A new method for the synthesis of amides from imines

Article abstract of DOI:10.1016/j.tetlet.2011.11.018

An efficient and straightforward method for the synthesis of amides by the reaction of imines and anhydrides in the presence of Et₃SiH/Zn is reported. Mild reaction conditions, good yields of products, short reaction times, and operational simplicity are advantages of this procedure.

Full text of DOI:10.1016/j.tetlet.2011.11.018

Tetrahedron Letters 53 (2012) 203–206
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Tetrahedron Letters
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A new method for the synthesis of amides from imines
⇑
Mohammad Ghaffarzadeh , Somaye Shahrivari Joghan, Fereshteh Faraji
Chemistry and Chemical Engineering Research Center of Iran (CCERCI), PO Box 14335-186, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and straightforward method for the synthesis of amides by the reaction of imines and anhy-
drides in the presence of Et3SiH/Zn is reported. Mild reaction conditions, good yields of products, short
reaction times, and operational simplicity are advantages of this procedure.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 21 August 2011
Revised 12 October 2011
Accepted 4 November 2011
Available online 10 November 2011
Keywords:
Amide
Imine
Triethylsilane
Reduction
Fentanyl
The formation of amides has attracted considerable interest due
to their importance in organic and bioorganic chemistry, their va-
lue as intermediates in organic synthesis and a wide range of appli-
cations in the chemical industry. The amide bond is an important
structural component of peptides, polymers, and many natural
products and pharmaceuticals.1–4 Numerous amides are biologi-
cally active and show antifungal, antihistamine, anthelmintic,
and antibacterial properties.5–8 Several methods have been de-
scribed for the synthesis of amides; these include (i) reaction of
an amine with a carboxylic acid, carboxylic acid derivatives, alde-
hydes, or alcohols,9–12 (ii) hydration of nitriles into primary
amides,13 (iii) coupling of amines with nitriles,9 (iv) coupling of ni-
triles with alcohols (Ritter reaction),14 (v) rearrangement of aldox-
imes into primary amides,9,11 (vi) Beckmann rearrangement of
ketoximes into secondary amides,9 (vii) coupling of aldoximes
and amines,9 (viii) palladium-catalyzed aminocarbonylation of aryl
halides, vinyl halides, or benzyl halides,9,15 (ix) N-arylation and N-
alkenylation of amides,9 (x) rearrangement of ketones into amides
with TMSN3,16 (xi) reaction of carboxylic acids with isocyanides,17
(xii) coupling of phosphazenes with carboxylic acids,18 and (xiii)
reaction of azides and thioacids.19
However, the use of imines as precursors for the synthesis of
amides has seldom been described. In 1988, Vasapollo and Alper
reported the diacylation of Schiff bases using catalytic quantities
of cobalt carbonyl and phase-transfer catalysis conditions.20
The oxidation of aldimines to amides using m-CPBA and
BF3ÁOEt2 was reported by Rhee and co-workers.21 Recently, the
synthesis of a-amino amides by the reaction of imines and isocya-
nates using TaCl5/Zn was described.22 Therefore, we sought to de-
velop a new, simple, and straightforward method for amide
formation from imines using the silicon-based reducing agent,
Et3SiH, in the presence of zinc dust.
Initially, we performed the reaction of N-benzylideneaniline
(1a), acetic anhydride (2a) and Et3SiH/Zn in THF at room tempera-
O
O
O
Et3SiH (4mmol)/Zn (1.2mmol)
Ph
+
Ph
N
Me
Ph
N
Me
O
Me
THF, r.t., 45min
Ph
1a (1 mmol)
2a (2 mmol)
3a (80%)
Scheme 1. Model reaction.
⇑
Corresponding author. Fax: +98 2144580762.
E-mail address: mghaffarzadeh@ccerci.ac.ir (M. Ghaffarzadeh).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.018

204
M. Ghaffarzadeh et al. / Tetrahedron Letters 53 (2012) 203–206
ture using different quantities of reagents. The best result was ob-
tained with a 1:2:4:1.2 ratio of N-benzylideneaniline, acetic anhy-
dride, Et3SiH and zinc (Scheme 1). When this reaction was carried
out without zinc the expected product was obtained only in trace
amount.
Next, the general efficiency of the method was studied for the
synthesis of a variety of amides and the results are summarized
in Table 1. Various imines 1a–k reacted efficiently with anhydrides
2a,b to afford the amides 3a–s under similar conditions (Scheme
2). Imines possessing electron-withdrawing and electron-releasing
Table 1
Synthesis of amides 3a–s
Product
Yield (%)
80
Product
Yield (%)
80
O
O
N
O
N
Cl
3a
3b
OMe
O
OMe
78
68
N
78
65
N
3d
Cl
3c
O
O
N
N
3e
Cl
3f
Cl
O
Cl
O
O
N
N
70
72
69
70
3g
3h
O
N
N
N
3i
3j
O
O
80
72
73
75
N
O
3k
3l
O
OMe
N
N
3n
3m
3o
Cl
O
O
OMe
65
86
70
65
N
N
3p
Cl
O
O
Cl
Cl
N
N
3r
3q
Cl
O
84
N
3s

