Latent Bronsted Base Solvent-Assisted Amide Formation from Amines and Acid Chlorides

Article abstract of DOI:10.1055/s-0037-1609342

Weakly basic amines, including even neutral amines such as nitroaniline and aminocarboxylic acids, react with acid chlorides very efficiently in N, N -dimethylacetamide (DMAC), without addition of a base, to give the corresponding amides in high yields. The role of DMAC and related solvents as latent Bronsted bases was studied in these amidation reactions. Less basic amines, such as aromatic amines, reacted with benzoyl chloride faster than more basic aliphatic amines.

Full text of DOI:10.1055/s-0037-1609342

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–Q
paper
A
en
R. Otsuka et al.
Paper
Synthesis
Latent Brønsted Base Solvent-Assisted Amide Formation from
Amines and Acid Chlorides
Rikuto Otsuka
proton-protection
H
N
H
MeCO2H
Kazuo Maruhashi
Tomohiko Ohwada*
Cl
H
NH2
0
0
0
0
0-
0
0
1
5-
3
9
0
0-
2
0
3
HCl
MeO
strong base
MeO
Graduate School of Pharmaceutical Sciences, The University of
Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
ohwada@mol.f.u-tokyo.ac.jp
H
NH3
Cl
amidation
NH2
N
Ph
HCl
O
weak base
O
Ph
Cl
Me
O
Me
Me
OH
N
N
Me
DMAC
Me
Me
weak base
Received: 19.01.2018
Accepted after revision: 20.02.2018
Published online: 20.03.2018
work as a base, the reaction would be more economic,
greener, and more practically useful. Therefore, in this
study we examined the effect of DMAC (1a) and related sol-
vents as latent bases in the amidation reaction of amines
and acid chlorides without addition of a base to neutralize
the formed HCl. We show here that DMAC can serve as a la-
tent Brønsted base catalyst;5 it was effective even in a stoi-
chiometric amount (one equivalent with respect to amine
and acyl chloride), and its effect leveled off at two equiva-
lents, indicating that it acts as a reagent rather than as a sol-
vent. In the reactions examined, simple addition of water
afforded the amide product either directly as a precipitate,
or after in situ recrystallization, and then suction filtration
followed by drying in vacuo afford the amide in 70–98%
yield with more than 99% purity on a gram scale. Thus, the
present methodology is convenient, low-cost, green, and
readily applicable for large-scale synthesis, as well as labo-
ratory-scale synthesis.
In DMAC (1a), 4-methoxybenzylamine (2a) and chloro-
acetyl chloride (3a) gave the corresponding amide 4a in 78%
yield after 2 hours at room temperature in the absence of a
base (Table 1, run 1). The yield of the amide 4a increased to
85%, taking account of additional product extracted from
the filtrate with ethyl acetate/n-hexane. The reaction yield
was unchanged after prolonged reaction (17 h, 79% yield)
(run 2). A typical gram-scale experimental procedure was
as follows: to a solution of acid chloride in DMAC was added
a solution of a slight molar excess of amine in DMAC cooled
in an ice-water bath. The mixture was stirred at ambient
temperature, and the product was precipitated by adding
water. The reverse order of addition, that is, addition of a
solution of acid chloride in DMAC to a solution of amine in
DMAC gave the same result (82% yield, for details, see the
Experimental Section). The reaction was essentially com-
plete within 3 hours. On the other hand, when the reaction
of 2a and 3a was carried out in a typical acylation solvent,
DOI: 10.1055/s-0037-1609342; Art ID: ss-2018-f0039-op
Abstract Weakly basic amines, including even neutral amines such as
nitroaniline and aminocarboxylic acids, react with acid chlorides very ef-
ficiently in N,N-dimethylacetamide (DMAC), without addition of a base,
to give the corresponding amides in high yields. The role of DMAC and
related solvents as latent Brønsted bases was studied in these amidation
reactions. Less basic amines, such as aromatic amines, reacted with
benzoyl chloride faster than more basic aliphatic amines.
Key words amide, N,N-dimethylacetamide, urea, Brønsted base,
amine, acid chloride
Amide bonds are found in the structures of many active
pharmaceutical ingredients (APIs) and related compounds,1
and amide bond-forming reactions are of continuing inter-
est.2 Amidation reaction of amines and acid chlorides is an
important traditional method in organic synthesis, and
many examples of amidation reactions of amines and acid
chlorides have been reported (approximately 300 000 hits
in the Reaxys® database). In these reactions, N,N-dimethyl-
formamide (DMF) and N,N-dimethylacetamide (DMAC)
have frequently been utilized as aprotic polar solvents, both
on an industrial and laboratory scale (approximately 1800
hits in the database for DMAC as a solvent). Polar solvents
can stabilize the charge-polarized transition state of the
nucleophilic substitution reaction of acid chloride with
amine. In about a half of the examples where DMAC was
used as a solvent, a base catalyst such as triethylamine, pyr-
idine and N,N-diisopropylethylamine (DIPEA, Hünig’s base)
was added.3 But, intriguingly, a base catalyst was not used
in the remaining half.4 Thus, although amidation of amines
and acid chlorides in DMAC is a common reaction, the full
significance of the presence or absence of a base catalyst in
this solvent is not still known. If the solvent itself could
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Q

B
R. Otsuka et al.
Paper
Synthesis
Table 1 Role of DMAC in Amidation Reaction
O
Cl
O
N
NH2
+
H
Cl
Cl
MeO
MeO
4a
3a
Run
Solvent 1
Additive
Temp (°C)
Time (h)
Yield (%) of amide 4a
1
2
DMAC
DMAC
CH2Cl2
CH2Cl2
acetone
EtOAc
–
–
–
–
–
–
23
23
23
23
23
23
23
23
23
23
23
23
23
23
2
17
2
78a (85)b
79a
3
49c
4
17
17
17
17
17
17
2
45c
5
38a
6
38a (49)b
55c
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
acetone
EtOAc
DMAC (0.5 equiv)
DMAC (1.0 equiv)
DMAC (2.0 equiv)
DMAC (2.0 equiv)
DMAC (2.0 equiv)
DMAC (2.0 equiv)
8
70c
9
82c
10
11
12
13
14
60c
17
17
2
73a
74a
CH2Cl2
CH2Cl2
N,N-dimethylaniline (2.0 equiv)
87c
Et3N (2.0 equiv)
2
53d
a Isolated yield of the precipitate.
b Total yield of the product (precipitate plus product extracted from filtrate) is shown in parentheses.
c Yield of the product obtained by extraction.
d The reaction mixture darkened and the reaction appeared to be complex. Yield of the product obtained by column chromatography.
CH2Cl2 (run 3), the reaction stopped at about 50% progress,
affording 45% yield of the amide 4a, even after an extended
reaction time of 17 hours (run 4). This is reasonable, be-
cause at 50% reaction, the nucleophilicity of the amine is
lost due to salt formation with the generated HCl as shown
below:
amine (see Scheme 1). The amidation of 2a and 3a in a mix-
ture of DMAC (2 equiv) and CH2Cl2 was rather slow as com-
pared with the reaction in neat DMAC, and when the reac-
tion was quenched after 2 hours, the yield was intermediate
(run 10, 60%). On the other hand, the use of triethylamine
as an additive in CH2Cl2 solvent afforded a dark, complex
mixture from which 4a was isolated in 53% yield by column
chromatography (run 14). Triethylamine would induce
deprotonation of the α-proton of 3a, affording a chloro-
ketene intermediate that might generate unidentified polar
by-products.6 Pyridine and DIPEA also produced a colored
reaction mixture. Thus, DMAC appears to be advantageous
compared with the other bases examined.
0.5 Amine 2 + 0.5 Acid chloride 3 + 0.5 HCl + 0.5 Amide 4 →
0.5 Amine 2·HCl + 0.5 Acid chloride 3 + 0.5 Amide 4
Similar results were obtained with acetone (38% yield)
and ethyl acetate (38% yield) (Table 1, runs 5 and 6).
When DMAC was pre-mixed with CH2Cl2 solvent (Table
1, runs 7–10), the yield of the corresponding amide 4a in-
creased with increasing amount of DMAC up to 2 equiva-
lents, at which point the yield of 4a (run 9, 82%) reached the
level obtained in neat DMAC (11 equiv) (run 2, 79%). Similar
results were obtained in acetone and ethyl acetate as sol-
vents (runs 11 and 12). When an external base, N,N-di-
methylaniline (2 equiv with respect to amine 2a or acid
chloride 3a) was added in CH2Cl2 solvent (run 13), the yield
of the amide 4a was about the same (87% yield, after ex-
traction) as that obtained by the addition of 2 equivalents
of DMAC in CH2Cl2 (run 9, 82%). These results suggest that
DMAC serves as a weak carbonyl-oxygen Brønsted base
R
R
Me
Me
O
Me
Me
OH
+
H
N
H
N
N
H
N
Cl
Cl
+
Me
Me
R’
N-protonated amine
R’
neutral amine O-protonated DMAC
DMAC
Scheme 1 Protonation equilibrium of amine and DMAC
We also examined the effects of other amide-containing
solvents (Tables 2 and 3).
Because ureas are more basic (pKBH+ = +0.8) than amides
as oxygen bases due to the increased electron density on
the oxygen atoms,5c we expected that they would also work
as latent bases and facilitate the amidation reaction. Indeed,
+
(pKBH = –0.19)5a–c to neutralize the HCl, releasing the free
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R. Otsuka et al.
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Synthesis
DMF and N-methyl-2-pyridone (NMP) worked as well as
DMAC (Table 2). The urea-type solvents [N,N′-dimethylpro-
pyleneurea (DMPU), tetramethylurea (TMU), and 1,3-di-
methyl-2-imidazolidinone (DMI)] also facilitated the reac-
tion to similar extent to the amide-type solvents.
shown in Tables 2 and 3 suggested that the urea-type sol-
vents also have latent basicity similar to the amide-type
solvents.
Table 3 Solvent Effects of Amidic Solvents
H
Table 2 Solvent Effects of Amidic Solvents
O
NH2
+
N
solvent (1)
Cl
Cl
Cl
O
O
Br
Br
O
4b
3a
2b
Cl
solvent (1)
NH2
N
Cl
+
H
Cl
MeO
Yield (%)a of
amide 4a
MeO
Run
1
Solvent 1
Temp
(°C)
Time
(h)
2a
3a
4a
Me
N
Me
O
Run
Solvent 1
Temp
(°C)
Time
(h)
Yield (%) of
amide 4a
23
23
1.5
90
88
Me
DMAC (1a)
Me
N
Me
O
Me
O
1
2
23
2
78a
70a
Me
N
2
3
1.5
1.5
DMAC (1a)
Me
DMF (1b)
H
Me
O
N
23
23
2
2
O
Me
DMF (1b)
H
Me
N
Me
Me
N
23
81
DMPU (1d)
O
3
4
75a
N
O
Me
NMP (1c)
Me
N
N
4
5
23
23
1.5
1.5
90
93
O
Me Me
TMU (1e)
Me
N
Me
Me
N
23
2
65a (64)b
O
DMPU (1d)
Me
Me
N
N
O
DMI (1f)
a Isolated yield of the precipitate.
Me
5
6
N
N
23
23
2
2
18a (60)b
51a (55)b
Me Me
TMU (1e)
The generality of the amide synthesis in DMAC was ex-
amined next and the results are summarized in Figure 1.
Among the combinations of aliphatic/aromatic and
amine/acid chloride examined, we found that aliphatic
amine-aliphatic acid chlorides 4a and 4c–f, aliphatic
amine-aromatic acid chlorides 4g–m, aromatic amine-ali-
phatic acid chlorides 4b, 4n,o, and aromatic amine-aromat-
ic acid chlorides 4p–r provided the amides in good to mod-
erate yields (51–91%) after simple aqueous workup and fil-
tration to collect the precipitated product, except oil
products. Interestingly, the combination of aromatic amines
and aromatic acid chlorides reacted more quickly than the
aliphatic counterparts, for example, 4b ↔ 4a and 4o ↔ 4d.
This is counterintuitive, because aromatic amines are
weaker bases than aliphatic amines in general, and there-
fore are less nucleophilic.
O
Me
Me
N
N
DMI (1f)
a Isolated yield of the precipitate.
b Yield of the product obtained by extraction.
However, in the case of the amine 2a and acid chloride
3a, the amide product 4a can be dissolved into a mixture of
water and the urea solvent upon aqueous workup; the iso-
lated yield of the precipitate was rather low, particularly in
the case of TMU (18% yield, Table 2, run 5). The product 4a
can be obtained by extraction procedure (60% in TMU, see
Table 2). DMPU was the best of the urea-type solvents, af-
fording 4a in 65% yield, as the solid precipitate (run 4).
