Short and practical synthesis of N′,N′-disubstituted N-aryl-1,2-ethylene-diamines by a decarboxylative ring-opening reaction under nucleophilic conditions

Article abstract of DOI:10.1055/s-2007-983810

A straightforward and practical synthesis of N′,N′- disubstituted N-aryl-1,2-ethylenediamines, starting from anilines, via N-aryloxazolidin-2-ones is described. A decarboxylative ring-opening reaction of N-aryloxazolidin-2-ones, using aliphatic secondary

Full text of DOI:10.1055/s-2007-983810

PAPER
2517
Short and Practical Synthesis of N¢,N¢-Disubstituted N-Aryl-1,2-Ethylene-
diamines by a Decarboxylative Ring-Opening Reaction under Nucleophilic
Conditions
S
hor
t
Synthesisof
a
N
¢
,N
¢
-Disu
s
bstituted
N
u
-Aryl-1,2-E
h
thylenediam
i
ines ro Morita, Takeshi Ishigaki, Kuniaki Kawamura, Katsuhiko Iseki*
Toray Industries Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan
Fax +81(467)322127; E-mail: Katsuhiko_Iseki@nts.toray.co.jp
Received 30 March 2007; revised 7 May 2007
by attack at the C-5 position under electrophilic condi-
Abstract: A straightforward and practical synthesis of N¢,N¢-disub-
stituted N-aryl-1,2-ethylenediamines, starting from anilines, via N-
aryloxazolidin-2-ones is described. A decarboxylative ring-opening
reaction of N-aryloxazolidin-2-ones, using aliphatic secondary
tions using aromatic amine hydrochloride salts, in contrast
to the urea formation which exclusively occurred by at-
tack at the C-2 carbonyl position under nucleophilic con-
amines, is the key step in this procedure. A one-pot synthesis of N- ditions with free aliphatic or aromatic amines [affording
N-(2-hydroxyethyl) urea].7
aryloxazolidin-2-ones is also described. N¢,N¢-Disubstituted N-aryl-
1,2-ethylenediamines are a useful building block for biologically
On the basis of the above background work, it was clear
that an improved decarboxylative ring opening reaction
would lead to a more direct and efficient, practical syn-
thetic method for the preparation of compounds of type 1
active compounds.
Key words: amines, cyclization, heterocycles, piperidines, ring
opening
(Scheme 1). In this communication, we report that nucleo-
philic conditions – heating in DMSO with a free aliphatic
The development of a practical method for the synthesis
secondary amine – promotes the desired decarboxylative
of substituted 1,2-ethylenediamines has been an important
ring opening reaction to afford compounds of type 1. We
goal because N¢,N¢-disubstituted N-aryl-1,2-ethylenedi-
also report the one-pot synthesis of N-aryloxazolidin-2-
amine moieties, which constitute an important class of
ones 2 from anilines.
substituted 1,2-ethylenediamines, are found in pharmaco-
logically active compounds1 with antihistamic2 and anti-
muscarinic activity.3 Although numerous synthetic
methods are known, short, practical methods are still in
demand. Two examples of synthetic routes to N¢,N¢-di-
substituted N-aryl-1,2-ethylenediamines of type 1 have
been reported. One employs the ring-opening reaction of
cyclic sulfamidates with secondary amines,4 though the
utility of this transformation is limited since the prepara-
tion of highly functionalized cyclic sulfamidates usually
requires multi-step sequences from commercially avail-
able starting materials. The second method, which pro-
ceeds in a few steps in low yield, uses a decarboxylative
ring opening reaction of oxazolidin-2-ones 2 reported by
Poindexter and co-workers.5,6 They described6 that the de-
carboxylative ring opening of oxazolidin-2-one occurred
For our preliminary studies, we selected N-(p-chlorophe-
nyl)oxazolidin-2-one and 4-hydroxylpiperidine hydro-
chloride as substrates and the reaction was carried out in
dimethyl sulfoxide (DMSO) at 100 °C (Table 1, entry 1).
DMSO was used as a practical solvent instead of 2-(2-
methoxyethoxy)ethanol (160–170 °C) employed in Poin-
dexter’s studies. After 24 hours heating, the desired prod-
uct 1e was observed in only 3% yield, probably due to the
relatively low temperature (100 °C vs 160–170 °C). To
our surprise, the decarboxylative ring opening reaction
gave the desired product 1 in higher yield (20%) under the
same conditions (100 °C, 24 h) using free 4-hydroxylpip-
eridine without any formation of undesired side products,
including the urea derivative (entry 2). The exact reasons
why no urea derivative was formed under nucleophilic
R2
O
n
Cl
O
Cl
NH
(1.25 equiv)
K2CO3 (2.5 equiv)
(3.0 equiv)
no additive
R2
O
n
R1
R1
R1
N
O
N
MeCN (0.5 M)
r.t. to reflux
DMSO (1.0 M)
110 °C
N
H2N
(1.0 equiv)
H
2
1
Scheme 1 Synthetic route to N¢,N¢-disubstituted N-aryl-1,2-ethylenediamines 1 via N-aryloxazolidin-2-ones 2
SYNTHESIS 2007, No. 16, pp 2517–2523
x
x.
x
x
.
