Copper-catalyzed oxidative amidation of aldehydes with amine salts: Synthesis of primary, secondary, and tertiary amides

Article abstract of DOI:10.1021/jo301252c

A practical method for the amidation of aldehydes with economic ammonium chloride or amine hydrochloride salts has been developed for the synthesis of a wide variety of amides by using inexpensive copper sulfate or copper(I) oxide as a catalyst and aqueous tert-butyl hydroperoxide as an oxidant. This amidation reaction is operationally straightforward and provides primary, secondary, and tertiary amides in good to excellent yields for most cases utilizing inexpensive and readily available reagents under mild conditions. In situ formation of amine salts from free amines extends the substrate scope of the reaction. Chiral amides are also synthesized from their corresponding chiral amines without detectable racemization. The practicality of this amide formation reaction has been demonstrated in an efficient synthesis of the antiarrhythmic drug N-acetylprocainamide.

Full text of DOI:10.1021/jo301252c

Article
pubs.acs.org/joc
Copper-Catalyzed Oxidative Amidation of Aldehydes with Amine
Salts: Synthesis of Primary, Secondary, and Tertiary Amides
Subhash Chandra Ghosh,† Joyce S. Y. Ngiam,† Abdul M. Seayad,† Dang Thanh Tuan,†
Christina L. L. Chai,†,‡ and Anqi Chen*,†
†Institute of Chemical and Engineering Sciences, Agency for Science, Technology and Research (A*STAR), 8 Biomedical Grove,
Neuros 07-01, Singapore 138665
‡Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543
S
* Supporting Information
ABSTRACT: A practical method for the amidation of aldehydes with economic ammonium chloride or amine hydrochloride
salts has been developed for the synthesis of a wide variety of amides by using inexpensive copper sulfate or copper(I) oxide as a
catalyst and aqueous tert-butyl hydroperoxide as an oxidant. This amidation reaction is operationally straightforward and provides
primary, secondary, and tertiary amides in good to excellent yields for most cases utilizing inexpensive and readily available
reagents under mild conditions. In situ formation of amine salts from free amines extends the substrate scope of the reaction.
Chiral amides are also synthesized from their corresponding chiral amines without detectable racemization. The practicality of
this amide formation reaction has been demonstrated in an efficient synthesis of the antiarrhythmic drug N-acetylprocainamide.
hazardous reagents, and generation of wastes that not only
reduce process efficiency but also pose environmental
problems. To address these challenging problems in amide
synthesis, a plethora of novel amide formation reactions have
been developed,5 such as catalytic acylation of amines with
carboxylic acid,6 dehydrogenative amidation of alcohol,7 amino
carbonylation of haloarenes,8 hydroamination of alkynes,9
transamidation of primary amides,10 and oxidative amidation
of aldehydes.11−21 Among these, oxidative amidation of
aldehydes with amine salts (Scheme 1) is highly synthetically
useful as both starting materials are readily available and less
hazardous than those traditionally used such as acid halides.
INTRODUCTION
■
Amide bond formation is one of the most often used
transformations in the synthesis of pharmaceuticals, fine
chemicals, and polymers (Figure 1).1 It is estimated that
more than 25% of known drugs contain an amide group.2 The
most frequently used amide formations involve the reaction of
an amine (including ammonia) with activated carboxylic acid
derivatives3 or coupling with carboxylic acids mediated by a
coupling reagent.4 These existing methods have several
common drawbacks, such as poor atom-efficiency, use of
Scheme 1. Oxidative Amidation of Aldehydes with Amine
Hydrochloride Salts
Oxidative amidation of aldehydes with amines was first
reported by Nakagawa et al. in 1966 by using stoichiometric
amounts of nickel peroxide as the oxidant.11 Subsequently,
several groups have developed new methods for the direct
conversion of amides from aldehydes using iodine,12 NBS,13
manganese oxide,14 3,3′,5,5′-tetra-tert-butyldiphenoquinone,15
and TBHP16 as oxidizing agents. More efficient catalytic
Received: June 16, 2012
Figure 1. Examples of molecules containing an amide group.
© XXXX American Chemical Society
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methods using N-heterocyclic carbene (NHC),17 copper/
silver,18 transition metals (Pd, Rh and Ru),19 and lanthanides20
have also been reported.
Table 1. Screening of Catalysts and Optimization of
Reaction Conditions for Secondary Amide Formation
a
Among these methods, oxidative amidation of aldehydes with
amine hydrochlorides using CuI−AgIO3 as the catalyst and
inexpensive aqueous tert-butyl hydroperoxide (T-Hydro) as the
oxidant reported by Li et al.18 is an attractive method for
exploration. This pioneering work provides an efficient and
greener method for amide formation. However, the reaction
requires a dual catalyst system and has a narrower substrate
scope, only applicable to the synthesis of secondary amides.
Hence the search of a less costly and simpler catalyst system
with broader subtract scope remains a challenge from a
practicality point of view. As part of our ongoing effort to
develop novel efficient methods for amide bond formation,21
we report herein an improved oxidative amidation of aldehydes
with amine salts for the synthesis of primary, secondary and
tertiary amides, using inexpensive and readily available copper
compounds as the catalysts.
b
T
yield
entry
catalyst
Cu2O
base
oxidant
solvent
(°C)
(%)
1
2
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
/
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
TBHP CH3CN
80
80
80
80
80
80
80
80
80
40
rt
84
75
70
66
65
69
69
82
86
86
88
CuCl
3
CuCl2.2H2O
CuBr
4
5
CuOAc
6
Cu(OAc)2
Cu(OTf)2
7
8
Cu powder
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
/
9
10
11
12
13
14
15
16
17
18
19
20
c
rt
74
/
CH3CN
rt
0
15
14
62
55
40
53
RESULTS AND DISCUSSION
■
TBHP CH3CN
TBHP CH3CN
TBHP DCM
TBHP DMF
TBHP THF
rt
At the outset, a model reaction of 4-methylbenzaldehyde and
glycine methyl ester hydrochloride to form methyl 2-(4-
methylbenzamido)acetate was chosen to identify the catalytic
system. With T-Hydro as the oxidant, a wide range of copper
salts were screened for the reaction and most of them provided
good to excellent yield of the amide (entries 1−9) with
CuSO4·5H2O (86%, entry 9) performed slightly better over
other catalysts. As CuSO4·5H2O is the least expensive among
the copper catalyst studied and gave best conversion, it was
selected for further optimization. Decreasing the reaction
temperature from 80 to 40 °C or ambient temperature did not
affect the reaction (entry 10−11), demonstrating the mildness
and convenience of operation. With 1 mol % catalyst loading,
the yield of amide decreased slightly to 74% (entry 12).
