Iminomalonate as a convenient electrophilic amination reagent for grignard reagents

Article abstract of DOI:10.1246/bcsj.75.1819

Diethyl 2-[N-(p-methoxyphenyl)imino]malonate underwent amination reactions with alkyl Grignard reagents to give N-aklylation products in good yields. The obtained N-alkylation products were readily converted into N-alkyl-panisidines by the oxidative removal of the malonate moiety. The p-methoxyphenyl group was subsequently deprotected to give primary amines.

Full text of DOI:10.1246/bcsj.75.1819

c. Jpn.
© 2002 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 75, 1819–1825 (2002) 1819
e Chemical
ciety of Ja-
n
e Chemical
ciety of Ja-
n
Iminomalonate as a Convenient Electrophilic Amination Reagent for
Grignard Reagents
Electrophilic Amination with Iminomalonate
Y. Niwa et al.
Yasuki Niwa, Kazuki Takayama, and Makoto Shimizu*
02
19
25
SJA8
09-2673
046
Department of Chemistry for Materials, Mie University, Tsu, Mie 514-8507
(Received February 25, 2002)
Diethyl 2-[N-(p-methoxyphenyl)imino]malonate underwent amination reactions with alkyl Grignard reagents to
give N-aklylation products in good yields. The obtained N-alkylation products were readily converted into N-alkyl-p-
anisidines by the oxidative removal of the malonate moiety. The p-methoxyphenyl group was subsequently deprotected
to give primary amines.
02
02
Electrophilic amination is a useful method for C–N bond
formation, and several reagents including azodicarboxylates
have been developed for this purpose.1,2 Recently, new re-
agents, such as oxaziridines,3 oximes,4 and oxime O-sul-
fonates,5 have also been developed as electrophilic amination
reagents. However, because amination reactions using these
reagents were not always readily carried out, the development
of a new electrophilic amination reagent has been highly desir-
Chart 1.
able. On the other hand, some N-alkylation reactions to α-imi-
no esters have been known.6 In particular, the Grignard re-
agent is one of the most convenient N-alkylation reagents for
α-imino esters. In our laboratory, we recently described the
coupling reactions of α-iminoacetates with dialkylaluminum
chloride to give N-monoalkylated 1,2-diamines in good
yields.7 During these studies we found that imines with two
electron-withdrawing substituents possessed good abilities to
react with nucleophiles on the nitrogen atom in a regioselective
manner. We studied these reactions in detail, and wish to re-
port that 2-[N-(p-methoxyphenyl)imino]malonate is an effi-
cient reagent for the electrophilic amination of Grignard re-
agents to give N-alkylation products and that the subsequent
oxidation of the malonate moiety affords N-alkyl-p-anisidines
in good yields.8
Scheme 1. Preparation of iminomalonate.
commercially available diethyl 2-oxomalonate (1)11 with p-
anisidine in 93% yield (Scheme 1):
To perform electrophilic amination, we screened the most
effective organometal. The ethylation of the imine 2 with sev-
eral organometals was examined as a model. As shown in
Table 1, diethylaluminum chloride showed a good tendency for
N-ethylation to give the desired 3a in 66% yield (entry 2),
whereas triethylborane afforded only the C-ethylation product
(entry 4). In a toluene solution, diethyl zinc gave N-ethylated
product 3a in 80% yield along with a C-ethylation product 4a
(entry 6). N-Ethylation product 3a was obtained in 84% yield
using ethylmagnesium bromide (entry 7). From the above re-
sults and the accessibility of nucleophiles, Grignard reagents
were chosen as nucleophiles. After an investigation into the
solvent effects and the molar amounts of the Grignard reagent,
1.5 molar amounts of ethylmagnesium bromide in THF was
found to be the most effective to give the N-ethylation product
3a in 91% yield (entry 10). In each case, the yield was deter-
Results and Discussion
The following sequence shows the present strategy (Chart
1). The new electrophilic amination methodology consists of
two reactions: 1) a nucleophilic addition to the nitrogen atom,
and 2) an oxidative removal of the malonate moiety. Among
various imine derivatives possessing electron-withdrawing
groups, iminomalonate was chosen as an amination reagent.
Several iminomalonates have already been known and used for
the synthesis of heterocycles.9,10 However, the nucleophilic
addition of organometals to this imine has not received much
attention. Due to a ready removal from the nitrogen atom after
the additon of nucleophiles, the p-methoxyphenyl group was
chosen as a substituent at the nitrogen.
1
An amination reagent, diethyl 2-[N-(p-methoxyphenyl)imi-
mined by H-NMR based on the relative intensity of the me-
thine proton to that of pyrazine as an internal standard because
no]malonate (2),10 was easily prepared by the condensation of

1820 Bull. Chem. Soc. Jpn., 75, No. 8 (2002)
Table 1. Ethylation of Iminomalonate 2 Using Several Organometals
Electrophilic Amination with Iminomalonate
Entry Et-Met (mol amt.)
Solvent
Time/min
Yield of 3a/% a)
Yield of 4a/% a)
1
2
3
4
5
6
7
8
9
EtAlCl2 (3.0)
Et2AlCl (3.0)
Et3Al (3.0)
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
Toluene
THF
Et2O
65
18
42
32
66
25
—
40
80
84
59
50
91
—
—
24
39
23
15
—
—
—
—
Et3B
(3.0)
27 h b)
56
Et2Zn (3.0)
Et2Zn (3.0)
EtMgBr (1.2)
EtMgBr (1.2)
EtMgBr (1.2)
EtMgBr (1.5)
17
60
10
17
Toluene
THF
10
30
1
a) Yields were determined by H NMR using pyrazine as an internal standard. b) Reaction was
carried out at –78 °C to reflux temperature.
Table 2. Oxidative Cleavage of N-Ethylation Product 3a
Entry
Oxidant (mol amt.)
