Mesoporous niobium oxide spheres as an effective catalyst for the transamidation of primary amides with amines

Article abstract of DOI:10.1002/adsc.201300717

Mesoporous niobium oxide spheres (MNOS), conveniently prepared by a novel antisolvent precipitation approach, have been shown to be an effective catalyst for the transamidation of primary amides with amines. This novel transamidation can be efficiently carried out under solvent-free conditions and is applicable to a wide range of primary amides and amines to provide N-alkyl amides in good to excellent yields. The catalyst is highly stable and reusable. The application of this transamidation reaction has been demonstrated in the synthesis of antidepressant drug moclobemide and other druglike compounds.

Full text of DOI:10.1002/adsc.201300717

FULL PAPERS
DOI: 10.1002/adsc.201300717
Mesoporous Niobium Oxide Spheres as an Effective Catalyst for
the Transamidation of Primary Amides with Amines
Subhash Chandra Ghosh,a,c Cheng Chao Li,b,d Hua Chun Zeng,b
Joyce S. Y. Ngiam,a Abdul M. Seayad,a and Anqi Chena,*
a
Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research (A*STAR), 8 Biomedical
Grove, Neuros #07-01, Singapore 138665
E-mail: chen_anqi@ices.a-star.edu.sg
Department of Chemical and Biomolecular Engineering and KAUST-NUS GCR Program, Faculty of Engineering,
b
National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260
Current address: CSIR – Central Salt & Marine Chemicals Research Institute, G.B. Marg, Bhavnagar Gujarat 364002,
c
India
d
Current address: Key Laboratory for Micro-Nano Optoelectronic Devices of Ministry of Education, Hunan University,
Changsha 410082, Peopleꢀs Republic of China
Received: August 9, 2013; Revised: November 20, 2013; Published online: February 6, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300717.
Abstract: Mesoporous niobium oxide spheres good to excellent yields. The catalyst is highly stable
(MNOS), conveniently prepared by a novel antisol- and reusable. The application of this transamidation
vent precipitation approach, have been shown to be reaction has been demonstrated in the synthesis of
an effective catalyst for the transamidation of pri- antidepressant drug moclobemide and other drug-
mary amides with amines. This novel transamidation like compounds.
can be efficiently carried out under solvent-free con-
ditions and is applicable to a wide range of primary Keywords: amides; amines; catalysis; niobium oxide;
amides and amines to provide N-alkyl amides in transamidation
Introduction
tion can become an attractive method for amide syn-
thesis as the reaction is simple in operation and atom-
The amide bond is one of the most ubiquitous func- efficient, especially for primary amides which form
tional groups found in natural products, polymers and ammonia as the only by-product. These advantages of
pharmaceuticals.[1] Consequently, amide formation has transamidation have led to a revitalization of the field
been one of the most studied transformations in or- with several novel methods being recently devel-
ganic synthesis. Conventional amide formation in- oped,[5–10] exemplified by the use of organocatalysts
ACTHNUTRGNEUNG
volves the use of either carboxylic acid derivatives [such as boron catalysts,[10c,d,g] PhI(OAc)2,[10f] l-pro-
(acyl halides or anhydrides) or coupling reagents in line,[9] hydroxylamine hydrochloride[7a]] or metal cata-
stoichiometric quantities,[2] resulting in poor atom effi- lysts [such as Sc(OTf)3,[5a,6] ZrCl4,[6] Yb
ACTHNUTRGENNUG HCATUNGTERN(NUNG OTf)3
[10b]
ACTHNUTRGNEUNG
ciency and formation of large amount of waste that Cp2ZrCl2,[7b] Cu(OAc)2 and CeO2[6]]. Some of us
[8]
poses potential environmental problems. These draw- have recently reported that mesoporous niobium
backs have promoted the development of numerous oxide spheres (MNOS) are an effective, recyclable
alternative amide formation methods aimed to cir- and highly stable solid acid catalyst for Friedel–Crafts
cumvent the existing problems.[3]
alkylation and esterification reactions.[11] We envi-
Transamidation of amides with amines under ther- sioned that this solid acid catalyst could potentially
mal conditions[4] is traditionally considered as an un- catalyze the transamidation reaction which is known
[6]
favorable method for amide synthesis due to the high to be affected by solid acids such as CeO2 and sup-
reaction temperatures required to break the amide ported HfCl4.[10e] In our continuing efforts in develop-
bond. The harsh reaction conditions often cause unde- ing efficient and environmentally benign amide for-
sired reactions, especially with functionalized mole- mation methods,[12] we report herein an efficient
cules. However, if efficient catalysts could be devel- transamidation of primary amides catalyzed by meso-
oped to lower the reaction temperature, transamida- porous niobium oxide under solvent-free conditions.
Adv. Synth. Catal. 2014, 356, 475 – 484
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Subhash Chandra Ghosh et al.
