Formation of Amides from Imines via Cyanide-Mediated Metal-Free Aerobic Oxidation

Article abstract of DOI:10.1021/acs.joc.5b01922

A new protocol for the direct formation of amides from imines derived from aromatic aldehydes via metal-free aerobic oxidation in the presence of cyanide is described. This protocol was applicable to various aldimines, and the desired amides were obtained in moderate to good yields. Mechanistic studies suggested that this aerobic oxidative amidation might proceed via the addition of cyanide to imines followed by proton transfer from carbon to nitrogen in the original imines, leading to carbanions of α-amino nitriles, which undergo subsequent oxidation with molecular oxygen in air to provide the desired amide compounds.

Full text of DOI:10.1021/acs.joc.5b01922

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Article
Formation of Amides from Imines via Cyanide-
Mediated Metal-Free Aerobic Oxidation
Hong-Ahn Seo, Yeon-Ho Cho, Ye-Sol Lee, and Cheol-Hong Cheon
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01922 • Publication Date (Web): 18 Nov 2015
Downloaded from http://pubs.acs.org on November 19, 2015
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Formation of Amides from Imines via Cyanide-Mediated
Metal-Free Aerobic Oxidation
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Hong-Ahn Seo,‡ Yeon-Ho Cho,‡ Ye-Sol Lee, and Cheol-Hong Cheon*
Department of Chemistry, Korea University, 145 Anamꢀro, Seongbukꢀgu, Seoul 02841,
Republic of Korea, Phone: +82ꢀ2ꢀ3290ꢀ3147; Fax: +82ꢀ2ꢀ3290ꢀ3121; eꢀmail:
cheon@korea.ac.kr
Abstract: A new protocol for the direct formation of amides from imines derived from
aromatic aldehydes via metalꢀfree aerobic oxidation in the presence of cyanide is described.
This protocol was applicable to various aldimines and the desired amides were obtained in
moderate to good yields. Mechanistic studies suggested that this aerobic oxidative amidation
might proceed via the addition of cyanide to imines followed by proton transfer from carbon
to nitrogen in the original imines leading to carbanions of αꢀaminonitriles, which undergo
subsequent oxidation with molecular oxygen in air to provide the desired amide compounds.
‡
These authors contributed equally.
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Introduction
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Ever since Strecker’s original report in 1850 on the three component reaction between
aldehydes, ammonia, and hydrogen cyanide (HCN),1 the addition of HCN to imines derived
from carbonyls and amines leading to αꢀaminonitriles has been the subject of great interest
because the resulting Strecker products I have been widely used as versatile intermediates in a
number of synthetic applications (Figure 1a).2,3 Although a similar addition of cyanide anion
(CNꢀ) to imines has been known for a long time, synthetic protocols utilizing the resulting
cyanide adducts II as synthetic intermediates have been far less developed than those with
HCN adducts I. This might be due to the fact that cyanide adducts II readily undergo an
elimination reaction (retroꢀStrecker reaction), which makes it difficult to maintain high
concentration of adducts II so that the rate of their conversion to the next step is reasonably
high (Figure 1b).4
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(a) addition of HCN to imines
R2
R2
H
H2N R2
R1
-H2O
HCN
O
N
N
- readily available
- utilized as
versatile intermediates
K > 1
R
R1
R
R
CN
R1
I
(b) addition of CN- to imines
R2
M+
R2
M+CN-
H2N R2
N
O
N
- not readily available
- can be utilized as
intermediates??
-H2O
R1
K < 1
R
CN
R
R1
R
R1
II
Figure 1. Comparison of the Addition Products of HCN and CNꢀ to Imines
Recently, our group initiated a program to develop novel synthetic protocols utilizing
cyanide adducts II as valuable synthetic intermediates. For example, we developed a protocol
for the synthesis of benzoxazoles from orthoꢀaminophenol and aldehydes via metalꢀfree
aerobic oxidative cyclization using cyanide as the catalyst (Scheme 1a).5 Imine A is unlikely
to undergo cyclization because 5ꢀendoꢀtrig cyclization is disfavored according to Baldwin’s
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rules.6 However, cyanide adduct II-a readily underwent cyclization through favored 5ꢀexoꢀtet
cyclization, and subsequent aerobic oxidation of the cyclized product provided benzoxazole B.
When we attempted to extend this method to the synthesis of benzimidazoles with orthoꢀ
phenylenediamine, intermediate II-b underwent 6ꢀexoꢀdig cyclization rather than the expected
5ꢀexoꢀtet cyclization leading to the formation of 2ꢀaminoquinoxaline C after aerobic oxidation
(Scheme 1b).7
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(a) previous work: synthesis of benzoxazoles
5-exo-tet
cyclization
OH
OH
CN-
O
N
CN
R
[Ox]
N
R
N
R
B
C
A
II-a
(b) previous work: synthesis of 2-aminoquinoxalines
N
C
6-exo-dig
cyclization
NH2
N
NH2
N
N
N
NH2
R
CN-
[Ox]
R
R
A'
II-b
(c) this work: conversion of imines to amides
tauto-
H
CN
CN
O
CN-
merization
[Ox]
H
Ar
R
R
R
R
N
Ar
N
Ar
N
N
Ar
H
H
II-c
III
Scheme 1. Synthetic Applications of Cyanide Adducts II to Organic Transformations via
Aerobic Oxidation.