Base
Temp/°C
Time/h
Yield/% a)
1
2
3
4
5
6
7
8
9
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OTfa)2 (1.5)
PhIO (1.5)
Air
KOH (2 M) b)
0 ~ rt
0 ~ 80
0 ~ rt
0 ~ rt
rt
50
rt
rt
rt
17.0
17.0
26.0
22.0
48.0
43.5
48.0
37.5
22.5
22
22
54
82
57
21
93
54
45
KOH (2 M) b)
KOH (2 M) b)
KOH (2 M) b)
KOHaq (0.44 mol. amt.)
KOHaq (0.44 mol. amt.)
KOHaq (0.44 mol. amt.)
KOHaq (0.88 mol. amt.)
KOHaq (0.44 mol. amt.)
Air
Air c)
Air c)
O2
a) Isolated yields. b) 1 M = 1 mol dm−3 c) Worked up with 10% aqueous Na2SO3.
in Scheme 2.6a The magnesium of the Grignard reagent initial-
ly coordinates to the ester carbonyl group of iminomalonate 2,
making the electron density of the nitrogen atom decrease;
alkyl group then attacks the nitrogen atom (A) to afford the
magnesium enolate (B), which in turn is hydrolyzed to give an
N-alkylation product (Scheme 2):
In order to obtain N-ethyl-p-anisidine (5a), the oxidative re-
moval of the malonate moiety was next examined (Table 2). It
is required to use an oxidant that induces α-hydroxylation of a
carbonyl compound, where the nitrogen moiety should be in-
tact. The use of (diacetoxyiodo)benzene was firstly attempt-
ed.12 However, N-ethyl-p-anisidine (5a) was obtained in only
22% yield (entries 1 & 2). Iodosylbenzene was proved to be
an effective oxidant for this reaction to give the desired product
5a in 82% yield (entry 4).13 Because oxidation with air is a
more inexpensive and convenient method,14 air oxidation was
next examined (entries 5–8). In this case, N-ethyl-p-anisidine
(5a) was obtained in 57% yield (entry 5). The yield was im-
proved up to 93% by treating with 10% aqueous Na2SO3 for
the work-up procedure (entry 7). In contrast, oxygen was not
Scheme 2. Mechanism of the amination reaction.
of the instability of N-ethylation product 3a. Although the N-
ethylation product 3a could not be always isolated, careful pu-
rification enabled the isolation of 3a, which was determined by
the LC-MS, 1H-NMR and IR spectra.
A plausible mechanism of this amination reaction is shown

Y. Niwa et al.
Bull. Chem. Soc. Jpn., 75, No. 8 (2002) 1821
Table 3. Synthesis of N-Alkyl-p-anisidine by Electrophilic Amination
Entry
R
Products
Yield of 3/%a), b)
Yield of 5/%c)
1
2
3
4
5
Methyl
Ethyl
Propyl
Butyl
Decyl
Dodecyl
3b, 5b
3a, 5a
3c, 5c
3d, 5d
3e, 5e
3f, 5f
98
91
81
63
93
79
92
79
84
98 (60) d)
78
6
94
7
8
9
Tetradecyl
Phenethyl
Cyclohexylmethyl
Isopropyl
Cyclohexyl
Benzyl
3g, 5g
3h, 5h
3i, 5i
3j, 5j
3k, 5k
3l, 5l
79
86
93
86
48
80
71
89
91
10 e), f)
11 e)
12 e)
13 e)
14 e)
57 g)
29 g)
64 g)
55 g)
67 h)
1
Phenyl
tert-Butyl
3m, 5m
3n, 5n
59
56 c)
1
a) Yields were determined by H NMR using pyrazine as internal standard. b) H-NMR
spectra of compounds 3 taken in CDCl3 showed no enol proton. c) Isolated yields. d) In
the parenthesis, butylmagnesium bromide was prepared from butyllithium and MgBr2. e)
Carried out at −95 °C. f) When first step was carried out at −78 °C, N-isopropyl-p-anisi-
dine (5j) was obtained in 23%. g) Overall yield from 2. h) Oxidative cleavage was per-
formed with iodosylbenzene.
the reagent of choice in terms of the product yield, although
the reaction time was shortened (entry 9). The low yield may
be caused by over-oxidation of the obtained amine 5a.
The mechanism of this oxidative removal with air is shown
below (Scheme 3). The α-proton of the N-alkylation product 3
is deprotonated under basic conditions. The formed enolate
(C) is then oxidized to give the intermidiate (D). This hydrop-
eroxide (D) is attacked by another enolate (C), or reduced dur-
ing the work-up to form the hemiaminal (E); a subsequent
elimimation reaction gives N-alkyl-p-anisidine 5.
sults are summarized in Table 3. Electrophilic amination using
primary alkyl Grignard reagents afforded the desired products
in good-to-excellent yields. Subsequent oxidative cleavage of
the N-alkylated products also proceeded smoothly to give N-
alkyl-p-anisidines. In entry 4, N-alkylation reaction was also
examined with Grignard reagent prepared from butyllithium
and MgBr2. In this case, the reaction proceeded similarly.
Various alkylations including secondary or tertiary alkyl and
aryl Grignard reagent could be carried out (entries 10–14). In
entries 10–13, an α-proton of the crude products 3 was clearly
identified in H NMR. However, other portions of the H
NMR spectra were not clear due to by-products and, therefore,
the overall yields of 5 from the imine 2 are shown. Although
isopropylation was conducted, N-isopropyl-p-anisidine (5j)
was obtained in 23% yield. This lower yield may be due to the
inefficiency of addition caused by the steric bulk of the Grig-
nard reagent. To improve the yield of N-isopropyl-p-anisidine
(5j), various conditions were examined. When the reaction
was carried out at −95 °C, the yield was improved to 57% (en-
try 10). However, additives such as CuI, BF3•OEt2, CeCl3, and
MgBr2 were not effective. The N-methylation and tert-butyla-
tion of α-iminoacetate were reported to be highly difficult.6a
In strong contrast to the previous observations, due to the in-
troduction of two ester groups into the imino carbon, the
present amination tolerates wide range or Grignard reagents,
and shows high regioselectivity onto the nitrogen atom for the
nucleophilic addition.
