Novel one-pot synthesis of N-alkyl arylamines from oxime ethers using organometallic reagents

Article abstract of DOI:10.1055/s-2007-980358

A novel one-pot synthesis of α,α-disubstituted secondary arylamines from oxime ethers has been developed by two separate additions of organometallic reagents. As a related arylamine construction, very efficient synthesis of N-(diallyl)methyl arylamines is

Full text of DOI:10.1055/s-2007-980358

LETTER
1403
Novel One-Pot Synthesis of N-Alkyl Arylamines from Oxime Ethers Using
Organometallic Reagents
O
ne-PotSynth
a
esisof
N
-
A
r
lkyl Ar
y
t
lamine
h
s
a P. Mukhopadhyay, Okiko Miyata, Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Fax +81(78)4417556; E-mail: taknaito@kobepharma-u.ac.jp
Received 15 February 2007
efficient one-pot synthesis of a,a-disubstituted secondary
Abstract: A novel one-pot synthesis of a,a-disubstituted secondary
arylamines from oxime ethers has been developed by two separate
additions of organometallic reagents. As a related arylamine con-
struction, very efficient synthesis of N-(diallyl)methyl arylamines is
achieved via domino reactions involving addition–eliminative re-
arrangement–addition reactions of acyclic and cyclic oxime ethers
with allylmagnesium bromide.
arylamines from oxime ethers.
Initially, we investigated the one-pot reaction of p-meth-
oxybenzaldehyde oxime ether 3a as a model compound
because in our previous report, the presence of a p-meth-
oxy group in the substrate promoted the reaction to afford
amines in good yields (Table 1).8 After formation of the
lithiated N-methoxy diarylamine from oxime ether 3a
(PhLi, BF3·Et2O, toluene, –78 °C), three equivalents of
PhLi were added to the same reaction flask at –20 °C. The
reaction gave the desired product 4a (33%) and also ad-
duct 6a (22%), the latter was formed by addition of only
PhLi to the oxime ether (Table 1, entry 1).9 In order to ob-
tain 4a exclusively, it was necessary to add four equiva-
lents of PhLi in the second step.10
Key words: one-pot synthesis, arylamine, oxime ether, Grignard
reagent, organolithium reagent, rearrangement
One-pot reactions are always challenging but interesting
tasks for organic chemists, particularly in cases where the
substrate shows complex behaviors with the reagents.
Compared with imines, the reaction of oxime ethers with
organometallic reagents is limited1 due to its less electro-
philic character, ease of a-deprotonation and aziridine for-
mation.2 Thus the addition reaction of organometallics to
oxime ethers is sometimes problematic and can give rise
to a variety of other products in addition to the desired
product. However, oxime ethers are attractive starting ma-
terials in the synthesis of amino compounds3 as cleavage
of the N–O bond of alkoxy amines is easier than the cleav-
age of the amine C–N bond. N-Alkyl arylamines are im-
portant organic compounds that are widely used as
precursors in the synthesis of important pharmaceutical4
and polymeric products.5 Oxime ethers are easily synthe-
sized from readily available carbonyl compounds and eas-
ily converted into amines or alkoxy amines via addition
reactions using a variety of reagents and catalysts.6 In con-
trast, very little is known7 about the direct transformation
of oxime ethers to a,a-disubstituted secondary aryl-
amines, taking advantage of the easily cleaved N–O bond.
To establish this reaction as a potential method in the
preparation of N-alkyl arylamines from oxime ethers, we
used a variety of organometallic reagents with the
substrate 3a and obtained the desired products 4a–f in
moderate to good yields (Table 1, entries 2–7). When
DIBAL-H was used as the hydrogen nucleophile in the
second step, six equivalents of the reagent were required
in order for the reaction to go to completion (Table 1,
entry 7). An aliphatic n-BuLi reacted to afford the desired
compound 4g in low yield (Table 1, entry 8).
OR3
R2
H
R4M and R5M
R5
R4
N
N
R1
toluene or CH2Cl2
R2
R1
M = Li, MgBr
2
1
R
R
R
1 = Ar, R
2 = H, R, Ar
3 = Me, Bn
i) addition
R4M
iii) addition
R5M
Recently, we have reported the domino elimination–rear-
rangement–addition reaction of N-alkoxy(arylmeth-
yl)amines to N-alkyl arylamines.8 Based on our previous
work, we have designed a one-pot synthesis of N-alkyl
arylamines from oxime ethers by combining three crucial
reactions (Scheme 1). These are the addition of a carbon
nucleophile to an oxime ether (1→A), eliminative rear-
rangement of the alkoxyamino group (A→B) and addition
of a carbon nucleophile to the resulting imine group
(B→2). Thus, we have succeeded in the first and an
OR3
R4
M
N
R4
ii) eliminative
rearrangement
N
R1
R2
R1
R2
A
B
Scheme 1
We then examined the substituent effect on the substrate
arylaldoxime ethers 3. One-pot reactions using both m-
methoxy aldoxime ether 3b and o-methoxy aldoxime
ether 3c proceeded to give two types of products 4h–k and
5h–k (Table 1, entries 9–12) as a mixture of two regio-
SYNLETT 2007, No. 9, pp 1403–1406
0
1.
