Zirconium-MOF-catalysed selective synthesis of α-hydroxyamide via the transfer hydrogenation of α-ketoamide

Article abstract of DOI:10.1039/c9nj00900k

This work reports the synthesis of α-hydroxy amide and its derivatives using zirconium-based metal-organic frameworks (Zr-MOFs). The Zr-MOF was prepared using a ligand containing different functionalities as a linker with different porosities. The catalyst efficiently facilitated the transfer hydrogenation of α-ketoamide to α-hydroxyamide. The reaction involved a green hydrogen source, namely isopropyl alcohol, which also acted as a solvent. The role of the ligand in the catalyst was optimized for the selective conversion of α-ketoamide to α-hydroxyamide. UiO-66 (Zr) crystal was efficiently used for the first time for the hydrogenation of α-ketoamide to α-hydroxyamide. The catalyst was recovered and recycled five times without any loss in activity and selectivity performance. The morphology, activity and stability of the UiO-66 (Zr) catalyst were analyzed using field emission gun scanning electron microscopy (FEG-SEM), X-ray diffraction (XRD), infra-red (IR) spectroscopy and thermogravimetric analysis (TGA). The existence of α-hydroxyamide and its derivatives was confirmed from ¹H and ¹³C-NMR.

Full text of DOI:10.1039/c9nj00900k

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Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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DOI: 10.1039/C9NJ00900K
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Zirconium–MOF catalysed selective synthesis of α-hydroxyamide
via transfer hydrogenation of α-ketoamide
Ashish A. Mishra† and Bhalchandra M. Bhanage†*
Received 00th January 20xx,
Accepted 00th January 20xx
This work reports the synthesis of α-hydroxy amide and its derivatives using zirconium-based metal-organic frameworks (Zr-
MOF’s). Zr-MOF is prepared by using a ligand containing different functionality as a linker with different porosity. The catalyst
used efficiently for transfer hydrogenation of α-ketoamide to α-hydroxyamide. The reaction involves a green hydrogen
source viz. isopropyl alcohol which also acts as a solvent. The role of the ligand in catalyst is optimized for the selective
conversion of α-ketoamide to α-hydroxyamide. UiO-66(Zr) crystal is efficiently used for the first time for hydrogenation of
α-ketoamide to α-hydroxyamide. The catalyst is recovered five times and recyled without any loss in activity and selectivity
performace. The morphology, activity and stability of UiO-66(Zr) catalyst has been analyzed using Field emission gun
scanning electron microscopy (FEG-SEM), X-Ray diffraction (XRD), Infra-Red (IR) Spectroscopy and Thermogravimetric
analysis (TGA). α-hydroxyamide and its derivatives are confirmed from 1H & 13C-NMR.
DOI: 10.1039/x0xx00000x
solvent and Ph3SiH along with tetra butyl ammonium fluoride
(TBAF) as catalyst[4c], but non recyclability of the catalyst, limits
the protocol. Additionally, they attempted to synthesize the
Introduction
α-hydroxyamides are the important class of molecules in drug
industry.[1] They are known for different biological activity, due
to the presence of active pharmacophore group.[2] α-
hydroxyamides are also used as ligands in enantioselective
organometallic catalytic reaction because of its multiple
same in the absence of metal catalyst by employing PMHS as a
[4d]
reducing agent in the presence of K3PO4 in 1,4-dioxan and
[4e]
Cs2CO3 in THF solvent. However, both the systems involve
hazardous base and nonenvironmental friendly solvent along
with non-recyclability of catalyst, even limited substrate scope
is observed in these protocols. Moreover, the workup issue also
observed using PMHS as reducing agent. All these restrict it to
some extent from large scale application. Even our group also
worked on hydrogenation and reduction of various strained
ketones.[5a] We have reported the synthesis of α-hydroxyamide
by the reduction of α-ketoamides, using CeO2 as L.A, in MeOH
which behaves both as a solvent as well as proton source and
NaBH4 as a reducing agent.[5b] Research in selective transfer
hydrogenation is therefore attracting notably interest and
extensive efforts is being done to develop appropriate catalytic
protocol.
attacking sites.[3]
Case Study:
O
O
O
H
H
N
N
N
O
O
OH
[I]
[III]
[II]
Figure 1: Resonating structures of α-ketoamides
In α-keto amide, the delocalized pair of electrons of amide
group increases electron density towards carbonyl group of
ketones which results in less electrophilic center, i.e.; it behaves
like iminone rather than α-keto amide. Hence, the use of only
reducing agent alone cannot reduce ketone of the α-keto
amide. Thus, for the reduction or transfer hydrogenation,
ketonic carbonyl center needs to be activated by the use of
either Bronsted acid (B.A) or Lewis acid (L.A).
Currently, we have developed a method which is highly feasible
for the synthesis of α-hydroxy amides by the use of UiO-66 (Zr),
as a recyclable heterogeneous catalyst in the presence of a
benign hydrogen source like isopropyl alcohol (IPA).
