Facile one-pot syntheses of amidines and enamines from oximes via Beckmann rearrangement using trifluoromethanesulfonic anhydride

Article abstract of DOI:10.1246/bcsj.77.1717

Iminocarbocation intermediates were in situ-generated by treating various oximes with trifluoromethanesulfonic anhydride (Tf₂O) in the presence of triethylamine in toluene and nucleophilic trapping with amines or sodium enolates under mild conditions afforded the corresponding amidines and enamines. Some of the thus-obtained enamines were converted to 2-substituted 4-oxo-3-quinolinecarboxylic acid derivatives by subsequent intramolecular Friedel-Crafts acylation.

Full text of DOI:10.1246/bcsj.77.1717

Ó 2004 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 77, 1717–1725 (2004) 1717
Facile One-Pot Syntheses of Amidines and Enamines from Oximes via
Beckmann Rearrangement Using Trifluoromethanesulfonic Anhydride
ꢀ;1;2
Tomofumi Takuwa,1 Tomofumi Minowa,1 Jim Yoshitaka Onishi,1 and Teruaki Mukaiyama
1The Kitasato Institute, Center for Basic Research, 6-15-5 (TCI), Toshima, Kita-ku, Tokyo 114-0003
2Kitasato Institute for Life Science, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
Received March 12, 2004; E-mail: mukaiyam@abeam.ocn.ne.jp
Iminocarbocation intermediates were in situ-generated by treating various oximes with trifluoromethanesulfonic
anhydride (Tf2O) in the presence of triethylamine in toluene and nucleophilic trapping with amines or sodium enolates
under mild conditions afforded the corresponding amidines and enamines. Some of the thus-obtained enamines were
converted to 2-substituted 4-oxo-3-quinolinecarboxylic acid derivatives by subsequent intramolecular Friedel–Crafts
acylation.
The Beckmann rearrangement is one of the most fundamen-
tal and frequently employed tools in organic synthesis for the
construction of nitrogen-containing skeletons, such as amides
or lactams.1 Since this rearrangement was first discovered by
Beckmann in 1886,2 many useful modified methods have been
developed and their reaction mechanisms have been studied in
detail. The Beckmann rearrangement usually proceeds by
treating oximes or oxime sulfonates with acids, including
Lewis acids, such as hydrochloric acid,1 sulfuric acid,1 poly-
phosphoric acid,3 formic acid, and boron trifluoride,1 or dehy-
drating agents, such as phosphoryl chloride,1 oxalyl chloride,4
phosgene,4 phosphorus pentachloride,1 thionyl chloride,1 and
1,10-carbonyldiimidazole,5 to form amides or lactams. The
mechanism of the Beckmann rearrangement can be explained
by considering the initial formation of an electron-deficient ni-
trogen atom by a partial ionization of the oxygen–nitrogen
bond of the oxime along with a simultaneous intramolecular
migration of the group anti to the departing hydroxy group
to produce the iminocarbocation, which is then converted to
the corresponding amides or lactams by a subsequent treatment
with water. On the other hand, it was also known that ꢀ-alky-
lated amines are formed via imines,6 amidines,7 thioimidates,8
imidoyl iodides,9 iminonitriles,8 aminophosphonates,10 and en-
aminones11 by trapping the iminocarbocation intermediates
formed from oximes or oxime sulfonates via the Beckmann re-
arrangement with various nucleophiles. For example, amidines
were synthesized by trapping iminocarbocations formed by the
Beckmann rearrangement of oximes,12,13 oxime sulfonates,7
oxime carbonates,1 and oxime phosphonates14 with primary
or secondary amines. Also, there are some reports on the for-
mations of amines6 or enamines11 by trapping the intermedi-
ates with the carbon nucleophiles. In some cases, however,
these reported procedures required the isolation of oxime sul-
fonates, or their products were obtained in low yields because
of the high reaction temperature. Then, the Beckmann rear-
rangement of oximes having a strong leaving groups such as
trifluoromathanesulfonate, was considered to proceed smooth-
ly under mild condition to produce the carbocation intermedi-
ate; however, there have been no examples reported on the re-
action to trap the iminocarbocation intermediates with amines
or carbon nucleophiles.15
A preliminary result on the syntheses of amidines and enam-
ines by trapping the iminocarbocation intermediates of the
Beckmann rearrangement derived from oximes was reported
in a previous communication.16 After screening the reaction
conditions of the above-mentioned reaction, various oximes
were found to react smoothly with trifluoromethanesulfonic
anhydride under mild conditions to generate the iminocarboca-
tions via the Beckmann rearrangement, and successive reac-
tions with amines or carbon nucleophiles afforded the ami-
dines or enamines. Some of the thus-formed enamines were
converted to 2-substituted 4-oxo-3-quinolinecarboxylic acid
derivatives that possessed antibacterial activities17 by the sub-
sequent intramolecular Friedel–Crafts acylation.18 Here, we
would like to describe in detail the facile one-pot syntheses
of amidines and enamines by trapping iminocarbocation inter-
mediates formed in situ by the Beckmann rearrangement of
oximes with amines or carbon nucleophiles.
Results and Discussion
Syntheses of Amidines. In the first place, the formation of
amidine was tried by trapping the carbocation intermediate
generated by the Beckmann rearrangement of benzophenone
oxime with trifluoromethanesulfonic anhydride and N-methyl-
aniline. The iminocarbocation intermediate was generated by
adding trifluoromethanesulfonic anhydride to the benzophe-
noneꢂoxime in the presence of triethylamine in toluene at
ꢁ78 C. After stirring the mixture for 5 min, N-methylaniline
was added and the reaction mixture was slowly warmed up to
room temperature. After an aqueous work up, N-methyl-N,N0-
diphenylbenzamidine was obtained in 95% yield. Similarly,
various amidines were prepared by the above-mentioned
one-pot procedure from the corresponding oximes. For exam-
ple, a treatment of benzophenone with aliphatic amines, such
as N-methylbenzylamine or morpholine, gave the correspond-
ing amidines in good yields (Table 1, Entries 2 and 3). In the
Published on the web September 10, 2004; DOI 10.1246/bcsj.77.1717

1718 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Beckmann Rearrangement
Table 1. Syntheses of Amidines by Trapping with Amines
Table 2. Amount of Nucleophile
R1
H
N
Ph
COOMe
COOMe
NH
OH
R2
OH
N
R3
R4
N
Tf2O, Et3N
N
Na
R3
Tf2O, Et3N
COOMe
N
R4
R2
Me
Toluene
-78 °C
R1
Ph
Me
Toluene
-78 °C
COOMe
14
H
N
Entry
Nucleophile
Equivalent
Yield/%a)
Entry
R1
R2
Product Yield/%a,b)
R3
Ph
R4
1
2
3
1.5
2.0
3.0
3b)
41
COOMe
Na
H
N
1
1
Ph
Ph
3
95c)
COOMe
Me
96
a) Isolated yields. b) The yield was determined by 1H NMR
analysis using 1,1,2,2-tetrachloroethane as an internal stand-
ard.
Me
Ph
N
2H
2
3
Ph
Ph
Ph
Ph
4
5
99
87
HN
O
Table 3. Effects of Solvents
COOMe
Ph
4
5
Ph
Ph
Me
Me
1
2
6
7
89
86
NH
Na
OH
Me
(3.0 eq.)
Tf2O, Et3N
N
COOMe
COOMe
Me
NH2
Solvent
-78 °C
-78 °C-rt
Ph
6
Ph
Ph
Me
Me
8
60
COOMe
14
NH2
Entry Solvent Yield/%a) Entry Solvent Yield/%a)
7
8
9
38
93
1
2
3
4
CH2Cl2
CH3CN
Hexane
AcOEt
53
5
6
7
8
DMF
THF
Toluene
Et2O
ND
58
96
91
50b)
41
Me
Et
Me
Et
1
10
9
10
1
2
11
12
99
99
65
ꢂ
a) Isolated yields. b) Reaction was proceeded at ꢁ50 C.
