Tandem synthesis of amides and secondary amines from esters with primary amines under solvent-free conditions

Article abstract of DOI:10.1002/adsc.201400319

An iridium(III)-catalyzed tandem synthesis of amides and amines from esters under solvent-free conditions is described. A commercially available iridium(III) complex, [Cp*IrCl₂]₂, with sodium acetate showed the best activity for the synthesis of amides and secondary amines. The amide was formed by ester-amide exchange which generates an alcohol in situ which is subsequently transformed to a secondary amine via hydrogen autotransfer. This synthetic protocol with high atom economy generates water as the sole by-product and can afford amides and amines from various esters in a one-pot reaction, expanding the synthetic versatility of ester transformations.

Full text of DOI:10.1002/adsc.201400319

FULL PAPERS
DOI: 10.1002/adsc.201400319
Tandem Synthesis of Amides and Secondary Amines from Esters
with Primary Amines under Solvent-Free Conditions
Jeongbin Lee,a,b Senthilkumar Muthaiah,b and Soon Hyeok Honga,b,*
a
Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 151-742, Republic of Korea
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea
b
Fax : (+82)-2-889-1568; phone: (+82)-2-880-6655; e-mail: soonhong@snu.ac.kr
Received: February 5, 2014; Revised: March 27, 2014; Published online: June 25, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400319.
Abstract: An iridiumACTHNUTRGENUGN(III)-catalyzed tandem synthesis synthetic protocol with high atom economy gener-
of amides and amines from esters under solvent-free ates water as the sole by-product and can afford
conditions is described. A commercially available amides and amines from various esters in a one-pot
iridiumACHTUNGTRENNUNG(III) complex, [Cp*IrCl2]2, with sodium ace- reaction, expanding the synthetic versatility of ester
tate showed the best activity for the synthesis of transformations.
amides and secondary amines. The amide was
formed by ester-amide exchange which generates an
alcohol in situ which is subsequently transformed to Keywords: amides; amines; esters; hydrogen trans-
a secondary amine via hydrogen autotransfer. This fer; iridium
Introduction
and are responsible for the pleasant aroma of vegeta-
ble oils. In biological systems, peptide bonds are
Esters are one of the most common functional groups formed by the enzymatic conversion of esters cata-
in nature and constitute an important class of carbox- lyzed by ribosomes. Many classical routes and catalyt-
ylic acid derivatives.[1] They are present in animal fats ic transformations of esters, including ester hydrolysis,
Scheme 1. Different methods for ester transformation.
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transesterification, and ester reduction to alcohol/al- the hydrogen autotransfer method. The mechanism
dehyde, are well documented.[1,2] In addition, the involves the dehydrogenation of the alcohol to the
ester-amide exchange reaction is an important process corresponding carbonyl compound followed by the
and catalytic methods have also been reported.[3]
formation of an imine and its reduction to an amine
Recently, the Mashima group demonstrated that by the metal-hydride complex formed in the first step.
a catalytic amount of sodium methoxide is capable of We focused on the fact that esters provide alcohols
converting various esters into amides under mild con- that can be used as an amine alkylation source.
ditions.[3a] The development of catalytic protocols for Hence we planned to develop a novel C N bond for-
À
such reactions has been oriented toward the efficient mation method involving the following: (i) the forma-
nucleophilic acyl substitutions of esters, with subse- tion of amide bonds by the nucleophilic acyl substitu-
quent liberation of the corresponding alcohol tion of esters with amines and (ii) the synthesis of sec-
(Scheme 1a). Methyl or ethyl esters have been com- ondary amines by the reaction of the in situ generated
monly used thereby producing methanol or ethanol, alcohols with primary amines by the borrowing hydro-
respectively, as the corresponding alcohol.
gen method. To the best of our knowledge, this is the
One-pot multiple functionalization facilitates more first report that documents the full utilization of
than two transformations forming several bonds with esters as the direct carbon sources for amides and
less waste and greater economic benefits.[4] Although amines in a one-pot sequential reaction.
numerous synthetic transformations of esters have
been reported, few attempts have been made to uti-
lize the generated alcohols from esters in an one-pot Results and Discussion
reaction. Such a reaction would be attractive as the
synthetic versatility of ester transformations could be In order to realize our plan, the reaction of benzyl
enhanced. The seminal work by the Milstein group in acetate (1a) with phenethylamine (2a) was chosen as
the synthesis of amides from esters demonstrated that the model reaction. Based on reported systems for
both the acyl and alkoxy parts of the ester starting the alkylation of amines with alcohols, we evaluated
material participated in the reaction by sequential a series of iridium[6] and ruthenium[7] catalytic systems
ruthenium-catalyzed transformations (Scheme 1b).[3b]
The transition metal-catalyzed alkylation of amines [RuAHCTUNGTRENNUNG
(Table 1). Initially the catalytic system consisting of
(p-cymene)Cl2]2, a phosphine ligand (dppf) and
[7c]
with alcohols is one of the most promising methods K2CO3 afforded 64% of N-2-(phenylethyl)acetam-
for the synthesis of secondary amines.[5] The reaction
proceeds by “borrowing hydrogen”, also known as
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Table 1. Optimization of reaction conditions.
