Three-component coupling using arynes and isocyanides: straightforward access to benzo-annulated nitrogen or oxygen heterocycles

Article abstract of DOI:10.1016/j.tet.2007.03.042

A variety of aldehydes, ketones, benzoquinones, or sulfonylimines were found to couple with arynes and isocyanides, giving iminodihydroisobenzofuran or iminoisoindoline derivatives of structural diversity in a straightforward manner. Nucleophilic addition

Full text of DOI:10.1016/j.tet.2007.03.042

Tetrahedron 63 (2007) 4793–4805
Three-component coupling using arynes and isocyanides:
straightforward access to benzo-annulated nitrogen or oxygen
heterocycles
*
Hiroto Yoshida, Hiroyuki Fukushima, Takami Morishita, Joji Ohshita and Atsutaka Kunai
*
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University, Higashi-Hiroshima 739-8527, Japan
Received 16 January 2007; revised 6 March 2007; accepted 7 March 2007
Available online 12 March 2007
Dedicated to Professor Tamejiro Hiyama on the occasion of his 60th birthday
Abstract—A variety of aldehydes, ketones, benzoquinones, or sulfonylimines were found to couple with arynes and isocyanides, giving
iminodihydroisobenzofuran or iminoisoindoline derivatives of structural diversity in a straightforward manner. Nucleophilic addition of iso-
cyanides to arynes, a first step of the three-component coupling, was proved to be reversible by the reaction of an unsymmetrical aryne.
Ó 2007 Elsevier Ltd. All rights reserved.
8
–10
1. Introduction
nucleophiles.
By selecting suitable electrophiles, various
benzo-annulated nitrogen or oxygen heterocycles can be
fabricated in a straightforward manner.
Arynes are powerful and useful reactive intermediates in
synthetic organic chemistry, which can be readily converted
into polysubstituted arenes and benzo-annulated structures,
Insertion reaction
1
being hardly accessible by conventional methods. Because
of the highly electrophilic character of arynes arising from
their low-lying LUMO, even neutral nucleophiles of dimin-
+
Nu
Nu
El
path B
2
El
-
ished nucleophilicity facilely add to arynes to produce zwit-
terions, which act as key intermediates in nucleophilic
coupling reactions (Scheme 1). In general, the resulting
Nu
El
3
Proton abstraction
Nu
aryl anion is apt to abstract a proton from the cationic site,
resulting in the formation of monosubstituted arenes (path
A). On the other hand, we have recently reported on conve-
+
Nu
4
Nu
path A
nient and general method for introducing two functionalities
into both ends of a triple bond of arynes via insertion
reactions into a nucleophilic–electrophilic s-bond, which
proceed through intramolecular nucleophilic substitution
-
H
El
Three-component coupling
Nu
5
,6
(
path B). Similar double functionalization, being accom-
+
panied by cyclization, should also be achievable by three-
component couplings through capturing the zwitterion
with a third component (electrophile) (path C), and the cou-
plings would be more attractive from a synthetic standpoint
in gaining molecular complexity and diversity, however,
Nu
path C
-
El
El
Scheme 1.
7
there has been a limited number of reports in the literature,
probably because control of the reactivity of arynes is diffi-
cult. Herein we disclose that the three-component coupling
of arynes occurs selectively by the use of isocyanides as
2. Results and discussion
.1. Three-component coupling of arynes, isocyanides,
and aldehydes
2
Keywords: Aryne; Isocyanide; Nitrogen heterocycle; Oxygen heterocycle;
Three-component coupling.
First we carried out the reaction of benzyne, prepared in situ
from 2-(trimethylsilyl)phenyl triflate (1a) and a fluoride
*
Corresponding authors. Tel.: +81 82 424 7724; fax: +81 82 424 5494;
e-mail addresses: yhiroto@hiroshima-u.ac.jp; akunai@hiroshima-u.ac.jp
1
1
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.042

4794
H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
ion (KF/18-crown-6), with tert-butyl isocyanide (2a) and
benzaldehyde (3a) in THF at 0 C, and observed that
1-naphthaldehyde (3b) or 4-methoxybenzaldehyde (3c)
also reacted with benzyne and 2a to give the respective prod-
ucts (4b or 4c) in moderate yields (entries 1 and 2). The re-
action of 1,1,3,3-tetramethylbutyl isocyanide (t-OcNC, 2b)
was found to proceed more effectively, affording 4d–4f in
good yields (entries 3–5). In addition, an electron-deficient
(3d), meta-substituted (3e), or sterically congested (3f)
aldehyde could participate in the reaction to provide the
variously substituted iminodihydroisobenzofurans (4g–4i,
entries 6–8). The thienyl group in 3g was compatible
ꢀ
a three-component coupling product, iminodihydroiso-
benzofuran 4a, was produced in 46% yield (entry 1,
1
2
Table 1). The reaction also proceeded efficiently in 1,2-
dimethoxyethane (DME, entry 2), whereas the use of diethyl
ether or 1,4-dioxane as a solvent retarded the reaction
(
entries 3 and 4). The reaction using an equimolar amount
of 1a and 2a gave only an 8% yield of 4a (entry 5), and
addition of excess 1a did not improve the yield at all
1
3
(
entry 6).
