Efficient demethylation of N,N-dimethylanilines with phenyl chloroformate in ionic liquids

Article abstract of DOI:10.1055/s-2006-951490

Demethylation of N,N-dimethylanilines was carried out in various ionic liquids and acetonitrile as well as under solvent-free conditions. We have demonstrated that their reactivity dramatically depends on the ionic liquid employed; [bmim]Cl showed the bes

Full text of DOI:10.1055/s-2006-951490

LETTER
2629
Efficient Demethylation of N,N-Dimethylanilines with Phenyl Chloroformate
in Ionic Liquids
Efficient
Dema
t
f
N
,
N-
D
imethylanil
m
ines i Imori,a Hideo Togo*a,b
a
Graduate School of Science and Technology, Chiba University, Yayoi-cho 1-33, Inage-ku 263-8522, Japan
b
Department of Chemistry, Faculty of Science, Chiba University, Yayoi-cho 1-33, Inage-ku 263-8522, Japan
E-mail: togo@faculty.chiba-u.jp
Received 24 July 2006
Table 1 Effects of Ionic liquids
Abstract: Demethylation of N,N-dimethylanilines was carried out
in various ionic liquids and acetonitrile as well as under solvent-free
conditions. We have demonstrated that their reactivity dramatically
depends on the ionic liquid employed; [bmim]Cl showed the best
reactivity.
Me
Me
ClCO2Ph (1.2 equiv)
solvent, 80 °C, 3 h
N
O
N
OPh
Me
Key words: N,N-dimethylaniline, demethylation, phenyl chloro-
formate, ionic liquid, phenyl N-methyl-N-arylcarbamate
Entry
1
Solvent
Yield (%)
24
MeCN (1.5 mL)
2
Solvent-free
25
N-Dealkylation, especially N-demethylation, is important
in organic synthesis as it can be applied to the demethyla-
tion of natural alkaloid products such as morphine to
noromorphine or oxymorphone to noroxymorphone,
respectively.1 N-Dealkylation of aliphatic and acyclic ter-
tiary amine to dialkylamines is well known.1 Initially,
tertiary amines were treated with cyanogen bromide (von
Braun reaction) to form the corresponding N,N-disubsti-
tuted cyanamide and alkyl bromide. Phosgene has also
been employed to effect N-dealkylation. Recently, these
reagents, due to their high toxicity and poor selectivity,
were replaced by chloroformates. In 1967, effective N-
demethylation of tertiary amines with phenyl chlorofor-
mate was reported.2 Generally, aliphatic tertiary amines
react smoothly with phenyl chloroformate to provide the
corresponding dealkylated N,N-dialkyl carbamates. Sub-
sequently, many related reagents such as 2,2,2-trichloro-
ethyl chloroformate,3a vinyl chloroformate,3b 1-
chloroethyl chloroformate,3c chlorothionoformate,3d and
acetic anhydride/boron trifluoride,3e were developed.
