Direct amide synthesis from alcohols and amines by phosphine-free ruthenium catalyst systems

Article abstract of DOI:10.1002/adsc.200900482

Amides are synthesized directly from alcohols and amines in high yields using an in situ generated catalyst from easily available ruthenium complexes such as the (p-cymene)ruthenium dichloride dimer, [Ru(p-cymeme)Cl ₂]₂, or the (benz

Full text of DOI:10.1002/adsc.200900482

FULL PAPERS
DOI: 10.1002/adsc.200900482
Direct Amide Synthesis from Alcohols and Amines by
Phosphine-Free Ruthenium Catalyst Systems
Subhash Chandra Ghosh,a Senthilkumar Muthaiah,a Yao Zhang,a Xiangya Xu,a
and Soon Hyeok Honga,*
a
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
Fax : (+65)-6791-1961; phone: (+65)-6513-2742; e-mail: hongsh@ntu.edu.sg
Received: July 10, 2009; Revised: August 23, 2009; Published online: October 21, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900482.
Abstract: Amides are synthesized directly from alco- comparable activity compared to previous phos-
hols and amines in high yields using an in situ gener- phine-based catalytic systems. The in situ generated
ated catalyst from easily available ruthenium com- catalyst from [Ru
plexes such as the (p-cymene)ruthenium dichloride and acetonitrile showed excellent activity toward re-
dimer, [Ru(p-cymeme)Cl2]2, or the (benzene)ruthe- actions with cyclic secondary amines such as piperi-
nium dichloride dimer, [Ru(benzene)Cl2]2, an N-het- dine and morpholine.
ACHTUGNERTN(NUNG benzene)Cl2]2, an NHC ligand,
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
erocyclic carbene (NHC) ligand, and a nitrogen con-
taining L-type ligand such as acetonitrile. The phos- Keywords: amides; N-heterocyclic carbenes; phos-
phine-free catalyst systems showed improved or phine-free conditions; ruthenium
Introduction
Particularly, the Madsen group showed that Ru-
AHCTUNGTERN(NGUN COD)Cl2 with an N-heterocyclic carbene (NHC) and
The amide bond is a key functional group in organic phosphine ligands also catalyzed the formation of the
chemistry.[1] It plays a major role in the elaboration amide rather than alkylation of the amine.[13b] Alkyla-
and composition of biological and chemical systems. tion of amines with alcohols using the ꢀborrowing hy-
Amides are typically synthesized by coupling of acti- drogenꢁ methodology has been well studied for ruthe-
vated carboxylic acid derivatives with amines.[2] Alter- nium or iridium complexes with phosphine ligands.[15]
native strategies toward the synthesis of amides are Despite their effectiveness in controlling reactivity
the Staudinger reaction,[3] the Schmidt reaction,[4] and selectivity in organometallic chemistry and homo-
Beckmann rearrangement,[5] aminocarbonylation of geneous catalysis, tertiary phosphines are often air-
haloarenes,[6] alkenes[7] and alkynes,[8] oxidative ami- sensitive and are subject to P C bond degradation at
À
dation of aldehydes,[9] hydrative amide synthesis with elevated temperatures.[16] We have made a conscious
alkynes[10] and the amidation of thio acids with effort to develop the amide formation reaction with
azides.[11] However, most of these methods require an an N-heterocyclic carbene ligand and ruthenium com-
equimolar amount of various reagents and generate plex combination under phosphine-free conditions.
larger amounts of by-products as waste. Therefore, Herein we report our catalyst systems using [Ru
the synthesis of amides under neutral conditions and cymene)Cl2]2 or [Ru(benzene)Cl2]2 complexes with an
without the generation of waste is a challenging N-heterocyclic carbene and readily available nitrogen
goal.[12]
containing L-type ligands.