Entry[a]
Catalyst (mol%)
Base (mol%)
Yield of 3a[b]
Yield of 4a[b]
1 (A)
2 (B)
3 (B)
4 (B)
5 (B)
[Ru
[Ru
[Ru
N
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
K2CO3 (10)
K2CO3 (5)
Na2CO3 (5)
NaHCO3 (5)
Cs2CO3 (5)
NaOMe (5)
NaOMe (2)
NaOAc (5)
NaOAc (2.5)
NaOAc (2.5)
NaOAc (2.5)
64%
50%
60%
41%
98%
63%
60%
80%
81%
62%
69%
63%
90%
73%
93%
99%
>99%
>99%
4%
24%
26%
9%
ACHTUNGTRENNUNG
G
16%
27%
31%
44%
38%
46%
57%
52%
73%
48%
66%
71%
73%
77%
6 (B)
7 (B)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
8 (A)
9 (A)
10 (A)
11 (A)
12 (A)
13 (A)
14 (A)
15 (A)
16 (A)
17 (C)
18 (D)
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
CHTUNGTRENNUNG
[a]
Reaction conditions: (A) solvent, toluene (0.8M); reaction temperature, 1158C; reaction time, 36 h; (B) solvent, xylene
(0.8M); reaction temperature, 1458C; reaction time, 36 h; (C) neat; reaction temperature, 1158C; reaction time, 36 h;
(D) neat; reaction temperature, 1158C; reaction time, 24 h.
GC yields using dodecane as the internal standard.
dppf=1,1’-bis(diphenylphosphino)ferrocene.
[b]
[c]
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Tandem Synthesis of Amides and Secondary Amines from Esters
the catalyst system to [Cp*IrCl2]2 and K2CO3[6e] result-
ed in improved yields (Table 1, entry 7). Therefore,
we investigated several other bases in combination
with [Cp*IrCl2]2 at different catalyst loadings
(Table 1, entries 7–18). Compared to the carbonate
bases, NaOMe showed better activity in toluene
under reflux for 36 h. However, on reducing the base
loading, the yields decreased, particularly that for 4a
(Table 1, entries 13 and 14). Gratifyingly, the use of
2.5 mol% of NaOAc in toluene under reflux for 36 h
afforded 3a and 4a in excellent and good yields, re-
spectively (Table 1, entry 16). The reduction of the
catalyst loading to 1.25 mol% did not affect the yields
of products (Table 1, entry 17). To our delight, the re-
action run without a solvent resulted in the highest
yield at a reduced reaction time of 24 h (Table 1,
entry 18).[8]
Table 2. Synthesis of amides and secondary amines from dif-
ferent amines and 1a.
With the optimized reaction conditions in hand
(Table 1, conditions D), amides and secondary amines
were synthesized from diverse esters and primary
amines. First, the reactions of 1a and various primary
amines were explored (Table 2); the corresponding
amides and secondary amines were obtained in good
to high yields. In general, the yields of amide were
higher than those of amines. Benzylamines afforded
both amides and secondary amines (Table 2, entries 2,
9–11). Cyclohexylamine (2e) and cyclopentylamine
(2f) also smoothly afforded the corresponding amides
and amines (Table 2, entries 5 and 6). In contrast, the
less basic aniline was not reactive for the synthesis of
both amides and amines as reported in other cases
(Table 2, entry 12).[3a,6d]
Next, the reactions of 2a with different esters were
investigated. Benzyl acetates with electron-withdraw-
ing and electron-donating substituents showed similar
results in the synthesis of the corresponding amides
(Table 3, entries 1 and 2). However, benzyl acetate
with an electron-donating substituent resulted in
slightly lower yields of secondary amine (Table 3,
entry 2). Benzyl benzoate (1d) was less successful in
this reaction than the acetate esters probably because
of the steric hindrance (Table 3, entry 3). However,
the length of the alkyl chains on the acyl part of
esters did not adversely affect the reaction (Table 3,
entries 4 and 7). The substituents on 1-methylbenzyl
acetate (1f) and piperonyl acetate (1g) interrupted
[a]
Reaction conditions: 1a (0.5 mmol, 1.0 equiv.),
(2.2 equiv.), [Cp*IrCl2]2 (1.25 mol%), NaOAc
(2.5 mol%), 24 h.
Isolated yields.
2
[b]
the corresponding amine formation (Table 3, entries 5 of catalyst retarded both the formation of amide and
and 6). n-Hexyl acetate (1i) also afforded 3a and N- amine.
hexyl-2-phenylethylamine (6i) (Table 3, entry 8).