with the reaction conditions (entry 9), and an aliphatic
aldehyde (3h or 3i) was also applicable to the reaction
(
entries 10 and 11). Besides 2a and 2b, 1-adamantyl iso-
Table 1. Three-component coupling of benzyne, tert-butyl isocyanide, and
benzaldehyde
a
cyanide (2c) could participate in the reaction to afford
the product in 77% yield (entry 12), whereas the reaction
of sterically less congested cyclohexyl (2d) or n-octyl
isocyanide (2e) resulted in the formation of a complex
mixture.
Nt-Bu
KF
TMS
OTf
t-Bu
N
C
O
1
8-crown-6
+
:
+
:
O
solvent, 0 °C
Ph
H
Ph
1a
2a
3a
4a
When 1-(trimethylsilyl)-2-naphthyl triflate (1b), a 1,2-
naphthalyne precursor, was allowed to react with 2b and
X
1
2
3
2
c, the imino moiety was selectively introduced into the
-position of the naphthalene ring to give 4n as the sole
b
Yield (%)
Entry
X
Solvent
Time (h)
1
2
3
4
5
6
2
2
2
2
1
3
THF
DME
2
2
47
6
2
5
46
45
34
12
8
product (Scheme 2). Exclusive formation of 4n was also
observed in the reaction of 2-(trimethylsilyl)-1-naphthyl
triflate (1c), which confirms the intermediacy of an aryne
in the three-component coupling. Other substituted arynes
could also be applied to the reaction. Thus, the reaction of
3-methylbenzyne (from 1d) or 3-methoxybenzyne (from
Et
2
O
c
Dioxane
THF
THF
44
a
ꢀ
The reaction was carried out in a solvent (1 mL) at 0 C using 1a, 2a
1
e) took place with perfect regioselectivity, where the imino
(0.15 mmol), 3a (0.30 mmol), KF, and 18-crown-6.
Isolated yield based on 2a.
Room temperature.
b
c
moiety was attached to the sterically less hindered position
of the aryne (Scheme 3). A fluoro substituent at 4-position
of an aryne (from 1f) controlled the regioselectivity to afford
4
1
q solely, whereas the reaction of 4-methylbenzyne (from
g) furnished almost equal amounts of regioisomeric prod-
Under the optimized reaction conditions, the three-
component coupling using various isocyanides and alde-
hydes was next examined. As described in Table 2,
0
ucts 4r and 4 r. A 4,5-disubstituted aryne (from 1h or 1i)
or sterically congested 3,6-dimethoxybenzyne (from 1j)
was also applicable to the reaction to give the corresponding
iminodihydroisobenzofurans (4s–4u).
Table 2. Three-component coupling of benzyne, isocyanides, and alde-
hydes
a
NR'
KF (4 eq)
R'
O
18-crown-6 (4 eq)
THF, 0 °C
1
a
+
:
N
C
+
O
TMS
R"
H
OMe
R"
OTf
2
3
4
1b
2
1
:
2
2
b, 3c
KF/18-crown-6
THF
0
00
b
Time (h) Yield (%) Product
Entry
R
R
0
°C, 13 h
O
1
2
3
4
5
6
7
8
9
t-Bu 2a 1-Naphthyl
3b
3c
3a
3b
3c
3d
3e
3f
5
2
7
5
7
7
5
5
7
5
7
49
37
65
73
73
69
65
61
50
50
40
77
4b
4c
4d
4e
4f
4g
4h
4i
OTf
Nt-Oc
n
t-Bu 2a 4-MeOC
t-Oc 2b Ph
6
H
4
4
TMS
4
4
0% from 1b
1% from 1c
t-Oc 2b 1-Naphthyl
t-Oc 2b 4-MeOC
t-Oc 2b 4-CF
t-Oc 2b 3-MeOC
t-Oc 2b 2,4-Me
1
c
6
H
4
3
C
6
H
4
Scheme 2.
6
H
4
2
C
6
H
3
t-Oc 2b 2-Thienyl
t-Oc 2b Et
t-Oc 2b t-Bu
3g
3h
3i
4j
4k
4l
10
11
12
Furthermore, an aldehyde bearing two reaction sites can be
employed for the three-component coupling. As depicted
in Scheme 4, terephthalaldehyde (3j) reacted with benzyne
and 2b to afford a 38% yield of 4v in 50:50 diastereomeric
ratio, whereas the reaction of isophthalaldehyde (3k) gave
a 65:35 ratio of the product (4w).