M. Ghaffarzadeh et al. / Tetrahedron Letters 53 (2012) 203–206
205
O
R2
R1
O
O
Et3SiH/Zn
R1
R
N
R
N
R2
O
R2
THF, r.t.,
45 min
+
1a-k
2a,b
3a-s
Scheme 2. Synthesis of amides 3a–s.
was monitored by TLC). After completion of the reaction, the mix-
ture was filtered, and H2O (20 mL) was added to the filtrate which
was extracted with CH2Cl2 (3 Â 5 mL). The combined organic layer
was dried over anhydrous MgSO4 and concentrated by rotary evap-
oration. The residue was purified by flash column chromatography
(EtOAc/petroleum ether).
O
N
N
Et
N
N
O
O
Et3SiH/Zn
Synthesis of N-(1-phenethylpiperidin-4-ylidene)aniline26 (4)
+
Et
O
Et
THF, r.t.,
1 h
A mixture of 1-phenethylpiperidin-4-one (2 mmol), aniline
(2 mmol), and a catalytic amount of p-TsOH (0.03 g) in toluene
was stirred at reflux with the removal of H2O using a Dean–Stark
trap for 24 h. The reaction mixture was cooled and the solvent
evaporated. The residue was recrystallized from n-hexane to afford
pure product 4 (0.22 g, 80%).
4
5 (84%)
Synthesis of fentanyl (5)
Scheme 3. Synthesis of fentanyl 5.
A mixture of 4 (1 mmol), propionic anhydride (2 mmol), Et3SiH
(4 mmol), and activated Zn dust (1.2 mmol) in THF (5 ml) was stir-
red at room temperature for 1 h. After completion of the reaction,
the mixture was filtered, and H2O (20 mL) was added to the filtrate
which was extracted with CH2Cl2 (3 Â 5 mL). The combined organ-
ic layer was dried over anhydrous MgSO4 and concentrated by ro-
tary evaporation. The residue was purified by flash column
chromatography (EtOAc/petroleum ether) to afford fentanyl (5)
substituents were also converted into the corresponding amides in
good yields (Table 1).
To explore further the potential of this method, we undertook
the synthesis of fentanyl (5) (Scheme 3) because of its high potency
and generally favorable pharmacological properties. Fentanyl, or 1-
(2-phenylethyl)-4-(N-propionylphenylamino)piperidine, is a well
known and clinically widely used narcotic analgesic, about 50–
100 times more potent than morphine in humans. Fentanyl is used
in anesthesiology and reanimatology as a means of premedication
in surgery, for initial narcosis, post-operation analgesic treatment,
pain relief in cases of myocardial infarction and chronic heart dis-
ease in oncological patients, and in neuroleptanalgesic treatment
in combination with neuroleptic drugs such as droperidol.23–25
Amides 3 apparently result from initial reduction of imine 1 by
Et3SiH/Zn to yield N-silylamine 6, which reacts with anhydride 2 to
afford the corresponding product (Scheme 4).
(0.28 g, 84%). Mp 84–85 °C (Lit.25 mp 82–83 °C). IR (KBr) (mmax
/
cmÀ1): 3057, 1656, 1612. MS, m/z: 336 (M+, 5), 245 (10), 188
(120), 189 (15), 91 (80), 77 (42), 57 (100). 1H NMR (500 MHz,
CDCl3): dH (ppm) 1.04 (t, J = 7.4 Hz, 3H), 1.48–1.58 (m, 4H), 1.95
(q, J = 7.4 Hz, 2H), 2.21 (m, 2H), 2.57–2.76 (m, 4H), 3.04 (m, 2H),
4.72 (m, 1H), 7.12 (m, 2H), 7.19 (m, 3H), 7.28 (m, 2H), 7.4 (m, 3H).
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for amide bond formation via the reaction of imines and anhy-
drides in the presence of Et3SiH/Zn at room temperature. We be-
lieve this method will find useful applications in amide chemistry.
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A mixture of imine (1 mmol), anhydride (2 mmol), Et3SiH
(4 mmol), and activated Zn dust (1.2 mmol) in THF (5 mL) was stir-
red at room temperature for 45 min (the progress of the reaction
O
O
O
R2
R1
R1
R1
R2
R2
O
Et3SiH/Zn
2
R
N
R
N
R
N
SiEt3
1
6
3
Scheme 4. Proposed mechanism.

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