Results and Discussion
oxide particles are uniform mesoporous spheres
(Figure 1) with 400–500 nm diameters and a specific
Niobium(V) oxide (Nb2O5) and its hydrated form surface area of 312 m2 gÀ1 (BET method) which is
(Nb2O5·nH2O) are inexpensive and well known solid much larger than that of commercial niobium oxide
acids with the latter possessing a strong acidity com- powder (54 m2 gÀ1).[10c]
parable to that of 70% H2SO4.[13f] Consequently,
In addition, an ammonia-temperature programmed
Nb2O5 has been used to promote many important re- desorption (NH3-TPD) determination showed that
actions, such as esterification, hydration of olefins and the prepared Nb2O5 spheres (MNOS) had a total
epoxides, condensation reactions, biodiesel production acidity (Lewis and Brønsted acids) of 3.23 mmol NH3/
etc.[13] However, their application in transamidation g whereas the commercially available Nb2O5 powder
has not been reported to date. In our recent work in essentially showed no ammonia absorption, revealing
developing novel materials for green and sustainable the great difference in their acidities. The NH3 de-
chemistry applications, we have established a conven- sorption profile of MNOS (Figure 2, solid line)
ient and cost-effective protocol for a scalable prepara- showed a broad desorption temperature range (ca.
tion of mesoporous niobium oxide spheres (MNOS)
by using an antisolvent precipitation approach.[11] The
sulfated mesoporous niobium oxide spheres have
been shown to be efficient catalysts for a number of
reactions including esterification, Friedel–Crafts alky-
lation and hydrolysis of esters.[11] To further explore
the potential application of the catalyst, we have
screened a number of other reactions and were de-
lighted to find that the non-sulfated MNOS effective-
ly catalyzes the transamidation of primary amides.
This is particularly noteworthy as the catalyst can be
prepared in a more convenient way without the sul-
fating step and the fact that transamidation is an im-
portant reaction of high relevance to pharmaceuticals
and fine chemicals.
The mesoporous niobium oxide spheres were pre-
pared from niobium(V) ethoxide according to our re-
ported novel antisolvent precipitation approach using
inexpensive diethylene glycol as a template reagent,
Figure 2. NH3-TPD (with a thermal conductivity detector)
profiles of prepared Nb2O5 spheres (MNOS) (solid line) and
acetone and water as the solvents.[11] These niobium commercial Nb2O5 powder (dashed line).
Figure 1. TEM images: (left) mesoporous niobium oxide spheres (MNOS) and (right) single MNOS particle.[11]
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Mesoporous Niobium Oxide Spheres as an Effective Catalyst
Table 1. Optimization of conditions for the MNOS-catalyzed transamidation of primary amides with amines.[a]
Entry
Catalyst (mol%)
Solvent
Time [h]
Temperature [8C][b]
Yield [%][c]
1
2
3
4
5
6
7
8
9
Nb2O5 (5)
Nb2O5 (5)
Nb2O5 (1)
Nb2O5 (0.1)
Nb2O5 (5)
Nb2O5 (5)
Nb2O5 (5)
Nb2O5 (5)[d]
no catalyst
–
–
–
–
8
140
140
140
140
140
160
160
140
140
72
93
65
15
<5
68
86
10
<5
24
24
24
24
24
24
24
24
toluene
xylene
mesitylene
–
–
[a]
The reactions were carried out with benzamide (1.0 mmol), n-hexylamine (2.0 mmol), Nb2O5 catalyst (loadings as indicat-
ed), under neat conditions (without solvent) or with a solvent (0.4 mL) at the indicated temperature.
External temperature of oil bath.
Yields were determined by quantitative GC analysis using dodecane as an internal standard.
From a commercial source.
[b]
[c]
[d]
100–4008C), indicating its high concentration of acid transamidation smoothly to provide the correspond-
sites of moderate strength.[11]
ing amides. Particularly noteworthy is that unprotect-
The initial screening reaction of benzamide (1a) ed amino alcohols (2h and 2k) underwent transamida-
with n-hexylamine (2a) provided N-hexylbenzamide tion without dehydration or transesterification, indi-
(3a) in 72% yield after 8 h at 1408C (Table 1, cating good chemoselectivity of this MNOS-catalyzed
entry 1). With this promising result, conditions for the transamidation.
reaction were optimized (Table 1). While prolonging
The generality of this MNOS-catalyzed transamida-
the reaction time to 24 h improved the yield to 93% tion was further demonstrated in the combination of
(entry 2), reducing the catalyst loading significantly a variety of primary amides with amines (Table 4).
decreased the yield (entries 3 and 4). The use of sol- Transamidation of nicotinamide (1i) with various
vents including toluene, xylene and mesitylene was amines (2h, 2i, 2l and 2m) afforded its N-substituted
not beneficial even at higher reaction temperatures analogues (3t–3w), providing a convenient access to
(entries 6 and 7). Nb2O5 from commercial sources af- this class of pharmaceutically important com-
forded only 10% of the amide product (entry 8) pounds.[14] The amidation of unsubstituted aliphatic
whereas negligible product was formed in the absence amide (1f) proceeded well with various amines (2c–
of the catalyst (entry 9). These results clearly indicat- 2f). However, the reactivity of a-substituted amide
ed the crucial role of MNOS in this transamidation (1j) was significantly reduced, possibly caused by the
reaction.
steric hindrance which rendered its effective coordi-
With the optimized conditions in hand, the sub- nation to the catalyst surface. Urea (1k) also under-
strate scope of this niobium oxide-catalyzed transami- went transamidation with amine (2n) to form the sub-
dation reaction was explored. This began with the re- stituted urea (3ac). The potential application of this
action of a range of primary amides with n-hexyl- MNOS-catalyszd transamidation was demonstrated in
ACHTUNGTRENNUNG
amine (Table 2). The results showed broad applicabili- the synthesis of moclobemide [Aurorixꢂ; 4-chloro-N-
ty of the reaction to primary amides including benz- (2-morpholin-4-ylethyl)benzamide] which is an anti-
ACHTUNGTRENNUNG
amides (1g–1i), providing the corresponding amides in obenzamide (1b) with 4-(2-aminoethyl)morpholine
good to excellent yields. In general electron-deficient (2m) under solvent-free conditions provided moclobe-
benzamides (1a and 1b) are more reactive than elec- mide (3ad) in 90% yield. This reaction was successful-
tron-rich ones (1c, 1d), which correlates well with the ly scaled up to 6 mmol in a shorter reaction time of
nucleophilic nature of the reaction.