Next, to gain mechanistic insights into the reaction,
Avoidance of organic solvent is an important issue a kinetic study was performed by monitoring the
in modern organic synthesis in order to reduce the progress of the reaction of 1a with 2a (Figure 1). At
environmental impact.[9] It is of much benefit for the initial stage of the reaction, the rate of the amide
large-scale synthesis. Gratifyingly, our developed con- formation was very rapid. Benzyl alcohol was detect-
ditions could be readily scaled up to gram quanti- ed by gas chromatography (GC) analysis, indicating
ties to obtain 3a and 4a from 1a (Table 4).[10] It is that the free alcohol was generated from the ester
notable that the reduced catalyst loading showed sim- before forming the secondary amine. At approximate-
ilar catalytic activity while the reaction with 0.3 mol% ly T=150 min, the rate of 4a formation surpassed
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Table 3. Synthesis of amides and secondary amines from dif-
Table 4. Gram-scale reaction.
ferent esters and 2a.
A
3a [%][b]
4a [%][b]
1.25
0.6
98
92
71
65
0.5
0.3
94
64
77[c]
17[c]
[a]
Equivalents same as that of the iridium catalyst.
Isolated yields.
GC yield with dodecane as the internal standard.
[b]
[c]
Figure 1. Reaction profile that shows the amount of product
formed. Reaction conditions: 1a (0.25 mmol, 1.0 equiv.), 2a
(2.2 equiv.), [Cp*IrCl2]2 (1.25 mol%), NaOAc (2.5 mol%),
1158C. The progress in the reaction was monitored by GC
analysis using dodecane as the internal standard.
[a]
Reaction conditions:
1
(0.5 mmol, 1.0 equiv.), 2a
(2.2 equiv.),
[Cp*IrCl2]2 (1.25 mol%), NaOAc
(2.5 mol%), 24 h.
Isolated yields.
[b]
tution of the ester with primary amine. Next, the in
situ generated alcohol is dehydrogenated and reacts
that of the alcohol formation thereby decreasing the with additional primary amine to form imine. Finally,
alcohol concentration. We also conducted comparable hydrogenation of imine by hydrogen transfer from
experiments to probe the reaction profile in absence the iridium hydride affords the secondary amine.
of iridium and base. As expected, the secondary
amine was not detected in the reaction without the
iridium complex. Furthermore, it also turned out that Conclusions
amide formation was accelerated by the iridium cata-
lyst from the initial time of the reaction (Figure 2).
Based on the conducted experiments and previous nomic method was developed for synthesizing amides
reports,[6,8,11]
probable mechanism for the and secondary amines in one-pot using a simple
[Cp*IrCl2]2-catalyzed synthesis of amides and secon- iridium(III) catalytic system under solvent-free condi-
In conclusion, an environmentally-friendly, atom-eco-
a
G
ACHTUNGTRENNUNG
dary amines from esters is suggested (Scheme 2). tions, generating water as the sole by-product. Various
First, the amide is formed by nucleophilic acyl substi- amides and secondary amines were synthesized effi-
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Tandem Synthesis of Amides and Secondary Amines from Esters
GC Analysis of the Reaction Profile
Inside an argon-filled glove box, [Cp*IrCl2]2 (2.5 mg,
1.25 mol%) and NaOAc (0.5 mg, 2.5 mol%) were added to
an oven-dried 4-mL vial equipped with septum screw cap.
Then 1a (36 mL, 0.25 mmol), 2a (69 mL, 0.55 mmol) were
added into the vial using micro-syringes after the vial had
been taken out of the glove box. The vials were individually
prepared for 0 min, 5 min, 10 min, 20 min, 40 min, 60 min,
90 min, 120 min and heated at 1158C. After the required
time, the vial was removed from heating, quickly cooled
down to a low temperature, the mixture diluted with di-
chloromethane and dodecane (22.7 mL, 0.1 mmol) as an in-
ternal standard was added to the vial. The sample was fil-
tered with celite before analysis by GC.
Figure 2. Reaction profile that shows the amount of amide
3a formed. Reaction conditions: 1a (0.25 mmol, 1.0 equiv.),
2a (2.0 equiv.), 1158C. The progress in the reaction was
monitored by GC analysis using dodecane as the internal
standard.
General Procedure for the Synthesis of Amides and
Secondary Amines with Different Primary Amines
(Table 2)
[Cp*IrCl2]2
(50 mg,
0.062 mmol),
NaOAc
(8.0 mg,
0.010 mmol) were added in an oven-dried vial inside the
glove box. The vial was taken out and the ester (0.50 mmol)
and amine (1.15 mmol) were added under an argon atmos-
phere. The mixture was heated to 1158C for 24 h before
being cooled to room temperature. Purification of the crude
product was performed by flash column chromatography.
All products were identified by spectral comparison with lit-
erature data.
ciently from their corresponding primary amines and
esters, even in gram-scale reactions. Notably, the cur-
rent method utilizes esters as the direct carbon source
for both amides and secondary amines.