2
0
0
7
Advanced online publication: 24.07.2007
DOI: 10.1055/s-2007-983810; Art ID: F06207SS
© Georg Thieme Verlag Stuttgart · New York

2518
Y. Morita et al.
PAPER
Table 1 Optimization of Reaction Conditionsa
HO
NH
Cl
HO
Cl
O
(1.1–3.0 equiv)
N
O
N
N
solvent (1.0 M)
temp. (70–150 °C)
24 h
H
2
1e
Entry
Solvents
DMSO
DMSO
PhMe
Temperature (°C)
Amine (equiv)
Yield (%)b
1
2
100
100
100
100
100
100
100
70
1.1(HCl salt)
3
20
5
1.1
1.1
1.1
1.1
2.0
3.0
3.0
3.0
3.0
3
4
DMF
17
20
49
57
17
81
95
5
n-BuOH
DMSO
DMSO
DMSO
DMSO
DMSO
6
7
8
9
110
150
10
a Using N-(p-chlorophenyl)oxazolidin-2-one (1 mmol).
b HPLC yield, i.e. area% at 254 nm: 100 × [1e]/[2 + 1e].
conditions using free amine are still unclear, however, this the desired compound 1 as the main product. It should be
interesting result prompted us to investigate various reac- noted that nucleophilic attack of the amines at the C-2 car-
tion conditions such as solvents, amount of amine and re- bonyl position was observed in the case of p-nitro-substi-
action temperatures in order to improve the yield. The tuted substrates 2 to give the undesired carbamates 3 as
results are shown in Table 1. Screening of various organic minor products (none of the corresponding urea deriva-
solvents (DMSO, toluene, DMF, n-BuOH) under the tives were formed). These results indicated that a strong
same conditions (100 °C, 24 h) showed that polar solvents electron-withdrawing substituent at the para position of
were more appropriate (entries 2, 4 and 5 vs 3). Better the N-phenyl group of substrate 2, activates not only the
yields were obtained by increasing the amount of amine C-5 position but also the C-2 carbonyl position.
(entries 2, 6 and 7) and reaction temperature (entries 8, 9
and 10). Again, undesired side products, resulting from
Since the congener of compound 2 is a useful material for
medicinally important molecules,8 a component in hair
reaction at the C-2 carbonyl position, such as urea and/or
dyes9 and a co-catalyst for metal catalysis,10 we set out to
carbamate derivatives were not observed at all under any
develop a practical synthetic process for the preparation of
N-aryloxazolidin-2-one (2), employing commercially
of the reaction conditions investigated.
The scope and limitations of the reaction were subse- available anilines. Preparative methods for the synthesis
quently studied using a range of aliphatic amines and N- of 2 are well known, with one typical and efficient method
aryloxazolidin-2-ones. The results of these investigations consisting of two steps:11 formation of N-aryl-2-chloro-
are summarized in Table 2. We also observed that the re- ethyl carbamate from anilines and 2-chloroethyl chloro-
action rate was influenced by the substitution effect at the formate in the presence of an organic base such as tertiary
para position of the N-phenyl group of substrate 2. The amine or an inorganic base such as sodium, potassium or
decarboxylative ring opening reaction of N-aryloxazoli- calcium carbonate, with the second step consisting of a
din-2-ones 2 (R1 = H, p-Cl, p-OMe) with secondary ali- strong base induced intramolecular cyclization of the iso-
phatic amines, proceeded somewhat slowly, to afford the lated carbamate. While both types of base (weak and
desired product 1 in excellent yield under the optimized strong) have been employed for N-acylation and intramo-
condition (entries 1–6). On the other hand, the reaction of lecular cyclization in this method, we attempted to im-
substrate 2 having a nitro group at the para position with prove the two-step reaction sequence to a one-pot method
various aliphatic secondary amines (pyrrolidine, piperi- using the same base. After an extensive investigation, we
dine, 4-hydroxypiperidine, hexamethyleneimine) went to found the practical one-pot condition shown in Table 3.
completion significantly faster (entries 7–10), to afford Thus, aniline was reacted with 2-chloroethyl chlorofor-
Synthesis 2007, No. 16, 2517–2523 © Thieme Stuttgart · New York

PAPER
Short Synthesis of N¢,N¢-Disubstituted N-Aryl-1,2-Ethylenediamines
2519
Table 2 Scope and Limitations of the Decarboxylative Ring Opening Reaction of N-Aryloxazolidin-2-ones with Aliphatic Secondary
Aminesa
R2
n
NH
R2
R2
O
n
n
R1
(3.0 equiv)
R1
R1
N
N
O
and
O
N
DMSO (1.0 M)
110 °C
N
H
N
H
O
2 (1.0 equiv)
1a–j
3g–j
Entry
R1
Amines
Time (d)
Product
1a
Yield (%) of 1b Ratio (1:3)c,d
e
1
2
H
Pyrrolidine
Piperidine
5
7
76
82
82
77
81
78
57
89
62
85
–
–
–
e
e
H
1b
1c
3
H
4-Hydroxypiperidine
Hexamethyleneimine
4-Hydroxypiperidine
4-Hydroxypiperidine
Pyrrolidine
5
4
H
8
1d
1e
10: 1
e
5
p-Cl
5
–
e
6
p-OMe
p-NO2
p-NO2
p-NO2
p-NO2
6
1f
–
7
24 h
36 h
21 h
36 h
1g
1.4:1 (3g)
13.4:1 (3h)
8.3:1 (3i)
6.1:1 (3j)
8
Piperidine
1h
1i
9
4-Hydroxypiperidine
Hexamethyleneimine
10
1j
a Using N-aryloxazolidin-2-one (1 mmol).
