Copper-catalyzed synthesis of weinreb amides by oxidative amidation of alcohols

Article abstract of DOI:10.1055/s-0034-1379583

A simple and efficient protocol has been developed for the oxidative amidation of alcohols to Weinreb amides using tert-butyl hydroperoxide as an oxidant and an inexpensive and air stable copper catalyst. The present protocol is advantageous as it uses commercially affordable alcohols as starting materials. The developed protocol also tolerates various substituted alcohols as starting materials to provide good to excellent yields of the desired products.

Full text of DOI:10.1055/s-0034-1379583

SYNTHESIS
0
0
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9
-
7
8
8
1
1
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3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2015, 47, 526–532
526
paper
Synthesis
S. L. Yedage, B. M. Bhanage
Paper
Copper-Catalyzed Synthesis of Weinreb Amides by Oxidative
Amidation of Alcohols
Subhash L. Yedage
Bhalchandra M. Bhanage*
O
O
Me
OH
O
Department of Chemistry, Institute of Chemical Technology, N.
+
HCl•
N
Me
HN
Parekh Marg, Matunga, Mumbai 400 019, India
bm.bhanage@gmail.com
+
9
1
2
(
2
3
)
3
6
1
1
0
2
0
TBHP, CaCO3
Me
Me
R
R
bm.bhanage@ictmumbai.edu.in
R = alkyl, alkoxy,
nitro, halo, heteroaryl
• one-step synthesis of Weinreb amide
• easily available starting materials
•
•
inexpensive catalytic system
high yield
Received: 20.08.2014
Accepted after revision: 31.10.2014
Published online: 20.11.2014
Weinreb amides are well established acylating agents in
organic chemistry. They are important due to their reactiv-
1
DOI: 10.1055/s-0034-1379583; Art ID: ss-2014-t0513-op
ity with organometallic reagents through stable metal-che-
lated intermediates. In addition, Weinreb amides can also
be easily transformed into a variety of compounds contain-
Abstract A simple and efficient protocol has been developed for the
oxidative amidation of alcohols to Weinreb amides using tert-butyl hy-
droperoxide as an oxidant and an inexpensive and air stable copper cat-
alyst. The present protocol is advantageous as it uses commercially af-
fordable alcohols as starting materials. The developed protocol also
tolerates various substituted alcohols as starting materials to provide
good to excellent yields of the desired products.
2
3
ing functional groups like aldehydes or ketones, ynones,
2
-acyloxazoles and β-lactams,4 trifluoromethyl ketones,
5
functionalized α-arylamino-α′-chloro ketones, and α,β-un-
saturated α′-halo ketones.6 Weinreb amides have been
7
widely used in the total synthesis of natural products.
Key words alcohol, amide, copper, oxidation, cross-coupling
O
O
Ph
N
OH
O
O
O
2
-magnesiated
N
Me
oxazoles
CF3
Me
R1 = PhCH2CH2
TMSCF3
1
R
= Ph
R1 = Ph
R2
O
O
Et
N
O
LiCH2X
O
2
Cl
X
R1
N
Me
R3
R2
R1 = PhN(Et)CH2
R4
Me
R3
R4
2
ortho olefination
R1 = Ph
R1 = Ph
LAH
DIBAL-H
R1 = Ph
O
O
O
R2
N
Me
O
Me
H
CO2n-Bu
Scheme 1 Applications of Weinreb amides
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27
Synthesis
S. L. Yedage, B. M. Bhanage
Paper
O
O
N
O
O
O
Cl
H
Lewis acid
C–H
activation
amidation
this work
O
O
OH
O
Me
Cu
oxidative amidation
O
transamidation
N
Me
NH2
+
ClH• HN
Me
Me
activating
agent
amino-
carbonylation
activating
agent
X
O
OH
O
X = Br, I
OR
Scheme 2 Oxidative amidation of alcohol to Weinreb amide and previous reports
Ackermann and co-workers have demonstrated the utility
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl and air as co-oxi-
dants along with TBHP (tert-butyl hydroperoxide) as the
primary oxidant for the synthesis of simple amides.
In continuation of our ongoing research on the develop-
of Weinreb amides as a directing group for ortho-olefina-
8
9
tion and ortho-oxygenation (Scheme 1).