11
–(CH2)5–
1
13
83
dride in the presence of 2.0 equivalents of triethylamine in tol-
uene at ꢁ78 ꢂC. After stirring the mixture for 5 min, 2.0 equiv-
alents of sodium enolate of dimethyl malonate dissolved in
tetrahydrofuran were added and the reaction mixture was slow-
ly warmed up to room temperature. After an aqueous work-up,
the desired enamine was obtained in 41% yield. Next, the ef-
fect of the amount of nucleophile on the yield was studied and
the enamine turned out to be obtained in 3% yield only when
1.5 equivalents of nucleophile were used. When 3.0 equiva-
lents of nucleophile were used (Table 2), on the other hand,
the desired product was obtained in high yield. After screening
the effect of still other solvents, such as dichloromethane, ace-
tonitrile, hexane, ethyl acetate, N,N-dimethylformamide, and
diethyl ether, on the above model reaction, toluene and diethyl
ether were found to be effective, and the desired products were
obtained in high yield (Table 3, Entries 7 and 8). Regarding the
effects of the bases, the generation of an iminocarbocation in-
termediate and facile trapping with carbon nucleophiles were
examined in the presence of several organic and inorganic bas-
es in toluene or diethyl ether. Then, the desired enamines were
obtained in low yields when pyridine was used (Table 4, En-
tries 3 and 8). In the case with potassium carbonate, the rear-
ranged products were obtained in 67% yield (toluene) and 49%
(ether), respectively (Table 4, Entries 4 and 9). The desired
product was obtained in high yield when triethylamine was
used in toluene (Table 4, Entry 1). On the other hand, the re-
action did not proceed at all, and no products were obtained
when other dehydrating agents, such as trifluoroacetic anhy-
dride, toluenesulfonic anhydride, toluenesulfonyl chloride,
p-nitrotoluenesulfonyl chloride, methanesulfonic anhydride,
and methanesulfonyl chloride, were used in place of trifluoro-
a) Isolated yields. b) All products were obtained as a single
isomer and the geometry of them were not determined. c)
The yield was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard.
case of acetophenone oxime, the reaction proceeded to give
the corresponding amidines in good yields by trapping the car-
bocation intermediates with secondary amines (Table 1, En-
tries 4 and 5), while the desired products were obtained in
low-to-moderate yields when the primary amines were used.
This was probably because the produced amidines also reacted
as nucleophiles with iminocarbocation intermediates (Table 1,
Entries 6 and 7). Although aliphatic oximes are generally con-
sidered to be less reactive, they reacted smoothly while also
giving the desired products in high yields (Table 1, Entries
8–10). According to this procedure, the yield of the rearranged
product of cyclic oxime was improved compared with those by
the conventional methods (Table 1, Entry 11).7
Syntheses of Enamines. Next, the trapping of iminocarbo-
cation intermediates with carbon nucleophiles, such as sodium
enolates, was tried in order to established a new method for the
formation of enamines by a one-pot procedure: that is, an in-
situ formation of iminocarbocations by a Beckmann rearrange-
ment of oximes, and a successive reaction of the thus-formed
carbocations with carbon nucleophiles afforded the enamines
under mild conditions. A similar example was reported by
Yamamoto and co-workers in which enamines were obtained
from oxime sulfonates and enol silyl ethers by using a Lewis
acid, such as diethylaluminum chloride.11 In the present ex-
periment, the carbocation intermediate was formed from aceto-
phenone and 1.5 equivalents of trifluoromethanesulfonic anhy-

T. Takuwa et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1719
Table 4. Effect of Bases
Table 5. Syntheses of Enamines by Trapping with Carbon
Nucleophiles
COOMe
Ph
NH
Na
OH
(3.0 eq.)
COOMe
R1
COOMe
Tf2O, Base
N
COOMe
COOMe
Na
(3.0 eq.)
OH
R2
NH
Nu
Tf2O, Et3N
Me
N
Solvent
-78 °C
-78°C-rt
Ph
Me
R2
COOMe
14
Toluene
-78 °C
R1
R1
R2
Product
Yield/%a)
Entry
Solvent
Base
Yield/%a)
Entry
Ph
Ph
1
2
3
4
5
Toluene
Toluene
Toluene
Toluene
Toluene
Et3N
iPr2EtN
Pyridine
K2CO3
DBU
96
72
NH
COOMe
1
96
Me
8b)
67
COOMe
14
18b)
NH
2
84
95
95
Et
COOMe
6
7
8
9
10
Et2O
Et2O
Et2O
Et2O
Et2O
Et3N
iPr2EtN
Pyridine
K2CO3
DBU
91
66
37b)
49
COOMe
15
4-MeOPh
4-NO2Ph
Ph
NH
3
4
Me
Me
COOMe
19
MeO
O2N
COOMe
a) Isolated yields. b) The yield was determined by 1H NMR
analysis using 1,1,2,2-tetrachloroethane as an internal
standard.
16
NH
COOMe
COOMe
H
N
17
R
TfOH
NH
NH
COOMe
5
6
7
8
81
COOMe
Toluene
reflux, 2 h
COOMe
Ph
R
COOMe
O
COOMe
18
14' R = Me 99%
18' R = Ph 55%
NH
COOMe
78
Me
Et
Me
Et
Scheme 1.
COOMe
19
methanesulfonic anhydride shown in the above reaction.
The reaction was further examined by using various aromat-
ic and aliphatic oximes (Table 5). As a result, the reactions
smoothly proceeded to afford the corresponding enamines in
good-to-high yields under mild conditions. When aromatic ox-
imes having electron-donating or electron-withdrawing groups
were used, the desired products were obtained in excellent
yields (Table 5, Entries 3 and 4). The reaction of aliphatic ox-
imes gave the corresponding oximes in good yields (Table 5,
Entries 6, 7, and 8). When an EZ mixture of butanone oxime
was used, the corresponding enamines were obtained in 89%
yields as a mixture of 22a formed by the migration of the ethyl
group of oxime to nitrogen, and 22b formed by the migration
of the methyl group of oxime to nitrogen (Table 5, Entry 9).
Concerning the cyclic oximes, seven- and eight-membered
ring oximes gave the corresponding enamines in good yields
while no products were obtained when six-membered ring ox-
ime was used (Table 5, Entries 10–12). It was thus considered
that the thus-obtained enamines would be converted to 2-
substituted 4-oxo-3-quinolinecarboxylic acid derivatives that
possess antibacterial activities by the subsequent intramolec-
ular Friedel–Crafts acylation. Actually, the intramolecular
Friedel–Crafts acylation of 14 and 18 proceeded to afford
cyclized 140 and 180, respectively, by treating with 2.0 equiva-
lents of trifluoromethanesulfonic acid in refluxing toluene for
two hours (Scheme 1).
NH
COOMe
73
COOMe
20
84b)
NH
Me
COOMe
COOMe
21
NH
COOMe
OH
COOMe
N
9
89b,c)
22a
E/Z = 74/26
NH
COOMe
COOMe
22b
OH
10
11

COOMe
ND
74
N
OH
COOMe
N
NH
23
H
N
12
60b)
COOMe
COOMe
OH
N
24
a) Isolated yields. b) The yield was determined by 1H NMR
analysis using 1,1,2,2-tetrachloroethane as an internal stand-
ard. c) The proportion of product was 22a/22b = 77/23.
Next, the reaction of the iminocarbocation intermediate de-
rived from acetophenone oxime with various sodium enolates
was tried. The iminocarbocation intermediates were smoothly

1720 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Beckmann Rearrangement
Table 6. Syntheses of Enamines by Trapping with Carbon Nucleophiles
Nucleophile
(3.0 eq.)