According to literature, α-hydroxyamide, are prepared by
UiO-66 (University of Oslo), a metal organic framework based
co-ordination polymer has been considered as heterogeneous,
highly ordered, crystalline, porous material.[6] Apart from
porosity, this metal organic framework (MOF) also exhibits
higher surface area which enhances its active site thereby
providing higher reaction rate and higher turnover frequency
(TOF).[7] Although it also possesses functionality of metal ions
and organic ligands which is an added advantage over non-
porous zeolitic materials. UiO-66 also have high influence of
larger channels which accelerates diffusion thereby increasing
interaction between reactant and active site. Fortunately, UiO-
selective
hydrogenation/reduction
Govindsamy et. al synthesized α-hydroxyamide using a reducing
of
α-ketoamides.
agent like PMHS (poly methoxy hydrosilane) in the presence of
[4b]
Ni(OAc)2[4a], 10 mol% K2PdCl4
in tetrahydro furan (THF)
Ashish A. Mishra, 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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66 shows unmatched chemical, thermal and hydrolytic stability However, none of these works include challenging CTH of
over other MOFs because of higher co-ordination number of conjugate keto compounds into its corresponding alcohol.
Zirconium in framework.[8] Nowadays, authors have well Although immobilization is a better technique in synthetic
explored UiO-66 as an efficient material in the field of catalysis organic chemistry and the absence of metal on UiO-66 along
for hydrogen storage[9a], transfer hydrogenation[9b], gas and with low catalyst loading is economical and environmentally
water adsorption.[9c] Chia and Dumesic in the year 2011 firstly benign.
View Article Online
DOI: 10.1039/C9NJ00900K
reported catalytic transfer hydrogenation (CTH) through Considering these facts, herein, we report for the first time an
Meerwein-Ponndorf-Verley (MPV) reaction using Zr metal as efficient method to convert α-keto amide selectively into α-
catalyst.[10a] They have converted levulinic acid (LA) to γ- hydroxyamide by application of UiO-66 as an efficient
valerolactone (GVL) via CTH in excellent yield with good chemo- heterogeneous catalyst for transfer hydrogenation in the
selectivity by employing an inexpensive, heterogeneous presence of isopropanol as hydrogen donor through MPV
catalyst viz. ZrO2. Later in 2013, Hwang et. al. reported the reaction.
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conversion of ketone of ethyl levulinate (EL) into alcohol of GVL,
Results and Discussion
Optimization of reaction conditions has been carried out by
by introducing UiO-66 and by screening different Zr-MOFs as
[9b]
catalyst.
They used EL as a model substrate to avoid basic
employing
1
mmol of α-ketoamide, i.e., 2-oxo-N-2-
sites of catalyst. Yamashita et. al. in the year 2017, reported the
same reaction of converting LA to GVL using UiO-66-SO3H as an
efficient catalyst.[10b] They explained the conversion of LA and
its ester derivatives into GVL by intramolecular
dealcoholiziation where Zr4+ & O2− shows acidic & basic pair
sites which are invariably distributed in UiO-66 framework and
the -SO3H groups are present at BDC linkers. Recently, Li and co-
workers reported CTH reaction of Levulinate ester (LE) into GVL
over ZrCO3[10c] using isopropanol as hydrogen donor. This group
showed that both Lewis acidic (Zr ions) and basic sites (-CO3 & -
OH ions) have the potential to show CTH reaction for converting
LE and LA into GVL. Lately, chemists started immobilizing metals
on Zr-MOF to promote transfer hydrogenation reaction. Ahn et
al. in 2017, reported Pd immobilized UiO-66NH2, as an effective
catalyst for CTH of nitrobenzene into aniline using formic acid
as hydrogen donor. [10d] Huber et. al. group worked parallel to
Ebitani group who reported in 2014, the same reaction by
immobilizing Zr onto ZrP[10e] and revealed it as an efficient solid
acidic support which has high ratio of Bronsted & Lewis acidic
sites. [10f, 10g]
diphenylacetamide as model substrate by dissolving in 4 ml of
isopropyl alcohol. UiO-66 (Zr) is added and the reaction is
carried out at 100 oC for 24 hr. It yields 80% of α-hydroxy amide
along with 15% of decarbonylation of α-keto amide into amide
(Table 1, entry 1). Further various catalyst has been screened
(Table 1, entry 2-6) like UiO-66 (Zr)-NH2, CeO2, Fe2O3, CuCl2,
RuCl3 for CTH reaction. Amongst them RuCl3 slightly dominated
the rest showing better activity for CTH reaction producing 58%
yield whereas Fe2O3 shows 24% yield and CuCl2 shows 20 %
yield. However, CeO2 doesn’t shows transfer hydrogenation
reaction. From these results it can be concluded that UiO-66 (Zr)
shows better activity for transfer hydrogenation reaction
whereas CeO2 fails for CTH reaction. Although in absence of
catalyst reaction doesn’t proceed (Table 1 entry 7) which
confirms importance of catalyst for the protocol. Next,
hydrogen source is screened Formic Acid: Tri-ethyl Amine [FA:
TEA] (5:2) (Table 1 entry 8) which shows 66% yield in toluene
solvent. Further NaBH4 (Table 1 entry 9), NaCNBH4 (Table 1
entry 10) are also screened in toluene solvent but doesn’t
provide CTH reaction, whereas molecular H2 (Table 1 entry 11)
in MeOH solvent produces 44% yield of desired product and
NaH (Table 1 entry 12) in dichloro methane (DCM) solvent
produces 45% yield of α-hydroxyamide. Thus, for CTH reaction
IPA dominates over FA: TEA as hydrogen source over UiO-66 (Zr)
catalyst whereas NaBH4, NaCNBH4 doesn’t involve in transfer
hydrogenation reaction. Even molecular hydrogenation doesn’t
show appreciable transfer hydrogenation with UiO-66 neither
NaH.