12 h. After recovery of the catalyst and removal of
The substrate scope was also examined by reacting excess amine by partition with water, the product
benzamide (1a) with a variety of amines (Table 3). (1.38 g 86%) was obtained by convenient crystalliza-
Benzylamines (2b–2f), aliphatic primary amines (2g– tion, demonstrating the scalability and practicality of
2i) and cyclic secondary amines (2j–2k) underwent this MNOS-catalyzed transamidation reaction.
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Subhash Chandra Ghosh et al.
Table 2. MNOS-catalysed transamidation of primary amides
with n-hexylamine.[a]
Table 3. Transamidation of benzamides with various
amines.[a]
[a]
The reactions were carried out with a primary amide
(2.0 mmol), n-hexylamine (4.0 mmol), Nb2O5 catalyst
(26 mg, 5 mol%) under neat conditions in a sealed tube
at 1608C.
[a]
The reaction was carried out with benzamide (2.0 mmol),
an amine (4.0 mmol), Nb2O5 catalyst (26 mg, 5 mol%)
under neat conditions in a sealed tube at 1608C.
Isolated yield.
[b]
Isolated yield.
[b]
Recyclability of the catalyst was also examined activity (Figure 3), demonstrating the robustness of
based on the optimal conditions for the transamida- the catalyst and its reusability.
tion of benzamide with n-hexylamine (Table 2,
Based on the known fact that Nb2O5 contains both
entry 1). The catalyst was recovered by simple centri- Lewis and Brønsted acid sites[11,13g] and both of which
fugation and drying at room temperature under re- have been shown to catalyze transamidation,[5f,7a,10c,e,f]
duced pressure (see the Experimental Section). After a possible mechanism is proposed as shown in
5 cycles, the catalyst showed no appreciable change in Figure 4. Primary amide (A) could be activated by co-
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Mesoporous Niobium Oxide Spheres as an Effective Catalyst
Table 4. Transamidation of various amides with various amines.[a]
[a]
The reaction was carried out with a primary amide (2.0 mmol), an amine (4.0 mmol), Nb2O5
catalyst (26 mg, 5 mol%) under neat conditions in a sealed tube at 1608C.
Isolated yield.
8 mmol of amine 2l were used.
[b]
[c]
ordination to the acid sites (denoted as A for both then released from III, thus making the active sites
Lewis and Brønsted acid sites) of MNOS. This would for further turnovers. The driving force for this reac-
facilitate the attack of amine (B) to the amide car- tion is the release of gaseous ammonia from the re-
bonyl group, leading to the formation of intermediate versible process, leading to the formation of the
(II) which could undergo reversible proton exchange amide containing a less volatile amine.
to form III. The amide product (C) and ammonia are
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Subhash Chandra Ghosh et al.
this transamidation catalyst has been demonstrated in
a gram-scale synthesis of the antidepressant drug mo-
clobemide.
Experimental Section
General Information
All reactions were carried out in oven-dried glassware
under an inert atmosphere of dry argon or nitrogen. All pri-
mary amides and amines were obtained from commercial
1
sources and used as received. H/13C NMR spectra were re-
corded at 400/100 MHz on a Bruker Advance III 400 spec-
trometer in CDCl3 unless otherwise stated, using either
TMS or the undeuterated solvent residual signal as the ref-
erence. Mass spectra were run with the electrospray ioniza-
tion time-of-flight (ESI-TOF) mode on an Agilent 6210
mass spectrometer. Solvents for moisture sensitive reactions
were obtained from a Glass Contour solvent purification
system under nitrogen. GC analysis was performed on an
Agilent 6890N GC system equipped with an HP-5 column
using dodecane as an internal standard. Flash column chro-
matography purification of compounds was carried out by
gradient elution using ethyl acetate (EA) in light petroleum
ether (PE) unless otherwise stated. NH3-TPD was per-
formed on a TPDRO-1100 apparatus (Thermo Electron
Corporation) equipped with a thermal conductivity detector
as described previously.[12]
Figure 3. Recycling experiment of MNOS catalyst for the
transamidation of benzamide with n-hexylamine. Yields
were determined by GC analysis.
General Procedure for the Transamidation of
Primary Amides with Amines using Mesoporous
Niobium Oxide Catalyst
An oven-dried Radleysꢂ carousel tube was charged with
mesoporous niobium oxide spheres (prepared according to
a reported protocol,[11] 26 mg, 5 mol%), a primary amide
(2 mmol) and the amine (4 mmol, 2 equiv.). The tube was
connected to an argon line and the reaction mixture was
heated at the specified temperature for 24 h. After being
cooled to room temperature, the crude product was purified
by flash chromatography on silica gel to obtain the amide
product.
Figure 4. Proposed mechanism of the mesoporous niobium
oxide spheres (MNOS)-catalyzed transamidation of primary
amides with amines.