Several methods with different starting materials such
1
0
11
12
13
18
as acids, acid chlorides, aldehydes, amides, esters/lac-
ment of facile and efficient protocols, herein, we have de-
14
15
tams or aminocarbonylation of aryl halides have been
reported for the synthesis of Weinreb amides (Scheme 2).
However, most of these methods suffer from one or more
drawbacks such as the necessity of an activator or a cou-
pling reagent, thermally unstable acid chlorides, toxic
carbon monoxide gas, the use of air- or moisture-sensitive
phosphine ligands, stoichiometric reagents, and expensive
veloped a simple and economical protocol for the synthesis
of Weinreb amides via oxidative amidation of alcohols with
N,O-dimethylhydroxylamine hydrochloride salt in the pres-
ence of Cu/TBHP catalytic system (Scheme 3).
10
11
OH
O
O
Me
O
cat., oxidant, base
solvent, temp, 24 h
N
Me
+
HCl•
HN
15
metal catalysts. Due to the growing synthetic utility of
Me
Me
16
Weinreb amides, the development of a simple and effi-
cient protocol for their synthesis is highly desirable. Recent-
ly, Chen and co-workers have reported the synthesis of
Weinreb amides using transition-metal-catalyzed oxidative
amidation with benzaldehyde as a starting material.12 How-
ever, a low yield of Weinreb amides and the use of only
benzaldehyde as a substrate are the limitations. Thus to de-
velop a widely applicable protocol for the oxidative synthe-
sis of Weinreb amides using an inexpensive and easily
available transition-metal catalyst under mild reaction con-
ditions is a worthy goal.
R
R
Scheme 3 Oxidative synthesis of Weinreb amides
To optimize the reaction conditions, benzyl alcohol (1a)
and N,O-dimethylhydroxylamine hydrochloride salt (2)
were chosen as model substrates for the oxidative amida-
tion reaction. A series of experiments was carried out to
study the effect of various reaction parameters such as cat-
alyst loading, base, solvent, oxidant, temperature, and time,
etc. on the yield of the product.
Earlier the same group has reported iron nitrate cata-
lyzed synthesis of simple amides from benzyl alcohols us-
ing amine hydrochloride salt. However, it involves two
steps. The first step is the preparation of aldehyde from al-
cohol followed by the conversion of the aldehyde into the
amide in the next step. In addition, it also requires TEMPO
Initially, commercially available copper precursors such
as CuSO ·5H O, CuO, CuCl, CuBr, CuI, CuCl ·H O, CuNO ·8H O,
4
2
2
2
3
2
17
Cu O, and Cu(OAc) ·H O using 70 wt% aqueous TBHP as oxi-
2 2 2
dant were screened for the oxidative amidation reaction
(Table 1, entries 1–9). Among these Cu(OAc) ·H O gave an
2
2
excellent yield of the desired product 3a and hence it was
selected for further optimization (entry 9). Other copper
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Synthesis
S. L. Yedage, B. M. Bhanage
Paper
catalysts provided the amide product 3a in a moderate to
poor yields (entries 1–8). The reaction was also performed
in the absence of the catalyst and it gave only a trace
amount of 3a product (entry 10).
It was also noted that decreasing the reaction time de-
creased the yield of 3a (Table 2, entry 16). Thus, 24 hours
were considered as an optimum reaction time for the com-
pletion of reaction (Table 1, entry 9). The effects of catalyst,
oxidant, and base loading were also studied. It was found
that 6 mol% catalyst, 1.2 mmol oxidant along with 1.2 mmol
base furnishes maximum yield of 3a (Table 1, entry 9). The
observations above indicate that all the three components,
copper catalyst, base, and oxidant are essential for the
Weinreb amide synthesis.
