A copper-catalysed amidation of aldehydes via N-hydroxysuccinimide ester formation

Article abstract of DOI:10.1039/c3ob41440j

A copper-catalysed oxidative amidation of aldehydes via N-hydroxysuccinimide ester formation is reported. The methodology employed to prepare amides directly from aldehydes has a very wide scope, is high yielding, and does not need dry conditions. This cross-coupling reaction appears to be simple and makes use of cheap, abundant and easily available reagents.

Full text of DOI:10.1039/c3ob41440j

Organic &
Biomolecular Chemistry
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A copper-catalysed amidation of aldehydes via
N-hydroxysuccinimide ester formation†
Cite this: Org. Biomol. Chem., 2013, 11,
8241
Monica Pilo, Andrea Porcheddu and Lidia De Luca*
Received 12th July 2013,
A copper-catalysed oxidative amidation of aldehydes via N-hydroxysuccinimide ester formation is
reported. The methodology employed to prepare amides directly from aldehydes has a very wide scope,
is high yielding, and does not need dry conditions. This cross-coupling reaction appears to be simple and
makes use of cheap, abundant and easily available reagents.
Accepted 14th October 2013
DOI: 10.1039/c3ob41440j
www.rsc.org/obc
Introduction
The amide functionality is one of the most significant func-
tional groups present in many natural products, polymers,
pharmaceuticals and synthetic intermediates. The classical
route to amides is the acylation of an amine with a previously
activated carboxylic acid (acid chlorides, mixed anhydrides,
carbonic anhydrides or active esters) in the presence of a
base.1
An elegant alternative approach is the one-pot oxidative
amidation of aldehydes, which are readily available starting
materials. This alternative process falls into two broad
categories. In the first one, a functionalized aldehyde (formyl-
cyclopropanes, α,β-unsaturated aldehydes,2 α-haloaldehydes
and epoxyaldehydes,3 aromatic or allylic aldehydes4) is cata-
lytically transformed into an active ester with an N-heterocyclic
carbene (NHC) catalyst and a co-catalyst, which is then reacted
with an amine (Scheme 1a).
In the second category, an aldehyde reacts with an amine
forming a hemiaminal intermediate, which is subsequently
oxidized to an amide, generally by the use of catalysts, such as
Cu,5 Rh,6 Ru,7 Pd,8 Ni9 and Fe (Scheme 1b).10
Nevertheless, the above mentioned methodologies often
suffer from drawbacks derived from the steric attributes of the
amine and the aldehyde, the use of expensive transition metal
catalysts, the limited substrate scope and the utilization of co-
reagents.
Therefore, the development of a new method for amide
synthesis of general applicability remains an area of active
research. The preparation of amides directly from aldehydes,
Scheme 1 (a) Amide formation from aldehydes via the N-heterocyclic carbene
(NHC) catalyst. (b) Oxidative amidation of aldehydes to amides via hemiaminal
formation.
through their transformation into activated esters, is a novel
strategy recently investigated in order to alleviate substrate
structural dependence. In this context, Yamamoto and co-
workers have reported two pioneering examples of oxidative
amidation of aldehydes via N-hydroxysuccinimide ester
(NHS ester) formation using N-hydroxysuccinimide, O2 and
Co(OAc)2,11 and N-hydroxysuccinimide and hypervalent iodine
reagents.12 The first methodology worked only with sterically
unhindered and electronically activated aldehydes and with a
few unhindered aliphatic amines, while the second procedure
worked only with primary and cyclic secondary aliphatic
unhindered amines. The above-described procedures used pre-
ferentially the amine hydrochloride salt to limit the oxidation
of the amine.
Barbas III and co-workers13 have also reported an innova-
tive example of organocatalytic activation of aromatic
aldehydes by a cross-coupling strategy to obtain aromatic
amides.
