One-pot transition-metal-free synthesis of weinreb amides directly from carboxylic acids

Article abstract of DOI:10.1055/s-0033-1340317

Weinreb amides were prepared directly from carboxylic acids, N,O-dimethylhydroxylamine, and phosphorus trichloride in one pot at 60 °C in toluene in high yields, thus avoiding the separation of the moisture and air sensitive intermediate P[NMe(OMe)]₃ in advance. Sterically hindered carboxylic acids also give the corresponding Weinreb amides in excellent yields. Various functional groups are tolerated on the carboxylic acid. The method, which is a simple process and gives high yields, is suitable for large-scale production. Georg Thieme Verlag KG Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340317

320▌
PAPER
pOapnere-Pot Transition-Metal-Free Synthesis of Weinreb Amides Directly from
Carboxylic Acids
Synthesis of Weinreb Amides Directly from Carboxylic Acids
Teng Niu,a Ke-Hu Wang,a Danfeng Huang,*a Changming Xu,a Yingpeng Su,a Yulai Hu,*a,b Ying Fua
a
College of Chemistry and Chemical Engineering, Northwest Normal University, Anning Road 967 (E), Lanzhou 730070, P. R. of China
Fax +86(931)7971989; E-mail: huangdf@nwnu.edu.cn; E-mail: huyl@nwnu.edu.cn
b
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Received: 16.09.2013; Accepted after revision: 08.11.2013
methylcarbamoyl chloride and an organoboronic acid30 or
Abstract: Weinreb amides were prepared directly from carboxylic
organostannanes;31 palladium-catalyzed Heck-type ami-
acids, N,O-dimethylhydroxylamine, and phosphorus trichloride in
nocarbonylation of aryl halides32,33 and heterocyclic-
one pot at 60 °C in toluene in high yields, thus avoiding the separa-
tion of the moisture and air sensitive intermediate P[NMe(OMe)]3
derived triflates34–36 with N,O-dimethylhydroxylamine
in advance. Sterically hindered carboxylic acids also give the corre- under a carbon monoxide atmosphere or solid sources of
carbon monoxide.37 These methods have the disadvantage
of using expensive transition-metal catalysts.
sponding Weinreb amides in excellent yields. Various functional
groups are tolerated on the carboxylic acid. The method, which is a
simple process and gives high yields, is suitable for large-scale pro-
In view of the importance of Weinreb amides in organic
synthesis, we are engaged in the development of simple
and practical methods for the preparation of Weinreb am-
ides, especially methods that are suitable for industry. In
a previous paper, we reported a very powerful reagent
tris[methoxy(methyl)amino]phosphine {P[NMe(OMe)]3},
prepared from phosphorus trichloride and N,O-dimethyl-
hydroxylamine, that can convert carboxylic acids into the
corresponding Weinreb amides in high yields.38 More im-
portantly, sterically hindered carboxylic acids can also be
converted into the corresponding Weinreb amides in high
yields in the presence of tris[methoxy(methyl)ami-
no]phosphine (Scheme 1).
duction.
Key words: Weinreb amides, carboxylic acids, one-pot reaction,
coupling, synthesis
Weinreb amides have been widely used in organic synthe-
sis since their first use in 1981 by Nahm and Weinreb.1–3
The main advantage of these amides over other carboxylic
acid derivatives is that they can cleanly react with
organometallics4–6 or hydride reducing agents7,8 to give
ketones or aldehydes in high yields without overaddition
products because of the stabilization of the tetrahedral in-
termediate by chelation. It was also reported that Weinreb
amides can react with Wittig reagents to give ketones.9,10
Weinreb amides are also widely employed in the total
synthesis of natural products.11,12
O
O
OMe
+
P[NMe(OMe)]3
R
N
R
OH
Me
Traditionally, Weinreb amides are obtained from carbox-
ylic acids13–15 or their derivatives such as acid chlo-
rides,1,16 esters,17,18 lactones,19 amides,20 and anhydrides.21
Among the reported methods, direct conversion of car-
boxylic acids into the corresponding Weinreb amides is
very attractive because of the easy availability of the start-
ing materials. However, expensive coupling reagents,
such as BOP,22 N,N′-dicyclohexylcarbodiimide,23 chloro-
formates,24 phosphonic derivates,25 2-chloro-1-methyl-
pyridinium iodide or 2-bromo-1-methylpyridinium
iodide,26 Deoxo-Fluor fluorinating reagent,27 and triazine
derivatives,28 are generally used in these transformations.
Although sterically hindered Weinreb amides can be suc-
cessfully obtained from carboxylic acids via mixed anhy-
drides with methanesulfonic acid,29 the yields are poor in
most cases. More recent alternative approaches for the
preparation of Weinreb amides focused on transition-
metal-catalyzed cross-coupling reactions including palla-
dium-catalyzed cross-coupling between N-methoxy-N-
Scheme 1 Synthesis of Weinreb amides from tris[methoxy(meth-
yl)amino]phosphine and carboxylic acids
However, there are some disadvantages to the use of
tris[methoxy(methyl)amino]phosphine, for example, it is
moisture and air sensitive and this can result in decompo-
sition during its separation and storage. To overcome
these disadvantages, here we disclose a very convenient
and efficient direct one-pot synthesis of Weinreb amides
from carboxylic acids and N,O-dimethylhydroxylamine
using inexpensive and commercially available phospho-
rus trichloride as a coupling reagent under transition-
metal-free conditions (Scheme 2).
O
O
OMe
Me
PCl3
OMe
+
HN
R
N
R
OH
Me
Scheme 2 Synthesis of Weinreb amides directly from carboxylic
acids using N,O-dimethylhydroxylamine and phosphorus trichloride
SYNTHESIS 2014, 46, 0320–0330
Advanced online publication: 12.12.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340317; Art ID: SS-2013-H0629-OP
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Weinreb Amides Directly from Carboxylic Acids
321
This method avoids the separate of the moisture- and air- 88% (entry 4). Thus, the best mole ratio of benzoic acid
sensitive intermediate tris[methoxy(methyl)amino]phos- (1a), phosphorus trichloride, and N,O-dimethylhydroxyl-
phine in advance, and all of the starting materials are com- amine (2) is 2:1:6. In order to develop a more convenient
mercially available. Sterically hindered carboxylic acids operation, the reaction temperature was lowed to 25 °C,
also give the corresponding Weinreb amides in high but the yield of 3a decreased to 83% (entry 5). However,
yields. Another advantage of this method is the wide tol- a higher yield of 3a was obtained if the reaction time was
erance of functional groups in substrates. Functional increased to eight hours at 25 °C (entry 6). The solvents
groups, such as methoxy, halide, ester, nitro, hydroxy, and also has some influence on the yield of 3a. For example,
formyl groups, hetarenes, such as furan and thiophene, 3a was obtained in 83% yield in dry toluene, 78% yield in
and unsaturation (alkenes and alkynes) are tolerated under dichloromethane, and 81% yield in diethyl ether in 0.5
the coupling conditions.
hours at 25 °C (entries 5, 8, and 10). If the toluene is not
dry and contains a trace of water, then this has a detrimen-
tal effect on the yield of 3a (entry 11).