Herein we report the development of another synthetic protocol using cyanide adducts
II as the intermediates: the direct formation of amides from imines via metalꢀfree aerobic
oxidation (Scheme 1c).8ꢀ11 This result is based on our recent finding of the unexpected
formation of amides from aromatic aldimines in the presence of cyanide, when we attempted
to utilize cyanide as a surrogate for isocyanide in the synthesis of imidazopyridines.
Mechanistic studies suggested that cyanide adducts II-c underwent tautomerization to
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generate benzylic anions III,12 and subsequent aerobic oxidation of III provided the
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corresponding amides.
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Results and Discussion
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Since we demonstrated that cyanide could be utilized as a surrogate for isocyanide in
the synthesis of 2ꢀaminoquinoxalines (Scheme 1b),7,13 we attempted to extend the usage of
cyanide as a surrogate for isocyanide to the synthesis of other nitrogenꢀcontaining
heteroaromatic compounds, such as imidazopyridine 2.14 For example, it was expected that
imidazopyridine 2 could be prepared from imine 1, derived from 2ꢀaminopyridine and
aldehyde, using cyanide as a surrogate for isocyanide via addition of cyanide to imine 1
followed by 5ꢀexoꢀdig cyclization (Scheme 2).
Scheme 2. Application of CNꢀ as a Surrogate for Isocyanide in the Synthesis of
Imidazopyridine 2.
Based on this idea, imine 1a, derived from 2ꢀaminopyridine and benzaldehyde, was
subjected to the aerobic oxidative cyclization conditions7 previously used for the synthesis of
2ꢀaminoquinoxalines. However, the expected imidazopyridine 2a was not observed; rather
unexpectedly, amide 3a was obtained as the major product (Scheme 3).10 Because the direct
conversion of imines to amides via aerobic oxidation in the presence of cyanide has been
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rarely reported in the literature even with the assistance of metal catalysts,11,15 we initially
suspected that the nitrogen atom in the pyridine ring of 1a might play a role in this aerobic
oxidative amidation reaction. Thus, we tested the same transformation with imine 1b, which
is derived from 3ꢀaminopyridine instead of 2ꢀaminopyridine. When 1b was subjected to the
above conditions, the formation of the corresponding amide 3b was again observed.
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NaCN (110 mol %)
4A MS, DMF
H
N
N
Ph
Ph
N
Ph
Ph
N
80 oC, 12 h
open flask
N
N
O
NH2
1a
2a
3a
41 %
not observed
H
N
N
Ph
same as above
O
N
N
1b
3b
45 %
Scheme 3. Unexpected Formation of Amides from Imines
Since these results strongly suggested that the nitrogen atom in the pyridine ring in
imine 1 is not required for the formation of amides from imines, the reaction conditions were
optimized using imine 4a, derived from aniline and benzaldehyde, as a model compound
(Table 1). Cyanide was found to play a crucial role in this protocol; amide 5a was obtained in
good yield in the presence of cyanide, whereas the amide formation did not occur at all in the
absence of cyanide (entries 1 and 2). When this reaction was performed under an argon
atmosphere, a negligible amount of 5a was observed, indicating that molecular oxygen in air
is the terminal oxidant in this transformation (entry 3). The choice of solvent was found to
have a strong influence on the formation of 5a (entries 1, and 4ꢀ8). Among the solvents tested,
5a was obtained in the best yield in DMF, and thus, DMF was chosen for further
investigations.
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Next, the effect of the amount of cyanide on the formation of 5a was examined
(entries 1, 2, and 9ꢀ11). The amount of cyanide was found to exert a strong influence on the
efficacy of this transformation. The yield of 5a increased with the amount of cyanide until a
stoichiometric amount of cyanide was used. However, the yield of 5a did not improve further
and reached a plateau when superꢀstoichiometric amounts of cyanide were used. Thus, we
decided to use a slight excess of cyanide (110 mol %) as the optimal amount.
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Table 1. Optimization of Reaction Conditions
CN
O
H
NaCN (x mol %)
4 A MS, solvent
temp (oC), time (h)
open flask
Ph
Ph
Ph
N
N
+
N
H
6a
5a
4a
entry
NaCN
(x mol %)
110
solvent
Temp (oC)
time (h)
yield of 5a (%)a
1
2
DMF
DMF
80
80
80
80
80
80
80
80
80
80
80
100
120
4
24
24
4
69
N.R.b
< 5
ꢀ
3c
4
110
110
110
110
110
110
50
DMF
DMSO
CH3CN
dioxane
toluene
iꢀPrOH
DMF
56
5
24
24
24
24
8
40
6
N.R.b
N.R.b
N.R.b
35
7
8
9
10
11
12
13
200
300
110
110
DMF
4
74
DMF
4
70
DMF
2
71 (13)d
70 (12)d
DMF
1
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14
110
110
DMF
DMF
120
120
2
2
81e
79
15f
6
b
c
d
a Isolated yield. No Reaction. Under an argon atmosphere. The number in parenthesis is
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e
f
the isolated yield of 6a. The isolated yield of 5a after basic hydrolysis. Sequential oneꢀpot
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protocol.