1
1
Next, the amination reaction was examined using a variety
of Grignard reagents followed by oxidative cleavage. The re-
The p-methoxyphenyl moiety of N-alkyl-p-anisidine was
readily deprotected with ammonium cerium(Ⅳ) nitrate to give
a primary amine (Scheme 4).15 N-Ethyl-p-anisidine (5a) was
Scheme 3. Mechanism of the oxidative cleavage.

1822 Bull. Chem. Soc. Jpn., 75, No. 8 (2002)
Electrophilic Amination with Iminomalonate
with brine, dried over anhydrous Na2SO4, and concentrated in vac-
1
uo. The yield was determined by H NMR using pyrazine as an
internal standard to indicate the formation of diethyl 2-[ethyl(p-
methoxyphenyl)amino]malonate in 91%. 1H NMR (CDCl3) δ
1.12 (t, J = 7.3 Hz, 3H), 1.27 (t, J = 7.3 Hz, 6H), 3.44 (q, J = 7.3
Hz, 2H), 3.76 (s, 3H), 4.24 (q, J = 7.3 Hz, 4H), 4.88 (s, 1H),
6.76–6.88 (m, 4H); IR (neat) 2950, 1760, 1620, 1520, 1260, 1040,
830, 760, 660, 570 cm−1. LC-MS (ESI) m /z 310 (M + H)+.
Diethyl 2-Ethyl-2-[(p-methoxyphenyl)amino]malonate (4a):
1H NMR (CDCl3) δ 0.77 (t, J = 7.6 Hz, 3H), 1.21 (t, J = 7.3 Hz,
6H), 2.29 (q, J = 7.6 Hz, 2H), 3.73 (s, 3H), 4.22 (q, J = 7.3 Hz,
4H), 4.81 (s, 1H), 6.61 (d, J = 8.9 Hz, 2H), 6.73 (d, J = 8.9 Hz,
2H); 13C NMR (CDCl3) δ 7.43, 13.98, 24.52, 55.56, 62.06, 69.14,
114.62, 116.86, 137.92, 152.92, 170.21; IR (neat) 3380, 2950,
Scheme 4. Removal of p-methoxyphenyl group.
firstly converted into benzylcarbamate 6a with benzyl chloro-
formate in 95% yield.16 This carbamate was exposed to CAN
in the usual manner to give benzyl N-ethylcarbamate (7a) in
92% yield.
1740, 1520, 1250, 1040, 830 cm−1
.
HRMS m/z calcd for
C16H23NO5 (M+): 309.1576, found: 309.1561.
Diethyl 2-[(p-Methoxyphenyl)methylamino]malonate (3b):
1H NMR (CDCl3) δ 1.28 (t, J = 7.3 Hz, 6H) 3.02 (s, 3H), 3.75 (s,
3H), 4.25 (q, J = 7.3 Hz, 4H), 4.98 (s, 1H), 6.72–6.91 (m, 4H); IR
Conclusion
(neat) 3350, 2920, 1520, 1240, 1050, 830 cm−1
.
Iminomalonate was found to be an efficient electrophilic
amination reagent for Grignard reagents. In particular, diethyl
2-[N-(p-methoxyphenyl)imino]malonate was proved to be the
most efficient amination reagent for primary alkyl Grignard re-
agents to give N-alkyl-p-anisidines in excellent yields, al-
though electrophillic amination of secondary, tertiary-alkyl
and aryl Grignard reagents gave slightly lower yields of the
amination products. In view of preparing the iminomalonate
and removing the p-methoxyphenyl moiety, this method is a
useful addition to the existing methodologies for electrophilic
amination.
Diethyl 2-[(p-Methoxyphenyl)propylamino]malonate (3c):
1H NMR (CDCl3) δ 0.86 (t, J = 7.3 Hz, 3H), 1.27 (t, J = 7.3 Hz,
6H), 1.46–1.60 (m, 2H), 3.31 (t, J = 7.3 Hz, 2H), 3.76 (s, 3H),
4.23 (q, J = 7.3 Hz, 4H), 4.87 (s, 1H), 6.81 (d, J = 9.6 Hz, 2H).
6.88 (d, J = 9.6 Hz, 2H); IR (neat) 3350, 2920, 1520, 1240, 1050,
830 cm−1
.
Diethyl 2-[Butyl(p-methoxyphenyl)amino]malonate (3d):
1H NMR (CDCl3) δ 0.89 (t, J = 7.3 Hz, 3H), 1.21–1.37 (m, 2H),
1.27 (t, J = 7.3 Hz, 6H), 1.40–1.54 (m, 2H), 3.35 (t, J = 7.6 Hz,
2H), 3.76 (s, 3H), 4.23 (q, J = 7.3 Hz, 4H), 4.86 (s, 1H), 6.81 (d, J
= 9.6 Hz, 2H), 6.88 (d, J = 9.6 Hz, 2H); IR (neat) 3370, 2950,
1530, 1250, 1060, 840 cm−1
.