Due to our interest in the use of iron- and copper-based
catalysts for the synthesis of amides,14 we tested the possibility
of performing a metal catalysed one-pot amidation of alde-
hydes via NHS ester formation.15
Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, Via Vienna 2,
Sassari, Italy. E-mail: ldeluca@uniss.it; Fax: +39-079-212069; Tel: +39-079-213529
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization of products, and copies of 1H NMR and 13C NMR
spectra are provided. See DOI: 10.1039/c3ob41440j
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Results and discussion
We started our investigation by treating p-methoxybenz-
aldehyde 1a with hydroxysuccinimide (NHS) 2. An overview of
the synthetic details is provided in Table 1. Using a catalytic
amount of FeCl3 as a catalyst and an aqueous solution of 70%
tert-butyl hydrogen peroxide (TBHP) in water as an oxidant
and in acetonitrile as a solvent, at reflux, the desired p-methoxy-
benzoate ester 3 was obtained in 35% yield16 (Table 1,
entry 1).
Scheme 2 One-pot synthesis of amides.
the desired amide 5a was obtained in 30 min in very good
yield (98%).16 The free amine can be used directly and prepa-
ration of amine salt is not necessary. It is noteworthy that in
these transformations, the N-hydroxysuccinimide used and the
excess of aldehyde could be recovered unmodified (Scheme 2).
To investigate the scope of the one-pot methodology for the
synthesis of amides, the procedure was tested with an array of
commercially available aldehydes and amines. Aromatic alde-
hydes with a wide range of functional groups, both electron-
donating groups, such as –OMe (Scheme 3, 5a and 5b) and
o- and p-benzylic C–H (Scheme 3, 5c and 5d), and withdrawing
groups, such as –NO2 (Scheme 3, 5k), were well tolerated pro-
viding the desired amides in excellent yields. Aromatic alde-
hydes with carbonyl substituents gave very good results too
(Scheme 3, 5j). The reaction carried out on aldehydes with
halide substituents, in different o-, m- and p- positions on the
aromatic ring, gave the corresponding amides in very high
yields, which could be further transformed by traditional
cross-coupling reactions (Scheme 3, 5g, 5h and 5i). To verify
the synthetic utility of the method, thiophene-2-carbaldehyde
was subjected to optimized conditions, giving the desired
heteroaryl amide (Scheme 3, 5l) in good yield. When trans-
cinnamaldehyde was employed, the corresponding unsaturated
amide (Scheme 3, 5q) was obtained without affecting the
double bond. Aliphatic linear aldehydes provided the resulting
aliphatic amides in good yields (Scheme 3, 5m, 5n and 5o),
and even aliphatic sterically hindered aldehydes (Scheme 3,
5p) gave the corresponding amides in satisfactory yield. The
reaction was tested with a series of secondary amines showing
excellent tolerance. Both very sterically hindered acyclic
(Scheme 3, 5m and 5q) and cyclic secondary amines
(Scheme 3, 5e, 5g, 5h and 5i) were shown to be effective in this
reaction. Furthermore, primary amines (Scheme 3, 5a, 5c, 5d,
5k and 5n), even with unsaturation (Scheme 3, 5j), gave the
corresponding N-monosubstituted amides in very good yields.
Less active primary (Scheme 3, 5b) and secondary anilines
(Scheme 3, 5p) also provided good yields of amides. It is to be
underlined that primary alcohols were compatible under the
optimized reaction conditions (Scheme 3, 5f). This procedure
is suitable for preparing the synthetically useful Weinreb
amide too (Scheme 3, 5r). Finally, in this reaction, the
optically pure L-valine methyl ester retained its optical purity
(Scheme 3, 5s).
In order to optimize the reaction conditions various para-
meters, such as catalyst, oxidant and temperature were varied.
We repeated the same reaction with the use of Cu(OAc)2·H2O
instead of FeCl3·6H2O, obtaining the product 3 with a signifi-
cant improvement in yield (99%) and a considerable decrease
of reaction time (Table 1, entry 2). When TBAI (nBu4NI) was
used as a catalyst, the reaction time increased considerably
(12 h, Table 1, entry 3). Moreover, employing TBAI the reaction
did not proceed on aliphatic aldehydes. Very poor results in
terms of yield were observed when employing tert-butyl peroxy-
benzoate that gave 34% yield (Table 1, entry 4). No product for-
mation was observed when using classical oxidants such as
H2O2 and oxone (Table 1, entries 5 and 6). When the reaction
was performed at room temperature the yield of ester 3
decreased (Table 1, entry 7). The use of TBHP in decane
(Table 1, entry 8) gave the same result as that obtained by the
use of aqueous TBHP. No product formation was observed
when the reaction was performed without the oxidant
(Table 1, entry 9) or without the catalyst (Table 1, entry 10).