Table 1 Screening of Copper Catalyst for the Amidation Reactiona
OH
O
O
Me
O
cat., TBHP, CaCO3
MeCN, 80 ºC, 24 h
N
Me
+
HCl• HN
Me
Me
2
3a
Table 2 Optimization of the Reaction Conditionsa
1a
Entry
Catalyst
Base
Oxidant
Yield (%)b
OH
O
Cu(OAc)2•H2O
oxidant, base
O
Me
O
1
2
3
4
5
6
7
8
9
CuSO
CuO
CuCl
CuBr
CuI
4
·5H
2
O
CaCO
CaCO
CaCO
CaCO
CaCO
CaCO
CaCO
CaCO
CaCO
CaCO
3
3
3
3
3
3
3
3
3
3
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
73
N
Me
+
HCl•HN
61
solvent, temp
time
Me
Me
15
1
a
2
3a
18
Entry
Base
Oxidant
Solvent
Yield (%)b
67
CuCl
2
·H
2
O
trace
4
1
2
3
4
5
6
7
8
9
NaHCO
CO
DBU
3
TBHP
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
63
57
trace
trace
0
CuNO
Cu
3
·8H
2
O
K
2
3
TBHP
O
42
TBHP
2
Cu(OAc)
2
·H
2
O
91
DABCO
–
TBHP
10
–
trace
TBHP
a
Reaction conditions: 1a (1 mmol), 2 (1.2 mmol), catalyst (6 mol%), TBHP
70 wt% in H O, 1.2 mmol), CaCO (1.2 mmol), MeCN (1 mL), 80 °C.
GC yields.
CaCO
CaCO
CaCO
CaCO
CaCO
CaCO
CaCO
3
3
3
3
3
3
3
TEMPO
MCPBA
(t-BuO)
trace
5
(
2
3
b
2
25
0
Next, the effect of various inorganic and organic bases
was studied (Table 1, entry 9, Table 2, entries 1–4) and it
was found that the base plays an important role to increase
the yield of 3a. Among these bases, CaCO provided the de-
sired product in 91% yield (Table 1, entry 9). It was observed
that the reaction does not proceed in the absence of base
H
2 2
O
1
1
0
1
–
0
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
1,4-dioxane
toluene
t-BuOH
MeCN
37
63
3
12
13
CaCO3
57
(
Table 2, entry 5). We further screened various oxidants
such as TBHP (5.0–6.0 M in decane), TEMPO, MCPBA, (t-
55c
1
1
4
5
6
CaCO
CaCO
CaCO
3
3
3
MeCN
87d
65e
BuO) , and H O to increase the reaction yield and it was
2
2
2
1
MeCN
observed that aqueous TBHP gave an excellent yield of the
desired product 3a (Table 1, entry 9, Table 2, entries 6–9).
Other oxidants delivered 3a in poor yield (Table 2, entries
a
2 2
Reaction conditions: 1a (1 mmol), 2 (1.2 mmol), Cu(OAc) ·H O (6 mol%),
oxidant (1.2 mmol), base (1.2 mmol), solvent (1 mL), 80 °C.
GC yields.
At 60 °C.
At 90 °C.
Time: 18 h.
b
c
6
–9). The product formation was not observed in the ab-
d
sence of an oxidant (Table 2, entry 10). Furthermore, the ef-
fect of various solvents on the reaction outcome was stud-
ied (Table 1, entry 9, Table 2, entries 11–13) and it was
found that the reaction works efficiently in acetonitrile (Ta-
ble 1, entry 9). The reaction temperature study showed that
a decrease in the reaction temperature decreases yield of
the desired product 3a (Table 2, entry 14). However, there
was no significant effect on the reaction outcome by in-
creasing the reaction temperature (Table 2, entry 15). The
optimum temperature to obtain good yield of the desired
Weinreb amide was observed to be 80 °C (Table 1, entry 9).
e
Thus, the optimized reaction conditions are: 1a (1
mmol), 2 (1.2 mmol), Cu(OAc) ·H O (6 mol%), TBHP (1.2
mmol), CaCO (1.2 mmol), and acetonitrile (1 mL) at 80 °C
2
2
3
for 24 hours.
The scope of the developed protocol was further investi-
gated for various alcohols containing different functional
groups at ortho-, meta-, and para-positions (Table 3). The
reaction of 1a with 2 furnished 89% yield of 3a (Table 3, en-
try 1).