Moreover, N-(2-acetoxyethyl) tertiary amines were con-
verted to the corresponding secondary amine under pho-
tochemical conditions (350 nm) in the presence of 4,4¢-
dimethoxybenzophenone.4 Once phenyl carbamates or
methyl carbamates derived from the reaction of tertiary
amines with phenyl chloroformate or methyl chlorofor-
mate are formed they can be smoothly converted to the
corresponding free secondary amines under mild condi-
tions, using (CH3)3SiI5a or TBAF/THF.5b However, the
dealkylation of N,N-dialkylanilines using chloroformate
esters to furnish the corresponding carbamate esters is ex-
tremely limited; long reaction times and drastic conditions
are required compared with aliphatic and acyclic tertiary
amines.2 For example, N,N-dimethylaniline reacts with
3
Solvent-free (NaCl, 3.0 equiv)
[bmim]SO3C8H17 (2.0 mL)
[emim]OTs (2.0 mL)
[bmpy]NTf2 (2.0 mL)
[bmpy]PF6 (2.0 mL)
[bmim]PF6 (2.0 mL)
[bmim]BF4 (2.0 mL)
[bmim]Br (2.0 mL)
[bdmim]Cl (2.0 mL)
[bmim]Cl (2.0 mL)
[bmim]Cl (4.0 mL)
[bmim]Cl (1.0 mL)
[bmim]Cl (0.5 mL)
[bmim]Cl (0.2 mL)
[bmim]Cl (0.1 mL)
[bmim]Cl (0.04 mL)
22
4
4
5
15
6
49
7
64
8
70
9
69
10
11
12
13
14
15
16
17
18
80
90
95
20
95
94
95
88
79
phenyl chloroformate at 100 °C to give the corresponding
phenyl N-phenyl-N-methylcarbamate after 60 hours in
80% yield.2
Ionic liquids have become very popular as organic reac-
tion media due to their ability to promote ionic reactions
and also from an environmental point of view.6 Thus,
these solvents possess many advantages, such as negli-
gible vapor pressure, non-flammability, high thermal
stability, and easy reusability. As a result they have been
successfully used in Friedel–Crafts reaction,7 hydrogena-
tion,8 Diels–Alder reactions,9 Heck, Suzuki, Sonogashira,
SYNLETT 2006, No. 16, pp 2629–2632
0
4
.1
0
.2
0
0
6
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-951490; Art ID: U09106ST
© Georg Thieme Verlag Stuttgart · New York

2630
S. Imori, H. Togo
LETTER
Table 2 Dealkylation of N,N-Dimethyl- and N,N-Diethylanilines20
R
R
ClCO2Ph (1.2 equiv)
R'
N
O
R'
N
OPh
solvent, ∆
R
Solvent (mL)
Temp (°C)
Time (h)
Yield (%)
O2N
Solvent-free
[bmim]Cl (2.0)
100
100
72
72
6 (94)a
99
Me
Me
N
Solvent-free
MeCN (1.5)
[bmim]Cl (2.0)
80
80
80
18
18
18
24 (76)a
25 (66)a
94
Me
Br
N
Me
Solvent-free
MeCN (1.5)
[bmim]Cl (2.0)
80
80
80
12
12
12
19 (80)a
32 (67)a
91
Me
Me
N
Solvent-free
MeCN (1.5)
[bmim]Cl (2.0)
80
80
80
6
6
6
66 (32)a
79 (20)a
85
Me
Me
Me
N
63 (35)a
99
Et
Et
Solvent-free
[bmim]Cl (2.0)
100
100
24
24
N
Solvent-free
MeCN (1.5)
[bmim]Cl (2.0)
80
80
80
2
2
2
66
60
94
Me
Me
H25C12
N
a Starting amine was recovered.
and olefin metathesis reactions,10 Michael additions,11 ox-
idation,12 condensation reaction,13 formation of imines,14
1,2-rearrangement,15 esterification of carboxylic acids
and carboxylates,16 Williamson ether synthesis,17 and
Grignard reaction.18 Recently, we also reported the highly
efficient esterification of carboxylic acids and phosphonic
acids with trialkyl orthoacetate in an ionic liquid.19 Here
as a part of our study on the development of organic reac-
tions with ionic liquids, we would like to report a dramatic
rate acceleration by ionic liquids in the reaction of inert
N,N-dimethylaniline with phenyl chloroformate; the reac-
tivity is markedly dependent on the ionic liquid employed.
All reactions proceeded under homogeneous conditions at
80 °C or 100 °C. The results for the reaction of N,N-di-
methylaniline with phenyl chloroformate in MeCN, under
Table 3 Reactivity of Chloroformates
Me
Me
reagent (1.2 equiv)
R
N
O
R
N
OPh
[bmim]Cl (2.0 mL), 80 °C
Me
Reagent
Time (h)
Yield (%)
1 (74)a
Me
Me
ClCO2Et
ClCO2Ph
3
3
N
95
ClCO2Et
ClCO2Ph
2
2
8 (82)a
94
Me
H25C12
N
Me
a Starting amine was recovered.