After the preparation of NHS ester was optimized, we investi-
gated the possibility of performing a one-pot transformation
of aldehydes into amides. Thus, when heptylamine was added
to the reaction mixture of p-methoxybenzaldheyde and NHS,
Table 1 Screening of reaction conditions
Entrya
Catalyst
Oxidant
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
FeCl3·6H2O
Cu(OAc)2·H2O
nBu4NI
TBHP
TBHP
TBHP
TBPB
8
1/2
12
8
8
8
8
1
8
8
35
99
95
34
—
—
25d
98
—
—
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
c
H2O2
Oxone
TBHP
TBHPe
f
—
g
10
—
TBHP
a Reaction conditions: p-methoxybenzaldehyde 1a (2 equiv.),
N-hydroxysuccinimide 2 (1 equiv.), oxidant (2 equiv.), and catalyst
(14 mol%) in acetonitrile at reflux. b Yields were calculated based on
NHS. c 10% H2O2 in water. d Reaction performed at room temperature.
In order to find experimental evidence for the reaction
mechanism, we carried out a series of electron spin resonance
(ESR) experiments under various reaction conditions. In our
system, we did not find any clear ESR signal corresponding
e Reaction performed with 5.5
M
TBHP in decane. f Reaction
g Reaction
performed without
performed
without
TBHP.
Cu(OAc)2·H2O.
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Scheme 5 Experiment to evaluate the reaction mechanism.
Investigations on the reaction mechanism are currently under-
way in our group.
Conclusions
In conclusion, a copper-catalysed oxidative amidation of alde-
hydes was developed. The methodology was employed to
prepare amides directly from aldehydes, both aliphatic,
aromatic and vinylic, and primary and secondary amines,
anilines, amino acids and amino alcohols. The procedure
reported herein has a wide scope, is high yielding, does not
need dry conditions and uses cheap and easily available
reagents.
Experimental section
All reagents and solvents were obtained from commercial
sources. All the reactions were carried out under an N2 atmos-
phere using standard techniques. Column chromatography
was generally performed on silica gel (pore size 60 Å and par-
ticle size 40–63 μm) and reactions were monitored by thin-
layer chromatography (TLC) analysis performed with Merck
Kieselgel 60 F254 plates and visualized using UV light at
1
254 nm and KMnO4 staining. H NMR and 13C NMR spectra
were measured on a Bruker Avance III 400 spectrometer
(400 MHz or 100 MHz, respectively) with CDCl3 as a solvent
and recorded in ppm relative to the internal standard tetra-
methylsilane. The peak patterns are indicated as follows: s,
singlet; d, doublet; t, triplet; m, multiplet; q, quartet; br,
broad. The coupling constants, J, are reported in hertz (Hz).
Melting points were determined in open capillary tubes and
are uncorrected. High resolution mass spectroscopy data of
the product were collected on a Waters Micromass GCT
instrument.
Scheme 3 One-pot synthesis of amides: investigation of aldehydes and
amines scope of the reaction.
Procedure for the preparation of 2,5-dioxopyrrolidin-1-yl
4-methoxybenzoate (3)
Scheme 4 Succinimide N-oxy (SINO) radicals and hemiaminal radicals.
TBHP (6 mmol, 0.8 mL of a 70 wt% solution in water) was
added to a mixture of p-methoxybenzaldehyde (6 mmol),
N-hydroxysuccinimide (3 mmol), and Cu(OAc)2·H2O (0.42 mmol,
0.08 g) in 15 mL of acetonitrile under an argon atmosphere.
The reaction mixture was heated in an oil bath at reflux for
40 min (the reaction was monitored by TLC until the dis-
appearance of N-hydroxysuccinimide). Then the mixture was
cooled to room temperature and was quenched with 50 mL of
a saturated solution of Na2SO3 and extracted three times with
20 mL of diethyl ether. The combined organic phases were
either to succinimide N-oxy (SINO) radicals or to hemiaminal
radicals (Scheme 4).17
However, the radicals may still be present in our system,
but the radical reaction is too fast to follow using conventional
spectrophotometry.18
When we introduced the radical scavenger TEMPO into the
reaction, the product 8 was obtained in good yield (Scheme 5).