b Isolated yield by chromatography.
c The structure of undesired product 3 was supported by 400 MHz 1H NMR, FT-IR and LC-MS analysis.
d The ratio (1:3) was determined by 400 MHz 1H NMR analysis of the crude product.
e Compound 3 was not observed.
mate (1.25 equiv) in the presence of potassium carbonate NMR [1H NMR (400 MHz), 13C NMR (100 MHz)] spectra were de-
termined on a JEOL-LA400 instrument unless otherwise noted.
(2.5 equiv) in acetonitrile at room temperature to afford N-
aryl-2-chloroethyl carbamate, which was then simply
1
Chemical shifts for H NMR are reported in ppm downfield from
TMS (d) as the internal standard. Chemical shifts for 13C NMR are
heated at reflux in order to induce intramolecular cycliza-
reported in ppm relative to the center line of the CDCl3 triplet at d =
tion to the desired product 2 in satisfactory yield. With
77.0 ppm. Infrared (IR) spectra were recorded on a JEOL-FT/IR-
410 and are reported in wavenumbers (cm–1). High resolution mass
spectra (HRMS) were obtained on a JEOL JMS-GC mate MS-
DIP20 quadrupole at 70 eV using direct probe insertion (70–
330 °C). Fast atom bombardment (FAB) mass spectra were ob-
tained with poly(ethylene glycol) as the matrix. Melting points
(mp), determined on a Yanaco Micro Melting Point Apparatus MP-
500, are uncorrected. All reagents and DMSO were of commercial
grades and were used without further purification. MeCN was dried
and distilled before use.
this result in hand, the substitution effect of anilines on the
one-pot reaction was then investigated. We were pleased
to find that all the para-substituted anilines, including
electron-donating (entry 4 and 8) and electron-withdraw-
ing (entry 2 and 9–12) substitution gave the product 2 in
good yield. However, the reaction was hampered by
ortho-disubstituted anilines, which afforded the product 2
in only moderate yield (entry 7). Steric effects may be the
principal factor for this lower yield.
N¢,N¢-Disubstituted N-Aryl-1,2-Ethylenediamines 1 (Table 2);
General Procedure
In conclusion, we have developed a short, practical syn-
thesis of N¢,N¢-disubstituted N-aryl-1,2-ethylenediamines
1, starting from anilines via N-aryloxazolidin-2-ones 2,
which were prepared in a one-pot procedure. The nucleo-
philic conditions required for the decarboxylative ring-
opening reaction of N-aryloxazolidin-2-ones 2 with free
aliphatic secondary amines was established. Further stud-
ies aimed at expanding the generality of this transforma-
tion are currently in progress.
To a stirred solution of N-aryloxazolidin-2-one 2 (1.0 mmol) in
DMSO (1.0 mL) under Ar atmosphere was added amine (3.0 mmol)
at r.t. and the mixture was heated at 110 °C with stirring. The mix-
ture was partitioned between EtOAc (4 mL) and H2O (2 mL). The
organic layer was washed with aq NaCl (6%, 3 × 2 mL), dried over
Na2SO4, filtered and evaporated under reduced pressure to give the
crude material. Purification by flash column chromatography on sil-
ica gel gave 1.
Synthesis 2007, No. 16, 2517–2523 © Thieme Stuttgart · New York

2520
Y. Morita et al.
PAPER
Table 3 One-Pot Preparation of N-Aryloxazolidin-2-ones under Optimal Conditionsa
O
Cl
Cl
O
O
(1.2 equiv)
inorganic base
R
O
R
N
O
R
H
80 °C
time
MeCN
0 °C to r.t.
1 h
N
O
NH2
Cl
2a–l
(1.0 equiv)
Entry
1
R
Time (h)b
72d
12e
15
Product
2a
Yield (%)c
4-Cl
4-Cl
H
77
78
84
88
90
92
52
67
79
80
79
78
2
2b
2c
3
4
4-Me
3-Me
2-Me
15
2d
2e
5
18
6
24
2f
7
2,4,6-Me
12
2g
8
4-MeO
4-Br
12
2h
2i
9
12
10
11
12
4-CO2Et
4-CN
12
2j
3f
2k
2l
4-NO2
5g
a Using 20 mmol anilines.
b Time after N-acylation step (1 h).
c Isolated yield of 2 after recrystallization.
d Na2CO3 was used as an inorganic base.
e 0.8 M based on the concentration of p-chloroaniline was used.
f N-Acylation step required 12 h.
g 2.0 equiv of 2-chloroethyl chloroformate was used.
N-[2-(Pyrrolidin-1-yl)ethyl]aniline (1a)13
Prepared as described in the general procedure from 2c (163 mg,
1.00 mmol). Purification on silica gel afforded pure 1a (144 mg,
76%) as a light-yellow oil.