Next, temperature scale is also optimized, where reaction
carried out at room temperature (Table 1 entry 14) but it
drastically reduced the yield to 20% with 40% conversion,
whereas reaction when carried out at 120 oC (Table 1 entry 15)
it results into 72% yield of desired product but on elongation of
time scale from 24 hr. to 48 hr. (Table 1 entry 16) the yield of
the expected product decreased to 68% with an increase in the
yield of decarbonylated product upto 30%. This suggested that
in presence of UiO-66 catalyst decarbonylation increases over
hydrogenation under certain condition. Although carrying out
reaction at 80 oC (Table 1 entry 17), shows better yield to 96%
yield of desired product. Further increasing time scale at 80 oC
Previous Work
K3PO4; PMHS
1,4-dioxan, r.t. 2h
O
OH
H
H
N
N
R1
R2
R1
R2
Cs2CO3; PMHS
2-MeTHF; r.t.
H
O
O
Govindsamy et. al
Our Previous Work
O
H
N
OH
H
NS-CeO2(cat.); NaBH4
MeOH, r.t., 30 min.
N
R1
R2
R1
R2
H
O
O
O
R1 = aryl; R2 = aryl
This Work
O
OH
H
H
UiO66-Zr(cat.); IPA
80oC, 24 hr.
N
N
R1
R2
R1
R2
H
O
R1 = aryl; R2 = aryl
-Chemoselective Transfer Hydrogenation
-Greener Hydrogen Source
-Greener Solvent
-Heterogeneous Recyclable Catalyst
Scheme 1: UiO66 catalysed chemo-selective transfer hydrogenation of α-keto
amide.
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from 24 hr. to 36 hr. (Table 1 entry 18) and 48 hr. (Table 1 entry solvent whereas the second loss of 15.25 wt% observed
View Article Online
DOI: 10.1039/C9NJ00900K
o
19) 96% and 95% yields were obtained respectively.
between 180 – 300 C indicates water vaporization and the third
Thus, the reaction when carried out using UiO-66 as the major loss of 24.4 wt% that occurred between 461 – 610 oC
catalyst, IPA as hydrogen as well as solvent source at 80 oC for
24 h gave 100 % conversion with a maximum yield of 96% (Table
1, entry 17).
UiO-66 prepared by known methods and has been
characterized by XRD, IR, TGA and SEM. XRD studies (Figure 2)
showed typical 2θ peaks at 7.18o (100%), 8.32o (33%), 25.54o
(26%). Powder XRD data collected at ambient atmosphere and
temperature on a diffractometer at 40 kV, 30 mA for
monochromatic Cu Kα (λ = 1.54056 Å) with scan speed 2o/min,
a sampling pitch of 0.02 ° showed 2θ peaks in the range of 4 –
80 o. According to Scherer’s formula Dhkl = 0.9λ/βcosθ, average
crystallite size of UiO-66 was found to be 23 nm having Full
Width Half Maxima (FWHM) of 0.3596 where β indicates line
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Figure 4: TGA ( ) and DTA ( ) images of UiO66.
broadening at half the maximum intensity and θ indicates Bragg
angle. XRD spectra was also recorded for the recycled catalyst
which showed same peak having slightly lower intensity
(Supplementary Data) which confirmed no loss of catalyst after
Table 1: Optimisation study for the hydrogenation of α-ketoamide
OH
O
O
H
H
N
N
reaction. FEG-SEM (Figure 3) studies revealed the morphology
N
UiO-66 (Zr); IPA
80oC, 24 hr.
H
+
O
O
1a
2a
3a
Entry
No.
Catalyst
Hydrogen
source
Temp.
in o
Time
hr.
Yield
2a
80
72
-
Conv.
in %
C
3a
15
10
-
1
UiO66
UiO66-NH2
CeO2
IPA
100
100
80
24
24
48
48
48
24
24
24
24
24
24
24
24
24
24
48
24
36
48
95
100
-
2
IPA
3
IPA
4
Fe2O3
IPA
80
24
20
58
-
-
50
30
100
-
5
CuCl2
IPA
80
-
6
RuCl3
IPA
80
-
7
-
IPA
100
100
100
100
rt
-
8a
9a
10a
11b
12c
13a
14
15
16
17
18
19
UiO66
UiO66
UiO66
UiO66
UiO66
UiO66-NH2
UiO66
UiO66
UiO66
UiO66
UiO66
UiO66
FA: TEA
NaBH4
NaCNBH4
H2
66
-
-
100
-
-
Figure 2: XRD peaks of UiO-66(Zr) and UiO-66NH2.