OH
Ph
Tf2O, Et3N
N
NH
Nu
Toluene
-78 °C
Ph
Me
Me
Entry
Nucleophile
Product
Yield/%a)
Entry
Nucleophile
Product
Yield/%a)
Ph
Ph
NH
NH
COOMe
Na
COSEt
Na
1
COOMe
96
6
COSEt
78c)
Me
Me
COOMe
CN
COOMe
CN
14
29
Ph
Ph
NH
NH
PO(OEt)2
Na
7
50
COMe
PO(OEt)2
Me
Me
CN
COOEt
CN
COMe
Na
2
94b)
25a
30
COOEt
Ph
Ph
COOEt
NH
SO2Ph
Na
N
69c)
89
8
9
SO2Ph
Me
CN
Me
O
CN
31
25b
Ph
Ph
NH
NH
NH
COSEt
Na
CON
Na
3
4
5
99
83
99
COSEt
CON
Me
Me
COSEt
CN
COSEt
CN
26
32
Ph
Ph
NH
SO2Ph
Na
CON
Na
SO2Ph
CON
10
11
99c)
Me
Me
SO2Ph
COOEt
SO2Ph
COOEt
27
33
Ph
Ph
NH
NH
COOMe
Na
COOEt
Na
COOMe
COOEt
74d)
Me
Me
CN
COSEt
CN
COSEt
28
34
a) Isolated yields. b) The proportion of product was C(25a)/O(25b) = 71/29. c) The yield was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. d) The proportion of product was 31/69.
trapped by the nucleophiles to afford the corresponding enam-
ines in good-to-high yields (Table 6). In the case of using so-
dium enolate of the ꢁ-keto ester for a nucleophile, a mixture of
C- and O-alkylated products was obtained in 94% combined
yield (Table 6, Entry 2). The reaction smoothly proceeded
when nucleophiles, such as sodium enolates of dithiomalonic
acid di-S-ethyl ester and bis(phenylsulfonyl)methane, were
used, and the desiresd products were obtained in high yields
(Table 6, Entries 3 and 4). When the sodium enolates of meth-
yl cyanoacetate, cyanothioacetic acid S-ethyl ester, cyano-
methylphosphonic acid diethyl ester, benzenesulfonylacetoni-
trile, and 3-oxo-3-pyrrolidine-1-yl-propiononitrile were used,
the corresponding enamines were obtained as a single product
in moderate-to-high yield, respectively (Table 6, Entries 5–9).
Similarly, a single product was obtained in the case of ethyl 3-
oxo-3-pyrrolidin-1-ylpropanoate, though its geometry has not
yet been determined (Table 6, Entry 10). The reaction of
O,S-diethyl monothiomalonate gave a mixture of two isomers,
which were not separated by thin-layer chromatography
(Table 6, Entry 11). Next, the trapping of an iminocarbocation
intermediate, derived from less reactive acetoxime with vari-
ous carbon nucleophiles, was examined, and the reaction
turned out to proceed smoothly and afforded the corresponding
enamines as a single product in moderate-to-high yields
(Table 7). Furthermore, when phenylsulfonylacetonitrile was
employed as a nucleophile together with DBU, the desired
product was obtained in 72% yield (Table 7, Entry 3).
In the case of using ketone enolates, the yields of the corre-
sponding products were low (Table 8). When sodium enolates
derived from several ketones were used, the desired products
were obtained in yields of between 14 to 35% (Table 8, Entries
2, 7, and 8). In the case of lithium enolate, the product was ob-
tained in only 20% yield (Table 8, Entry 4), while still no prod-
ucts were obtained when the other metal enolates and ammo-
nium enolate, such as potassium and tetrabutyl ammonium,
were used.
A proposed reaction mechanism is shown in Scheme 2. Ini-
tially, the oxime was activated with trifluoromethanesulfonic
anhydride to form a reactive oxime trifluoromethanesulfonate
(1). The successive elimination of a triflate anion from (1)
caused a rearrangement of R1 to the nitrogen atom to form imi-
nocarbocation (2), which in turn was trapped with amine to
give the corresponding amidine (3), or imine (4) upon a treat-
ment with a carbon nucleophile, such as sodium malonate. The

T. Takuwa et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1721
thus-formed imine (4) was converted to enamine (5) via 1,3-
proton-shift. The geometry of enamines such as 28, 29, 30,
31, 32, 35, 36, and 39 was determined by observations of
the broadened signal in the lower magnetic field (9.78–12.4
ppm) due to the hydrogen-bonded NH proton in the H NMR
spectra of the products.
amidines and enamines was established by trapping iminocar-
bocation intermediates, generated in situ via a Beckmann rear-
rangement of ketoximes using trifluoromethanesulfonic anhy-
dride, with amines and carbon nucleophiles under mild condi-
tions without using Lewis acids. Some enamines formed by
the above reactions were converted to 2-substituted 4-oxo-3-
quinolinecarboxylic acid derivatives upon a treatment with
trifluoromethanesulfonic acid.
1
Conclusion
A new and efficient method for the one-pot syntheses of
Experimental
General. All of the melting points were determined on a
Yanagimoto micro melting-point apparatus (Yanaco MP-S3) and
were uncorrected. Infrared (IR) spectra were recorded on a Horiba
FT 300 FT-IR spectrometer. H NMR spectra were recorded on a
JEOL EX270 (270 MHz) spectrometer; chemical shifts (ꢂ) are re-
ported in parts per million relative to tetramethylsilane. Splitting
Table 7. Syntheses of Enamines by Trapping with Carbon
Nucleophiles
Nucleophile
(3.0 eq.)
1
OH
Me
Me
Me
Tf2O, Et3N
N
NH
Nu
Toluene
-78 °C
Me
Entry
Nucleophile
Product
Yield/%a)
Table 8. Syntheses of Enamines by Trapping with Carbon
Nucleophiles
Me
Me
NH
COOMe
Na
Nucleophile
(3.0 eq.)
COOMe
COOMe
SO2Ph
1
2
3
4
5
19
35
36
37
38
78
OH
Me
Me
Tf2O, Et3N
N
NH
Nu
COOMe
COOMe
Toluene
-78 °C
R
Me
Me
Me
NH
COOMe
Na
Entry
Oxime
Nucleophile
Product
Yield/%a)
99
72
71
57
CN
CN
NH
1
2
3
18
ONa
30b)
30c,d)
Me
Me
SO2Ph
DBU
Ph
OLi
CN
4
5
6
20
Me
OH
CN
O
HN
N
Ph
Me
Me
Me
OK
Ph
Me
NH
Me
Me
CN
Na
ND
ND
CN
CN
41
Ph
CN
ONBu4
Ph
NH
SO2Ph
Na
SO2Ph
Me
OH
Me
Ph
SO2Ph
ONa
N
N
OH
N
7
8
14
SO2Ph
Ph
Ph
Me
NH
42
CON
Na
CON
CN
NH
6
7
39
40
70
Me
Me
Me
Ph
CN
ONa
OH
Me
OH
N
35d)
COSEt
Na
49b)
COSEt
43
COSEt
COSEt
a) Isolated yields. b) 4.0 eq. of nucleophile was used. c) 5.0 eq.
of nucleophile was used. d) The yield was determined by
1H NMR analysis using 1,1,2,2-tetrachloroethane as an inter-
nal standard.
a) Isolated yields. b) The yield was determined by 1H NMR
analysis using 1,1,2,2-tetrachloroethane as an internal stand-
ard.
R1
R3
N
R3
HN
R4
N
R4
R2
OH
R2
O
(3)
OTf
R2
N
Tf
Et3N
Tf
R2
N
R1
N
R1
R2
R1
R1
R1
N
HN
H
R5
TfOH
(1)
(2)
R5
R6
R2
R5
R6
(5)
Na
R6
(4)
Scheme 2.