N-2-(Phenylethyl)acetamide (3a):[12] 1H NMR (300 MHz,
CDCl3): d=7.36–7.20 (m, 5H), 5.52 (bs, 1H), 3.53 (dd, J=
12.9, 6.9 Hz, 2H), 2.83 (t, J=6.9 Hz, 2H), 1.95 (s, 3H).
N-Benzyl-2-phenethylamine (4a):[13] 1H NMR (300 MHz,
CDCl3): d=7.31–7.15 (m, 10H), 3.78 (s, 2H), 2.90–2.86 (m,
2H), 2.83–2.78 (m, 2H), 1.53 (s, 1H).
Experimental Section
General Considerations
Unless otherwise noted, all reactions were carried out using
a 4-mL vial in an argon-filled glove box. NMR spectra were
recorded in CDCl3 and residue solvent signals were used as
a reference. Chemical shifts were reported in ppm and cou-
pling constants in Hz. Multiplicity is indicated by one or
more of the following: s (singlet); d (doublet); t (triplet): q
(quartet); spt (septet); m (multiplet). All reagents and sol-
vents, unless otherwise noted, were purchased from com-
mercial suppliers and used as received without further pu-
rification. Esters 1b–1i were either purchased or synthesized
according to the literature.
N-Benzylacetamide (3b):[12] 1H NMR (300 MHz, CDCl3):
d=7.34–7.24 (m, 5H), 6.09 (bs, 1H), 4.38 (d, J=5.7 Hz,
2H), 1.98 (s, 3H), 1.24 (s, 1H).
N-Benzyl-1-phenylmethanamine
(4b):[13]
1H NMR
(300 MHz, CDCl3): d=7.26–7.16 (m, 10H), 3.73 (s, 4H),
1.65 (s, 1H).
N-(3-Phenylpropyl)acetamide (3c):[12] 1H NMR (300 MHz,
CDCl3): d=7.40–7.31 (m, 2H), 7.30–7.20 (m, 3H), 5.82 (bs,
1H), 3.41–3.27 (m, 2H), 2.78–2.62 (m, 2H), 2.00 (s, 3H),
1.91 (dt, J=14.6, 7.5 Hz, 2H).
Scheme 2. Proposed mechanism.
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N-Benzyl-3-phenylpropan-1-amine
(4c):[14]
1H NMR
N-(4-Chlorobenzyl)acetamide
(3k):[12]
1H NMR
(500 MHz, CDCl3): d=7.28 (d, J=6.8 Hz, 2H), 7.19 (d, J=
7.9 Hz, 2H), 5.89 (bs, 1H), 4.37 (d, J=5.1 Hz, 2H), 2.01 (s,
J=3.8 Hz, 3H).
(300 MHz, CDCl3): d=7.28–7.10 (m, 10H), 3.73 (s, 2H),
2.64–2.59 (m, 4H), 1.82–1.78 (m, 2H), 1.50 (s, 1H).
N-Heptylacetamide (3d):[15] 1H NMR (300 MHz, CDCl3):
d=5.74 (bs, 1H), 3.26–3.12 (m, 2H), 1.94 (s, 3H), 1.50–1.40
(m, 2H), 1.30–1.21 (m, 8H), 0.85 (t, J=6.7 Hz, 3H).
N-Benzylheptan-1-amine (4d):[16] 1H NMR (300 MHz,
CDCl3): d=7.27–7.19 (m, 5H), 3.73 (s, 2H), 2.57 (t, J=
7.2 Hz, 2H), 1.55 (s, 1H), 1.48–1.43 (m, 2H), 1.25–1.23 (m,
8H), 0.82 (t, J=6.5 Hz, 3H).
N-(4-Chlorobenzyl)benzylamine
(500 MHz, CDCl3): d=7.35–7.19 (m, 9H), 3.76–3.71 (m,
(4k):[24]
1H NMR
4H), 1.61 (s, 1H).
N-Phenylacetamide (3l):[25] 1H NMR (400 MHz, CDCl3):
d=7.50 (d, J=7.8 Hz, 2H), 7.33 (t, J=8.0 Hz, 2H), 7.07–
7.16 (m, 1H), 2.19 (s, 3H).
N-Benzylaniline (4l):[6b] 1H NMR (500 MHz, CDCl3): d=
7.34–7.41 (m, 4H), 7.27–7.32 (m, 1H), 7.18–7.23 (m, 2H),
6.74–6.79 (m, 1H), 6.68 (dd, J=8.8, 1.0 Hz, 2H), 4.35 (s,
2H).
N-Cyclohexylacetamide (3e):[17] 1H NMR (300 MHz,
CDCl3): d=5.57 (bs, 1H), 3.74–3.68 (m, 1H), 1.94 (s, 3H),
1.92–1.86 (m, 2H), 1.75–1.49 (m, 3H), 1.42–1.21 (m, 2H),
1.20–0.97 (m, 3H).