At the beginning of our investigation, benzoic acid (1a)
was used as a model substrate in the reaction with phos-
phorus trichloride and N,O-dimethylhydroxylamine (2) to After the optimization of the reaction conditions, the gen-
optimize the conditions (Table 1). Heating benzoic acid erality of this method was examined using different car-
(1a) with phosphorus trichloride, N,O-dimethylhydroxyl- boxylic acids.
amine (2), and triethylamine (to trap the HCl released) in
toluene at 60 °C gave the corresponding product 3a in
75% yield after 0.5 hours (entry 1). In order to increase the
yield of 3a, the amount of N,O-dimethylhydroxylamine
(2) was increased to 3.5 mmol and the yield of 3a in-
creased to 84% (entry 2). Finally, 3a was obtained in 97%
yield using 6 mmol of N,O-dimethylhydroxylamine (2) in
the absence of triethylamine at 60 °C in 0.5 hours (entry
As showed in Table 2, different aromatic acids were sub-
jected to the optimized reaction conditions. Various aro-
matic acids with either electron-donating or electron-
withdrawing groups on the phenyl ring gave the desired
products in excellent yields under the optimized condi-
tions. As shown in Table 2, the position of substituents on
phenyl ring has little effect on the reaction yield. Many
functional groups, such as halide, ether, nitro, and cyano,
3). Increasing the ratio of benzoic acid (1a) to phosphorus
on the phenyl ring or the use of hetaryl groups are compat-
ible with the reaction. However, the yields of products
were lower when hydroxy or formyl substituents were on
trichloride
and
N,O-dimethylhydroxylamine
(2)
(1a/PCl3/2) from 2:1:6 mmol to 2.5:1:6 mmol had some
influence on the yield of 3a; the yield of 3a decreased to
Table 1 Optimization of the Reaction Conditions
O
O
OMe
PCl3
OMe
Me
OH
N
HN
+
Me
1a
2
3a
Entry
1a (mmol)
PCl3 (mmol) 2 (mmol)
Et3N (mmol) Solventa
Time (h)
Temp (°C) Yieldb (%)
1
2
2
1
1
1
1
1
1
1
1
1
1
1
1
3
3
3
0
0
0
0
0
0
0
0
0
6
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
Et2O
0.5
0.5
0.5
0.5
0.5
8
60
60
60
60
25
25
40
25
25
25
60
60
75
84
97
88
83
95
92
78
94
81
83
82
2
3.5
6
3
2
4
2.5
2
6
5
6
6
2
6
7
2
6
0.5
0.5
8
8
2
6
9
2
6
10
11
12
2
6
0.5
0.5
0.5
2
6
toluenec
toluene
2
6d
a All solvents were purified and dried by standard procedures.
b Yield of isolated product after column chromatography based upon benzoic acid.
c Toluene was used directly as received and not dried.
d NHMe(OMe)·HCl was used instead of NHMe(OMe).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 320–330

322
T. Niu et al.
PAPER
on the yield of product. With 4-formylbenzoic acid as the
substrate, the yield of 3p was only 20% under the opti-
mized conditions. The reason was that the formyl group
reacts with N,O-dimethylhydroxylamine (2) to give an ox-
ime ether that consumes the amine. So the molar ratio of
1p/PCl3/2 was changed to 1:1:6 and the yield of 3p in-
creased to 65%.
Table 2 Preparation of Aromatic, Heterocyclic, and α,β-Unsaturated
Weinreb Amidesa,b
O
O
OMe
PCl3, toluene
60 °C, 0.5 h
OMe
HN
+
R
OH
R
N
Me
Me
1
2
3a–r
Entry
R
Product
Yield (%)
The experimental results also indicate that α,β-unsaturat-
ed carboxylic acids are converted into the corresponding
Weinreb amides 3q and 3r in excellent yields.
1
2
Ph
3a
3b
3c
3d
3e
3f
97, 96c
98
4-MeC6H4
4-MeOC6H4
4-ClC6H4
We also synthesized the product 3a in excellent yield
(96%) using 0.1 mol 1a as substrate. The experimental re-
sult indicates that this method has potential application in
industry.
3
98
4
99
5
3,5-(O2N)2C6H3
2-MeC6H4
2-IC6H4
96
Aliphatic acids and protected amino acid can also react
with N,O-dimethylhydroxylamine (2) in the presence of
phosphorus trichloride at 60 °C to give the corresponding
Weinreb amides (Tables 3 and 4).
6
96
7
3g
3h
3i
93
8
2-O2NC6H4
4-O2NC6H4
1-naphthyl
94
Excellent yields were obtained with the different aliphatic
acids (Table 3) with most yields above 90% under the op-
9
99
10
11
3j
99
Table 3 Preparation of Aliphatic Weinreb Amidesa
2-furyl
3k
99
S
O
O
OMe
Me
OMe
12
13
3l
97
97
PCl3, toluene
60 °C, 0.5 h
+
HN
R
N
S
R
OH
Me
5a–p
MeO2C
N
4
2
3m
Entry
R
Product
Yieldb (%)
14
15
16
17
18
4-NCC6H4
3n
3o
3p
3q
3r
97
1
2
i-Pr
5a
5b
5c
5d
5e
5f
95
88
98
98
93
97
85
97
90
94
94
93
95
94
94
95
3,5-(HO)2C6H3
4-OHCC6H4
50, 71,d 12e
20, 65f
97
t-Bu
3
CHPh2
(E)-4-MeOC6H4CH=CH
CH=CMe2
4
1-adamantyl
82
5
2-tetrahydrofuryl
Cy
a Reaction conditions: 1 (2 mmol), PCl3 (1 mmol), 2 (6 mmol), dry tol-
uene, 60 °C, 0.5 h.
6
b Yields of isolated products after column chromatography based
upon carboxylic acids.
7
CH2CH=CH2
(CH2)3C≡CH
CMe2CO2Me
CH2Cl
5g
5h
5i
8
c Reaction conditions: 1a (0.2 mol), PCl3 (0.1 mol), 2 (0.6 mol), dry
toluene, 60 °C, 0.5 h.
9
d The molar ratio of 1o/PCl3/2 was 2:1.5:12.
e Reaction conditions: 1o (2 mmol), PCl3 (1 mmol), 2 (6 mmol), Et3N
(4 mmol), dry toluene, 60 °C, 0.5 h.
10
11
12
13
14
15
16
5j
f The molar ratio of 1p/PCl3/2 was 1:1:6.
(CH2)2Cl
5k
5l
(CH2)4Br
(CH2)5Br
5m
5n
5o
5p
the phenyl ring. For example, when 3,5-dihydroxybenzoic
acid was used as the substrate, the yield of 3o is only 50%
under the optimized conditions. It was thought that the
two hydroxy groups on the phenyl ring were sufficiently
acidic to react with N,O-dimethylhydroxylamine (2) and
form salts that consumed the amine during the reaction.
Thus, changing the molar ratio of 1o/PCl3/2 to 2:1.5:12,
increased the yield of 3o to 71%. Adding another base
such as triethylamine has no benefit on the yield of 3o.
The formyl group was also found to have a great influence
(CH2)5I
(CH2)10Me
(CH2)14Me
a Reaction conditions: 4 (2 mmol), PCl3 (1 mmol), 2 (6 mmol), dry tol-
uene, 60 °C, 0.5 h.
b Yields of isolated products after column chromatography based upon
carboxylic acids.
Synthesis 2014, 46, 320–330
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Weinreb Amides Directly from Carboxylic Acids
323
timized conditions. Carbon–carbon double bond and tri-
ple bond and halides, including chlorine, bromine, and
iodine, are tolerated in the aliphatic chain. Most impor-
tantly, this method is also suited to the use of sterically
hindered carboxylic acids giving products 5c–e in 93–
98% yield. These results are rarely be reached by other
methods.35
O
O
O
O
MeO
MeO
OMe
PCl3, toluene
60 °C, 0.5 h
+
N
X
N
2
HO
X
OH
Me
Me
9a–j
8
O
Me
N
Me
O
N
OMe
N
OMe
MeO
N
Me
9b: 86%
O
O
O
Me
Protected amino acids react with N,O-dimethylhydroxyl-
amine (2) in the presence of phosphorus trichloride at 60
°C to give the corresponding Weinreb amides with reten-
tion of configuration (Table 4); the enantiomers of 7a–g
were not detected. Changing the protecting group has no
significant effect on the product yield.