This result supports the involvement of radical species
(either acyl or acetal radicals) in the reaction mechanism.
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dried over anhydrous Na2SO4 and the solvent was evaporated
N-Butyl-2-methylbenzamide (5d). 0.49 g, 85%. Pale yellow
under reduced pressure. The crude product was purified by oil. Purified by flash chromatography (v/v petroleum ether–
1
silica gel column chromatography to provide compound 3 AcOEt = 4/1), Rf = 0.21; H NMR (400 MHz, CDCl3) δ 7.34–7.28
(0.73 g, 99%). White solid, mp 142–145 °C.19 Purified by flash (m 2H), 7.22–7.17 (m, 2H), 5.88 (br s, 1H), 3.42 (q, J = 6.3 Hz,
chromatography (v/v petroleum ether–Et2O = 3/2), Rf = 0.13; 2H), 2.44 (s, 3H), 1.63–1.55 (m, 2H), 1.47–1.37 (m, 2H), 0.97 (t,
1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 7.1 Hz, 2H), 6.99 (d, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.1, 136.8,
J = 8.1 Hz, 2H), 3.91 (s, 3H), 2.92 (s, 4H); 13C NMR (100 MHz, 135.7, 130.8, 129.5, 126.6, 125.5, 39.5, 31.7, 20.1, 19.6, 13.8.
CDCl3) δ 169.5, 164.9, 161.5, 132.9, 117.1, 114.2, 55.6, 25.7. Analysis of the spectroscopic data matched the reported
Analysis of the spectroscopic data matched the reported data.14a
data.19
Phenyl(piperidin-1-yl)methanone (5e). 0.49 g, 88%. Colour-
less oil. Purified by flash chromatography (v/v petroleum
ether–AcOEt = 3.5/1.5), Rf = 0.18; 1H NMR (400 MHz, CDCl3)
General procedure for the preparation of amides 5a–q
TBHP (6 mmol, 0.8 mL of a 70 wt% solution in water) was δ 7.23 (m, 5H), 3.55 (br s, 2H), 3.18 (br s, 2H), 1.51–1.35
added to a mixture of aldehyde (6 mmol), N-hydroxysuccin- (m, 6H); 13C NMR (100 MHz, CDCl3) δ 170.1, 136.4, 129.2,
imide (3 mmol), and Cu(OAc)2·H2O (0.42 mmol, 0.08 g) in 128.2, 126.6, 48.6, 42.9, 26.4, 25.5, 24.4. Analysis of the spectro-
15 mL of acetonitrile under an argon atmosphere. The reaction scopic data matched the reported data.22
mixture was heated in an oil bath at reflux for 40 min (the reac-
N-(2-Hydroxyethyl)benzamide (5f). 0.41 g, 76%. White solid,
tion was monitored by TLC until the disappearance of mp 57–59 °C.23 Purified by flash chromatography (AcOEt), Rf =
N-hydroxysuccinimide). Then the mixture was cooled to room 0.21; 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 7.5 Hz, 2H),
temperature. An amine (8 mmol) was added to the mixture in 7.53–7.41 (m, 3H), 6.88 (br s, 1H), 3.87–3.82 (m, 2H), 3.65–3.61
one portion. After 30 min (the reaction was monitored by TLC (m, 2H), 3.17 (br s, 1H); 13C NMR (100 MHz, CDCl3) δ 168.8,
until the disappearance of NHS ester), the reaction mixture 134.0, 131.6, 128.5, 127.0, 61.7, 42.8. Analysis of the spectro-
was quenched with 50 mL of a saturated solution of Na2SO3 scopic data matched the reported data.23
and extracted three times with 20 mL of diethyl ether. The
(4-Chlorophenyl)(morpholino)methanone (5g). 0.63 g, 93%.
combined organic phases were washed with a 1 M solution of White solid, mp 74–75 °C.24 Purified by flash chromatography
KHSO4 and then dried over anhydrous Na2SO4 and the solvent (v/v petroleum ether–AcOEt = 4/3), Rf = 0.33; 1H NMR
was evaporated under reduced pressure. The crude product (400 MHz, CDCl3) δ 7.42–7.36 (m, 4H), 3.72–3.49 (m, 8H);
was purified by silica gel column chromatography to provide 13C NMR (100 MHz, CDCl3) δ 169.4, 136.0, 133.6, 128.9, 128.7,
the desired amide.