1-[2-(Phenylamino)ethyl]piperidin-4-ol (1c)1b
To a stirred solution of 2c (200 mg, 1.23 mmol) in DMSO (1.23 mL)
under Ar atmosphere was added 4-hydroxypiperidine (372 mg, 3.68
mmol) at r.t. and the mixture was heated at 110 °C with stirring for
5 d. The mixture was partitioned between EtOAc (4 mL) and H2O
(2 mL). The organic layer was washed with aq NaCl (6%, 3 × 2
mL), dried over Na2SO4, filtered and evaporated under reduced
pressure to give the crude material. Purification by flash column
chromatography on silica gel afforded pure 1c (221 mg, 82%) as a
light-brown oil.
IR (film): 3385, 2962, 2789, 1602, 1506, 1320, 1147 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.77–1.80 (m, 4 H), 2.52–2.55 (m,
4 H), 2.74 (t, J = 6.4 Hz, 2 H), 3.19 (t, J = 6.0 Hz, 2 H), 4.25 (br s,
1 H), 6.64 (d, J = 7.6 Hz, 2 H), 6.69 (t, J = 7.6 Hz, 1 H), 7.17 (t,
J = 8.0 Hz, 2 H).
IR (film): 3400, 1603, 1507, 1391, 1260, 1064 cm–1.
N-[2-(Piperidin-1-yl)ethyl]aniline (1b)13
Prepared as described in the general procedure from 2c (163 mg,
1.00 mmol). Purification on silica gel afforded pure 1b (168 mg,
82%) as a light-brown oil.
IR (film): 3379, 2934, 1603, 1505, 1430, 1304, 1260 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.45 (m, 2 H), 1.57 (dt, J = 5.6,
11.2 Hz, 4 H), 2.39 (m, 4 H), 2.57 (t, J = 6.4 Hz, 2 H), 3.15 (t,
J = 6.4 Hz, 2 H), 4.32 (br s, 1 H), 6.64 (dd, J = 1.6, 8.8 Hz, 2 H),
6.69 (ddd, J = 1.2, 2.0, 9.2 Hz, 1 H), 7.18 (ddd, J = 1.2, 2.8, 8.8 Hz,
2 H).
1H NMR (400 MHz, CDCl3): d = 1.54–1.63 (m, 2 H), 1.88–1.93 (m,
2 H), 2.18 (br t, J = 10.0 Hz, 2 H), 2.62 (t, J = 6.0 Hz, 2 H), 2.77–
2.80 (m, 2 H), 3.15 (t, J = 6.0 Hz, 2 H), 3.72 (m, 1 H), 6.64 (dd, J =
1.2, 8.8 Hz, 2 H), 6.70 (ddd, J = 1.2, 4.2, 9.2 Hz, 1 H), 7.18 (ddd,
J = 2.8, 4.4, 9.6 Hz, 2 H).
HRMS (FAB): m/z calcd for C13H20N2O: 220.1576; found:
220.1568.
N-[2-(Azepan-1-yl)ethyl]aniline (1d)
Prepared as described in the general procedure from 2c (163 mg,
1.00 mmol). Purification on silica gel afforded pure 1d (169 mg,
77%) as a light-brown oil.
HRMS (FAB): m/z calcd for C13H20N2: 204.1627; found: 204.1627.
Synthesis 2007, No. 16, 2517–2523 © Thieme Stuttgart · New York

PAPER
Short Synthesis of N¢,N¢-Disubstituted N-Aryl-1,2-Ethylenediamines
2521
IR (film): 3369, 2923, 2850, 1603, 1505, 1482, 1429, 1318 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.85–1.90 (m, 4 H), 3.31 (t,
J = 6.8 Hz, 2 H), 3.40 (t, J = 6.8 Hz, 2 H), 3.47 (dd, J = 5.2, 10.4
Hz, 2 H), 3.38 (t, J = 5.2 Hz, 2 H), 5.33 (br s, 1 H), 6.55 (d, J = 9.2
Hz, 2 H), 8.09 (d, J = 9.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 24.8, 45.8, 46.3, 63.0, 110.9,
126.3, 137.8, 153.3, 155.1.
1H NMR (400 MHz, CDCl3): d = 1.61 (m, 8 H), 2.63–2.66 (m, 4 H),
2.75 (t, J = 6.0 Hz, 2 H), 3.10 (t, J = 6.0 Hz, 2 H), 4.40 (br s, 1 H),
6.64 (d, J = 11.6 Hz, 2 H), 6.69 (t, J = 7.6 Hz, 1 H), 7.18 (t, J = 7.6
Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 26.9, 28.2, 41.2, 54.9, 56.0, 112.8,
116.9, 129.0, 148.7.
HRMS (FAB): m/z [M + H]+ calcd for C13H18N3O4: 280.1297;
found: 280.1297.
HRMS (FAB): m/z [M + H]+ calcd for C14H23N2: 219.1861; found:
219.1853.
4-Nitro-N-[2-(piperidin-1-yl)ethyl]aniline (1h)15 and 2-(4-Nitro-
phenylamino)ethyl Piperidine-1-carboxylate (3h)
Prepared as described in the general procedure from 2l (208 mg,
1.00 mmol). Purification on silica gel afforded pure 1h (223 mg,
89%) as a yellow oil and 3h (39 mg) as a yellow amorphous solid.