Control experiments (entries 13−15) revealed that an oxidant
(T-Hydro, entry 13), a copper catalyst (entry 14), and a base
(entry 15) are all necessary for the amide formation. The effect
of solvents was investigated, and it was found that acetonitrile is
superior to other solvents (entries 16−20). Screening a range of
bases revealed that CaCO3 performed best among other bases
including K2CO3, Na2CO3, and NaHCO3 (not included in
Table 1). Other oxidants including H2O2, NaOCl, NaO2Cl,
PhI(OAc)2, TEMPO, Oxone, and air were also screened, but in
all cases only 0−5% amide product formation was observed
(not included in Table 1).
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
rt
CaCO3
CaCO3
CaCO3
CaCO3
CaCO3
rt
rt
rt
TBHP toluene
rt
d
TBHP CH3CN +
H2O
rt
36
a
The reaction was carried out with 4-methylbenzaldehyde (1.0 mmol),
glycine methyl ester HCl salt (1.2 mmol), base (1.1 mmol), oxidant
(70 wt% TBHP in water, 1.1 mmol), Cu catalyst (5 mol % unless
otherwise mentioned), and solvent (0.2 mL) at the temperature
indicated overnight. Yields were determined by quantitative GC
analysis using dodecane as an internal standard. 1 mol % of catalyst
b
c
d
was used. CH3CN/H2O = 1:1 (v/v), 0.2 mL.
reaction was applied successfully to the synthesis of an
antiarrhythmic drug, N-acetylprocainamide (3t), from 4-
acetamidobenzaldehyde and 2-diethylaminoethylamine hydro-
chloride salt generated in situ from the free amine.
Encouraged by the facile synthesis of secondary amides from
primary amine salts, the scope of the reaction was extended to
the formation of more challenging tertiary amides which were
not previously accessible.18 However, the reaction of
benzaldehyde with sarcosine methyl ester hydrochloride (4f)
gave only 60% yield of the desired amide (5f) after 24 h
reaction at room temperature with unreacted starting materials
being recovered (Table 3). It was suspected that the slower
reaction rate could be due to the increased steric hindrance of
secondary amine. We reoptimized the reaction conditions and
delighted to find that the reaction carried out at 60 °C for 6 h
afforded the desired amide in 92% yield (5f). Under these
conditions, a range of tertiary amides were obtained in good to
excellent yield (5a−q). Interestingly, electron-deficient alde-
hydes gave much improved yields (5j−m) than in the case of
secondary amides. The broad applicability of this reaction was
well demonstrated in its substrate scope for both secondary
amine salts and aldehydes as well as good compatibility with
various functional groups (5c−f, i−m). Similar to the case of
secondary amide formation, chiral amide (5e) was obtained
with methyl L-prolinate hydrochloride. Nevertheless, aliphatic
aldehydes remained difficult substrates, giving tertiary amides in
only moderate yields (5o−p). When methoxymethylamine
To understand the substrate scope of this reaction, a wide
range of aldehydes and amine hydrochlorides were reacted
under the optimized reaction conditions (Table 2). Good to
excellent yields of secondary amides were obtained in most
cases (3a−g). However, with sterically bulky tert-butyl amine
hydrochloride a diminished yield was obtained (3j). Electron-
donating or electron-withdrawing substituents on aldehydes
produce good to excellent yields of secondary amides (3k−p),
indicating that the reaction is not sensitive to electronic effects.
Various functional groups such as ester, alcohol, and alkyl
chlorides are well-suited for this reaction. Chiral amine salt
derived from L-amino acids provided chiral amides in high
yields (3d−f) without detectable racemization when compared
with the HPLC chromatograms of the racemic compounds.
Aliphatic (3q, r) and heteroaromatic (3s) aldehydes were less
favored substrates, providing lower yields of amide products
similar to the results reported by other groups.18,20a The
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a
Table 2. CuSO4-Catalyzed Synthesis of Secondary Amides from Aldehydes and Primary Amine Hydrochloride Salts
a
Reactions were carried out with an aldehyde (1.0 mmol), primary amine hydrochloride salt (1.2 mmol), calcium carbonate (1.1 mmol), and TBHP
b
c
(70 wt % in water, 1.1 mmol) in acetonitrile (0.2 mL) at room temperature under argon atmosphere. Isolated yields. Reaction was carried out by in
situ HCl salt formation. Reaction was carried out at 60 °C. 4-Methoxybenzoic acid (18%) was also isolated. The salt 2k was formed in situ by
d
e
f
reaction with concd HCl.
hydrochloride was used, Weinreb amide 5g was obtained in
moderate yield. As Weinreb amides which are versatile
synthetic intermediates,22 this novel method for their
preparation warrants further exploration.
oxide was found to be the most effective although the yield
remained at ∼30%. We then realized that the low solubility of
ammonium chloride in acetonitrile could be detrimental to the
reaction. This was indeed proved to be a key factor because
addition of water significantly improved the yield (entries 4 and
5). A ratio of acetonitrile/water = 2:1 was found to be the
optimal solvent system for this reaction. With this encouraging
improvement, a wide variety of inorganic and organic bases,
including K2CO3, Cs2CO3, LiOH, Na2CO3, NaHCO3, CaO,
1,8-diazabicycloundec-7-ene (DBU), and N, N-diisopropyle-
thylamine (DIPEA), were screened (not included in Table 4),
and K2CO3 was found most effective for this transformation
(entry 6). Further optimization concluded that with 1.5 equiv
of TBHP and at an elevated reaction temperature of 80 °C,
66% yield of the desired amide was obtained in only 4 h of
reaction time (entry 7). A variety of ammonium sources
including ammonium hydroxide (42%, entry 8), ammonium
Given the prevalence of the primary amides in biological,
pharmaceutical, synthetic, and polymer chemistry,23 we sought
to extend our facile and economic amidation method to
primary amides using inexpensive ammonium chlorides as an
ammonia source. However, our initial reaction of 4-
methylbenzaldehyde with ammonium chloride using the
previous conditions for tertiary amide formation was
disappointing, with 4-methylbenzamide formed in only 18%
yield (Table 4, entry 1). The major byproduct was identified as
the corresponding carboxylic acid, which was formed by
competitive oxidation reaction of the aldehyde. After screening
a range of copper salts, including CuCl, CuCl2·2H2O, CuBr,
Cu(OAc)2, CuOAc, Cu2O, Cu(OTf)2, and CuI, copper(I)
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a
Table 3. CuSO4-Catalyzed Synthesis of Tertiary Amides from Aldehydes and Secondary Amine Hydrochloride Salts
a
The reactions were carried out with an aldehyde (1.0 mmol), a secondary amine hydrochloride salt (1.2 mmol), calcium carbonate (1.1 mmol), and
b
c
TBHP (70 wt % in water, 1.1 mmol) in acetonitrile (0.2 mL) at 60 °C for 6 h under argon atmosphere. Isolated yields. Reaction was carried out at
room temperature for 24 h. Formation of 4-methoxybenzoic acid (20%) was observed.
d
carbonate (54%, entry 9), ammonium sulfate (52%, entry 10),
and ammonium acetate (44%, entry 11) were also screened,
and ammonium chloride used initially was found to be the best.
