Direct alkenylation of arylamines at the ortho-position

Article abstract of DOI:10.1016/j.tetlet.2004.06.024

Treatment of magnesium alkylidene carbenoids, which were generated from 1-chlorovinyl p-tolyl sulfoxides with isopropylmagnesium chloride at -78°C in toluene, with N-lithio arylamines gave ortho-alkenylated arylamines in moderate to good yields. The reaction was found to proceed in a highly stereospecific manner at the carbenoid carbon. This reaction offers a quite novel and direct alkenylation of arylamines at the ortho-position of the aromatic ring.

Full text of DOI:10.1016/j.tetlet.2004.06.024

n
Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5785–5789
Direct alkenylation of arylamines at the ortho-position
*
Tsuyoshi Satoh, Yumi Ogino and Masatomo Nakamura
Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 13 May 2004; revised 2 June 2004; accepted 4 June 2004
Abstract—Treatment of magnesium alkylidene carbenoids, which were generated from 1-chlorovinyl p-tolyl sulfoxides with iso-
propylmagnesium chloride at )78 °C in toluene, with N-lithio arylamines gave ortho-alkenylated arylamines in moderate to good
yields. The reaction was found to proceed in a highly stereospecific manner at the carbenoid carbon. This reaction offers a quite
novel and direct alkenylation of arylamines at the ortho-position of the aromatic ring.
Ó 2004 Elsevier Ltd. All rights reserved.
Arylamines are obviously one of the most important
and fundamental compounds in organic chemistry
because arylamines have been widely used as the mate-
rial for medicine, dyes, and other chemical products. In
view of this importance of arylamines, innumerable
studies have been carried out concerning their chemistry
We recently reported a new method for the generation
of magnesium alkylidene carbenoids 2 from 1-chloro-
3
vinyl p-tolyl sulfoxides 1 with a Grignard reagent via
4
sulfoxide–magnesium exchange reaction. From the
generated magnesium alkylidene carbenoids, a new
5
method for the synthesis of tetra-substituted olefins and
6
allenes was realized. In continuation of our interest in
1
and synthesis.
the development of new synthetic methods by utilizing
the generated magnesium alkylidene carbenoids 2 in
organic synthesis, we investigated the reaction of 2 with
N-lithio amides and found that the reaction with N-
lithio arylamines gave ortho-alkenylated arylamines 3 in
moderate to good yields (Scheme 1).
The alkylation of the aromatic ring of arylamines is
quite important chemistry for the synthesis of deriva-
tives of arylamines; however, this is not a so easily
accessible process. An even more difficult process is the
direct alkenylation of the arylamines. To the best of our
knowledge, only one report concerning the direct alken-
ylation of arylamines on the aromatic ring has been
5
1-Chlorovinyl p-tolyl sulfoxide 4 in dry toluene was
2
published by Sartori and co-workers. The authors
treated with t-BuMgCl (0.12 equiv) at )78 °C to remove
a trace of moisture in the reaction mixture. After 10 min,
i-PrMgCl (2.8 equiv) was added to the reaction mixture.
The sulfoxide–magnesium exchange reaction took place
synthesized 1,1-diarylethylenes directly from substituted
anilines and phenylacetylene in the presence of mont-
morillonite KSF.
NRLi
X
O
R1
R2
STol
Cl
R1
R2
MgCl
Cl
R1
R2
i-PrMgCl
H
NHR
Toluene
-78 ~ -10 ˚C
-78 ˚C
X
1
2
3
Scheme 1.
Keywords: Sulfoxide; Sulfoxide–magnesium exchange reaction; Magnesium alkylidene carbenoid; Alkenylation; ortho-Alkenylated arylamine.
*
Corresponding author. Tel.: +81-3-5228-8272; fax: +81-3-3235-2214; e-mail: tsatoh@ch.kagu.tus.ac.jp
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.024