9a: 95%
9c: 97%
O
O
O
Me
N
OMe
OMe
MeO
MeO
N
N
N
OMe
Me
Me
Me
O
9d: 89%
MeO
Me
O
O
OMe
Me
N
N
Me
N
N
Table 4 Preparation of Chiral Weinreb Amides from Protected
Amino Acidsa
Me
MeO
MeO
O
O
O
O
9e: 96%
9g: 90%
OMe
Me
9f: 96%
PCl3, toluene
60 °C, 0.5 h
R
OMe
R
+
HN
N
OH
O
O
O
S
NHX Me
NHX
OMe
O
OMe
N
N
MeO
N
N
6
2
7a–g
Me
Me
Me
Me
Entry
R
X
Product
Yieldb (%)
9h: 92%
Me
1
2
3
Bn
Ph
Ts
Ts
Ts
7a
7b
7c
93
89
97
N
MeO
OMe
N
O
Me
9i: 91%
Me
Scheme 3 Preparation of bis-Weinreb amides. Reaction conditions:
8 (1 mmol), PCl3 (2 mmol), 2 (12 mmol), dry toluene, 60 °C, 0.5 h;
yields of isolated products after column chromatography based upon
carboxylic acids.
4
7d
86
N
Ts
5
6
7
Me
Boc
Boc
Boc
7e
7f
93
95
91
product 9i with retention of configuration was formed in
91% yield. cis-But-2-enedioic acid gave the correspond-
ing Z product 9j in 55% yield with retention of configura-
tion at 60 °C, and the E product 9i with changed
configuration was formed in 37% yield (Scheme 4). If the
reaction was carried out at a lower temperature, such as 0
°C in toluene for 24 hours, the yield of 9j increased to
80% and 9i decreased to 9% (Scheme 4). The result indi-
cates that the isomerization may be reduced by conducting
the reaction at lower temperatures.
Ph
Bn
7g
a Reaction conditions: 6 (2 mmol), PCl3 (1 mmol), 2 (6 mmol), dry tol-
uene, 60 °C, 0.5 h.
b Yield of isolated product after column chromatography based upon
carboxylic acids.
Aromatic and aliphatic dioic acids react smoothly to give
the bis-Weinreb amides in high yields in the presence of
phosphorus trichloride and N,O-dimethylhydroxylamine
(2) at 60 °C (Scheme 3).
The role of phosphorus trichloride in the one-pot synthesis
of Weinreb amides was also investigated. Usually, phos-
phorus trichloride is used as a coupling reagent to trans-
form carboxylic acids into carboxylic chlorides, and then
carboxylic chlorides reacted with amines to produce
Interestingly, when the reaction was carried out with
trans-but-2-enedioic acid at 60 °C, the corresponding E
O
Me
N
O
MeO
Me
O
O
OMe
Me
PCl3, 2
OH
OH
MeO
N
N
+
OMe
N
toluene
O
Me
O
9j
9i
reaction conditions:
60 °C, 0.5 h 55%
37%
16%
9%
20 °C, 2 h
0 °C, 24 h
75%
80%
Scheme 4 Reaction of phosphorus trichloride, N,O-dimethylhydroxylamine (2), and cis-but-2-enedioic acid at different temperatures
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 320–330

324
T. Niu et al.
PAPER
N-Methoxy-N-methylbenzamide (3a);38,39 Typical Procedure
amides (Scheme 5). We believed that this path was also
involved in our one-pot reaction (path A). On the other
hand, we reported previously that Weinreb amides could
be obtained from carboxylic acids and tris[meth-
oxy(methyl)amino]phosphine, which was prepared from
N,O-dimethylhydroxylamine and phosphorus trichloride
(path B).38 Thus, it is believed that both paths A and B are
involved in our one-pot procedure (path C). This was con-
firmed by the following experimental results: (1) N,O-di-
methylhydroxylamine and benzoic acid were mixed in
toluene, then a solution of phosphorus trichloride in dry
toluene was added to give 3a in 97% yield; (2) N,O-di-
methylhydroxylamine and phosphorus trichloride were
mixed in toluene, then a solution of benzoic acid in dry
toluene was added to give 3a in 95% yield.
A solution of NHMe(OMe) (0.360 g, 6.0 mmol) and benzoic acid
(0.244 g, 2.0 mmol) was stirred in dry toluene (10 mL) at 0 °C for
10 min. A solution of PCl3 (0.137 g, 1.0 mmol) in dry toluene (2
mL) was then added dropwise to the mixture. The mixture was
warmed to r.t. slowly and then stirred at 60 °C for 0.5 h. When the
reaction was complete (TLC monitoring), the mixture was cooled to
r.t. The mixture was then quenched with sat. NaHCO3 soln (20 mL)
and extracted with EtOAc (3 × 10 mL). The combined organic lay-
ers were dried (anhyd MgSO4). The solvent was removed in vacuo.
The product was purified by column chromatography (silica gel, pe-
troleum ether–EtOAc, 3:2) to give pure 3a as a colorless oil; yield:
320 mg (97%).
IR (neat): 3061, 2968, 2936, 2819, 1644, 1576, 1451, 1416, 1377
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.68–7.65 (m, 2 H), 7.47–7.38 (m,
3 H), 3.56 (s, 3 H), 3.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.9, 134.1, 130.5, 128.1, 127.9,
60.1, 33.8.
O
PCl3
NHMe(OMe)
path A
3a, 95%a
MS (70 eV): m/z (%) = 165 (3), 105 (100), 77 (56), 51 (11).
Ph
Cl
O
P[NMe(OMe)]3
N-Methoxy-N,4-dimethylbenzamide (3b)38,39
3a, 94%38
Ph
OH
Path B
Colorless oil; yield: 351 mg (98%).
1a
PCl3, NHMe(OMe)
3a, 97%b
IR (neat): 2930, 1643, 1568, 1513, 1457, 1416, 1373, 1179, 981
cm–1.
95%c
path C
1H NMR (400 MHz, CDCl3): δ = 7.60–7.58 (m, 2 H), 7.21–7.19 (m,
2 H), 3.56 (s, 3 H), 3.35 (s, 3 H), 2.39 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.9, 140.9, 131.1, 128.6, 128.3,
60.9, 33.8, 21.4.
Scheme 5 Investigation of the role of phosphorus trichloride in the
preparation of Weinreb amides. Reaction conditions: a NHMe(OMe)
(6.0 mmol), BzCl (2.0 mmol), dry toluene (10 mL), 0 °C to r.t., 8 h.
b
1. NHMe(OMe) (6.0 mmol), BzOH (2.0 mmol), dry toluene (10
mL), 0 °C, 10 min; 2. addition of PCl3 (1.0 mmol), dry toluene (2 mL),
dropwise. c 1. PCl3 (1.0 mmol), NHMe(OMe) (6.0 mmol), dry toluene
(10 mL), 0 °C, 10 min; 2. addition of BzOH (2.0 mmol), dry toluene
(2 mL) dropwise.
MS (70 eV): m/z (%) = 179 (6), 119 (100), 91 (95), 89 (13), 77 (18),
76 (14), 65 (35), 39 (10).