0
6.
2
0
0
7
Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980358; Art ID: U01107ST
© Georg Thieme Verlag Stuttgart · New York

1404
P. P. Mukhopadhyay et al.
LETTER
Table 1 One-Pot Reaction of Oxime Ethers 3 with Organometallic Reagents
OMe
H
N
H
OMe
H
i) BF3⋅Et2O, R2Li (1.5 equiv)
toluene, –78 °C, 1 h
R3
R3
N
N
N
R1
+
R2
+
ii) R3M, –20 °C to r.t.
30 min
H
R1
R1
R1
3
6 (R2 = Ph)
4
5 (R2 = Ph)
Entry
1
Oxime ether R1
R2Li
R3M (equiv)
PhLi (3)
Yield of 4 (%)
Yield of 5 (%)
Yield of 6 (%)
3a
3a
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
3d
3e
3e
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
m-OMe
m-OMe
o-OMe
o-OMe
p-Me
PhLi
PhLi
PhLi
PhLi
PhLi
PhLi
PhLi
n-BuLi
PhLi
PhLi
PhLi
PhLi
PhLi
PhLi
PhLi
PhLi
PhLi
4a
4a
4b
4c
4d
4e
4f
33
63
68
67
56
53
63
27
19
12
42
39
59
54
51
32
24
5a
5a
5b
5c
5d
5e
5f
–
6a
6a
6b
6c
6d
6e
6f
22
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
2
PhLi (4)
–
3
n-BuLi (4)
MeLi (4)
–
4
–
5
EtLi (4)
–
6
AllylMgBr (4)
DIBAL-H (6)
n-BuLi (4)
PhLi (4)
–
7
–
8
4g
4h
4i
5g
5h
5i
–
6g
6h
6i
9
37
26
18
14
–
10
11
12
13
14
15
16
17
n-BuLi (4)
PhLi (4)
4j
5j
6j
n-BuLi (4)
PhLi (4)
4k
4l
5k
5l
6k
6l
p-Me
n-BuLi (4)
AllylMgBr (4)
PhLi (4)
4m
4n
4o
4p
5m
5n
5o
5p
–
6m
6n
6o
6p
p-Me
–
H
–
H
n-BuLi (4)
–
isomers formed by rearrangement of the parent aryl group In order to check the generality of our one-pot procedure,
and the newly added phenyl group, respectively. When we we next employed the enolizable oxime ethers 7 which
used p-methyl substituted and unsubstituted arylaldoxime gave the corresponding amines 4q–s in moderate yields
ethers 3d and 3e as substrate, the corresponding amines (Table 2). Since enolizable oxime ethers and their related
4l–p were isolated in moderate to low yields (Table 1, imines sometimes do not tolerate nucleophilic addition re-
entries 13–17).
actions, our newly found one-pot synthesis is a promising
approach in the synthesis of N-alkyl arylamines.
Table 2 One-Pot Reaction of Enolizable Oxime Ethers 7 with Or-
We then investigated the reaction of aryl oxime ethers 3
with allylmagnesium bromide as the nucleophile and
found an efficient domino-type reaction involving nucleo-
philic addition, eliminative rearrangement and nucleo-
philic addition (Table 3).
ganometallic Reagents
OBn
H
N
R3
R2
i) BF3⋅Et2O, PhLi (1.5 equiv)
toluene, –78 °C, 1 h
N
R2
R1
ii) R3M (4 equiv), –20 °C to r.t.