Despite numerous effects, we were not able to further improve the yield of 5a higher
than 70% yield, and a careful analysis of the reaction mixture revealed that αꢀiminonitrile 6a16
was also formed albeit in low yield. Because αꢀiminonitriles could be converted to the
corresponding amides via hydrolysis,17 we attempted to convert 6a into 5a at the elevated
reaction temperature (entries 1, 12, and 13). Rather disappointingly, the yield of 5a did not
improve, and 6a was still obtained in similar yields even at higher temperatures, although the
reaction rate accelerated at high temperature. However, when the reaction mixture was treated
with a NaOH solution after complete consumption of 4a, 5a was obtained in 81% yield (entry
14). Finally, we further developed a oneꢀpot protocol for the synthesis of 5a directly from the
aldehyde and aniline without isolation of imine 4a. When 4a, prepared in situ from
benzaldehyde and aniline, was subjected to the standard aerobic oxidation conditions, the
yield of 5a was similar to that obtained using isolated imine 4a, after treatment of the reaction
mixture with an aqueous basic solution (entry 15).18
With these optimized conditions in hand, we explored the substrate scope for this
transformation (Table 2). Various aromatic aldehydes could be applied to this protocol, and
amides 5 were obtained in good yields (entries 1ꢀ9). The electronic properties of the
aldehydes exerted some influence on this transformation; aldehydes bearing electron donating
groups (entries 2 and 3) provided the corresponding amides in better yields than those with
electron withdrawing substituents (entries 4ꢀ6). More sterically hindered orthoꢀsubstituted
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aldehydes were also amenable to this protocol, and the corresponding amides 5 were obtained
in good yields (entries 7–9). This protocol was further extended to fused aromatic aldehydes
and heteroaromatic aldehydes, and the desired products were obtained in moderate to good
yields (entries 10ꢀ14). Next, we investigated the effect of the electronic properties of aniline
derivatives on this transformation (entries 1, 15 and 16). The electronic nature of anilines was
found to have only small influence on the yield of this transformation; aniline derivatives
bearing either electronꢀrich or electronꢀdeficient substituents provided the desired products in
slightly lower yields than aniline itself.
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Table 2. Substrate Scope
NaCN (110 mol %)
Ar'
O
O
N
8)
H2N Ar' (
4 A MS, DMF
Ar'
o
Ar
N
Ar
H
EtOH, 80 oC
120 C, open flask
Ar
H
H
7
then, NaOH (1 N), rt
5
not isolated
entry
1
Amide (5)
Ar
Ar’
Ph
yield (%)a
C6H5
79
76
67
60
57
77
71
81
64
69
56
5a
5b
5c
5d
5e
5f
2
4ꢀMeOC6H4
4ꢀMeC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3
4
4ꢀClC6H4
5
4ꢀBrC6H4
6
4ꢀMeCO2C6H4
2ꢀMeOC6H4
2ꢀMeC6H4
2ꢀClC6H4
7
5g
5h
5i
8
9
10
11
1ꢀNaphthyl
2ꢀNaphthyl
5j
5k
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2ꢀFuryl
2ꢀThienyl
2ꢀPyridinyl
C6H5
Ph
48
71
83
65
62
5l
13
Ph
5m
5n
5o
5p
14
Ph
15
4ꢀBrC6H4
4ꢀMeOC6H4
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16
C6H5
aIsolated yield.
We further investigated other imines derived from different amines than anilines for
this aerobic oxidative amidation reaction (Scheme 4). When a precursor 9 of Boc imine 10
was subjected to the standard conditions in the presence of K2CO3, the corresponding Boc
imine 10 in situ generated readily underwent the oxidative amidation reaction, but the Boc
group in the resulting amide 11 was removed to provide benzamide 11-H in 60% yield (eq. 1).
K2CO3 (1.1 equiv.)