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Synthesis
S. L. Yedage, B. M. Bhanage
Paper
Table 3 Synthesis of Weinreb Amides by Oxidative Amidation of Alco-
hols
product 3k in good yield (entry 11). However meta-dinitro-
substituted benzyl alcohol 1l did not result into the desired
Weinreb amide 3l even on extending the reaction time up
to 30 hours (entry 12). The heteroaromatic alcohol furan-3-
ylmethanol (1m) also easily underwent the oxidative ami-
dation reaction and provided excellent yield of the desired
product 3m (entry 13). In addition, the aliphatic alcohols
a
Cu(OAc)2•H2O
TBHP, CaCO3
O
O
Me
O
RCH2OH
+
HCl•HN
R
N
Me
MeCN, 80 °C
Me
Me
2
4 h
1a–p
2
3a–p
1
n and 1o also showed moderate conversion and gave ac-
Entry
Substrate
R
Product
Yield (%)b
ceptable yields of the respective products 3n and 3o (en-
tries 14 and 15). It was further noted that the reaction of
ethanol (1p) with 2 failed to provide desired amidation
product 3p (entry 16).
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
Ph
3a
3b
3c
3d
3e
3f
89
87
85
90
77
83
84
90
81
4-MeC
6
6
H
4
3-MeC
H
4
To understand the reaction pathway control experi-
ments were carried out. A literature study1
0,12,19
points out
4-MeOC
2-MeOC
6
H
4
4
that some groups have reported the synthesis of Weinreb
amides from benzaldehyde or benzoic acid with N,O-di-
methylhydroxylamine hydrochloride salt. Hence the reac-
tion of benzaldehyde and benzoic acid with N,O-dimethyl-
hydroxylamine hydrochloride salt was performed separate-
ly to confirm the reaction intermediates. However, only
benzaldehyde furnished an excellent yield of the desired
product 3a (89%); whereas benzoic acid failed to provide 3a
6
H
2-naphthyl
1g
1h
1i
2-ClC
3-ClC
4-ClC
6
6
6
H
H
H
4
4
4
3g
3h
3i
1
1
1
1
1
1
0
1
2
3
4
5
6
1j
3-F
4-O
3,5-(O
3
COC
NC
N)
6
H
4
3j
85
70c
1k
1l
2
6
H
4
3k
3l
(
Scheme 4). Furthermore, the reaction of 1a was performed
2
2
C
6
H
4
0
in the absence of amine hydrochloride salt and it was ob-
served that benzaldehyde was formed upto 94% (Scheme 4).
However, the reaction of 1a with 2 in the presence of radi-
cal scavenger such as TEMPO gave only trace amount of de-
sired product 3a (Scheme 4). Thus, the control experiments
indicate that the reaction most probably proceeds through
a radical pathway.
1m
1n
1o
1p
2-thienyl
Bn
3m
3n
3o
3p
90
40
2-MeOC
Me
6
H
4
CH
2
42
1
0
a
Reaction conditions: 1a (1 mmol), 2 (1.2 mmol), Cu(OAc)
2
·H
2
O (6 mol%),
3
TBHP (1.2 mmol), CaCO (1.2 mmol), MeCN (1 mL), 80 °C, 24 h.
b
Yield of isolated product.
Time: 30 h.
c
O
standard
OH
It was observed that benzyl alcohols possessing elec-
H
conditions
+
no amine salt
tron-donating substituents such as methyl and methoxy
groups efficiently undergo amidation reaction with N,O-di-
methylhydroxylamine to afford the corresponding Weinreb
amides 3b–e in excellent yields (Table 3, entries 2–5).
Therefore, it can be concluded that the position of the sub-
stituents on the phenyl ring of benzyl alcohol marginally
affects the reaction yield. Product 3d was obtained in high-
er yields as compared to 3e because of steric hindrance of
methoxy group in 3e (entries 4 and 5). Naphthalen-2-yl-
methanol (1f) also reacted efficiently with 2 to provide the
desired product 3f with 83% yield (entry 6). It was observed
that the chloro-substituted benzyl alcohol easily undergoes
oxidative amidation reaction and results into the corre-
sponding products in good to excellent yields (entries 7–9).