N-Methoxy-N-methyl-4-anisamide (3c)38,39
Colorless oil; yield: 382 mg (98%).
IR (neat): 3284, 3072, 2935, 2842, 1637, 1512, 1460, 1421, 1373,
1254, 1174, 1027, 980, 842, 756 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.75–7.71 (m, 2 H), 6.92–6.89 (m,
2 H), 3.85 (s, 3 H), 3.56 (s, 3 H), 3.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.4, 161.5, 130.5, 125.9, 113.2,
In summary, we have developed a convenient and effi-
cient one-pot synthesis of Weinreb amides directly from
carboxylic acids and N,O-dimethylhydroxylamine using
phosphorus trichloride as the coupling reagent under
transition-metal-free conditions. The reagents phosphorus
trichloride and N,O-dimethylhydroxylamine used in the
60.8, 55.3, 33.9.
reactions are inexpensive and commercially available. MS (70 eV): m/z (%) = 195 (1.95), 135 (100), 107 (19), 92 (9), 77
(15).
The other advantages of this method are mild reaction
conditions, excellent yields, and convenient operation.
The method has potential application in industry. It can be
widely applied to transform different kinds of carboxylic
acids such as aromatic, aliphatic, and chiral amino acids
into the corresponding Weinreb amides in excellent
yields.
4-Chloro-N-methoxy-N-methylbenzamide (3d)38,39
Colorless oil; yield: 395 mg (99%).
IR (neat): 3067, 2970, 2936, 2819, 1644, 1595, 1462, 1417, 1378,
1275, 1213, 1172, 1092, 1065, 981, 841, 747 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.67–7.65 (m, 2 H), 7.39–7.37 (m,
2 H), 3.54 (s, 3 H), 3.31 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.7, 136.7, 132.3, 129.8, 128.3,
61.1, 33.5.
Melting points of isolated products are uncorrected. IR spectra were
measured using an Alpha Centauri FT-IR spectrophotometer. H
1
MS (70 eV): m/z (%) = 199 (3), 168 (0.70), 152 (3), 141 (32), 139
NMR spectra were recorded on a Mercury plus 400 MHz spectrom-
eter in CDCl3 with TMS as internal standard. 13C NMR spectra were
obtained at 100 MHz in CDCl3 with TMS as internal standard using
a Mercury Plus 400 MHz spectrometer. MS-EI was measured on a
HP5988A mass spectrometer. PCl3 was distilled to remove HCl pri-
or to use. NHMe(OMe)·HCl was distilled in the presence of Et3N.
All solvents used were purified and dried by standard procedure.
Other materials were used as received and without further purifica-
tion. Column chromatography was performed on silica gel 300–400
mesh. Experimental procedure for the synthesis of 3, 5, 7, 9 are sim-
ilar to the synthesis of 3a.
(100), 111 (35), 75 (12).
N-Methoxy-N-methyl-3,5-dinitrobenzamide (3e)38,39
Light yellow solid; yield: 489 mg (96%); mp 99–101 °C.
IR (neat): 3091, 2930, 1652, 1541, 1453, 1417, 1377, 1199, 1167,
1116, 1062, 987 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.15–9.12 (m, 1 H), 8.92–8.89 (m,
2 H), 3.62 (s, 3 H), 3.46 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.6, 148.1, 137.1, 128.8, 120.4,
61.7, 33.1.
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Synthesis of Weinreb Amides Directly from Carboxylic Acids
325
MS (70 eV): m/z (%) = 255 (1), 224 (2), 208 (3), 198 (100), 195
(41), 167 (13), 155 (81), 149 (19), 91 (67), 65 (10).
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 3.6 Hz, 1 H), 7.15 (d,
J = 3.6 Hz, 1 H), 6.51 (dd, J = 3.6, 3.2 Hz, 1 H), 3.77 (s, 3 H), 3.56
(s, 3 H).
N-Methoxy-N,2-dimethylbenzamide (3f)40
13C NMR (100 MHz, CDCl3): δ = 159.1, 145.7, 145.2, 117.3, 111.5,
61.3, 33.1.
Colorless oil; yield: 344 mg (96%).
IR (neat): 3059, 2968, 2933, 2820, 1652, 1452, 1416, 1378, 1219,
1198, 1167, 1060, 987, 885, 771 cm–1.
MS (70 eV): m/z (%) = 155 (6), 125 (15), 95 (100), 40 (12).
1H NMR (400 MHz, CDCl3): δ = 7.32–7.29 (m, 2 H), 7.28–7.19 (m,
2 H), 3.49 (br s, 3 H), 3.31 (br s, 3 H), 2.34 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.6, 134.9, 134.4, 129.8, 128.9,
N-Methoxy-N-methylthieno[3,2-b]thiophene-2-carboxamide
(3l)38,39
White solid; yield: 440 mg (97%); mp 80–83 °C.
IR (neat): 3085, 2929, 1622, 1498, 1457, 1408, 1379, 1197, 1128,
1040, 975, 710 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.16 (s, 1 H), 7.55 (d, J = 5.2 Hz,
1 H), 7.27 (d, J = 5.6 Hz, 1 H), 3.82 (s, 3 H), 3.41 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.4, 144.7, 138.4, 135.0, 131.1,
126.4, 119.5, 61.7, 33.2.
125.8, 125.1, 60.7, 32.1, 18.8.
MS (70 eV): m/z (%) = 179 (1), 91 (72), 65 (13), 51 (1), 41 (1).
2-Iodo-N-methoxy-N-methylbenzamide (3g)41
White solid; yield: 541 mg (93%); mp 56–57 °C.
IR (neat): 3412, 2926, 1581, 1488, 1461, 1389, 1209, 1164, 1014,
978 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.0 Hz, 1 H), 7.39 (t,
J = 7.6 Hz, 1 H), 7.30–7.23 (m, 1 H), 7.14–7.05 (m, 1 H), 3.46 (s, 3
H), 3.39 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 170.6, 141.6, 138.8, 130.3, 127.3,
126.5, 125.4, 92.4, 61.4, 32.5.
MS (70 eV): m/z (%) = 227 (15), 167 (100), 139 (25), 95 (12), 69
(4), 45 (2), 40 (4).
Methyl 6-(N-methoxy-N-methylcarbamoyl)pyridine-2-carbox-
ylate (3m)
White solid; yield: 435 mg (97%); mp 73–75 °C.
IR (neat): 3412, 3106, 2986, 2938, 1845, 1740, 1629, 1542, 1515,
1464, 1200, 981 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.19–8.13 (m, 1 H), 7.92 (t, J = 8.0
Hz, 1 H), 7.77 (s, 1 H), 3.96 (s, 3 H), 3.80 (s, 3 H), 3.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.7, 165.1, 153.3, 146.5, 137.7,
MS (70 eV): m/z (%) = 291 (5), 232 (7), 231 (100), 203 (27), 104
(4), 76 (18), 50 (8).
N-Methoxy-N-methyl-2-nitrobenzamide (3h)40
White solid; yield: 395 mg (94%); mp 52–53 °C.
IR (neat): 3424, 2932, 1668, 1575, 1527, 1419, 1380, 1350, 987,
852, 789, 765, 717, 570 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.0 Hz, 1 H), 7.71 (t,
J = 7.6 Hz, 1 H), 7.60–7.50 (m, 2 H), 3.35 (s, 3 H), 3.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.8, 145.8, 133.9, 131.5, 130.0,
128.4, 123.9, 61.3, 33.4.
127.9, 125.9, 61.7, 52.8, 32.6.
HRMS (ESI): m/z [M + H]+ calcd for C10H13N2O4: 225.0870; found:
225.0871.