66.8, 48.1, 42.6. Analysis of the spectroscopic data matched the
N-Heptyl-4-methoxybenzamide (5a). 0.73 g, 98%. Pale yellow reported data.22
oil. Purified by flash chromatography (v/v petroleum ether–
AcOEt = 4/1.5), Rf = 0.31; H NMR (400 MHz, CDCl3) δ 7.75 (d, Colourless oil. Purified by flash chromatography (v/v pet-
(3-Chlorophenyl)(morpholino)methanone (5h). 0.63 g, 93%.
1
J = 8.9 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 6.42 (br s, 1H), 3.82 (s, roleum ether–AcOEt = 5/3), Rf = 0.31; 1H NMR (400 MHz,
3H), 3.40 (q, J = 5.9 Hz, 2H), 1.62–1.55 (m, 2H), 1.35–1.26 (m, CDCl3) δ 7.44–7.42 (m, 2H), 7.38 (t, J = 7.4 Hz, 1H), 7.31–7.28
8H), 0.88 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) (m, 2H), 3.77–3.46 (m, 8H); 13C NMR (100 MHz, CDCl3)
δ 167.1, 161.9, 128.7, 127.1, 113.6, 55.3, 40.1, 31.7, 29.7, 29.0, δ 168.8, 137.0, 134.7, 130.0, 129.9, 127.3, 125.1, 66.8, 48.2,
27.0, 22.6, 14.0; HRMS (EI) ([M+]) calcd for C15H23NO2: 42.6. Analysis of the spectroscopic data matched the reported
2 491 729, found: 2 491 725.
data.24
(2-Chlorophenyl)(morpholino)methanone (5i). 0.61 g, 90%.
4-Methoxy-N-phenylbenzamide (5b). 0.68 g, 88%. White
solid, mp 172–175 °C.20 Purified by flash chromatography (v/v White solid, mp 72–73 °C.22 Purified by flash chromatography
petroleum ether–AcOEt
= 3.7/1.3), Rf =
0.33; 1H NMR (v/v petroleum ether–AcOEt = 2/3), Rf = 0.34; 1H NMR
(400 MHz, CDCl3) δ 7.87 (d, J = 8.8 Hz, 2H), 7.74 (br s, 1H), (400 MHz, CDCl3) δ 7.44–7.28 (m, 4H), 3.93–3.87 (m, 1H),
7.65 (d, J = 8.7 Hz, 2H), 7.39 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 3.81–3.78 (m, 3H), 3.74–3.69 (m, 1H), 3.64–3.58 (m, 1H),
7.4 Hz, 1H), 7.00 (d, J = 8.9 Hz, 2H), 3.90 (s, 3H); 13C NMR 3.34–3.28 (m, 1H), 3.26–3.19 (m, 1H); 13C NMR (100 MHz,
(100 MHz, CDCl3) δ 165.2, 162.5, 138.1, 129.1, 128.9, 127.1, CDCl3) δ 166.9, 135.3, 130.3, 130.2, 129.7, 127.8, 127.3, 66.8,
124.3, 120.1, 114.0, 55.5. Analysis of the spectroscopic data 66.7, 47.1, 42.1 (some signals are overlapping). Analysis of the
matched the reported data.20
spectroscopic data matched the reported data.25
N-Butyl-4-methylbenzamide (5c). 0.47 g, 83%. White solid,
N-Allyl-4-ethanoylbenzamide (5j). 0.59 g, 97%. Pale yellow
mp 53–55 °C.21 Purified by flash chromatography (v/v pet- solid, mp 108–110 °C. Purified by flash chromatography (v/v
roleum ether–AcOEt = 4/1), Rf = 0.17; 1H NMR (400 MHz, petroleum ether–AcOEt = 2/3), Rf = 0.35; 1H NMR (400 MHz,
CDCl3) δ 7.68 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.59 CDCl3) δ 7.98 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.6 Hz, 2H),
(br s, 1H), 3.40 (q, J = 5.8 Hz, 2H), 2.63 (s, 3H), 1.60–1.53 (m, 6.64 (br s, 1H), 5.99–5.89 (m, 1H), 5.29–5.18 (m, 1H), 4.11–4.08
2H), 1.42–1.32 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (m, 3H), 2.63 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 197.5,
(100 MHz, CDCl3) δ 167.6, 141.5, 132.0, 129.1, 126.9, 39.8, 166.4, 139.1, 138.4, 133.8, 128.5, 127.3, 116.9, 42.6, 26.8;
31.8, 21.4, 20.2, 13.8. Analysis of the spectroscopic data HRMS (EI) ([M+]) Calcd for C12H13NO2: 2 030 946, found:
matched the reported data.21
2 030 943.