N-Benzylcyclohexanamine (4e):[18] 1H NMR (300 MHz,
CDCl3): d=7.36–7.11 (m, 5H), 3.76 (s, 2H), 2.52–2.37 (m,
1H), 1.87 (d, J=11.3 Hz, 2H), 1.74–1.62 (m, 2H), 1.60–1.43
(m, 2H), 1.29–0.99 (m, 5H).
General Procedure for the Synthesis of Amides and
Secondary Amines with Different Esters (Table 3)
N-(4-Chlorobenzyl)phenethylamine
(300 MHz, CDCl3): d=7.32–7.19 (m, 9H), 3.77 (s, 2H),
2.91–2.79 (m, 4H), 1.52 (s, 1H).
(6b):[26]
1H NMR
N-Cyclopentylamide (3f):[17] 1H NMR (400 MHz, CDCl3):
d=5.80 (bs, 1H), 4.22–4.10 (m, 1H), 1.99–1.93 (m, 2H), 1.91
(s, 3H), 1.68–1.59 (m, 2H), 1.59–1.49 (m, 2H), 1.34 (td, J=
12.8, 6.5 Hz, 2H).
N-(4-Methoxybenzyl)phenethylamine (6c):[26] 1H NMR
(300 MHz, CDCl3): d=7.31–7.10 (m, 5H), 7.09 (d, J=
8.5 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 3.77 (s, 2H), 3.75 (s,
3H), 2.87–2.82 (m, 2H), 2.77–2.72 (m, 2H), 1.52 (s, 1H).
N-Phenethylbenzamide (5d):[12] 1H NMR (300 MHz,
CDCl3): d=7.70 (d, 2H), 7.47–7.22 (m, 8H), 6.33 (bs, 1H),
3.74–3.67 (m, 2H), 2.93 (t, J=7.0 Hz, 2H).
N-Benzylcyclopentanamine (4f):[19] 1H NMR (400 MHz,
CDCl3): d=7.26–7.16 (m, 5H), 3.71 (s, 2H), 3.05 (p, J=
6.7 Hz, 1H), 1.83–1.75 (m, 2H), 1.68–1.59 (m, 2H), 1.51–
1.42 (m, 2H), 1.32 (td, J=14.0, 7.8 Hz, 2H), 0.39 (s, 1H).
N-(4-Methoxyphenethyl)acetamide
(3g):[20]
1H NMR
(500 MHz, CDCl3): d=7.10 (d, J=8.7 Hz, 2H), 6.84 (d, J=
8.7 Hz, 2H), 5.54 (bs, 1H), 3.78 (s, 3H), 3.50–3.42 (m, 2H),
2.74 (t, J=7.0 Hz, 2H), 1.93 (s, 3H).
N-Phenethylpropionamide (5e):[27] 1H NMR (300 MHz,
CDCl3): d=7.26–7.10 (m, 5H), 5.50 (bs, 1H), 3.44 (m, 2H),
2.74 (t, J=7.0 Hz, 2H), 2.08 (q, J=7.6 Hz, 2H), 1.04 (t, J=
7.6 Hz, 3H).
N-(4-Methoxyphenethyl)benzylamine (4g):[21] 1H NMR
(300 MHz, CDCl3): d=7.31–7.15 (m, 5H), 7.09 (d, J=
8.5 Hz, 2H), 6.80 (d, J=8.6 Hz, 2H), 3.77 (s, 2H), 3.75 (s,
3H), 2.89–2.80 (m, 2H), 2.79–2.69 (m, 2H), 1.52 (s, 1H).
N-(1-Methylbenzyl)phenethylamine (6f):[7a] 1H NMR
(300 MHz, CDCl3): d=7.33–7.13 (m, 10H), 3.78 (q, J=
6.6 Hz, 1H), 2.81–2.68 (m, 4H), 1.33 (d, J=6.6 Hz, 3H).
N-(2-Phenylethyl)-1,3-benzodioxole-5-methanamine (6g):
1H NMR (300 MHz, CDCl3): d=7.31–7.17 (m, 5H), 6.79 (s,
1H), 6.71–6.73 (m, 2H), 5.91 (s, 2H), 3.70 (s, 2H), 2.92–2.85
(m, 2H), 2.84–2.77 (m, 2H), 1.52 (s, 1H); 13C NMR
(75 MHz, CDCl3): d=147.6, 146.4, 140.0, 134.2, 128.7, 128.4,
126.1, 121.1, 108.6, 108.0, 100.8, 53.6, 50.3, 36.3; HR-MS
(FAB): m/z=256.1338, calcd. for C16H18NO2 [M+H]+:
256.1339.
N-(3-Fluorophenethyl)acetamide
(3h):[22]
1H NMR
(500 MHz, CDCl3): d=7.29–7.25 (m, 2H), 6.98–6.88 (m,
3H), 5.44 (bs, 1H), 3.53–3.49 (m, 2H), 2.82 (t, J=7.0 Hz,
2H), 1.95 (s, 3H).