-
-
-
44
45
64
20
72
68
96
96
95
-
-
NaH
FA: TEA
IPA
rt
-
-
100
rt
-
100
40
100
100
100
100
100
-
IPA
120
120
80
25
30
-
IPA
IPA
Figure 3: SEM images of a) & b) UiO66 (Zr).
IPA
80
-
of both the catalysts. UiO-66(Zr) and UiO-66(Zr)-NH2 which
were recorded on TESCAN MIRA 3 model at 10kV. TGA-DTG of
the catalyst is shown in Figure 4. TGA shows that the catalyst
undergoes weight loss three times. First loss of 6.2 wt%
IPA
80
-
Standard Condition: 5 mol% catalyst in 4 mL IPA solvent taken with 1 mmol of
reactant 1a; a) Solvent used 4 mL of toluene; b) Solvent used 5 mL of MeOH; c)
Solvent used 4 mL of DCM.
o
observed between 38-113 C, may be due to initial loss of
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signifies decomposition of the organic linkers. DTG curve for the (Zr) towards electron withdrawing group present at para (1k)
catalyst shows the peak temperature corresponding to position rather than that of electron donating group at para
View Article Online
DOI: 10.1039/C9NJ00900K
maximum rate of decomposition at each weight loss range. position (1h). (Scheme 2)
Following inflection point are obtained from DTG curve 98.2 oC In accordance with the experiments results and literature
(6.2 wt%), 257.2 oC (15.25 wt%), 585.2 oC (24.4 wt%).
survey a plausible reaction mechanism has been proposed.
With the optimized conditions in hand for the selective transfer According to proposed mechanism initially isopropanol binds
hydrogenation of α-keto amide to α-hydroxy amide we focused with Zr-catalyst where alcoholic oxygen of IPA is linked with Zr
our attention on scope and generality of the reaction by metal and alcoholic hydrogen is bound with oxygen (μ3–O) of
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[8b,
screening various derivatives of α-keto amides. Electron Zr-MOF [Zr6(μ3–O)4(μ3–OH)4 core]
11]. Finally, with the
donating group and electron withdrawing group present on substrate it forms a 6 -membered intermediate which
benzene ring attached to the keto group of the α-keto amides undergoes transfer hydrogenation to α-hydroxy amide and
affects the reactivity.
acetone as other product.
O
OH
Sensitive functional group doesn’t get affected during reaction.
Even electron withdrawing groups showed good yield of
product whereas electron donating group comparably yielded
less product. Electron withdrawing group at para position -F
(1j), -Cl (1k), -Br (1l) and -C6H5 (1f) along with electron donating
group at meta position like -Me (1c), -OMe (1g) showed increase
in yield of product as it has less electron density at carbonyl
carbon. Electron withdrawing groups at meta position -Cl (1m)
along with electron donating group at para position -Me (1d), -
OMe (1e and 1h) induces more electron density at carbonyl
carbon which decreases hydrogenation of ketone into
corresponding alcohols. Compound like (1b, 1i) did not affect
the yield of product, as substituents at benzene ring attached to
the amide group of α-keto amides doesn’t take part in reaction.
Heterocyclic compound like (1n, 1o and 1p) did not affect the
reaction yield and underwent CTH smoothly to produce 2n, 2o
and 2p respectively.
H
H
N
N
UiO-66 (Zr); IPA
24 hr., 80 oC
O
O
R
R
R = -OMe (2h; 30%)
-Cl (2k, 70%)
R = -OMe (1h)
-Cl (1k)
Scheme 2: Intermolecular competition between 1h & 1k for CTH of α-keto amide into α-
hydroxy amide; Substrate (1 mmol), 5 mol% catalyst in 4 ml of IPA solvent; Yields are
based on GC-MS.
O
O
OH
H
NH2
O
H
H
O
H
O
Table 2: Substrate Study for the hydrogenation of α-ketoamide
N
H
O
O
O
H
O
OH
H
O
H
N
H
N
H
UiO66-Zr, IPA
24 hr., 80 o
O
O
C
O
2a
1a
OH
OH
OH
H
N
H
N
H
N
O
H
N
O
O
O
= Zr
2b (92%)
2c (94%)
2d (91%)
O
OH
OH
H
OH
H
H
N
N
O
N
Scheme 3: Plausible Mechanism for transfer hydrogenation of α-keto amide into α-
hydroxy amide using Zr-MOF (UiO-66) [8b]
O
O
O
O
O
2e (89%)
2f (96%)
2g (93%)
Furthermore, recyclable study also has been carried out and the
catalyst has been effectively recycled and was found to be
efficient until the 5th recycle without any loss in its crystallinity
as confirmed by XRD. (See Supplementary data Fig. 3 & Fig. 7)
The recyclability of UiO-66 (Zr) has been performed after each
catalytic run, by isolating the above catalyst through
centrifugation followed by washing thrice with isopropyl
OH
OH
H
I
OH
H
H
N
N
N
O
O
O
F
2h (88%)
2i (92%)
2j (94%)
OH
OH
H
OH
H
H
N
Cl
N
N
O
O
O
Cl
Br
2k (93%)
2l (93%)
2m (88%)
OH
OH
OH
o
H
H
N
H
alcohol which then dried under vacuum at 100 C for 18 h.