1-Ad 2c 4-MeOC
6
H
4
3c 24
4m
a
ꢀ
The reaction was carried out in THF (1 mL) at 0 C using 1a (0.30 mmol),
(0.15 mmol), 3 (0.30 mmol), KF (0.60 mmol), and 18-crown-6
0.60 mmol).
2
(
b
Isolated yield based on 2.

H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
4795
Nt-Oc
2.2. Three-component coupling of benzyne, isocyanides,
and ketones
3
6
R
O
2
TMS
4
KF/18-crown-6
THF, 0 °C
R
+
2b
+
3c
Similar tothecase of aldehydes, several ketonescouldbe used
as electrophiles (Scheme 5). Thus, acetophenone (5a) was
coupled with benzyne and 2b to give the three-component
coupling product (6a), although the yield was rather low,
which should be ascribable to the reduced electrophilicity and
steric hindrance of the carbonyl moiety. Introduction of such
an electron-withdrawing group as chloro (5b) or trifluoro-
5
1
OTf
1
4
OMe
1
d: 6-Me
e: 3-MeO
f: 4-F
1
1
1
1
1
g: 4-Me
h: 4,5-Me2
0
i: 4,5- –(CH ) –
methyl (5c) into the 4 -position of an acetophenone increased
the yield to some extent. Moreover, the reaction of trifluoro-
2
3
1
j: 3,6-(MeO)2
acetophenone (5d) afforded a 42% yield of 6d, and benzil
(
Nt-Oc
Nt-Oc
Nt-Oc
5e), a 1,2-diketone, underwent the coupling to furnish 6e.
O
O
O
Nt-Oc
F
O
KF/18-crown-6
THF, 0 °C
Me
OMe
1a
+
2b
+
O
R2
R1 R2
R1
6
OMe
OMe
4p: 16% (16 h)
Nt-Oc
OMe
4q: 38% (18 h)
5
4
o: 45% (8 h)
5a: R1 = Me, R2 = Ph
b: R = Me, R = 4-ClC H
5c: R = Me, R = 4-CF3C6H4
5d: R = CF , R = Ph
1
2
5
6 4
Nt-Oc
1
2
Me
1
2
O
O
3
1
2
Me
5e: R = Ph, R = Bz
+
Nt-Oc
Nt-Oc
Nt-Oc
OMe
OMe
O
O
O
4r
4'r
Me
6c: 25% (14 h)
5
8% (11 h, ratio = 51:49)
Me
a: 18% (6 h)
Me
6b: 33% (6 h)
Cl
CF3
Nt-Oc
Nt-Oc
OMe Nt-Oc
6
Me
Me
O
O
O
Nt-Oc
Nt-Oc
OMe
O
O
F3C
OMe
s: 61% (11 h)
OMe
OMe
4u: 26% (36 h)
O
4
4t: 31% (22 h)
6
d: 42% (22 h)
6e: 20% (7 h)
Scheme 3.
Scheme 5.
In contrast, no trace of the three-component coupling
product was obtained with 4 -methoxyacetophenone (5f),
0
cyclohexanone (5g), benzophenone (5h), 2-butanone (5i),
(E)-1,2-dibenzoylethene(5j),or1,3-indandione(5k)(Chart1).
t-OcN
OHC
O
H
H
O
O
O
Me
4
v: 38%
(dr = 50 : 50)
OMe
CHO
O
3
j
5f
5g
5h
Nt-Oc
1
a (5 eq), 2b (2.5 eq)
KF (10 eq)
8-crown-6 (10 eq)
THF, 0 °C, 7 h
O
O
O
O
1
O
Nt-Oc
5
i
5j
5k
CHO
H
H
O
O
Chart 1.
4
w: 35%
(dr = 65 : 35)
CHO
k
2.3. Three-component coupling of benzyne, isocyanides,
and benzoquinones
3
Nt-Oc
We next investigated the reaction of benzoquinones, because
they can be regarded as electron-deficient ketones. As shown
Scheme 4.

4796
H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
in Scheme 6, treatment of benzoquinone 5l with benzyne and
b provided a spiro type of iminodihydroisobenzofuran (6f).
Table 3. Three-component coupling of benzyne, isocyanides and sulfonyli-
mines
a
2
NR'
The reaction of di-tert-butylbenzoquinone (5m or 5n) took
place more smoothly, leading to the formation of the prod-
ucts in 51 or 52% yield, respectively. In the latter case, the
predominant isomer was 6h arising from cyclization at the
less congested carbonyl group.