Increasing the amount of ammonium chloride (2.5 equiv) did
not improve the yield any further (67%, entry 12).
cinnamaldehyde also afforded moderate yield of the primary
amide (6q). Functional groups such as ester, cyano, and
halogens are tolerant under the reaction conditions. Using
15NH4Cl as a convenient nitrogen isotope labeling reagent, the
synthesis of a 15N-isotope labeled primary amide (6r) was
successfully demonstrated. This provides a facile access to 15N-
isotope-labeled primary amides which are valuable for chemical,
biological, and medical studies.24
The mechanism of this copper-catalyzed oxidative amidation
can be assumed to be similar to what has been proposed by Li
et al.18 and that of the iron-catalyzed reaction suggested by us,21
i.e., the reaction proceeds via a hemiaminal intermediate that is
oxidized to amide via a free-radical mechanism (Scheme 2).
The free-radical nature of the reaction is confirmed by the
addition of 2,6-di-tert-butyl-4-methylphenol (BHT, 1 equiv)
which completely inhibited the formation of the amide product.
Similar to the case of iron-catalyzed amidation reaction, it was
found that the use of amines salts is necessary to avoid N-
oxidation of free amines by TBHP25 while the use of insoluble
With the optimized reaction conditions, the amidation
reaction of a variety of aromatic, unsaturated, and hetero-
aromatic aldehydes with ammonium chloride were performed.
The corresponding primary amides were obtained in moderate
to good yields (Table 5). In general, electron-neutral and -rich
substrates (6a, 6b, 6c, and 6e) gave better yields than electron-
deficient ones (6i−o). Substituents at different positions of the
phenyl ring affected the yield of the amide to some extent, such
that substituents present at the para (6b, 6e) and meta
positions (6c) were more reactive than those at the ortho
position (6d, 6f). The lower reactivity of ortho-substituted
substrates may be attributed to steric factors. The steric
sensitivities of the reaction is also observed with 1-
naphthaldehyde, which is less reactive than 2-naphthaldehyde.
All electron-deficient aldehydes gave moderate yields of the
primary amides (6i−n). Conjugated aldehydes such as
D
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Table 4. Catalyst Screening and Condition Optimization for
the Primary Amide Formation
Table 5. Cu2O-Catalyzed Synthesis of Primary Amides from
Aldehydes and Ammonium Chloride
a
a,b
b
T
time yield
entry
catalyst
solvent
base
(°C) (h)
(%)
1
2
3
4
CuSO4·5H2O ACN
CaCO3
CaCO3
CaCO3
CaCO3
60
60
40
40
6
6
18
32
31
45
Cu2O
Cu2O
Cu2O
ACN
ACN
24
24
ACN + H2O
(10:1)
5
6
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
ACN + H2O
(2:1)
CaCO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
40
40
80
80
80
80
80
80
24
24
4
51
54
ACN + H2O
(2:1)
c
7
ACN + H2O
(2:1)
66
d
8
ACN + H2O
(2:1)
4
42
e
9
ACN + H2O
(2:1)
4
54
f
10
11
12
ACN + H2O
(2:1)
4
52
g
ACN + H2O
(2:1)
4
44
h
ACN + H2O
(2:1)
4
67
a
The reactions were carried out with an aldehyde (1.0 equiv),
ammonium chloride (1.8 equiv), potassium carbonate (1.1 equiv), and
TBHP (70 wt % in water, 1.5 equiv) in 0.2 mL of acetonitrile and 0.1
a
The reactions were carried out with 4-methylbenzaldehyde (1.0
equiv), a copper catalyst (5 mol %), ammonium chloride (1.8 equiv), a
base (1.1 equiv), and TBHP (70 wt % in water, 1.1 equiv) in 0.2 mL of
acetonitrile with or without water at 80 °C for 6−24 h in a closed
b
mL of water at 80 °C for 4 h in a closed vessel. Isolated yields.
Scheme 2. Proposed Mechanism for Cu-Catalyzed Oxidative
Amidation of Aldehydes with Amine Salts
b
vessel, unless otherwise noted. Yields were determined by
quantitative GC analysis with dodecane as an internal standard. 1.5
c
d
equiv of TBHP was used. Ammonium hydroxide was used.
e
f
Ammonium carbonate was used. Ammonium sulfate was used.
Ammonium acetate was used. 2.5 equiv of ammonium chloride was
g
h
used with 1.5 equiv of TBHP and 1.5 equiv of K2CO3. ACN =
acetonitrile.
dodecane as an internal standard. Flash column chromatography
purification of compounds was carried out by gradient elution using
ethyl acetate (EA) in light petroleum ether (PE) unless otherwise
stated. Enantiomeric excess for chiral amide products was determined
by HPLC analysis using a chiral HPLC column and a UV detector.
General Procedure for the Oxidative Amidation of
Aldehydes with Primary Amine Hydrochloride Salts. To a
mixture of CuSO4·5H2O (12.5 mg, 0.05 mmol, 5.0 mol %), primary
amine hydrochloride salt 2 (1.2 mmol, 1.2 equiv), and CaCO3 (110
mg, 1.1 mmol, 1.1 equiv) in acetonitrile (0.2 mL) were added aldehyde
1 (1 mmol, 1 equiv) and TBHP (70 wt % in H2O, 0.16 mL, 1.1 mmol,
1.1 equiv) under argon atmosphere at room temperature. The reaction
vessel was capped and allowed to stir at room temperature overnight.
The volatiles were removed under reduced pressure, and the crude
product was purified by flash chromatography on silica gel by gradient
elution with ethyl acetate in petroleum ether to obtain the amide
product 3. All secondary amides were identified by full spectroscopic
characterization and comparison with literature or analogous literature
data.
CaCO3 as the base enables slow formation of the amine and
thus minimizes the undesired amine oxidation reactions.
CONCLUSION
■
In conclusion, we have identified inexpensive CuSO4·5H2O as a
catalyst for the efficient oxidative amidation of aldehydes with
amine hydrochloride salts for the synthesis of secondary and
tertiary amides. Furthermore, we have, for the first time,
achieved the formation of primary amides by oxidative
amidation of aldehydes with inexpensive ammonium chloride
by using Cu2O as a catalyst. These novel cost-effective amide
formation reactions provide practical alternatives for the
synthesis of amides under mild conditions.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were carried out in oven-
dried glassware under an inert atmosphere of dry argon or nitrogen.