N
N
Finally, it is used for the next catalytic run. This method helps in
recovery of maximum amount of catalyst after each cycle. After
3rd cycle small loss of 1% and after 5th cycle loss of 5% in
recovery is observed may be because of washing and handling.
Although catalyst UiO-66 (Zr) possess excellent catalytic
recyclability towards hydrogenation of α-keto amide.
S
O
O
O
O
N
2n (91%)
2o (89%)
2p (89%)
Standard Conditions: 1 mmol of reactant dissolved in 4 ml of IPA solvent; 5 mol%
catalyst. Yields are based on GC-MS study.
In order to understand the effect of catalytic activity and
selectivity, intramolecular competition experiments were
carried out by mixing 1h and 1k in equal ratios under optimized
reaction conditions. The reaction showed selectivity of UiO-66
UiO-66 (Zr) possess structural defects because of modulators
[12a] like glacial acetic acid and HCl. The missing linkers creates
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coordinatively unsaturated Zr atoms which results into opening Chromatography Silica Gel 60 F254 purchased from Merck
View Article Online
of Lewis acidic sites thus makes it highly active for catalytic Specialities Pvt. Ltd. Silica gel for column DchOrI:o1m0.1a0t3o9g/rCa9pNhJy00(190000K-
[12b]
reaction.
Hence, this Lewis acidic sites are responsible for 200 mesh) purchased from SRL, India. NMR spectra were
high selectivity and high catalytic activity for transfer recorded with 500 MHz for 1H NMR and 126 MHz for 13C NMR
hydrogenation reaction. Experimental results observed through spectrometer. The chemical shifts are reported in parts per
reaction are quite sufficient to understand the Lewis acidic million related to tetramethyl silane as an internal standard and
1
nature of UiO-66 (Zr).
the coupling constant J in hertz. H NMR spectra are reported
Apart from this further kinetic investigation for the reaction has relative to residual DMSO-d6 (d=2.50 ppm). 13C NMR are
been carried out as shown in Figure 5. After 4 h 30% substrate reported relative to DMSO-d6 (d=39.52 ppm). The reaction was
i.e.; α-ketoamide gets converted into 26% product α-hydroxy monitored by GC and TLC. The products were analysed by GC-
amide which after 8 h becomes 50%. At 18 h 15% α-ketoamide MS and FT-IR (cm-1).
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exist which get converted into 82% of α-hydroxy amide. Finally, Synthesis of UiO-66 and its functionalised analogue: [13a]
at 24 h 96% yield of α-hydroxy amide was obtained.
Typical UiO-66 (Zr-MOF) gel preparation involves reflux method
in which 14.5 mmol (2.4 g) of Terephthalic acid dissolved in DMF
(60 ml) at room temperature in 100 ml round bottom flask.
Followed to the mixture, 10 mmol (3.22 g) of ZrOCl2.8H2O added
and after 15 min. 37% HCl (1.5 ml) added into it along with 2 ml
of glacial acetic acid. Reaction mixture stirred for 30 min. and
hydroxyl amide
keto amide
100
80
60
40
20
0
o
then introduced into oven for 2 h at 100 C. Finally result into
white homogeneous gel which is recovered by filtration, re-
dispersed in DMF and thrice by methanol. Obtained gel then
finally dried at 100 oC which further used for reaction and also
analysed by XRD, SEM, FT-IR and TGA
Similarly, UiO-66-NH2 gel prepared by reflux method using 10
mmol (1.82 g) of 2-amino-terphthalic acid which is dissolved in
mixture of 36 ml H2O and 150 mmol (8.6 ml) of acetic acid at
room temperature in 100 ml of round bottom flask. After 10
minutes 10 mmol (3.22 g) of ZrOCl2.8H2O was added to the
solution with continuous stirring and kept for 15-20 min. Molar
ratio of ZrOCl2.8H2O: UiO-66-NH2: H2O: CH3COOH mixture are
1:1:200:15. Reaction mixture then introduced into oven for 24
0
10
20
30
40
50
Time in hr.
Figure 5: Time course for CTH of α-keto amide into α-hydroxy amide (Substrate 1 mmol,
5 mol% catalyst dissolved in 4 ml of IPA) Yields are based on GC-MS analysis.
Conclusions
o
hr at 100 C. Next day after cooling at room temperature gel
In conclusion, the use of heterogeneous UiO-66 (Zr) MOF as an
active catalyst provides an efficient method for catalytic
transfer hydrogenation of α-keto amide into α-hydroxy amide.