When the aromatic amine such as an aniline derivative
2b was used, the reaction proceeded also efficiently to give
the corresponding amide 4b as a precipitate in good yields
in DMF, DMPU, TMU, and DMI, respectively, similar to the
result found in DMAC (up to 90% yield, Table 3). These data
To understand the above results, we studied the amida-
tion reaction of practically neutral amines in DMAC (Figure
2). The amines studied included anilines substituted with a
strongly electron-withdrawing group, for example, ester,
nitro, and cyano groups (5a–f). We found that DMAC af-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Q

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R. Otsuka et al.
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Synthesis
N
O
O
H
N
Cl
Cl
Cl
Cl
O
N
H
N
N
H
Cl
O
Br
MeO
O
Cl
4e
4b
4a
4c
4d
(23 °C, 1.5 h, 90%)a
(23 °C, 2 h, 78%)a
(23 °C, 2 h, 84%)b
(23 °C, 3 h, 89%)c
(23 °C, 1.5 h, 62%)a
F
N
O
O
O
H
N
O
4i
N
H
N
H
N
H
O
Cl
Cl
F
MeO
4g
4h
4j
4f
(23 °C, 2 h, 82%)a
(23 °C, 1.5 h, 67%)a
(23 °C, 4 h, 81%)b
(23 °C, 17 h, 70%)a
(23 °C, 2 h, 77%)a
O
O
O
CH3
N
N
H
N
N
H
N
H
Cl
O
MeO
N
Cl
O
MeO
MeO
F
Cl
4k
4l
4m
4n
4o
(23 °C, 0.5 h, 72%)a
(23 °C, 1.5 h, 51%)a
(23 °C, 1.5 h, 67%)a
(23 °C, 5 h, 64%)a
(0 °C, 5 min, 89%)a
Br
O
O
N
N
N
H
O
F
F
N
Cl
4p
(23 °C, 3 h, 94%)a
4q
(23 °C, 2 h, 91%)a
4r
(23 °C, 45 min, 84%)a
Figure 1 Generality of amidation in DMAC. a Isolated yield. b Product obtained as an oil. Isolated yield obtained by column chromatography. c Product
solidified after extraction.
forded a high yield of amide within a short reaction time
(up to 98% yield, Figure 2). On the other hand, the pKBH+ val-
H2N
n CO2H
H3N
n CO2
ues of nitroanilines have been determined to be 2.46 (meta,
in water) and 1.01 (para, in water), respectively,7 and they
are neutral rather than basic.
CO2H
H
H
N
N
HO2C
The reaction is likely to be influenced by the competi-
tion for protonation between two weak bases, that is,
amine and DMAC, which would increase the concentration
of the neutral amine (Scheme 1).
It should be noted that aminocarboxylic acids are zwit-
terionic (Scheme 2). When the benzoylation of aminocar-
boxylic acids, such as anthranilic acid (6a), and amino acids
6b–d in DMAC was examined, high yields of the N-benzoyl
products were obtained (Scheme 2).
O
O
6a
6b
(23 °C, 1.5 h, 95%)a
(23 °C, 4 h, 70%)a
H
N
HO2C
H
N
HO2C
Me
O
O
Me
6d
6c
(23 °C, 21 h, 77%)a
(23 °C, 26 h, 75%)b
Scheme 2 Amidation of aminocarboxylic acids in DMAC. a Isolated
yield of the product. b Yield of the product obtained by extraction.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Q

E
R. Otsuka et al.
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Synthesis
Finally, the reactivities of the aliphatic amine 2a and ar-
omatic amine 2d were compared toward benzoyl chloride
in DMAC in the presence of various acid or base additives
(Table 4).
As the amount of acetic acid was increased, the yield of
amide product 4s derived from the aromatic amine 2d, a
less basic amine, was increased as compared with the case
of amide 4l derived from the aliphatic amine 2a, a more ba-
sic amine, and selective amidation of the aromatic amide 4s
proceeded in 92% yield without formation of the alternative
aliphatic amide 4l (Table 4, runs 1 and 2) (proton-protective
effect of 2a, see also the graphical abstract).8
On the other hand, in the presence of triethylamine in
DMAC (Table 4, run 3), the aliphatic amide 4l was formed to
a greater extent than the aromatic amide 4s, probably be-
cause the generated HCl was completely neutralized, and
the intrinsic difference in nucleophilicity between the ali-
phatic amine 2a and the aromatic amine 2d controlled the
product distribution. In the absence of the additive, the re-
action in DMAC provided a biased but coexisting distribu-
tion of the amides, that is, a 1:2 mixture of 4l and 4s, favor-
ing 4s (run 4). These results are consistent with our hypoth-
esis that less basic aromatic amines react faster than more
basic aliphatic amines in DMAC, as implied by the results
obtained with various combinations of acid chlorides and
amines (Figure 1).
In conclusion, our findings indicate that the present re-
action of acid chlorides with amines in amide-type and
urea-type solvents in the absence of an added base pro-
ceeds in high yield, and is applicable to a broad range of
amines. These solvents work as a latent Brønsted base. This
methodology is expected to be practically useful for large-
scale synthesis, offering a low-cost, green approach that is
practically convenient, especially in terms of ease of purifi-
cation. Further studies of the reaction mechanism are in
progress.
H
H
N
N
Me
Me
O
O
O
O
C
O
C
O
Me
Me
5a–1
5a–2
(23 °C, 2.5 h, 96%)
(23 °C, 3 h, 93%)
CO2Me
NO2
H
N
H
N
O
O
5b
5c
(23 °C, 1.5 h, 89%)
(23 °C, 4 h, 87%)
H
N
H
N
O
O
NO2
O2N
5d
5e
(23 °C, 1.5 h, 97%)
(0 °C, 2 h, 98%)
H
N
O
NC
5f
(23 °C, 2 h, 96%)
Figure 2 Amidation of neutral amines in DMAC. Isolated yields are
shown.
Table 4 Selective Amidation Among Two Amines in DMAC in the Pres-
ence of Additives
Melting points were determined with a Yanaco micro melting point
apparatus without correction. 1H NMR (400 MHz) and 13C NMR spec-
tra (100 MHz) were recorded on a Bruker Avance 400 spectrometer.
Chemical shifts are shown in ppm (δ) values, and the coupling con-
stants are shown in hertz (Hz). Chemical shifts were calibrated with
internal TMS or with the solvent peak for the 1H and 13C NMR spectra.
Standard abbreviations are used to denote signal multiplicities. Elec-
tron spray ionization time-of-flight mass spectra (ESI-TOF MS) were
recorded on a Bruker micrOTOF-05 to give high-resolution mass spec-
tra (HRMS). Combustion analysis were carried out in the facility cen-
ter of this graduate school. All the reagents and solvents were com-
mercially available and used without further purification. In all cases,
the yield of the amide product was calculated on the basis of the
amount of the acid chloride.
O
Cl
NH2
N
H
O
MeO
MeO
(5 mmol)
NH2
2a
(5 mmol)
3b
4l
+
+
additive
H
DMAC (10 mL)
N
O
4s
(5 mmol)
2d
Run
Additive
Temp
(°C)
Time
(h)
Yield (%) of am-
ide 4l/4s
1
2
3
4
AcOH (2 equiv)a
AcOH (5 equiv)a
Et3N (2 equiv)a
–
23
23
23
23
3
3
3
3
8:78b [9:91]c
0:92b [0:100]c
60:28b [68:32]c
29:66b [31:69]c
The reaction schemes with numbering of the compounds are illus-
trated in the Supporting Information.
Amide Formation of 4a (Table 1, run 1)
a Equivalent amounts with respect to the total amount of amines (10
To a pre-cooled solution of acid chloride 3a (1.1315 g, 10.02 mmol) in
DMAC (5 mL) at 0 °C (ice-water bath) was added a solution of amine
2a (1.4370 g, 10.48 mmol) in DMAC (5 mL) over 3 min and the reac-
tion mixture was stirred at 0 °C for 10 min. A white precipitate was
formed. The ice-water bath was replaced with a water bath and the
mmol).
b Yields of compounds based on the 1H NMR spectra of the isolated precipi-
tate.
c Ratios of amides are shown in square brackets.
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F
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mixture was stirred at 23 °C for 2 h. The completion of the reaction
was confirmed by TLC. H2O (30 mL) was added to the reaction vessel,
and a white precipitate was formed. The whole was stirred for 5 h at
23 °C. The resultant precipitate was collected by suction filtration,
and the solid was washed with H2O (70 mL) and dried in vacuum.
Amide 4a was obtained as a white solid (1.6713 g, 78%). The precipi-
tate was pure enough to give a satisfactory combustion analysis with-
out further purification. To check the remaining amount of 4a in the
filtrate, the filtrate was extracted with CH2Cl2 (4 × 20 mL). The com-
bined organic fractions were washed with H2O (3 × 50 mL) and dried
(MgSO4). The organic solvent was evaporated to give a colorless liquid
(1.0910 g), which was mixture of 4a and DMAC. The calculated
amount of 4a in the extract was 0.1420 g (6.6%) on the basis of the
integration of the 1H NMR signals. Therefore, the total yield of the
product 4a (precipitate plus product extracted from filtrate) is 85%;
colorless plates; mp 102 °C.
Anal. Calcd for C10H12ClNO2: C, 56.22; H, 5.66; N, 6.56. Found: C,
56.08; H, 5.69; N, 6.63.
Amide Formation of 4a (Table 1, run 3)
A solution of acid chloride 3a (1.3344 g, 11.82 mmol) in CH2Cl2 (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2a (1.4400 g, 10.50 mmol) in CH2Cl2 (5 mL) was added over 5
min with stirring at 0 °C. The mixture was stirred at 0 °C for 10 min.
The ice-water bath was replaced with a water bath and the mixture
was stirred at 23 °C for 2 h. H2O (30 mL) was added. The mixture was
extracted with CH2Cl2 (3 × 20 mL) and the combined organic fractions
were washed twice with H2O (80 mL in total) and dried (MgSO4). The
solvent was evaporated to give 4a as a white solid, which was dried in
vacuum (1.1042 g, 49%). The product was pure enough to give a satis-
factory combustion analysis without further purification. The prod-
uct was identical with the authentic compound in terms of 1H NMR
(CDCl3) and the combustion analysis. Solid NaOH (1.35 g) was added
to basify the aqueous fraction. The aqueous phase was extracted with
CH2Cl2 (3 × 20 mL), the combined organic layers were dried (MgSO4),
and the solvent was evaporated to give the recovered amine 2a as a
colorless oil (0.6280 g, 46% recovery).
1H NMR (400 MHz, CDCl3): δ = 7.220 (2 H, d, J = 8.8 Hz), 6.880 (2 H, d,
J = 8.8 Hz), 6.832 (1 H, br), 4.418 (2 H, d, J = 5.6 Hz), 4.075 (2 H, s),
3.800 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 165.79, 159.35, 129.45, 129.32,
114.30, 55.41, 43.46, 42.71.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H12ClNO2Na: 236.0449;
found: 236.0451.
Amide Formation of 4a (Table 1, run 4)
Anal. Calcd for C10H12ClNO2: C, 56.22; H, 5.66; N, 6.56. Found: C,
55.98; H, 5.63; N, 6.61
A solution of acid chloride 3a (1.3261 g, 11.74 mmol) in CH2Cl2 (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2a (1.2448 g, 9.07 mmol) in CH2Cl2 (5 mL) was added over 3
min with stirring at 0 °C. A white precipitate was formed and the
mixture was stirred at 0 °C for 10 min. The ice-water bath was re-
placed with a water bath and the mixture was stirred at 23 °C for 17
h. H2O (30 mL) was added. The mixture was extracted with CH2Cl2
(3 × 20 mL), the combined organic fractions were washed thrice with
H2O (150 mL in total), and dried (MgSO4). The solvent was evaporated
to give 4a as a white solid, which was dried in vacuum (0.8788 g,
45%). The product was pure enough to give a satisfactory combustion
analysis without further purification. The product was identical with
the authentic compound in terms of 1H NMR (CDCl3) and the combus-
tion analysis. Solid NaOH (0.96 g) was added to basify the aqueous
fraction. The aqueous fraction was extracted with CH2Cl2 (4 × 20 mL),
the combined organic layers were dried (MgSO4), and the solvent was
evaporated to give the recovered amine 2a as a colorless oil (0.5663 g,
45% recovery).
Reverse Addition: Addition of Acid Chloride to Amine
To a pre-cooled solution of amine 2a (1.4423 g, 10.51 mmol) at 0 °C
(ice-water bath) was added a solution of 3a (1.1357 g, 10.06 mmol) in
DMAC (5 mL) over 5 min. A white precipitate was formed. The reac-
tion mixture was stirred at 0 °C for 10 min. The ice-water bath was
replaced with a water bath and the mixture was stirred at 23 °C for 2
h. The completion of the reaction was confirmed by TLC. H2O (40 mL)
was added to the reaction vessel to give a white precipitate. The
whole was stirred for overnight at 23 °C. The resultant precipitate was
collected by suction filtration, and washed with H2O, and dried in
vacuum. Amide 4a was obtained as a white solid (1.7549 g, 82%). The
precipitate was pure enough to give a satisfactory combustion analy-
sis without further purification. The product was identical with the
authentic compound in terms of 1H NMR (CDCl3) and combustion
analysis.