In ortho-, meta-, and para-chloro-substituted benzyl alco-
hol, meta-substituted substrates gave higher yields. It was
found that [3-trifluoromethoxy)phenyl]methanol (1j) also
offers good yield of the desired product 3j (entry 10). 4-Ni-
trobenzyl alcohol (1k) with a strong electron-withdrawing
group was also well tolerated and provided the desired
1a
94%
O
standard
conditions
O
O
O
H
O
Me
N
Me
Me
+
HCl•HN
Me
Me
2
3a
89%
O
standard
Me conditions
O
O
N
+
HCl•HN
Me
OH
Me
2
3a
%
0
Cu(OAc)2•H2O
CaCO3, TBHP (aq)
O Me
TEMPO
O
O
OH
+
N
Me
HCl•HN
MeCN, 24 h
80 °C
Me
Me
1a
2
3a
trace
Scheme 4 Control experiments
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Synthesis
S. L. Yedage, B. M. Bhanage
Paper
Based on the outcome of the control experiments
Scheme 4) and literature survey,11b,17 a plausible reaction
obtained with a PerkinElmer Clarus 400 instrument with an ELITE-1
column. Mass spectrometry was performed with a Shimadzu instru-
ment in electrospray ionization (ESI) mode.
(
mechanism is proposed, which proceeds through an amino
alcohol intermediate as shown in Scheme 5. Initially, benzyl
alcohol (1a) gets converted into benzyl radical A in the
presence of TBHP as the oxidant. Subsequently, Cu(II) ab-
stracts the electron from A and converts it into the onium
ion B. After this, N,O-dimethylhydroxylamine couples with
B to give the hemiaminal intermediate C. Next, the tert-bu-
tylperoxy radical reacts with C and form the amino alcohol
radical D. The electron of amino alcohol radical is abstract-
ed by Cu(II) to afford the onium ion E. The catalytic cycle
closes with deprotonation of E resulting in the final product
Oxidative Synthesis of Weinreb Amides 3 from Benzyl Alcohols 1
and N,O-Dimethylhydroxylamine Hydrochloride Salt (2); General
Procedure
An oven-dried 15 mL glass vial with a magnetic stirrer bar was
charged with Cu(OAc) ·H O (12 mg, 6 mol%), N,O-dimethylhydroxyl-
2
2
amine hydrochloride (2; 117 mg, 1.2 mmol), the respective benzyl al-
cohol 1 (1 mmol), aq 70% TBHP (0.17 mL, 1.2 mmol), CaCO (120 mg,
3
1.2 mmol) in MeCN (1 mL). The glass vial was flushed with N three
2
times and the contents were stirred at r.t. for 1 h. Then the reaction
mixture was stirred for 24 h at 80 °C. After completion of the reaction,
the mixture was cooled to r.t. All volatiles were removed under vacu-
um. The product was extracted with EtOAc (20 mL) and the organic
layer was washed with sat. aq NaHCO3 (20 mL), dried (Na SO ), and
3a.
In summary, we have developed an efficient protocol for
2
4
the synthesis of Weinreb amide by oxidative amidation of
alcohol with tert-butyl hydroperoxide using an inexpensive
and easily available copper catalyst. This protocol is appli-
cable to a wide range of alcohols possessing electron-donat-
ing and electron-withdrawing groups as well as heteroaro-
matic alcohol substrates for the synthesis of Weinreb am-
ides and it gave good to excellent yields. Mild reaction
conditions, economical starting materials, and an inexpen-
sive catalytic system are additional advantages of the pres-
ent system.
the solvent removed under vacuum. The Weinreb amide product 3
was purified by column chromatography (silica gel, 100–200 mesh)
using a gradient of petroleum ether (bp 60–80 °C) and EtOAc. All the
amides were identified by GC-MS, H, and C NMR spectroscopic
analysis.
1
13
N-Methoxy-N-methylbenzamide (3a)20a
[
CAS Reg. No. 6919-61-5]
Yield: 146 mg (89%); colorless oil.
IR (film): 2922, 1638, 1236, 1090 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 7.67–7.65 (d, J = 10 Hz, 2 H), 7.45–7.38
3
(
m, 3 H), 3.55 (s, 3 H), 3.35 (s, 3 H).
13C NMR (125 MHz, CDCl
33.7.
GC-MS: m/z (%) = 165 (3, [M ]), 105 (100), 91 (0.5), 77 (59), 51 (20), 40
3).