N-(3-Fluorophenethyl)benzylamine
(4h):
1H NMR
(500 MHz, CDCl3): d=7.30–7.21 (m, 6H), 6.99 (d, J=
7.3 Hz, 1H), 6.97–6.87 (m, 2H), 3.81 (s, 2H), 2.93 (t, J=
6.8 Hz, 1H), 2.84 (t, J=6.8 Hz, 2H), 1.47 (s, 1H); 13C NMR
(126 MHz, CDCl3): d=162.9 (d, J=245.1 Hz), 142.5 (d, J=
7.23 Hz), 140.0, 129.8 (d, J=8.6 Hz), 128.4, 128.0, 126.9,
124.3 (d, J=2.9 Hz), 115.5 (d, J=20.98 Hz), 113.0 (d, J=
20.98 Hz), 53.8, 50.1, 36.0; 19F NMR (376 MHz, CDCl3): d=
À113.58; HR-MS (FAB): m/z=230.1345, calcd. for
C15H17FN [M+H]+: 230.1347.
N-Phenethyl-4-phenylbutanamide
(5h):[28]
1H NMR
(300 MHz, CDCl3): d=7.32–7.14 (m, 10H), 5.53 (bs, 1H),
3.56–3.50 (m, 2H), 2.80 (t, J=7.0 Hz, 2H), 2.61 (t, J=
7.5 Hz, 2H), 2.11 (t, J=7.6 Hz, 2H), 2.01–1.86 (m, 2H).
N-Hexyl-2-phenylethylamine (6i):[29] 1H NMR (300 MHz,
CDCl3): d=7.34–7.24 (m, 5H), 3.34–3.28 (m, 2H), 3.25–3.11
(m, 2H), 3.04–2.90 (m, 2H), 2.02–1.87 (m, 2H), 1.64 (bs,
1H), 1.43–1.33 (m, 2H), 1.33–1.24 (m, 4H), 0.84 (t, J=
6.6 Hz, 3H), 1.63 (s, 1H).
N-(4-Methylbenzyl)acetamide (3i):[12] 1H NMR (300 MHz,
CDCl3): d=7.19–7.13 (m, 4H), 5.85 (bs, 1H), 4.38 (d, J=
5.6 Hz, 2H), 2.34 (s, 3H), 2.01 (s, 3H).
N-(4-Methylbenzyl)benzylamine
(4i):[23]
1H NMR
(300 MHz, CDCl3): d=7.40–7.18 (m, 9H), 3.89–3.81 (m,
4H), 2.39 (s, 3H), 1.76 (s, 1H).
N-(4-Methoxybenzyl)acetamide
(3j):[12]
1H NMR
(500 MHz, CDCl3): d=7.19 (d, J=8.4 Hz, 2H), 6.88 (d, J=
8.2 Hz, 2H), 5.97 (bs, 1H), 4.33 (d, J=5.6 Hz, 2H), 3.79 (s,
3H), 1.98 (s, 3H).
Acknowledgements
This work was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea
(NRF-2012R1A1A1004077) and the Institute for Basic Sci-
ence (IBS), funded by the Ministry of Science, ICT & Future
Planning in Korea, and the Seoul National University Re-
N-(4-Methoxybenzyl)benzylamine
(4j):[19]
1H NMR
(500 MHz, CDCl3): d=7.28–7.22 (m, 4H), 6.81–6.78 (m,
3H), 6.79 (d, J=8.7 Hz, 2H), 3.72 (s, 5H), 3.67 (s, 2H), 1.76
(s, 1H).
2658
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Adv. Synth. Catal. 2014, 356, 2653 – 2660

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Tandem Synthesis of Amides and Secondary Amines from Esters
search Grant. We thank the National Center for Inter-Univer-
sity Research Facilities of Seoul National University
(NCIRF) and the Korean Basic Science Institute (Daegu) for
HR-MS analysis.
[7] a) A. J. A. Watson, A. C. Maxwell, J. M. J. Williams, J.
Org. Chem. 2011, 76, 2328–2331; b) S. Bꢁhn, S. Imm, K.
Mevius, L. Neubert, A. Tillack, J. M. J. Williams, M.
Beller, Chem. Eur. J. 2010, 16, 3590–3593;
c) M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C.
Maxwell, H. C. Maytum, A. J. A. Watson, J. M. J. Wil-
liams, J. Am. Chem. Soc. 2009, 131, 1766–1774; d) D.
Hollmann, A. Tillack, D. Michalik, R. Jackstell, M.
Beller, Chem. Asian J. 2007, 2, 403–410; e) Y. Tsuji,
K. T. Huh, Y. Watanabe, J. Org. Chem. 1987, 52, 1673–
1680.