1722 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Beckmann Rearrangement
patterns are designed as s, singlet; d, doublet; t, triplet; q, quartet;
m, multiplet; br, broad. 13C NMR spectra were recorded on a
JEOL EX270 (68 MHz) spectrometer with complete proton de-
coupling. Chemical shifts are reported in parts per million relative
to tetramethylsilane with the solvent resonance as the internal
standard (CDCl3; ꢂ 77.0). High-resolution mass spectra (HRMS)
were recorded on a JEOL-700T mass spectrometer. Elemental
analysis were performed on vario EL III (elementar), DX-500
(DIONEX), and UV2200 (SHIMADZU). Analytical TLC was
performed on Merck precoated TLC plates (silica gel 60 GF254,
0.25 mm). Silica-gel columm chromatography was carried out
on a Merck silica gel 60 (0.063–0.200 mm). Preparative thin-layer
chromatography (PTLC) was carried out on a silica-gel Wacogel
B-5F. Solvents were freshly distilled when dry solvents were
needed. Some oximes were purchased from Tokyo Kasei Kogyo,
Kanto Chemical, Aldrich Chemical or Merck, and were used after
purification by distillation or recrystallization. Other oximes were
prepared according to literature procedures.19
53.2, 121.3, 122.3 (ꢃ2), 125.8, 126.8, 126.9, 128.5 (ꢃ2), 128.6
(ꢃ2), 138.3, 151.8, 156.9.
N,N0-Diphenylacetamidine (8):21 White solid; mp 133–134
ꢂC; IR (neat, cmꢁ1) 3433, 3401, 3356, 3000, 1712, 1365, 1219;
1H NMR (270 MHz, CDCl3) ꢂ 1.92 (s, 3H), 6.95–7.00 (m, 2H),
7.14–7.27 (m, 8H); 13C NMR (68 MHz, CDCl3) ꢂ 18.8, 121.0,
122.6, 128.8, 145.1, 152.4.
N-Benzyl-N0-phenylacetamidine (9): Colorless oil; IR (neat,
1
cmꢁ1) 3433, 3401, 3356, 3000, 1712, 1365, 1219; H NMR (270
MHz, CDCl3) ꢂ 1.82 (br, 3H), 4.50 (br, 2H), 6.79 (d, J ¼ 7:6 Hz,
2H), 6.93–6.99 (m, 1H), 7.21–7.35 (m, 7H); 13C NMR (68 MHz,
CDCl3) ꢂ 17.7, 45.8, 121.9 (ꢃ2), 122.1 (ꢃ2), 127.2 (ꢃ2),
127.9, 128.5 (ꢃ2), 128.7, 138.9, 151.2, 155.1; HRMS (FAB)
Calcd for C15H17N2: ½M þ Hꢄþ 225.1386. Found: m=z 225.1405.
N,N0-Dimethyl-N-phenylacetamidine (10):22 Colorless oil;
IR (neat, cmꢁ1) 3679, 2352, 1643, 1272, 1164; 1H NMR (270
MHz, CDCl3) ꢂ 2.05 (s, 3H), 3.19 (s, 3H), 3.50 (s, 3H), 7.25 (d,
J ¼ 5:6 Hz, 2H), 7.39–7.50 (m, 3H); 13C NMR (68 MHz, CDCl3)
ꢂ 16.6, 31.6, 40.9, 126.2 (ꢃ2), 129.5, 130.5 (ꢃ2), 142.5, 164.8.
N0-Ethyl-N-methyl-N-phenylpropionamidine (11): Color-
less oil; IR (neat, cmꢁ1) 3224, 3170, 2352, 1635, 1272, 1257;
1H NMR (270 MHz, CDCl3) ꢂ 1.04 (t, J ¼ 7:7 Hz, 3H), 1.38 (t,
J ¼ 7:3 Hz, 3H), 2.36 (q, J ¼ 7:7 Hz, 2H), 3.47 (s, 3H), 3.51–
3.61 (m, 2H), 7.22–7.25 (m, 2H), 7.42–7.47 (m, 3H); 13C NMR
(68 MHz, CDCl3) ꢂ 10.8, 15.0, 21.9, 40.3, 41.3, 126.2 (ꢃ2),
129.7, 130.4 (ꢃ2), 141.9, 167.4; HRMS (FAB) Calcd for
C12H19N2: ½M þ Hꢄþ 191.1543. Found: m=z 191.1547.
General Procedure for Syntheses of Amidines (Table 1). To
a solution of benzophenone oxime (0.25 mmol) and triethylamine
(0.50 mmol) in toluene (3.0 mL) was added a trifluoromethanesul-
fonic anhydride (0.38 mmol) under an argon atmosphere at ꢁ78
ꢂC. After stirring for 5 min, N-methylaniline (0.50 mmol) was
added and the reaction mixture was slowly warmed up to room
temperature. After stirring for 1 h, the reaction mixture was
quenched with water (5.0 mL), and the aqueous layer was extract-
ed with ethyl acetate (30 mL). The organic layer was dried
(Na2SO4), filtrated and evaporated, and the resulting residue
was purified by preparative TLC to afford N-methyl-N,N0-diphen-
N-Benzyl-N0-ethyl-N-methylpropionamidine (12):
Color-
less oil; IR (neat, cmꢁ1) 3540, 2360, 1241, 1157, 1033; H NMR
(270 MHz, CDCl3) ꢂ 1.11–1.21 (m, 6H), 2.56 (q, J ¼ 7:8 Hz, 2H),
3.03 (s, 3H), 3.41 (q, J ¼ 7:9 Hz, 2H), 4.59 (s, 2H), 7.02 (d, J ¼
6:6 Hz, 2H), 7.15–7.29 (m, 3H); 13C NMR (68 MHz, CDCl3) ꢂ
10.6, 21.0, 34.2, 40.1, 54.4, 128.2, 128.5, 128.6, 129.0, 129.2,
134.7, 167.4; HRMS (FAB) Calcd for C13H21N2: ½M þ Hꢄþ
205.1699. Found: m=z 205.1721.
1
ylbenzamidine (3)7 in 95% yield as a colorless oil: IR (neat, cmꢁ1
)
3910, 3424, 2360, 1581, 1357, 694; 1H NMR (270 MHz, CDCl3) ꢂ
3.57 (s, 3H), 6.61 (d, J ¼ 7:8 Hz, 2H), 6.77 (t, J ¼ 7:3 Hz, 1H),
6.97–7.14 (m, 12H); 13C NMR (68 MHz, CDCl3) ꢂ 40.2, 121.1,
122.7 (ꢃ2), 124.9, 126.9 (ꢃ2), 127.4 (ꢃ2), 128.0, 128.1 (ꢃ2),
128.5 (ꢃ2), 130.1 (ꢃ2), 133.3, 146.0, 150.5, 159.4.
N-Benzyl-N-methyl-N0-phenylbenzamidine (4):
Colorless
Methylphenyl[4,5,6,7-tetrahydroazepin-2(3H)-yl]amine
(13):23 Colorless oil; IR (neat, cmꢁ1) 3332, 3293, 3255, 2923,
oil; IR (neat, cmꢁ1) 3023, 2915, 2360, 1581, 1072; 1H NMR
(270 MHz, CDCl3) ꢂ 2.90 (br, 3H), 4.45 (br, 2H), 6.54–6.57 (m,
2H), 6.65–6.71 (m, 1H), 6.91–6.99 (m, 2H), 7.08–7.35 (m,
10H); 13C NMR (68 MHz, CDCl3) ꢂ 35.9, 53.8, 120.76, 122.84
(ꢃ2), 127.0 (ꢃ2), 127.3, 127.9 (ꢃ2), 128.0 (ꢃ2), 128.3, 128.4
(ꢃ2), 128.7 (ꢃ2), 133.5, 138.0, 151.1, 160.8; HRMS (FAB) Calcd
for C21H21N2: ½M þ Hꢄþ 301.1699. Found: m=z 301.1705.
N-(ꢀ-Morpholin-4-ylbenzylidene)aniline (5):14 White solid;
mp 85–87 ꢂC; IR (KBr, cmꢁ1) 3880, 3718, 3208, 2715, 2591,
1
1635, 1272, 1257; H NMR (270 MHz, CDCl3) ꢂ 1.59–1.78 (m,
6H), 2.50 (t, J ¼ 5:1 Hz, 2H), 3.53 (s, 3H), 3.62 (br, 2H), 7.21–
7.26 (m, 2H), 7.44–7.52 (m, 3H); 13C NMR (68 MHz, CDCl3) ꢂ
23.1, 27.2, 29.5, 29.8, 41.3, 45.2, 126.1 (ꢃ2), 129.5, 130.5
(ꢃ2), 142.4, 169.6.