5786
T. Satoh et al. / Tetrahedron Letters 45 (2004) 5785–5789
NHLi
O
O
O
STol
Cl
i-PrMgCl
O
O
MgCl
Cl
O
O
H
O
O
H
NH2
Toluene
-78 ˚C to
-10 ˚C, 49%
NH
-78 ˚C
5
6
7
4
Scheme 2.
6
b
rapidly to give the magnesium alkylidene carbenoid 5.
colorless crystalline product in 49% yield. The prod-
uct showed C15 as the molecular formula
and N–H absorption on its IR spectrum. At this stage
two products, alkenyl aniline 6 and enamine 7, were
1
expected to be produced. H NMR showed two NH
First, reaction of 5 with N-lithio piperidine and N-lithio
n-hexylamine was investigated; however, only a rather
complex mixture was obtained with these N-lithio
alkylamines.
H19NO
2
protons and only four aromatic protons (d 6.69 (1H, d),
6.73 (1H, t), 6.98 (1H, d), 7.06 (1H, t)). From the
Next, the reaction was investigated with N-litho aryl-
amines. N-Litho aniline (3 equiv) was added to the
solution of the magnesium alkylidene carbenoid 5 at
13
coupling pattern of these aromatic protons and
C
NMR, the structure of the product was unambiguously
determined to be the ortho-alkenylated aniline 6
(Scheme 2).
)
78 °C and the temperature of the reaction mixture was
gradually allowed to warm to )10 °C. We obtained a
Table 1. Synthesis of ortho-alkenylated arylamines by the reaction of the magnesium alkylidene carbenoid 5 and N-lithio arylamines
a
Entry
Arylamine
ortho-Alkenylated arylamine
(Yield/%)
O
O
H
X=OCH3
X=Cl
(44)
(28)
NH2
1
2
X
NH2
X
O
O
H
CH3
NH2
3
(32)
NH2
CH3
NH2
CH3
8
b
4
5
––
CH3
H3CO
H
O
O
H
NH2
NH2
NH2
3
H CO
10 (13)
9
(30)
OCH3
O
O
H
H
NHCH3
6
7
NHCH3
(38)
(66)
O
O
NH2
NH2
NH2
O
O
H
NH2
8
(60)
a
Three equivalents of N-lithio arylamines were reacted with 5.
No para-alkenylated product was obtained.
b

T. Satoh et al. / Tetrahedron Letters 45 (2004) 5785–5789
5787
We were somewhat surprised and pleased by this result
because no report has been published on the reaction of
anilines with alkylidene carbenes (or carbenoids). In
addition, this reaction is a quite novel and direct alken-
ylation of arylamines on the aromatic ring. We investi-
gated the generality of this reaction of 5 with other
N-lithio arylamines and the results are summarized in
Table 1.
and the mechanism of this reaction will be discussed
later. N-Methylaniline gave an o-alkenylated product
(entry 6). Interestingly, the reaction with 1-aminonaph-
thalene and 1-aminoanthracene gave much better yields
(entries 7 and 8).
7
We further studied this reaction using 1-chlorovinyl p-
tolyl sulfoxide 11 derived from acetone and the results
are summarized in Table 2. Entries 1 and 2 show that
quite similar yields were obtained with aniline and p-
anisidine. The reaction with m-anisidine again gave two
products and the main product was found to be a more
sterically hindered compound (entry 3). N-Methylanil-
ine gave much better yield compared with the result in
Table 1. Again, much better yields were obtained from
the reaction of 11 with 1-aminonaphthalene and 1-
aminoanthracene (entries 5 and 6).
The reaction with the aniline having an electron-
donating group (OCH ) at the 4-position gave a similar
3
yield (entry 1); however, the aniline having an electron
withdrawing group (Cl) gave a markedly diminished
yield (entry 2). The reaction with o-toluidine gave the
o-alkenylated aniline 8 (entry 3). Interestingly, 2,6-di-
methylaniline gave no p-alkenylated aniline. This result
indicated that this reaction only gives o-alkenylated
products.
Next, we investigated the stereochemistry of these
reactions. The stereoisomers 12E and 12Z were synthe-
sized from 2-cyclohexenone and the reaction was
carried out with 1-aminonaphthalene and 1-amino-
anthracene. The results are summarized in Table 3.
The result shown in entry 5 is quite interesting. The
reaction with m-anisidine gave two o-alkenylated prod-
ucts 9 and 10. The main product 9 was found to have the
alkenyl group at a more hindered position. The reason
8
Table 2. Synthesis of ortho-alkenylated arylamines by the reaction of the magnesium alkylidene carbenoid derived from 11 and N-lithio arylamines
NRLi
O
X
CH3
CH3
STol
Cl
CH3
CH3
H
NHR
i-PrMgCl
Toluene
-
78 ~ -10 ˚C
-78 ˚C
X
11
a
Entry
Arylamine
ortho-Alkenylated arylamine
(Yield/%)
CH3
CH3
H
X=H
(43)
(43)
NH2
1
2
X
NH2
X=OCH3
X
CH3
H
CH3
H
NH2
H3CO
NH2
CH3
3
CH3
3
NH2
H CO
OCH3
22)
(29)
(
CH3
CH3
H
H
NHCH3
NH2
4
5
NHCH3
(46)
(81)
CH3
CH3
NH2
NH2
CH3
CH3
H
NH2
6
(79)
a
Three equivalents of N-lithio arylamines were reacted with the carbenoid derived from 11.