KF (4 eq)
R'
NTs
H
18-crown-6 (4 eq)
THF, rt
1
a
+
:
N
C
+
NTs
R"
R"
Ts: SO p-tol
2
2
7
8
2
1
:
2
Nt-Oc
b
Time (h) Yield (%) Product
0
00
Entry
R
R
O
O
1
2
3
4
5
6
7
8
9
t-Oc 2b Ph
t-Oc 2b 4-MeOC
t-Oc 2b 4-CF
t-Oc 2b 2,4-Me
t-Oc 2b Mesityl
t-Oc 2b 1-Naphthyl
t-Oc 2b 2-Thienyl
t-Bu 2a Ph
7a
7b
5
9
64
61
44
66
68
59
64
55
35
23
46
8a
8b
8c
8d
8e
8f
8g
8h
8i
KF/18-crown-6
R3
+
1a
+
2b
6 4
H
THF, 0 °C
R3
3
C
6
H
4
7c 24
7d 18
7e 24
7f 19
7g 16
7a 19
7a 24
O
5
2 6 3
C H
O
6
5
5
5
l: R3 = H
3
m: R = 2,5-t-Bu2
n: R = 2,6-t-Bu2
3
1-Ad 2c Ph
Cy 2d Ph
n-Oc 2e Ph
1
11
0
7a
7a 22
6
8j
8k
Nt-Oc
Nt-Oc
a
O
O
The reaction was carried out in THF (2 mL) at room temperature using
1
t-Bu
a (0.60 mmol), 2 (0.30 mmol), 7 (0.60 mmol), KF (1.2 mmol), and
18-crown-6 (1.2 mmol).
Isolated yield based on 2.
b
t-Bu
O
O
6f: 32% (6 h)
6g: 51% (8 h)
also applicable to the reaction, giving the corresponding iso-
indolines (8b–8f) in modest to good yields (entries 2–6). In
addition, the reaction of an aldimine bearing a thienyl moi-
ety (7g) took place smoothly to provide 8g in 64% yield (en-
try 7). Tertiary alkyl isocyanides (2a or 2c), cyclohexyl (2d),
or n-octyl isocyanide (2e) could also participate in the reac-
tion to afford 8h–8k, although the yields were relatively low
Nt-Oc
Nt-Oc
O
O
t-Bu
+
t-Bu
t-Bu
t-Bu
O
O
(entries 8–11). As shown in Figure 1, configuration of the
imine unit of the product has been determined to be E by
an X-ray diffraction study of 8b.
6h
6'h
52% (6 h, ratio = 80:20)
1
4
Scheme 6.
Variously substituted iminoisoindolines were accessible
straightforwardly through the reaction of substituted arynes
(Scheme 7). Thus, 4,5-disubstituted aryne (from 1h, 1i, or
Unfortunately, the desired iminodihydroisobenzofurans
were not formed at all in the reaction of other benzoquinones
listed in Chart 2.
O
O
O
O
Cl
Cl
O
5o
O
5q
5p
Chart 2.
2.4. Three-component coupling of arynes, isocyanides,
and sulfonylimines
By changing electrophiles from carbonyl compounds to im-
ines, the three-component coupling could also be utilized for
direct synthesis of five-membered nitrogen heterocycles.
When the reaction of N-tosylbenzaldimine (7a) with benz-
yne and 2b was conducted in THF at room temperature,
the three-component coupling product N-(3-phenyl-2-tosyl-
isoindolinylidene)-tert-octylamine (8a) was formed in 64%
yield (entry 1, Table 3). An electron-rich (7b), electron-
deficient (7c), or sterically hindered (7d–7f) aldimine was
Figure 1.

H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
4797
Nt-Oc
NTs
1
k) reacted efficiently with 2b and 7b, affording the corre-
Nt-Oc
Me
sponding product (8l–8n) in 78, 75, or 68% yield, whereas
the reaction of 2,3-naphthalyne (from 1l) resulted in a low
yield of 8o. Such a sterically congested aryne as 3,6-di-
methylbenzyne (from 1m) or 3,6-dimethoxybenzyne (from
NTs
1g
Me
+
1j) could also be applied to the reaction, leading to the
formation of the respective isoindoline (8p or 8q) in 71 or
OMe
OMe
8r
8'r
4
3% yield.
76% (50 h, ratio = 50:50)
Nt-Oc
Nt-Oc
NTs
R
NTs
2
b, 7b
1e
3
2
TMS
KF/18-crown-6
THF, rt
4
KF/18-crown-6
THF, rt
R
+
2b
+
7b
OMe
Me
5
1
OTf
6
1
8
OMe
8s
OMe
1
h: 4,5-Me2
5
7% (60 h)
1
1
1
1
1
i: 4,5- –(CH ) –
2
3
j: 3,6-(MeO)
2
2
k: 4,5- –(CH ) –
Nt-Oc
Nt-Oc
NTs
4
l: 4,5- –(CH) –
4
m: 3,6-Me2
NTs
1d
+
Me
Nt-Oc
Nt-Oc
Nt-Oc
Me
Me
NTs
NTs
NTs
OMe
OMe
8't
8t
74% (60 h, ratio = 75:25)
Scheme 8.