General Procedure for Syntheses of Enamines (Table 6–8).
To a solution of acetophenone oxime (0.25 mmol) and triethyl-
amine (0.50 mmol) in toluene (3.0 mL) was added trifluorometh-
anesulfonic anhydride (0.38 mmol) under an argon atmosphere at
ꢁ78 ꢂC. After stirring for 5 min, freshly prepared sodium enolate
of methyl malonate dissolved in THF (0.30 M, 2.5 mL) was added
and the reaction mixture was slowly warmed up to room temper-
ature. After stirring for 1 h, the reaction mixture was quenched
with water (5.0 mL), and the aqueous layer was extracted with
ethyl acetate (30 mL). The organic layer was dried (Na2SO4), fil-
trated and evaporated, and the resulting residue was purified by
preparative TLC to afford 2-(1-phenylaminoethylidene)malonic
acid dimethyl ester (14) in 96% yield as a colorless oil; IR (neat,
1
1866; H NMR (270 MHz, CDCl3) ꢂ 3.47 (br, 4H), 3.76 (t, J ¼
4:9 Hz, 4H), 6.58 (dd, J ¼ 8:2, 1.0 Hz, 2H), 6.76 (t, J ¼ 7:4
Hz, 1H), 7.01 (t, J ¼ 7:6 Hz, 2H), 7.11–7.15 (m, 2H), 7.22–7.27
(m, 3H); 13C NMR (68 MHz, C6D6) ꢂ 66.7 (ꢃ4), 121.6, 123.1
(ꢃ2), 127.6 (ꢃ2), 128.0 (ꢃ2), 128.6 (ꢃ2), 129.3, 133.6, 151.6,
160.2.
N-Methyl-N,N0-diphenylacetamidine (6):14 Colorless oil; IR
(neat, cmꢁ1) 3964, 3617, 3563, 1581, 1373, 694; 1H NMR (270
MHz, CDCl3) ꢂ 1.67 (s, 3H), 3.33 (s, 3H), 6.75 (d, J ¼ 7:7 Hz,
2H), 6.91 (t, J ¼ 7:3 Hz, 1H), 7.13–7.56 (m, 7H); 13C NMR (68
MHz, CDCl3) ꢂ 16.9, 39.5, 122.0, 122.2, 125.9, 126.5, 127.4,
128.3, 128.7 (ꢃ2), 129.0, 129.3 (ꢃ2), 146.0, 160.2.
1
cmꢁ1) 2360, 2329, 1720, 1658, 1581, 1249; H NMR (270 MHz,
CDCl3) ꢂ 1.95 (s, 3H), 3.62 (s, 3H), 3.66 (s, 3H), 6.97 (d, J ¼ 7:8
Hz, 2H), 7.12 (t, J ¼ 7:4 Hz, 1H), 7.21–7.27 (m, 2H), 11.18 (br,
1H); 13C NMR (68 MHz, CDCl3) ꢂ 18.1, 51.2, 51.9, 93.7, 125.7
(ꢃ2), 126.3, 129.1 (ꢃ2), 137.7, 162.0, 168.78, 168.82; HRMS
(FAB) Calcd for C13H16NO4: ½M þ Hꢄþ 250.1074. Found: m=z
250.1096.
N-Benzyl-N-methyl-N0-phenylacetamidine (7):20 Colorless
oil; IR (neat, cmꢁ1) 3903, 2360, 2329, 1612, 1481, 1226, 732;
1H NMR (270 MHz, CDCl3) ꢂ 1.88 (s, 3H), 2.98 (s, 3H), 4.62
(s, 2H), 6.72 (d, J ¼ 7:3 Hz, 2H), 6.91 (t, J ¼ 6:5 Hz, 1H),
7.18–7.35 (m, 7H); 13C NMR (68 MHz, CDCl3) ꢂ 15.0, 36.1,

T. Takuwa et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1723
2-(1-Phenylaminopropylidene)malonic Acid Dimethyl Ester
(15): Colorless oil; IR (neat, cmꢁ1) 3980, 1712, 1650, 1581,
1442, 1249; H NMR (270 MHz, CDCl3) ꢂ 0.91 (t, J ¼ 7:5 Hz,
2.94 (d, J ¼ 5:1 Hz, 0.69H), 3.22–3.32 (m, 1.54H), 3.63 (s,
0.69H), 3.70 (s, 2.31H), 9.69 (br, 1H); 13C NMR (68 MHz,
CDCl3) ꢂ 12.3, 15.1, 16.7, 23.1, 29.4, 38.1, 41.1, 50.8, 51.7,
52.5, 90.3, 90.7, 164.4 (ꢃ2), 166.7, 169.1, 169.3, 169.8; HRMS
(FAB) Calcd for C9H16NO4: ½M þ Hꢄþ 202.1074. Found: m=z
202.1095.
2-(Azocan-2-ylidene)malonic Acid Dimethyl Ester (23):
White solid; mp 53–55 ꢂC; IR (KBr, cmꢁ1) 2923, 2908, 1812,
1643, 1103; 1H NMR (270 MHz, CDCl3) ꢂ 1.50–1.60 (m, 6H),
1.77 (br, 2H), 2.55 (t, J ¼ 6:5 Hz, 2H), 3.38–3.45 (m, 2H), 3.66
(s, 3H), 3.71 (s, 3H), 9.96 (br, 1H); 13C NMR (68 MHz, CDCl3)
ꢂ 25.0, 25.4, 27.1, 29.8, 32.3, 41.8, 50.8, 51.7, 89.9, 169.2,
169.4, 169.5; HRMS (FAB) Calcd for C12H20NO4: ½M þ Hꢄþ
242.1387. Found: m=z 242.1401.
1
3H), 2.35 (q, J ¼ 7:5 Hz, 2H), 3.63 (s, 3H), 3.68 (s, 3H), 7.04
(d, J ¼ 7:4 Hz, 2H), 7.14–7.29 (m, 3H), 11.0 (br, 1H); 13C NMR
(68 MHz, CDCl3) ꢂ 13.1, 23.1, 51.2, 52.0, 92.9, 126.5 (ꢃ2),
126.7, 129.2 (ꢃ2), 137.8, 167.3, 168.9, 169.1; HRMS (FAB)
Calcd for C14H18NO4: ½M þ Hꢄþ 264.1230. Found: m=z 264.1255.
2-[1-(4-Methoxyphenylamino)ethylidene]malonic Acid Di-
methyl Ester (16): Colorless oil; IR (neat, cmꢁ1) 2360, 2329,
1
1712, 1650, 1581, 1241; H NMR (270 MHz, CDCl3) ꢂ 1.98 (s,
3H), 3.71 (s, 3H), 3.74 (s, 3H), 3.78 (s, 3H), 6.85 (d, J ¼ 8:7
Hz, 2H), 7.00 (d, J ¼ 8:6 Hz, 2H), 11.1 (s, 1H); 13C NMR (68
MHz, CDCl3) ꢂ 18.1, 51.1, 51.9, 55.4, 92.9, 114.3 (ꢃ2), 127.4
(ꢃ2), 130.5, 158.1, 163.0, 168.9, 169.0; HRMS (FAB) Calcd for
C14H18NO5: ½M þ Hꢄþ 280.1180. Found: m=z 280.1201.
2-(Azonan-2-yliden)malonic Acid Dimethyl Ester (24):
White solid; mp 51 ꢂC; IR (KBr, cmꢁ1) 3856, 3648, 3340,
3000, 1735, 1635, 1249; 1H NMR (270 MHz, CDCl3) ꢂ 1.24–
1.72 (m, 10H), 2.53 (t, J ¼ 6:1 Hz, 2H), 3.36–3.46 (m, 2H),
3.64 (s, 3H), 3.69 (s, 3H), 9.95 (br, 1H); 13C NMR (68 MHz,
CDCl3) ꢂ 22.0, 25.3, 26.2, 28.7, 29.6, 30.2, 43.7, 50.8, 51.7,
89.9, 169.5, 169.6, 169.9; HRMS (FAB) Calcd for C13H22NO4:
½M þ Hꢄþ 256.1543. Found: m=z 256.1549.