Amide Formation of 4a (Table 1, run 2)
A solution of acid chloride 3a (1.1045 g, 9.78 mmol) in DMAC (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2a (1.4012 g, 10.22 mmol) in DMAC (5 mL) was added over 4
min with stirring at 0 °C. A white precipitate was formed and the
mixture was stirred at 0 °C for 10 min. The ice-water bath was re-
placed with a water bath and the mixture was stirred at 23 °C for 17
h. H2O (30 mL) was added and the mixture was stirred for 23 h at
23 °C. The resultant precipitate was collected by suction filtration,
washed with H2O (100 mL), and dried in vacuum. Amide 4a was ob-
tained as a white solid (1.6547 g, 79%). The precipitate was pure
enough to give a satisfactory combustion analysis without further pu-
rification. The product 4a was identical with the authentic compound
in terms of 1H NMR (CDCl3) and combustion analysis.
Amide Formation of 4a (Table 1, run 5)
A solution of acid chloride 3a (1.1301 g, 10.01 mmol) in acetone (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). A solution
of amine 2a (1.4388 g, 10.49 mmol) in acetone (5 mL) was added over
3 min with stirring at 0 °C and the mixture was stirred at 0 °C for 10
min. The ice-water bath was replaced with a water bath and the
whole was stirred at 23 °C for 17 h. H2O (30 mL) was added to give a
white precipitate and the suspension was stirred for 4 h. The solid
was filtered by suction, washed with H2O (100 mL), and dried in vacu-
um. Absence of product in the filtrate was checked by TLC. Product 4a
was obtained as a white solid (0.8124 g, 38%). The precipitate was
pure enough to give a satisfactory combustion analysis without fur-
ther purification. The product was identical with the authentic com-
pound in terms of 1H NMR (CDCl3) and combustion analysis.
1H NMR (400 MHz, CDCl3): δ = 7.227 (2 H, d, J = 8.8 Hz), 6.886 (2 H, d,
J = 8.7 Hz), 6.784 (1 H, br s), 4.429 (2 H, d, J = 5.7 Hz), 4.093 (2 H, s),
3.808 (3 H, s).
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Synthesis
Amide Formation of 4a (Table 1, run 6)
2a (1.4384 g, 10.49 mmol) in DMAC/CH2Cl2 (5 mL) was added over 3
min with stirring at 0 °C and the mixture was stirred at 0 °C for 10
min. The ice-water bath was replaced with a water bath and the mix-
ture was stirred at 23 °C for 17 h. H2O (30 mL) was added and the
mixture was extracted with CH2Cl2 (4 × 20 mL). The combined organic
fractions were washed with H2O (3 × 50 mL) and dried (MgSO4). The
solvent was evaporated to give 4a as a white solid, which was dried in
vacuum (1.7519 g, 82%). The product was pure enough to give a satis-
factory combustion analysis without further purification. The prod-
uct was identical with the authentic compound in terms of 1H NMR
(CDCl3) and combustion analysis.
A solution of acid chloride 3a (1.1336 g, 10.04 mmol) in EtOAc (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). While stirring and
cooling at 0 °C, a solution of amine 2a (1.4433 g, 10.52 mmol) in
EtOAc (5 mL) was added over 4 min. The mixture was stirred at 0 °C
for 10 min. The ice-water bath was replaced with a water bath and the
mixture was stirred at 23 °C for 17 h. H2O (30 mL) was added and the
whole was stirred for 15 h. The solid was filtered by suction, washed
with H2O (100 mL), and dried in vacuum. Amide 4a was obtained as a
white solid (0.8124 g, 38%). The filtrate was extracted with CH2Cl2 (4
× 20 mL), the combined organic fractions were washed with H2O (3 ×
50 mL), and dried (MgSO4). The solvent was evaporated to give an ad-
ditional amount of 4a (0.2302 g) as a white solid, which was dried in
vacuum. The combined yield of 4a was 49% (1.0426 g). The product
was pure enough to give a satisfactory combustion analysis without
further purification. The product was identical with the authentic
compound in terms of 1H NMR (CDCl3) and combustion analysis.
Amide Formation of 4a (Table 1, run 10)
CH2Cl2 was added to DMAC (1.7376 g, 19.99 mmol, 2 equiv) to make a
total 10 mL solution of the DMAC/CH2Cl2 solvent mixture. A solution
of acid chloride 3a (1.1336 g, 10.04 mmol) in DMAC/CH2Cl2 (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2a (1.4426 g, 10.52 mmol) in DMAC/CH2Cl2 (5 mL) was added
over 3 min with stirring at 0 °C and the whole was stirred at 0 °C for
10 min. The ice-water bath was replaced with a water bath and the
mixture was stirred at 23 °C for 2 h. H2O (30 mL) was added. The mix-
ture was extracted with CH2Cl2 (4 × 20 mL), the combined organic
fractions were washed with H2O (3 × 50 mL), and dried (MgSO4). The
solvent was evaporated to give 4a as a white solid, which was dried in
vacuum (1.2890 g, 60%). The product was pure enough to give a satis-
factory combustion analysis without further purification. The prod-
uct was identical with the authentic compound in terms of 1H NMR
(CDCl3) and combustion analysis.
Amide Formation of 4a (Table 1, run 7)
CH2Cl2 was added to DMAC (0.4341 g, 4.98 mmol, 0.5 equiv) to make a
total 10 mL solution. A solution of acid chloride 3a (1.1383 g, 10.08
mmol) in the above CH2Cl2/DMAC solvent mixture (5 mL) was pre-
pared at r.t. The solution was transferred to a 30 mL round-bottomed
flask and cooled to 0 °C (ice-water bath). A solution of amine 2a
(1.4469 g, 10.547 mmol) in CH2Cl2/DMAC (5 mL) was added over 4
min. The mixture was stirred at 0 °C for 12 min. The ice-water bath
was replaced with a water bath and the whole was stirred at 23 °C for
17 h. H2O (30 mL) was added and the mixture was extracted with
CH2Cl2 (4 × 20 mL), the combined organic fractions were washed with
H2O (3 × 50 mL), and dried (MgSO4). The solvent was evaporated to
give a white solid, which was dried in vacuum to give 4a (1.1791 g,
55%). The product was pure enough to give a satisfactory combustion
analysis without further purification. The product was identical with
the authentic compound in terms of 1H NMR (CDCl3) and combustion
analysis.
Amide Formation of 4a (Table 1, run 11)
Acetone was added to DMAC (1.7431 g, 20.01 mmol, 2 equiv) to make
a total 10 mL solution of DMAC/acetone solvent mixture. A solution of
acid chloride 3a (1.1360 g, 10.06 mmol) in DMAC/acetone (5 mL) was
prepared at r.t. The solution was transferred to a 30 mL round-bot-
tomed flask and cooled to 0 °C (ice-water bath). A solution of amine
2a (1.4497 g, 10.57 mmol) in DMAC/acetone (5 mL) was added over 3
min with stirring at 0 °C. The mixture was stirred at 0 °C for 10 min.
The ice-water bath was replaced with a water bath and the mixture
was stirred at 23 °C for 17 h. H2O (30 mL) was added to give a white
precipitate, which was stirred for 22 h. The solid was filtered by suc-
tion, washed with H2O (70 mL), and dried in vacuum to give 4a as a
white solid (1.5788 g, 73%). The precipitate was pure enough to give a
satisfactory combustion analysis without further purification. The
product was identical with the authentic compound in terms of 1H
NMR (CDCl3) and combustion analysis.
Amide Formation of 4a (Table 1, run 8)
CH2Cl2 was added to DMAC (0.8725 g, 10.02 mmol, 1 equiv) to make a
total 10 mL volume of the solvent mixture DMAC/CH2Cl2. A solution
of acid chloride 3a (1.1329 g, 10.03 mmol) in DMAC/CH2Cl2 (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2a (1.4385 g, 10.486 mmol) in DMAC/CH2Cl2 (5 mL) was added
over 4 min. The mixture was stirred at 0 °C for 10 min. The ice-water
bath was replaced with a water bath and the mixture was stirred at
23 °C for 17 h. H2O (30 mL) was added. The mixture was extracted
with CH2Cl2 (4 × 20 mL), the combined organic fractions were washed
with H2O (3 × 50 mL), and dried (MgSO4). The solvent was evaporated
to give a white solid, which was dried in vacuum to give 4a (1.5062 g,
70%). The product was pure enough to give a satisfactory combustion
analysis without further purification. The product was identical with
the authentic compound in terms of 1H NMR (CDCl3) and combustion
analysis.
Amide Formation of 4a (Table 1, run 12)
EtOAc was added to DMAC (1.7483 g, 20.07 mmol, 2 equiv) to make a
total 10 mL solution of DMAC/EtOAc solvent mixture. A solution of
acid chloride 3a (1.1232 g, 9.95 mmol) in DMAC/EtOAc (5 mL) was
prepared at r.t. The solution was transferred to a 30 mL round-bot-
tomed flask and cooled to 0 °C (ice-water bath). A solution of amine
2a (1.4362 g, 10.47 mmol) in DMAC/EtOAc (5 mL) was added over 3
min with stirring at 0 °C. The mixture was stirred at 0 °C for 10 min.
The ice-water bath was replaced with a water bath and the mixture
was stirred at 23 °C for 17 h. The completion of the reaction was con-
firmed by TLC. H2O (30 mL) was added to give a white precipitate and
the mixture was stirred for 2 h. The solid was filtered by suction,
washed with H2O (60 mL), and dried in vacuum to give 4a as a white
solid (1.5788 g, 74%). The precipitate was pure enough to give a satis-
Amide Formation of 4a (Table 1, run 9)
CH2Cl2 was added to DMAC (1.7683 g, 20.30 mmol, 2 equiv) to make a
total 10 mL solution of DMAC/CH2Cl2 solvent mixture. A solution of
acid chloride 3a (1.1303 g, 10.01 mmol) in DMAC/CH2Cl2 (5 mL) was
prepared at r.t. The solution was transferred to a 30 mL round-bot-
tomed flask and cooled to 0 °C (ice-water bath). A solution of amine
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H
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Synthesis
factory combustion analysis without further purification. The prod-
uct was identical with the authentic compound in terms of 1H NMR
(CDCl3) and combustion analysis.
mixture was stirred at 0 °C for 5 min. The ice-water bath was replaced
with a water bath and the mixture was stirred at 23 °C for 2 h. H2O
(30 mL) was added to the reaction vessel and the resultant precipitate
was collected by suction filtration, washed with H2O, and dried in
vacuum. Amide 4a was obtained as a white solid (1.6086 g, 75%). The
precipitate was pure enough to give a satisfactory combustion analy-
sis without further purification. The product was identical with the
authentic compound in terms of 1H NMR (CDCl3) and combustion
analysis.
Amide Formation of 4a (Table 1, run 13)
CH2Cl2 was added to N,N-dimethylaniline (2.4331 g, 20.08 mmol) to
make a total 5 mL solution of N,N-dimethylaniline/CH2Cl2 solvent
mixture. A solution of acid chloride 3a (1.1316 g, 10.02 mmol) in
CH2Cl2 (5 mL) was prepared at r.t. The solution was transferred to a 30
mL round-bottomed flask and cooled to 0 °C (ice-water bath). A solu-
tion of amine 2a (1.4435 g, 10.52 mmol) in N,N-dimethylaniline/CH2-
Cl2 (5 mL) was added over 3 min with stirring at 0 °C. The whole was
stirred at 0 °C for 10 min. The ice-water bath was replaced with a wa-
ter bath and the mixture was stirred at 23 °C for 2 h. H2O (30 mL) was
added. The mixture was extracted with CH2Cl2 (4 × 20 mL), the com-
bined organic fractions were washed with 0.01 M aq HCl (3 × 50 mL),
and dried (MgSO4). The solvent was evaporated to give 4a as a white
solid, which was washed with H2O (50 mL) and n-hexane (50 mL), fol-
lowed by drying in vacuum (1.8619 g, 87%). The product was pure
enough to give a satisfactory combustion analysis without further pu-
rification.
Amide Formation of 4a (Table 2, run 4)
Precipitation Method: A solution of acid chloride 3a (1.1294 g, 10.0
mmol) in DMPU (5 mL) was prepared at r.t. The solution was trans-
ferred to a 30 mL round-bottomed flask and cooled to 0 °C (ice-water
bath). While stirring and cooling at 0 °C, a solution of amine 2a
(1.4351 g, 10.46 mmol) in DMPU (5 mL) was added over 3 min. The
mixture was stirred at 0 °C for 10 min. The ice-water bath was re-
placed with a water bath and the mixture was stirred at 23 °C for 2 h.