Catalyst Recycling Experiments
Conclusions
Upon completion of the reaction (transamidation of benza-
mide with n-hexylamine, Table 2, entry 1), the mixture was
diluted with methanol and chloroform (2 mL each). Dodec-
ane (50 mL) was added and 0.2 mL was injected in the GC
for analysis. The remaining solution was centrifuged to sepa-
rate the catalyst by removing the supernatant liquid. The
solid residue was washed with ethyl acetate and centrifuged
to remove the solvent. This procedure was repeated for
three times. The solid residue (catalyst) obtained was dried
under vacuum before being used for another round of reac-
tion.
Mesoporous niobium oxide spheres, conveniently pre-
pared by a novel antisolvent precipitation approach,
have been shown to be a highly efficient catalyst for
the transamidation of primary amides with amines.
This transamidation catalyst is applicable to aliphatic,
aromatic and heteroaromatic amides and a broad
range of amines, providing a convenient access to N-
alkyl amides in high yields. The reaction is compatible
with several functional groups and can be carried out
efficiently under solvent-free conditions without the
formation of hazardous by-products. The MNOS cata-
lyst is highly stable and reusable for five times with
Compound Characterization Data
N-Hexylbenzamide (3a):[12d] White solid; yield: 380 mg
1
negligible loss of activity. The potential application of (92%); H NMR (400 MHz, CDCl3): d=7.79–7.73 (m, 2H),
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Mesoporous Niobium Oxide Spheres as an Effective Catalyst
7.52–7.45 (m, 1H), 7.45–7.38 (m, 2H), 6.15 (s, 1H), 3.45 (td,
J=7.2, 5.9 Hz, 2H), 1.69–1.55 (m, 3H), 1.45–1.25 (m, 6H),
0.90 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
167.6, 135.1, 131.4, 128.7, 127.0, 40.3, 31.6, 29.8, 26.8, 22.7,
14.1; HR-MS (ESI): m/z=228.1361 [M+Na]+, calcd. for
C13H19NNaO: 228.1364.
1H), 8.68 (dd, J=4.8, 1.5 Hz, 1H), 8.11 (dt, J=7.9, 1.9 Hz,
1H), 7.42–7.31 (m, 1H), 6.48 (s, 1H), 3.45 (dd, J=13.1,
7.1 Hz, 2H), 1.60 (dd, J=14.7, 7.6 Hz, 2H), 1.45–1.21 (m,
6H), 0.88 (t, J=7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=165.7, 152.0, 147.8, 135.4, 130.8, 123.7, 77.5, 77.2, 76.8,
40.4, 31.6, 29.7, 26.8, 22.6, 14.1; HR-MS (ESI): m/z=
229.1322 [M+Na]+, calcd. for C12H18N2NaO: 229.1317.
N-Benzylbenzamide (3j):[12d] White solid; yield: 325 mg
(77%); 1H NMR (400 MHz, CDCl3): d=7.79 (dd, J=5.3,
3.3 Hz, 2H), 7.54–7.47 (m, 1H), 7.47–7.39 (m, 2H), 7.39–
7.32 (m, 4H), 7.32–7.27 (m, 1H), 6.42 (brs, 1H), 4.65 (d, J=
5.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=167.5, 138.3,
134.6, 131.7, 128.9, 128.7, 128.1, 127.8, 127.1, 44.3; HR-MS
(ESI): m/z=234.0899 [M+Na]+, calcd. for C14H13NNaO:
234.0895.
N-Hexyl-4-chlorobenzamide (3b):[16] White solid; yield:
460 mg (96%); 1H NMR (400 MHz, CDCl3): d=7.76–7.63
(m, 2H), 7.43–7.31 (m, 2H), 6.28 (s, 1H), 3.48–3.33 (m, 2H),
1.67–1.48 (m, 2H), 1.41–1.24 (m, 6H), 0.97–0.80 (m, 3H);
13C NMR (100 MHz, CDCl3): d=166.6, 137.6, 133.4, 128.9,
128.4, 40.4, 31.6, 29.7, 26.8, 22.7, 14.1; HR-MS (ESI): m/z=
262.0978 [M+Na]+, calcd. for C13H18ClNNaO: 262.0975.
N-Hexyl-4-methylbenzamide (3c):[12d] White solid; yield:
335 mg (76%); 1H NMR (400 MHz, CDCl3): d=7.59–7.49
(m, 2H), 7.11 (dd, J=7.6, 1.4 Hz, 2H), 6.05 (s, 1H), 3.36–
3.26 (m, 2H), 2.27 (s, 3H), 1.54–1.44 (m, 2H), 1.31–1.17 (m,
6H), 0.84–0.74 (m, 3H); 13C NMR (100 MHz, CDCl3): d=
167.6, 141.7, 132.2, 129.3, 126.9, 40.2, 31.6, 29.8, 26.8, 22.7,
21.5, 14.1; HR-MS (ESI): m/z=242.1507 [M+Na]+, calcd.
for C14H21NNaO: 242.1521.
N-(4-Chlorobenzyl)benzamide (3k):[9] White solid; yield:
374 mg (76%); 1H NMR (400 MHz, CDCl3): d=7.89–7.74
(m, 2H), 7.57–7.48 (m, 1H), 7.49–7.40 (m, 2H), 7.34–7.28
(m, 4H), 6.57 (s, 1H), 4.62 (d, J=5.8 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=167.5, 137.0, 134.3, 133.5, 131.8,
129.3, 129.0, 128.8, 127.1, 43.5; HR-MS (ESI): m/z=
268.0514 [M+Na]+, calcd. for C14H12ClNNaO: 268.0505.