Recently, the Milstein group reported environmen-
tally friendly direct amidation of alcohols and amines
ACHTUNGTRENNUNG(p-
AHCTUNGTRENNUNG
with liberating two molecules of hydrogen using a Results and Discussion
ruthenium PNN pincer complex without any base or
acid promoters.[12] Since then, several groups have re- A model reaction of 2-phenylethanol with benzyl-
ported the synthesis of amides from alcohols and
ACHTUNGTRENaNUNG mine to afford N-benzyl-2-phenylacetamide was
amines using ruthenium[13] and rhodium[14] catalysts. chosen (Table 1). In an initial attempt to generate the
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Table 1. Optimization of reaction conditions.
Entry
Catalyst
RuCl3
Ligand
NHC precursor
Base
Time [h]
Yield[d]
1[a]
pyridine
pyridine
PCy3
1
1
1
1
1
1
2
3
5
4
1
1
1
1
1
1
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
KO-t-Bu
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
24
24
24
24
24
24
24
24
24
48
24
48
24
48
24
48
24
48
48
48
24
24
48
48
48
48
3%
54%
0%
2[b]
[Ru
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(p-cymene)Cl2]2
A
3[b]
N
R
N
N
R
E
T
N
E
N
R
N
N
R
N
U
4[b]
CH3CN
pyridine
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
pyridine
pyridine
pyridine
pyridine
CH3CN
CH3CN
pyridine
CH3CN
pyridine
CH3CN
pyridine
CH3CN
none
55%
59%
58%
34%
19%
15%
62%
89%
96%
89%
90%
90%
93%
89%
90%
83%
84%
16%
65%
3%
5[b]
6[b]
7[b]
8[b]
9[b]
10[c]
11[c]
12[c]
13[c]
14[c]
15[c]
16[c]
17[c]
18[c]
19[a]
20[a]
21[a]
22[a]
23[c]
24[c]
25[c]
26[c]
1
1
1
1
1
1
RuCl
RuCl
N
RuCp*Cl2
Ru(COD)Cl2
[Ru(p-cymene)Cl2]2
[Ru(benzene)Cl2]2
[Ru(p-cymene)Cl2]2
[Ru(benzene)Cl2]2
N
R
N
R
C
none
none
1
7%
3%
20%
none
1
[a]
5 mol% Ru catalyst, 5 mol% NHC precursor, 5 mol% ligand, 15 mol% base.
5 mol% Ru catalyst, 10 mol% NHC precursor, 10 mol% ligand, 30 mol% base.
2.5 mol% Ru catalyst, 5 mol% NHC precursor, 5 mol% ligand, 15 mol% base.
Determined by GC.
[b]
[c]
[d]
catalyst in situ using anhydrous RuCl3, an L-type the NHC precursors examined (Figure 1), 1 showed
ligand, imidazolium salt 1 and potassium tert-butoxide the best activity (entries 4 and 7–12).
as a base in refluxing toluene was unsuccessful
A dramatic improvement of this catalytic system
(entry 1). Most of the starting materials remained un- was achieved by changing the base from potassium
reacted and only 3% of the desired product was tert-butoxide to sodium hydride (89%, entry 11). Run-
found on GC after 24 h. By changing the ruthenium ning the reaction for an extended time, 48 h, did not
precatalyst to [Ru
ACHTUNGTRENNUNG
was significantly increased to 54% with the help of a tries 13–16). In the case of [RuAHCNUTGTRENNUNG
pyridine ligand (entry 2). Various L-type ligands such pyridine ligand showed slightly better activity than
as acetonitrile, phosphines, and dimethyl fumarate acetonitrile (entries 15–18). On the other hand, in the
were screened but only acetonitrile showed compara- case of [Ru
ble activity with pyridine (entry 4). It is interesting to
see economical and readily available nitrogen-con-
taining pyridine and acetonitrile ligands working
more efficiently than phosphines. The Madsen group
reported that phosphines such as tricyclohexylphos-
phine (PCy3) and tricyclopentylphosphine (PCyp3)
ACHTUNGRTEN(NUNG benzene)Cl2]2, acetonitrile showed a
make Ru
ACHTUNGTRENNUNG(COD)Cl2 with N-hetercocyclic carbene
ligand active toward the amide synthesis.[13b] Among Figure 1. NHC precursors.