The completion of the reaction was confirmed by TLC, and H2O (30
mL) was added to give a white precipitate. The mixture was stirred for
17 h and the solid obtained was filtered by suction. The filtration res-
idue was washed with H2O (70 mL) and dried in vacuum to give 4a as
a white solid (1.3800 g, 65%). The precipitate was pure enough to give
a satisfactory combustion analysis without further purification. The
product was identical with the authentic compound in terms of 1H
NMR (CDCl3) and combustion analysis.
Amide Formation of 4a (Table 1, run 14)
CH2Cl2 was added to Et3N (2.0332 g, 20.09 mmol) to make a total 10
mL solution of Et3N/CH2Cl2 solvent mixture. A solution of acid chlo-
ride 3a (1.1313 g, 10.02 mmol) in Et3N/CH2Cl2 (5 mL) was prepared at
r.t. The solution was transferred to a 30 mL round-bottomed flask and
cooled to 0 °C (ice-water bath). A solution of amine 2a (1.4373 g,
10.48 mmol) in Et3N/CH2Cl2 (5 mL) was added over 5 min with stir-
ring at 0 °C. The mixture was stirred at 0 °C for 10 min. The ice-water
bath was replaced with a water bath and the mixture was stirred at
23 °C for 2 h. H2O (30 mL) and aq 2 M HCl (8 mL) were added. The
mixture was extracted with CH2Cl2 (4 × 20 mL), the combined organic
fractions were washed with H2O (3 × 50 mL), and dried (MgSO4). The
solvent was evaporated to give a black solid. The solid was dried in
vacuum (1.5088 g). The product was purified by open-chromatogra-
phy (EtOAc/hexane 1:1) to give 4a (1.1329 g, 53%). The product was
pure enough to give a satisfactory combustion analysis without fur-
ther purification. The product was identical with the authentic com-
pound in terms of 1H NMR (CDCl3) and combustion analysis.
Extraction Method: To acid chloride 3a (1.1324 g, 10.03 mmol) was
added DMPU (5 mL) over 4 min at 0 °C (ice-water bath). To this solu-
tion was added a solution of amine 2a (1.3758 g, 10.03 mmol) in
DMPU (5 mL) over 5 min at 0 °C with stirring. The mixture was stirred
at 0 °C for 5 min. The ice-water bath was replaced with a water bath
and the mixture was stirred at 23 °C for 2 h. Pale yellow viscous solu-
tion was obtained. The completion of the reaction was confirmed by
TLC, and H2O (80 mL) was added to give a white precipitate. The mix-
ture was extracted with EtOAc (60 mL). The organic layer was washed
with H2O (280 mL in total) repeatedly. The filtration residue was
dried (MgSO4) and the solvent was evaporated to give 4a as a white
power (1.3736 g, 64%). The product was pure enough to give a satis-
factory combustion analysis without further purification. The prod-
uct was identical with the authentic compound in terms of 1H NMR
(CDCl3) and combustion analysis.
Amide Formation of 4a (Table 2, run 2)
Amide Formation of 4a (Table 2, run 5)
A solution of acid chloride 3a (1.1353 g, 10.05 mmol) in DMF (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2a (1.4460 g, 10.54 mmol) in DMF (5 mL) was added over 3
min with stirring at 0 °C and the mixture was stirred at 0 °C for 10
min. The ice-water bath was replaced with a water bath and the mix-
ture was stirred at 25 °C for 2 h. The completion of the reaction was
confirmed by TLC, and H2O (30 mL) was added to give a white precip-
itate. The mixture was stirred for 21 h. The solid was filtered by suc-
tion, washed with H2O (80 mL), and dried in vacuum. Amide 4a was
obtained as a white solid (1.5134 g, 70%). The precipitate was pure
enough to give a satisfactory combustion analysis without further pu-
rification. The product was identical with the authentic compound in
terms of 1H NMR (CDCl3) and combustion analysis.
Precipitation Method: To a pre-cooled solution of acid chloride 3a
(1.1417 g, 10.11 mmol) in TMU (5 mL) at 0 °C (ice-water bath) was
added a solution of amine 2a (1.4426 g, 10.52 mmol) in TMU (5 mL)
over 4 min. The mixture was stirred at 0 °C for 30 min. The ice-water
bath was replaced with a water bath and the mixture was stirred at
23 °C for 2 h. H2O (60 mL) was added to the reaction vessel and the
resultant white precipitate was collected by suction filtration,
washed with H2O, and dried in vacuum. Amide 4a was obtained as a
white solid (386.0 mg, 18%). The precipitate was pure enough to give
a satisfactory combustion analysis without further purification. The
product was identical with the authentic compound in terms of 1H
NMR (CDCl3) and combustion analysis.
Extraction Method: To a pre-cooled solution of acid chloride 3a
(1.1305 g, 10.01 mmol) in TMU (5 mL) at 0 °C (ice-water bath) was
added a solution of amine 2a (1.3778 g, 10.04 mmol) in TMU (5 mL)
over 2 min at 0 °C. A white precipitate was formed and the mixture
was stirred at 0 °C for 5 min. The ice-water bath was replaced with a
water bath and the whole was stirred at 23 °C for 2 h. H2O (40 mL)
Amide Formation of 4a (Table 2, run 3)
To a pre-cooled solution of acid chloride 3a (1.1283 g, 9.99 mmol) in
NMP (5 mL) at 0 °C (ice-water bath) was added a solution of amine 2a
(1.4619 g, 10.66 mmol) in NMP (5 mL) over 2 min and the reaction
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Synthesis
was added to the reaction vessel, and the suspension with the white
precipitate was extracted with EtOAc (180 mL), and the organic layer
was washed with H2O (200 mL) and dried (MgSO4). Evaporation of the
organic solvent gave 4a as a white solid (1.2852 g, 60%). The product
was pure enough to give a satisfactory combustion analysis without
further purification. The product was identical with the authentic
compound in terms of 1H NMR (CDCl3) and combustion analysis.
pure enough to give a satisfactory combustion analysis without fur-
ther purification. The product was identical with the authentic com-
pound in terms of 1H NMR (CDCl3) and combustion analysis.
Amide Formation of 4b (Table 3, run 3)
To a pre-cooled solution of acid chloride 3a (1.1222 g, 9.94 mmol) in
DMPU (5 mL) prepared at 0 °C (ice-water bath), was added a solution
of amine 2a (1.7196 g, 10.00 mmol) in DMPU (5 mL) over 2 min. The
whole was stirred at 0 °C for 10 min. No precipitate was formed. The
ice-water bath was replaced with a water bath and the mixture was
stirred at 23 °C for 1.5 h. H2O (80 mL) was added to the reaction ves-
sel, and the resultant white precipitate was collected by suction filtra-
tion, washed with H2O, and dried in vacuum. Amide 4b was obtained
as a white solid (2.0077 g, 81%). The precipitate was pure enough to
give a satisfactory combustion analysis without further purification.
The product was identical with the authentic compound in terms of
1H NMR (CDCl3) and combustion analysis.
Amide Formation of 4a (Table 2, run 6)
Precipitation Method: To a pre-cooled solution of acid chloride 3a
(1.1263 g, 9.97 mmol) in DMI (5 mL) at 0 °C (ice-water bath) was add-
ed a solution of amine 2a (1.4574 g, 10.47 mmol) in DMI (5 mL) over 2
min. The mixture was stirred at 0 °C for 20 min. The ice-water bath
was replaced with a water bath and the mixture was stirred at 23 °C
for 2 h. H2O (20 mL) was added to the reaction vessel and the resul-
tant white precipitate was collected by suction filtration, and washed
with H2O, and dried in vacuum. Amide 4a was obtained as a white
solid (1.0840 g, 51%). The precipitate was pure enough to give a satis-
factory combustion analysis without further purification. The prod-
uct was identical with the authentic compound in terms of 1H NMR
(CDCl3) and combustion analysis.
Amide Formation of 4b (Table 3, run 4)
A solution of acid chloride 3a (1.1526 g, 10.21 mmol) in TMU (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 5 °C (ice-water bath). While stirring and
cooling at 5 °C, a solution of amine 2b (1.8148 g, 10.55 mmol) in TMU
(5 mL) was added over 5 min. The mixture was stirred at 5 °C for 10
min. The ice bath was replaced with a water bath and the mixture
was stirred at 23 °C for 1.5 h. The completion of the reaction was con-
firmed by TLC, and H2O (30 mL) was added. The mixture with the
white precipitate formed was stirred overnight. The solid was filtered
by suction, washed with H2O (100 mL), and dried in vacuum. Amide
4b was obtained (2.2709 g, 90%) as a white solid. The precipitate was
pure enough to give a satisfactory combustion analysis without fur-
ther purification. The product was identical with the authentic com-
pound in terms of 1H NMR (CDCl3) and combustion analysis.
Extraction Method: To a pre-cooled solution of acid chloride 3a
(1.1275 g, 9.98 mmol) in TMU (5 mL) prepared at 0 °C (ice-water bath)
was added a solution of amine 2a (1.3795 g, 10.06 mmol) in TMU (5
mL) over 3 min at 0 °C. A white precipitate was formed and the mix-
ture was stirred at 0 °C for 5 min. The ice-water bath was replaced
with a water bath and the whole was stirred at 23 °C for 2 h. H2O (50
mL) was added to the reaction vessel, and a white precipitate formed.
The whole was extracted with EtOAc (80 mL) and the organic layer
was repeatedly washed with H2O (200 mL in total), and dried (Mg-
SO4). Evaporation of the organic solvent gave 4a as a white solid
(1.1778 g, 55%). The product was identical with the authentic com-
pound in terms of 1H NMR (CDCl3) and combustion analysis.
Amide Formation of 4b (Table 3, run 1)
Amide Formation of 4b (Table 3, run 5)
A solution of acid chloride 3a (1.0934 g, 9.68 mmol) in DMAC (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2b (1.8025 g, 10.48 mmol) in DMAC (5 mL) was added over 5
min with stirring at 0 °C and the mixture was stirred at 0 °C for 10
min. The ice bath was replaced with a water bath and the mixture
was stirred 23 °C for 1.5 h. Completion of reaction was confirmed by
TLC, and H2O (30 mL) was added to give a white precipitate. After stir-
ring the mixture overnight, the solid was filtered by suction, washed
with H2O (100 mL), and dried in vacuum. Amide 4b was obtained as a
white solid (2.1606 g, 90%). The product was pure enough to give a
satisfactory combustion analysis without further purification.
A solution of acid chloride 3a (1.1451 g, 10.14 mmol) in DMI (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). While stirring and
cooling at 0 °C, a solution of amine 2b (1.8394 g, 10.69 mmol) in DMI
(5 mL) was added over 5 min. The mixture turned yellow and was
stirred at 0 °C for 10 min. The ice bath was replaced with a water bath
and the mixture was stirred at 23 °C for 1.5 h. The completion of the
reaction was confirmed by TLC, and H2O (30 mL) was added. The mix-
ture became pale yellow and a white precipitate was formed. The
mixture was stirred overnight. The solid was filtered by suction,
washed with H2O (100 mL), and dried in vacuum. Amide 4b was ob-
tained as a white solid (2.3506 g, 93%). The product was identical
1
with the authentic compound in terms of H NMR (CDCl3) and com-
bustion analysis.
Amide Formation of 4b (Table 3, run 2)
A solution of acid chloride 3a (1.1276 g, 9.98 mmol) in DMF (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2b (1.8398 g, 10.69 mmol) in DMF (5 mL) was added over 5
min with stirring at 0 °C and the mixture was stirred at 0 °C for 10
min. The ice-water bath was replaced with a water bath and the mix-
ture was stirred at 23 °C for 1.5 h. The completion of the reaction was
confirmed by TLC, and H2O (30 mL) was added. A white precipitate
was formed and the mixture was stirred for 17 h. The solid was fil-
tered by suction, washed with H2O (100 mL), and dried in vacuum.
Amide 4b was obtained as a white solid (2.1918 g, 88%), which was
Amide Formation of 4c (Figure 1)
To a pre-cooled solution of acid chloride 3-4c (1.1269 g, 9.98 mmol)
in DMAC (5 mL) to 0 °C (ice-water bath) was added a solution of
amine 2-4c (2.0800 g, 10.54 mmol) in DMAC (5 mL) over 4 min. The
ice bath was replaced with a water bath and the mixture was stirred
at 23 °C for 2 h. The completion of the reaction was confirmed by TLC,
and H2O (20 mL) was added. The oily product formed was extracted
with EtOAc (100 mL in total) and the combined organic fractions
were washed with brine (200 mL). The organic fraction was evaporat-
ed to give a colorless viscous oil, which was flash-column chromato-
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R. Otsuka et al.
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graphed with EtOAc/n-hexane (1:4) to give 2.3008 g (84%) of 4c as a
colorless oil. The product was pure enough to give a satisfactory com-
bustion analysis without further purification.