solvent-free conditions, under solvent-free conditions ity or charge density. The amount of ionic liquid is also
with NaCl, and in various ionic liquids are shown in important; we found 0.2–2.0 mL was optimal for 1 mmol
Table 1. Among them, [bmim]Cl showed the best reactiv- substrate (Table 1, entries 12–18).
ity, while [bdmim]Cl and [bmim]Br also showed high re-
Based on these results, various N,N-dimethylaniline de-
activity. However, [bmim]BF4, [bmim]PF6, [bmpy]PF6,
rivatives were treated with phenyl chloroformate in
and [bmpy]NTf2 showed moderate reactivity, and finally
[bmim]Cl and under solvent-free conditions. In every
[emim]OTs and [bmim]O3SC8H17 (1-butyl-3-methylimi-
reaction, the [bmim]Cl matrix promotes the reaction
dazolium octanesulfonate) showed poorer reactivity than
efficiently, especially for dimethylanilines bearing elec-
solvent-free or MeCN conditions. In all cases showing
tron-withdrawing groups, as shown in Table 2.
poor reactivity it was possible to recover the starting
We also looked at the reactivity of phenyl chlorofomate
amines. Thus, the results indicate that the reactivity de-
versus ethyl chloroformate (Table 3) with phenyl chloro-
pends on the size of the anionic group in the ionic liquid;
formate showing much higher reactivity in [bmim]Cl for
more specifically the reactivity is affected by ionic polar-
both substrates tested (Table 3).
Synlett 2006, No. 16, 2629–2632 © Thieme Stuttgart · New York

LETTER
Efficient Demethylation of N,N-Dimethylanilines
2631
Table 4 Solution versus Solvent-Free Conditions
In summary, demethylation of N,N-dimethylanilines was
carried out in various ionic liquids, under solvent-free
conditions, and in acetonitrile. Their reactivity dramati-
cally depends on the ionic liquid employed, with
[bmim]Cl showing the best reactivity.
Bu
ClCO2Ph (1.2 equiv)
N
solvent, 100 °C, 48 h
Me
O
N
Bu
OPh
+
N
O
OPh
Me
Acknowledgment
A
B
The present study was partly supported by a Grant-in-Aid for
Scientific Research on Priority Areas from the Ministry of Science,
Education, Sports, and Culture of Japan.
A
B
[bmim]Cl (2.0 mL)
Solvent-free
83%
46%
35%
16%
29%
7%
References and Notes
MeCN (1.5 mL, reflux)
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S.; Prager, R. F. Tetrahedron Lett. 1998, 39, 4387.
(e) Dave, P. R. J. Org. Chem. 1996, 61, 5453.
Table 5 Effect of Recycling [bmim]PF6
Me
Me
ClCO2Ph (1.2 equiv)
N
N
O
[bmim]PF6 (2.0 mL),
100 °C, 6 h
Me
OPh
(4) Cossy, J.; Rakotoarisoa, H. Tetrahedron Lett. 2000, 41,
2097.
Regeneration
Yield (%)
0
1
2
3
4
78
78
79
82
88
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1231.
Next we looked at the selectivity of the reaction when two
alkyl groups were present on the substrate. The selective
demethylation of N-butyl-N-methylaniline with phenyl
chloroformate in [bmim]Cl gave a higher reactivity and
selectivity than the reaction performed under solvent-free
conditions or in MeCN (Table 4).
Finally we tried to recycle the ionic liquid and to reuse it
in further reactions. Unfortunately, [bmim]Cl cannot be
conveniently extracted from the reaction mixture by stan-
dard procedures since it is soluble in water and cannot be
washed with water after the extraction. However, the pure
product can be obtained directly by distillation of the re-
action mixture, and the remaining ionic liquid was reused
for further demethylation reactions, maintaining the high
yield of the carbamate ester. Fortunately, [bmim]PF6 can
be recovered by the standard extraction method since it is
not soluble in water. Thus, after the extraction of the car-
bamate ester with ethyl acetate, the recovered [bmim]PF6
was washed with water once and dried on a vacuum
pump. It was then reused for the same demethylation
reaction and the high yield of the carbamate ester was
maintained (Table 5).