All aldehydes and amine hydrochloride salts were obtained from
N-Ethylbenzamide (3a).21 White solid; 111 mg, 74% yield. 1H
NMR (400 MHz, CDCl3): δ 7.80−7.76 (m,2H), 7.53−7.48 (m, 1H),
7.47−7.41 (m, 2H), 6.15 (brs, 1H), 3.51 (qd, J = 7.3, 5.7 Hz, 2H), 1.28
(t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 167.5, 134.8,
131.3, 128.5, 126.8, 34.9, 14.9.
commercial sources and used as received. H/13C NMR spectra were
1
measured at 400/100 MHz, respectively, in CDCl3 unless otherwise
stated, using either TMS or the undeuterated solvent residual signal as
the reference. Chemical shifts are given in ppm, and J values are given
in hertz. Optical rotations were measured using an automatic digital
polarimeter. Mass spectra were obtained by the electrospray ionization
time-of-flight (ESI-TOF) mass spectrometry. Anhydrous solvents were
used for moisture-sensitive reactions. GC yields were obtained using
N-Benzylbenzamide (3b).21 White solid; 181 mg, 86% yield. H
1
NMR (400 MHz, CDCl3): δ 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,
E
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CDCl3): δ 167.5, 138.3, 134.6, 131.7, 128.9, 128.7, 128.1, 127.8, 127.1,
44.3.
N-(4-Chlorobenzoyl)glycine Methyl Ester (3m).21 White solid: 176
1
mg, 77% yield. H NMR (400 MHz, CDCl3): δ 7.78−7.72 (m, 2H),
N-Benzoylglycine Methyl Ester (3c).21 White solid; 161 mg, 83%
7.46−7.39 (m, 2H), 6.64 (br s, 1H), 4.24 (d, J = 5.0 Hz, 2H), 3.81 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 170.4, 166.3, 138.1, 132.0,
128.9, 128.5, 52.5, 41.7.
1
yield. H NMR (400 MHz, CD3OD): δ 7.86−7.84 (m, 2H), 7.57−
7.54 (m, 1H), 7.52−7.45 (m, 2H), 4.12 (s, 2H), 3.75 (s, 3H). 13C
NMR (100 MHz, CD3OD): δ 171.9, 170.5, 135.0, 133.0, 129.6, 128.4,
52.6, 42.4.
N-(4-Bromobenzoyl)glycine Methyl Ester (3n).21 White solid; 218
1
mg, 80% yield. H NMR (400 MHz, CDCl3): δ 7.70−7.64 (m, 2H),
N-Benzoyl L-phenylalanine Methyl Ester (3d).21 White solid; 285
mg, 96% yield. [α]25D = +98.1 (c 1, CHCl3) [lit.21 [α]24D = +96.8 (c 1,
CHCl3)]. 1H NMR (400 MHz, CDCl3): δ 7.79−7.70 (m, 2H), 7.56−
7.48 (m, 1H), 7.48−7.40 (m, 2H), 7.33−7.26 (m, 3H), 7.17 (dd, J =
7.8, 1.5 Hz, 2H), 6.60 (d, J = 7.1 Hz, 1H), 5.08 (dt, J = 7.5, 5.7 Hz,
1H), 4.23 (q, J = 7.1 Hz, 2H), 3.28 (qd, J = 13.8, 5.7 Hz, 2H), 1.29 (t,
J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 171.8, 166.9, 136.1,
134.2, 131.9, 129.6, 128.8, 128.7, 127.3, 127.1, 61.8, 53.7, 38.1, 14.3.
N-Benzoyl-L-valine Methyl Ester (3e).21 White solid; 206 mg, 88%
yield. [α]25D = +42.7 (c 1, CHCl3) [lit.21 [α]24D = +43.0 (c 1, CHCl3)].
HPLC (column: Chiracel AD-H, n-hexane/IPA 90/10 (v/v), flow
7.60−7.55 (m, 2H), 6.67 (brs, 1H), 4.23 (d, J = 5.1 Hz, 2H), 3.80 (s,
3H). 13C NMR (100 MHz, CDCl3): δ 170.5, 166.6, 132.6, 132.0,
128.8, 126.7, 52.6, 41.9.
Methyl 4-((2-Methoxy-2-oxoethyl)carbamoyl)benzoate (3o).21
1
White solid; 181 mg, 72% yield. H NMR (400 MHz, CDCl3): δ
8.16−8.07 (m, 2H), 7.93−7.82 (m, 2H), 6.68 (s, 1H), 4.27 (d, J = 5.0
Hz, 2H), 3.95 (s, 3H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
170.32, 166.52, 166.21, 137.56, 133.09, 129.91, 127.14, 52.57, 52.40,
41.80.
N-(4-Cyanobenzoyl)glycine Methyl Ester (3p).21 White solid; 116
1
mg, 46% yield. Mp: 157−161 °C. H NMR (400 MHz, CDCl3): δ
1
rate: 0.5 mL/min) tR 18.837 min, ee = 99%. H NMR (400 MHz,
7.95−7.87 (m, 2H), 7.79−7.71 (m, 2H), 6.72 (br s, 1H), 4.25 (d, J =
5.0 Hz, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.2,
165.6, 137.6, 132.5, 127.8, 117.9, 115.5, 52.6, 41.8. HRMS (ESI): m/z
= 241.0591 [M + Na]+, calcd for C11H10N2NaO3 241.0589.
N-Cyclohexanoylglycine Methyl Ester (3q).21 White solid; 84 mg,
42% yield. 1H NMR (400 MHz, CDCl3): δ 5.98 (br s, 1H), 4.03 (d, J
= 5.1 Hz, 2H), 3.75 (s, 3H), 2.15 (tt, J = 11.7, 3.5 Hz, 1H), 1.89−1.86
(m, 2H), 1.80−1.74 (m, 2H), 1.69−1.60 (m, 2H), 1.44 (qd, J = 12.2,
2.9 Hz, 2H), 1.34−1.17 (m, 3H). 13C NMR (100 MHz, CDCl3): δ
176.3, 170.8, 52.5, 45.3, 41.2, 29.7, 25.9, 25.8.
CDCl3): δ 7.80 (dd, J = 8.3, 1.1 Hz, 2H), 7.62−7.37 (m, 3H), 6.64 (d,
J = 7.5 Hz, 1H), 4.78 (dd, J = 8.6, 4.9 Hz, 1H), 3.77 (s, 3H), 2.27 (qd,
J = 11.9, 6.9 Hz, 1H), 1.00 (dd, J = 9.1, 6.9 Hz, 6H). 13C NMR (100
MHz, CDCl3): δ 172.8, 167.4, 134.3, 131.8, 128.7, 127.2, 57.6, 52.3,
31.8, 19.1, 18.1.
N-Benzoyl-D/L-valine Methyl Ester.21 White solid; 208 mg, 89%
yield. HPLC (column: Chiracel AD-H, n-hexane/IPA 90/10 (v/v),
flow rate: 0.5 mL/min) tR‑D 14.669, tR‑L 18.799 min, ee = 0%. 1H NMR
(400 MHz, CDCl3): δ 7.80 (dd, J = 8.3, 1.1 Hz, 2H), 7.62−7.37 (m,
3H), 6.64 (d, J = 7.5 Hz, 1H), 4.78 (dd, J = 8.6, 4.9 Hz, 1H), 3.77 (s,
3H), 2.27 (qd, J = 11.9, 6.9 Hz, 1H), 1.00 (dd, J = 9.1, 6.9 Hz, 6H).