1H NMR (400 MHz, CDCl3): δ = 7.392–7.148 (10 H, m), 4.613 (2 H, s),
HRMS (ESI-TOF): m/z [M + H]+) calcd for C9H10Cl2NO+: 218.0134;
found: 218.0137.
Anal. Calcd for C9H9Cl2NO: C, 49.57; H, 4.16; N, 6.42. Found: C, 49.37;
H, 4.18; N, 6.43.
4.509 (2 H, s), 4.141 (2 H, s).
13C NMR (100 MHz, CDCl3): δ = 167.28, 136.32, 135.60, 129.08,
Amide Formation of 4f (Figure 1)
128.69, 128.19, 127.94, 127.64, 126.40, 50.23, 48.60, 41.31.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H16ClNONa+: 296.08126;
found: 296.08137.
A solution of acid chloride 3-4f (1.5344 g, 9.93 mmol) in DMAC (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2-4f (1.4389 g, 10.49 mmol) in DMAC (5 mL) was added over 4
min with stirring at 0 °C. A white precipitate was formed and the
mixture was stirred at 0 °C for 12 min. The ice-water bath was re-
placed with a water bath and the mixture was stirred at 23 °C for 2 h.
The completion of the reaction was confirmed by TLC. H2O (30 mL)
was added and the mixture was stirred for 18 h. The mixture was ex-
tracted with CH2Cl2 (4 × 20 mL) and the combined organic fraction
was washed with H2O (3 × 50 mL). The organic fraction was dried
(MgSO4), and the solvent was evaporated to give a white solid, which
was dried in vacuum (2.0831 g, 82%). The solid was washed with H2O
(100 mL), filtered, and dried in vacuum to give 4f (1.5137 g, 60%); col-
orless needles; mp 139–140 °C (MeOH). The product was pure
enough to give a satisfactory combustion analysis without further pu-
rification.
Anal. Calcd for C16H16ClNO: C, 70.20; H, 5.89; N, 5.12. Found: C, 70.27;
H, 6.04; N, 5.10.
Amide Formation of 4d (Figure 1)
To a pre-cooled solution of acid chloride 3-4d (1.1255 g, 9.97 mmol)
in DMAC (5 mL) at 0 °C (ice-water bath) was added a solution of
amine 2-4d (1.3964 g, 10.48 mmol) in DMAC (5 mL) over 4 min and
the mixture was stirred at 0 °C for 10 min. A yellow precipitate was
formed. The ice-water bath was replaced with a water bath and the
whole was stirred at 23 °C for 3 h. The completion of the reaction was
confirmed by TLC. H2O (30 mL) and 2 M aq HCl (2 mL) were added to
the reaction vessel. The mixture was extracted with EtOAc/n-hexane
(2:1 v/v, 4 × 25 mL) and the combined organic layers were washed
with H2O (2 × 50 mL). The organic fraction was dried (MgSO4), and the
solvent evaporated to give 4d as a pale yellow solid (1.8638 g, 89%);
mp 50–51 °C (colorless plates after recrystallization from MeOH). The
product was pure enough to give a satisfactory combustion analysis
without further purification.
1H NMR (400 MHz, CDCl3): δ = 7.249 (4 H, m), 4.231 (2 H, s), 3.833 (2
H, t, J = 6.7 Hz), 2.744 (2 H, t, J = 6.3 Hz), 2.001 (2 H, t, J = 6.7 Hz).
13C NMR (100 MHz, CDCl3): δ = 166.2, 138.5, 128.8, 126.7, 126.2,
123.8, 44.0, 42.0, 26.7, 23.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H12ClNONa+: 232.0500;
1H NMR (400 MHz, CDCl3): δ = 7.366–7.294 (5 H, m), 7.107 (2 H, ddd,
J = 8.7, 2.9, 2.1 Hz), 6.824 (2 H, ddd, J = 8.7, 2.9, 2.0 Hz), 4.345 (2 H, d,
J = 5.7 Hz), 3.782 (3 H, s), 3.617 (2 H, s).
13C NMR (100 MHz, CDCl3): δ = 170.72, 158.90, 134.79, 130.17,
129.38, 128.98, 128.84, 127.31, 113.98, 55.23, 43.78, 43.04.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H17NO2Na+: 278.11515;
found: 278.11732.
Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C, 75.21;
H, 6.77; N, 5.47.
found: 232.0505.
Amide Formation of 4g (Figure 1)
Anal. Calcd for C11H12ClNO: C, 63.01; H, 5.77; N, 6.68. Found: C, 62.87;
H, 5.84; N, 6.68.
A solution of acid chloride 3-4g (1.4247 g, 10.14 mmol) in DMAC (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). While stir-
ring and cooling at 0 °C, a solution of amine 2-4g (2.2351 g, 11.33
mmol) in DMAC (5 mL) was added over 8 min at 0 °C. The mixture
was stirred at 0 °C for 10 min. The ice bath was replaced with a water
bath and the mixture was stirred at 23 °C for 1.5 h. The completion of
the reaction was confirmed by TLC, and H2O (20 mL) was added. A
white precipitate was formed and the mixture was stirred overnight.
The solid was filtered by suction, washed with H2O (100 mL), and
dried in vacuum. The precipitated amide 4g was obtained as a white
powder (2.0365 g, 67%); mp 144–145 °C; mp 145–146 °C (colorless
needles after recrystallized from MeOH). The product was pure
enough to give a satisfactory combustion analysis without further pu-
rification.
Amide Formation of 4e (Figure 1)
A solution of acid chloride 3-4e (1.1367 g, 10.07 mmol) in DMAC (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). A solution
of amine 2-4e (1.4868 g, 10.50 mmol) in DMAC (5 mL) was added
over 5 min with stirring at 0 °C. The mixture was stirred at 0 °C for 14
min. A white precipitate was formed. The ice-water bath was replaced
with a water bath and the mixture was stirred at 23 °C for 1.5 h. The
completion of the reaction was confirmed by TLC, and H2O (30 mL)
was added. A white precipitate was formed and the mixture was
stirred for 14 h. The solid was filtered by suction, washed with H2O
(100 mL) and dried in vacuum to give 4e as a white powder (1.3640 g,
62%); mp 76–77 °C; mp 75–77 °C (colorless needles after recrystalli-
zation from MeOH). The product was pure enough to give a satisfacto-
ry combustion analysis without further purification.
1H NMR (400 MHz, CDCl3): δ = 7.571 (2 H, d, J = 7.2 Hz), 7.44 (1 H, tt,
J = 7.4, 1.2 Hz), 7.372–7.213 (12 H, m), 4.325 (1 H, t, J = 8.0 Hz), 4.089
(2 H, dd, J = 8.0 Hz, 6.0 Hz).
13C NMR (100 MHz, CDCl3): δ = 167.60, 141.95, 134.70, 131.53,
128.93, 128.65, 128.21, 127.05, 126.90, 50.65, 44.38.
1H NMR (400 MHz, CDCl3): δ = 7.414–7.359 (2 H, m), 7.270 (1 H, dd,
J = 3.9, 3.5 Hz), 7.247 (1 H, dd, J = 3.3, 3.3 Hz), 7.068 (1 H, br s), 4.587
(2 H, d, J = 6.1 Hz), 4.086 (2 H, s).
13C NMR (100 MHz, CDCl3): δ = 165.96, 134.89, 133.89, 130.35,
129.81, 129.42, 127.33, 42.75, 41.95.
HRMS (ESI-TOF): m/z [M + Na]+) calcd for C21H19NONa: 324.1359;
found: 324.1363.
Anal. Calcd for C21H19NO: C, 83.69; H,6.35; N, 4.65. Found: C, 83.40; H,
6.50; N, 4.66.
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Amide Formation of 4h (Figure 1)
was obtained as a white powder (2.0227 g, 77%); mp 107–108 °C; mp
107–109 °C (colorless prisms after recrystallization from MeOH). The
product was pure enough to give a satisfactory combustion analysis
without further purification.
1H NMR (400 MHz, CDCl3): δ = 7.791 (2 H, dddd, J = 8.9, 5.3, 3.0, 2.2
Hz), 7.446 (1 H, dd, J = 5.8, 3.4 Hz), 7.385 (1 H, dd, J = 5.6, 3.6 Hz),
7.266–7.223 (2 H, m), 7.094 (2 H, dd, J = 8.6, 8.6 Hz), 6.660 (1 H, s),
4.700 (2 H, s).
To a pre-cooled solution of acid chloride 3-4h (1.4000 g, 9.96 mmol)
in DMAC (5 mL) (prepared at 0 °C in an ice-water bath) was added a
solution of amine 2-4h (1.4838 g, 10.48 mmol) in DMAC (5 mL) over 3
min at 0 °C and stirred at 0 °C for 10 min. A white precipitate was
formed. The ice-water bath was replaced with a water bath and the
mixture was stirred at 23 °C for 4 h. The completion of the reaction
was confirmed by TLC. H2O (40 mL) was added to the reaction vessel
to give a white precipitate and the mixture was stirred for 14 h at
23 °C. The resultant precipitate was collected by suction filtration, the
solid was washed with H2O (70 mL), and dried in vacuum. Amide 4h
was obtained as a white solid (1.9768 g, 81%); mp 119–121 °C (color-
less plates after frecrystallization from MeOH). The product was pure
enough to give a satisfactory combustion analysis without further pu-
rification.
13C NMR (100 MHz, CDCl3): δ = 166.1, 165.1 (d, 1JC,F = 285 Hz), 135.6,
4
3
133.8, 130.5 (d, JC,F = 3.0 Hz), 130.5, 129.7, 129.5 (d, JC,F = 9.3 Hz),
129.2, 127.3, 115.7 (d, 2JC,F = 22 Hz), 42.2.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H11ClFNONa+: 286.0405;
found: 286.0415.
Anal. Calcd for C14H11ClFNO: C, 63.77; H, 4.20; N, 5.31. Found: C,
63.63; H, 4.40; N, 5.31.
1H NMR (400 MHz, CDCl3): δ = 7.786 (2 H, d, J = 7.0 Hz), 7.525–7.739
(5 H, m), 7.255–7.237 (2 H, m), 6.621 (1 H, br s), 4.732 (2 H, d, J = 6.0
Hz).
Amide Formation of 4k (Figure 1)
13C NMR (100 MHz, CDCl3): δ = 167.5, 135.7, 134.4, 133.9, 131.8,
130.6, 129.7, 129.2, 128.8, 127.3, 127.1, 42.2.
HRMS (ESI-TOF): m/z [M + Na]+) calcd for C14H12ClNONa+: 268.0500;
found: 268.0513.
A solution of acid chloride 3-4k (1.0476 g, 5.95 mmol) in DMAC (3
mL) was prepared at r.t. The solution was transferred into a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). While stir-
ring and cooling at 0 °C, a solution of amine 2-4k (0.8560 g, 6.24
mmol) in DMAC (3 mL) was added over 3 min. The mixture was
stirred at 0 °C for 4 min. The ice-water bath was replaced with a water
bath and the mixture was stirred at 23 °C for 0.5 h. The completion of
the reaction was confirmed by TLC, and H2O (20 mL) was added. An
increase in the white precipitate was noted and the mixture was
stirred for 19 h. The solid was filtered by suction, washed with H2O
(100 mL), and dried in vacuum. Amide 4k was obtained as a white
solid (1.1792 g, 72%); mp 139 °C; colorless powder after recrystallized
from MeOH. The product was pure enough to give a satisfactory com-
bustion analysis without further purification.
1H NMR (400 MHz, CDCl3): δ = 8.731 (1 H, dd, J = 2.5, 0.7 Hz), 8.084 (1
H, dd, J = 8.3, 2.5 Hz), 7.390 (1 H, dd, J = 8.3, 0.7 Hz), 7.257 (2 H, ddd,
J = 8.3, 3.2, 1.9 Hz), 6.871 (2 H, ddd, J = 8.8, 2.9, 2.0 Hz), 6.631 (1 H, br),
4.557 (2 H, d, J = 5.4 Hz), 3.796 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 164.49, 159.42, 154.36, 148.05,
140.16, 138.18, 129.55, 129.12, 124.52, 114.372, 55.45, 43.97.
Anal. Calcd for C14H12ClNO: C, 68.44; H, 4.92; N, 5.70. Found: C, 68.23;
H, 5.15; N, 5.73.
Amide Formation of 4i (Figure 1)
To a pre-cooled solution of acid chloride 3-4i (1.5871 g, 10.02 mmol)
in DMAC (5 mL) at 0 °C (ice-water bath) was added a solution of
amine 2-4i (2.0790 g, 10.54 mmol) in DMAC (5 mL) over 3 min and
the mixture was stirred at 0 °C for 3 min. A white precipitate was
formed. The ice-water bath was replaced with a water bath and the
mixture was stirred at 23 °C for 18 h. The completion of the reaction
was confirmed by TLC. H2O (30 mL) was added to the reaction vessel,
the resultant white precipitate was collected by suction filtration,
washed with H2O, and dried in vacuum. The product was contaminat-
ed with 4-fluorobenzoic acid. Therefore, the solid was dissolved in
CH2Cl2 (100 mL), and the organic layer was washed with sat. aq NaH-
CO3 (50 mL) and brine (40 mL), and dried (MgSO4). Evaporation of the
solvent gave 4i as a white power (2.2358 g, 70%); mp 93–95 °C. The
product was pure enough to give a satisfactory combustion analysis
without further purification.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H14ClN2O2+: 277.0738;
found: 277.0731.