): δ = 169.9, 134.0, 130.5, 128.1, 127.9, 61.0,
All reactions were carried out in oven-dried glassware. All derivatives
of alcohol, N,O-dimethylhydroxylamine hydrochloride, aq 70% TBHP,
3
Cu(OAc) , and MeCN were purchased from Aldrich, Alfa Aesar, Spec-
+
2
trochem, and Thomas Baker. Analytical TLC was performed with 60
F254 silica gel plates (0.25 mm thickness). Column chromatography
was performed with silica gel (100–200 mesh). NMR spectra were re-
(
N-Methoxy-N,4-dimethylbenzamide (3b)10e
1
13
[CAS Reg. No. 122334-36-5]
corded on Bruker ( H NMR at 300 MHz, C NMR at 75 MHz) and Agi-
1
13
lent Technologies ( H NMR at 500 MHz, C NMR at 125 MHz) spec-
trometers. The chemical shifts are reported in ppm relative to TMS as
an internal standard and the coupling constant in Hz. GC yields were
Yield: 155 mg (87%); yellow oil.
1
H NMR (500 MHz, CDCl ): δ = 7.59–7.58 (m, 2 H), 7.20–7.19 (m, 2 H),
3
3
.55 (s, 3 H), 3.34 (s, 3 H).
Me
NH•HCl
MeO
t-BuOOH
CaCO3
[
O]
Me
t-BuO•
+OH
OH
OH
OH
H
N
H
Cu(II) Cu(I)
•
OMe
H
•
OH
MeO
N
+
+
H
–
H2O
Me
1a
A
B
C
t-BuO•
+
O
OH
OH
Cu(I) Cu(II)
[O]
OMe
OMe
OMe
+
•
N
N
N
t-BuOH
– H+
Me
Me
Me
3a
D
E
Scheme 5 Plausible reaction mechanism for the oxidative amidation of benzyl alcohol to Weinreb amide
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 526–532

5
31
Synthesis
S. L. Yedage, B. M. Bhanage
Paper
13
+
C NMR (125 MHz, CDCl ): δ = 169.9, 140.8, 131.1, 128.6, 128.3, 60.9,
GC-MS: m/z (%) = 199 (5, [M ]), 168 (1), 139 (100), 111 (43), 85 (3), 75
3
33.8, 21.4.
(23), 50 (9).
N-Methoxy-N,3-dimethylbenzamide (3c)20b
CAS Reg. No. 135754-82-4]
4-Chloro-N-methoxy-N-methylbenzamide (3i)20b
[
[CAS Reg. No. 122334-37-6]
Yield: 152 mg (85%); yellow oil.
Yield: 161 mg (81%); yellow oil.
1
1
H NMR (500 MHz, CDCl ): δ = 7.46–7.43 (m, 2 H), 7.29–7.26 (m, 2 H),
H NMR (500 MHz, CDCl ): δ = 7.65 (d, J = 10 Hz, 2 H), 7.37 (d, J = 10
3
3
3
.56 (s, 3 H), 3.34 (s, 3 H), 2.37 (s, 3 H).
Hz, 2 H), 3.53 (s, 3 H), 3.35 (s, 3 H).
13
13
C NMR (125 MHz, CDCl ): δ = 170.2, 137.7, 134.1, 131.2, 128.6,
C NMR (125 MHz, CDCl ): δ = 168.6, 136.7, 132.2, 129.8, 128.2, 61.0,
3
3
127.8, 125.0, 60.9, 33.9, 21.3.
33.5.
N,4-Dimethoxy-N-methylbenzamide (3d)10e
CAS Reg. No. 52898-49-4]
N-Methoxy-N-methyl-3-(trifluoromethoxy)benzamide (3j)20c
[CAS Reg. No. 1203575-93-2]
[
Yield: 175 mg (90%); yellow oil.
Yield: 219 mg (85%); yellow oil.
1
IR (film): 2922, 1644, 1236, 1090 cm–1
H NMR (500 MHz, CDCl ): δ = 7.73–7.71 (m, 2 H), 6.90–6.88 (m, 2 H),
.
3
3
.83 (s, 1 H), 3.55 (s, 1 H), 3.34 (s, 3 H).