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N-Heptyl-4-nitrobenzamide (5k). 0.68 g, 86%. Pale yellow CDCl3) δ (mixture of rotamers) 5q′: 7.78 (d, J = 15.6 Hz 1H,
solid, mp 78–81 °C. Purified by flash chromatography (v/v pet- H-3), 7.54 (d, J = 6.6 Hz, 2H), 7.20–7.41 (m, 8H), 6.90 (d, J =
roleum ether–AcOEt = 4/1), Rf = 0.23; 1H NMR (400 MHz, 15.6 Hz, H-2), 4.71 (s, 2H), 3.09 (s, 3H), 5q″: 7.80 (d, J =
CDCl3) δ 8.31 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 8.8 Hz, 2H), 6.18 15.6 Hz, 1H, H-3), 7.46 (d, J = 5.4 Hz, 2H), 7.20–7.41 (m, 8H),
(br s, 1H), 3.5 (q, J = 7.1 Hz, 2H), 1.69–1.60 (m, 4H), 1.42–1.31 6.96 (d, J = 15.6 Hz, H-2), 4.75 (s, 2H), 3.11 (s, 3H); 13C NMR
(m, 6H), 0.91 (t J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) (100 MHz, CDCl3) δ 166.9, 166.4, 142.8, 137.1, 135.0, 136.4,
δ 165.5, 149.5, 140.4, 128.0, 123.8, 40.5, 31.7, 29.5, 28.9, 26.9, 129.4, 129.4, 128.7, 128.5, 128.5, 128.4, 127.8, 127.6, 127.6,
22.5, 14.1. HRMS (EI) ([M+]) Calcd for C14H20N2O3: 2 641 474, 127.1, 126.2, 117.1, 53.2, 51.0, 34.7, 34.1 (some signals are
found: 2 641 472.
overlapping). Analysis of the spectroscopic data matched the
N-(2-Methoxyethyl)thiophene-2-carboxamide (5l). 0.41 g, reported data.27
73%. White solid, mp 84–87 °C. Purified by flash chromato-
1
General procedure for the preparation of amides (5r–s)
graphy (v/v petroleum ether–AcOEt = 1/4), Rf = 0.41; H NMR
(400 MHz, CDCl3) δ 7.53–7.51 (m, 1H), 7.49–7.47 (m, 1H), TBHP (6 mmol, 0.8 mL of a 70 wt% solution in water) was
7.09–7.06 8m, 1H), 6.50 (br s, 1H), 3.65–3.61 (m, 2H), added to a mixture of aldehyde (6 mmol), N-hydroxysuccin-
3.57–3.55 (m, 2H), 3.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ imide (3 mmol), and Cu(OAc)2·H2O (0.42 mmol, 0.08 g) in
161.9, 138.9, 129.9, 127.9, 127.5, 71.1, 58.8, 39.6; HRMS (EI) 15 mL of acetonitrile under an argon atmosphere. The reaction
([M+]) Calcd for C8H11NO2S: 1 850 510, found: 1 850 512.