N-(4-Fluorobenzyl)benzamide (3l):[20] White solid; yield:
311 mg (68%); 1H NMR (400 MHz, CDCl3): d=7.83–7.75
(m, 2H), 7.55–7.47 (m, 1H), 7.46–7.38 (m, 2H), 7.36–7.27
(m, 2H), 7.07–6.98 (m, 2H), 6.52 (s, 1H), 4.60 (d, J=5.7 Hz,
2H); 13C NMR (100 MHz, CDCl3): d=167.5, 162.4 (d, J=
244 Hz, C-F coupling), 134.4, 134.2 (d, J=4 Hz, C-F cou-
pling), 131.8, 129.7 (d, J=8 Hz, C-F coupling), 128.7, 127.1,
115.7 (d, J=21 Hz, C-F coupling) 43.5; HR-MS (ESI):
m/z=252.0809 [M+Na]+, calcd. for C14H12FNNaO:
252.0801.
N-Hexyl-4-methoxybenzamide (3d):[16] White solid; yield:
343 mg (73%); 1H NMR (400 MHz, CDCl3): d=7.80–7.66
(m, 2H), 6.98–6.85 (m, 2H), 6.09 (s, 1H), 3.83 (s, 3H), 3.42
(td, J=7.3, 5.7 Hz, 2H), 1.66–1.51 (m, 2H), 1.40–1.26 (m,
6H), 0.93–0.85 (m, 3H); 13C NMR (100 MHz, CDCl3): d=
167.2, 162.2, 128.7, 127.3, 113.8, 55.5, 40.2, 31.7, 29.9, 26.8,
22.7, 14.1; HR-MS (ESI): m/z=258.1456 [M+Na]+, calcd.
for C14H21NNaO2: 258.1470.
N-Hexyl-2-hydroxy-2-phenylacetamide (3e): White solid;
1
yield: 348 mg (74%); H NMR (400 MHz, CDCl3): d=7.42–
7.30 (m, 5H), 6.01 (s, 1H), 5.01 (s, 1H), 3.25 (dd, J=13.4,
6.9 Hz, 2H), 1.55–1.37 (m, 3H), 1.40–1.14 (m, 8H), 0.94–
0.80 (m, 4H); 13C NMR (100 MHz, CDCl3): d=172.1, 139.8,
129.1, 128.8, 127.0, 74.3, 39.8, 31.5, 29.5, 26.5, 22.6, 14.1; HR-
N-(4-Methoxybenzyl)benzamide (3m):[9] White solid;
1
yield: 324 mg (67%); H NMR (400 MHz, CDCl3): d=7.85–
7.72 (m, 2H), 7.54–7.38 (m, 3H), 7.31–7.26 (m, 2H), 6.97–
6.80 (m, 2H), 6.55–6.23 (m, 1H), 4.57 (d, J=5.5 Hz, 2H),
3.80 (s, 3H); 13C NMR (100 MHz, CDCl3): d=167.4, 159.3,
134.6, 131.6, 130.4, 129.4, 128.7, 127.1, 114.3, 55.4, 43.8; HR-
MS
(ESI):
m/z=258.1475
[M+Na]+,
calcd.
for
C14H21NNaO2: 258.1470.
N-Hexylhexanamide (3f):[16] White solid; yield: 359 mg
1
(90%); H NMR (400 MHz, CDCl3): d=5.36 (s, 1H), 3.30–
MS
(ESI):
m/z=264.1003
[M+Na]+,
calcd.
for
3.18 (m, 2H), 2.21–2.09 (m, 2H), 1.70–1.60 (m, 2H), 1.54–
1.43 (m, 2H), 1.40–1.19 (m, 10H), 0.97–0.80 (m, 6H);
13C NMR (100 MHz, CDCl3): d=173.2, 39.7, 37.1, 31.6, 29.8,
26.7, 25.7, 22.7, 22.6, 14.1, 14.1; HR-MS (ESI): m/z=
222.1830 [M+Na]+, calcd. for C12H25NNaO: 222.1834.
N-Hexylthiophene-2-carboxamide (3g):[17] White solid;
C15H15NNaO2: 264.1000.
N-(1-Phenylethyl)benzamide (3n):[21] White solid; yield:
299 mg (66%); 1H NMR (400 MHz, CDCl3): d=7.85–7.72
(m, 2H), 7.52–7.45 (m, 1H), 7.45–7.32 (m, 6H), 7.32–7.26
(m, 1H), 6.42 (brs, 1H), 5.34 (dt, J=14.3, 7.0 Hz, 1H), 1.61
(d, J=6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=166.7,
143.3, 134.8, 131.6, 128.9, 128.7, 127.6, 127.1, 126.4, 49.4,
21.9. HR-MS (ESI): m/z=248.1061 [M+Na]+, calcd. for
C15H15NNaO: 248.1051.
1
yield: 330 mg (78%); H NMR (400 MHz, CDCl3): d=7.47
(dt, J=9.8, 4.6 Hz, 2H), 7.06 (dt, J=8.6, 3.6 Hz, 1H), 6.13
(s, 1H), 3.51–3.34 (m, 2H), 1.68–1.53 (m, 2H), 1.42–1.25 (m,
6H), 0.97–0.82 (m, 3H); 13C NMR (100 MHz, CDCl3): d=
162.0, 139.4, 129.7, 127.9, 127.6, 40.2, 31.6, 29.8, 26.7, 22.7,
14.1; HR-MS (ESI): m/z=234.0935 [M+Na]+, calcd. for
C11H17NNaOS: 234.0929.