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Direct Amide Synthesis from Alcohols and Amines
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Table 2. Direct amide synthesis from alcohols and amines.
Entry
Alcohol
Amine
Amide
Yield [%][a]
Conditions A[b]
Conditions B[c]
1
2
3
4
5
6
7
8
90
98
97
99
91
45
77
19
96
97
91
95
92
60
70
19
9
92
72
94
92
10
11
12
64
63
80
90
13
14
58[d]
69[d]
0[d]
0[d]
15
16
19[d]
55[e]
78
25[d]
23[e]
93
17
[a]
Isolated yields.
[b]
Conditions A: [Ru
uene at reflux for 36 h.
Conditions B: [Ru(benzene)Cl2]2 (2.5 mol%), NHC precursor (5 mol%), NaH (15 mol%), acetonitrile (5 mol%) in tolu-
ACHTUNGRTNEN(UNG p-cymene)Cl2]2 (2.5 mol%), NHC precursor (5 mol%), NaH (15 mol%), and pyridine (5 mol%) in tol-
[c]
AHCTUNGTRENNUNG
ene at reflux for 36 h.
In mesitylene at 1638C for 36 h.
1 mol% catalyst loading, GC yields.
[d]
[e]
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Subhash Chandra Ghosh et al.
FULL PAPERS
slightly better activity than pyridine (entries 11–14). to the more electron-donating N-heterocyclic carbene
Other ruthenium complexes such as [RuCl2A(PPh3)3], ligand system.
RuCp*Cl2, and Ru(COD)Cl2 showed lower activity In the case of non-cyclic secondary amines such as
than [Ru(p-cymene)Cl2]2 and [Ru(benzene)Cl2]2 N-benzylmethylamine, our system showed an im-
under the given conditions (entries 19–22). In the ab- provement over Madsenꢁs Ru(COD)Cl2 catalytic
CTHUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
sence of the N-heterocyclic carbene ligand, the amide system under the same conditions (entry 13, vs. 40%
formation was very low with the observation of ~90% with Madsenꢁs catalyst system).[13b] However, with
of starting materials and trace amounts of N-benzyl 2- sterically hindered secondary amines such as diben-
phenylacetamide by alkylation of the amine (en- zylamine, the reaction did not proceed at all
tries 23 and 24). A nitrogen-based L-type ligand is (entry 14). Also, the less basic aniline was less reac-
also essential for the facile formation of amide. With- tive even at 1638C in mesitylene (entry 15). These
out pyridine or acetonitrile, we also observed that limitation has also been observed with other rutheni-
most of the starting materials remained unreacted um catalyst systems demonstrating challenges in this
with 3–20% of N-benzyl 2-phenylacetamide formation area.[12,13]
(entries 25 and 26).
Although our catalytic systems showed comparable
From the screening results, we chose two sets of or a slightly improved activity compared with Mad-
conditions to explore the scope and limitation of our senꢁs system under basic conditions, the turnover
methods
mene)Cl2]2, 5 mol% pyridine, 5 mol% NHC salt 1, catalyst under neutral conditions (entry 16, vs. 960
and 15 mol% NaH) and conditions B (2.5 mol% TONs with Milsteinꢁs system). [Ru(p-cymene)Cl2]2 ex-
[Ru(benzene)Cl2]2, 5 mol% acetonitrile, 5 mol% hibited higher TONs than [Ru(benzene)Cl2]2 (55 vs.