30 min
R1
According to the related reaction of aldoxime ether report-
ed by the Pornet group,11 we investigated the same reac-
tion procedure using ketoxime ether 3f as substrate and
diethyl ether as solvent. The reaction at room temperature
for 12 hours gave N-(diallyl)methyl arylamine 8b in only
50% yield and also gave polymeric products. In order to
develop efficient domino-type reactions applicable to
both aldoxime and ketoxime ethers, we first investigated
the solvent effect in the reaction of aldoxime ether 3a with
4
7a: R1 = R2 = Me
7b: R1 = Ph(CH2)2; R2 = H
Entry
Oxime ether
R3M
Yield (%)
4q 42
1
2
3
7a
7a
7b
PhLi
AllylMgBr
PhLi
4r 42
4s 33
Synlett 2007, No. 9, 1403–1406 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of N-Alkyl Arylamines
1405
Table 3 Preparation of Dihomoallylic Secondary Amines and Azepines Using a Domino-Type Reaction with Allylmagnesium Bromide
OMe
N
H
N
AllylMgBr (4 equiv)
R2
R1
R1
R2
CH2Cl2, r.t.
R
R
3
8
Entry
1 a
2 a
3
Oxime ether
R1
R
H
H
H
H
H
H
H
H
H
H
–
R2
H
Solvent
toluene
hexane
THF
Time (min)
Yield (%)
8a
3a
3a
3a
3a
3f
p-OMe
p-OMe
p-OMe
p-OMe
p-OMe
p-Me
p-Br
H
20
30
180
1
83
H
8a
49 b
89
H
8a
4a
H
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8a
98
5
Ph
Me
Me
Ph
Me
Me
–
45
45
45
45
45
45
45
90
90
90
90
8b
8c
quant
98
6
3g
3h
3i
7
8d
8e
quant
98
8
9
3j
o-OMe
m-Me
–
8f
99
10
11c
12
13
14
15
3k
3l
8g
99
8h
8I
63
3m
3n
3o
3p
H
-OCH2CH2-
-SCH2CH2-
98
H
8j
91
H
-CH2CH2CH2-
-CH2CH2CH2-
8k
8l
96
p-OMe
quant
a These reactions were performed using 2.5 equivalents of allylmagnesium bromide at –78 °C.
b Compound 3a (24%) was recovered.
c Methyl (3-pyridyl)ketoxime ether was used as substrate.
allylmagnesium bromide. Although toluene and tetrahy- ethers 3g–l afforded (diallyl)methylamines 8c–h under
drofuran were effective solvents, hexane gave a low yield the optimized conditions (Table 3, entries 6–11).
of our desired (diallyl)methylamine 8a probably due to
the low solubility (Table 3, entries 1–3). Using dichloro-
The efficiency of our procedure is highlighted by the short
syntheses of diallylazepines 8i–l in excellent yields at
methane as a non-coordinating solvent gave us an ex-
room temperature in 90 minutes (Table 3, entries 12–15).
cellent result as follows. Reaction of aldoxime ether 3a
These compounds are core structures in pharmaceuticals
with allylmagnesium bromide (2.5 equiv) in dry CH2Cl2
because of their proven biological activity.13
at –78 °C resulted in the production of (diallyl)methyl-
In conclusion, we have developed a one-pot synthesis of
N-alkyl arylamines from readily available oxime ethers
amine 8a within one minute and in 98% yield (Table 3,
entry 4). Even when 1.2 equivalents of allylmagnesium
and organometallic reagents. Additionally, N-(dial-
bromide was used, the only product was the amine 8a
lyl)methyl arylamines were effectively prepared by
(46%) and also recovered substrate 3a (38%). This result
domino-type reactions of oxime ethers with allylmagne-
shows that the domino-type reaction involving nucleo-
sium bromide.
philic addition, eliminative rearrangement and nucleo-
philic addition takes place very efficiently to form
arylamines in CH2Cl2. With this encouraging result in
hand, we further investigated the reaction of ketoxime
ether 3f with allylmagnesium bromide. The reaction re-
quired four equivalents of allylmagnesium bromide to
proceed smoothly, but the expected product 8b was pro-
duced in quantitative yield (Table 3, entry 5) within 45
minutes at room temperature.12 Similarly, other ketoxime
Acknowledgment
We are grateful to acknowledge the research Grants-in-Aid for
Scientific Research (B) (to T.N.) and (C) (to O.M.) from the Japan
Society for the Promotion of Science (JSPS) and Scientific
Research on Priority Areas (A) (to T.N.) from the Ministry of
Education, Culture, Sports, and Technology. P.P.M. thanks the
JSPS for a research grant and postdoctoral fellowship.