4-Cyano-N-methoxy-N-methylbenzamide (3n)9
White solid; yield: 369 mg (97%); mp 77–78 °C.
IR (neat): 3412, 2932, 1653, 1560, 1461, 1380 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.74 (d, J = 8.0 Hz, 2 H), 7.67 (d,
J = 8.0 Hz, 2 H), 3.49 (s, 3 H), 3.34 (s, 3 H).
MS (70 eV): m/z (%) = 211 (3), 152 (7), 151 (68), 150 (100), 121
(24), 104 (18), 93 (11), 76 (26), 51 (38).
N-Methoxy-N-methyl-4-nitrobenzamide (3i)40
White solid; yield: 416 mg (99%); mp 73–74 °C.
13C NMR (100 MHz, CDCl3): δ = 167.8, 138.2, 131.8, 128.8, 118.1,
114.0, 61.3, 33.2.
IR (neat): 3448, 1653, 1599, 1560, 1521, 1458, 1377, 1350, 1065,
993 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.24 (d, J = 8.8 Hz, 2 H), 7.82 (d,
J = 8.8 Hz, 2 H), 3.51 (s, 3 H), 3.37 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 148.8, 140.0, 129.2, 123.2,
61.3, 33.1.
MS (70 eV): m/z (%) = 190 (4), 131 (11), 130 (100), 102 (45), 75
(9), 51 (5).
3,5-Dihydroxy-N-methoxy-N-methybenzamide (3o)
White solid; yield: 280 mg (71%); mp 134–136 °C.
IR (neat): 3208, 2914, 2848, 1593, 1560, 1545, 1509, 1458, 1380,
1026 cm–1.
1H NMR (400 MHz, DMSO-d6): δ = 9.49 (s, 2 H), 6.38 (s, 2 H), 6.30
(s, 1 H), 3.53 (s, 3 H), 3.18 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 169.3, 158.1, 136.2, 105.7,
104.4, 60.7, 33.7.
HRMS (ESI): m/z [M + H]+ calcd for C9H12NO4: 198.0761; found:
198.0757.
MS (70 eV): m/z (%) = 211 (3), 150 (100), 120 (9), 104 (22), 92
(14), 76 (13), 50 (6).
N-Methoxy-N-methyl-1-naphthamide (3j)40
White solid; yield: 426 mg (99%); mp 41–42 °C.
IR (neat): 3460, 2926, 1638, 1458, 1425, 1380, 1023 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.81–7.74 (m, 3 H), 7.62–7.43 (m,
4 H), 3.53 (s, 3 H), 3.37 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.0, 133.3, 133.0, 129.7, 129.5,
128.3, 126.8, 126.2, 124.8, 124.7, 124.3, 61.3, 32.8.
4-Formyl-N-methoxy-N-methylbenzamide (3p)
White solid; yield: 251 mg (65%); mp 60–62 °C.
IR (neat): 3424, 2914, 1701, 1638, 1569, 1506, 1458, 1383, 1062
cm–1.
1H NMR (400 MHz, CDCl3): δ = 10.07 (s, 1 H), 7.89 (d, J = 8.0 Hz,
2 H), 7.77 (d, J = 8.4 Hz, 2 H), 3.54 (s, 3 H), 3.38 (s, 3 H).
MS (70 eV): m/z (%) = 216 (1), 215 (5), 156 (12), 156 (100), 150
(9), 128 (6), 127 (56), 77 (7), 63 (4).
N-Methoxy-N-methylfuran-2-carboxamide (3k)38,39
Colorless oil; yield: 307 mg (99%).
13C NMR (100 MHz, CDCl3): δ = 191.6, 168.7, 139.8, 137.4, 129.3,
IR (neat): 3284, 3136, 2936, 1640, 1564, 1479, 1420, 1174, 1022,
981, 763 cm–1.
128.6, 61.2, 33.3.
HRMS (ESI): m/z [M + H]+ calcd for C10H12NO3: 194.0812; found:
194.0810.
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326
T. Niu et al.
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(E)-N-Methoxy-3-(4-methoxyphenyl)-N-methylacrylamide
(3q)40
MS (70 eV): m/z (%) = 223 (2), 163 (5), 135 (100), 107 (10), 93
(34), 91 (22), 81 (16), 79 (72), 67 (25), 53 (9), 41 (13).
White solid; yield: 429 mg (97%); mp 46–47 °C.
N-Methoxy-N-methyltetrahydrofuran-2-carboxamide (5e)44
Colorless oil; yield: 296 mg (93%).
IR (neat): 3448, 2932, 1653, 1602, 1575, 1512, 1458, 1377, 170,
1029 cm–1.
IR (neat): 3506, 2972, 2947, 2878, 1668, 1458, 1390, 1356, 1321,
1180, 999 cm–1.
1H NMR (400 MHz, CDCl3): δ = 4.78 (s, 1 H), 4.07–3.88 (m, 2 H),
3.72 (s, 3 H), 3.21 (s, 3 H), 2.22–2.16 (m, 1 H), 2.10–1.95 (m, 2 H),
1.95–1.86 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 173.8, 74.9, 69.2, 61.2, 32.1, 29.3,
25.5.
1H NMR (400 MHz, CDCl3): δ = 7.67 (d, J = 15.6 Hz, 1 H), 7.50 (d,
J = 8.8 Hz, 2 H), 6.95–6.82 (m, 3 H), 3.81 (s, 3 H), 3.74 (s, 3 H),
3.28 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.3, 161.0, 143.0, 129.6, 127.8,
114.2, 113.3, 61.7, 55.3, 32.5.
MS (70 eV): m/z (%) = 22 (1), 221 (3), 162 (11), 161 (100), 133
(29), 118 (5), 89 (6), 77 (5), 63 (2).
MS (70 eV): m/z (%) = 159 (14), 130 (6), 102 (7), 71 (100), 61 (12),
43 (53), 41 (27).
N-Methoxy-N,3-dimethylbut-2-enamide (3r)42
Colorless oil; yield: 235 mg (82%).
N-Methoxy-N-methylcyclohexanecarboxamide (5f)38,39
Colorless oil; yield: 322 mg (97%).
IR (neat): 3437, 2966, 2935, 1653, 1447, 1410, 1366, 1319, 1176,
1109 cm–1.
IR (neat): 2930, 2856, 1662, 1448, 1416, 1385, 1348, 1175, 1093,
994 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.69 (s, 3 H), 3.18 (s, 3 H), 2.68
(m, 1 H), 1.81–1.67 (m, 5 H), 1.52–1.43 (m, 2 H), 1.35–1.22 (m, 3
H).
13C NMR (100 MHz, CDCl3): δ = 177.4, 77.3, 61.4, 39.8, 32.1, 28.9,
1H NMR (400 MHz, CDCl3): δ = 6.12 (s, 1 H), 3.68 (s, 3 H), 3.20
(s, 3 H), 2.14 (s, 3 H), 1.91 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 168.0, 114.2, 61.3, 32.1, 27.6,
20.1.
MS (70 eV): m/z (%) = 143 (5), 84 (5), 83 (100), 55 (36), 39 (6).
N-Methoxy-N-methylisobutyramide (5a)43
25.6.
Colorless oil; yield: 514 mg (95%).
MS (70 eV): m/z (%) = 171 (3), 139 (11), 111 (42), 83 (100), 55
(54), 40 (29).
IR (neat): 3502, 2972, 2938, 1660, 1465, 1387, 1093, 998 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.70 (s, 3 H), 3.19 (s, 3 H), 2.99–
2.96 (m, 1 H), 1.13 (d, J = 6.4 Hz, 6 H).