1-[2-(4-Chlorophenylamino)ethyl]piperidin-4-ol (1e)
Prepared as described in the general procedure from 2c (163 mg,
1.00 mmol). Purification on silica gel afforded pure 1e (208 mg,
81%) as a light-yellow solid.
Mp 84–86 °C.
1h
IR (film): 3367, 2935, 1602, 1503, 1468, 1306, 1111 cm–1.
IR (film): 3364, 3097, 2927, 2830, 1603, 1511, 1474, 1450, 1319,
1265, 1173, 1122, 1067 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.48 (m, 2 H), 1.59 (dd, J = 5.6,
11.2 Hz, 4 H), 1.83 (m, 1 H), 2.41 (m, 3 H), 2.60 (t, J = 6.0 Hz,
2 H), 3.22 (dd, J = 5.2, 10.8 Hz, 2 H), 5.38 (br s, 1 H), 6.53 (dd,
J = 10.4, 3.2 Hz, 2 H), 8.09 (dd, J = 3.2, 10.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 23.3, 41.3, 53.6, 53.8, 110.8,
126.2, 137.3, 153.4.
1H NMR (400 MHz, CDCl3): d = 1.48 (br s, 1 H), 1.54–1.63 (m,
2 H), 1.89–1.93 (m, 2 H), 2.19 (br t, J = 9.6 Hz, 2 H), 2.61 (t, J = 6.0
Hz, 2 H), 2.76–2.79 (m, 2 H), 3.12 (dd, J = 5.6, 16.8 Hz, 2 H), 3.73
(m, 1 H), 4.36 (br s, 1 H), 6.55 (dd, J = 3.2, 9.6 Hz, 2 H), 7.12 (dd,
J = 3.2, 10.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 34.2, 40.5, 50.8, 56.3, 113.8,
121.6, 128.9, 147.0.
HRMS (FAB): m/z calcd for C13H19N3O2: 249.1477; found:
249.1480.
HRMS (FAB): m/z [M + H]+ calcd for C13H20ON2Cl: 255.1264;
found: 255.1260.
3h
IR (film): 2936, 2360, 1685, 1601, 1307, 1234, 1111 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.50–1.62 (m, 6 H), 2.42 (m, 1 H),
3.41–3.49 (m, 5 H), 4.36 (t, J = 4.8 Hz, 2 H), 5.25 (br s, 1 H), 6.55
(d, J = 9.2 Hz, 2 H), 8.09 (d, J = 9.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 24.2, 44.9, 63.3, 111.0, 126.3,
126.4, 138.0, 154.6, 155.6.
1-[2-(4-Methoxyphenylamino)ethyl]piperidin-4-ol (1f)
Prepared as described in the general procedure from 2h (200 mg,
1.04 mmol). Purification on silica gel afforded pure 1f (202 mg,
78%) as a light-brown oil.
IR (film): 3366, 2942, 2830, 1513, 1235, 1065 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.54–1.63 (m, 2 H), 1.87–1.91 (m,
2 H), 2.17 (br t, J = 12.0 Hz, 2 H), 2.61 (t, J = 4.0 Hz, 2 H), 2.67–
2.69 (m, 2 H), 3.11 (t, J = 4.0 Hz, 2 H), 3.69–3.75 (m, 4 H), 6.62 (d,
J = 8.0 Hz, 2 H), 6.79 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 34.2, 40.4, 50.7, 56.4, 67.5, 112.8,
117.1, 129.0, 148.3.
HRMS (FAB): m/z calcd for C14H19N3O4: 239.1376; found:
239.1368.
1-[2-(4-Nitrophenylamino)ethyl]piperidin-4-ol (1i) and 2-(4-Ni-
trophenylamino)ethyl 4-Hydroxypiperidine-1-carboxylate (3i)
Prepared as described in the general procedure from 2l (208 mg,
1.00 mmol). Purification on silica gel afforded pure 1i (158 mg,
62%) as a yellow solid and 3i (21 mg) as a yellow amorphous soild.
HRMS (FAB): m/z calcd for C14H22N2O2: 219.1681; found:
219.1699.
1i
4-Nitro-N-[2-(pyrrolidin-1-yl)ethyl]aniline (1g)14 and 2-(4-Ni-
trophenylamino)ethyl Pyrrolidine-1-carboxylate (3g)
Prepared as described in the general procedure from 2l (208 mg,
1.00 mmol). Purification on silica gel afforded pure 1g (135 mg,
57%) as a light-brown oil and 3g (102 mg) as a yellow amorphous
solid.
Mp 134–135 °C.
IR (film): 3363, 2941, 1602, 1470, 1306, 1112, 1065 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.59–1.65 (m, 2 H), 1.94 (m, 2 H),
2.22 (t, J = 8.8 Hz, 2 H), 2.65 (t, J = 5.2 Hz, 2 H), 2.77–2.80 (m,
2 H), 3.23 (dd, J = 10.8, 5.2 Hz, 2 H), 3.77 (m, 1 H), 5.23 (br s,
1 H), 6.54 (d, J = 8.4 Hz, 2 H), 8.10 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 34.4, 39.6, 50.6, 55.7, 72.8, 111.1,
126.4, 137.8, 153.3.