This method not only produced high yielded of various
pharmaceutically important α-hydroxy amides but also
provided greener route for its synthesis by employing IPA as
both the hydrogen source as well as the solvent for selective
transfer hydrogenation of unusual class of α-keto amides. The
heterogeneous UiO-66 (Zr) MOF catalyst was recycled for 5
times and proved to be efficient for catalytic transfer
hydrogenation reaction. The mentioned protocol could also be
an attractive alternative for the transfer hydrogenation reaction
of unusual class of ketones into corresponding alcohols which
has wide scope for further investigations.
precipitate is filtered. Further precipitates are washed with
water and ethanol at 70 C respectively to remove further
o
presence of ligands and unreacted metal precursor followed by
o
drying overnight at 100 C which is used for reaction and also
analysed by XRD, SEM, FT-IR and TGA
Synthesis of α-keto amide: [13b]
100 ml round bottom flask employed with 10 mmol of ketone
and its derivatives dissolved in 30 ml of acetonitrile in which 20
mmol (2.2 g) SeO2 is introduced and stirred thoroughly. Slowly
into which 10 mmol of primary amine and 20 mmol of triethyl
amine is added at 100 oC for 8-15 h. Product formation
determined by the help of Thin Layer Chromatography (TLC)
after which solution is extracted with ethyl acetate, water. For
removal of base conc. HCl is added in portion (3 x 5 ml) after
which organic layer is washed with brine solution and dried over
anhydrous Na2SO4, filtered and solvent removed under vacuum
on rotary evaporator. Resulting mixture then purified using
silica gel column chromatography (eluent: n-hexane-ethyl
acetate, 80-20) to obtain pure α-keto amide.
Experimental Section
General:
Preparation of UiO-66 and its functionalised catalyst chemicals
are used as ZrOCl2.8H2O, glacial acetic acid from s d fine
chemical limited, Terephthalic acid and 2-amino-terphthalic
acid from Sigma Aldrich, DMF purchased from High Purity
Laboratory Chemicals, conc. HCl from Advent. For preparation
of α-keto amide SeO2 and NaBH4 were purchased from, HPLC
and s d fine chemical limited, and acetophenone derivatives
purchased from alfa aesar & sigma Aldrich. Thin Layer
2-hydroxy-N-2-diphenylacetamide (2a): Yield = 218 mg (96%);
Colourless solid; mp = 151-152oC; Rf = 0.40 (n-hexane: ethyl
1
acetate, 80:20 v/v); H NMR (500 MHz, DMSO-d6) δ 9.94 (s, 1H),
7.68 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5 Hz,
2H), 7.27 (t, J = 7.8 Hz, 2H), 7.03 (t, J = 7.3 Hz, 1H), 6.52 (s, 1H),
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5.10 (s, 2H); 13C NMR (126 MHz, DMSO-d6) δ 171.64, 141.31, d6) δ 9.86 (s, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.42 (d, J V=ie8w.5ArtHiclze,O2nHlin)e,
138.97, 129.04, 128.51, 128.02, 127.01, 123.96, 120.11, 74.45. 7.28 (d, J = 7.6 Hz, 2H), 7.03 (t, J = 7.6 Hz, D1OHI):,160..190039(d/C,9JN=J800.690H0zK,
2-hydroxy-2-phenyl-N-(p-tolyl)acetamide (2b): Yield = 222 mg 2H), 6.31 (d, J = 4.6 Hz, 1H), 5.03 (d, J = 4.6 Hz, 1H), 3.72 (s, 3H);
o
(92%); Colourless solid; mp = 167-169 C; Rf = 0.43 (n-hexane : 13C NMR (126 MHz, DMSO-d6) δ 171.87, 159.23, 139.02, 133.37,
1
ethyl acetate, 80:20 v/v); H NMR (500 MHz, DMSO-d6) δ 9.77 129.04, 128.25, 123.90, 120.06, 113.93, 74.02, 55.52.
(s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 7.5 Hz, 2H), 7.30 (t, J 2-hydroxy-N-(2-iodophenyl)-2-phenylacetamide (2i): Yield =
= 7.5 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 7.04 (d, J = 8.3 Hz, 2H), 6.40 325 mg (92%); Yellow solid; mp = 46-47 oC; Rf = 0.46 (n-hexane:
1
(s, 1H), 5.06 (s, 1H), 2.17 (s, 3H); 13C NMR (126 MHz, DMSO-d6) ethyl acetate, 80:20 v/v); H NMR (500 MHz, DMSO-d6) δ 9.52
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δ 171.37, 141.36, 136.45, 132.87, 129.42, 128.50, 128.00, (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.87 (dd, J = 7.9, 1.4 Hz, 1H), 7.51
126.99, 120.09, 74.38, 20.89.