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T. Satoh et al. / Tetrahedron Letters 45 (2004) 5785–5789
Table 3. The reaction of the magnesium alkylidene carbenoids derived from E- and Z-1-chlorovinyl p-tolyl sulfoxides (12E and 12Z) with N-lithio
1-aminonaphthalene and N-lithio 1-aminoanthracene
a
Entry
Arylamine
Product
b
E=Z
(Yield/%)
(65)
Cl
NH2
H
NH2
1
3:97
S(O)Tol
1
1
2E
2Z
S(O)Tol
Cl
NH2
NH2
2
3
95:5
(71)
(69)
NH2
NH2
H
H
Cl
22:78
S(O)Tol
1
2E
S(O)Tol
Cl
NH2
4
84:16
(66)
1
2Z
H NH2
a
Three equivalents of N-lithio 1-aminonaphthalene and N-lithio 1-aminoanthracene were reacted with 12E and 12Z.
1
b
The ratio of E=Z was determined from their H NMR.
R1
Cl
R2
S(O)Tol
1
4
5
i-PrMgCl
Cl
R1
R2
R1
Cl
NHLi
NH
R2
R1
MgCl
NH
R1
H
MgCl
MgCl
NH
Li
NH2
1
R
R
R2
R2
H
R
13
R
R
16
17
A
O
O
Cl
O
O
Cl
MgCl
NH
MgCl
NH
9
10
H3CO
C
OCH3
B
Scheme 3.
Quite interestingly, the reaction of the carbenoids
derived from 12E and 12Z with 1-aminonaphthalene
gave Z-o-alkenylated 1-aminonaphthalene and E-o-alk-
enylated 1-aminonaphthalene, respectively, with high
stereospecificity (entries 1 and 2). The reaction of 12E
and 12Z with 1-aminoanthracene gave also the o-alke-
nylated 1-aminoanthracenes, though the stereospecific-
ity was somewhat lower (entries 3 and 4).
Finally, based on the stereochemical aspects of the re-
sults shown in Tables 1–3, the mechanism and the ste-
reochemistry of this reaction are proposed as follows
(Scheme 3). The N-lithio arylamine is present in the
resonance form, lithium a-imino carbanion 13. On the
other hand, the magnesium alkylidene carbenoid 15 was
generated stereospecifically from 1-chlorovinyl p-tolyl
sulfoxide 14 with i-PrMgCl at )78 °C. The reaction of 13

T. Satoh et al. / Tetrahedron Letters 45 (2004) 5785–5789
5789
with 15 takes place via the intermediate A with inversion
References and notes
of the configuration at the carbenoid carbon to give 16.
The product 17 is derived from 16 with proton transfer
from carbon or nitrogen. The inversion of the configu-
ration in the reaction of lithium alkylidene carbenoids
with alkyllithium has been reported by Walborsky and
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4
The result shown in Table 1, entry 5, can be explained
from the intermediates B and C in Scheme 3. Two
lithium a-imino carbanions were expected to generate
from N-lithio m-anisidine. These carbanions react with
the magnesium alkylidene carbenoid 5 via chelated
intermediates B and C. As the intermediate B has chel-
ation between magnesium and nitrogen and oxygen, the
intermediate B is more likely to be present in the reac-
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In conclusion, we have found a quite novel and direct
alkenylation of arylamines at the ortho-position of the
aromatic ring. We are continuing to study the scope and
limitation of this chemistry.
8. Satoh, T.; Kawashima, T.; Takahashi, S.; Sakai, K.
Tetrahedron 2003, 59, 9599–9607.
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This work was supported by a grant from the Ministry
of Education, Culture, Sports, Science and Technology
of Japan to promote multi-disciplinary research project,
which is gratefully acknowledged.
1