HRMS (FAB): m/z [M + H]+ calcd for C13H20N3O3: 266.1505;
found: 266.1511.
1g
IR (film): 2960, 2803, 1602, 1505, 1471, 1307, 1185, 1111 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.82 (dd, J = 2.8, 6.4 Hz, 4 H),
2.56–2.59 (m, 4 H), 2.78 (t, J = 6.0 Hz, 2 H), 3.27 (dd, J = 5.2, 10.8
Hz, 2 H), 5.41 (br s, 1 H), 6.54 (dt, J = 3.2, 10.0 Hz, 2 H), 8.08 (dt,
J = 3.2, 10.0 Hz, 2 H).
HRMS (FAB): m/z [M + H]+ calcd for C12H17N3O2: 235.1321;
found: 235.1317.
3i
IR (film): 3356, 1682, 1601, 1473, 1307, 1228, 1112, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.52 (m, 2 H), 1.86 (m, 2 H), 3.16
(m, 2 H), 3.48 (dd, J = 5.2, 10.4 Hz, 2 H), 3.86–3.91 (m, 2 H), 4.37
(m, 2 H), 5.18 (br s, 1 H), 6.56 (d, J = 9.2 Hz, 2 H), 8.09 (d, J = 9.2
Hz, 2 H).
3g
IR (film): 3322, 2360, 1685, 1601, 1440, 1300, 1271, 1139, 1106
cm–1.
Synthesis 2007, No. 16, 2517–2523 © Thieme Stuttgart · New York

2522
Y. Morita et al.
PAPER
N-[2-(Azepan-1-yl)ethyl]-4-nitroaniline (1j) and 2-(4-Nitrophe-
nylamino)ethyl Azepane-1-carboxylate (3j)
Prepared as described in the general procedure from 2l (208 mg,
1.00 mmol). Purification on silica gel afforded pure 1j (225 mg,
85%) as a yellow oil and 3j (53 mg) as a yellow amorphous solid.
ane–EtOAc, 4:1) afforded pure 2d (3.12 g, 88%) as a solid. Physical
and spectroscopic data were identical to those previously de-
scribed.17
N-(3-Methylphenyl)oxazolidin-2-one (2e)8
Prepared as described in the general procedure from 3-methyl-
aniline (2.14 g, 20.0 mmol). Purification by recrystallization (n-
hexane–EtOAc, 4:1) afforded pure 2e (3.20 g, 90%) as a solid.
Physical and spectroscopic data were identical to those previously
described.8
1j
IR (film): 3367, 2924, 1602, 1470, 1319, 1306, 1111 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.63–1.77 (m, 8 H), 2.67 (d,
J = 5.2 Hz, 4 H), 2.79 (t, J = 6.0 Hz, 2 H), 3.18 (dd, J = 5.2, 10.0
Hz, 2 H), 5.47 (br s, 1 H), 6.53 (dt, J = 3.2, 10.4 Hz, 2 H), 8.09 (dd,
J = 3.2, 10.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 26.9, 28.0, 54.7, 55.0, 110.9,
126.2, 137.3, 153.5.
N-(2-Methylphenyl)oxazolidin-2-one (2f)
Prepared as described in the general procedure from 2-methyl-
aniline (2.14 g, 20.0 mmol). Purification on silica gel afforded pure
2f (3.26 g, 92%) as a light-brown oil.
IR (film): 3468, 1748, 1497, 1411, 1224, 1142, 1038 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.32 (s, 3 H), 3.96 (dd, J = 6.4, 8.0
Hz, 2 H), 4.53 (dd, J = 8.0, 8.8 Hz, 2 H), 7.24–7.26 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 17.7, 47.5, 62.1, 126.1, 126.6,
127.8, 131.0, 135.6, 135.8, 156.4.
HRMS (FAB): m/z calcd for C14H21N3O2: 263.1634; found:
263.1638.
3j
IR (film): 3340, 2928, 1682, 1601, 1322, 1307, 1111, 835 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.52–1.71 (m, 8 H), 3.36 (t,
J = 6.0 Hz, 2 H), 3.43–3.49 (m, 4 H), 4.38 (t, J = 6.0 Hz, 2 H), 5.29
(br s, 1 H), 6.55 (d, J = 9.2 Hz, 2 H), 8.09 (d, J = 9.2 Hz, 2 H).
HRMS (FAB): m/z [M + H]+ calcd for C10H12NO2: 178.0868;
found: 178.0867.
13C NMR (100 MHz, CDCl3): d = 26.8, 28.1, 43.6, 46.6, 63.2, 110.9,
N-(2,4,6-Trimethylphenyl)oxazolidin-2-one (2g)
126.3, 137.9, 153.2, 156.5.
Prepared as described in the general procedure from 2,4,6-trimeth-
ylaniline (2.71 g, 20.0 mmol). Purification by recrystallization (n-
hexane–EtOAc, 5:2) afforded pure 2g (2.15 g, 52%) as a solid.
HRMS (FAB): m/z calcd for C15H21N3O4: 307.1532; found:
307.1538.