OMe
l: 78% (48 h)
OMe
OMe
8n: 68% (48 h)
8
8m: 75% (44 h)
1
5
depicted in Scheme 9. Subsequent nucleophilic attack of
the resulting zwitterion (9) to an electrophile gives 10, which
then undergoes intramolecular cyclization to provide the
product. The observed perfect regioselectivity in the reaction
of 1,2-naphthalyne can be rationally explained by steric ef-
fect, which favors the nucleophilic attack at 2-position of
the naphthalene ring with avoiding a steric repulsion be-
tween peri hydrogen and an incoming isocyanide. Owing
to a strong electron-withdrawing effect of a fluoro substitu-
ent, the developing negative charge at the meta position (vs
para) would be stabilized to a greater extent in the transition
state for the addition of an isocyanide to 4-fluorobenzyne,
Nt-Oc
Me
Nt-Oc
OMe
Nt-Oc
NTs
NTs
NTs
Me
OMe
OMe
o: 31% (66 h)
OMe
8p: 71% (48 h)
OMe
8q: 43% (48 h)
8
Scheme 7.
1
6
Furthermore, the three-component coupling of unsymmetri-
cal arynes was carried out in order to clarify the regioselec-
tivities (Scheme 8). When 4-methylbenzyne (from 1g) was
treated with 2b and 7b, an equal amount of regioisomers
which results in the regioselective formation of 4q. In con-
trast, steric and electronic effects around the triple bond
would be negligible in the reaction of 4-methylbenzyne,
and equal addition of an isocyanide to both ends of the triple
bond occurs. Exclusive formation of 4p or 8s can be attrib-
uted to an electron-withdrawing inductive effect (ꢁI effect)
of a methoxy moiety together with a steric effect, both of
which direct the nucleophilic attack toward the meta position
0
(
8r and 8 r) was produced in 76% yield, implying that
the three-component coupling using sulfonylimines also
proceeds through an aryne intermediate. The reaction of
3
-methoxybenzyne (from 1e) with 7b took place with the
1
7
same regioselectivity as that with 3c, giving 8s exclusively,
where the imino moiety was introduced into the meta posi-
tion of the methoxy group. In marked contrast, opposite re-
gioselectivity to the case of 3c was observed in the reaction
of the methoxy moiety. In the cases of 3-methylbenzyne,
the different regioselectivities depended on electrophiles
would be ascribable to reversibility in the nucleophilic addi-
1
8
tion of an isocyanide to 3-methylbenzyne (Scheme 10).
0
of 3-methylbenzyne (from 1d) with 7b (8t/8 t¼75:25), de-
Thus, the zwitterion bearing the anionic moiety at the
meta position of the methyl group (9a) would be thermody-
namically stable among two possible zwitterions owing to an
electron-donating character of the methyl group (+I effect).
In contrast, formation of another zwitterion (9b) should be
kinetically favored because of less steric repulsion between
the methyl group and an incoming isocyanide. Therefore,
a sulfonylimine of low reactivity toward 9 as compared
with an aldehyde gave 8t predominantly, since kinetically
spite using the same isocyanide, which demonstrates that
electrophiles govern the regioselectivities (cf. Scheme 3).
2
.5. Reaction pathway
The three-component coupling would be commenced by
a nucleophilic addition of an isocyanide to an aryne, as

4798
H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
NR'
X
generated zwitterion 9b should isomerize to thermodynam-
ically stable 9a prior to the reaction with the sulfonyl-
imine. To the contrary, an aldehyde would readily react
with 9b to provide 4o exclusively.
X
R
+
R'NC
R'
+
R
19
R1 R2
R2
R1
3. Conclusion
+
+
R'
N
N
C
C
We have demonstrated that a variety of arynes, despite their
transient nature, can be utilized in selective three-component
coupling reactions by the use of isocyanides and suitable
electrophiles. Based on the present reactions, benzo-
annulated iminodihydroisobenzofurans or iminoisoindo-
lines of structural complexity and diversity, which are
difficult to obtain by conventional methods, can be synthe-
sized straightforwardly. In the reactions with 3-methylben-
zyne, differences in reactivities of electrophiles have been
found to govern regioselectivities, which demonstrates that
nucleophilic addition of isocyanides to arynes, a first step
of the reactions, is reversible.