–
conditions
A
(2.5 mol% [Ru(p-cy- numbers (TONs) are less than those of the Milstein
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
NHC salt 1, and 15 mol% NaH) in toluene at 1208C. 23) presumably due to the better stability from the
The reaction time was further optimized and we stronger p-coordination of p-cymene than benzene.
found that there is no substantial increase of product Further investigations on electronic and steric effects
after 24 h. However, we chose a longer reaction time, of related ligands will be necessary to develop more
36 h, to completely consume the starting primary al- improved catalytic systems.
cohols for the purpose of easier isolation.[17]
We believe that the mechanism of our catalytic
A range of amides were synthesized with good to system is the same as that previously suggested
excellent isolated yields under our systems (Table 2). (Scheme 1).[12,13] Interestingly, on the contrary to the
Excellent yields of amides were obtained from the re- observation of Madsenꢁs group, we observed amide
action of sterically unhindered alcohols and amines formation from benzaldehyde and benzylamine with
for both reaction conditions (entries 1–5). The amida- our catalytic systems with the concurrent formation of
tion of 1-hexanol with 2-aminoheptane yielded 45% the imine (Table 3). However, lower conversions com-
using [RuACHTUNGTRENNUNG(p-cymene)Cl2]2, while [RuACHUTNTGERN(NUGN benzene)Cl2]2 pared with the one from alcohol (48% from benzalde-
reached a better yield of 60% of the corresponding hyde vs. 78% from benzyl alcohol, conditions A, and
amide (entry 6). Reaction of 2-methylbutanol with 11% vs. 93%, conditions B, entry 17 in Table 2 and
benzylamine afforded 70–77% yield of corresponding Table 3) suggest that Madsen groupꢁs postulation that
amide (entry 7), while neopentyl alcohol with benzyl- the aldehyde generated from the alcohol stays coordi-
amine gave just 19% yield of the corresponding nated to the metal is valid for the facile formation of
amide (entry 8). These results indicate that the ruthe- amide. The better conversion of benzaldehyde with
nium-catalyzed direct amide formation is sensitive to more electron-rich [RuACHTUNTGRNEUNG(p-cymene)Cl2]2 also suggests
steric hindrance as reported by others.[12,13] Intramo- that coordination to the aldehyde carbonyl is impor-
lecular amidation was also carried out by using 5-ami- tant to lead to amide formation. Various metal com-
nopentanol with excellent yield (entry 9). The use of plexes have been reported for the oxidative amidation
5-hexen-1-ol gave the hexanamide with 100% reduc- of aldehydes.[9]
tion of double bond (entry 10) as observed by Mad-
senꢁs group as well.[13b]
In the case of cyclic secondary amines such as pi-
peridine (entry 11) and morpholine (entry 12),
[Ru
ACHTUNGTRENNUNG
pholine) affords better yield than [RuACHTUNGTRENNNUG
(64%, piperidine, and 63%, morpholine). While pre-
paring this manuscript, the Williams group reported
that [RuACHTUNGTRENNUNG(p-cymene)Cl2]2 and a bis(diphenylphosphi-
no)butane-based catalytic system showed moderate
catalytic activity in the morpholine case.[13a] The im-
proved activity of our catalytic system is probably due Scheme 1. Proposed mechanism.
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Table 3. Reaction between benzaldehyde and benzylamine under conditions A and B.
Entry
Conditions
A: ([Ru(p-cymene)Cl2]2)
Amide [%][a]
Imine [%][a]
1
2
G
48
11
14
60
B: ([Ru(benzene)Cl2]2)
ACHTUNGTRENNUNG
[a]
GC yields.
room temperature and the solvent was removed under
vacuum and the residue was purified by silica gel flash
column chromatography to afford the amide. All the amides
were identified by spectral comparison with literature data
or with analogous literature data.[19]
N-Benzyl-2-phenylacetamide: Purified by silica gel
column chromatography (hexane:EA 3:1, Rf =0.26) to
afford it as a white solid. Isolated yields; conditions A:
90%, conditions B: 96%. 1H NMR (CDCl3): d=7.39–7.26
(m, 10H), 5.70 (bs, 1H), 4.41 (d, 2H, J=5.9 Hz), 3.62 (s,
2H); 13C NMR (CDCl3): d=171.1, 138.3, 135.0, 129.6, 129.2,
128.8, 127.7, 127.6, 47.9, 43.7; HR-MS (ESI): m/z=226.1236
[MH+], calcd. for C15H16NO: 226.1232.
