GaCl3-Catalyzed ortho-ethynylation reaction of N-benzylanilines

Article abstract of DOI:10.1016/j.tetlet.2004.03.187

Lithiated N-benzylanilines were ethynylated at the ortho-position with silylchloroethyne at 120°C in the presence of a catalytic amount of GaCl₃. Trimethylsilylated N-methylaniline could also be used for this transformation.

Full text of DOI:10.1016/j.tetlet.2004.03.187

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4333–4335
GaCl -Catalyzed ortho-ethynylation reaction of N-benzylanilines
3
Ryo Amemiya, Akiko Fujii and Masahiko Yamaguchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba Sendai 980-8578, Japan
Received 9 March 2004; revised 25 March 2004; accepted 31 March 2004
Abstract—Lithiated N-benzylanilines were ethynylated at the ortho-position with silylchloroethyne at 120 °C in the presence of a
catalytic amount of GaCl . Trimethylsilylated N-methylaniline could also be used for this transformation.
3
Ó 2004 Elsevier Ltd. All rights reserved.
ortho-Ethynylanilines are versatile intermediates for the
synthesis of indoles, and a variety of methods have been
investigated for the cyclization. Introduction of an
catalytic ortho-ethynylation of anilines. Following
problems, however, were conceivable: Aniline itself did
not react with chlorosilylethyne in the presence of
1
ethynyl groupto the aniline nuclei therefore is an
important transformation in organic synthesis. The
most common method to prepare the ethynylanilines is
the Sonogashira coupling reaction of ortho-haloanilines
with terminal alkynes. The Stille coupling using stan-
3
nylated alkynes was also reported. These methods,
3
GaCl , which was probably due to the lower acidity of
the amine proton; GaCl could readily be deactivated by
3
the basic amino groupof anilines. Use of N-metalated
anilines, therefore, was examined to overcome such
problems.
2
9
however, require multi-step preparation of the haloge-
nated substrates particularly in case of substituted
anilines. Taylor reported the coupling reaction of ortho-
N-Trimethylsilyl-N-methylaniline 1 prepared from N-
methylaniline 4 was initially selected as the substrate to
examine the GaCl
of 1 in o-dichlorobenzene was treated with a stoichio-
metric amount of GaCl (1 equiv) at room temperature
3
-catalyzed ethynylation. A solution
4
thallated anilines with alkynyl copper reagents. The
reaction also required the preparation of the ortho-
thallated anilines using stoichiometric amount of toxic
thallium reagent. Yamamoto developed the ethynyl-
ation reaction of N-benzyl-N-phenyl-O-(trimethylsilyl)-
hydroxyamine prepared from aniline with excess tri-
3
for 10 min, to which chlorotriethylsilylethyne 2 (1 equiv)
in o-dichlorobenzene was added. The mixture was
heated at 90 °C for 1 h, and workupwith 2 M NaOH
gave N-methyl-2-(triethylsilylethynyl)aniline 3 in 52%
yield with the recovered N-methylaniline 4 in 11% yield
(Table 1, entry 1). This result indicated that the trans-
5
alkynylaluminum. This reaction gave mixtures of the
ortho- and para-isomers. Direct and catalytic introduc-
tion of ethynyl group to aniline nuclei apparently is the
most convenient and straightforward. Previously, we
developed ortho-ethenylation reaction of anilines with
acetylene using stoichiometric amounts of SnCl –Bu N
metalation of 1 with GaCl and the carbogallation of the
3
resulted organogallium intermediate with 2 did occur.
The material balance could be improved by treating the
reaction mixture with excess ethylenediamine at 100 °C
for 30 min giving 3 in 60% yield with the recovered 4 in
23% yield (entry 2). The reaction mixture of 1, 2, and
4
3
6
reagent. We also reported the catalytic ortho-ethynyl-
ation reaction of phenols with chlorosilylethyne using
GaCl . The latter reaction proceeded via carbometa-
lation (carbogallation) between phenoxygallium and
7
3
GaCl
3
(1 equiv) treated at 90 °C for 1 h showed a single
1
N–Me peak at d 3.36 by H NMR. It disappeared after
the treatment with ethylenediamine, and the peaks of 3
(d 2.90) and 4 (d 2.89) were observed. The results
chlorosilylethyne, which was followed by the b-elimi-
8
nation of GaCl
3
. It was considered that the addition–
elimination methodology could be applied to the
showed that GaCl formed strong complex with 3 and 4,
3
which could be liberated by ethylenediamine.
The next examination was directed to the development
of the catalytic reaction by liberating 3 from the com-
Keywords: N-Benzylaniline; ortho-Ethynylation; Gallium(III) chloride;
Chloroethyne; Catalysis.
*
Corresponding author. Tel.: +81-222176812; fax: +81-222176811;
e-mail: yama@mail.pharm.tohoku.ac.jp
plex with GaCl
mechanism is as follows: GaCl reacts with silylated 5
3
during the reaction. A plausible
3
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.187