R
R
-
X
-
R1 R2
10
9
1
,2-naphthalyne
Nu
H
Nu
>
>
>
>
H
sterically favored
4
-fluorobenzyne
4. Experimental
Nu
Nu
F
4.1. General
F
electronically favored
All manipulations of oxygen- and moisture-sensitive mate-
rials were conducted with a standard Schlenk technique
under a purified argon atmosphere. Nuclear magnetic reso-
4
-methylbenzyne
Nu
Nu
1
Me
nance spectra were taken on a JEOL EX-270 ( H, 270 MHz;
C, 67.8 MHz) spectrometer or a JEOL Lambda-400 ( H,
1
3
1
-
1
3
Me
400 MHz; C, 99.5 MHz) spectrometer using residual chlo-
roform ( H), CDCl ( C), or THF-d ( C) as an internal
1
13
13
3
8
3
-methoxybenzyne
standard. High-resolution mass spectra were obtained with
a Hitachi M-80B spectrometer or a JEOL JMS-HX110A
spectrometer. Melting points were measured with Yanaco
Micro Melting Point apparatus and are uncorrected. The
preparative recycling gel permeation chromatography was
performed with GL Science PU 614 equipped with Shodex
GPC H-2001L and -2002L columns (benzene as an eluant).
Column chromatography was carried out using Merck
Aluminum oxide 90 active neutral or Merck Kieselgel 60.
Unless otherwise noted, commercially available reagents
were used without purification. THF was distilled from
sodium/benzophenone ketyl. MeCN was distilled from
phosphorus pentoxide. 18-Crown-6 was recrystallized
from distilled MeCN. KF (spray dried) was vacuum dried
OMe
Nu
Nu
>
>
OMe
electronically and sterically favored
Scheme 9.
+
t-Oc
+
N
Me
-
t-Oc
Me
N
-
Me
ꢀ
at 100 C for 12 h.
+
2b
9
a: thermodynamic
9b: kinetic
4
.2. Aryne precursors
-(Trimethylsilyl)phenyl triflate (1a), 1-(trimethylsilyl)-2-
naphthyl triflate (1b), 2-(trimethylsilyl)-1-naphthyl triflate
1
1
7b
3c
2
2
0
5
a
21
(
3-methoxy-2-(trimethylsilyl)phenyl triflate (1e), 4-fluoro-
1c),
6-methyl-2-(trimethylsilyl)phenyl triflate (1d),
2
2
Me
Nt-Oc
Nt-Oc
8
a,23
2
thylsilyl)phenyl triflate (1g), 4,5-dimethyl-2-(trimethyl-
silyl)phenyl triflate (1h),
triflate (1i), 3,6-dimethoxy-2-(trimethylsilyl)phenyl tri-
-(trimethylsilyl)phenyl triflate (1f),
4-methyl-2-(trime-
NTs
O
24
2
5
6-(trimethylsilyl)-5-indanyl
Me
2
5
2
5
flate (1j), 3-(trimethylsilyl)-5,6,7,8-tetrahydro-2-naphthyl
5
b
5b
5b
OMe
OMe
4o
triflate (1k), 3-(trimethylsilyl)-2-naphthyl triflate (1l),
and 3,6-dimethyl-2-(trimethylsilyl)phenyl triflate (1m)
were prepared according to literature procedures.
8t
Scheme 10.

H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
4799
4
.3. Isocyanides
4.5.5. N-[3-(1-Naphthyl)-(3H)-isobenzofuranylidene]-
tert-octylamine (4e). Isolated in 73% yield as a white pow-
der: mp 96–100 C; H NMR (CDCl ) d 1.03 (s, 9H), 1.48 (s,
3
ꢀ
6H), 1.78 (s, 2H), 7.19 (s, 1H), 7.23–7.25 (m, 1H), 7.36–7.45
1
tert-Butyl isocyanide (2a), tert-octyl isocyanide (2b), cyclo-
hexyl isocyanide (2d), and n-octyl isocyanide (2e) were syn-
thesized from the corresponding amines by a literature
(m, 4H), 7.53–7.64 (m, 2H), 7.84–7.94 (m, 3H), 8.19–8.22
(m, 1H); C NMR (THF-d ) d 30.9, 31.0, 32.4, 32.7, 56.3,
2
6
13
method. 1-Adamantyl isocyanide (2c) was prepared ac-
8
2
7
cording to a literature procedure.
.4. Sulfonylimines
All sulfonylimines were prepared according to a literature
57.9, 82.9, 123.1, 124.4, 125.2, 126.0, 126.7, 127.3, 128.8,
129.3, 129.7, 129.9, 131.6, 132.2, 133.5, 135.2, 136.0,
+
4
146.6, 154.6. HRMS Calcd for C H NO: M , 371.2249.
26 29
Found: m/z 371.2237.
2
8
method.