Anal. Calcd for C14H13ClN2O2: C, 60.77; H, 4.74; N, 10.12. Found: C,
60.68; H, 4.87; N, 10.10.
1H NMR (400 MHz, CDCl3): δ = 7.497 (2 H, dd, J = 8.8, 5.2 Hz), 7.377–
7.137 (10 H, m), 7.051 (2 H, t, J = 8.8 Hz), 4.697 (2 H, s), 4.406 (2 H, s).
Amide Formation of 4l (Figure 1)
1
13C NMR (100 MHz, CDCl3): δ = 171.29, 163.3 (d, JC,F = 248 Hz),
A solution of acid chloride 3-4l (1.4187 g, 10.09 mmol) in DMAC (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). A solution
of amine 2-4l (1.4443 g, 10.53 mmol) in DMAC (5 mL) was added over
4 min with stirring at 0 °C. A white precipitate was formed and the
mixture was stirred at 0 °C for 10 min. The ice-water bath was re-
placed with a water bath and the mixture was stirred at 23 °C for 1.5
h. The completion of the reaction was confirmed by TLC, and H2O (30
mL) was added. The white precipitate formed was dissolved and was
formed again. The mixture was stirred for 17 h. The solid was filtered
by suction, washed with H2O (100 mL), and dried in vacuum. Amide
4l was obtained as a white solid (1.2393 g, 51%); mp 96–98 °C (pre-
cipitate, colorless fine needles); mp 101 °C (colorless needles, recrys-
tallized from MeOH). The product was pure enough to give a satisfac-
tory combustion analysis without further purification.
136.72, 136.24, 132.13, 132.09, 129.02, 128.94, 128.80, 128.39,
127.62, 126.83, 115.6 (2JC,F = 22 Hz), 51.57, 47.15.
Anal. Calcd for C21H18FNO: C, 78.98; H, 5.68; N, 4.39. Found: C, 78.73;
H, 5.92; N, 4.39.
Amide Formation of 4j (Figure 1)
A solution of acid chloride 3-4j (1.5893 g, 10.02 mmol) in DMAC (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). A solution
of amine 2-4j (1.4865 g, 10.50 mmol) in DMAC (5 mL) was added over
5 min with stirring at 0 °C. The mixture was stirred at 0 °C for 10 min.
The ice-water bath was replaced with a water bath and the mixture
was stirred at 23 °C for 2 h. The completion of the reaction was con-
firmed by TLC, and H2O (30 mL) was added. A white precipitate was
formed and the mixture was stirred for 13 h. The solid was filtered by
suction, washed with H2O (100 mL), and dried in vacuum. Amide 4j
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1H NMR (400 MHz, CDCl3): δ = 8.127 (1 H, dd, J = 9.0, 5.4 Hz), 7.790 (2
H, dd, J = 8.9, 5.3 Hz), 7.285 (2 H, ddd, J = 8.7, 3.0, 2.1 Hz), 7.177–7.072
(3 H, m), 6.891 (2 H, ddd, J = 8.7, 3.0, 2.1 Hz), 4.573 (2 H, d, J = 5.4 Hz),
3.808 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 167.25, 159.04, 134.38, 131.43,
130.23, 129.24, 128.50, 126.91, 114.08, 55.26, 43.56.
Anal. Calcd for C9H10ClNO: C, 58.87; H, 5.49; N, 7.63. Found (precipi-
tate): C, 58.78; H, 5.56; N, 7.60.
Amide Formation of 4o (Figure 1)
To a pre-cooled solution of acid chloride 3-4o (1.1235 g, 9.95 mmol)
in DMAC (5 mL) at 0 °C (ice-water bath) was added a solution of
amine 2-4o (1.2549 g, 10.53 mmol) in DMAC (5 mL) over 5 min at
0 °C. A large amount of white precipitate was immediately formed.
The resultant precipitate was collected by suction filtration, and the
solid was dried in vacuum to give 4o as colorless needles (1.7290 g,
89%); mp 135–136 °C. The product was pure enough to give a satisfac-
tory combustion analysis without further purification.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H15NO2Na+: 264.09950;
found: 264.09937.
Anal. Calcd for C15H15NO2: C, 74.67; H, 6.27; N, 5.81. Found (precipi-
tate): C, 74.66; H, 6.38; N, 5.70. Found (crystal): C, 74.46; H, 6.38; N,
5.83.
1H NMR (400 MHz, CDCl3): δ = 8.202 (1 H, d, J = 8.0 Hz), 7.213 (2 H, dd,
J = 8.8, 8.0 Hz), 7.060 (1 H, dd, J = 7.6, 7.2 Hz), 4.153–4.111 (4 H, m),
3.225 (2 H, t, J = 8.4 Hz).
13C NMR (100 MHz, CDCl3): δ = 163.89, 142.40, 131.13, 127.61,
124.60, 124.43, 117.23, 47.77, 43.09, 28.11.
Amide Formation of 4m (Figure 1)
A solution of acid chloride 3-4m (1.5893 g, 10.02 mmol) in DMAC (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). A solution
of amine 2-4m (1.4391 g, 10.49 mmol) in DMAC (5 mL) was added
over 4 min with stirring at 0 °C. A white precipitate was formed and
the mixture was stirred at 0 °C for 10 min. The ice-water bath was re-
placed with a water bath and the mixture was stirred at 23 °C for 1.5
h. The completion of the reaction was confirmed by TLC, and H2O (30
mL) was added. The white precipitate formed was dissolved and was
formed again. The mixture was stirred for 18 h. The solid was filtered
by suction, washed with H2O (100 mL), and dried in vacuum. Amide
4m was obtained as a white solid (1.7441 g, 67%)mp 117–118 °C
(colorless plates after recrystallized from MeOH). The product was
pure enough to give a satisfactory combustion analysis without fur-
ther purification.
1H NMR (400 MHz, CDCl3): δ = 7.778 (2 H, d, J = 7.0 Hz), 7.497 (1 H, t,
J = 7.3 Hz), 7.420 (2 H, d, d, J = 7.8, 5.4 Hz), 7.290 (2 H, d, J = 8.8 Hz),
6.889 (2 H, d, J = 8.7 Hz), 4.580 (2 H, d, J = 5.6 Hz), 3.806 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 166.18, 165.92, 163.42, 159.12,
130.58, 130.55, 130.08, 129.28, 129.20, 115.65, 115.43, 114.13, 55.28,
43.66.
HRMS (ESI-TOF): m/z [N + Na]+ calcd for C10H10ClNONa+: 218.03431;
found: 218.03411.
Anal. Calcd for C10H10ClNO: C, 61.39; H, 5.15; N, 7.16. Found: C, 61.13;
H, 5.26; N, 7.15.
Amide Formation of 4p (Figure 1)
A solution of acid chloride 3-4p (1.5672 g, 9.88 mmol) in DMAC (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). While stir-
ring and cooling at 0 °C, a solution of amine 2-4p (1.7920 g, 10.42
mmol) in DMAC (5 mL) was added over 4 min. The mixture was
stirred at 0 °C for 10 min. The ice-water bath was replaced with a wa-
ter bath and the mixture was stirred at 23 °C for 3 h. The completion
of the reaction was confirmed by TLC, and H2O (30 mL) was added. A
white precipitate was formed and the mixture was stirred for 15 h.
The solid was filtered by suction, washed with H2O (100 mL) and
dried in vacuum. Amide 4p was obtained as a white solid (2.7391 g,
94%); mp 168–176 °C (colorless needles after recrystallization from
MeOH). The product was pure enough to give a satisfactory combus-
tion analysis without further purification
1H NMR (400 MHz, CDCl3): δ = 7.878 (2 H, dd, J = 8.9, 5.2 Hz), 7.741 (1
H, br s), 7.511 (4 H, dddd, J = 10.4, 9.1, 2.4, 2.4 Hz), 7.177 (2 H, dd, J =
8.8, 8.4 Hz).
13C NMR (100 MHz, DMSO-d6): δ = 164.52, 164.13 (1JC,F = 248 Hz),
138.47, 131.44, 131.12, 131.09, 130.48, 130.39, 122.23, 115.40, 115.4
(2JC,F = 22 Hz).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H14FNO2Na+: 282.09008;
found: 282.08946.
Anal. Calcd for C15H14FNO2: C, 69.49; H, 5.44; N, 5.40. Found (crystal):
C, 69.37; H, 5.63; N, 5.44.
Amide Formation of 4n (Figure 1)
To a pre-cooled solution of acid chloride 3-4n (1.1219 g, 9.93 mmol)
in DMAC (5 mL) at 0 °C (ice-water bath) was added a solution of
amine 2-4n (1.1122 g, 10.38 mmol) in DMAC (5 mL) over 3 minand
the mixture was stirred at 0 °C for 10 min. A white precipitate was
formed. The ice-water bath was replaced with a water bath and the
mixture was stirred at 23 °C for 5 h. H2O (30 mL) was added to the
reaction vessel, and a white precipitate appeared. The whole was
stirred for 1 h at 23 °C. The resultant precipitate was collected by suc-
tion filtration, and the solid was washed with H2O (60 mL), and dried
in vacuum. Amide 4n was obtained as a white solid (1.1619 g, 64%);
mp 67–68 °C (colorless plates after recrystallization from toluene).
The product was pure enough to give a satisfactory combustion anal-
ysis without further purification.
1H NMR (400 MHz, CDCl3): δ = 7.459 (2 H, dd, J = 7.7, 7.0 Hz), 7.270–
7.255 (1 H, m), 7.260–7.240 (2 H, m), 3.851 (2 H, s), 3.322 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 166.4, 142.8, 130.2, 128.7, 127.2, 41.7,
38.1.
HRMS (ESI-TOF): m/z [N + Na]+ calcd for C9H10ClNONa+: 206.0343;
found: 206.0345.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H10BrFNO+: 293.9924;
found: 293.9920.
Anal. Calcd for C13H9BrFNO: C, 53.09; H, 3.08; N, 4.76. Found: C,
53.08; H, 3.34; N, 4.73.
Amide Formation of 4q (Figure 1)
A solution of acid chloride 3-4q (1.6248 g, 10.25 mmol) in DMAC (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). A solution
of amine 2-4q (1.2728 g, 10.68 mmol) in DMAC (5 mL) was added
over 5 min with stirring at 0 °C. A white precipitate was formed im-
mediately and the mixture was stirred at 0 °C for 10 min. The ice bath
was replaced with a water bath and the mixture was stirred at 23 °C
for 2 h. The completion of the reaction was confirmed by TLC, and
H2O (20 mL) was added. The preformed precipitate was dissolved
once and another white precipitate was formed. The mixture was
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R. Otsuka et al.
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stirred overnight. The solid was filtered by suction, washed with H2O
(100 mL), and dried in vacuum to give 4q (2.2605 g, 91%) as a white
solid; mp 104–105 °C (pale red powder); mp 101–102 °C (colorless
rods after recrystallization from MeOH). The product was pure
enough to give a satisfactory combustion analysis without further pu-
rification.
1H NMR (400 MHz, CDCl3): δ = 8.064 (3 H, d, J = 6.8 Hz), 7.882 (2 H, d,
J = 6.8 Hz), 7.750 (2 H, d, J = 8.8 Hz), 7.573 (1 H, dd, J = 7.6, 7.2 Hz),
7.495 (2 H, dd, J = 8.4, 8.0 Hz), 4.097 (2 H, d, J = 6.4 Hz), 2.088 (1 H,
sept, J = 6.8 Hz), 1.023 (6 H, d, J = 6.8 Hz).
13C NMR (100 MHz, CDCl3): δ = 166.12, 165.80, 142.04, 134.53,
132.20, 130.83, 128.88, 127.07, 126.20, 119.18, 70.96, 27.89, 19.20.
1H NMR (400 MHz, CDCl3): δ = 8.850–7.600 (1 H, br), 7.500 (2 H, dd,
J = 8.4, 5.6 Hz), 7.154 (2 H, dd, J = 11.6, 7.6 Hz), 7.057 (2 H, dd, J = 8.6,
8.6 Hz), 6.958 (1 H, d, J = 6.4 Hz), 4.010 (2 H, br), 3.050 (2 H, t, J = 8.4
Hz).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C18H19NO3Na+: 320.12571;
found: 320.12618.
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.42;
H, 6.57; N, 4.77.