Diethyl 2-[Decyl(p-methoxyphenyl)amino]malonate (3e):
1H NMR (CDCl3) δ 0.87 (t, J = 6.9 Hz, 3H), 1.18–1.34 (m, 20H),
1.47–1.50 (m, 2H), 3.33 (t, J = 7.3 Hz, 2H), 3.76 (s, 3H), 4.23 (q,
J = 7.3 Hz, 4H), 4.86 (s, 1H), 6.81 (d, J = 9.2 Hz, 2H), 6.87 (d, J
= 9.2 Hz, 2H); IR (neat) 3350, 2900, 2840, 1750, 1530, 1480,
Experimental
General Aspects. Infrared spectra were determined on a
JASCO IR-810 spectrometer. 1H NMR and 13C-NMR spectra
were recorded with a JEOL EX-270 or a JEOL α-500 spectrome-
ter using tetramethylsilane as an internal standard. HRMS were
determined with a JEOL JMX-AX505HA. THF and ether were
distilled from sodium diphenylketyl before use. Ethanol was dis-
tilled from sodium ethoxide. Preparative TLC purification was
carried out using silica gel (Merck Kiesel Gel PF254).
1250, 1190, 1050, 830 cm−1
.
Diethyl 2-[Dodecyl(p-methoxyphenyl)amino]malonate (3f):
1H NMR (CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.18–1.30 (m, 24H),
1.48–1.50 (m, 2H), 3.33 (t, J = 7.3 Hz, 2H), 3.76 (s, 3H), 4.23 (q,
J = 7.3 Hz, 4H), 4.86 (s, 1H), 6.81 (d, J = 9.6 Hz, 2H), 6.87 (d, J
= 9.6 Hz, 2H); IR (neat) 2900, 1750, 1530, 1480, 1260, 1180,
Diethyl 2-[N-(p-Methoxyphenyl)imino]malonate (2):10 To
a solution of p-anisidine (812.9 mg, 6.6 mmol) in benzene (30
mL) were added diethyl 2-oxomalonate (0.963 mL, 6.0 mmol) and
p-toluenesulfonic acid (57.1 mg, 0.3 mmol) under an argon atmo-
sphere. The reaction mixture was heated at reflux for 20 h with
azeotropic removal. The solvent was evaporated, and the residue
was purified with Kugelrohr distillation to give the title product in
93% yield (bp 138 °C/43 Pa). 1H NMR (CDCl3) δ 1.18 (t, J = 7.3
Hz, 3H), 1.40 (t, J = 7.3 Hz, 3H), 3.81 (s, 3H), 4.25 (q, J = 7.3
Hz, 2H), 4.44 (q, J = 7.3 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 7.08
(d, J = 8.9 Hz, 2H); 13C NMR (CDCl3) δ 13.78, 14.05, 55.40,
62.03, 62.79, 114.20, 122.59, 140.20, 150.18, 159.23, 161.33,
1050, 840 cm−1
Diethyl
.
2-[(p-Methoxyphenyl)tetradecylamino]malonate
(3g): 1H-NMR (CDCl3) δ 0.88 (t, J = 6.6 Hz, 3H), 1.26–1.30
(m, 28H), 1.50 (br, 2H), 3.34 (t, J = 7.9 Hz, 2H), 3.76 (s, 3H),
4.23 (q, J = 7.3 Hz, 4H), 4.86 (s, 1H), 6.81 (d, J = 9.2 Hz, 2H),
6.87 (d, J = 9.2 Hz, 2H). IR (neat) 2900, 1750, 1530, 1480, 1260,
1180, 1050, 840 cm−1
Diethyl
.
2-[(p-Methoxyphenyl)phenethylamino]malonate
(3h): 1H NMR (CDCl3) δ 1.26 (t, J = 6.9 Hz, 6H), 2.81 (t, J =
7.3 Hz, 2H), 3.62 (t, J = 7.3 Hz, 2H), 3.78 (s, 3H), 4.19 (q, J =
6.9 Hz, 4H), 4.89 (s, 1H), 6.85 (d, J = 7.9 Hz, 2H), 6.95 (d, J =
7.9 Hz, 2H), 7.16–7.31 (m, 5H).
163.40; IR (neat) 2950, 1750, 1510, 1260, 1080, 860 cm−1
.
Diethyl 2-[Ethyl(p-methoxyphenyl)amino]malonate (3a):
Under an argon atmosphere, to a solution of diethyl 2-[N-(p-meth-
oxyphenyl)imino]malonate (83.8 mg, 0.300 mmol) in THF (5.00
mL), EtMgBr (0.542 mL, 0.450 mmol, 0.83 M in THF) was slow-
ly added at −78 °C. After 30 min, saturated aqueous NaHCO3
was added, and the whole mixture was then extracted with ethyl
acetate (10 mL × 3). The combined organic extracts were washed
Diethyl 2-[Cyclohexylmethyl(p-methoxyphenyl)amino]mal-
onate (3i): 1H NMR (CDCl3) δ 0.85–0.89 (m, 2H), 1.05–1.24
(m, 3H), 1.26 (t, J = 7.3 Hz, 6H), 1.38–1.46 (m, 1H), 1.59–1.77
(m, 5H), 3.20 (d, J = 7.3 Hz, 2H), 3.75 (s, 3H), 4.19–4.26 (m,
4H), 4.80 (s, 1H), 6.81 (d, J = 9.2 Hz, 2H), 6.98 (d, J = 9.2 Hz,
2H).
Diethyl
2-[tert-Butyl(p-methoxyphenyl)amino]malonate

Y. Niwa et al.
Bull. Chem. Soc. Jpn., 75, No. 8 (2002) 1823
(3n): 1H NMR (CDCl3) δ 1.07 (t, J = 7.3 Hz, 6H), 1.12 (s, 9H),
3.69 (s, 3H), 3.99 (q, J = 7.3 Hz, 4H), 4.77 (s, 1H), 6.66 (d, J =
8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3) δ 13.88,
29.60, 55.18, 56.18, 61.05, 65.48, 112.78, 133.35, 137.61, 157.37,
169.88; IR (neat) 2950, 1760, 1620, 1520, 1475, 1380, 1055, 855
cm−1. HRMS m/z: calcd for C18H27NO5 (M+): 337.1889, found:
337.1888.