Conclusions
We have demonstrated an improved method for the
amidation of amines with alcohols or aldehydes using
commercially available ruthenium complexes, an N-
heterocyclic carbene ligand, and the economical pyri-
dine or acetonitrile ligand. The phosphine-free pro-
cess will provide alternative opportunities for the
preparation of the fundamental amide functional
group.
Experimental Section
N-Hexyl-2-phenylacetamide: Purified by silica gel column
chromatography (hexane:EA 3:1, Rf =0.28) to afford a
white solid. Isolated yields: conditions A: 98%, conditions
General Information
1
B: 97%. H NMR (CDCl3): d=7.35–7.26 (m, 5H), 5.47 (bs,
All reactions were carried out in oven-dried glassware
under an inert atmosphere of dry argon or nitrogen. All al-
cohols and amines were obtained from Aldrich or Alfa
Aesar and used as received. Imidazolium salts 1–3 were syn-
thesized by literature procedures.[18] Toluene was dried over
a Pure Solv solvent purification system. Analytical TLC was
performed on a Merck 60 F254 silica gel plates (0.25 mm
thickness). Column chromatography was performed on
Merck 60 silica gel (230–400 mesh). NMR spectra were re-
1H), 3.56 (s, 2H), 3.19 (q, 2H, J=6.8 Hz), 1.43–1.37 (m,
2H), 1.29–1.17 (m, 6H), 0.85 (t, J=6.8 Hz); 13C NMR
(CDCl3): d=171.0, 135.2, 129.6, 129.2, 127.5, 44.0, 39.8, 31.5,
29.6, 26.7, 22.7, 14.1; HR-MS (ESI): m/z=220.1698 [MH+],
calcd. for C14H22NO: 220.1701.
N-Pentyl-2-phenylacetamide: Purified by silica gel column
chromatography (hexane:EA 3:1, Rf =0.28) to afford a
white solid. Isolated yields: conditions A: 97%, conditions
1
corded on
a
JEOL ECA400 (1H NMR at 400 MHz;
B: 91%. H NMR (CDCl3): d=7.37–7.24 (m, 5H), 5.46 (bs,
13C NMR at 100 MHz) spectrometer. Tetramethysilane was
used as reference, and the chemical shifts were reported in
ppm and the coupling constants in Hz. GC yields were ob-
tained on an Agilent 7890A instrument equipped with an
HP-5 column using dodecane as an internal standard. Mass
spectrometry was performed by Waters Q-Tof Premier Mi-
cromass instrument, using the electro spray ionization (ESI)
mode.
1H), 3.56 (s, 2H), 3.21–3.16 (m, 2H), 1.41 (p, 2H, J=
6.8 Hz), 1.30–1.17 (m, 4H), 0.85 (t, 3H, J=7.2 Hz);
13C NMR (CDCl3): d=171.0, 135.2, 129.6, 129.2, 127.4, 44.0,
39.7, 29.3, 29.1, 22.4, 14.1; HR-MS (ESI): m/z=206.1547
[MH+], calcd. for C13H20NO: 206.1545.