mixture was heated in an oil bath at reflux for 40 min (the reac-
N,N-Dibenzylheptanamide (5m). 0.91 g, 98%. Colourless oil. tion was monitored by TLC until the disappearance of
Purified by flash chromatography (v/v petroleum ether–AcOEt N-hydroxysuccinimide). Then the mixture was cooled to room
= 3.5/1.5), Rf = 0.20; 1H NMR (400 MHz, CDCl3) δ 7.39–7.19 (m, temperature. An amine hydrochloride (8 mmol) and triethyl-
10H), 4.64 (s, 2H), 4.48 (s, 2H), 2.45 (d, J = 7.4 Hz, 2H), amine (8 mmol) were added to the mixture. After 30 min (the
1.78–1.71 (m, 2H), 1.40–1.28 (m, 6H), 0.91 (t, J = 6.8 Hz, 3H); reaction was monitored by TLC until the disappearance of
13C NMR (100 MHz, CDCl3) δ 173.8, 137.6, 136.7, 128.9, 128.6, NHS ester), the reaction mixture was quenched with 50 mL of
128.3, 127.6, 127.3, 126.4, 49.9, 48.1, 33.3, 31.6, 29.1, 25.4, a saturated solution of Na2SO3 and extracted three times with
22.5, 14.1. Analysis of the spectroscopic data matched the 20 mL of diethyl ether. The combined organic phases were
reported data.14a,b
washed with a 1 M solution of KHSO4 and then dried over
N-(3-Phenylpropyl)nonanamide (5n). 0.68 g, 83%. White anhydrous Na2SO4 and the solvent was evaporated under
solid, mp 49–52 °C. Purified by flash chromatography (v/v pet- reduced pressure. The crude product was purified by silica gel
1
roleum ether–AcOEt = 3.5/1.5), Rf = 0.29; H NMR (400 MHz, column chromatography to provide the desired amide.
CDCl3) δ 7.33–7.19 (m, 5H), 5.39 (br s, 1H), 3.32 (q, J = 5.9 Hz,
N-Methoxy-N-methylbenzamide (5r). 0.37 g, 75%. Colourless
2H), 2.68 (t, J = 7.8 Hz, 2H), 2.14 (t, J = 7.4 Hz, 2H), 1.91–1.83 oil. Purified by flash chromatography (v/v petroleum ether–
1
(m, 2H), 1.66–1.57 (m, 2H), 1.28 (m, 10H), 0.90 (m, J = 6.7 Hz, AcOEt = 3/2), Rf = 0.27; H NMR (400 MHz, CDCl3) δ 6.68 (dd,
3H); 13C NMR (100 MHz, CDCl3) δ 173.2, 141.5, 128.5, 128.3, J = 6.8, 1.6 Hz, 1H), 7.49–7.39 (m, 3H), 3.57 (s, 3H), 3.38 (s,
126.0, 39.2, 36.9, 33.4, 31.9, 31.3, 29.6, 29.5, 29.3, 25.8, 22.7, 3H); 13C NMR (100 MHz, CDCl3) δ 169.9, 134.1, 130.5, 128.1,
14.2. HRMS (EI) ([M+]) calcd for C18H29NO: 2 752 249, found: 127.9, 61.1, 33.8. Analysis of the spectroscopic data matched
2 752 247.