N-(Heptan-2-yl)benzamide (3o):[22] White solid; yield:
330 mg (75%); 1H NMR (400 MHz, CDCl3): d=7.80–7.70
(m, 2H), 7.47–7.36 (m, 3H), 5.93 (brs, 1H), 4.26–4.11 (m,
1H), 1.62–1.44 (m, 2H), 1.44–1.26 (m, 6H), 1.22 (dd, J=6.6,
2.0 Hz, 3H), 0.88 (t, J=6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=166.9, 135.3, 131.3, 128.6, 126.9, 45.9, 37.2, 31.8,
25.9, 22.7, 21.2, 14.1; HR-MS (ESI): m/z=242.1505 [M+
Na]+, calcd. for C14H21NNaO: 242.1521.
N-Hexylfuran-2-carboxamide (3h):[18] White solid; yield:
367 mg (94%); 1H NMR (400 MHz, CDCl3): d=7.42 (dd,
J=1.7, 0.8 Hz, 1H), 7.09 (dd, J=3.5, 0.7 Hz, 1H), 6.49 (dd,
J=3.5, 1.8 Hz, 1H), 6.32 (s, 1H), 3.48–3.36 (m, 2H), 1.66–
1.51 (m, 2H), 1.47–1.19 (m, 6H), 0.89 (t, J=6.9 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=158.5, 148.4, 143.8, 114.0,
112.2, 39.3, 31.6, 29.8, 26.7, 22.7, 14.1; HR-MS (ESI): m/z=
218.1150 [M+Na]+, calcd. for C11H17NNaO2: 218.1157.
N-Hexylnicotinamide (3i):[19] White solid; yield: 371 mg
N-(5-Hydroxypentyl)benzamide (3p):[12b] White solid;
1
yield: 359 mg (87%); H NMR (400 MHz, CDCl3): d=7.75
(dd, J=5.3, 3.3 Hz, 2H), 7.52–7.46 (m, 1H), 7.46–7.39 (m,
2H), 6.18 (s, 1H), 3.67 (t, J=6.4 Hz, 2H), 3.48 (dd, J=12.9,
6.9 Hz, 2H), 1.72–1.58 (m, 4H), 1.53–1.42 (m, 2H);
13C NMR (100 MHz, CDCl3): d=167.8, 134.9, 131.5, 128.7,
1
(90%); H NMR (400 MHz, CDCl3): d=8.97 (d, J=1.7 Hz,
Adv. Synth. Catal. 2014, 356, 475 – 484
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Subhash Chandra Ghosh et al.
127.0, 62.8, 40.1, 32.4, 29.6, 23.3; HR-MS (ESI): m/z=
230.1165 [M+Na]+, calcd. for C12H17NNaO2: 230.1157.
N-[2-(Diethylamino)ethyl]benzamide (3q):[23] White solid;
5.9 Hz, 2H), 2.22–2.14 (m, 2H), 1.68–1.57 (m, 2H), 1.34–
1.24 (m, 4H), 0.91–0.85 (m, 3H); 13C NMR (100 MHz,
CDCl3): d=173.3, 137.2, 133.3, 129.2, 128.9, 42.9, 36.8, 31.6,
25.5, 22.5, 14.0; HR-MS (ESI): m/z=240.1139 [M+H]+,
calcd. for C13H19ClNO: 240.1155.
1
yield: 406 mg (92%); H NMR (400 MHz, CDCl3): d=7.80–
7.74 (m, 2H), 7.51–7.35 (m, 3H), 7.01 (s, 1H), 3.47 (dd, J=
6.3, 5.5 Hz, 2H), 2.67–2.62 (m, 2H), 2.56 (q, J=7.1 Hz, 4H),
1.03 (t, J=7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3): d=
167.4, 134.9, 131.3, 128.6, 127.0, 51.5, 46.9, 37.4, 12.0; HR-
N-(4-Fluorobenzyl)hexanamide (3y): White solid; yield:
424 mg (95%); 1H NMR (400 MHz, CDCl3): d=7.26–7.20
(m, 2H), 7.06–6.91 (m, 2H), 5.85 (s, 1H), 4.38 (d, J=5.8 Hz,
2H), 2.25–2.14 (m, 2H), 1.71–1.57 (m, 2H), 1.37–1.23 (m,
4H), 0.94–0.83 (m, 3H); 13C NMR (100 MHz, CDCl3): d=
173.2, 162.9 (d, J=244 Hz, C-F coupling), 134.5 (d, J=4 Hz,
C-F coupling), 129.6 (d, J=8 Hz, C-F coupling), 115.6 (d,
J=21 Hz, C-F coupling), 42.9, 36.8, 31.6, 25.6, 22.5, 14.0;
HR-MS (ESI): m/z=246.1272 [M+Na]+, calcd. for
C13H18FNNaO: 246.1270.
MS
(ESI):
m/z=243.1479
[M+Na]+,
calcd.
for
C13H20N2NaO: 243.1473.