= 8.9 Hz, 2H), The N-H proton could not be detected; 13C NMR
(CDCl3) δ 14.09, 22.67, 27.19, 29.34, 29.46, 29.59, 29.65, 29.67,
29.69, 31.91, 45.03, 55.81, 114.00, 114.89, 142.87, 151.95; IR
(CHCl3) 3400, 2820, 1610, 1520, 1475, 1320, 1260, 1050, 850
cm−1. HRMS m/z: calcd for C21H37NO (M+): 319.2875, found:
319.2846.
N-Phenethyl-p-anisidine (5h):18 1H NMR (CDCl3) δ 2.90 (t,
J = 6.9 Hz, 2H), 3.35 (t, J = 6.9 Hz, 2H), 3.74 (s, 3H), 6.58 (d, J
= 8.9 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), 7.20–7.34 (m, 5H), The
N-H proton could not be detected; 13C NMR (CDCl3) δ 35.58,
46.04, 55.78, 114.38, 114.92, 126.35, 128.31, 128.56, 128.77,
139.38, 142.21, 152.18; IR (neat) 3360, 3000, 2900, 2800, 1520,
N-Ethyl-p-anisidine (5a): The crude product, including di-
ethyl 2-[ethyl(p-methoxyphenyl)amino]malonate (0.274 mmol),
was vigorously stirred in a mixture of 1.0 M KOHaq (0.121 mL)
and EtOH (3.48 mL). After 48 h, 10% Na2SO3aq was added to
this mixture. EtOH was then evaporated, and the residue was ex-
tracted with ethyl acetate (10 mL × 3). The combined organic ex-
tracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by prepar-
ative TLC on silica gel (ethyl acetate/hexane =1:10) to give N-
ethyl-p-anisidine (38.5 mg, 93%). 1H NMR (CDCl3) δ 1.24 (t, J
= 7.3 Hz, 3H), 3.11 (q, J = 7.3 Hz, 2H), 3.74 (s, 3H), 6.59 (d, J =
8.9 Hz, 2H), 6.78 (d, J = 8.9 Hz, 2H), The N-H proton could not
be detected; 13C NMR (CDCl3) δ 14.95, 39.48, 55.80, 114.14,
114.89, 142.68, 152.09; IR (neat) 2880, 1530, 1260, 1050, 830
cm−ꢀ. HRMS m/z: Calcd for C9H13NO (M+): 151.0997, found:
151.0981.
1250, 1050, 830, 750, 710 cm−1
.
N-Cyclohexylmethyl-p-anisidine (5i): 1H NMR (CDCl3) δ
0.91–1.07 (m, 2H), 1.10–1.37 (m, 3H), 1.45–1.83 (m, 6H), 2.90
(d, J = 6.6 Hz, 2H), 3.22 (br, 1H), 3.74 (s, 3H), 6.56 (d, J = 8.9
Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), The N-H proton could not be
detected; 13C NMR (CDCl3) δ 25.95, 26.57, 31.29, 37.57, 51.63,
55.79, 62.03, 113.88, 114.89, 142.92, 151.80; IR (neat) 3360,
2910, 2820, 1530, 1270, 1250, 1050, 830 cm−1. HRMS m/z: calcd
for C14H21NO (M+): 219.1623, found: 291.1634.
N-Isopropyl-p-anisidine (5j):2g Under an argon atmosphere,
to a solution of diethyl 2-[N-(p-methoxyphenyl)imino]malonate
(83.8 mg, 0.300 mmol) in THF (5.00 mL), isopropylmagnesium
bromide (0.542 mL, 0.450 mmol, 0.83 M in THF) was slowly add-
ed at –95 °C. After 30 min, saturated aqueous NaHCO3 was add-
ed, and the whole mixture was then extracted with ethyl acetate
(10 mL × 3). The combined organic extracts were washed with
brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
Then, the crude product was vigorously stirred in a mixture of 1.0
M KOHaq (0.114 mL) and EtOH (3.30 mL). After 48 h, 10%
Na2SO3aq was added to this mixture. EtOH was then evaporated,
and the residue was extracted with ethyl acetate (10 mL × 3). The
combined organic extracts were washed with brine, dried over an-
hydrous Na2SO4, and concentrated in vacuo. The crude product
was purified by preparative TLC on silica gel (ethyl acetate/hex-
ane =1:15, twice) to give N-isopropyl-p-anisidine (28.2 mg,
57%). 1H NMR (CDCl3) δ 1.19 (d, J = 6.3 Hz, 6H), 3.48–3.61
(m, 1H), 3.74 (s, 3H), 6.57 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.9
Hz, 2H), The N-H proton could not be detected; 13C NMR
(CDCl3) δ 23.07, 45.24, 55.79, 114.93, 141.73, 151.95; IR (neat)
N-Methyl-p-anisidine (5b):17 1H NMR (CDCl3) δ 2.80 (s,
3H), 3.75 (s, 3H), 6.60 (d, J = 8.2 Hz, 2H), 6.80 (d, J = 8.2 Hz,
2H), The N-H proton could not be detected; 13C NMR (CDCl3) δ
31.66, 55.84, 113.73, 114.90, 143.54, 152.16; IR (neat) 3360,
2930, 1530, 1250, 830, 420 cm−1
.
N-Propyl-p-anisidine (5c): 1H NMR (CDCl3) δ 0.99 (t, J =
7.3 Hz, 3H), 1.56–1.69 (m, 2H), 3.03 (t, J = 7.3 Hz, 2H), 3.75 (s,
3H), 6.58 (d, J = 9.2 Hz, 2H), 6.78 (d, J = 9.2 Hz, 2H), The N-H
proton could not be detected; 13C NMR (CDCl3) δ 11.62, 13.98,
22.80, 46.84, 55.83, 114.03, 114.90, 142.81, 151.97; IR (neat)
3350, 2920, 1530, 1240, 1050, 830 cm−1. HRMS m/z: calcd for
C10H15NO (M+): 165.1154, found: 165.1145.