4334
R. Amemiya et al. / Tetrahedron Letters 45 (2004) 4333–4335
Table 1. ortho-Ethynylation reaction N-trimethylsilyl-N-methylaniline
a
Entry
GaCl
3
/mol %
Temp/°C
Time/h
Workupmethod
Yield/%
3
4
1
2
3
4
5
100
100
20
90
90
1
1
1
3
3
A
B
A
A
B
52
60
20
38
43
11
23
55
26
53
90
20
20
120
120
a
Method A: Treated with 2 M NaOH–THF at room temperature. Method B: Treated with ethylenediamine at 100 °C for 30 min, and then with 2 M
NaOH–THF.
(
R ¼ SiMe
3
) to generate gallated aniline 6, and carbo-
metalation of 6 and 2 provides vinylgallium 7. The
o-dichlorobenzene at 0 °C, which was followed by GaCl
3
(1 equiv) and 2 (3 equiv). The reaction mixture was
heated at 90 °C for 1 h, and N-benzyl-2-(triethylsilyl-
ethynyl)aniline 10 was obtained in 65% yield (Table 2,
b-elimination of 7 leads to the o-ethynylated aniline 8
regenerating GaCl
with a catalytic amount of GaCl
1 equiv) in o-dichlorobenzene at 90 °C for 1 h, 3 was
3
(Scheme 1). When 1 was treated
10
3
(20 mol %) and 2
entry 1). The amount of GaCl
3
could be reduced to
(
20 mol %, when the reaction was conducted at 120 °C for
3 h giving 10 in 58% yield (TON 2.9) (entry 2).
1
1
obtained in 20% yield (Table 1, entry 3). The yield
increased to 38% by reacting at 120 °C for 3 h (entry 4).
The same procedures followed by the workup with
ethylenediamine gave 3 with the turn over number
N-Methylaniline 4 was ethynylated in low yield under
the catalytic conditions, and required a stoichiometric
amount of GaCl for the modest yield of 3 (entries 3 and
3
(
TON) 2.2 (entry 5).
4). N-Butylaniline gave the product in 52% yield under
the catalytic conditions (entry 5). The substituents at the
benzyl groupwere not influential (entries 6 and 7). The
substituent effect on the nitrogen atom is considered to
be related to the solubility of the lithiated 5 (M ¼ Li) or
organogallium intermediate 6. Aniline lacking the N-
substituent did not give the ethynylated product.
We next conducted the direct ortho-ethynylation of N-
alkylanilines without forming the silylated derivative 5
(
M ¼ SiMe ). N-Benzylaniline itself did not react in the
3
absence of base under the same conditions, and was
recovered quantitatively. Several metalated derivatives,
therefore, were examined, and it turned out that lithi-
ated 5 (M ¼ Li) gave favorable results. Butyllithium
(
1 equiv) was added to a solution of N-benzylaniline 9 in
Table 2. ortho-Ethynylation reaction of N-alkylanilines
Entry
R
X
Yield/%
a
1
PhCH
PhCH
Me 4
Me 4
2
9
9
H
65 10
58 10
2
2
H
a
3
H
55 3
19 3
4
5
6
7
8
9
H
n-C
p-MeOC
p-FC
4
H
9
H
52
60
6
H
4
CH
2
H
6
H
4
CH
2
H
59
PhCH
PhCH
PhCH
PhCH
PhCH
PhCH
PhCH
PhCH
2
2
2
2
2
2
2
2
3,4,5-MeO
4-MeO
4-Me
3,5-MeO
3,5-Me
4-F
85
75
1
1
1
1
1
1
0
1
2
3
4
5
74
59
60
47
4-Cl
3-Me
38
70 (41 + 29)
b
a
3
Reaction was conducted at 90 °C for 1 h with 100 mol % of GaCl .
Yields of 1,2,5-substituted and 1,2,3-substituted anilines.
b
Scheme 1. Catalytic ortho-ethynylation reaction of N-alkylanilines.