1
13C NMR (400 MHz, CDCl3): δ = 168.0, 163.9 (d, JC,F= 249 Hz), 142.6,
2
133.1, 132.5, 129.7, 129.6, 127.3, 125.1, 124.1, 115.7 (d, JC,F= 22 Hz),
Amide Formation of 5a-2 (Figure 2)
50.8, 28.2.
A solution of acid chloride 3-5a2 (1.3828 g, 9.87 mmol) in DMAC (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). A solution
of amine 2a (1.8565 g, 10.36 mmol) in DMAC (5 mL) was added over 3
min with stirring at 0 °C and the mixture was stirred at 0 °C for 10
min. The ice-water bath was replaced with a water bath and the mix-
ture was stirred at 23 °C for 3 h. After the addition of H2O (30 mL), the
mixture was extracted with CH2Cl2 (4 × 20 mL), the combined organic
fractions were washed with H2O (3 × 50 mL), and dried (MgSO4). The
solvent was evaporated to give the amide 5a-2 as a white solid, which
was dried in vacuum (2.6013 g, 93%); mp 97–99 °C (colorless needles,
after recrystallization from MeOH). The product was pure enough to
give a satisfactory combustion analysis without further purification.
1H NMR (400 MHz, CDCl3): δ = 8.210 (1 H, s), 8.028 (2 H, d, J = 8.6 Hz),
7.872 (2 H, d, J = 7.4 Hz), 7.745 (2 H, d, J = 8.6 Hz), 7.552 (1 H, dd, J =
7.2, 7.1 Hz), 7.467 (2 H, dd, J = 7.8, 7.7 Hz), 5.232 (1 H, sept, J = 6.2 Hz),
1.365 (6 H, d, J = 6.2 Hz).
13C NMR (100 MHz, CDCl3): δ = 166.05, 165.79, 142.16, 134.68,
132.29, 130.90, 128.97, 127.24, 126.70, 119.31, 68.46, 22.10.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H12FNONa+: 264.0795;
found: 264.0791.
Anal. Calcd for C15H12FNO: C, 74.68; H, 5.01; N, 5.81. Found: C, 74.47;
H, 5.03; N, 5.88.
Amide Formation of 4r (Figure 1)
A solution of acid chloride 3-4r (1.0557 g, 6.00 mmol) in DMAC (3 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2-4r (0.7543 g, 6.33 mmol) in DMAC (3 mL) was added over 3
min with stirring at 0 °C. The mixture was stirred at 0 °C for 4 min.
The ice-water bath was replaced with a water bath and the mixture
was stirred at 23 °C for 45 min. The completion of the reaction was
confirmed by TLC, and H2O (20 mL) was added. A white precipitate
was formed and the mixture was stirred for 17 h. The solid was fil-
tered by suction, washed with H2O (100 mL), and dried in vacuum.
Amide 4r was obtained as a white solid (1.3105 g, 84%); mp 132–
134 °C (colorless prisms, after recrystallization from MeOH). The
product was pure enough to give a satisfactory combustion analysis
without further purification.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H17NO3Na+: 306.1101;
found: 306.1115.
1H NMR (400 MHz, CDCl3): δ = 8.613 (1 H, d, J = 2.0 Hz), 8.188 (1 H, br
s), 7.873 (1 H, dd, J = 8.2, 2.4 Hz), 7.442 (1 H, dd, J = 8.2, 0.7 Hz), 7.245
(2 H, d, J = 7.8 Hz), 7.079 (1 H, br s), 4.087 (2 H, br s), 3.167 (2 H, t, J =
8.2 Hz).
Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 71.89;
H, 6.16; N, 4.98.
Amide Formation of 5b (Figure 2)
13C NMR (100 MHz, CDCl3): δ = 165.2, 153.3, 148.5, 142.3, 137.9,
To a pre-cooled solution of acid chloride 3-5b (1.4040 g, 9.99 mmol)
in DMAC (5 mL) at 0 °C (ice-water bath) was added a solution of
amine 2-5b (1.5264 g, 10.10 mmol) in DMAC (5 mL) over 2 min and
the mixture was stirred at 0 °C for 10 min. A white precipitate was
formed. The ice-water bath was replaced with a water bath and the
mixture was stirred at 23 °C for 1.5 h. The completion of the reaction
was confirmed by TLC. H2O (50 mL) was added to the reaction vessel,
and the resultant precipitate was collected by suction filtration,
washed with H2O, and dried in vacuum. Amide 5b was obtained as a
white solid (2.2723 g, 89%); mp 99–100 °C (white powder after re-
crystallization from water-DMAC). The product was pure enough to
give a satisfactory combustion analysis without further purification.
1H NMR (400 MHz, CDCl3): δ = 12.044 (1 H, s), 8.931 (1 H, s), 8.068 (3
H, dd, J = 10.0, 8.8 Hz), 7.068 (1 H, ddd, J = 8.8, 7.2, 1.6 Hz), 7.563–
7.511 (3 H, m), 7.123 (1 H, dd, J = 8.0, 7.6 Hz), 3.962 (3 H, s).
13C NMR (100 MHz, CDCl3): δ = 169.04, 165.69, 141.85, 134.81,
131.92, 130.92, 128.78, 127.35, 122.58, 120.43, 115.12, 52.45.
131.8, 127.6, 125.2, 124.8, 124.5, 50.8, 28.3.
HRMS (ESI-TOF): m/z [N + H]+ calcd for C14H12ClN2O+: 259.0633;
found: 259.0647.
Anal. Calcd for C14H11ClN2O: C, 65.00; H, 4.29; N, 10.83. Found: C,
64.62; H, 4.50; N, 10.85.
Amide Formation of 5a-1 (Figure 2)
To a pre-cooled solution of acid chloride 3-5a1 (1.4072 g, 10.01
mmol) in DMAC (5 mL) at 0 °C (ice-water bath) was added a solution
of amine 2-5a1 (1.9390 g, 10.03 mmol) in DMAC (5 mL) was added
over 3 min and the mixture was stirred at 0 °C (ice-water bath) for 20
min. A white precipitate was formed. The ice-water bath was replaced
with a water bath and the mixture was stirred at 23 °C for 2.5 h. The
completion of the reaction was confirmed by TLC. H2O (40 mL) was
added to the reaction vessel, and the resultant precipitate was collect-
ed by suction filtration, and washed with H2O, and dried in vacuum.
Amide 5a-1 was obtained as a white solid (2.8470 g, 96%); mp 128.5–
129.0 °C (colorless needles after recrystallization from water-DMAC).
The product was pure enough to give a satisfactory combustion anal-
ysis without further purification.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C15H13NO3Na+: 278.07876;
found: 278.07938.
Anal. Calcd for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.41;
H, 5.24; N, 5.51.
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Amide Formation of 5c (Figure 2)
(pale green powder after recrystallization from water-DMAC). The
product was pure enough to give a satisfactory combustion analysis
without further purification.
1H NMR (400 MHz, DMSO-d6): δ = 10.820 (1 H, br s), 8.279 (2 H, d, J =
9.2 Hz), 8.079 (2 H, d, J = 9.2 Hz), 8.079 (2 H, d, J = 9.6 Hz), 7.990 (2 H,
d, J = 7.6 Hz), 7.654 (2 H, dd, J = 7.2, 7.2 Hz), 7.572 (2 H, dd, J = 8.0, 8.0
Hz).
13C NMR (100 MHz, DMSO-d6): δ = 166.29, 145.51, 142.46, 134.23,
132.18, 128.52, 127.92, 124.80, 119.83.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H10N2O3Na+: 265.05836;
found: 265.05815.
A solution of acid chloride 3-5c (1.4035 g, 9.99 mmol) in DMAC (5 mL)
was prepared at r.t. The solution was transferred to a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). While stirring and
cooling at 0 °C, a solution of amine 2-5c (1.4482 g, 10.49 mmol) in
DMAC (5 mL) was added over 3 min, and the mixture was stirred at
0 °C for 10 min. The ice-water bath was replaced with a water bath
and the mixture was stirred at 23 °C for 4 h. The completion of the
reaction was confirmed by TLC, and H2O (30 mL) was added. A yellow
precipitate was formed and the mixture was stirred for 21 h. The solid
was filtered by suction, washed with H2O (100 mL), and dried in vacu-
um. Amide 5c was obtained as a white solid (2.1020 g, 87%); mp 94 °C
(yellow needles after recrystallization from water-DMAC). The prod-
uct was pure enough to give a satisfactory combustion analysis with-
out further purification.
Anal. Calcd for C13H10N2O3: C, 64.46; H, 4.16; N, 11.56. Found: C,
64.26; H, 4.29; N, 11.60.
1H NMR (400 MHz, CDCl3): δ = 9.015 (1 H, dd, J = 8.5, 1.3 Hz), 8.288 (1
H, dd, J = 8.5, 1.5 Hz), 8.005 (2 H, d, J = 6.9 Hz), 7.725 (1 H, td, J = 7.9,
1.5 Hz), 7.617 (1 H, dd, J = 7.4, 7.2 Hz), 7.548 (2 H, dd, J = 7.6, 7.0 Hz),
7.231 (1 H, ddd, J = 7.9, 7.8, 1.3 Hz).
13C NMR (100 MHz, CDCl3): δ = 165.92, 136.61, 136.37, 135.51,
134.19, 132.81, 129.21, 127.52, 126.08, 123.47, 122.29.
Amide Formation of 5f (Figure 2)
A solution of acid chloride 3-5f (1.4051 g, 10.00 mmol) in DMAC (5
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). While stir-
ring and cooling at 0 °C, a solution of amine 2-5f (1.2370 g, 10.47
mmol) in DMAC (5 mL) was added over 4 min. The mixture was
stirred at 0 °C for 10 min. The ice-water bath was replaced with a wa-
ter bath and the mixture was stirred at 23 °C for 2 h. The completion
of the reaction was confirmed by TLC, and H2O (30 mL) was added. A
white precipitate was formed and the mixture was stirred for 15 h.
The solid was filtered by suction, washed with water (100 mL), and
dried in vacuum. Amide 5f was obtained as a white solid was ob-
tained (2.1417 g, 96%); mp 165–167 °C (colorless powder after recrys-
tallized from MeOH). The product was pure enough to give a satisfac-
tory combustion analysis without further purification.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H10N2O3Na+: 265.0584;
found: 265.0587.
Anal. Calcd for C13H10N2O3: C, 64.46; H, 4.16; N, 11.56. Found: C,
64.22; H, 4.38; N, 11.51.
Amide Formation of 5d (Figure 2)
To a pre-cooled solution of acid chloride 3-5d (1.4071 g, 10.01 mmol)
in DMAC (5 mL) at 0 °C (ice-water bath) was added a solution of
amine 2a-5d (1.3863 g, 10.04 mmol) in DMAC (5 mL) over 1 min and
the mixture was stirred at 0 °C for 20 min. The ice-water bath was re-
placed with a water bath and the mixture was stirred at 23 °C for 1.5
h. H2O (20 mL) was added to the reaction vessel, and the resultant
white precipitate was collected by suction filtration, and washed with
H2O, and dried in vacuum. Amide 5d was obtained as a white solid
(2.3405 g, 97%); mp 158–159 °C (colorless fine needles after recrys-
tallization from water-DMAC). The product was pure enough to give a
satisfactory combustion analysis without further purification.
1H NMR (400 MHz, DMSO-d6): δ = 10.717 (1 H, s), 8.835 (1 H, dd, J =
2.0, 2.0 Hz), 8.220 (1 H, ddd, J = 8.0, 2.4, 0.8 Hz), 8.020 (2 H, d, J = 8.0
Hz), 8.969 (1 H, ddd, J = 8.0, 2.4, 0.8 Hz), 7.645 (2 H, dd, J = 7.2, 6.8 Hz),
7.578 (2 H, dd, J = 7.2, 6.8 Hz).
13C NMR (100 MHz, DMSO-d6): δ = 166.04, 147.89, 140.39, 134.24,
132.03, 130.02, 128.50, 127.78, 126.13, 118.09, 114.32.
1H NMR (400 MHz, CDCl3): δ = 8.027 (1 H, br s), 7.876 (2 H, d, J = 7.0
Hz), 7.801 (2 H, d, J = 8.9 Hz), 7.662 (2 H, d, J = 8.8 Hz), 7.601 (1 H, dd,
J = 7.6, 7.3 Hz), 7.518 (2 H, dd, J = 7.7, 7.2 Hz).
13C NMR (100 MHz, CDCl3): δ = 166.2, 143.5, 134.4, 133.1, 132.1,
128.5, 127.9, 120.2, 119.1, 105.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H10N2ONa+: 245.0685;
found: 245.0688.
Anal. Calcd for C14H10N2O : C, 75.66; H, 4.54; N, 12.60. Found: C,
75.63; H, 4.69; N, 12.62.