Mp 93–94 °C.
N-Aryloxazolidine-2-ones (Table 3); General Procedure
To a stirred mixture of K2CO3 (50.0 mmol) and aniline (20.0 mmol)
in MeCN (40.0 mL) under Ar atmosphere was added 2-chloroethyl
chloroformate (25.0 mmol) over 5 min at r.t. and the reaction was
stirred for 1 h. The reaction mixture was heated at reflux for the time
indicated in Table 3 then cooled and partitioned between EtOAc (50
mL) and H2O (75 mL). The aqueous layer was extracted with
EtOAc (3 × 50 mL) and the combined organic extracts were washed
with aq NaCl (12%, 50 mL), dried over MgSO4, filtered and evap-
orated under reduced pressure to give the crude material. Purifica-
tions were performed by recrystallization or flash column
chromatography on silica gel.
IR (film): 3459, 1848, 1747, 1410, 1282, 1229, 1114, 1038 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.25 (s, 9 H), 3.82 (t, J = 8.0 Hz,
2 H), 4.54 (t, J = 8.0 Hz, 2 H), 6.93 (s, 2 H).
13C NMR (100 MHz, CDCl3): d = 17.3, 20.7, 45.9, 62.2, 129.2,
131.3, 136.1, 138.1, 156.6.
HRMS (FAB): m/z [M + H]+ calcd for C12H16NO2: 206.1181;
found: 206.1183.
N-(4-Methoxyphenyl)oxazolidin-2-one (2h)8
Prepared as described in the general procedure from 4-methoxy-
aniline (2.50 g, 20.3 mmol). Purification by recrystallization (n-
hexane–EtOAc, 3:1) afforded pure 2h (2.63 g, 67%) as a solid.
Physical and spectroscopic data were identical to those previously
described.8
N-(4-Chlorophenyl)oxazolidin-2-one (2b)16
Prepared as described in the general procedure, with the following
changes to the scale: K2CO3 (13.55 g, 98.0 mmol), 4-chloroaniline
(5.00 g, 39.2 mmol), MeCN (50.0 mL), 2-chloroethyl chlorofor-
mate (4.45 mL, 43.1 mmol). Purification by recrystallization (n-
hexane–EtOAc, 4:1) at 80 °C afforded pure 2b as a solid (6.02 g,
78%).
N-(4-Bromophenyl)oxazolidin-2-one (2i)16
Prepared as described in the general procedure from 4-bromoaniline
(3.44 g, 20.0 mmol). Purification by recrystallization (n-hexane–
EtOAc, 1:1) afforded pure 2i (3.83 g, 79%) as a solid.
IR (film): 3456, 1735, 1500, 1479, 1425, 1406, 1322, 1219, 1128
cm–1.
IR (film): 1740, 1489, 1477, 1416, 1400, 1314, 1219, 1128 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.05 (dd, J = 6.4, 8.0 Hz, 2 H),
4.50 (dd, J = 6.4, 9.2 Hz, 2 H), 7.34 (dt, J = 3.2, 10.0 Hz, 2 H), 7.34
(dt, J = 3.2, 10.0 Hz, 2 H).
1H NMR (400 MHz, CDCl3): d = 4.05 (t, J = 8.0 Hz, 2 H), 4.50 (t,
J = 8.0 Hz, 2 H), 7.44–7.50 (m, 4 H).
N-(4-Ethoxycarbonylphenyl)oxazolidin-2-one (2j)10
Prepared as described in the general procedure from 4-ethoxycar-
bonylaniline (3.30 g, 20.0 mmol). Purification by recrystallization
(n-hexane–EtOAc, 1:1) afforded pure 2j (3.74 g, 80%) as a solid.
N-Phenyloxazolidin-2-one (2c)8
Prepared as described in the general procedure from aniline (1.87 g,
20.0 mmol). Purification by recrystallization (n-hexane–EtOAc,
4:1) afforded pure 2c (2.74 g, 84%) as a solid. Physical and spectro-
scopic data were identical to those previously described.8
IR (film): 1749, 1732, 1702, 1401, 1280, 1189 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40 (t, J = 8.0 Hz, 3 H), 4.11 (dd,
J = 4.0, 8.0 Hz, 2 H), 4.38 (dd, J = 8.0, 12.0 Hz, 2 H), 4.53 (dd,
J = 8.0, 12.0 Hz, 2 H), 7.63 (d, J = 12.0 Hz, 2 H), 8.07 (d, J = 8.0
Hz, 2 H).
N-(4-Methylphenyl)oxazolidin-2-one (2d)17
Prepared as described in the general procedure from 4-methyla-
niline (2.14 g, 20.0 mmol). Purification by recrystallization (n-hex-
Synthesis 2007, No. 16, 2517–2523 © Thieme Stuttgart · New York

PAPER
Short Synthesis of N¢,N¢-Disubstituted N-Aryl-1,2-Ethylenediamines
2523
N-(4-Cyanophenyl)oxazolidin-2-one (2k)8
(2) (a) Hopff, H.; Spaenig, H.; Schuster, C. US 2623880, 1952.
(b) Cross, P. E.; Leeming, P. R. UK 1306450, 1973.
(c) Parimoo, P.; Grabowski, B. F.; Haney, W. G. Jr. J.