N-Benzoyl-L-leucine Methyl Ester (3f).26 White solid; 214 mg, 86%
yield. [α]25 = +25.3 (c 1.3, CHCl3) [lit.26 [α]19 = +39.9 (c 1,
N-Hexanoylglycine Methyl Ester (3r).21 Pale yellow liquid; 83 mg,
44% yield. 1H NMR (400 MHz, CDCl3): δ 6.01 (br s, 1H), 4.04 (d, J
= 5.2 Hz, 2H), 3.75 (s, 3H), 2.23 (t, J = 7.4 Hz, 2H), 1.64 (qd, J = 7.4,
2.1 Hz, 2H), 1.35−1.24 (m, 4H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 173.5, 170.7, 52.4, 41.3, 36.5, 31.5, 25.4, 22.5,
14.0.
D
D
1
CHCl3)]. H NMR (400 MHz, CDCl3): δ 7.80−7.77(m, 2H), 7.49−
7.46 (m, 1H), 7.42−7.39 9 m, 2H), 6.62 (d, J = 7.9 Hz, 1H), 4.88−
4.83 (m, 1H), 1.82−1.64 (m, 3H), 0.96 (dd, J = 7.2, 6.3 Hz, 6H). 13C
NMR (100 MHz, CDCl3): δ 173.8, 167.2, 134.1, 131.8, 128.7, 127.2,
52.4, 51.3, 42.0, 25.1, 22.9, 22.2. HRMS (ESI): m/z = 272.1260 [M +
Na]+, calcd for C14H19NNaO3 272.1263.
Methyl 2-(1-Methyl-1H-indole-3-carboxamido)acetate (3s).21
1
White solid; 121 mg, 49% yield. H NMR (400 MHz, CDCl3): δ
7.65 (d, J = 8.0 Hz, 1H), 7.40−7.30 (m, 2H), 7.16 (ddd, J = 7.9, 6.8,
1.1 Hz, 1H), 6.95 (s, 1H), 6.68 (br s, 1H), 4.24 (d, J = 5.2 Hz, 2H),
4.04 (s, 3H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 170.4,
162.5, 139.2, 131.1, 126.0, 124.3, 122.0, 120.6, 110.2, 104.5, 52.5, 41.3,
31.5.
N-(2-Chloroethyl)benzamide (3g).21 White solid; 168 mg, 92%
yield; 1H NMR (400 MHz, CDCl3): δ 7.83−7.74 (m, 2H), 7.56−7.48
(m, 1H), 7.49−7.39 (m, 2H), 6.62 (br s, 1H), 3.85−3.77 (m, 2H),
3.73 (dd, J = 8.1, 3.1 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ 167.8,
134.3, 131.9, 128.8, 127.1, 44.3, 41.8.
N-Acetylprocainamide (3t).21 Pale yellow solid; 225 mg, 81% yield.
1H NMR (400 MHz, CD3OD): δ 7.83−7.75 (m, 2H), 7.65 (d, J = 8.8
N-(5-Hydroxypentyl)benzamide (3h).27 White solid; 104 mg, 50%
yield. 1H NMR (400 MHz, CDCl3): δ 7.86−7.71 (m, 2H), 7.49−7.45
(m, 1H), 7.44−7.33 (m, 2H), 6.46 (br s, 1H), 3.64 (t, J = 6.3 Hz, 2H),
3.50−3.30 (m, 2H), 2.18 (br s, 1H), 1.76−1.54 (m, 4H), 1.54−1.35
(m, 2H). 13C NMR (100 MHz, CDCl3): δ 167.9, 134.7, 131.5, 128.6,
127.0, 62.6, 40.0, 32.2, 29.5, 23.2. HRMS (ESI): m/z = 230.1153 [M +
Na]+, calcd for C12H17NNaO2 230.1157
Hz, 2H), 3.53−3.45 (m, 2H), 2.71 (dd, J = 7.7, 6.6 Hz, 2H), 2.65 (q, J
= 7.2 Hz, 4H), 2.14 (s, 3H), 1.09 (t, J = 7.2 Hz, 6H). 13C NMR (100
MHz, CD3OD): δ 171.8, 169.5, 143.2, 130.6, 129.1, 120.3, 52.6, 48.2,
38.3, 23.9, 11.6.
General Procedure for the Oxidative Amidation of
Aldehydes with Secondary Amine Hydrochloride Salts. To a
mixture of CuSO4·5H2O (12.5 mg, 0.05 mmol, 5.0 mol %), secondary
amine hydrochloride salt 4 (1.2 mmol, 1.2 equiv), and CaCO3 (110
mg, 1.1 mmol, 1.1 equiv) in acetonitrile (0.2 mL) were added aldehyde
1 (1 mmol, 1 equiv) and TBHP (70 wt % in H2O, 0.16 mL, 1.1 mmol,
1.1 equiv) under argon atmosphere at room temperature. The reaction
vessel was capped and allowed to stir at 60 °C for 6 h. The volatiles
were removed under reduced pressure and the crude product was
purified by flash chromatography on silica gel by gradient elution with
ethyl acetate in petroleum ether to obtain the amide product 5. All
tertiary amides were identified by full spectroscopic characterization
and comparison with literature or analogous literature data.
N,N-Dimethylbenzamide (5a).21 Colorless liquid; 100 mg, 67%
yield. 1H NMR (400 MHz, CDCl3): δ 7.44−7.36 (m, 5H), 3.10 (br s,
3H), 2.98 (br s, 3H). 13C NMR (100 MHz, CDCl3): δ 171.6, 136.4,
129.5, 128.3, 127.0, 39.6, 35.3. HRMS (ESI): m/z = 172.0740 [M +
Na]+, calcd for C9H11NNaO 172.0738.
N-(trans-4-Hydroxycyclohexyl)benzamides (3i).21 White solid;
107 mg, 49% yield. 1H NMR (400 MHz, CD3OD): δ 7.80−7.77
(m, 2H), 7.53−7.50 (m, 1H), 7.49−7.41 (m, 2H), 3.88−3.82 (m, 1H),
3.57−3.55 (m, 1H), 2.00 (d, J = 10.0 Hz, 4H), 1.50−1.36 (m, 4H).
13C NMR (100 MHz, CD3OD): δ 169.8, 136.0, 132.5, 129.5, 128.3,
70.5, 49.9, 35.1, 31.5.
N-tert-Butylbenzamide (3j).21 White solid; 84 mg, 47% yield. H
1
NMR (400 MHz, CDCl3): δ 7.74−7.67 (m, 2H), 7.48−7.42 (m, 1H),
7.41−7.34 (m, 2H), 5.98 (br s, 1H), 1.46 (s, 9H). 13C NMR (100
MHz, CDCl3): δ 167.0, 136.1, 131.1, 128.5, 126.8, 51.7, 29.0.