Boc
Boc
O
[Ox]
HN
NaCN (110 mol%)
N
H
( 1 )
Ph
N
4A MS, DMF, 120 oC
Ph
Ts
Ph
H
H
open flask
10
11-H
9
not isolated
60 %
Boc
Ts
Boc
N
[Ox]
O
HN
same as above
( 2 )
Boc
except 60 oC
Ph
N
H
Ph
Ph
H
10
9
11
76 %
not isolated
NaCN (110 mol%)
O
O
Bn
H
O
N
( 3 )
4A MS, DMF, 120 oC
open flask
Ph
N
Ph
+
Ph
N
H
14
Ph
Ph
Ph
H
13
10 %
12
7 %
NaCN (110 mol%)
Ts
N
( 4 )
complex mixture
4A MS, DMF, 120 oC
open flask
H
15
Scheme 4. Investigation of Amine Sources
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o
However, when the same transformation was performed at 60 C, the desired Boc
protected amide 11 was obtained in 76% yield without any concomitant formation of 11-H
(eq. 2).20 Unfortunately, however, other imines derived from other amine sources, such benzyl
amine and tosyl amine, were found not to be applicable to this aerobic oxidative amidation;
benzyl imine 12 afforded the corresponding amide 13 and imide 14 only in low yields (~10%)
(eq. 3), while tosyl imine 15 provided a complex mixture (eq. 4).
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With these results in hand, we attempted to elucidate the reaction mechanism for this
cyanideꢀmediated aerobic oxidative amidation of imines. As cyanide was found to play a
critical role in this transformation, cyanide adduct II might be the key intermediate. From
intermediate II, there might be two possible reaction pathways for the aerobic oxidative
amidation reaction (Scheme 5).19
hydride
transfer
Ar'
H
Ar'
O
H2O
N
N
(pathway a)
oxdative
pathway
Ar
CN
Ar
5
6
Ar'
Ar'
H
CN-
N
H
N
Ar
CN
Ar
proton
transfer
H
Ar'
O
H
Ar'
4
II
N
air
N
(pathway b)
oxygenative
pathway
Ar
Ar
CN
5
III
Scheme 5. Possible Reaction Pathways
Intermediate II might first undergo oxidation through hydride transfer to form αꢀ
iminonitrile 6, with subsequent hydrolysis of 6 affording the desired amide 5 (pathway a;
oxidative pathway). On the other hand, proton transfer from the αꢀcarbon atom to the nitrogen
atom in intermediate II might take place to generate anion III,12 which subsequently
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undergoes reaction with molecular oxygen to furnish amide 5 (pathway b; oxygenative
pathway).18,19(b)
6
7
8
9
Since the formation of αꢀiminonitriles 6 was observed during the optimization of the
reaction conditions, we initially suspected that amides 5 might be formed through hydrolysis
of αꢀiminonitriles 617. Under such a scenario, it was expected that water would play a role in
this transformation. To test this idea, we carried out a few controlled experiments (Scheme 6).
When the reaction was performed in the absence of molecular sieves (i.e., in the presence of
water), the yield of 5a was not improved, and 5a and 6a were obtained in similar level of
yields regardless of the presence of molecular sieves (eq. 5). Furthermore, when the isolated
αꢀiminonitrile 6a was directly subjected to hydrolysis in wet organic solvent, 6a did not
undergo the hydrolysis at 120 oC even after 24 h (eq. 6). Instead, strong basic conditions (1 N
NaOH) were needed to hydrolyze αꢀiminonitrile 6a into amide 5a. These results led us to rule
out the possibility that the amides would be formed via the hydrolysis of αꢀiminonitriles even
though 6 was observed in the reaction mixture. Based on these experimental results in
conjunction with the previous reports on dimerization of aldimines where intermediate III
was considered to be formed from cyanide adduct II via tautomerization,12,15 we believe that
the formation of amides from imines in the presence of cyanide would proceed via pathway b.
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Ph
Ph
H
O
N
N
NaCN (110 mol %)
Ph
+
4 A MS, DMF, 120 oC, 1 h
open flask
( 5 )
Ph
N
Ph
CN
Ph
Ph
H
5a
70
6a
4a
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without 4 A MS
65
10
Ph
O
H2O (5 vol %)
N
Ph
( 6 )
DMF, 120 oC, 24 h
open flask
Ph
N
CN
H
5a
6a
trace
with 1 N NaOH, 10 min
quantitative
Scheme 6. Test of Iminonitrile 4a as an Intermediate in the Aerobic Oxidative Amidation
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Conclusions
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In conclusion, we reported the direct formation of amides from imines in the presence
of cyanide via metalꢀfree aerobic oxidation. Various aromatic aldehydes were applicable to
this protocol and the desired amides were obtained in good to high yields. Furthermore, other
imines derived from other amine sources than aniline could be applied to this protocol
although the yields of the corresponding amides showed a dependence on the choice of
amines. Mechanistic studies suggested that this aerobic oxidative amidation might proceed via
the addition of cyanide to imines, followed by the proton transfer leading to carbanions of αꢀ
aminonitriles, and subsequent aerobic oxidation. The elucidation of the detailed reaction
mechanism and further application of this method are currently underway in our laboratory.