N-Methoxy-N-methylbut-3-enamide (5g)45
Colorless oil; yield: 219 mg (85%).
13C NMR (100 MHz, CDCl3): δ = 178.4, 61.4, 32.3, 29.8, 19.1.
IR (neat): 3430, 3076, 2932, 1665, 1560, 1545, 1461, 1029 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.04–5.92 (m, 1 H), 5.21–5.14 (m,
2 H), 3.71 (s, 3 H), 3.24 (d, J = 6.4 Hz, 2 H), 3.19 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 172.3, 131.7, 118.0, 62.2, 36.9,
MS (70 eV): m/z (%) = 131 (7), 71 (59), 61 (18), 43 (100).
N-Methoxy-N-methylpivalamide (5b)38,39
Colorless oil; yield: 255 mg (88%).
32.0.
IR (neat): 2964, 2929, 1651, 1483, 1460, 1401, 1352, 1164, 995
cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 3 H), 3.18 (s, 3 H), 1.25
MS (70 eV): m/z (%) = 129 (9), 98 (4), 69 (34), 68 (6), 61 (97), 60
(9), 46 (13), 42 (9), 41 (100), 39 (22).
N-Methoxy-N-methylhex-5-ynamide (5h)46
Colorless oil; yield: 300 mg (97%).
IR (neat): 3280, 2938, 1656, 1422, 1386, 1179, 1107, 993, 627 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 3 H), 3.17 (s, 3 H), 2.60–
2.56 (m, 2 H), 2.31–2.27 (m, 2 H), 1.98–1.97 (m, 1 H), 1.90–1.83
(m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 173.8, 83.8, 68.8, 61.2, 32.1, 30.4,
23.1, 17.9.
(s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 179.2, 60.6, 39.4, 33.7, 27.1.
MS (70 eV): m/z (%) = 145 (3), 130 (3), 86 (39), 61 (29), 57 (100),
56 (23), 45 (29), 39 (77), 35 (41).
N-Methoxy-N-methyl-2,2-diphenylacetamide (5c)35
White solid; yield: 499 mg (98%); mp 112–113 °C.
IR (neat): 3406, 3022, 2962, 2932, 1815, 1653, 1599, 1491, 1449,
1383, 1167, 1077, 993 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.34–7.28 (m, 8 H), 7.26–7.21 (m,
MS (70 eV): m/z (%) = 155 (8), 96 (6), 95 (100), 67 (43), 61 (50),
55 (36), 41 (36), 39 (16).
2 H), 5.54 (s, 1 H), 3.49 (s, 3 H), 3.23 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.7, 139.4, 128.9, 128.4, 126.9,
61.4, 52.9, 32.4.
Methyl 2-(N-Methoxy-N-methylcarbamoyl)-2-methylpropano-
ate (5i)
Colorless oil; yield: 340 mg (90%).
MS (70 eV): m/z (%) = 255 (1), 195 (5), 194 (35), 168 (14), 167
(100), 165 (39), 152 (20), 83 (3).
IR (neat): 3406, 2980, 2938, 1743, 1665, 1542, 1458, 1386, 1266,
1191, 1143, 999 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 3 H), 3.60 (s, 3 H), 3.17
N-Methoxy-N-methyladamantane-1-carboxamide (5d)38,39
White solid; yield: 437 mg (98%); mp 59–60 °C.
(s, 3 H), 1.38 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 174.1, 60.5, 51.9, 48.4, 33.1, 23.0.
IR (neat): 2905, 2852, 2667, 1734, 1641, 1547, 1450, 1352, 1310,
1180, 999 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 3 H), 3.17 (s, 3 H), 2.00
(br s, 9 H), 1.75 (br s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 178.4, 60.8, 42.1, 37.9, 36.7, 33.9,
MS (70 eV): m/z (%) = 191 (2), 159 (44), 130 (100), 101 (7), 88
(85), 69 (8), 60 (51).
HRMS (ESI): m/z [M + H]+ calcd for C8H16NO4: 190.1074; found:
190.1077.
28.3.
2-Chloro-N-methoxy-N-methylacetamide (5j)47
White solid; yield: 259 mg (94%); mp 35–37 °C.
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327
IR (neat): 3402, 2963, 1719, 1647, 1560, 1542, 1422, 1389, 1179,
999, 783 cm–1.
MS (70 eV): m/z (%) = 271 (0.3), 244 (12), 183 (75), 109 (21), 95
(32), 85 (29), 71 (38), 61 (100), 57 (87).
1H NMR (400 MHz, CDCl3): δ = 4.22 (s, 2 H), 3.72 (s, 3 H), 3.20
(s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.5, 61.6, 40.7, 32.5.
N-Methoxy-N-methylpalmitamide (5p)50
White solid; yield: 257 mg (95%); mp 28–29 °C.
IR (neat): 3439, 2924, 2853, 1671, 1462, 1382, 1002, 913 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 3 H), 3.18 (s, 3 H), 2.41
(t, J = 7.6 Hz, 2 H), 1.64–1.61 (m, 2 H), 1.30–1.25 (m, 24 H), 0.88
(t, J = 6.8 Hz, 3 H).
MS (70 eV): m/z (%) = 139 (2), 137 (5), 107 (9), 79 (11), 77 (39),
61 (100), 58(19), 49 (23), 46 (25).
3-Chloro-N-methoxy-N-methylpropanamide (5k)38,39
Colorless oil; yield: 285 mg (94%).
13C NMR (100 MHz, CDCl3): δ = 175.1, 61.4, 32.2, 29.9, 29.8, 29.7,
29.7, 29.6, 24.9, 22.9, 14.4.
IR (neat): 3312, 2971, 2940, 2823, 1665, 1427, 1389, 1319, 1298,
1180, 1105, 992 cm–1.
MS (70 eV): m/z (%) = 300 (3), 240 (15), 239 (93), 95 (25), 85 (36),
71 (51), 61 (100), 57 (70).
1H NMR (400 MHz, CDCl3): δ = 3.84–3.72 (m, 2 H), 3.17 (s, 3 H),
3.21 (s, 3 H), 2.94–2.91 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 170.7, 61.3, 39.2, 34.9, 32.0.
(S)-N-Methoxy-N-methyl-2-(4-methylphenylsulfonamido)-3-
phenylpropanamide (7a)51
20
White solid; yield: 673 mg (93%); mp 91–92 °C; [α]D +13.1 (c
MS (70 eV): m/z (%) = 151 (16), 153 (5), 152 (2), 116 (6), 91 (33),
93 (10), 86 (7), 61 (100).
0.36, MeOH).
IR (neat): 3029, 2931, 2869, 1658, 1601, 1449, 1386, 1332, 1159,
1088, 1026, 987 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.59–7.58 (m, 2 H), 7.24–7.18 (m,
5 H), 7.10–7.08 (m, 2 H), 5.39 (d, J = 9.2 Hz, 1 H), 4.56–4.50 (m, 1
H), 3.43 (s, 3 H), 2.96 (s, 3 H), 2.86–2.81 (m, 2 H), 2.38 (s, 3 H).
5-Bromo-N-methoxy-N-methylpentanamide (5l)9
Colorless oil; yield: 417 mg (93%).
IR (neat): 3487, 2939, 1733, 1660, 1447, 1418, 1387, 1240, 994
cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.69 (s, 3 H), 3.43 (t, J = 6.8 Hz,
2 H), 3.19 (s, 3 H), 2.47 (t, J = 7.2 Hz, 2 H), 1.96–1.75 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 175.6, 143.3, 136.9, 135.8, 129.5,
129.4, 128.4, 127.2, 126.9, 61.2, 54.0, 39.7, 32.0, 21.5.