N-Butyl-p-anisidine (5d):17 1H NMR (CDCl3) δ 0.95 (t, J =
7.3 Hz, 3H), 1.35–1.49 (m, 2H), 1.54–1.64 (m, 2H), 3.07 (t, J =
6.9 Hz, 2H), 3.75 (s, 3H), 6.59 (d, J = 8.9 Hz, 2H), 6.78 (d, J =
8.9 Hz, 2H), The N-H proton could not be detected; 13C NMR
(CDCl3) δ 13.89, 20.29, 31.74, 44.73, 55.79, 114.05, 114.88,
142.76, 151.99; IR (neat) 3370, 2940, 1530, 1250, 1060, 830
cm−1
.
3350, 2940, 1525, 1470, 1240, 1180, 1050, 830, 760, 530 cm−1
.
N-Decyl-p-anisidine (5e): 1H NMR (CDCl3) δ 0.88 (t, J =
6.9 Hz, 3H), 1.27–1.37 (m, 14H), 1.54–1.64 (m, 2H), 3.05 (t, J =
7.3 Hz, 2H), 3.74 (s, 3H), 6.57 (d, J = 8.9 Hz, 2H), 6.78 (d, J =
8.9 Hz, 2H), The N-H proton could not be detected; 13C NMR
(CDCl3) δ 14.08, 22.65, 27.19, 29.30, 29.46, 29.55, 29.59, 29.68,
31.87, 45.04, 55.80, 114.01, 114.89, 142.85, 151.95; IR (neat)
N-Cyclohexyl-p-anisidine (5k): The reaction was carried
out as in the case with 5j using cyclohexylmagnesium bromide
(0.662 mL, 0.450 mmol, 0.68 M in THF), and N-cyclohexyl-p-
anisidine (18.2 mg, 29%) was obtained. 1H NMR (CDCl3) δ
1.04–1.43 (m, 5H), 1.61–1.79 (m, 3H), 2.01–2.06 (m, 2H), 3.10–
3.21 (m, 1H), 3.74 (s, 3H), 6.57 (d, J = 8.6 Hz, 2H), 6.76 (d, J =
8.6 Hz, 2H), The N-H proton could not be detected; 13C NMR
(CDCl3) δ 14.09, 15.25, 22.63, 25.06, 25.97, 31.57, 33.60, 52.84,
55.81, 65.83, 114.89, 114.91, 141.53, 151.91; IR (CHCl3) 3390,
3400, 2820, 1610, 1530, 1480, 1250, 1050, 830 cm−1
. HRMS
m/z: calcd for C17H29NO (M+): 263.2249, found: 263.2239.
N-Dodecyl-p-anisidine (5f): 1H NMR (CDCl3) δ 0.88 (t, J =
6.9 Hz, 3H), 1.18–1.37 (m, 18H), 1.54–1.61 (m, 2H), 3.05 (t, J =
7.3 Hz, 2H), 3.74 (s, 3H), 6.57 (d, J = 8.9 Hz, 2H), 6.78 (d, J =
8.9 Hz, 2H), The N-H proton could not be detected; 13C NMR
(CDCl3) δ 14.10, 22.68, 27.19, 29.33, 29.47, 29.60, 29.62, 29.65,
29.68, 31.91, 45.07, 55.83, 114.05, 114.90, 142.82, 151.99; IR
(CHCl3) 3400, 2900, 2820, 1520, 1475, 1300, 1260, 1050, 850
cm−1. HRMS m/z: calcd for C19H33NO (M+): 291.2562, found:
291.2548.
2970, 2910, 2830, 1520, 1460, 1300, 1250, 830 cm−1
m/z: calcd for C13H19NO (M+) 205.1467, found 205.1470.
. HRMS
N-Benzyl-p-anisidine (5l):17 The reaction was carried out as
in the case with 5j using benzylmagnesium chloride (1.17 mL,
0.450 mmol, 0.39 M in THF), and N-benzyl-p-anisidine (40.8 mg,
64%) was obtained. 1H NMR (CDCl3) δ 3.74 (s, 3H), 4.28 (s,
2H), 6.60 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 7.24–7.38
(m, 5H), The N-H proton could not be detected; 13C NMR
(CDCl3) δ 49.31, 55.79, 114.21, 114.90, 127.17, 127.56, 128.57,
139.57, 142.29, 152.27; IR (neat) 3400, 2820, 1530, 1260, 840
N-Tetradecyl-p-anisidine (5g): 1H NMR (CDCl3) δ 0.88 (t,
J = 7.3 Hz, 3H), 1.14–1.37 (m, 22H), 1.54–1.64 (m, 2H), 3.05 (t,
J = 6.9 Hz, 2H), 3.75 (s, 3H), 6.57 (d, J = 8.9 Hz, 2H), 6.78 (d, J
cm−1
.

1824 Bull. Chem. Soc. Jpn., 75, No. 8 (2002)
Electrophilic Amination with Iminomalonate
N-Phenyl-p-anisidine (5m):19 The reaction was carried out
as in the case with 5j using phenylmagnesium bromide (0.616 mL,
0.450 mmol, 0.73 M in THF), and N-phenyl-p-anisidine (32.5 mg,
55%) was obtained. 1H NMR (CDCl3) δ 3.84 (s, 3H), 6.83–7.26
(m, 9H), The N-H proton could not be detected; 13C NMR
(CDCl3) δ 55.54, 114.64, 115.64, 119.54, 122.18, 129.27, 135.70,
145.12, 155.26; IR (CHCl3) 3400, 2820, 1610, 1520, 1510, 1475,
1320, 1310, 1260, 1190, 1050, 850 cm−1. HRMS m/z: calcd for
C13H13NO (M+) 199.0997, found 199.0973.