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Experiment Section
General. All reactions were carried out in ovenꢀ or flameꢀdried glassware in an open flask
unless otherwise noted. Except as otherwise indicated, all reactions were magnetically stirred
and monitored by analytical thin layer chromatography (TLC) using preꢀcoated silica gel
glass plates (0.25 mm) with F254 indicator. Visualization was accomplished by UV light (254
nm), with combination of potassium permanganate and/or phosphomolybdic acid solution as
an indicator. Flash column chromatography was performed using silica gel 60 (230 – 400
mesh). Yields refer to chromatographically and spectroscopically pure compounds, unless
otherwise noted. Commercial grade reagents and solvents were used without further
purification. Liquid aldehydes were purified by fractional distillation and solid aldehydes
1
were purified by a column chromatography on silica. H NMR spectra were recorded on
either a 300 or 400 MHz spectrometer. Tetramethylsilane (δ: 0.0 ppm) was used as an internal
1
standard for H NMR. The proton spectra are reported as follows δ (position of proton,
multiplicity, coupling constant J, number of protons). Multiplicities are indicated by s
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(singlet), d (doublet), t (triplet), q (quartet), p (quintet), h (septet), m (multiplet) and br
(broad).
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General procedure for metalꢀfree aerobic oxidative amidation (Table 2). To a 50 mL twoꢀ
necked round bottomed flask equipped with a condenser were added amine 8 (1.1 mmol,
1.1 equiv.) and ethanol (10 mL). To the above solution was added aryl aldehyde 7 (1.0
mmol, 1.0 equiv.), and the reaction mixture was allowed to stirred at 80 oC and monitored
by TLC. After complete consumption of aldehyde 7, the reaction mixture was concentrated
under reduced pressure to afford the crude product of imine. Without further purification
of the resulting imine, the crude mixture was dissolved in DMF (10 mL), and sodium
cyanide (1.1 mmol, 1.1 equiv.) and molecular sieves were added to the reaction mixture.
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o
Then, the reaction mixture was stirred at 120 C until all the imine was completely
consumed. On the complete consumption of the imine, NaOH solution (1.0 N) was added
to the reaction mixture and the reaction mixture was allowed to stir at room temperature
for 10 min. The crude mixture was extracted with ether and the organic layer was
combined, dried over MgSO4, and concentrated. The resulting crude mixture was purified
by flash column chromatography on silica to provide the expected amide 5.
Nꢀ(Pyridinꢀ2ꢀyl)benzamide (3a)
The desired product 3a was obtained as a yellow solid (81 mg, 41% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:2): Rf = 0.50 (ethyl acetate/hexanes =
2:1). The spectroscopic data were in good agreement with the literature.21 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.77 (br, 1H), 8.38 (d, J = 4.1 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H),
8.02 (d, J = 8.0 Hz, 2H), 7.83 (t, J = 7.7 Hz, 1H), 7.46 ꢀ 7.62 (m, 4H).
Nꢀ(Pyridinꢀ3ꢀyl)benzamide (3b)
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The desired product 3b was obtained as a yellow solid (85 mg, 45% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:4): Rf = 0.30 (ethyl acetate/hexanes =
1:4). The spectroscopic data were in good agreement with the literature.22 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.45 (br, 1H), 8.92 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 4.7 Hz, 1H),
8.20 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 7.2 Hz, 2H), 7.52ꢀ7.63 (m, 3H), 7.36 ꢀ 7.41 (m, 1H).
NꢀPhenylbenzamide (5a)
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The desired product 5a was obtained as a white solid (147 mg, 79% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.30 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.23 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.24 (br, 1H), 7.94 (d, J = 7.2 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H),
7.48 ꢀ 7.62 (m, 3H), 7.34 (t, J = 7.7 Hz, 2H), 7.09 (t, J = 7.2 Hz, 1H).
4ꢀMethoxyꢀNꢀphenylbenzamide (5b)
The desired product 5b was obtained as a yellow solid (173 mg, 76% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.40 (ethyl acetate/hexanes =
1:3). The spectroscopic data were in good agreement with the literature.23 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.07 (br, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H),
7.32 (t, J = 7.7 Hz, 2H), 7.01 ꢀ 7.10 (m, 3H), 3.82 (s, 3H).
4ꢀMethylꢀNꢀphenylbenzamide (5c)
The desired product 5c was obtained as a white solid (133 mg, 67% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.40 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.23 1H NMR (300
MHz, CDCl3, ppm): δ 7.77 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.7 Hz, 2H), 7.37 (t, J = 7.7 Hz,
2H), 7.29 (t, J = 7.7 Hz, 2H), 7.15 (t, J = 7.3 Hz, 1H), 2.43 (s, 3H).
4ꢀChloroꢀNꢀphenylbenzamide (5d)
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The desired product 5d was obtained as a white solid (139 mg, 60% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.30 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.23 1H NMR (300
MHz, CDCl3, ppm): δ 7.82 (d, J = 8.2 Hz, 2H), 7.73 (br, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.48
(d, J = 8.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.17 (t, J =7.4 Hz, 1H).
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4ꢀBromoꢀNꢀphenylbenzamide (5e)
The desired product 5e was obtained as a yellow solid (133 mg, 57% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.30 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.23 1H NMR (400
MHz, CDCl3, ppm): δ 7.75 (d, J = 8.2 Hz, 2H), 7.63 (dd, J = 7.8 Hz, J = 4.7 Hz, 4H), 7.39 (t,
J = 7.8 Hz, 2H), 7.15 – 7.20 (m, 1H).