1
H NMR (500 MHz, CDCl ): δ = 7.63 (d, J = 8 Hz, 1 H), 7.57 (s, 1 H), 7.44
3
13
C NMR (125 MHz, CDCl ): δ = 169.3, 161.5, 130.5, 125.9, 113.2, 60.8,
(m, 1 H), 7.30 (m, 1 H), 3.54 (s, 1 H), 3.36 (s, 1 H).
3
55.2, 33.8.
13
C NMR (125 MHz, CDCl ): δ = 168.0, 148.6, 135.7, 129.5, 129.4,
3
1
26.7, 123.0, 121.0, 61.1, 33.4.
N,2-Dimethoxy-N-methylbenzamide (3e)15a
CAS Reg. No. 130250-62-3]
+
GC-MS: m/z (%) = 249 (4, [M ]), 218 (1), 189 (100), 161 (27), 95 (38),
[
75 (7), 64 (8), 40 (3).
Yield: 150 mg (77%); yellow oil.
N-Methoxy-N-methyl-4-nitrobenzamide (3k)20d,e
[CAS Reg. No. 52898-51-8]
1
H NMR (500 MHz, CDCl ): δ = 7.32–7.28 (m, 1 H), 7.22–7.21 (m, 1 H),
3
6.93–6.88 (m, 2 H), 3.79 (s, 3 H), 3.51–3.34 (m, 3 H), 3.26 (br s, 3 H).
13
C NMR (125 MHz, CDCl ): δ = 169.6, 155.7, 130.5, 127.6, 125.3,
Yield: 147 mg (70%); yellow solid; mp 73–74 °C.
3
120.4, 61.0, 55.7, 32.6.
IR (KBr): 3116, 2925, 2852, 1524, 975 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 8.27–8.25 (m, 2 H), 7.84–7.83 (m, 2 H),
.52 (s, 3 H), 3.39 (s, 3 H).
3
N-Methoxy-N-methyl-2-naphthamide (3f)15d
CAS Reg. No.113443-62-2]
3
[
13
C NMR (125 MHz, CDCl ): δ = 167.7, 148.8, 140.0, 129.2, 123.2, 61.4,
3
Yield: 178 mg (83%); yellow oil.
3
3.1.
1
H NMR (500 MHz, CDCl ): δ = 8.22 (s, 1 H), 7.91–7.89 (m, 3 H), 7.85–
+
3
GC-MS: m/z (%) = 210 (4, [M ]), 179 (2), 150 (100), 120 (17), 104 (40),
2 (23), 76 (31), 50 (16).
7.50 (m, 3 H), 3.56 (s, 3 H), 3.41 (s, 3 H).
9
13
C NMR (125 MHz, CDCl ): δ = 169.8, 134.2, 132.4, 131.3, 128.8,
3
N-Methoxy-N-methylfuran-3-carboxamide (3m)20e
CAS Reg. No. 148900-66-7]
1
28.6, 127.6, 127.5, 127.3, 126.5, 125.0, 61.1, 33.8.
[
2
-Chloro-N-methoxy-N-methylbenzamide (3g)20b
Yield: 139 mg (90%); yellow-red liquid.
[
CAS Reg. No. 289686-74-4]
1
H NMR (500 MHz, CDCl ): δ = 8.02 (s, 1 H), 7.40 (s, 1 H), 6.85 (m, 1 H),
3
Yield: 167 mg (84%); colorless oil.
IR (film): 2921, 1655, 1236, 1089 cm–1
3
.70 (s, 3 H), 3.32 (s, 3 H).
.
13
C NMR (125 MHz, CDCl ): δ = 163.1, 146.4, 142.6, 119.6, 111.2, 61.0,
3
1
H NMR (500 MHz, CDCl ): δ = 7.41–7.39 (m, 1 H), 7.33–7.28 (m, 3 H),
32.7.
3
3
.46 (s, 3 H), 3.38 (s, 3 H).
N-Methoxy-N-methyl-2-phenylacetamide (3n)5
[CAS Reg. No. 95092-10-7]
13
C NMR (125 MHz, CDCl ): δ = 168.5, 135.2, 130.6, 130.1, 129.2,
3
127.6, 126.4, 61.3, 32.2.