References
[1] a) R. Larock, Comprehensive Organic Transformations,
Wiley-VCH, New York, 1999; b) B. M. Trost, I. Flem-
ing, Comprehensive Organic Synthesis, Vol. 6, Perga-
mon Press, New York, 1991.
[2] a) L. R. Gahan, S. J. Smith, A. Neves, G. Schenk, Eur.
J. Inorg. Chem. 2009, 2745; b) C. Montalbetti, V.
Falque, Tetrahedron 2005, 61, 10827–10852.
[8] K. Fujita, A. Komatsubara, R. Yamaguchi, Tetrahedron
2009, 65, 3624–3628.
[9] a) M. C. Bryan, B. Dillon, L. G. Hamann, G. J. Hughes,
M. E. Kopach, E. A. Peterson, M. Pourashraf, I.
Raheem, P. Richardson, D. Richter, H. F. Sneddon, J.
Med. Chem. 2013, 56, 6007–6021; b) F. Kerton, R. Mar-
riott, in: Alternative Solvents for Green Chemistry, The
Royal Society of Chemistry, 2013, pp 51–81; c) F. T. K.
Tanaka, in: Solvent-Free Organic Synthesis, Wiley-
VCH, UK, 2009; d) P. J. Walsh, H. Li, C. A. de Parrodi,
Chem. Rev. 2007, 107, 2503–2545; e) J. M. DeSimone,
Science 2002, 297, 799–803.
[3] a) T. Ohshima, Y. Hayashi, K. Agura, Y. Fujii, A. Yosh-
iyama, K. Mashima, Chem. Commun. 2012, 48, 5434;
b) B. Gnanaprakasam, D. Milstein, J. Am. Chem. Soc.
2011, 133, 1682–1685; c) C. Chen, Y. Zhang, S. H.
Hong, J. Org. Chem. 2011, 76, 10005–10010; d) X.
Yang, V. B. Birman, Org. Lett. 2009, 11, 1499–1502;
e) K. E. Price, C. Larrivee-Aboussafy, B. M. Lillie,
R. W. McLaughlin, J. Mustakis, K. W. Hettenbach, J. M.
Hawkins, R. Vaidyanathan, Org. Lett. 2009, 11, 2003–
2006; f) C. Sabot, K. A. Kumar, S. Meunier, C. Mios-
kowski, Tetrahedron Lett. 2007, 48, 3863–3866; g) M.
Movassaghi, M. A. Schmidt, Org. Lett. 2005, 7, 2453–
2456; h) C. Han, J. P. Lee, E. Lobkovsky, J. A. Porco, J.
Am. Chem. Soc. 2005, 127, 10039–10044; i) Y. Kuroki,
K. Ishihara, N. Hanaki, S. Ohara, H. Yamamoto, Bull.
Chem. Soc. Jpn. 1998, 71, 1221–1230; j) K. Ishihara, Y.
Kuroki, N. Hanaki, S. Ohara, H. Yamamoto, J. Am.
Chem. Soc. 1996, 118, 1569–1570.
[10] [N-(2-Phenylethyl)-N-(phenylmethyl)benzene]ethanam-
AHCTUNGTREGUNiNN ne was observed as a by-product (7% in the case of
a 1.25 mol% catalyst loading).
[11] a) P. Fristrup, M. Tursky, R. Madsen, Org. Biomol.
Chem. 2012, 10, 2569–2577; b) H. Li, G. Lu, J. Jiang, F.
Huang, Z.-X. Wang, Organometallics 2011, 30, 2349–
2363; c) K. Fujita, T. Yoshida, Y. Imori, R. Yamaguchi,
Org. Lett. 2011, 13, 2278–2281; d) M. Zhu, K. Fujita, R.
Yamaguchi, Org. Lett. 2010, 12, 1336–1339; e) R. Ya-
maguchi, Z. Mingwen, S. Kawagoe, C. Asai, K. Fujita,
Synthesis 2009, 1220–1223; f) R. Yamaguchi, S. Kawa-
goe, C. Asai, K. Fujita, Org. Lett. 2008, 10, 181–184;
g) O. Pꢃmies, J.-E. Bꢁckvall, Chem. Eur. J. 2001, 7,
5052–5058.
[4] a) N. T. Patil, V. S. Shinde, B. Gajula, Org. Biomol.
Chem. 2012, 10, 211–224; b) S. J. Broadwater, S. L.
Roth, K. E. Price, M. Kobaslija, D. T. McQuade, Org.
Biomol. Chem. 2005, 3, 2899–2906; c) A. Ajamian, J. L.
Gleason, Angew. Chem. 2004, 116, 3842–3848; Angew.
Chem. Int. Ed. 2004, 43, 3754–3760.
[12] S. N. Rao, D. C. Mohan, S. Adimurthy, Org. Lett. 2013,
15, 1496–1499.
[5] a) Y. Zhang, C.-S. Lim, D. S. B. Sim, H.-J. Pan, Y. Zhao,
Angew. Chem. Int. Ed. 2014, 53, 1399–1403; b) K.-i.