4ꢀMethoxycarbonylꢀNꢀphenylꢀbenzamide (5f)
The desired product 5f was obtained as a yellow solid (196 mg, 77% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:4): Rf = 0.30 (ethyl acetate/hexanes =
1:4). The spectroscopic data were in good agreement with the literature.24 1H NMR (400
MHz, CDCl3, ppm): δ 8.16 (d, J = 7.8 Hz, 2H), 7.94 (d, J = 7.8 Hz, 2H), 7.82 (br, 1H), 7.65
(d, J = 7.8 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.19 (m, 1H), 3.97 (s, 3H).
2ꢀMethoxyꢀNꢀphenylbenzamide (5g)
The desired product 5g was obtained as a white solid (161 mg, 71% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.30 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.24 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.10 (br, 1H), 7.72 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H),
7.49 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.4 Hz, 2H), 7.17 (d, J = 8.3 Hz, 1H), 7.01 – 7.10 (m,
2H), 3.88 (s, 3H).
2ꢀMethylꢀNꢀphenylbenzamide (5h)
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The desired product 5h was obtained as a white solid (171 mg, 81% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:8): Rf = 0.60 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.23 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.28 (br, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.24 – 7.47 (m, 6H), 7.07
(t, J = 7.3 Hz, 1H), 2.37 (s, 3H).
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2ꢀChloroꢀNꢀphenylbenzamide (5i)
The desired product 5i was obtained as a yellow solid (148 mg, 64% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.30 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.23 1H NMR (400
MHz, CDCl3, ppm): δ.7.89 (br, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.35 –
7.48 (m, 5H), 7.18 (t, J = 7.2 Hz, 1H).
NꢀPhenylꢀ1ꢀnaphthalamide (5j)
The desired product 5j was obtained as a white solid (170 mg, 69% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.30 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.23 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.57 (br, 1H), 8.13 – 8.20 (m, 1H), 7.99 – 8.10 (m, 2H), 7.71 –
7.83 (m, 3H), 7.55 – 7.63 (m, 3H), 7.36 (t, J = 7.8 Hz, 2H), 7.11 (t, J = 7.3 Hz, 1H).
NꢀPhenylꢀ2ꢀnaphthalamide (5k)
The desired product 5k was obtained as a yellow solid (139 mg, 56% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.30 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.25 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.43 (br, 1H), 8.57 (s, 1H), 7.98 ꢀ 8.11 (m, 4H), 7.82 (d, J = 8.0
Hz, 2H), 7.59 ꢀ 7.66 (m, 2H), 7.37 (t, J = 7.3 Hz, 2H), 7.11 (t, J = 7.0 Hz, 1H).
NꢀPhenylꢀfuranꢀ2ꢀcarboxamide (5l)
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The desired product 5l was obtained as a dark brown solid (90 mg, 48% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:4): Rf = 0.30 (ethyl acetate/hexanes =
1:4). The spectroscopic data were in good agreement with the literature.23 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.17 (br, 1H), 7.92 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.32 (t, J =
7.7 Hz, 3H), 7.10 (t, J = 7.4 Hz, 1H), 6.67 – 6.71 (m, 1H).
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NꢀPhenylꢀthiophenꢀ2ꢀcarboxamide (5m)
The desired product 5m was obtained as a yellow solid (144 mg, 71% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.30 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.25 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.21 (br, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.84 (d, J = 5.0 Hz, 1H),
7.70 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 7.7 Hz, 2H) 7.19 ꢀ 7.24 (m, 1H) 7.09 (t, J = 7.3 Hz, 1H).
NꢀPhenyl picolinamide (5n)
The desired product 5n was obtained as a yellow solid (164 mg, 83% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:3): Rf = 0.40 (ethyl acetate/hexanes =
1:3). The spectroscopic data were in good agreement with the literature.23 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.62 (br, 1H), 8.73 (d, J = 4.1 Hz, 1H), 8.12 ꢀ 8.20 (m, 1H), 8.06
(t, J = 7.6 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.62 ꢀ 7.70 (m, 1H), 7.35 (t, J = 7.7 Hz, 2H), 7.11
(t, J = 7.2 Hz, 1H).
Nꢀ(4ꢀBromophenyl)benzamide (5o)
The desired product 5o was obtained as a yellow solid (176 mg, 65% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:8): Rf = 0.50 (ethyl acetate/hexanes =
1:5). The spectroscopic data were in good agreement with the literature.26 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.36 (br, 1H), 7.93 (d, J = 7.7 Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H),
7.49 – 7.62 (m, 5H).