Pharm. Sci. 1972, 61, 974.
(3) (a) Pratesi, P.; Villa, L.; Ferri, V.; Grana, E.; Sossi, D.
Farmaco, Ed. Sci. 1969, 24, 313. (b) Cappello, B.; Silipo,
C.; Vittoria, A. Farmaco, Ed. Sci. 1984, 39, 991.
(4) For a recent review, see: Meléndez, R. E.; Lubell, W. D.
Tetrahedron 2003, 59, 2581; and references cited therein.
(5) (a) Poindexter, G. S. J. Heterocycl. Chem. 1983, 20, 1431.
(b) Poindexter, G. S. US 4381401, 1983. (c) Rooney, P. C.;
Nutt, M. O. US 5491263, 1996.
(6) Poindexter, G. S.; Owens, D. A.; Dolan, P. L.; Woo, E. J.
Org. Chem. 1992, 57, 6257; and references cited therein.
(7) (a) For a review, see: Dyen, M. E.; Swern, D. Chem. Rev.
1967, 67, 197. For selected examples, see: (b) Najer, H.;
Chabrier, P.; Giudicelli, R.; Menin, J.; Duchemin, J. Bull.
Soc. Chim. Fr. 1959, 1841. (c) Gabriel, S.; Eschenbach, G.
Ber. Dtsch. Chem. Ges. 1897, 30, 2494.
Prepared as described in the general procedure from 4-cyanocar-
bonylaniline (2.36 g, 20.0 mmol). Purification by recrystallization
(n-hexane–EtOAc, 1:5) afforded pure 2k (2.95 g, 79%) as a solid.
Physical and spectroscopic data were identical to those previously
described.8
N-(4-Nitrophenyl)oxazolidin-2-one (2l)8
Prepared as described in the general procedure, with the following
changes. Scale: K2CO3 (5.50 g, 40.0 mmol), 4-nitroaniline (2.50 g,
18.1 mmol), MeCN (40.0 mL), 2-chloroethyl chloroformate (2.05
mL, 19.9 mmol). After 1 h, further 2-chloroethyl chloroformate
(1.68 mL, 16.3 mmol) was added and the reaction mixture was
stirred for 1 h then heated at reflux for 12 h. After work-up as de-
scribed in the general procedure, purification by recrystallization
(n-hexane–EtOAc, 1:1) at 80 °C gave pure 2l as a solid (2.80 g,
75%). Physical and spectroscopic data were identical to those pre-
viously described.8
(8) Mallesham, B.; Rajesh, B. M.; Rajamohan, R.; Srinivas, D.;
Trehan, S. Org. Lett. 2003, 5, 963; and references cited
therein.
(9) For a review, see: Lang, G.; Junino, A. US 4910341, 1990.
(10) Harada, M.; Matsushita, A.; Yoshii, K. Jpn. Kokai Tokkyo
Koho 147578, 1998.
(11) For a review, see: Pankratov, V. A.; Frenkel, Ts. M.;
Fainleib, A. M. Russian Chem. Rev. 1983, 52, 576; Recently
Pd and Cu-catalyzed coupling of oxazolidine-2-ones with
aryl halides was reported, see: ref 8 and 12.
(12) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(13) Wright, Wm. B. Jr.; Brabander, H. J.; Hardy, R. A. Jr. J. Org.
Chem. 1961, 26, 476.
Acknowledgment
We gratefully thank Professor Hisashi Yamamoto (The University
of Chicago) for valuable discussions on the chemistry of the ring-
opening reaction. The authors thank Professor Tohru Fukuyama
(Graduate School of Pharmaceutical Sciences, The University of
Tokyo) for fruitful discussions and Dr. Tohru Miyazaki (Graduate
School of Pharmaceutical Sciences, The University of Tokyo) for
HRMS-FAB measurements. The authors also thank Mr. Tomoyuki
Odashima (Toray Industries, Inc.) for NMR support.
References
(14) (a) Hoeglund, I. P. J.; Silver, S.; Engstroem, M. T.; Salo, H.;
Tauber, A.; Kyyroenen, H.-K.; Saarenketo, P.; Hoffren,
A.-M.; Kokko, K.; Pohjanoksa, K.; Sallinen, J.; Savola,
J.-M.; Wurster, S.; Kallatsa, O. A. J. Med. Chem. 2006, 49,
6351. (b) Sablle, S. EP 1568683 A2, 2005.
(1) (a) Roth, G. J.; Heckel, A.; Walter, R.; Meel, J. V.;
Redemann, N.; Tontsch-Grunt, U.; Spevak, W.; Hilberg, F.
US 6762180, 2004. (b) Sato, S.; Yukawa, H.; Kihara, Y.;
Koga, N.; Saito, M.; Nishi, T. WO 9304042, 1992.
(15) Stubbins, J. F.; Soine, T. O. J. Pharm. Sci. 1966, 55, 1093.
(16) Mckay, A. F.; Braun, R. O. J. Org. Chem. 1951, 16, 1829.
(17) Chiang, G. C. H.; Olsson, T. Org. Lett. 2004, 6, 3079.
Synthesis 2007, No. 16, 2517–2523 © Thieme Stuttgart · New York