13C NMR (100 MHz, CDCl3): δ = 173.9, 61.2, 33.3, 32.2, 32.1, 30.8,
23.2.
MS (70 eV): m/z (%) = 362 (0.58), 347 (0.24), 316 (12), 274 (88),
271 (68), 155 (96), 131 (12), 119 (12), 91 (100), 71 (14).
MS (70 eV): m/z (%) = 225 (4), 224 (5), 165 (43), 144 (11), 137
(26), 135 (29), 61 (100), 55 (93).
(S)-N-Methoxy-N-methyl-2-(4-methylphenylsulfonamido)-2-
phenylacetamide (7b)52
White solid; yield: 669 mg (89%); mp 138–140 °C; [α]D20 +88.43 (c
0.32, MeOH).
6-Bromo-N-methoxy-N-methylhexanamide (5m)48
Colorless oil; yield: 452 mg (95%).
IR (neat): 3283, 3063, 2926, 2859, 1659, 1600, 1449, 1383, 1331,
1160, 1090, 991 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.62–7.60 (m, 2 H), 7.26–7.17 (m,
7 H), 6.03 (d, J = 6.4 Hz, 1 H), 5.43 (d, J = 7.6 Hz, 1 H), 3.28 (s, 3
H), 2.99 (s, 3 H), 2.37 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 169.9, 143.2, 137.2, 136.3, 129.3,
128.7, 128.3, 127.7, 127.1, 61.0, 26.9, 32.3, 21.5.
IR (neat): 3450, 2932, 1731, 1656, 1458, 1386, 1176, 996 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.69 (s, 3 H), 3.42 (t, J = 6.8 Hz,
2 H), 3.18 (s, 3 H), 2.44 (t, J = 7.2 Hz, 2 H), 1.94–1.85 (m, 2 H),
1.72–1.60 (m, 2 H), 1.54–1.45 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 174.3, 61.2, 33.7, 32.5, 32.1, 31.6,
27.9, 23.7.
MS (70 eV): m/z (%) = 238 (1), 179 (30), 177 (32), 103 (12), 74
(22), 69 (100), 61 (68).
MS (70 eV): m/z (%) = 260 (100), 155 (56), 91 (51), 77 (4), 65 (6).
(S)-N-Methoxy-N-methyl-2-(4-methylphenylsulfonami-
do)propanamide (7c)52
6-Iodo-N-methoxy-N-methylhexanamide (5n)
Colorless oil; yield: 536 mg (94%).
White solid; yield: 555 mg (97%); mp 71–72 °C; [α]D20 +35 (c 2.1
in CH2Cl2).
IR (neat): 3430, 2932, 1656, 1458, 1383, 1170, 996 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.71 (s, 3 H), 3.22 (t, J = 6.8 Hz,
2 H), 3.18 (s, 3 H), 2.45 (d, J = 6.0 Hz, 2 H), 1.90–1.82 (m, 2 H),
1.69–1.62 (m, 2 H), 1.49–1.45 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 174.1, 61.1, 33.1, 31.9, 31.4, 30.1,
23.3, 6.8.
IR (neat): 3248, 3063, 2980, 2937, 1659, 1600, 1447, 1387, 1333,
1159, 1091, 987 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 8.0 Hz, 2 H), 7.28 (d,
J = 7.6 Hz, 2 H), 5.57 (d, J = 8.8 Hz, 1 H), 4.34 (t, J = 7.6 Hz, 1 H),
3.56 (s, 3 H), 2.99 (s, 3 H), 2.41 (s, 3 H), 1.31–1.26 (m, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C8H17INO2: 286.0298; found:
286.0302.
13C NMR (100 MHz, CDCl3): δ = 172.3, 143.4, 136.9, 129.5, 127.3,
61.4, 48.8, 32.1, 21.5, 19.9.
N-Methoxy-N-methyldodecanamide (5o)49
Colorless oil; yield: 457 mg (94%).
MS (70 eV): m/z (%) = 286 (0.015), 259 (3), 226 (2), 198 (100), 155
(87), 91 (65), 65 (10).
IR (neat): 3446, 2925, 2854, 1671, 1463, 1413, 1382, 1176, 999
cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.67 (s, 3 H), 3.17 (s, 3 H), 2.41
(t, J = 6.8 Hz, 2 H), 1.70–1.59 (m, 2 H), 1.30–1.27 (m, 16 H), 0.87
(t, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.8, 61.2, 32.1, 31.9, 29.7, 29.6,
29.5, 29.4, 29.4, 29.3 24.6, 22.6, 14.1.
(S)-N-Methoxy-N-methyl-1-tosylpyrrolidine-2-carboxamide
(7d)
20
White solid; yield: 592 mg (86%); mp 93–95 °C; [α]D –118.9 (c
0.37, MeOH).
IR (neat): 3335, 2974, 2950, 2881, 1675, 1597, 1450, 1391, 1342,
1197, 1158, 1096, 997 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.81–7.77 (m, 2 H), 7.31–7.29 (m,
2 H), 4.84–4.83 (m, 1 H), 3.78 (s, 3 H), 3.45–3.38 (m, 2 H), 3.19 (s,
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1H NMR (400 MHz, CDCl3): δ = 3.75 (s, 6 H), 3.25 (s, 6 H).
3 H), 2.42 (s, 3 H), 2.11–1.97 (m, 2 H), 1.92–1.86 (m, 1 H), 1.78–
1.73 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.3, 143.3, 135.8, 129.5, 127.5,
61.3, 57.8, 48.3, 32.2, 30.1, 24.7, 21.5.
HRMS (ESI): m/z [M + H]+ calcd for C14H21N2O4S: 313.1217;
13CNMR (100MHz, CDCl3): δ = 164.9, 62.0, 31.2.
MS (70 eV): m/z (%) = 176 (13), 145 (59), 88 (100), 60 (84).
N1,N5-Dimethoxy-N1,N5-dimethylglutaramide (9c)38,39
Colorless oil; yield: 423 mg (97%).
found: 313.1220.
IR (neat): 3316, 2939, 2826, 1662, 1446, 1418, 1385, 1355, 1179,
1112, 993 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 6 H), 3.18 (s, 6 H), 2.53
(t, J = 7.2 Hz, 4 H), 2.01–1.94 (m, 2 H).
tert-Butyl (S)-{1-[Methoxy(methyl)amino]-1-oxopropan-2-
yl}carbamate (7e)27
20
White solid; yield: 431 mg (93%); mp 148–150 °C; [α]D –27 (c
0.47, MeOH).
13C NMR (100 MHz, CDCl3): δ = 174.1, 61.2, 32.1, 31.0, 19.4.
IR (neat): 3450, 3296, 3045, 2976, 2933, 1704, 1660, 1541, 1451,
1424, 1388, 1363, 1067, 981, 586 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.25 (s, 1 H), 4.69 (s, 1 H), 3.77
(s, 3 H), 3.21 (s, 3 H), 1.44 (s, 9 H), 1.31 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.7, 155.2, 79.5, 61.6, 46.5,
32.1, 8.4, 18.7.
MS (70 eV): m/z (%) = 219 (0.11), 158 (100), 130 (74), 98 (13), 69
(11), 62 (40), 55 (61), 42 (64).
N1,N4-Dimethoxy-N1,N4-dimethylsuccinamide (9d)55
White solid; yield: 363 mg (89%); mp 74–75 °C.