Nꢀ(4ꢀMethoxyphenyl)benzamide (5p)
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The desired product 5p was obtained as a yellow solid (141 mg, 62% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:4): Rf = 0.40 (ethyl acetate/hexanes =
1:3). The spectroscopic data were in good agreement with the literature.23 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.12 (br, 1H), 7.93 (d, J = 6.9 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H),
7.47 ꢀ 7.59 (m, 3H), 6.91 (d, J = 9.1 Hz, 2H), 3.73 (s, 3H).
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Benzamide (11-H)
The desired product 11-H was obtained as a white solid (72 mg, 60% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:1): Rf = 0.30 (ethyl acetate/hexanes =
1:1). The spectroscopic data were in good agreement with the literature.9(b) 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 7.96 (br, 1H), 7.85 (d, J = 7.4 Hz, 1H), 7.47 ꢀ 7.53 (m, 1H), 7.40 ꢀ
7.47 (m, 2H), 7.35 (br, 1H).
Nꢀ(tertꢀButyloxycarbonyl)benzamide (11)
The desired product 11 was obtained as a white solid (165 mg, 76% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:3): Rf = 0.30 (ethyl acetate/hexanes =
1:3). The spectroscopic data were in good agreement with the literature.20 1H NMR (300
MHz, DMSOꢀd6, ppm): δ 10.66 (br, 1H), 7.82 (d, J = 7.7 Hz, 2H), 7.54 – 7.61 (m, 1H), 7.42 –
7.50 (m, 2H), 1.46 (s, 9H).
NꢀBenzylbenzamide (13)
The desired product 13 was obtained as a white solid (21 mg, 10% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.70 (ethyl acetate/hexanes =
1:1). The spectroscopic data were in good agreement with the literature.9(a) 1H NMR (300
MHz, CDCl3, ppm): δ 7.74 – 7.84 (m, 2H), 7.29 – 7.53 (m, 8H), 6.46 (br, 1H), 4.65 (d, J = 5.5
Hz, 2H).
N,2ꢀDiphenylacetamide (14)
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The desired product 14 was obtained as a white solid (15 mg, 7% yield) after column
chromatography on silica (ethyl acetate/hexanes = 1:5): Rf = 0.60 (ethyl acetate/hexanes =
1:1). The spectroscopic data were in good agreement with the literature.20 1H NMR (300
MHz, CDCl3, ppm): δ 8.90 (br, 1H), 7.88 (d, J = 7.4 Hz, 4H), 7.58 – 7.67 (m, 2H), 7.52 (t, J =
7.6 Hz, 4H).
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Notes
The authors declare no competing financial interests.
Acknowledgements
This work was supported by grants from the National Research Foundation of Korea (NRF)
funded by the Korean Government (NRFꢀ2013R1A1A1008434 and NRFꢀ20100020209). We
are also thankful for an NRF grant (NRFꢀ2014ꢀ011165, Center for New Directions in
Organic Synthesis).
Supporting Information
NMR spectra of all compounds . This material is available free of charge via the Internet at
http://pubs.acs.org.
References
1. Strecker, A. Liebigs Ann. Chem. 1850, 75, 27.
2. For reviews on the Strecker reaction, see: (a) Metz, A. E.; Kozlowski, M. C. J. Org.
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Davie, E. A. C.; Mennen, S. M.; Xu, Y.; Miller, S. J. Chem. Rev. 2007, 107, 5759.
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3. For reviews on the applications of the anions of Strecker products, see: (a) Opatz, T.
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Synthesis 2009, 1941. (b) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359.
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7. Cho, Y.ꢀH.; Kim, K.ꢀH.; Cheon, C.ꢀH. J. Org. Chem. 2014, 79, 901.
8. Most oxidative amidations of aldehydes with amines proceed via the corresponding
carbinolamine intermediates rather than the imines. For a review on the oxidative
amidation of aldehydes, see: EkoueꢀKovi, K.; Wolf, C. Chem. Eur. J. 2008, 14, 6302.
9. For examples of oxidative amidation of aldehydes with an oxidant, see: (a) Ghosh, S.
C.; Ngiam, J. S. Y.; Chai, C. L. L.; Seayad, A. M.; Dang, T. T.; Chen, A. Adv. Synth.
Catal. 2012, 354, 1407. (b) Ghosh, S. C.; Ngiam, J. S. Y.; Seayad, A. M.; Tuan, D. T.;
Chai, C. L. L.; Chen, A. J. Org. Chem. 2012, 77, 8007. (c) Reddy, K. R.; Maheswari,
C. U.; Venkateshwar, M.; Kantam, M. L. Eur. J. Org. Chem. 2008, 3619. (d) Ekoueꢀ
Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429. (e) Yoo, W.ꢀJ.; Li, C.ꢀJ. J. Am. Chem.
Soc. 2006, 128, 13064.
10.For examples of oxidative amidation of aldehydes via aerobic oxidation, see: (a) with
a photocatalyst: Leow, D. Org. Lett. 2014, 16, 5812. (b) with a copper catalyst: Zhu,
M.; Fujita, K; Yamaguchi, R. J. Org. Chem. 2012, 77, 9102.