the reported data.28
N-Benzylnonanamide (5o). 0.59 g, 80%. White solid, mp
N-Benzoyl-L-valine methyl ester (5s). 0.65 g, 93%. White
70–73 °C.26 Purified by flash chromatography (v/v petroleum solid, mp 84–87 °C. [α]2D5 +42.8 (c 1 in CHCl3). HPLC (column:
1
ether–AcOEt = 3.8/1.2), Rf = 0.38; H NMR (400 MHz, CDCl3) δ Chiralpak IA, n-hexane–IPA 90/10 (v/v), flow rate 0.5 mL
7.38–7.28 (m, 5H), 5.69 (br s, 1H), 4.47 (d, J = 5.7 Hz, 2H), 2.23 min−1), tR 19.414, ee = 99%. Purified by flash chromatography
(t, J = 7.4 Hz, 2H), 1.69–1.64 (m, 2H), 1.37–1.29 (m, 10H), 0.90 (v/v petroleum ether–AcOEt = 4/1), Rf = 0.2; 1H NMR (400 MHz,
(t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 172.9, 138.4, CDCl3) δ 7.81 (d, J = 7.3 Hz, 2H), 7.54–7.43 (m 3H), 6.68 (br s,
128.7, 127.8, 127.5, 43.6, 36.9, 31.8, 29.3, 29.3, 29.1, 25.8, 22.6, 1H), 4.79 (dd, J = 8.5, 4.9 Hz, 1H), 3.78 (s, 3H), 2.29 (m, 1H),
14.1. Analysis of the spectroscopic data matched the reported 1.00 (dd, J = 9.1, 6.9 Hz, 6H); 13C NMR (100 MHz, CDCl3)
data.26
δ 172.6, 167.2, 134.1, 131.6, 128.5, 126.9, 57.3, 52.2, 31.6, 18.9,
N,3,3-Trimethyl-N-p-tolylbutanamide (5p). 0.43 g, 65%. Pale 17.9. Analysis of the spectroscopic data matched the reported
yellow oil. Purified by flash chromatography (v/v petroleum data.29
1
ether–AcOEt = 4.5/0.5), Rf = 0.14; H NMR (400 MHz, CDCl3) δ
7.21 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 3.24 (s, 3H),
Preparation of 2,2,6,6-tetramethylpiperidin-1-yl benzoate (8)
2.39 (s, 3H), 2.05 (s, 2H), 0.97 (s, 9H); 13C NMR (100 MHz, TBHP (6 mmol, 0.8 mL of a 70 wt% solution in water) was
CDCl3) δ 172.2, 142.2, 137.3, 130.2, 127.3, 45.4, 37.4, 31.4, 29.9, added to a mixture of benzaldehyde (6 mmol), N-hydroxy-
21.1; HRMS (EI) ([M+]) calcd for C14H21NO: 2 191 623, found: succinimide (1.5 mmol), 2,2,6,6-tetramethyl-1-piperidinyloxy
2 191 626.
(1.5 mmol), and Cu(OAc)2·H2O (0.42 mmol, 0.08 g) in 15 mL of
N-Benzyl-N-methyl-3-phenylprop-2-enamide (5q). 0.71 g, acetonitrile under an argon atmosphere. The reaction mixture
93%. Pale yellow oil. Purified by flash chromatography (v/v pet- was heated in an oil bath at reflux for 50 min. Then the
1
roleum ether–AcOEt = 3.5/1.5), Rf = 0.28; H NMR (400 MHz, mixture was cooled at room temperature and was quenched
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Organic & Biomolecular Chemistry
with 50 mL of a saturated solution of Na2SO3 and extracted 11 H. Yao and K. Yamamoto, Chem. Asian J., 2012, 7,
three times with 20 mL of diethyl ether. The combined organic 1542.
phases were dried over anhydrous Na2SO4 and the solvent was 12 H. Yao and K. Yamamoto, Tetrahedron Lett., 2012, 53,
evaporated under reduced pressure. The crude product was 5094.
purified by silica gel column chromatography (v/v diethyl 13 B. Tan, N. Toda and C. F. Barbas III, Angew. Chem., Int. Ed.,
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13C NMR (75 MHz, CDCl3) δ : 166.3; 132.8; 129.7; 129.5; 128.4;
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60.4; 39.1; 31.9; 20.9; 17.1. Analysis of the spectroscopic data 15 NHS esters gave better results than NHPI esters, see ref. 11
matched the reported data.14a,b
and 12.
16 All the yields were calculated based on NHS (limiting
reagent) as is customary: see for example ref. 13, 14 and
(a) Z. Liu, J. Zhang, S. Chen, E. Shi, Y. Xu and X. Wan,
Angew. Chem., Int. Ed., 2012, 51, 323; (b) K. Xu, Y. Hu,
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Acknowledgements
This work was financially supported by Regione Autonoma
della Sardegna within the project: “High-throughput screening
(HTS) per l’identificazione di nuove molecule per il tratta-
mento della Sclerosi Laterale Amiotrofica e della Malattia di
Parkinson” and by MIUR (Ministero dell’Istruzione, dell’Uni-
versità e della Ricerca) within the project PRIN titled “DNA a
quadruple elica: sintesi, studi strutturali, interazioni e loro
implicazioni biologiche, quali nuovi farmaci antitumorali e
antivirali”.
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8246 | Org. Biomol. Chem., 2013, 11, 8241–8246
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