho position i.e.; 2nd and 6th position.
Apart from that isopropyl group at di-ortho (2nd and 6th position)
and para i.e.; 4th position also has been studied which shows
89% yield (2l). It clearly reflects electron donating group
showing (+I effect) promotes transfer hydrogenation process
Scheme 2: Possible Mechanism for complete and partial CTH of α–keto amide
100
80
60
40
20
0
but lesser than (-I effect) as it deactivates carbonyl carbon of
ketone from electrophilic nature. After that substituted
aromatic part of amide is studied, keeping -Me group (2i) at
para position without any substitution on aromatic of ketone it
shows 93% yield whereas when ortho position is substituted
with -I group (2j) then it shows 87% yield.
To further explore wide substrate applicability of this protocol
β-aminol synthesis has been studied. In this derivative study,
initially when ortho position of aromatic part of ketone
substituted with -F it shows 93% yield. Reaction progress when
α-keto amide along with 5 ml of IPA and 30 mg of catalyst is
heated at 80 oC and after 3 h FA: TEA (5:4) is added into it, so it
can be concluded that reaction progress for β-aminol via
synthesis of α-hydroxyl amide. Thus, it can also be predicted
that α-keto amide converted to 97% of 2aa via 98% of 2a.
Similarly, 93% of 2ab product is obtained via 98% of 2b and 92%
of 2ac product obtained via 95% 2c. After that 90% of 2ad is
obtained when -Br group is present at ortho position. However,
with EDG like -Me and -OMe group when present at ortho
position shows slightly lower yield like 2ae produced in 85%
yield via 89% of 2e whereas 87% yield of 2af is produced. When
-OMe group are present at 2nd and 3rd position it shows same
yield of 89% as observed in 2ag from table 3 similarly yield
remain same when -OMe group present at 2nd and 5th position.
Now to understand the effect of substitution for β-aminol
synthesis EWG like -F (2ak), -Cl (2al), -Br(2am), -I (2aj) are
substituted on the aromatic part of amide, which shows good
yield of about 90% like for 2aj 87%, 2ak 93% and >90% for both
2al and 2am. In these cases, it can be understood that EWG
showing (-I effect) favours transfer hydrogenation which
employed β-aminol synthesis in larger amount, where all the 2j
(α-hydroxyl amide) converted into 2aj (β-aminol). In the case of
2an -Br at para position and -Me at meta position shows dual
effect (-I effect of -Br and +I effect of Me) for its yield of about
86% however when -Me is present at both meta and para
1
2
3
4
5
Run (Recycling Index)
Figure 6: Recycling study of Ru-g-C3N4 catalyst under the optimised condition for
complete transfer hydrogenation of α-ketoamide into β-aminol
Based on the results obtained from control experiment (†see
ESI) and previous report in literature, plausible reaction
mechanism for selective synthesis of β-aminol has been
proposed in Scheme 2. Initially Ru-catalyst (A), catalysed
transfer hydrogenation of ketone part of α-ketoamide (1a),
leads to the formation of penta-co-ordinated intermediate [B]
where Ru binds with carbonyl oxygen of ketonic part and
nitrogen of amide substrate (1a), which finally leads to the
generation of 6 membered intermediate (C) with IPA. Finally, it
converts into α-hydroxyl amide (2a) which on prolonged
exposure in front of excess Ru–catalyst (A) leads to the
formation of complex (2a) where [Ru] binds with carbonyl
oxygen of amide because of the presence of high electron
density, further FA: TEA (5:4) generates HCOO- where electron
rich oxygen binds with catalyst ultimately generates
membered intermediate (D) which finally produces hemi-
6
aminol intermediate (E). Intermediate (E) may undergo direct
[16]
dehydration into compound (F)
[may be because hydrogen
of nitrogen is more acidic, as it also leads to the formation of
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Representative papers for synthesis of β-aVmieiwnAorlti:cleNO.nliCne.
Mamillapallia and G. Sekar, RSC Advances., 2014, 105, 61077–
61085; N. C. Mamillapallia and G. SekaDr,OCI:h1e0m.10.3C9o/Dm0mNJ.,021607144H,
58, 7881–7884.
D. Addis, S. Das, K. Junge and M. Beller, Angew. Chem. Int. Ed.,
2011, 50, 6004–6011
V. K. Vyas and B. M. Bhanage, Org. Lett., 2016, 18, 6436–6439;
G. V. More and B. M. Bhanage, Org. Biomol. Chem., 2017, 15,
5263–5267; V. K. Vyas, R. C. Knighton, B. M. Bhanage and M.
Wills, Org. Lett., 2018, 20, 975–978; R. Knighton, V. K. Vyas, L.
H. Mailey, B. M. Bhanage and M. Wills, J. Organomet. Chem.,
2018, 875, 72–79.
Representative papers for Graphitic-C3N4: a) X. Chen, J.
Zhang, X. Fu, M. Antonietti and X. Wang, J. Am. Chem. Soc.
2009, 131, 11658–11659; b) Y. Wang, X. Wang and M.
Antonietti, Angew. Chem., Int. Ed., 2012, 51, 68–89; c) S.
Kumar, T. Surendar, A. Baruah and V. Shanker, J. Mater. Chem.
A., 2013, 1, 5333–5340; d) A. Kumar, P. Kumar, C. Joshi, S.
Ponnada, A. K. Pathak, A. Ali, B. Sreedhar and S. L. Jain, Green
Chem., 2016, 18, 2514–2521.
stable conjugated product F] which finally produces targeted β–
aminol (2aa).
Further, catalyst was recycled five times for the same complete
CTH reaction and 4th recycled catalyst has been characterized
which shows retention of metal loaded on it. (†Fig. S5 in ESI)
XRD pattern, FEG-SEM images and EDX spectra confirms no
change in morphology, retention of metal on the g-C3N4.