Shimizu, N. Imaiida, K. Kon, S. M. A. Hakim Siddiki,
A. Satsuma, ACS Catal. 2013, 3, 998–1005; c) A.
Wetzel, S. Wçckel, M. Schelwies, M. K. Brinks, F. Ro-
minger, P. Hofmann, M. Limbach, Org. Lett. 2013, 15,
266–269; d) T. Suzuki, Chem. Rev. 2011, 111, 1825–
1845; e) S. Bꢁhn, S. Imm, L. Neubert, M. Zhang, H.
Neumann, M. Beller, ChemCatChem 2011, 3, 1853–
1864; f) A. J. A. Watson, J. M. J. Williams, Science 2010,
329, 635–636; g) G. E. Dobereiner, R. H. Crabtree,
Chem. Rev. 2010, 110, 681–703; h) G. Guillena, D. J.
Ramꢂn, M. Yus, Chem. Rev. 2010, 110, 1611–1641.
[6] a) I. Cumpstey, S. Agrawal, K. E. Borbas, B. Martin-
Matute, Chem. Commun. 2011, 47, 7827–7829; b) K.
Fujita, Y. Enoki, R. Yamaguchi, Tetrahedron 2008, 64,
1943–1954; c) K. Fujita, R. Yamaguchi, Synlett 2005,
2005, 560–571; d) K. Fujita, T. Fujii, R. Yamaguchi,
Org. Lett. 2004, 6, 3525–3528; e) K. Fujita, Z. Li, N.
Ozeki, R. Yamaguchi, Tetrahedron Lett. 2003, 44, 2687–
2690; f) K. Fujita, K. Yamamoto, R. Yamaguchi, Org.
Lett. 2002, 4, 2691–2694; g) S. Sakaguchi, T. Yamaga, Y.
Ishii, J. Org. Chem. 2001, 66, 4710–4712.
[13] Y.-H. Chang, Y. Nakajima, F. Ozawa, Organometallics
2013, 32, 2210–2215.
[14] S. Li, K. Huang, J. Zhang, W. Wu, X. Zhang, Org. Lett.
2013, 15, 3078–3081.
[15] S. Kumar, R. Sharma, M. Garcia, J. Kamel, C. McCar-
thy, A. Muth, O. Phanstiel, J. Org. Chem. 2012, 77,
10835–10845.
[16] B. T. Cho, S. K. Kang, Tetrahedron 2005, 61, 5725–5734.
[17] Q. Michaudel, D. Thevenet, P. S. Baran, J. Am. Chem.
Soc. 2012, 134, 2547–2550.
[18] Q. Lei, Y. Wei, D. Talwar, C. Wang, D. Xue, J. Xiao,
Chem. Eur. J. 2013, 19, 4021–4029.
[19] O.-Y. Lee, K.-L. Law, D. Yang, Org. Lett. 2009, 11,
3302–3305.
[20] P. J. Garratt, S. Travard, S. Vonhoff, A. Tsotinis, D.
Sugden, J. Med. Chem. 1996, 39, 1797–1805.
[21] C. Brinkmann, A. G. M. Barrett, M. S. Hill, P. A. Pro-
copiou, J. Am. Chem. Soc. 2012, 134, 2193–2207.
[22] M. Langlois, B. Bremont, S. Shen, A. Poncet, J. An-
drieux, S. Sicsic, I. Serraz, M. Mathe-Allainmat, P.
Renard, P. Delagrange, J. Med. Chem. 1995, 38, 2050–
2060.
Adv. Synth. Catal. 2014, 356, 2653 – 2660
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
2659

FULL PAPERS
Jeongbin Lee et al.
[23] F. Nador, Y. Moglie, A. Ciolino, A. Pierini, V. Dorn,
M. Yus, F. Alonso, G. Radivoy, Tetrahedron Lett. 2012,
53, 3156–3160.
[24] X. Cui, Y. Zhang, F. Shi, Y. Deng, Chem. Eur. J. 2011,
17, 2587–2591.
[26] A. G. M. Barrett, C. Brinkmann, M. R. Crimmin, M. S.
Hill, P. Hunt, P. A. Procopiou, J. Am. Chem. Soc. 2009,
131, 12906–12907.
[27] K. Singh, K. Singh, Tetrahedron 2009, 65, 10395–10399.
[28] A. M. Dumas, G. A. Molander, J. W. Bode, Angew.
Chem. 2012, 124, 5781–5784; Angew. Chem. Int. Ed.
2012, 51, 5683–5686.
[25] S. M. Mali, R. D. Bhaisare, H. N. Gopi, J. Org. Chem.
2013, 78, 5550–5555.
[29] S. Sato, T. Sakamoto, E. Miyazawa, Y. Kikugawa, Tetra-
hedron 2004, 60, 7899–7906.
2660
asc.wiley-vch.de
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 2653 – 2660