References
a) P. Dembech, G. Seconi, and A. Ricci, Chem. Eur. J., 6,
1281 (2000). b) C. Greck and P. Genêt, Synlett, 1997, 741. c) E.
Erdik and M. Ay, Chem. Rev., 89, 1947 (1989).
1
2
a) R. W. Hoffmann, B. Hölzer, and O. Knopff, Org. Lett., 3,
1945 (2001). b) S. Fioravanti, A. Morreale, L. Pellacani, and P. A.
Tardella, Tetrahedron Lett., 42, 1171 (2001). c) G. Cardillo, L.
Gianotti, R. Perciaccante, and A. Tolomelli, J. Org. Chem., 66,
8657 (2001). d) P. C. B. Page, M. J. McKenzie, S. M. Allin, and
D. R. Buckle, Tetrahedron, 56, 9683 (2000). e) D. A. Evans and
D. S. Johnson, Org. Lett., 1, 595 (1999). f) D. K. An, K.
Hirakawa, S. Okamoto, and F. Sato, Tetrahedron Lett., 40, 3737
(1999). g) P. Bernardi, P. Dembech, G. Fabbri, A. Ricci, and G.
Seconi, J. Org. Chem., 64, 641 (1999). h) R. Velarde-Ortiz, A.
Guijarro, and R. D. Rieke, Tetrahedron Lett., 39, 9157 (1998).
N-(tert-Butyl)-p-anisidine (5n):20 To a solution of potassium
hydroxide (337 mg, 6 mmol) in ethanol (3.0 mL) was added a eth-
anol (0.5 mL) solution of diethyl 2-[tert-butyl(p-methoxyphen-
yl)amino]malonate (42.3 mg, 0.125 mmol) and subsequently io-
dosylbenzene (41.4 mg, 0.188 mmol) at 0 °C. After stirring for 19
h at room temperature and an additional 22 h at 50 °C, solvent was
removed in vacuo, and then sat. NH4Claq was added. This mix-
ture was extracted with ethyl acetate (5 mL × 3). All organic ex-
tracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. Purification was performed by preparative
TLC on silica gel (ethyl acetate/hexane =1:10, 3 times) to give N-
(tert-butyl)-p-anisidine (15.1 mg, 67%). 1H NMR (CDCl3) δ 1.21
(s, 9H), 2.09 (br, 1H), 3.76 (s, 3H), 6.75–6.83 (m, 4H), The N-H
proton could not be detected; 13C NMR (CDCl3) δ 30.07, 52.36,
55.50, 114.03, 122.92, 154.39; IR (neat) 2950, 1655, 1530, 1375,
3
a) A. Armstrong, M. A. Atkin, and S. Swallow, Tetrahe-
dron: Asymmetry, 12, 535 (2001). b) P. C. B. Page, V. L. Murrell,
C. Limousin, D. D. P. Laffan, D. Bethell, A. M. Z. Slawin, and T.
A. D. Smith, J. Org. Chem., 65, 4204 (2000). c) A. Armstrong, M.
A. Atkin, and S. Swallow, Tetrahedron Lett., 41, 2247 (2000). d)
D. Enders, C. Poiesz, and R. Joseph, Tetrahedron: Asymmetry, 9,
3709 (1998). e) J. Vidal, S. Damestoy, L. Guy, J.-C. Hannachi, A.
Aubry, and A. Collet, Chem. Eur. J., 3, 1691 (1997). f) J. Vidal, L.
Guy, S. Stérin, and A. Collet, J. Org. Chem., 58, 4791 (1993). g)
S. Andreae, E. Schmitz, J.-P. Wulf, and B. Schulz, Liebigs. Ann.
Chem., 1992, 239. h) S. Andreae and E. Schmitz, Synthesis, 1991,
327.
1240, 1050, 840 cm−1
Benzyl N-Ethyl-N-(p-methoxyphenyl)carbamate (6a):
.
To
a mixture of N-ethyl-p-anisidine (5a) (590 mg, 3.9 mmol), THF
(2.0 mL) and aqueous Na2CO3 solution (10 mL, 4.0 M), benzyl
chloroformate (0.628 mL, 4.4 mmol) and aqueous Na2CO3 solu-
tion (5 mL, 4.0 M), were successively added at 0 °C. After stirring
for 3 h at room temperature, water was added, and the whole mix-
ture was extracted with ethyl acetate (10 mL × 3). The combined
extracts were dried over anhydrous Na2SO4, and concentrated in
vacuo. The crude product was purified by flash chromatography
(ethyl acetate/hexane=1:10) to give the title product (1.06 g,
93%). 1H NMR (CDCl3) δ 1.13 (t, J = 7.3 Hz, 3H), 3.68 (q, J =
7.3 Hz, 2H), 3.79 (s, 3H), 5.13 (br, 2H), 6.87 (d, J = 8.9 Hz, 2H),
7.08–7.36 (m, 7H); 13C NMR (CDCl3) δ 13.56, 45.47, 55.34,
66.84, 114.12, 127.65, 128.29, 128.55, 136.87, 155.41, 158.08; IR
(neat) 2950, 2920, 1720, 1700, 1620, 1520, 1255, 1165, 1040, 850
cm−1. HRMS m/z: calcd for C17H19NO3 (M+) 285.1365, found:
285.1367.
4
5
G. Alvernhe and A. Laurent, Tetrahedron Lett., 1972, 1007.
a) H. Tsutsui, T. Ichikawa, and K. Narasaka, Bull. Chem.
Soc. Jpn., 72, 1869 (1999). b) E. Erdik, and T. Daskapan, J.
Chem. Soc., Perkin Trans. 1, 1999, 3139. c) E. Erdik and T.
Daskapan, Synth. Commun., 29, 3989 (1999). d) H. Tsutsui, Y.
Hayashi, and K. Narasaka, Chem. Lett., 1997, 317. e) E. Erdik
and M. Ay, Synth. React. Inorg. Met. -Org. Chem., 19, 663 (1989).
f) R. A. Hagopian, M. J. Therien, and J. R. Murdoch, J. Am. Chem.