(d, J = 7.7 Hz, 2H), 7.45 – 7.33 (m, 3H), 7.33 – 7.27 (m, 1H), 6.99
2-hydroxy-N-phenyl-2-(m-tolyl)acetamide (2c): Yield = 226 mg (d, J = 4.1 Hz, 1H), 6.90 (td, J = 7.7, 1.5 Hz, 1H), 5.15 (d, J = 4.1
o
(91%); Colourless solid; mp = 165-166 C; Rf = 0.48 (n-hexane : Hz, 1H); 13C NMR (126 MHz, DMSO-d6) δ 171.30, 140.87, 139.39,
1
ethyl acetate, 80:20 v/v); H NMR (500 MHz, DMSO-d6) δ 9.87 138.58, 129.42, 128.64, 128.26, 127.19, 126.75, 122.16, 92.07,
(s, 1H), 7.68 (d, J = 10.2 Hz, 2H), 7.30 (d, J = 10.2 Hz, 2H), 7.27 (d, 74.13.
J = 8.5 Hz, 2H), 7.22 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.4 Hz, 1H), 2-(4-fluorophenyl)-2-hydroxy-N-phenylacetamide (2j): Yield =
o
7.03 (t, J = 7.4 Hz, 1H), 6.37 (d, J = 4.7 Hz, 1H), 5.04 (d, J = 4.7 Hz, 232 mg (94%); Colourless solid; mp = 100-101 C; Rf = 0.54 (n-
1H), 2.29 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 171.62, hexane: ethyl acetate, 80:20 v/v); 1H NMR (500 MHz, DMSO-d6)
141.20, 138.98, 137.57, 129.05, 128.65, 128.44, 127.58, 124.16, δ 9.92 (s, 1H), 7.67 (d, J = 7.6 Hz, 2H), 7.53 (dd, J = 8.9, 5.6 Hz,
123.94, 120.07, 74.45, 21.54.
2H), 7.34 – 7.23 (m, 2H), 7.17 (t, J = 8.9 Hz, 2H), 7.04 (t, J = 7.4
2-hydroxy-N-phenyl-2-(p-tolyl)acetamide (2d): Yield = 219 mg Hz, 1H), 6.49 (d, J = 4.8 Hz, 1H), 5.10 (d, J = 4.8 Hz, 1H); 13C NMR
o
(85%); Colourless solid; mp = 109-110 C; Rf = 0.51 (n-hexane : (126 MHz, DMSO-d6) δ 171.45, 163.06, 161.13, 138.88, 137.51,
1
ethyl acetate, 80:20 v/v); H NMR (500 MHz, DMSO-d6) δ 9.89 137.49, 129.06, 128.99, 128.92, 124.04, 120.14, 115.39, 115.22,
(s, 1H), 7.66 (d, J = 7.8 Hz, 2H), 7.36 (d, J = 7.9 Hz, 2H), 7.26 (t, J 73.67.
= 7.9 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 7.02 (t, J = 7.3 Hz, 1H), 6.40 2-(4-chlorophenyl)-2-hydroxy-N-phenylacetamide (2k): Yield =
o
(s, 1H), 5.03 (s, 1H), 2.25 (s, 3H); 13C NMR (126 MHz, DMSO-d6) 243 mg (93%); Colourless solid; mp =108-109 C; Rf = 0.54 (n-
δ 171.76, 139.00, 138.35, 137.16, 129.05, 126.93, 123.89, hexane: ethyl acetate, 80:20 v/v); 1H NMR (500 MHz, DMSO-d6)
120.05, 74.25, 21.16.
δ 9.93 (s, 1H), 7.70 – 7.64 (m, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.42
2-hydroxy-2-(4-methoxyphenyl)-N-(p-tolyl)acetamide
(2e): (dd, J = 6.4, 4.5 Hz, 2H), 7.32 – 7.24 (m, 2H), 7.04 (t, J = 7.4 Hz,
o
Yield = 241 mg (89%); Colourless solid; mp = 117-119 C; Rf = 1H), 6.53 (dd, J = 4.8, 1.1 Hz, 1H), 5.11 (d, J = 4.8 Hz, 1H); 13C
1
0.45 (n-hexane : ethyl acetate, 80:20 v/v); H NMR (500 MHz, NMR (126 MHz, DMSO-d6) δ 171.21, 140.26, 138.86, 132.65,
DMSO-d6) δ 9.82 (s, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 8.6 129.06, 128.81, 128.53, 124.06, 120.16, 73.66.
Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 6.32 (s, 2-(4-bromophenyl)-2-hydroxy-N-phenylacetamide (2l): Yield =
o
1H), 5.02 (s, 1H), 3.71 (s, 3H), 2.22 (s, 3H); 13C NMR (126 MHz, 284 mg (93%); Colourless solid; mp = 127-129 C; Rf = 0.55 (n-
DMSO-d6) δ 171.69, 159.19, 136.47, 133.43, 132.85, 129.42, hexane: ethyl acetate, 80:20 v/v); 1H NMR (500 MHz, DMSO-d6)
128.25, 120.05, 113.90, 73.90, 55.51, 20.87.