2-[1-(4-Nitrophenylamino)ethylidene]malonic Acid Dimeth-
yl Ester (17): White solid; mp 111–112 ꢂC; IR (KBr, cmꢁ1
)
2854, 2360, 1697, 1589, 1272; 1H NMR (270 MHz, CDCl3) ꢂ
2.19 (s, 3H), 3.74 (s, 3H), 3.78 (s, 3H), 7.17 (dd, J ¼ 7:3, 2.0
Hz, 2H), 8.21 (dd, J ¼ 7:0, 2.1 Hz, 2H), 11.5 (s, 1H); 13C NMR
(68 MHz, CDCl3) ꢂ 18.4, 51.7, 52.3, 98.2, 123.6 (ꢃ2), 125.0
(ꢃ2), 144.1, 144.3, 158.6, 168.0, 168.4; Found: C, 53.02; H,
4.87; N, 9.42%. Calcd for C13H14N2O6: C, 53.06; H, 4.80; N,
9.52%.
2-Acetyl-3-phenylaminobut-2-enoic Acid Ethyl Ester
(25a):24
Colorless oil; IR (neat, cmꢁ1) 3293, 2977, 2360,
1697, 1573, 1226; 1H NMR (270 MHz, CDCl3) ꢂ 1.23 (t, J ¼
7:1 Hz, 3H), 2.04 (s, 3H), 2.22 (s, 3H), 4.15 (q, J ¼ 7:1 Hz,
2H), 7.00 (d, J ¼ 7:8 Hz, 2H), 7.16 (t, J ¼ 7:2 Hz, 1H), 7.24–
7.30 (m, 2H), 13.8 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 14.3,
18.7, 29.6, 60.4, 104.8, 125.7 (ꢃ2), 126.8, 129.1 (ꢃ2), 137.4,
164.9, 169.8, 195.7.
2-[Phenyl(phenylamino)methylene]malonic Acid Dimethyl
Ester (18):
White solid; mp 113–114 ꢂC; IR (KBr, cmꢁ1
)
3910, 2360, 2329, 1712, 1596; 1H NMR (270 MHz, CDCl3) ꢂ
3.28 (s, 3H), 3.77 (s, 3H), 6.62–6.65 (m, 2H), 6.90–7.09 (m,
3H), 7.20–7.30 (m, 5H), 11.1 (br, 1H); 13C NMR (68 MHz,
CDCl3) ꢂ 51.5, 51.7, 96.8, 123.5 (ꢃ2), 124.4, 128.2 (ꢃ2), 128.3
(ꢃ2), 128.5 (ꢃ2), 129.4, 133.6, 138.6, 161.2, 167.9, 168.2; Found:
C, 69.04; H, 5.46; N, 4.48%. Calcd for C18H17NO4: C, 69.44; H,
5.50; N, 4.50%.
3-(N-Phenylacetimidoyloxy)but-2-enoic Acid Ethyl Ester
(25b):24
Colorless oil; IR (neat, cmꢁ1) 3980, 3810, 3702,
2360, 2329, 1689, 1195; 1H NMR (270 MHz, CDCl3) ꢂ 1.26 (t,
J ¼ 7:1 Hz, 3H), 1.99 (s, 3H), 2.12 (d, J ¼ 1:0 Hz, 3H), 4.14
(q, J ¼ 7:1 Hz, 2H), 5.59 (d, J ¼ 1:0 Hz, 1H), 6.74 (dd,
J ¼ 8:3, 1.0 Hz, 2H), 6.99–7.05 (m, 1H), 7.22–7.32 (m, 2H);
13C NMR (68 MHz, CDCl3) ꢂ 14.2, 21.1, 21.7, 60.4, 107.7,
120.8 (ꢃ2), 123.2, 128.8 (ꢃ2), 147.9, 162.5, 163.9, 170.9.
2-(1-Phenylaminoethylidene)dithiomalonic Acid Di-S-ethyl
Ester (26): Colorless oil; IR (neat, cmꢁ1) 2969, 2931, 1658,
1581; 1H NMR (270 MHz, CDCl3) ꢂ 1.14–1.27 (m, 6H), 1.92
(s, 3H), 2.79–2.92 (m, 4H), 7.00 (d, J ¼ 7:6 Hz, 2H), 7.13–7.30
(m, 3H), 11.9 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 14.3,
14.9, 17.6, 23.4, 25.2, 112.1, 125.6 (ꢃ2), 126.6, 129.1, (ꢃ2),
137.2, 157.2, 186.2, 194.5; HRMS (FAB) Calcd for
C15H29NO2S2: ½M þ Hꢄþ 310. 0930. Found: m=z 310.0938.
[2,2-Bis(phenylsulfonyl)-1-methylvinyl]aniline (27): Brown
2-(1-Methylaminoethylidene)malonic Acid Dimethyl Ester
(19): Colorless oil; IR (neat, cmꢁ1) 3247, 2946, 2360, 1650,
1596, 1257; 1H NMR (270 MHz, CDCl3) ꢂ 2.06 (s, 3H), 2.91
(d, J ¼ 5:1 Hz, 3H), 3.63 (s, 3H), 3.69 (s, 3H), 9.71 (br, 1H);
13C NMR (68 MHz, CDCl3) ꢂ 16.6, 30.0, 50.8, 51.7, 91.0,
165.6, 169.17, 169.24; HRMS (FAB) Calcd for C8H14NO4: ½M þ
Hꢄþ 188.0917. Found: m=z 188.0936.
2-(1-Ethylaminopropylidene)malonic Acid Dimethyl Ester
(20): Colorless oil; IR (neat, cmꢁ1) 3625, 2969, 2345, 1712,
1650, 1596, 1257; 1H NMR (270 MHz, CDCl3) ꢂ 1.16 (t, J ¼
7:5 Hz, 3H), 1.23 (t, J ¼ 7:3 Hz, 3H), 2.38 (q, J ¼ 7:5 Hz, 2H),
3.24–3.34 (m, 2H), 3.64 (s, 3H), 3.70 (s, 3H), 9.58 (s, 1H);
13C NMR (68 MHz, CDCl3) ꢂ 12.7, 15.4, 23.3, 37.6, 50.8, 51.7,
90.0, 168.8 (ꢃ2), 169.4; HRMS (FAB) Calcd for C10H18NO4:
½M þ Hꢄþ 216.1231. Found: m=z 216.1251.
ꢂ
solid; mp 125–130 C; IR (KBr, cmꢁ1) 3239, 3054, 1558, 1365;
1H NMR (270 MHz, CDCl3) ꢂ 2.23 (s, 3H), 7.08–8.13 (m,
15H), 11.2 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 19.6, 106.7
(ꢃ2), 126.3 (ꢃ2), 126.7 (ꢃ2), 127.0 (ꢃ2), 128.6 (ꢃ2) 128.8
(ꢃ2), 129.5 (ꢃ2), 132.5, 132.7, 136.1, 144.4, 164.8; HRMS
(FAB) Calcd for C21H20NO4S2: ½M þ Hꢄþ 414.0828. Found:
m=z 414.0821.