N-(4-Methylbenzoyl)glycine Methyl Ester (3k).21 White solid; 172
1
mg, 83% yield. H NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.2 Hz,
2H), 7.25 (d, J = 7.9 Hz, 2H), 6.61 (br s, 1H), 4.25 (d, J = 5.0 Hz,
2H), 3.80 (s, 3H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): I
170.6, 167.3, 142.3, 130.8, 129.3, 127.1, 52.5, 41.7, 21.5.
N-(4-Methoxybenzoyl)glycine Methyl Ester (3l).21 White solid; 141
N,N-Diethylbenzamide (5b).21 Colorless liquid; 115 mg, 65% yield.
1H NMR (400 MHz, CDCl3): δ 7.46−7.30 (m, 5H), 3.40 (br s, 4H),
1
mg, 63% yield; H NMR (400 MHz, CDCl3) δ 7.82−7.74 (m, 2H),
6.97−6.88 (m, 2H), 6.61 (br s, 1H), 4.23 (d, J = 5.1 Hz, 2H), 3.85 (s,
3H), 3.79 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.7, 166.9,
162.4, 128.9, 125.9, 113.8, 77.3, 77.0, 76.7, 55.4, 52.4, 41.7.
1.17 (br s, 6H). 13C NMR (100 MHz, CDCl3): δ 171.3, 137.3, 129.1,
128.4, 126.3, 43.21, 39.20, 14.11, 12.93.
F
dx.doi.org/10.1021/jo301252c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1-Benzoylpiperidin-4-one (5c).28 Colorless liquid: 134 mg, 70%
yield. 1H NMR (400 MHz, CDCl3): δ 7.95−6.95 (m, 15H), 3.85 (br s,
4H), 2.50 (br s, 4H). 13C NMR (100 MHz, CDCl3): δ 206.7, 171.1,
135.3, 130.4, 128.8, 127.1, 59.5, 41.3. HRMS (ESI): m/z = 226.0829
[M + Na]+, calcd for C12H13NNaO2 226.0844.
(400 MHz, CDCl3): δ 6.67 (br s, 2H), 4.24 (s, 1.2H), 4.01 (s, 0.8H),
3.92−3.79 (m, 9H), 3.79−3.71 (m, 3H), 3.07 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 172.0, 169.6, 153.4, 139.5, 130.9, 104.7, 104.1, 61.0,
56.4, 56.4, 53.4, 53.3, 52.5, 52.3, 49.2, 38.9, 34.5.
N-Cyclohexanoylsarcosine Methyl Ester (5o).21 Colorless liquid;
N-Benzoylmorpholine (5d).21 Colorless liquid; 150 mg, 78% yield.
1H NMR (400 MHz, CDCl3): δ 7.05 (s, 5H), 3.78−3.27 (br s, 8H).
13C NMR (100 MHz, CDCl3): δ 170.5, 135.5, 130.0, 128.7, 127.2,
67.0, 48.2, 42.5.
1
113 mg, 53% yield as a 4.1 mixture of rotamers. H NMR (400 MHz,
CDCl3): δ 4.08 (s, 1.6 H), 4.07 (s, 0.4H) 3.77 (s, 0.6H), 3.70 (s,
2.4H), 3.09 (s, 2.4H), 2.94 (s, 0.6H), 2.54 (tt, J = 11.4, 3.1 Hz, 0.8H),
2.34−2.22 (m, 0.2H), 1.77−1.64(m, 5H), 1.56−1.41 (m, 2H), 1.36−
1.17 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 176.9, 170.1, 52.1,
51.5, 49.5, 42.7, 40.8, 40.6, 36.5, 35.1, 29.5, 29.1, 29.0, 25.9, 25.9, 25.5.
N-Hexanoylsarcosine Methyl Ester (5p).21 Colorless liquid; 86 mg,
43% yield as a 4:1 mixture of rotamers. 1H NMR (400 MHz, CDCl3):
δ 4.11 (s, 1.6H), 4.04 (s, 0.4H), 3.76 (s, 0.6H), 3.71 (s, 2.4H), 3.06 (s,
2.4H), 2.96 (s, 0.6H), 2.42−2.31 (t, J = 7.5 Hz, 1.6H), 2.21 (t, J = 7.5
Hz, 0.4H), 1.72−1.56 (m, 2H), 1.32 (dd, J = 8.6, 5.6 Hz, 4H), 0.95−
0.83 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 174.1, 173.6, 170.1,
169.7, 52.5, 52.1, 51.7, 49.4, 36.7, 35.0, 33.2, 33.0, 31.7, 24.9, 24.7,
22.6, 14.1.
N-Benzoyl-L-proline Methyl Ester (5e).21 Colorless liquid: 192 mg,
82% yield as a 4:1 mixture of rotamers. [α]25D = −102.6 (c 1, CHCl3)
[lit.21 [α]24D = −103.4 (c 1, CHCl3)]. 1H NMR (400 MHz, CDCl3): δ
7.60−7.55 (m, 1.6H), 7.41 (dt, J = 6.8, 5.2 Hz, 3.4H), 4.70 (dd, J = 8.3,
5.2 Hz, 0.8H), 4.35 (d, J = 6.7 Hz, 0.2H), 3.80 (s, 3H), 3.69−3.63 (m,
1H), 3.62−3.49 (m, 1H), 2.36−2.31 (m, 1H), 2.14−1.81 (m, 3H). 13C
NMR (100 MHz, CDCl3): δ 172.8, 169.7, 136.2, 130.2, 128.4, 128.2,
127.3, 126.5, 61.4, 59.1, 52.2, 49.9, 46.5, 31.5, 29.4, 25.4, 22.7.
N-Benzoylsarcosine Methyl Ester (5f).21 Colorless liquid; 191 mg,
92% yield in a 2:1 mixture of rotamers. 1H NMR (400 MHz, CDCl3):
δ 7.47−7.42 (m, 5H), 4.29 (s, 1.3H), 4.00 (s, 0.7H), 3.79 (s, 2H), 3.75
(s, 1H), 3.12 (s, 1H), 3.04 (s, 2H). 13C NMR (100 MHz, CDCl3): δ
172.2, 169.6, 135.6, 130.0, 128.7, 128.5, 127.3, 126.7, 53.3, 52.3, 49.2,
38.8, 34.4.
Methyl 2-(N,1-Dimethyl-1H-indole-3-carboxamido)acetate
(5q).21 Colorless liquid; 179 mg, 69% yield. H NMR (400 MHz,
1
CDCl3): δ 7.63 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.33−
7.27 (m, 1H), 7.18−7.12 (m, 1H), 6.71 (br s, 1H), 4.32 (s, 2H), 3.85
(s, 3H), 3.79 (s, 3H), 3.23 (br s, 3H). 13C NMR (100 MHz, CDCl3):
δ 169.5, 165.2, 138.3, 138.0, 131.3, 126.4, 125.2, 123.5, 121.6, 120.3,
109.9, 104.2, 53.4, 52.3, 49.1, 38.7, 34.4, 31.1.