11.There are a few examples of oxidative amidation of aldehydes in the presence of
cyanide using a strong oxidant. See: (a) Gilman, N. W. Chem. Commun. 1971, 733.
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(b) Enders, D.; Amaya, A. S.; Pierre, F. New J. Chem. 1999, 261. (c) Foot, J. S.;
Kanno, H.; Giblin, G. M. P.; Taylor, R. J. K. Synthesis 2003, 1055.
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12.This type of tautomerization in cyanide adducts was utilized in the dimerization of
aldimines in the presence of cyanide. See: (a) Reich, B. J. E.; Justice, A. K.;
Beckstead, B. T.; Reibenspies, J. H.; Miller, S. A. J. Org. Chem. 2004, 69, 1357. (b)
Reich, B. J. E.; Greenwald, E. E.; Justice, A. K.; Beckstead, B. T.; Reibenspies, J. H.;
North, S. W.; Miller, S. A. J. Org. Chem. 2005, 70, 8409. (c) Ogle, J. W.; Zhang, J.;
Reibenspies, J. H.; Abboud, K. A.; Miller, S. A. Org. Lett. 2008, 10, 3677.
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13.Previously, 2ꢀaminoquinoxalines C were prepared from orthoꢀphenylenediamine,
aldehydes, and isocyanide via a multicomponent reaction. See: Kravavin, M.;
Shkavrov, S.; Parchinsky, V.; Kukhryakov, K. J. Org. Chem. 2009, 74, 2627.
14.For the synthesis of 3ꢀaminoimidazo[1,2ꢀa]pyridine 2 with isocyanide, see: Blackburn,
C.; Guan, B. Tetrahedron Lett. 2000, 41, 1495.
15.The formation of amides from aldimines in the presence of cyanide in DMSO was
observed as a side reaction during the dimerization of aldimines with cyanide,
although DMSO was considered the terminal oxidant in previous reports. See: (a)
Walia, J. S.; Guillot, L.; Singh, J.; Chattha, M. S.; Satyanarayana, M. J. Org. Chem.
1972, 37, 135. (b) Walia, J. S.; Singh, J.; Chattha, M. S.; Satyanarayana, M.
Tetrahedron Lett. 1969, 10, 195.
16.Jursic, B. S.; Douelle, F.; Bowdy, K.; Stevens, E. D. Tetrahedron Lett. 2002, 43, 5361.
17.(a) Fontaine, P.; Chiaroni, A.; Masson, G.; Zhu, J. Org. Lett. 2008, 10, 1509. (b)
Gualtierotti, J.ꢀB.; Schumacher, X.; Fontaine, P.; Masson, G.; Wang, Q.; Zhu, J.
Chem. Eur. J. 2012, 18, 14812. (c) Gualtierotti, J.ꢀB.; Schumacher, X.; Wang, Q.; Zhu,
J. Synthesis 2013, 1380.
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18.When benzaldehyde, aniline, and NaCN were subjected to the standard conditions, no
desired product was obtained. Instead, the benzoylated benzoin product, which is the
trimer of benzaldehyde, was obtained as the major product. For the trimerization of
aldehydes in the presence of cyanide, see: Kim, Y.ꢀJ.; Kim, N. Y.; Cheon, C.ꢀH. Org.
Lett. 2014, 16, 2514.
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19.Similar mechanisms were proposed for aerobic oxidative esterification of aldehydes.
(a) For a review, see: Allen, S. E.; Walvoord, R. R.; PadillaꢀSalinas, R.; Kozlowski,
M. C. Chem. Rev. 2013, 113, 6234. (b) For a recent example, see: Delany, E. G.;
Fagan, C.ꢀL.; Gundala, S.; Mari, A.; Broja, T.; Zeitler, K.; Connon, S. J. Chem.
Commun. 2013, 49, 6510, and references therein.
20.For the synthesis of Boc protected amides via oxidation of Boc imines, see: Martinelli,
F.; Palmieri, A.; Petrini, M. Eur. J. Org. Chem. 2010, 5085.
21.Londregan, A. T.; Storer, G.; Wooten, C.; Yang, X.; Warmus, J. Tetrahedron Lett.
2009, 50, 1986.
22.Kim, B. R.; Lee, H.ꢀG.; Kang, S.ꢀB.; Sung, G. H.; Kim, J.ꢀJ.; Park, J. K.; Lee, S.ꢀG.;
Yoon, Y.ꢀJ. Synthesis 2011, 42.
23.Wang, Y.; Zhu, D.; Tang, L.; Wang, S.; Wang, Z. Angew. Chem. Int. Ed. 2011, 50,
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24.Schneider, T. L.; Halloran, K. T.; Hillner, J. A.; Conry, R. R.; Linton, B. R. Chem. Eur.
J. 2013, 19, 15101.
25.Du, J.; Luo, K.; Zhang, X. RSC Adv. 2014, 4, 54539.
26.Lee, C. K.; Yu, J. S.; Ji, Y. R. J. Heterocycl. Chem. 2002, 39, 1219.
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