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Synlett 2006, No. 16, 2629–2632 © Thieme Stuttgart · New York

2632
S. Imori, H. Togo
LETTER
Phenyl N-Methyl-N-phenylcarbamate; Distillation
Method: A flask containing [bmim]Cl (4.0 mL) was dried
under reduced pressure by a vacuum pump for 2 h at 80 °C.
Then, N,N-dimethylaniline (20.0 mmol)and phenyl
chloroformate (1.2 equiv) were added to the flask. The
resulting mixture was stirred and heated at 80 °C for 3 h.
Then the reaction mixture was distilled to give pure phenyl
N-methyl-N-phenylcarbamate in 90% yield; bp 155 °C
(1 mmHg).
Phenyl N-Methyl-N-p-bromophenylcarbamate:
Colorless oil; bp 210 °C (1 mmHg). IR (neat): 1720, 1590,
1200, 830, 740, 690 cm–1. 1H NMR (CDCl3, TMS):
d = 7.49–7.45 (2 H, m), 7.34–7.09 (7 H, m), 3.38 (3 H, s).
13C NMR (CDCl3, TMS): d = 153.5 (q), 151.0 (q), 141.8 (q),
131.9 (2 t), 129.1 (2 t), 127.2 (t), 125.3 (2 t), 121.4 (2 t),
121.4 (q), 38.1 (p). HRMS (FAB): m/z calcd for
C14H13BrNO2 (M + H): 306.0130; found: 306.0137.
Phenyl N-Methyl-N-p-methylphenylcarbamate:
Colorless oil; bp 170 °C (1 mmHg). IR (neat): 1720, 1595,
1205, 820, 740, 690 cm–1. 1H NMR (CDCl3, TMS):
d = 7.33–7.08 (9 H, m), 3.38 (3 H, s), 2.34 (3 H, s). 13C NMR
(CDCl3, TMS): d = 154.0 (q), 151.3 (q), 140.3 (q), 136.4 (q),
129.6 (2 t), 129.1 (2 t), 125.7 (t), 125.2 (2 t), 121.6 (2 t), 38.2
(p), 20.9 (p). HRMS (FAB): m/z calcd for C15H16NO2 (M +
H): 242.1181; found: 242.1190.
Phenyl N-Methyl-N-m-nitrophenylcarbamate: Colorless
oil; bp 240 °C (1 mmHg). IR (neat): 1740, 1600, 1200, 810,
750, 695 cm–1. 1H NMR (CDCl3, TMS): d = 8.27–8.26 (1 H,
m), 8.07–8.05 (1 H, m), 7.75–7.73 (1 H, m), 7.54–7.50 (1 H,
m), 7.37–7.33 (2 H, m), 7.20–7.13 (3 H, m), 3.48 (3 H, s).
13C NMR (CDCl3, TMS): d = 153.3 (q), 150.6 (q), 148.3 (q),
143.8 (q), 131.3 (t), 129.5 (t), 129.2 (2 t), 125.6 (t), 121.3 (2
t), 120.7 (t), 120.1 (t), 37.5 (p). HRMS (FAB): m/z calcd for
C14H13N2O4 (M + H): 273.0875; found: 273.0879.
Phenyl N-Methyl-N-naphthylcarbamate: White solid; mp
86–87 °C. IR (paraffin): 1720, 1595, 1200, 695 cm–1. 1H
NMR (CDCl3, TMS): d = 8.00–6.92 (12 H), 3.49–3.41 (3
H). 13C NMR (CDCl3, TMS): d = 154.6 (q), 151.2 (q), 139.1
(q), 134.4 (q), 130.0 (q), 128.9 (2 t), 128.4 (t), 128.1 (t),
126.8 (t), 126.2 (t), 125.6 (t), 125.1 (t), 124.7 (t), 122.2 (t),
121.4 (2 t), 38.4 (p). HRMS (FAB): m/z calcd for C18H16NO2
(M + H): 278.1181; found: 278.1165.