δ 9.90 (s, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H),
2-hydroxy-2-(naphthalen-1-yl)-N-phenylacetamide (2f): Yield 7.38 (d, J = 8.5 Hz, 2H), 7.25 (t, J = 7.9 Hz, 2H), 7.01 (t, J = 7.4 Hz,
= 266 mg (96%); Colourless solid; mp = 187-188 oC; Rf = 0.51 (n- 1H), 6.50 (d, J = 4.8 Hz, 1H), 5.08 (d, J = 4.8 Hz, 1H); 13C NMR
hexane: ethyl acetate, 80:20 v/v); 1H NMR (500 MHz, DMSO-d6) (126 MHz, DMSO-d6) δ 171.17, 140.24, 138.83, 132.62, 129.05,
δ 10.07 (s, 1H), 8.35 (d, J = 8.2 Hz, 1H), 7.97 – 7.91 (m, 1H), 7.88 128.80, 128.52, 124.01, 120.13, 73.69.
(d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 7.2 Hz, 1H), 2-(3-chlorophenyl)-2-hydroxy-N-phenylacetamide (2m): Yield
7.57 – 7.48 (m, 3H), 7.29 (t, J = 7.9 Hz, 2H), 7.05 (t, J = 7.4 Hz, = 230 mg (88%); Colourless solid; mp = 154-155 oC; Rf = 0.51 (n-
1H), 6.65 (dd, J = 4.8, 1.6 Hz, 1H), 5.80 (d, J = 4.8 Hz, 1H); 13C hexane: ethyl acetate, 80:20 v/v); 1H NMR (500 MHz, DMSO-d6)
NMR (126 MHz, DMSO-d6) δ 171.60, 138.98, 137.44, 133.89, δ 9.98 (s, 1H), 7.66 (d, J = 8.3 Hz, 2H), 7.56 (s, 1H), 7.46 (d, J =
131.40, 129.06, 128.84, 128.66, 126.42, 126.08, 126.00, 125.72, 7.3 Hz, 1H), 7.42 – 7.31 (m, 2H), 7.27 (t, J = 7.8 Hz, 2H), 7.03 (t, J
125.11, 124.01, 120.23, 72.50.
= 7.4 Hz, 1H), 6.65 (s, 1H), 5.12 (s, 1H); 13C NMR (126 MHz,
2-hydroxy-2-(3-methoxyphenyl)-N-phenylacetamide
(2g): DMSO-d6) δ 171.04, 143.72, 138.83, 133.23, 130.46, 129.07,
Yield = 239 mg (93%); Colourless solid; mp = 90-91 oC; Rf = 0.48 127.95, 126.72, 125.61, 124.09, 120.15, 73.67.
(n-hexane : ethyl acetate, 80:20 v/v); 1H NMR (500 MHz, DMSO- 2-(furan-2-yl)-2-hydroxy-N-phenylacetamide (2n): Yield = 205
d6) δ 9.89 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.31 – 7.23 (m, 3H), mg (91%); Colourless solid; mp = 128-129 C; Rf = 0.55 (n-
o
7.08 (dd, J = 10.4, 4.6 Hz, 2H), 7.06 – 7.02 (m, 1H), 6.85 (dd, J = hexane: ethyl acetate, 80:20 v/v); 1H NMR (500 MHz, DMSO-d6)
8.2, 2.6 Hz, 1H), 6.42 (d, J = 4.8 Hz, 1H), 5.06 (d, J = 4.8 Hz, 1H), δ 9.89 (s, 1H), 7.68 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 5 Hz, 1H), 7.28
3.74 (s, 3H); 13C NMR (126 MHz, DMSO-d6) δ 171.48, 159.53, (t, J = 7.7 Hz, 2H), 7.04 (t, J = 7.3 Hz, 1H), 6.45 (d, J = 5.5 Hz, 1H),
142.80, 138.97, 129.59, 129.06, 123.96, 120.10, 119.18, 113.37, 6.39 (s, 1H), 6.37 (s, 1H), 5.12 (d, J = 5.5 Hz, 1H); 13C NMR (126
112.65, 74.35, 55.48.
MHz, DMSO-d6) δ 169.34, 153.20, 143.06, 138.19, 129.23,
(2h): 124.54, 120.17, 111.00, 108.75, 68.07.
2-hydroxy-2-(4-methoxyphenyl)-N-phenylacetamide
Yield = 226 mg (88%); Colourless solid; mp = 97-98oC; Rf = 0.51 2-hydroxy-N-phenyl-2-(thiophen-2-yl)acetamide (2o): Yield =
(n-hexane : ethyl acetate, 80:20 v/v); 1H NMR (500 MHz, DMSO- 207 mg (89%); Colourless solid; mp = 141-142 C; Rf = 0.56 (n-
o
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hexane : ethyl acetate, 80:20 v/v); 1H NMR (500 MHz, DMSO-d6) [6] A. K. Cheetham, G. Ferey and T. Loiseau, Angew. Chem., Int.
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Conflicts of interest
“There are no conflicts to declare”.
Acknowledgements
Author AAM is thankful to the Department of Science and
Technology (DST), New Delhi, India, for providing Senior
Research Fellowship (SRF).
Keywords: α-keto amide • α-hydroxy amide • UiO-66 • catalytic
transfer hydrogenation • heterogenous catalyst
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Zirconium–MOF catalysed selective synthesis of α-hydroxyamide via transfer
hydrogenation of α-ketoamide
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Ashish A. Mishra† and 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