N-Methoxy-N-methylbenzamide (5g).21 Colorless liquid; 69 mg,
42% yield. 1H NMR (400 MHz, CDCl3): δ 7.70−7.62 (m, 2H), 7.47−
7.36 (m, 3H), 3.55 (s, 3H), 3.35 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 170.0, 134.2, 130.5, 128.1, 128.0, 61.0, 33.8.
General Procedure for the Conversion of Aldehydes to
Primary Amides. To a mixture of Cu2O (7 mg, 0.05 mmol, 5.0 mol
%), NH4Cl (134 mg, 2.5 mmol, 2.5 equiv), and K2CO3 (207 mg, 1.5
mmol, 1.5 equiv) in acetonitrile (0.2 mL) and water (0.1 mL) were
added an aldehyde 1 (1 mmol, 1 equiv) and TBHP (70 wt % in H2O,
0.22 mL, 1.5 equiv) under argon atmosphere at room temperature.
The reaction vessel was capped and allowed to stir for 4 h at 80 °C.
The reaction mixture was then concentrated and purified by silica gel
column chromatography (EtOAc/petroleum ether) to provide the
corresponding primary amide 6. The amides were identified by full
spectroscopic characterization and comparison with literature data.
N-(4-Methylbenzoyl)sarcosine Methyl Ester (5h).21 Colorless
1
liquid; 170 mg, 77% yield as a 2:1 mixture of rotamers. H NMR
(400 MHz, CDCl3): δ 7.37 (br s, 2H), 7.21 (d, J = 6.4 Hz, 2H), 4.27
(s, 1.3H), 4.01 (s, 0.7H), 3.78 (s, 3H), 3.06 (s, 3H), 2.38 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 172.2, 169.6, 140.0, 132.5, 129.2, 129.0,
127.3, 126.7, 53.3, 52.1, 49.1, 41.7, 38.7, 34.3, 21.4.
N-(4-Methoxybenzoyl)sarcosine Methyl Ester (5i).21 Colorless
1
liquid; 142 mg, 60% yield as a mixture of rotamers. H NMR (400
MHz, CDCl3): δ 7.42 (br s, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.21 (brs,
2H), 3.81 (s, 3H), 3.75 (s, 3H), 3.07 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 171.9, 170.6, 169.7, 167.0, 162.3, 160.9, 129.2, 129.0, 128.7,
127.5, 126.0, 113.7, 55.3,53.3, 52.1, 49.3, 41.6, 38.9, 34.5.
Benzamide (6a).29 White solid; 76 mg, 62% yield. H NMR (400
1
MHz, CDCl3): δ 7.81 (d, J = 7.2 Hz, 2H), 7.53−7.50 (m, 1H), 7.44−
7.41 (m, 2H), 6.30 (brs, 2H). 13C NMR (100 MHz, CDCl3): δ 169.9,
133.5, 132.1, 128.7, 127.5. HRMS (ESI): m/z =144.0424 [M + Na]+,
calcd for C7H7NNaO 144.0425.
N-(4-Chlorobenzoyl)sarcosine Methyl Ester (5j).21 Colorless
1
liquid; 179 mg, 74% yield as a 2:1 mixture of rotamers. H NMR
(400 MHz, CD3OD): δ 7.53−7.48 (m, 3.33H), 7.37 (d, J = 8.1 Hz,
0.67H), 4.30 (s, 1.33H), 4.10 (s, 0.67H), 3.80 (s, 2H), 3.74 (s, 1H),
3.11 (s, 1H), 3.07 (s, 2H). 13C NMR (100 MHz, CD3OD): δ 173.7,
173.3, 171.2, 171.0, 140.1, 137.3, 137.2, 135.5, 135.2, 132.3, 130.0,
129.9, 129.7, 129.4, 54.0, 52.9, 52.7, 50.2, 39.3, 34.9. .
p-Methoxybenzamide (6b).29 White solid; 91 mg, 60% yield. H
1
NMR (400 MHz, acetone-d6): δ 7.94−7.90 (m, 2H), 7.38 (brs, 1H),
6.98−6.95 (m, 2H), 6.65 (brs, 1H), 3.84 (s, 3H). 13C NMR (100
MHz, acetone-d6): δ 168.7, 163.1, 130.2, 127.6, 114.2, 55.7. HRMS
(ESI): m/z =174.0528 [M + Na]+, calcd for C8H9NNaO2 174.0531.
N-(4-Bromobenzoyl)sarcosine Methyl Ester (5k).21 Colorless
1
liquid; 215 mg, 75% yield as a 2:1 mixture of rotamers. H NMR
m-Methoxybenzamide (6c).29 White solid; 89 mg, 59% yield. H
1
(400 MHz, CD3OD): δ 7.66−7.60 (m, 2H), 7.40 (d, J = 8.3 Hz,
1.33H), 7.28 (d, J = 8.1 Hz, 0.67H), 4.28 (s, 1.33H), 4.07 (s, 0.67H),
3.78 (s, 2H), 3.72 (s, 1H), 3.09 (s, 1H), 3.04 (s, 2H). 13C NMR (100
MHz, CD3OD): δ 171.8, 171.4, 169.3, 169.1, 134.1, 133.8, 131.2,
131.1, 130.9, 130.6, 128.4, 128.2, 127.7, 126.8, 123.6, 123.4, 52.1, 51.1,
50.9, 48.4, 37.5, 33.1.
NMR (400 MHz, CDCl3): δ 7.44−7.42 (m, 1H), 7.35−7.31 (m, 2H),
7.07−7.05 (m, 1H), 6.08 (brs, 2H), 3.85 (s, 3H). 13C NMR (100
MHz, CDCl3): δ= 169.5, 160.0, 134.9, 129.7, 119.3, 118.4, 112.7, 55.6.
HRMS (ESI): m/z =152.0710 [M + H]+, calcd for C8H10NO2
152.0712.
o-Methoxybenzamide (6d).29 White solid; 62 mg, 41% yield. H
1
N-(4-Nitrobenzoyl)sarcosine Methyl Ester (5l).21 Colorless liquid;
1
NMR (400 MHz, CDCl3): δ 8.21 (dd, J = 7.8, 1.8 Hz, 1H), 7.72 (brs,
1H), 7.48−7.41 (m, 1H), 7.07 (m, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.06
(brs, 1H), 3.96 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 167.2, 157.9,
133.5, 132.7, 121.4, 120.9, 111.5, 56.1. HRMS (ESI): m/z =174.0525
[M + Na]+, calcd for C8H9NNaO2 174.0531.