N-Benzoyl-4-benzylpiperazine (3r):[24] White solid; yield:
503 mg (90%); 1H NMR (400 MHz, CDCl3): d=7.39 (s,
5H), 7.34–7.31 (m, 5H), 3.79 (brs, 2H), 3.54 (s, 2H), 3.43 (s,
2H), 2.61–2.30 (m, 4H); 13C NMR (100 MHz, CDCl3): d=
170.4, 136.0, 129.8, 129.3, 128.7, 128.6, 128.5, 127.5, 127.2,
63.0, 52.9, 47.8, 42.3; HR-MS (ESI): m/z=303.1468 [M+
Na]+, calcd. for C18H20N2NaO: 303.1473.
N-(4-Methoxybenzyl)hexanamide (3z):[10c] White solid;
1
yield: 347 mg (74%); H NMR (400 MHz, CDCl3): d=7.23–
N-Benzoyl-(S)-prolinol (3s):[25] White sticky solid; yield:
312 mg (76%); 1H NMR (400 MHz, CDCl3): d=7.49 (dd,
J=7.4, 1.8 Hz, 2H), 7.40 (t, J=6.2 Hz, 3H), 4.39 (d, J=
6.5 Hz, 1H), 3.94 (s, 1H), 3.85–3.63 (m, 2H), 3.60–3.34 (m,
2H), 2.23–2.07 (m, 1H), 1.96–1.49 (m, 3H); 13C NMR
(100 MHz, CDCl3): d=172.3, 136.8, 130.3, 128.7, 128.5,
127.1, 67.3, 61.6, 51.2, 28.6, 25.1; HR-MS (ESI): m/z=
228.1006 [M+Na]+, calcd. for C12H15NNaO2: 228.1000.
N-(5-Hydroxypentyl)nicotinamide (3t): White solid; yield:
409 mg (98%); 1H NMR (400 MHz, CDCl3): d=8.96 (dd,
J=2.1, 0.6 Hz, 1H), 8.64 (dd, J=3.4, 1.2 Hz, 1H), 8.16–8.06
(m, 1H), 7.35 (ddd, J=7.8, 4.9, 0.6 Hz, 1H), 7.02 (d, J=
15.6 Hz, 1H), 3.63 (t, J=6.1 Hz, 2H), 3.47–3.44 (m, 2H),
2.47–2.44 (m, 2H), 1.72–1.32 (m, 4H); 13C NMR (100 MHz,
CDCl3): d=165.9, 152.0, 147.9, 135.5, 130.7, 123.7, 62.4, 40.2,
32.1, 29.2, 23.3; HR-MS (ESI): m/z=231.1105 [M+Na]+,
calcd. for C11H16N2NaO: 231.1109.
7.16 (m, 2H), 6.90–6.82 (m, 2H), 5.69 (s, 1H), 4.36 (d, J=
5.5 Hz, 2H), 3.79 (s, 3H), 2.23–2.13 (m, 2H), 1.70–1.59 (m,
2H), 1.37–1.26 (m, 4H), 0.92–0.85 (m, 3H); 13C NMR
(100 MHz, CDCl3): d=173.0, 159.2, 130.7, 129.3, 114.2, 55.4,
43.2, 36.9, 31.6, 25.6, 22.5, 14.1; HR-MS (ESI): m/z=
236.1657 [M+H]+, calcd. for C14H22NO2: 236.1651.
N-(1-Phenylethyl)hexanamide (3aa):[27] White solid; yield:
399 mg (91%); 1H NMR (400 MHz, CDCl3): d=7.43–7.19
(m, 5H), 5.78 (brs, 1H), 5.16 (dt, J=15.1, 7.1 Hz, 1H), 2.18
(dd, J=8.2, 7.1 Hz, 2H), 1.71–1.59 (m, 2H), 1.50 (d, J=
6.9 Hz, 3H), 1.39–1.26 (m, 4H), 0.95–0.85 (m, 3H);
13C NMR (100 MHz, CDCl3): d=172.3, 143.5, 128.7, 127.4,
126.3, 48.7, 37.0, 31.6, 25.6, 22.5, 21.8, 14.0; HR-MS (ESI):
m/z=242.1525 [M+Na]+, calcd. for C14H21NNaO: 242.1521.
N-Phenethyl-2-propylpentanamide (3ab):[28] White solid;
1
yield: 75 mg (15%); H NMR (400 MHz, CDCl3): d=7.34–
7.27 (m, 2H), 7.25–7.17 (m, 3H), 5.41 (s, 1H), 3.59–3.49 (m,
2H), 2.87–2.77 (m, 2H), 1.99–1.87 (m, 1H), 1.62–1.48 (m,
2H), 1.38–1.12 (m, 6H), 0.86 (t, J=7.1 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=176.0, 139.1, 128.9, 128.7, 126.6, 47.9,
40.4, 36.1, 35.4, 20.9, 14.2; HR-MS (ESI): m/z=248.2012
[M+H]+, calcd. for C16H26NO: 248.2014.
N-[2-(Diethylamino)ethyl]nicotinamide (3u):[12d] White
solid; yield: 420 mg (95%); 1H NMR (400 MHz, CDCl3):
d=9.00–8.93 (m, 1H), 8.69 (dd, J=4.8, 1.6 Hz, 1H), 8.15–
8.08 (m, 1H), 7.36 (ddd, J=7.9, 4.8, 0.8 Hz, 1H), 7.11 (s,
1H), 3.48 (dd, J=6.1, 5.5 Hz, 2H), 2.70–2.62 (m, 2H), 2.56
(q, J=7.1 Hz, 4H), 1.03 (t, J=7.1 Hz, 6H); 13C NMR
(100 MHz, CDCl3): d=165.4, 152.2, 148.1, 135.2, 130.5,
123.6, 51.3, 46.9, 37.4, 12.1; HR-MS (ESI): m/z=222.1603
[M+H]+, calcd. for C12H20N3O: 222.1606.