R. Amemiya et al. / Tetrahedron Letters 45 (2004) 4333–4335
4335
This catalytic reaction could be applied to substituted
N-benzylanilines. Substrates possessing electron-donat-
ing substituent at the aniline nuclei gave the ortho-
ethynylanilines in higher yields and TON (entries 8–12).
The yields decreased when halogen groups were
attached at the para-position (entries 13 and 14). Two
regioisomers were obtained in equal amounts in the case
of meta-methylaniline (entry 15). No reaction occurred
with ortho-methoxyaniline or a-naphtylamine possess-
ing the ortho-substituents.
5. Fujiwara, J.; Fukutani, Y.; Sano, H.; Maruoka, K.;
Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 7177.
6
7
8
. Yamaguchi, M.; Arisawa, M.; Hirama, M. Chem. Com-
mun. 1998, 1399.
. Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am.
Chem. Soc. 2002, 124, 8528.
. See the followings for the ethynylation reaction of gallium
enolates. Arisawa, M.; Amemiya, R.; Yamaguchi, M. Org.
Lett. 2002, 4, 2209; Amemiya, R.; Fujii, A.; Arisawa, M.;
Yamaguchi, M. Chem. Lett. 2003, 32, 298; Amemiya, R.;
Fujii, A.; Arisawa, M.; Yamaguchi, M. J. Organomet.
Chem. 2003, 686, 94.
9
. Kanetani, F.; Okada, E.; Neguro, K. Bull. Chem. Soc. Jpn.
1
In summary, N-benzylanilines are ethynylated at the
ortho-position with chlorotriethylsilylethyne in the
presence of a catalytic amount of GaCl . The addition–
3
elimination process of organogallium compound to
chlorosilylethyne is successfully employed in the intro-
duction of ethynyl groupto aniline nuclei.
986, 59, 2517.
0. H NMR (400 MHz, CDCl
1
1
3
) d 0.62 (6H, q, J ¼ 7:6 Hz),
0
(
.97 (9H, t, J ¼ 8:0 Hz), 4.37 (2H, d, J ¼ 5:2 Hz), 5.04
1H, s, br), 6.55 (1H, d, J ¼ 8:0 Hz), 6.60 (1H, t,
13
J ¼ 7:6 Hz), 7.14 (1H, t, J ¼ 8:0 Hz), 7.26 (1H, d,
J ¼ 6:8 Hz), 7.30–7.37 (5H, m). C NMR (100 MHz,
CDCl ) d 4.6, 7.7, 47.9, 97.7, 103.3, 107.6, 109.5, 116.2,
3
1
3
1
3
27.1, 127.2, 128.5, 129.9, 131.9, 138.7, 149.1. IR (neat)
À1
þ
398, 2954, 2142, 1602, 1575 cm . MS (EI) m=z 321 (M ,
00%). HRMS Calcd for C21H27NSi: 321.1913. Found:
21.1890.
Acknowledgement
1
1. Typical procedures for the catalytic ortho-ethynylation of
N-benzylaniline (9): Under an argon atmosphere, 1.6 M
butyllithium in hexane (0.3 mL, 0.5 mmol) was added to a
solution of 9 (92 mg, 0.5 mmol) in o-dichlorobenzene
The authors thank JSPS for financial support.
(
temperature for 5 min. 1.0 M GaCl (20 mol %) in meth-
1 mL) at 0 °C, and the mixture was stirred at the
References and notes
3
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added, and the solution was heated at 100 °C for 30 min.
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6
1, 5804, also see references cited therein.
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1
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4
2
4
and concentrated. The residue was purified by flash
column chromatography (hexane/ethyl acetate ¼ 100/3)
to give 10 (94 mg, 58%).
2
85, C9.