IR (neat): 3437, 2941, 2831, 1652, 1454, 1422, 1390, 1192, 992
cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.75 (s, 6 H), 3.19 (s, 6 H), 2.78
MS (70 eV): m/z (%) = 234 (0.02), 233 (0.15), 172 (11), 159 (18),
116 (31), 88 (35), 61 (29), 57 (100), 44 (49), 41 (16).
(s, 4 H).
tert-Butyl (S)-{2-[Methoxy(methyl)amino]-2-oxo-1-phenyl-
ethyl}carbamate (7f)53
13C NMR (100 MHz, CDCl3): δ = 173.4, 61.1, 32.1, 26.3.
White solid; yield: 559 mg (95%); mp 151–152 °C; [α]D20 +104.6 (c
0.39, MeOH).
MS (70 eV): m/z (%) = 204 (0.04), 192 (5), 144 (100), 116 (7), 88
(5), 76 (11).
IR (neat): 3423, 3335, 2976, 2936, 1663, 1490, 1386, 1247, 1167,
1048, 992 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H), 5.79 (s, 1 H),
N1,N4-Dimethoxy-N1,N4-dimethylterephthalamide (9e)56
White solid; yield: 484 mg (96%); mp 172–173 °C.
5.72 (s, 1 H), 3.46 (s, 3 H), 3.19 (s, 3 H), 1.42 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 171.3, 154.9, 138.0, 128.7, 128.1,
127.9, 79.7, 61.1, 54.9, 32.3, 28.3.
IR (neat): 3424, 2914, 1701, 1638, 1569, 1506, 1458, 1422, 1383,
1206, 1062, 912 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.71 (s, 4 H), 3.54 (s, 6 H), 3.37
(s, 6 H).
MS (70 eV): m/z (%) = 294 (0.02), 172 (11), 159 (18), 116 (30), 88
13C NMR (100 MHz, CDCl3): δ = 169.4, 136.3, 128.1, 61.4, 33.8.
(37), 61 (32), 57 (100).
MS (70 eV): m/z (%) = 252 (2), 192 (100), 133 (25), 132 (18), 104
(27), 76 (13).
tert-Butyl (S)-{1-[Methoxy(methyl)amino]-1-oxo-3-phenylpro-
pan-2-yl}carbamate (7g)27
White solid; yield: 560 mg (91%); mp 83–84 °C; [α]D20 +4.2 (c 1.5,
MeOH).
N1,N2-Dimethoxy-N1,N2-dimethylphthalamide (9f)
White solid; yield: 484 mg (96%); mp 115–117 °C.
IR (neat): 3322, 2976, 2935, 1708, 1661, 1498, 1455, 1389, 1367,
1048, 988 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.30–7.16 (m, 5 H), 5.17 (d, J =
8.0 Hz, 1 H), 4.95 (d, J = 6.4 Hz, 1 H), 3.66 (s, 3 H), 3.17 (s, 3 H),
3.06 (m, 1 H), 2.88 (m, 1 H), 1.39 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 172.2, 155.1, 136.5, 129.4, 128.3,
126.7, 79.5, 61.5, 51.4, 38.8, 31.9, 28.2.
IR (neat): 3439, 2972, 2937, 2821, 1648, 1595, 1461, 1416, 1379,
1209, 1166, 1113, 990 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.51 (s, 2 H), 7.45–7.43 (m, 2 H),
3.58 (s, 6 H), 3.31 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 169.2, 134.1, 128.9, 127.5, 60.9,
33.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H17N2O4: 253.1183; found:
253.1186.
MS (70 eV): m/z (%) = 308 (0.05), 248 (11), 192 (43), 164 (67), 146
(19), 131 (18), 120 (57), 117 (39), 91 (30), 61 (18), 57 (100), 41
(13).
N1,N3-Dimethoxy-N1,N3-dimethylisophthalamide (9g)
White solid; yield: 454 mg (90%); mp 41–42 °C.
N1,N6-Dimethoxy-N1,N6-dimethyladipamide (9a)38,39
White solid; yield: 441 mg (95%); mp 151–153 °C.
IR (neat): 2974, 2932, 1638, 1464, 1410, 1380, 1230, 1170, 1059,
969 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 1.2 Hz, 1 H), 7.78 (dd,
J = 8.0, 1.6 Hz, 2 H), 7.49–7.45 (m, 1 H), 3.55 (s, 6 H), 3.37 (s, 6 H).
IR (neat): 2941, 2826, 1658, 1458, 1387, 1324, 1180, 1116, 995,
935 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 6 H), 3.18 (s, 6 H), 2.46
(br s, 4 H), 1.71–1.67 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 169.0, 133.8, 130.4, 128.0, 127.9,
61.1, 33.6.
13C NMR (100 MHz, CDCl3): δ = 174.2, 61.0, 32.0, 31.4, 24.2.
MS (70 eV): m/z (%) = 252 (2), 192 (100), 133 (31), 104 (24), 76
(21).
HRMS (ESI): m/z [M + H]+ calcd for C12H17N2O4: 253.1183; found:
MS (70 eV): m/z (%) = 232 (9), 202 (7), 185 (11), 183 (12), 172
(100), 144 (33), 141 (12), 118 (10), 111 (51), 97 (11), 91 (23), 83
(39), 55 (56), 40 (77).
253.1187.
N1,N2-Dimethoxy-N1,N2-dimethyloxalamide (9b)54
N2,N5-Dimethoxy-N2,N5-dimethylthiophene-2,5-dicarbox-
amide (9h)
White solid; yield: 475 mg (92%); mp 83–84 °C.
White solid; yield: 303 mg (86%); mp 92–93 °C.
IR (neat): 3442, 2984, 2942, 1678, 1658, 1494, 1458, 1402, 1379,
1179, 976 cm–1.
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Synthesis of Weinreb Amides Directly from Carboxylic Acids
329
IR (neat): 3484, 975, 2937, 1630, 1519, 1458, 1380, 1026, 976, 839
cm–1.
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1H NMR (400 MHz, CDCl3): δ = 7.89 (s, 2 H), 3.79 (s, 6 H), 3.38
(s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 161.9, 138.4, 133.2, 61.6, 33.1.
HRMS (ESI): m/z [M + H]+ calcd for C10H15N2O4S: 259.0747;
Found: 259.0749.
(E)-N1,N4-Dimethoxy-N1,N4-dimethylfumaramide (9i)38,39
White solid; yield: 372 mg (91%); mp 92–94 °C.
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38, 2685.
IR (neat): 3111, 2978, 2916, 1641, 1474, 1424, 1381, 1234, 1182,
1097, 996 cm–1.
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1H NMR (400 MHz, CDCl3): δ = 7.51 (s, 2 H), 3.75 (s, 6 H), 3.30
(s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 165.3, 130.4, 62.2, 32.3.
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(Z)-N1,N4-Dimethoxy-N1,N4-dimethylfumaramide (9j)38,39
Colorless oil; yield: 327 mg (80%).
IR (neat): 2939, 2825, 1651, 1437, 1392, 1340, 1182, 997 cm–1.
1H NMR (400 MHz, CDCl3): δ = 6.58 (s, 2 H), 3.71 (s, 6 H), 3.25
(s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 166.6, 129.0, 61.5, 31.9.
MS (70 eV): m/z (%) = 202 (0.04), 142 (100), 113 (19), 82 (12).
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Acknowledgment
This work was financially supported by National Natural Science
Foundation of China (Grant Nos. 21062016); Key Laboratory Poly-
mer Materials of Gansu Province (Northwest Normal University);
Bioactive Product Engineering Research Center for Gansu Distinc-
tive Plants; State Key Laboratory of Applied Organic Chemistry,
Lanzhou University.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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