Phenyl N-Butyl-N-phenylcarbamate: Colorless oil; bp
150 °C (1 mmHg). IR (neat): 1720, 1595, 1200, 745, 690
cm–1. 1H NMR (CDCl3, TMS): d = 7.42–7.09 (10 H, m),
3.78–3.74 (2 H, m), 1.66–1.59 (2 H, m), 1.40–1.31 (2 H, m),
0.93–0.89 (3 H, t, J = 7.3 Hz). 13C NMR (CDCl3, TMS):
d = 153.8 (q), 151.3 (q), 141.5 (q), 129.1 (2 t), 129.0 (2 t),
127.3 (t), 126.9 (t), 125.1 (2 t), 121.5 (2 t), 50.6 (s), 30.2 (s),
19.8 (s), 13.7 (p). HRMS (FAB): m/z calcd for C17H20NO2
(M + H): 270.1494; found: 270.1488.
Phenyl N-Ethyl-N-phenylcarbamate: Colorless oil; bp
160 °C (1 mmHg). IR (neat): 1720, 1595, 1200, 750, 690
cm–1. 1H NMR (CDCl3, TMS): d = 7.42–7.08 (10 H, m),
3.83–3.79 (2 H, m), 1.24–1.21 (3 H, m). 13C NMR (CDCl3,
TMS): d = 153.6 (q), 151.3 (q), 142.8 (q), 129.1 (2 t), 129.0
(2 t), 127.3 (t), 126.9 (t), 125.1 (2 t), 121.5 (2 t), 45.8 (s), 13.8
(p). HRMS (FAB): m/z calcd for C15H16NO2 (M + H):
242.1181; found: 242.1170.
Phenyl N-Methyl-N-dodecylcarbamate: Colorless oil; bp
180 °C (1 mmHg). IR (neat): 1730, 750, 690 cm–1. 1H NMR
(CDCl3, TMS): d = 7.36–7.37 (2 H, m), 7.20–7.09 (3 H, m),
3.43–3.31 (2 H), 3.06–2.98 (3 H), 1.63 (2 H), 1.32–1.26 (18
H, m), 0.91–0.86 (3 H, m). 13C NMR (CDCl3, TMS):
d = 153.6 (q), 151.3 (q), 142.8 (q), 129.1 (2 t), 129.0 (2 t),
127.3 (t), 126.9 (t), 125.1 (2 t), 121.5 (2 t), 45.8 (s), 13.8 (p).
HRMS (FAB): m/z calcd for C20H34NO2 (M + H): 320.2590;
found: 320.2596.
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(20) Phenyl N-Methyl-N-phenylcarbamate; Typical
Procedure: A flask containing [bmim]Cl (2.0 mL) was dried
under reduced pressure by a vacuum pump for 2 h at 80 °C.
Then, N,N-dimethylaniline (1.0 mmol) and phenyl
chloroformate (1.2 equiv) were added to the flask. The
resulting mixture was stirred and heated at 80 °C for 3 h.
Then H2O (3 mL) was added and the reaction mixture was
extracted with EtOAc (20 × 5 mL). The combined extract
was condensed to give a residue; the purity of the product
was about 50% due to the presence of phenyl chloroformate
and a little ionic liquid. The residue was purified by
preparative TLC (hexane–EtOAc, 7:1) to give pure phenyl
N-methyl-N-phenylcarbamate in 95% yield; colorless oil; bp
155 °C (1 mmHg). IR (neat): 1730, 1600, 1205, 740, 695
cm–1. 1H NMR (CDCl3, TMS): d = 7.39–7.09 (10 H, m),
3.39 (3 H, s). The following abbreviations are used in 13
C
spectral data: p, s, t, q, for primary, secondary, tertiary, and
quarternary carbon, respectively. 13C NMR (CDCl3, TMS):
d = 153.9 (q), 151.2 (q), 142.8 (q), 129.1 (2 t), 128.9 (2 t),
126.5 (t), 125.8 (t), 125.3 (2 t), 121.5 (2 t), 38.1 (p). HRMS
(FAB): m/z calcd for C14H14NO2 (M + H): 228.1025;
found: 228.1012.
Synlett 2006, No. 16, 2629–2632 © Thieme Stuttgart · New York