Amide Formation of 6a (Scheme 2)
To a pre-cooled solution of acid chloride 3-6a (1.4057 g, 10.00 mmol)
in DMAC (5 mL), a solution of amine 2-6a (1.3716 g, 10.00 mmol) in
DMAC (5 mL) was added over 5 min at 0 °C (ice-water bath) and the
mixture was stirred at 0 °C for 5 min. The ice-water bath was replaced
with a water bath and the mixture was stirred at 23 °C for 1.5 h. H2O
(40 mL) was added to the reaction vessel, and the white precipitate
was collected by suction filtration, washed with H2O, and dried in
vacuum. Amide 6a was obtained as a white solid (2.2910 g, 95%); mp
182.2–183 °C (coloress fine needles after recrystallization from
water-DMAC). The product was pure enough to give a satisfactory
combustion analysis without further purification.
1H NMR (400 MHz, DMSO-d6): δ = 13.817 (1 H, br s), 12.204 (1 H, s),
8.742 (1 H, dd, J = 8.6, 1.2 Hz), 8.082 (1 H, dd, J = 7.8, 2.0 Hz), 7.981 (2
H, dd, J = 7.8, 1.2 Hz), 7.683 (1 H, td, J = 8.0, 1.6 Hz), 7.647 (1 H, td, J =
7.2, 1.6 Hz), 7.608 (2 H, td, J = 6.8, 1.6 Hz), 7.227 (1 H, t, d, J = 7.4,
1.2Hz).
HRMS (ESI-TOF): m/z [N + Na]+ calcd for C13H10N2O3Na+: 265.05836;
found: 265.05828.
Anal. Calcd for C13H10N2O3: C, 64.46; H, 4.16; N, 11.56. Found: C,
64.66; H, 4.38; N, 11.65.
Amide Formation of 5e (Figure 2)
To a pre-cooled solution of acid chloride 3-5e (1.4028 g, 9.98 mmol)
in DMAC (5 mL) at 0 °C (ice-water bath) was added a solution of
amine 2a-5e (1.4101 g, 10.20 mmol) in DMAC (5 mL) over 3 min and
the mixture was stirred at 0 °C for 2 h. H2O (50 mL) was added to the
reaction vessel, and the white precipitate formed was collected by
suction filtration, and washed with H2O, and dried in vacuum. Amide
5e was obtained as a white solid (2.3573 g, 98%); mp 201–202 °C
13C NMR (100 MHz, DMSO-d6): δ = 170.04, 164.70, 141.14, 134.54,
134.35, 132.20, 131.30, 129.00, 127.03, 122.95, 119.89, 116.51.
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HRMS (ESI-TOF): [M – H]– calcd for C14H10NO3–: 240.06662; found:
240.06760.
ture was stirred at 23 ° C for 26 h. MeOH (5 mL) was added to the re-
action vessel and the mixture was stirred for 5 h. Aq 2 M HCl (5 mL)
was added and the mixture was extracted with Et2O (3 × 30 mL). The
combined organic fractions were dried (MgSO4) and the solvent was
evaporated to afford a colorless liquid (1.8638 g), which was open-
chromatographed (CHCl3/MeOH/AcOH 90:10:1) to give the amide 6d
(1.6565 g, 75%); mp 133–136 °C (colorless rods after recrystallization
from water-DMAC). The product was pure enough to give a satisfacto-
ry combustion analysis without further purification.
1H NMR (400 MHz, CDCl3): δ = 9.393 (1 H, br s), 7.812 (2 H, d, J = 6.9
Hz), 7.535 (1 H, dd, J = 7.5, 7.2 Hz), 7.458 (2 H, dd, J = 7.6, 7.5 Hz),
6.644 (1 H, d, J = 8.4 Hz), 4.810 (1 H, dd, J = 8.5, 4.8 Hz), 2.414–2.334 (1
H, m), 1.056 (6 H, dd, J = 10.3, 6.9 Hz).
Anal. Calcd for C14H11NO3: C, 69.70; H, 4.60; N, 5.81. Found: C, 69.93;
H, 4.82; N, 5.90.
Amide Formation of 6b (Scheme 2)
To a pre-cooled solution of acid chloride 3-6b (1.4039 g, 9.99 mmol)
in DMAC (5 mL) at 0 °C (ice-water bath) was added the neat amino
acid 2-6b (748.0 mg, 9.96 mmol) over 1 min at 0 °C and the mixture
was stirred at 0 °C for 20 min. The ice-water bath was replaced with a
water bath and the mixture was stirred at 23 °C for 4 h. The comple-
tion of the reaction was confirmed by TLC. H2O (11 mL) was added to
the reaction vessel, and the resultant precipitate was collected by suc-
tion filtration, and dried in vacuum. Amide 6b was obtained as a
white solid (1.2561 g, 70%); mp 190.5–190.7 °C (colorless fine needles
after recrystallization from water-DMAC). The product was pure
enough to give a satisfactory combustion analysis without further pu-
rification.
1H NMR (400 MHz, DMSO-d6): δ = 12.611 (1 H, br s), 8.847 (1 H, t, J =
5.8 Hz), 7.881 (2 H, d, J = 7.2 Hz), 7.551 (1 H, dd, J = 7.6, 7.2 Hz), 7.483
(2 H, dd, J = 7.6, 6.8 Hz), 3.938 (2 H, d, J = 6.0 Hz).
13C NMR (100 MHz, DMSO-d6): δ = 171.39, 166.51, 133.86, 131.46,
128.39, 127.27, 41.25.
13C NMR (100 MHz, CDCl3): δ = 175.80, 168.28, 133.88, 132.11,
128.80, 127.28, 57.70, 31.45, 19.16, 17.94.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H15NO3Na+: 244.0944;
found: 244.0947.
Anal. Calcd for C12H15NO3: C, 65.14; H, 6.83; N, 6.33. Found: C, 64.97;
H, 6.93; N, 6.43.
Experiments of Table 4
Formation of Amide 4s
HRMS (ESI-TOF): m/z [M – H]– calcd for C9H8NO3–: 178.05097; found:
178.05185.
A solution of acid chloride 3b (1.4129 g, 10.05 mmol) in DMAC (5 mL)
was prepared at r.t. The solution was transferred into a 30 mL round-
bottomed flask and cooled to 0 °C (ice-water bath). A solution of
amine 2d (0.9779 g, 10.50 mmol) in DMAC (5 mL) was added over 3
min with stirring at 0 °C. The mixture was stirred at 0 °C for 10 min.
The ice bath was replaced with a water bath and the mixture was
stirred at 23 °C for 2 h. The completion of the reaction was confirmed
by TLC, and H2O (30 mL) was added. A white precipitate was formed
and the mixture was stirred for 2 h. The solid was filtered by suction,
washed with H2O (100 mL), and dried in vacuum to give 4s (1.8857 g,
95%) as a white solid. mp 164–166 °C (colorless plates after recrystal-
lized from MeOH). The product was pure enough to give a satisfactory
combustion analysis without further purification.
1H NMR (400 MHz, CDCl3): δ = 7.877 (2 H, d, J = 6.9 Hz), 7.807 (1 H, br
s), 7.647 (2 H, d, J = 8.4 Hz), 7.562 (1 H, t, J = 7.3 Hz), 7.497 (2 H, dd, J =
7.6, 7.0 Hz), 7.384 (2 H, dd, J = 8.5, 7.5 Hz), 7.162 (1 H, t, J = 7.4 Hz).
13C NMR (100 MHz, CDCl3): δ = 165.84, 138.05, 135.17, 132.02,
129.28, 128.97, 127.15, 124.74, 120.31.
Anal. Calcd for C9H9NO3 + 0.1H2O: C, 59.73; H, 5.12; N, 7.74. Found: C,
59.85; H, 5.02; N, 7.87.
Amide Formation of 6c (Scheme 2)
A solution of acid chloride 3-6c (1.4031 g, 9.98 mmol) in DMAC (10
mL) was prepared at r.t. The solution was transferred to a 30 mL
round-bottomed flask and cooled to 0 °C (ice-water bath). While stir-
ring and cooling at 0 °C, neat valine (2-6c; 1.7290 g, 10.47 mmol) was
added over 9 min at 0 °C and the mixture was stirred at 0 °C for 10
min. The ice-water bath was replaced with a water bath and the mix-
ture was stirred at 23 °C for 21 h. H2O (30 mL) was added to give a
white precipitate and the mixture was stirred for 7 h. The solid was
filtered by suction, washed with H2O (150 mL), and dried in vacuum.
Amide 6c was obtained as a white solid (2.0819 g, 77%): mp 137–
138 °C (white powder after recrystallization from water-DMAC). The
product was pure enough to give a satisfactory combustion analysis
without further purification.
1H NMR (400 MHz, CDCl3): δ = 7.687 (2 H, d, J = 7.0 Hz), 7.519 (1 H, t,
J = 7.4 Hz), 7.421 (2 H, dd, J = 7.8, 7.2 Hz), 7.341–7.274 (3 H, m), 7.213
(2 H, d, J = 6.3 Hz), 6.546 (1 H, d, J = 7.2 Hz), 5.082 (1 H, ddd, J = 7.3,
7.3, 7.3 Hz), 3.376 (1 H, dd, J = 38.6, 5.6 Hz), 3.280 (1 H, dd, J = 38.6, 5.6
Hz).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C13H11NONa+: 220.0733;
found: 220.0703.
Anal. Calcd for C13H11NO: C, 79.17; H, 5.62; N, 7.10. Found: C, 78.92;
H, 5.85; N, 7.13.
Amide Formation (Table 4, run 1)
13C NMR (100 MHz, CDCl3): δ = 174.9, 167.9, 135.8, 133.6, 132.2,
A 30 mL round-bottomed flask equipped with a stirring bar was
charged with an aromatic amine 2d (0.4918 g, 5.28 mmol) and an ali-
phatic amine 2a (0.7054 g, 5.14 mmol). The flask was immersed into
an ice-water bath (0 °C). DMAC (5 mL) and AcOH (1.2331 g, 20.54
mmol) were added with stirring. A solution of acid chloride 3b
(0.7039 g, 5.008 mmol) in DMAC (5 mL) was added over 7 min at 0 °C
and the mixture was stirred at 0 °C for 25 min. The ice-water bath was
replaced with a water bath and the mixture was stirred at 23 °C for 3
h. H2O (30 mL) was added to give a white precipitate and the mixture
was stirred for 1 h. The solid was filtered by suction, washed with H2O
(60 mL), and dried in vacuum. The mixture of the amide products was
separated by column chromatography (EtOAc/n-hexane 1:4). The ra-
129.6, 128.9, 128.8, 127.5, 127.2, 57.8, 37.4.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H15NO3Na+: 292.0944;
found: 292.0959.
Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.04;
H, 5.80; N, 5.28.
Amide Formation of 6d (Scheme 2)
To a pre-cooled solution of acid chloride 3-6d (1.3990 g, 9.95 mmol)
in DMAC (10 mL) at 0 °C (ice-water bath) was added the amino acid 2-
6d (1.2298 g, 10.50 mmol) and the mixture was stirred at 0 °C for 10
min. The ice-water bath was replaced with a water bath and the mix-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Q

P
R. Otsuka et al.
Paper
Synthesis
tio of the amides was determined by the integration of 1H NMR sig-
nals in comparison of the authentic amides 4s (see above) and 4l (see
Table 4). Yields of the products were 0.7727g (78%) for 4s and 0.0944
g (8%) for 4l, respectively.
Funding Information
This work was supported financially by the University of Tokyo. All
authors acknowledge this support.
)(
Amide Formation (Table 4, run 2)
Supporting Information
A 30 mL round-bottomed flask equipped with a stirring bar was
charged with an aromatic amine 2d (0.4865 g, 5.22 mmol) and ali-
phatic amine 2a (0.7059 g, 5.15 mmol). The flask was immersed into
an ice-water bath (0 °C). DMAC (5 mL) and AcOH (3.0567 g, 50.90
mmol) were added with stirring. A solution of acid chloride 3b
(0.7048 g, 5.01 mmol) in DMAC (5 mL) was added over 3 min and the
mixture was stirred at 0 °C for 10 min. The ice-water bath was re-
placed with a water bath and the whole was stirred at 23 °C for 3 h.
H2O (40 mL) was added to give a white precipitate and the mixture
was stirred for 3 h. The solid was filtered by suction, washed with H2O
(80 mL), and dried in vacuum to give 4s (0.9090 g, 92%). The product
was identical with the authentic compound in terms of 1H NMR (CD-
Cl3) and combustion analysis.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609342.
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References
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Amide Formation (Table 4, run 3)
A 30 mL-round-bottomed flask equipped with a stirring bar was
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H2O (100 mL), and dried in vacuum. The mixture of the amide prod-
ucts was separated by column chromatography (EtOAc/n-hexane 1:4).
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nals. Yields of the products were 0.2794 g (28%) for 4s and 0.7317 g
(60%) for 4l.
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A 30 mL round-bottomed flask equipped with a stirring bar was
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The yields of the amide products were 0.6482 g (66%) for 4s and
0.3298 g (29%) for 4l, respectively.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Q

Q
R. Otsuka et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–Q