+
GC-MS: m/z (%) = 199 (2, [M ]), 168 (1), 139 (100), 111 (28), 85 (2), 75
Yield: 71 mg (40%); yellow oil.
(20), 50 (9).
IR (film): 2922, 1724, 1656, 1382, 1091 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 7.35–7.22 (m, 5 H), 3.79 (s, 2 H), 3.60
3
3
-Chloro-N-methoxy-N-methylbenzamide (3h)20b
CAS Reg. No. 145959-21-3]
(s, 3 H), 3.20 (s, 3 H).
[
13
C NMR (125 MHz, CDCl ): δ = 172.4, 134.9, 129.3, 128.4, 126.7, 61.2,
3
Yield: 179 mg (90%); colorless oil.
IR (film): 2923, 1644, 1236, 1090 cm–1
3
9.4, 32.2.
.
+
GC-MS: m/z (%) = 179 (5, [M ]), 148 (3), 118 (38.2), 91 (100), 65 (18).
1
H NMR (500 MHz, CDCl ): δ = 7.66 (s, 1 H), 7.56 (d, J = 5 Hz, 1 H), 7.42
3
N-Methoxy-2-(4-methoxyphenyl)-N-methylacetamide (3o)20f
[CAS Reg. No. 148900-66-7]
(
1
d, J = 10 Hz, 1 H), 7.41–7.32 (m, 1 H), 3.54 (s, 3 H), 3.34 (s, 3 H).
3
C NMR (125 MHz, CDCl ): δ = 168.3, 135.6, 133.9, 130.6, 129.3,
3
128.3, 126.3, 61.1, 33.5.
Yield: 87 mg (42%); yellow oil.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 526–532

5
32
Synthesis
S. L. Yedage, B. M. Bhanage
Paper
1
H NMR (500 MHz, CDCl ): δ = 7.21–7.19 (m, 2 H), 6.86–6.84 (m, 2 H),
.78 (s, 3 H), 3.70 (s, 2 H), 3.61 (s, 3 H), 3.18 (s, 3 H).
Ohkihara, R.; Tani, S.; Kunishima, M. Chem. Pharm. Bull. 2004,
52, 470. (d) So, R. C.; Ndonye, R.; Izmirian, D. P.; Richardson, S.
K.; Guerrera, R. L.; Howell, A. R. J. Org. Chem. 2004, 69, 3233.
3
3
13
C NMR (125 MHz, CDCl ): δ = 172.6, 158.4, 130.2, 130.2, 126.9,
3
(e) Niu, T.; Wang, K.; Huang, D.; Xu, C.; Su, Y.; Fu, Y. Synthesis
1
13.9, 61.2, 55.2, 38.4, 32.2.
2014, 46, 320.
(
11) (a) Krishnamoorthy, R.; Lam, S. Q.; Manley, C. M.; Herr, R. J.
J. Org. Chem. 2010, 75, 1251. (b) Kerr, W. J.; Morrison, A. J.;
Pazicky, M.; Weber, T. Org. Lett. 2012, 14, 2250.
Acknowledgment
(
12) (a) Ghosh, S.; Ngiam, J.; Chai, C.; Seayad, A.; Dang, T.; Chen, A.
Adv. Synth. Catal. 2012, 354, 1407. (b) Ghosh, S.; Seayad, J.; Tuan,
D.; Chai, C.; Chen, A. J. Org. Chem. 2012, 77, 8007. (c) Nemoto,
H.; Ma, R.; Moriguchi, H.; Kawamura, T.; Kamiya, M.; Shibuya,
M. J. Org. Chem. 2007, 72, 9850.
S.L.Y. is thankful to Council of Scientific and Industrial Research
(CSIR), New Delhi, India for providing a Junior Research Fellowship
JRF).
(
(
13) Dineen, T. A.; Zajac, M. A.; Myers, A. G. J. Am. Chem. 2006, 128,
Supporting Information
16406.
Supporting information for this article is available online at
(14) (a) Shimizu, T.; Osako, K.; Nakata, T. Tetrahedron Lett. 1997, 38,
2685. (b) Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.
Tetrahedron Lett. 1995, 36, 5461.
http://dx.doi.org/10.1055/s-0034-1379583.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 526–532