N-Pentylhexanamide: Purified by silica gel column chro-
matography (hexane:EA 3:1, Rf =0.30) to afford a white
solid. Isolated yields: conditions A: 99%, conditions B:
95%. 1H NMR (CDCl3): d=5.86 (bs, 1H), 3.20–3.15 (m,
2H), 2.11 (t, 2H, J=7.7 Hz), 1.58 (p, 2H, J=8.2 Hz), 1.45
(p, 2H, J=7.2 Hz), 1.27–1.23 (m, 8H), 0.86–0.82 (m, 6H);
13C NMR (CDCl3): d=173.4, 39.6, 36.9, 31.6, 29.5, 29.2, 25.7,
22.5, 22.4, 14.1, 14.0; HR-MS (ESI): m/z=186.1852 [MH+],
calcd. for C11H24NO: 186.1858.
N-Benzylhexanamide: Purified by silica gel column chro-
matography (hexane:EA 3:1, Rf =0.28) to afford a white
solid. Isolated yields: conditions A: 91%, conditions B:
92%. 1H NMR (CDCl3): d=7.30–7.26 (m, 5H), 5.94 (bs,
1H), 4.41 (d, 2H, J=5.9 Hz), 2.19 (t, 2H, J=7.4 Hz), 1.66
(p, 2H, J=7.7 Hz), 1.32–1.28 (m, 4H), 0.88 (t, 3H, J=
6.8 Hz); 13C NMR (CDCl3): d=173.2, 138.6, 128.9, 128.0,
127.7, 43.7, 37.0, 31.7, 25.7, 22.6, 14.1; HR-MS (ESI): m/z=
206.1548 [MH+], calcd. for C13H20NO: 206.1545.
General Procedure for Amide Synthesis
[Ru
ACHTUNGTRENNUNG(p-cymene)Cl2]2 (A, 15.3 mg, 0.025 mmol) or [RuHCATUNGTRNE(NUGN ben-
ACHTUNGTRENNUNGzene)Cl2]2 (B; 12.5 mg, 0.025 mmol), 1,3-diisopropylimidazo-
lium bromide (11.7 mg, 0.05 mmol), NaH (3.6 mg,
0.15 mmol) and pyridine (A, 4 mL, 0.05 mmol) or acetoni-
trile (B, 2.6 mL, 0.05 mmol), were placed in an oven-dried
Schlenk tube inside the glove box; toluene (0.6 mL) was
added to the mixture there. The Schlenk tube was taken out
and heated to reflux in an oil bath under an argon atmos-
phere. The flask was removed from the oil bath after 20 min
and the alcohol (1 mmol) and the amine (1.1 mmol) were
added. The mixture was heated to reflux under an argon at-
mosphere for 36 h. The reaction mixture was cooled to
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N-(1-Methylhexyl)hexanamide: Purified by silica gel
column chromatography (hexane:EA 3:1, Rf =0.30) to
afford a colorless liquid. Isolated yields: conditions A: 45%,
conditions B: 69%. It contains 1:1.4 mixture of two rotam-
ers. HR-MS (ESI):
m/z=240.1391 [MH+], calcd. for C16H18NO: 240.1388.
1
1
Major rotamer: H NMR (CDCl3): d=7.31–7.21 (m, 9H),
conditions B: 60%. H NMR (CDCl3): d=5.71 (d, 1H, J=
7.10–7.08 (m, 1H), 4.60 (s, 2H), 3.78 (s, 2H), 2.88 (s, 3H);
13C NMR (CDCl3): d=171.3, 137.3, 135.0, 129.0, 128.9,
128.6, 128.1, 126.9, 126.4, 51.0, 41.3, 35.3.
7.7 Hz), 3.92–3.86 (m, 1H), 2.08 (t, 2H, J=7.3 Hz), 1.55 (p,
2H, J=7.7 Hz), 1.39–1.15 (m, 12H), 1.04 (d, 3H, J=
6.8 Hz), 0.84–0.80 (m, 6H); 13C NMR (CDCl3): d=172.6,
45.1, 37.0, 36.9, 31.8, 31.5, 25.8, 25.7, 22.7, 22.5, 21.1, 14.1,
14.0; HR-MS (ESI): m/z=214.2169 [MH+], calcd. for
C13H28NO: 214.2171.