4.5.6. N-[3-(4-Methoxyphenyl)-(3H)-isobenzofuranyl-
idene]-tert-octylamine (4f). Isolated in 73% yield as a color-
1
4.5. Three-component coupling of arynes, isocyanides,
and carbonyl compounds: a general procedure
less oil: H NMR (CDCl ) d 1.02 (s, 9H), 1.44 (s, 6H), 1.75
3
(s, 2H), 3.80 (s, 3H), 6.33 (s, 1H), 6.88 (d, J¼8.7 Hz, 2H),
7
.11–7.14 (m, 1H), 7.19 (d, J¼8.7 Hz, 2H), 7.38–7.41 (m,
1
3
To a THF solution (1.0 mL) of KF (0.035 g, 0.60 mmol), 18-
crown-6 (0.16 g, 0.60 mmol), an isocyanide (0.15 mmol),
and a carbonyl compound (0.30 mmol) was added an aryne
precursor (0.30 mmol), and the resulting mixture was stirred
2H), 7.77–7.81 (m, 1H); C NMR (THF-d ) d 30.86, 30.92,
8
32.4, 32.7, 55.4, 56.2, 57.8, 85.5, 114.8, 123.0, 124.1, 128.9,
129.1, 131.6, 132.5, 147.2, 161.1. HRMS Calcd for
+
C H NO : M ꢁMe, 336.1964. Found: m/z 336.1985.
2
2
26
2
ꢀ
at 0 C. The mixture was diluted with ethyl acetate, filtered
through a Celite plug, and concentrated. Alumina column
chromatography (25% ethyl acetate/hexane as an eluant, Ac-
tivity III) followed by gel permeation chromatography gave
the corresponding product.
4.5.7. N-[3-(4-Trifluoromethylphenyl)-(3H)-isobenzofur-
anylidene]-tert-octylamine (4g). Isolated in 69% yield as
a yellow oil: H NMR (CDCl ) d 1.04 (s, 9H), 1.48 (s,
3
1
6H), 1.78 (s, 2H), 6.42 (s, 1H), 7.14–7.17 (m, 1H), 7.40–
7
.44 (m, 4H), 7.64 (d, J¼8.5 Hz, 2H), 7.81–7.85 (m, 1H);
1
3
4.5.1. N-(3-Phenyl-(3H)-isobenzofuranylidene)-tert-
butylamine (4a). Isolated in 46% yield as a colorless oil:
C NMR (THF-d ) d 30.8, 31.0, 32.4, 32.8, 56.3, 58.0,
8
84.5, 122.9, 124.4, 124.5 (JC–F¼272.1 Hz), 126.4 (J
¼
C–F
1
H NMR (CDCl ) d 1.44 (s, 9H), 6.39 (s, 1H), 7.13–7.17
3
3.3 Hz), 127.8, 129.0, 129.6, 131.1 (J ¼32.8 Hz), 132.0,
C–F
1
3
(
(
m, 1H), 7.26–7.42 (m, 7H), 7.86–7.90 (m, 1H); C NMR
THF-d ) d 30.52, 53.95, 85.49, 121.01, 122.72, 124.08,
132.7, 145.2, 154.2. HRMS Calcd for C H F NO:
2
3 26 3
+
M ꢁMe, 389.1966. Found: m/z 389.1974.
8
1
27.14, 129.03, 129.33, 131.61, 132.67, 140.71, 146.99,
+
1
Found: m/z 250.1238.
55.44. HRMS Calcd for C H ON: M ꢁMe, 250.1231.
4.5.8. N-[3-(3-Methoxyphenyl)-(3H)-isobenzofuranyl-
idene]-tert-octylamine (4h). Isolated in 65% yield as a col-
1
7 16
1
orless oil: H NMR (CDCl ) d 1.04 (s, 9H), 1.48 (s, 6H), 1.78
3
4.5.2. N-[3-(1-Naphthyl)-(3H)-isobenzofuranylidene]-
tert-butylamine (4b). Isolated in 49% yield as a colorless
oil: H NMR (CDCl ) d 1.44 (s, 9H), 7.18–7.24 (m, 2H),
3
(s, 2H), 3.77 (s, 3H), 6.34 (s, 1H), 6.80–6.92 (m, 3H), 7.15–
1
3
7.18 (m, 1H), 7.28–7.41 (m, 3H), 7.78–7.83 (m, 1H);
NMR (THF-d ) d 30.8, 31.0, 32.4, 32.8, 55.4, 56.2, 57.9,
C
1
8
7
8
8
1
1
3
.35–7.46 (m, 4H), 7.52–7.62 (m, 2H), 7.84–7.94 (m, 3H),
.16 (d, J¼7.6 Hz, 1H); C NMR (CDCl ) d 30.1, 53.8,
85.4, 112.7, 114.6, 119.2, 122.9, 124.1, 129.2, 130.4,
131.7, 132.8, 142.3, 147.0, 154.7, 161.1. HRMS Calcd for
1
3
3
+
2.3, 122.1, 123.3, 123.8, 124.6, 125.4, 125.9, 126.6,
28.3, 128.7, 129.0, 129.2, 131.0, 131.9, 134.0, 134.4,
C H NO : M ꢁMe, 336.1964. Found: m/z 336.1974.