2-(1-t-Butylaminoethylidene)malonic Acid Dimethyl Ester
(21): Colorless oil; IR (neat, cmꢁ1) 3617, 3292, 2360, 2321,
1735, 1604, 1218; 1H NMR (270 MHz, CDCl3) ꢂ 1.36 (s, 9H),
2.14 (s, 3H), 3.69 (s, 6H), 10.1 (br, 1H); 13C NMR (68 MHz,
CDCl3) ꢂ 18.0, 30.9 (ꢃ3), 41.1, 52.5, 52.8, 91.3, 164.1 (ꢃ2),
166.7; HRMS (FAB) Calcd for C11H20NO4: ½M þ Hꢄþ
230.1387. Found: m=z 230.1414.
2-(1-Ethylaminoethylidene)malonic Acid Dimethyl Ester
(22a) and 2-(1-Methylaminopropylidene)malonic Acid Di-
methyl Ester (22b): Isolated as a mixture of 22a and 22b
(22a/22b = 77/23): Colorless oil; IR (neat, cmꢁ1) 3571, 2977,
2352, 2321, 1712, 1650, 1596, 1257; 1H NMR (270 MHz, CDCl3)
ꢂ 1.12–1.23 (m, 3H), 2.06 (s, 2.31H), 2.39 (q, J ¼ 7:4 Hz, 0.46H),
2-Cyano-3-phenylaminobut-2-enoic Acid Methyl Ester
(28):25 White solid; mp 119–120 ꢂC; IR (KBr, cmꢁ1) 3201,
2198, 1681, 1658, 1596, 1295; 1H NMR (270 MHz, CDCl3) ꢂ
2.14 (s, 3H), 3.68 (s, 3H), 7.01 (d, J ¼ 7:6 Hz, 2H), 7.21–7.64
(m, 3H), 11.3 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 18.9,
51.7, 73.5, 118.4, 125.5 (ꢃ2), 127.5, 129.4 (ꢃ2), 136.5, 168.3,
168.4.
2-Cyano-3-phenylaminobut-2-enethioic Acid S-Ethyl Ester

1724 Bull. Chem. Soc. Jpn., 77, No. 9 (2004)
Beckmann Rearrangement
ꢂ
(29): Brown solid; mp 73–75 C; IR (KBr, cmꢁ1) 2190, 1604,
(m, 3H), 7.87–7.90 (m, 2H), 8.57 (br, 1H); 13C NMR (68 MHz,
CDCl3) ꢂ 18.7, 31.3, 80.9, 117.0, 126.3 (ꢃ2), 129.1 (ꢃ2),
133.2, 141.8, 166.0; HRMS (FAB) Calcd for C11H11N2O2S: [M
ꢁ H]ꢁ 235.0547. Found: m=z 235.0556.
1
1581, 1558, 1226; H NMR (270 MHz, CDCl3) ꢂ 1.14–1.27 (m,
6H), 1.92 (s, 3H), 2.79–2.92 (m, 4H), 7.00 (d, J ¼ 7:6 Hz, 2H),
7.13–7.30 (m, 3H), 11.9 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ
14.3, 14.9, 17.6, 23.4, 25.2, 112.1, 125.6 (ꢃ2), 126.6, 129.1
(ꢃ2), 137.2, 157.2, 186.2, 194.5; HRMS (FAB) Calcd for
C13H15N2OS: ½M þ Hꢄþ 247.0900. Found: m=z 247.0918.
(1-Cyano-2-phenylamino-1-propenyl)phosphonic Acid Di-
2-(1-Methylaminoethylidene)malononitrile (37):27 Color-
less oil; IR (neat, cmꢁ1) 3409, 3224, 2815, 2360, 2321, 2198,
1604, 1403; 1H NMR (270 MHz, CDCl3) ꢂ 2.18 (s, 3H), 2.97
(d, J ¼ 4:9 Hz, 3H), 7.20 (br, 1H); 13C NMR (68 MHz, CDCl3)
ꢂ 17.0, 31.1, 100.4, 115.2, 115.9, 172.1.
ethyl Ester (30): White solid; mp 99–100 C; IR (KBr, cmꢁ1
)
ꢂ
3224, 2985, 2183, 1604, 1025; 1H NMR (270 MHz, CDCl3) ꢂ
1.291 (t, J ¼ 7:1 Hz, 3H), 1.294 (t, J ¼ 7:0 Hz, 3H), 2.16 (s,
3H), 4.02–4.13 (m, 4H), 6.98 (dd, J ¼ 7:7, 0.5 Hz, 2H), 7.15–
7.29 (m, 3H), 10.6 (s, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 16.2,
16.3, 19.7, 19.9, 62.9, 63.0, 119.0, 125.6 (ꢃ2), 127.0, 129.3
(ꢃ2), 137.3, 170.4; Found: C, 56.96; H, 6.51; N, 9.65; P,
10.27%. Calcd for C14H19N2O3P: C, 57.14; H, 6.51; N, 9.52; P,
10.53%.
[1-Methyl-2,2-bis(phenylsulfonyl)vinyl]methylamine (38):
White solid; mp 113–114 ꢂC; IR (KBr, cmꢁ1) 3317, 1589,
1450, 1358, 1303, 1141, 1079; 1H NMR (270 MHz, CDCl3) ꢂ
2.26 (s, 3H), 2.93 (d, J ¼ 4:9 Hz, 3H), 7.46–8.02 (m, 10H),
9.56 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 17.6, 31.0, 103.9,
126.4, 126.7, 128.4, 128.7, 128.9, 129.2, 129.4, 129.6, 132.0,
132.3, 144.4, 145.0, 167.0; HRMS (FAB) Calcd for
C16H18NO4S2: ½M þ Hꢄþ 352.0672. Found: m=z 352.0666.
3-Methylamino-2-(1-pyrrolidinecarbonyl)but-2-enenitrile
(39): Colorless oil; IR (neat, cmꢁ1) 2939, 2869, 2183, 1643,
1604, 1581, 1434, 1389; 1H NMR (270 MHz, CDCl3) ꢂ 1.81
(br, 4H), 2.19 (s, 3H), 2.91 (d, J ¼ 5:1 Hz, 3H), 3.45 (br, 4H),
10.6 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 17.6, 24.3, 26.1,
30.4, 46.0, 47.6, 71.4, 121.5, 167.4,169.7; HRMS (FAB) Calcd
for C10H16N3O: ½M þ Hꢄþ 194.1288. Found: m=z 194.1301.
2-(1-Methylaminoethylidene)dithiomalonic Acid Di-S-ethyl
Ester (40): Colorless oil; IR (neat, cmꢁ1) 2924, 1643, 1589,
1219; 1H NMR (270 MHz, CDCl3) ꢂ 1.26 (t, J ¼ 7:2 Hz, 6H),
2.01 (s, 3H), 2.86–2.97 (m, 6H), 10.4 (br, 1H); 13C NMR (68
MHz, CDCl3) ꢂ 14.7 (ꢃ2), 16.6, 23.6, 24.4, 29.9, 110.6, 161.0;
HRMS (FAB) Calcd for C10H18NO2S2: ½M þ Hꢄþ 248.0774.
Found: m=z 248.0778.
3-Phenylamino-2-phenylsulfonylbut-2-enenitrile
(31):
White solid; mp 175–176 ꢂC; IR (KBr, cmꢁ1) 3278, 2345,
1
2190, 1573, 1389, 1141; H NMR (270 MHz, CDCl3) ꢂ 2.11 (s,
3H), 7.07 (d, J ¼ 7:6 Hz, 2H), 7.28–7.41 (m, 3H), 7.49–7.63
(m, 3H), 7.91–7.95 (m, 2H), 10.1 (br, 1H); 13C NMR (68 MHz,
CDCl3) ꢂ 19.9, 116.2, 126.0, 126.7, 128.2, 129.3, 129.7, 133.6,
136.2, 141.4, 164.1; Found: C, 64.17; H, 4.80; N, 9.37; S,
10.69%. Calcd for C16H14N2O2S: C, 64.41; H, 4.73; N, 9.39; S,
10.75%.
3-Phenylamino-2-(1-pyrrolidinecarbonyl)but-2-enenitrile
(32): White solid; mp 107–109 ꢂC; IR (KBr, cmꢁ1) 2969, 2877,
1
2190, 1581, 1434, 1373; H NMR (270 MHz, CDCl3) ꢂ 1.85 (br,
4H), 2.20 (s, 3H), 3.48–3.69 (m, 4H), 7.03 (d, J ¼ 7:8 Hz, 2H),
7.17–7.34 (m, 3H), 12.4 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ
18.9, 24.1, 26.8, 47.0, 48.8, 74.1, 120.6, 125.2 (ꢃ2), 126.6,
129.2, 137.5, 166.8, 167.4; HRMS (FAB) Calcd for C15H18N3O:
½M þ Hꢄþ 256.1444. Found: m=z 256.1453.