1
Minor rotamer: H NMR (CDCl3): d=7.31–7.21 (m, 9H),
7.10–7.08 (m, 1H), 4.51 (s, 2H), 3.75 (s, 2H), 2.94 (s, 3H);
13C NMR (CDCl3): d=171.6, 136.5, 135.2, 129.0, 128.9,
128.8, 127.7, 127.4, 126.9, 53.7, 40.9, 34.1.
N-Benzyl-2-methylbutanamide: Purified by silica gel
column chromatography (hexane:EA 3:1, Rf =0.26) to
afford a white solid. Isolated yields: conditions A: 77%,
conditions B: 70%. 1H NMR (CDCl3): d=7.30–7.25 (m,
5H), 6.19 (bs, 1H), 4.45–4.37 (m, 2H), 2.19–2.12 (m, 1H),
1.73–1.62 (m, 1H), 1.48–1.41 (m, 1H), 1.15 (d, 3H, J=
N,2-Diphenylacetamide: Purified by silica gel column
chromatography (hexane:EA 4:1, Rf =0.31) to afford a
white solid. Isolated yields: conditions A: 19%, conditions
B: 25%. 1H NMR (CDCl3): d=7.42–7.24 (m, 10H), 7.12–
7.05 (m, 1H), 3.71 (s, 2H); 13C NMR (CDCl3): d=169.4,
137.8, 134.6, 129.7, 129.4, 129.1, 127.8, 124.6, 120.0, 45.0;
HR-MS (ESI): m/z=212.1079 [MH+], calcd. for C14H14NO:
212.1075.
6.8 Hz), 0.91 (t, 3H, J=7.2 Hz); 13C NMR
ACTHNUTRGNEU(GN CDCl3): d=
176.6, 138.7, 128.7, 127.8, 127.4, 43.4, 43.2, 27.4, 17.7, 12.1;
HR-MS (ESI): m/z=192.1384 [MH+], calcd. for C12H18NO:
192.1388.
N-Benzylpivalamide: Purified by silica gel column chro-
matography (hexane:EA 3:1, Rf =0.26) to afford a white
solid. Isolated yields: conditions A: 19%, conditions B:
19%. 1H NMR (CDCl3): d=7.35–7.25 (m, 5H), 5.93 (bs,
1H), 4.43 (d, 2H, J=5.9 Hz), 1.24 (s, 9H); 13C NMR
(CDCl3): d=178.5, 138.8, 128.9, 127.8, 127.6, 43.8, 38.9, 27.8;
HR-MS (ESI): m/z=192.1390 [MH+], calcd. for C12H18NO:
192.1388.
Piperidin-2-one: Purified by silica gel column chromatog-
raphy (CH2Cl2:MeOH 19:1, Rf =0.30) to afford a white
solid. Isolated yields: conditions A: 92%, conditions B:
94%. 1H NMR (CDCl3): d=7.52 (bs, 1H), 3.19–3.16 (m,
2H), 2.21 (t, 2H, J=6.4 Hz), 1.72–1.60 (m, 4H); 13C NMR
(CDCl3): d=172.9, 42.0, 31.4, 22.1, 20.8; HR-MS (ESI):
m/z=100.0761 [MH+], calcd. for C5H10NO: 100.0762.
Phenyl(piperidin-1-yl)methanone: Purified by silica gel
column chromatography (hexane:EA 3:1, Rf =0.31) to
Acknowledgements
We are grateful to the National Research Foundation for gen-
erous support of this research and Nanyang Technological
University for graduate student scholarships to Z.Y. and X.X.
We thank Professor Sunggak Kim for helpful discussion on
the manuscript.
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1
conditions B: 80%. H NMR (CDCl3): d=7.37
G
(bs, 2H), 3.33 (bs, 2H), 1.66–1.50 (m, 6H); 13C NMR
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