Soc., 106, 5753 (1984).
6
a) J.-C. Fiaud and H. B. Kagan, Tetrahedron Lett., 1971,
1019. b) Y. Yamamoto and W. Ito, Tetrahedron, 44, 5415 (1988).
c) K. Uneyama, F. Yan, S. Hirama, and T. Katagiri, Tetrahedron
Lett., 37, 2045 (1996). d) M. P. Bertrand, L. Feray, R. Nouguier,
and P. Perfetti, Synlett, 1999, 1148.
Benzyl N-Ethylcarbamate (7a):21 To an acetonitrile (1.2
mL) solution of benzyl N-ethyl-N-(p-methoxyphenyl)carbamate
(42.8 mg, 0.150 mmol), a solution of ammonium cerium(Ⅳ) ni-
trate (247 mg, 0.450 mmol) in water (1.6 mL) was slowly added at
−15 °C. This mixture was allowed to warm to −10 °C with stir-
ring for 30 min. The reaction mixture was diluted with water (10
mL) and extracted with ethyl acetate (5 mL × 3). The organic ex-
tracts were washed with 5% NaHCO3aq (10 mL), and the aqueous
layer was extracted with ethyl acetate (5 mL × 2). The combined
organic extracts were washed with 10% NaHSO3aq, 5%
NaHCO3aq, and brine, and then dried over anhydrous Na2SO4,
and concentrated in vacuo. The crude product was purified by
preparative TLC on silica gel (ethyl acetate/hexane =1:10) to give
benzyl N-ethylcarbamate (24.8 mg, 92%). 1H NMR (CDCl3) δ
1.13 (t, J = 7.3 Hz, 3H), 3.23 (quint, J = 7.3 Hz, 2H), 4.75 (br,
1H), 5.09 (s, 2H), 7.26–7.35 (m, 5H); 13C NMR (CDCl3) δ 15.19,
35.88, 66.49, 128.02, 128.06, 128.46, 136.65, 156.25; IR (neat)
7
(2001).
8
M. Shimizu and Y. Niwa, Tetrahedron Lett., 42, 2829
Preliminary results have already been reported as a com-
munication. See, Y. Niwa, K. Takayama, and M. Shimizu, Tetra-
hedron Lett., 42, 5473 (2001).
9
a) L. F. Tietze and M. Bratz, Liebigs. Ann. Chem., 1989,
559. b) L. F. Tietze and M. Bratz, Chem Ber., 122, 997 (1989). c)
L. F. Tietze, M. Bratz, and M. Pretor, Chem Ber., 122, 1955
(1989). d) J. Frank, G. Stoll, and H. Musso, Liebigs. Ann. Chem.,
1986, 1990. e) A. V. Prosyanik, A. S. Moskalenko, J. Moretti, A.
Forni, G. Torre, and R. G. Kostyanovskii, J. Org. Chem. USSR, 21,
431 (1986). f) A. V. Prosyanik, D. V. Fedoseenko, and V. I.
Markov, J. Org. Chem. USSR, 21, 1494 (1986).
10 a) B. K. Banik, M. S. Manhas, E. W. Robb, and A. K. Bose,
Heterocycles, 44, 405 (1997). b) K. Oka and S. Hara, Tetrahedron
Lett., 1977, 2939. c) A. K. Bose, M. Tsai, and J. C. Kapur, Tetra-
hedron Lett., 1974, 3547.
3310, 2950, 1710, 1545, 1460, 1270, 1030 cm−1
.
11 a) L. F. Tietze and M. Bratz, Org. Synth., 71, 214 (1992).
b) H. H. Wasserman and W. T. Han, Tetrahedron Lett., 25, 3743

Y. Niwa et al.
Bull. Chem. Soc. Jpn., 75, No. 8 (2002) 1825
(1984). c) M. E. Jung, K. Shishido, and L. H. Davis, J. Org.
Chem., 47, 891 (1982). d) S. N. Pardo and R. G. Salomon, J. Org.
Chem., 46, 2598 (1981). e) A. W. Dox, Org. Synth., Coll. Vol. 1,
266 (1941). f) E. Gilman and T. B. Johnson, J. Am. Chem. Soc.,
50, 3341 (1928).
12 a) R. M. Moriarty, O. Prakash, P. Karalis, and I. Prakash,
Tetrahedron Lett., 25, 4745 (1984). b) R. M. Moriarty and H. Hu,
Tetrahedron Lett., 22, 2747 (1981).
13 R. M. Moriarty, H. Hu, and S. C. Gupta, Tetrahedron Lett.,
22, 1283 (1981).
14 L. Crombie and P. J. Godin, J. Chem. Soc., 1961, 2861.
15 D. R. Kronenthal, C. Y. Han, and M. K. Taylor, J. Org.
Chem., 47, 2765 (1982).
1, 1989, 2455.
17 Compared with a commercial sample.
18 a) M. Beller, O. R. Thiel, H. Tranthwein, and C. G.
Hartung, Chem. Eur. J., 6, 2513 (2000). b) M. Takamatsu and M.
Sekiya, Chem. Pharm. Bull., 29, 616 (1981).
19 U. Pindur and D. Keilhofer, Liebigs. Ann. Chem., 1993,
943.
20 J. R. Gage and J. M. Wagner, J. Org. Chem., 60, 2613
(1995).
21 a) M. A. H. Fahmy and T. R. Fukuto, J. Agric. Food Chem.,
29, 567 (1981). b) P. Berntsson, A. Brandstrom, U. Junggren, L.
Palmer, S. E. Sjostrand, and G. Sundell, Acta. Pharm. Suec., 14,
229 (1977).
16 G. B. Jones and C. J. Moody, J. Chem. Soc., Perkin Trans.