Synlett 2007, No. 9, 1403–1406 © Thieme Stuttgart · New York

1406
P. P. Mukhopadhyay et al.
LETTER
(10) Typical procedure for the one-pot synthesis of amine 4m
(Table 1, entry 14 ): The oxime ether 3d (100 mg, 0.67
mmol) was dissolved in dry toluene (5 mL) under N2 and
cooled to –78 °C. BF3·Et2O (0.1 mL, 0.80 mmol) was added
and the mixture was stirred for 15 min. PhLi (1.92 mol/L in
n-butyl ether, 0.42 mL, 0.80 mmol) was added dropwise
over 15 min. After 1 h, the reaction mixture was allowed to
warm up to –20 °C. Then n-BuLi (1.6 mol/L in n-hexane, 1.7
mL, 2.7 mmol) was added at –20 °C and the mixture was
stirred at r.t. for 0.5 h. The reaction mixture was quenched at
0 °C with aq sat. NH4Cl solution (0.5 mL) and extracted with
CHCl3 (3 × 10 mL). The extracts were combined, dried
(MgSO4) and concentrated under reduced pressure. The
residue was purified by preparative TLC (n-hexane–EtOAc,
8: 1) to give the amine 4m (92 mg, 54%) as a pale yellow oil.
IR (neat): 3413 cm–1; 1H NMR (300 MHz, CDCl3):
References and Notes
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d = 7.35–7.17 (m, 5 H), 6.88 (br d, J = 8.5 Hz, 2 H), 6.42 (br
d, J = 8.5 Hz, 2 H), 4.25 (t, J = 6.5 Hz, 1 H), 3.93 (br s, 1 H),
2.17 (s, 3 H), 1.81–1.73 (m, 2 H), 1.41–1.24 (m, 4 H), 0.88
(br t, J = 7.0 Hz, 3 H); 13C NMR (75.5 MHz, CDCl3):
d = 145.2, 144.5, 129.5, 128.5, 126.7, 126.4, 126.2, 113.3,
58.5, 38.7, 28.5, 22.6, 20.3, 13.9; HRMS (ESI+): m/z calcd
for C18H23N: 253.1830; found: 253.1828.
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(12) Typical procedure for the domino-type reaction in the
synthesis of(diallyl)methylamine 8b (Table 3, entry 5):
Allylmagnesium bromide (1 mol/L in Et2O, 1.8 mL, 1.8
mmol) was added to a r.t. solution of oxime ether 3f (110 mg,
0.46 mmol) in dry CH2Cl2 (2.3 mL). After being stirred at the
same temperature for 45 min, the mixture was quenched
with aq sat. NH4Cl solution (1 mL) at 0 °C, extracted with
CHCl3 (4 × 10 mL) and washed with brine. The organic
phase was dried over MgSO4 and concentrated under
reduced pressure. The oily mass was filtered through a short
column of silica gel to give compound 8b (133.3 mg) in
quantitative yield, as a colorless oil. IR (neat): 3376 cm–1; 1H
NMR (300 MHz, CDCl3): d = 7.46 (br d, J = 8.0 Hz, 2 H),
7.34 (br t, J = 8.0 Hz, 2 H), 7.24 (br t, J = 7.5 Hz, 1 H), 6.59
(br d, J = 8.5 Hz, 2 H), 6.28 (br d, J = 8.5 Hz, 2 H), 5.66–
5.52 (m, 2 H), 5.08–4.99 (m, 4 H), 3.66 (s, 3 H), 2.79 (dd,
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(7) (a) Uno et al. observed very low yields (4% and 8%) of two
different amine side products during their study on the
addition of organolithium reagents to the O-tert-
butyldimethylsilyl (TBDMS) derivative of an oxime in the
presence of a Lewis acid: Uno, H.; Terakawa, T.; Suzuki, H.
Synlett 1991, 559. (b) The Yamamoto group3d has reported
the N–O bond cleavage of oxime sulphonates by Grignard
reagents to synthesize a,a-disubstituted amines.
J = 6.5, 13.5 Hz, 2 H), 2.63 (dd, J = 8.0, 13.5 Hz, 2 H); 13
C
NMR (75.5 MHz, CDCl3): d = 151.8, 145.2, 139.7, 133.4,
128.3, 126.6, 126.5, 118.7, 116.6, 114.3, 59.9, 55.5, 42.5;
HRMS (ESI+): m/z calcd for C20H23NO: 293.1779; found:
293.1782.
(8) Miyata, O.; Ishikawa, T.; Ueda, M.; Naito, T. Synlett 2006,
2219.
(9) The addition product 6a was the only product isolated (63%)
when the first reaction was continued for one hour without
the second addition.
(13) Le Count, D. J. In Comprehensive Heterocyclic Chemistry,
Vol. 9; Katritzky, A. R.; Rees, C. W.; Scriven, E. F.;
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1–43.
Synlett 2007, No. 9, 1403–1406 © Thieme Stuttgart · New York