1,3-Diphenethylurea (3ac):[29] White solid; yield: 418 mg
1
(78%); H NMR (400 MHz, CDCl3): d=7.30 (t, J=7.3 Hz,
4H), 7.25–7.19 (m, 2H), 7.19–7.13 (m, 4H), 3.41 (t, J=
6.9 Hz, 4H), 2.79 (t, J=6.8 Hz, 4H); 13C NMR (100 MHz,
CDCl3): d=158.1, 139.2, 129.0, 128.8, 126.6, 41.8, 36.5; HR-
N-(Phenylethyl)nicotinamide (3v):[26] White solid; yield:
389 mg (86%); 1H NMR (400 MHz, CDCl3): d=8.85 (s,
1H), 8.75–8.57 (m, 1H), 8.12–7.97 (m, 1H), 7.39–7.27 (m,
3H), 7.26–7.14 (m, 3H), 6.36 (brs, 1H), 3.82–3.64 (m, 2H),
3.05–2.87 (m, 2H); 13C NMR (100 MHz, CDCl3): d=165.7,
152.2, 147.8, 138.8, 135.2, 130.5, 128.9, 126.8, 123.6, 41.3,
35.7; HR-MS (ESI): m/z=249.1001 [M+Na]+, calcd. for
C14H14N2NaO: 249.1004.
MS
C17H20N2NaO: 291.1473.
4-Chloro-N-(2-morpholinoethyl)benzamide
(ESI):
m/z=291.1479
[M+Na]+,
calcd.
for
(moclobe-
mide, 3ad):[12c] White solid; yield: 484 mg (90%); H NMR
(400 MHz, CDCl3): d=7.75–7.68 (m, 2H), 7.44–7.37 (m,
2H), 6.78 (s, 1H), 3.76–3.69 (m, 4H), 3.54 (dd, J=11.4,
5.5 Hz, 2H), 2.60 (t, J=6.0 Hz, 2H), 2.53–2.47 (m, 4H);
13C NMR (100 MHz, CDCl3): d=166.5, 137.8, 133.1, 129.0,
128.5, 67.1, 57.0, 53.5, 36.2; HR-MS (ESI): m/z=291.0882
[M+Na]+, calcd. for C13H17ClN2NaO2: 291.0876.
1
N-Phenylnicotinamide (3w):[17] White solid; yield: 332 mg
(84%); 1H NMR (400 MHz, CDCl3): d=9.06 (dd, J=2.4,
1.0 Hz, 1H), 8.68 (dd, J=4.9, 1.7 Hz, 1H), 8.61 (s, 1H), 8.16
(dt, J=7.9, 1.9 Hz, 1H), 7.65–7.57 (m, 2H), 7.40–7.28 (m,
3H), 7.19–7.11 (m, 1H); 13C NMR (100 MHz, CDCl3): d=
164.2, 152.3, 148.0, 137.7, 135.7, 131.0, 129.2, 125.1, 123.8,
120.8; HR-MS (ESI): m/z=221.0690 [M+Na]+, calcd. for
C12H10N2NaO: 221.0691.
Gram-Scale Synthesis of Moclobemide (3ad)
4-Chlorobenzamide (1b, 0.93 g, 6 mmol), 2-morpholinoe-
than-1-amine (2n, 1.17 g, 9.0 mmol) and MNOS catalyst
(80 mg, 0.30 mmol, 5 mol%) were added to a Radleysꢂ car-
ousel tube. The mixture was heated at 155–1608C in an oil
bath with stirring under an argon atomsphere until the start-
N-(4-Chlorobenzyl)hexanamide (3x):[10e] White solid;
1
yield: 461 mg (96%); H NMR (400 MHz, CDCl3): d=7.30–
7.24 (m, 2H), 7.20–7.13 (m, 2H), 5.99 (s, 1H), 4.36 (d, J=
482
asc.wiley-vch.de
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Adv. Synth. Catal. 2014, 356, 475 – 484

FULL PAPERS
Mesoporous Niobium Oxide Spheres as an Effective Catalyst
ing material was consumed (12 h as judged by TLC). The
mixture was allowed to cool and EA (10 mL) was added
just before the precipitation occurred. The pale yellow sus-
pension was allowed to settle, the supernantant was deca-
nted and the solid residues were washed with EA (2ꢃ
5 mL). The combine organic layer was washed with water
(2ꢃ10 mL) (to remove the excess amine) and brine. After
drying and evaporation of the solvent, the crude product
was recrystallized from ethyl acetate in hexane (2:3) to pro-
vide moclobemide as a white solid; yield: 1.38 g (86%). The
characterization data were in agreement with those reported
above for 3ad.
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Acknowledgements
This work was supported by GlaxoSmithKline (GSK), Singa-
pore Economic Development Board (EDB) under GSK-Sin-
gapore Partnership for Green and Sustainable Manufacture,
and the Institute of Chemical and Engineering Sciences
(ICES), Agency for Science, Technology and Research
(A*STAR), Singapore. We thank Mr. Jeffery Ng (ICES) for
carrying out the NH3-TPD analysis.
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