3-Methylamino-1-phenylbut-2-en-1-one (41):28
Colorless
1
oil; IR (neat, cmꢁ1) 2360, 2329, 1604, 1319,740; H NMR (270
MHz, CDCl3) ꢂ 2.00 (s, 3H), 2.95 (d, J ¼ 5:3 Hz, 3H), 5.62 (s,
1H), 7.28–7.34 (m, 3H), 7.74–7.80 (m, 2H), 11.3 (br, 1H);
13C NMR (68 MHz, CDCl3) ꢂ 19.4, 29.8, 91.9, 126.7 (ꢃ2),
128.0, (ꢃ2), 130.2, 140.3, 165.8, 187.4.
3-Phenylamino-2-(1-pyrrolidinecarbonyl)but-2-enoic Acid
Ethyl Ester (33): Colorless oil; IR (neat, cmꢁ1) 1735, 1643,
1
1441, 1250; H NMR (270 MHz, CDCl3) ꢂ 1.18 (t, J ¼ 7:2 Hz,
3H), 1.81–1.87 (m, 4H), 1.90 (s, 3H), 3.29–3.47 (m, 4H), 4.10
(q, J ¼ 7:2 Hz, 2H), 6.99 (d, J ¼ 7:6 Hz, 2H), 7.07–7.27 (m,
3H), 10.8 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 14.7, 17.2,
24.8, 25.9, 45.5, 47.8, 59.4, 97.4, 125.2 (ꢃ2), 125.6, 129.0
(ꢃ2), 138.3, 157.7, 167.1, 167.3; HRMS (FAB) Calcd for
C17H23N2O3: ½M þ Hꢄþ 303.1703. Found: m=z 303.1727.
2-Phenylaminohept-2-en-4-one (42):29
Colorless oil; IR
(neat, cmꢁ1) 2954, 2931, 2877, 1604, 1573; 1H NMR (270
MHz, CDCl3) ꢂ 0.90 (t, J ¼ 7:3 Hz, 3H), 1.53–1.67 (m, 2H),
1.94 (s, 3H), 2.25 (t, J ¼ 7:6 Hz, 2H), 5.11 (s, 1H), 7.02–7.29
(m, 5H), 12.5 (s, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 14.2, 19.5,
20.1, 44.4, 97.2, 124.5 (ꢃ2), 125.3, 129.0 (ꢃ2), 138.7, 160.0,
199.0.
2-(1-Phenylaminoethylidene)monothiomanonic Acid S-Eth-
yl Ester (34): Obtained as EZ mixture; Colorless oil; IR (neat,
cmꢁ1) 1697, 1651, 1573, 1250, 1173, 1172; 1H NMR (270
MHz, CDCl3) ꢂ 1.24–1.61 (m, 3H), 2.03 (s, 0.93H), 2.13 (s,
2.07H), 2.81–2.96 (m, 2H), 4.15–4.32 (m, 2H), 7.06–7.11 (m,
2H), 7.19–7.39 (m, 3H), 11.2 (br, 0.31H), 12.8 (br, 0.69H);
13C NMR (68 MHz, CDCl3) ꢂ 14.3, 14.4, 14.7, 14.8, 17.7, 19.1,
23.5, 24.7, 59.9, 60.8, 101.6, 103.5, 125.6 (ꢃ2), 125.9 (ꢃ2),
126.3, 126.9 (ꢃ2), 129.1, 129.2 (ꢃ2), 137.3, 137.8, 160.0,
163.0, 167.7, 168.4, 189.8, 193.6; HRMS (FAB) Calcd for
C15H20NO3S: ½M þ Hꢄþ 294.1158. Found: m=z 294.1172.
2,2-Dimethyl-5-phenylaminohex-4-en-3-one (43):30 Color-
1
less oil; IR (neat, cmꢁ1) 2962, 1604, 1296, 1126; H NMR (270
MHz, CDCl3) ꢂ 1.10 (s, 9H), 1.96 (s, 3H), 5.27 (s, 1H), 7.01–
7.27 (m, 5H), 12.6 (br, 1H); 13C NMR (68 MHz, CDCl3) ꢂ 20.5,
27.9 (ꢃ2), 41.7, 92.9, 124.4, 125.2 (ꢃ2), 128.9 (ꢃ2), 138.8,
160.7. 204.7.
General Procedure for Syntheses of 2-Substituted 4-Oxo-3-
quinolinecarboxylic Acid Derivatives (Scheme 1). To a solu-
tion of 14 (0.16 mmol) in toluene (1.0 mL) was added a trifluoro-
methanesulfonic acid (0.32 mmol) under an argon atmosphere at
room temperature. The reaction mixture was gently refluxed for
2 h. After the reaction mixture was cooled down to room temper-
ature, the reaction was quenched with water (5.0 mL), and the
precipitate was filtrated and washed with ethyl acetate to afford
2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid methyl
2-Cyano-3-methylaminobut-2-enoic Acid Methyl Ester
ꢂ
(35):26 White solid; 119–122 C; IR (KBr, cmꢁ1) 3810, 3494,
2198, 1666, 1280; 1H NMR (270 MHz, CDCl3) ꢂ 2.22 (s, 3H),
2.99 (d, J ¼ 5:3 Hz, 3H), 3.67 (s, 3H), 9.78 (br, 1H); 13C NMR
(68 MHz, CDCl3) ꢂ 17.6, 30.7, 51.3, 71.0, 119.2, 168.9, 170.2.
3-Methylamino-2-phenylsulfonylbut-2-enenitrile (36): Col-
orless oil; IR (neat, cmꢁ1) 3363, 2329, 1604, 1126; 1H NMR (270
MHz, CDCl3) ꢂ 2.19 (s, 3H), 3.00 (d, J ¼ 5:1 Hz, 3H), 7.47–7.59
ester (140) as a white solid; mp 189–192 ꢂC; IR (KBr, cmꢁ1
)
1651, 1458, 1411, 1296, 1219, 1173; 1H NMR (270 MHz,
DMSO-d6) ꢂ 2.39 (s, 3H), 3.75 (s, 3H), 7.35 (t, J ¼ 7:1 Hz,

T. Takuwa et al.
Bull. Chem. Soc. Jpn., 77, No. 9 (2004) 1725
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1H), 7.54 (d, J ¼ 8:2 Hz, 1H), 7.65–7.71 (m, 1H), 8.05 (dd,
J ¼ 8:2, 1.5 Hz, 1H), 12.0 (br, 1H); 13C NMR (68 MHz,
DMSO-d6) ꢂ 18.4, 51.8, 114.2, 118.0, 123.9, 124.2, 124.9,
132.3, 139.0, 149.5, 167.0, 172.9; HRMS (FAB) Calcd for
C12H12NO3: ½M þ Hꢄþ 218.0812. Found: m=z 218.0832.
4-Oxo-2-phenyl-1,4-dihydroquinoline-3-carboxylic
Acid
Methyl Ester (180): White solid; mp 175–178 ꢂC; IR (KBr,
cmꢁ1) 1666, 1643, 1450, 1427, 1288, 1234, 1157; 1H NMR
(270 MHz, DMSO-d6) ꢂ 3.49 (s, 3H), 7.39–7.42 (m, 1H), 7.56
(br, 5H), 7.70 (s, 2H), 8.11 (d, J ¼ 7:9 Hz, 1H), 12.1 (br, 1H);
13C NMR (68 MHz, DMSO-d6) ꢂ 51.7, 115.2, 118.7, 124.1,
124.4, 124.8, 128.0 (ꢃ2), 128.6 (ꢃ2), 130.3, 132.4, 133.5,
139.4, 149.2, 166.8, 173.4; HRMS (FAB) Calcd for C17H14NO3:
½M þ Hꢄþ 280.0968. Found: m=z 280.0959.
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This study was supported in part by the Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT) and the JSPS postdoctoral
fellowship for foreign researchers.
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The authors wish to thank Yamanouchi Pharmaceutical
CO., LTD. for mass spectrometry analysis and elemental
analysis.
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