179 mg, 71% yield as a 7:3 mixture of rotamers. H NMR (400 MHz,
CDCl3): δ 8.29−8.20 (m, 2H), 7.65 (d, J = 8.5 Hz, 1.4H), 7.58 (d, J =
8.2 Hz, 0.6H), 4.30 (s, 1.4H), 3.93 (s, 0.6H), 3.81 (s, 2H), 3.75 (s,
1H), 3.14 (s, 1H), 3.02 (s, 2H). 13C NMR (100 MHz, CDCl3): δ
169.9, 169.0, 148.6, 141.5, 135.0, 131.2, 128.2, 127.8, 124.0, 123.8,
123.6, 52.8, 52.6, 52.4, 49.0, 38.5, 34.5.
p-Methylbenzamide (6e).29 White solid; 84 mg, 62% yield. 1H
NMR (400 MHz, CDCl3): δ 7.71 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.3
Hz, 2H), 6.02 (brs, 2H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 169.4, 142.7, 130.6, 129.4, 127.5, 21.6. HRMS (ESI): m/z =136.0761
[M + H]+, calcd for C8H10NO: 136.0762.
N-(4-Cyanobenzoyl)sarcosine Methyl Ester (5m).21 Colorless
1
liquid; 161 mg, 69% yield as a 7:3 mixture of rotamers; H NMR
(400 MHz, CDCl3): δ 7.69 (dd, J = 14.9, 8.2 Hz, 2H), 7.56 (d, J = 8.2
Hz, 1.4H), 7.48 (d, J = 8.1 Hz, 0.6H), 4.26 (s, 1.4H), 3.91 (s, 0.6H),
3.77 (s, 2H), 3.72 (s, 1H), 3.10 (s, 1H), 2.99 (s, 2H). 13C NMR (100
MHz, CDCl3): δ 170.1, 169.2, 169.1, 140.1, 139.8, 132.6, 132.4, 127.9,
127.4, 118.2, 113.7, 52.9, 52.7, 52.5, 49.0, 38.6, 34.5.
o-Methylbenzamide (6f).29 White solid; 49 mg, 36% yield. 1H
NMR (400 MHz, CDCl3): δ 7.45 (d, J = 7.6 Hz, 1H), 7.35−7.34 (m,
1H), 7.23 (m, 2H), 5.79 (brs, 2H), 2.50 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 171.9, 136.4, 135.0, 131.2, 130.4, 126.9, 125.7, 20.0. HRMS
(ESI): m/z =136.0761 [M + H]+, calcd for C8H10NO 136.0762.
N-(3,4,5-Trimethoxybenzoyl)sarcosine Methyl Ester (5n).21 Color-
1
less liquid; 182 mg, 61% yield as a 3:2 mixture of rotamers. H NMR
G
dx.doi.org/10.1021/jo301252c | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Naphthalene-2-carboxamide (6g).29 White solid; 81 mg, 47%
ASSOCIATED CONTENT
■
1
yield. H NMR (400 MHz, CD3OD): δ 8.45 (s, 1H) 8.02−7.97 (m,
S
* Supporting Information
1H) 7.96−7.91 (m, 3H), 7.63−7.55 (m, 2H). 13C NMR (100 MHz,
CD3OD): δ 171.0, 134.9, 132.6, 130.7, 128.6, 127.8, 127.7, 127.4,
127.3, 126.3, 123.6. HRMS (ESI): m/z =194.0579 [M + Na]+, calcd
for C11H9NNaO 194.0582.
1
Copies of H and 13C NMR spectra of amide products and
HPLC chromatograms of racemic and chiral compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
Naphthalene-1-carboxamide (6h).29 White solid; 67 mg, 39%
yield. 1H NMR (400 MHz, CD3OD): δ 8.32−8.26 (m, 1H), 7.98 (d, J
= 8.3 Hz, 1H), 7.92 (dd, J = 7.2, 2.2 Hz, 1H), 7.68 (dd, J = 7.0, 1.0 Hz,
1H), 7.59−7.48 (m, 3H). 13C NMR (100 MHz, CD3OD): δ 175.1,
135.2, 131.7, 131.3, 129.4, 127.9, 127.4, 126.4, 125.9. HRMS (ESI):
m/z =194.0583 [M + Na]+, calcd for C11H9NNaO 194.0582.
p-Chlorobenzamide (6i).29 White solid; 75 mg, 48% yield. 1H
NMR (400 MHz, CDCl3): δ 7.76 (d, J = 8.5 Hz, 2H), 7.43 (d, J = 8.5
Hz, 2H), 6.07 (brs, 1H), 5.76 (brs, 1H).13C NMR (100 MHz,
CDCl3): δ 168.3, 138.5, 131.7, 129.0, 128.9. HRMS (ESI): m/z
=178.0032 [M + Na]+, calcd for C7H6ClNNaO 178.0036.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chen_anqi@ices.a-star.edu.sg.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by ‘‘The GSK Singapore Partnership for
Green and Sustainable Manufacturing’’ and the Institute of
Chemical and Engineering Sciences, Agency for Science,
Technology and Research, Singapore.
p-Bromobenzamide (6j).29 White solid; 90 mg, 45% yield. 1H
NMR (400 MHz, DMSO-d6): δ 8.03 (brs, 1H), 7.81 (d, J = 9.1 Hz,
2H), 7.66 (d, J = 9.1 Hz, 2H), 7.43 (brs, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 166.8, 133.4, 131.2, 129.6, 125.0. HRMS (ESI): m/z
=221.9527 [M + Na]+, calcd for C7H6BrNNaO 221.9530.
p-Fluorobenzamide (6k).29 White solid; 60 mg, 43% yield. 1H
NMR (400 MHz, CDCl3): δ 7.96−7.71 (m, 2H), 7.22−7.02 (m, 2H),
5.95 (brs, 2H). 13C NMR (100 MHz, CDCl3): δ 168.1, 166.3, 163.8,
129.8, 129.7, 115.8, 115.6. HRMS (ESI): m/z =162.0323 [M + Na]+,
calcd for C7H6FNNaO 162.0331.
REFERENCES
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Methyl 4-carbamoylbenzoate (6m).29 White solid; 84 mg, 47%
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1
yield. H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.5 Hz, 2H), 7.87
(d, J = 8.5 Hz, 2H), 6.13 (brs, 1H), 5.72 (brs, 1H), 3.95 (s, 3H). 13C
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4-(Trifluoromethyl)benzamides (6n).29 White solid; 84 mg, 44%
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MHz, DMSO-d6): δ 166.7, 138.1, 131.3, 131.0, 130.7, 128.3, 125.3,
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3-Pyridinecarboxamide (6o).29 White solid; 44 mg, 36% yield. H
1
NMR (400 MHz, CD3OD and CDCl3): δ 8.99 (s, 1H), 8.71−8.58 (m,
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CD3OD and CDCl3): δ 168.8, 152.1, 148.7, 136.6, 130.2, 124.2.
HRMS (ESI): m/z =145.0374 [M + Na]+, calcd for C6H6N2NaO
145.0378.
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1
36% yield. H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8 Hz, 1H),
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1
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The Journal of Organic Chemistry
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dx.doi.org/10.1021/jo301252c | J. Org. Chem. XXXX, XXX, XXX−XXX