Although at the same time, reactivity for the catalyst also has
been observed which shows not much reduction in the yield of
product. (Fig. 6)
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Conclusions
In conclusion remarks efficient, sustainable and easy handy
protocol has been achieved where catalytic transfer
hydrogenation process can be modulated either for partial
selective or for complete hydrogenation reaction of α–keto
amide. Heterogeneous Ru-g-C3N4 catalyst has been developed
and has been comparatively studied with different metal like Ni
and Pd on same support. Protocol involves activity and
reactivity of Ru catalyst for CTH process in eco-friendly solvent
like IPA and F/T ratio about 1.25 for desired compound β-
aminol. Catalyst has been recycled and it is further
characterized where no effect observed in its reactivity neither
any reasonable loss has been observed after reaction. Different
derivatives of α-hydroxyl amide and β-aminol has been
synthesized and has been characterized with NMR
spectroscopy. Based on literature study, possible mechanism
has been drawn for the CTH of α–keto amide.
10 X. Wang, K. Maeda, A. Thomas, K. Takanabe, G. Xin, J. M.
Carlsson, K. Domen and M. Antonietti, Nat. Mater., 2009, 8,
76–80; Priti Sharma and Yoel Sasson, Catal. Commun., 2017,
102, 48–52; Priti Sharma and Yoel Sasson, Green Chem., 2017,
19, 844; X.C. Wang, K. Maeda, A. Thomas, K. Takanabe, G.J.
Xin and M. Carlsson, Nat. Mater., 2013, 280, 967.
11 K. Maeda, X. Wang, Y. Nishihara, D. Lu, M. Antonietti and K.
Domen, J. Phys. Chem. C., 2009, 113, 4940–4947; L. Ge, C. Han
and J. Liu, Y. Li, Appl. Catal. A, 2011, 409, 215–222.
12 a) S. Yea, R. Wanga, Ming-Zai Wuc and Yu-Peng Yuan, Appl
Surf Sci., 2015, 358, 15-27; b) L. Ge, C. Han, J. Liu and Y. Li,
Appl. Catal. A: Gen., 2011, 409, 215; c) Y. Hou, A.B. Laursen, J.
Zhang, G. Zhang, Y. Zhu, X.C. Wang, S. Dahl and I.
Chorkendorff, Angew. Chem. Int. Ed., 2013, 52, 3621; L. Ge, C.
Han, X. Xiao and L. Guo, Int. J. Hydrogen Energy, 2013, 38,
6960; d) S.W. Cao, X.F. Liu, Y.P. Yuan, Z.Y. Zhang, J. Fang, S.C.J.
Loo, J. Barber, T.C. Sum and C. Xue, Phys. Chem. Chem. Phys.,
2013, 15, 18363; J. Hong, Y. Wang, W. Zhang and R. Xu,
ChemSusChem, 2013, 6, 2263; e) J.G. Yu, S. Wang, B. Cheng, Z.
Lin and F. Huang, Catal. Sci. Technol., 2013, 3, 1782.
13 J. Liu, T. Zhang, Z. Wang, G. Dawson and W. Chen, J. Mater.
Chem., 2011, 21, 14398–14401.
14 a) F. Dong, L. Wu, Y. Sun, M. Fu, Z. Wu and S. C. Lee, J. Mater.
Chem., 2011, 21, 15171–15174; b) X. Chen, L. Zhang, B. Zhang,
X. Guo and X. Mu, Sci. Rep., 2016, 6, 28558.
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and C. Yoon, Materials, 2015, 8, 3442; b) M. A. Ernst and W.
G. Sloof, Surf. Interface Anal., 2008, 40, 334–337
16 Y. Pan, Z. Luo, X. Xu, H. Zhao, J. Han, L. Xu, Q. Fan and J. Xiaoc,
Adv. Synth. Catal. 2019, 361, 3800– 3806
Conflicts of interest
“There are no conflicts to declare”.
Acknowledgements
Author AAM is thankful to the Department of Science and
Technology (DST-INSPIRE), New Delhi, India, for providing
Senior Research Fellowship (SRF).
Notes and references
1
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2
3
4
5
Representative papers for synthesis of α–hydroxyl amide: a)
N. C. Mamillapallia and G. Sekar, Adv. Synth. Catal., 2015, 357,
3273 –3283; b) A. Muthukumar, N. C. Mamillapalli and G.
Sekar, Adv. Synth. Catal., 2016, 358, 643–652; c) G. Kumar, A.
Muthukumar and G. Sekar, Eur. J. Org. Chem., 2017, 4883–
4890; d) R. Ye, F. Hao, G. Liu, Q. Zuo, L. Deng, Z. Jina and J. Wu,
Org. Chem. Front., 2019, 6, 3562-3565.
Representative papers of our lab for synthesis of α–hydroxyl
amide: a) A. A. Mishra and B. M. Bhanage, Asian J. Org. Chem.,
2018, 7, 922–931; b) A. A. Mishra and B. M. Bhanage, New J.
Chem., 2019, 43, 6160–6167; c) A. A. Mishra and B. M.
Bhanage, ChemistrySelect., 2019, 4, 14032–14035.
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Graphical Abstract
Ru–g-C3N4 as highly active heterogeneous catalyst for transfer hydrogenation
9
of α–keto amide into β–aminol or α–hydroxyl amide
Ashish A. Mishra, Shivkumar R. Chaurasia, Prof. Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology,
Nathalal Parekh Marg, Matunga, Mumbai 400019, India;
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Fax: (+91)-22-24145614; phone:(+91)-22-3361-1111/2222
E-mail: bm.bhanage@gmail.com ; bm.bhanage@ictmumbai.edu.in