2
2
26
2
+
45.4, 156.1. HRMS Calcd for C H NO: M ꢁMe,
4.5.9. N-[3-(2,4-Dimethylphenyl)-(3H)-isobenzofuranyl-
idene]-tert-octylamine (4i). Isolated in 61% yield as a white
2
1 18
00.1387. Found: m/z 300.1349.
ꢀ
1
powder: mp 79–81 C; H NMR (CDCl ) d 1.02 (s, 9H), 1.44
3
4
.5.3. N-[3-(4-Methoxyphenyl)-(3H)-isobenzofuranyl-
idene]-tert-butylamine (4c). Isolated in 37% yield as awhite
(s, 6H), 1.75 (s, 2H), 2.31 (s, 3H), 2.42 (s, 3H), 6.60 (s, 1H),
6.89–6.93 (m, 2H), 7.04 (s, 1H), 7.12–7.16 (m, 1H), 7.39–
7.42 (m, 2H), 7.79–7.82 (m, 1H); C NMR (THF-d8)
ꢀ
1
13
powder: mp 86–89 C; H NMR (CDCl ) d 1.41 (s, 9H), 3.80
3
(
1
s, 3H), 6.34 (s, 1H), 6.88 (d, J¼8.7 Hz, 2H), 7.11–7.13 (m,
d 19.3, 21.1, 30.8, 30.9, 32.4, 32.7, 56.2, 57.8, 83.5, 123.0,
124.2, 127.5, 128.2, 129.1, 131.6, 132.4, 133.8, 135.1,
H), 7.18 (d, J¼8.7 Hz, 2H), 7.37–7.44 (m, 2H), 7.83–7.85
1
3
(
m, 1H); C NMR (CDCl ) d 30.03, 53.65, 55.27, 84.70,
3
137.1, 138.9, 146.5, 154.9. HRMS Calcd for C H NO:
24 31
+
1
1
14.11, 121.96, 123.50, 128.05, 128.43, 131.10, 131.19,
31.59, 145.96, 156.23, 159.82. HRMS: Calcd for
M , 349.2406. Found: m/z 349.2416.
+
C H O N: M , 295.1571. Found: m/z 295.1530.
19 21 2
4.5.10. N-[3-(2-Thienyl)-(3H)-isobenzofuranylidene]-
tert-octylamine (4j). Isolated in 50% yield as a colorless
1
4.5.4. N-(3-Phenyl-(3H)-isobenzofuranylidene)-tert-
octylamine (4d). Isolated in 65% yield as a yellow oil: H
NMR (CDCl ) d 1.03 (s, 9H), 1.47 (s, 6H), 1.77 (s, 2H),
3
6
7
5
1
oil: H NMR (CDCl ) d 1.00 (s, 9H), 1.44 (s, 3H), 1.45 (s,
3
1
3H), 1.71 (d, J¼14.4 Hz, 1H), 1.82 (d, J¼14.4 Hz, 1H),
6.64 (s, 1H), 7.00 (dd, J¼4.9 Hz, 3.5 Hz, 1H), 7.12 (d,
13
.37 (s, 1H), 7.13–7.17 (m, 1H), 7.27–7.41 (m, 7H), 7.78–
.82 (m, 1H); C NMR (THF-d ) d 30.9, 32.4, 32.7, 56.2,
J¼3.1 Hz, 1H), 7.28–7.32 (m, 2H), 7.41–7.49 (m, 2H),
1
3
7.81 (d, J¼7.2 Hz, 1H); C NMR (CDCl ) d 30.40, 30.44,
8
3
7.9, 85.6, 122.9, 124.2, 127.4, 129.2, 129.5, 129.7, 131.8,
33.0, 140.7, 147.1, 152.5. HRMS Calcd for C H NO:
31.8, 32.0, 54.8, 57.5, 80.0, 122.1, 123.7, 126.0, 126.5,
126.7, 128.9, 131.0, 131.9, 142.5, 144.7, 153.5. HRMS
Calcd for C H NOS: M , 327.1657. Found: m/z 327.1630.
2
2 27
+
+
M , 321.2093. Found: m/z 321.2100.
2
0 25

4800
H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
4.5.11. N-(3-Ethyl-(3H)-isobenzofuranylidene)-tert-
octylamine (4k). Isolated in 50% yield as a yellow oil: H
128.5, 130.4, 130.8, 133.5, 154.3, 154.6, 159.5. HRMS
Calcd for C H NO : M , 381.2304. Found: m/z 381.2358.
24 31 3
1
+
NMR (CDCl ) d 0.96 (t, J¼8.0 Hz, 3H), 1.06 (s, 9H), 1.41
3
(
s, 6H), 1.70–1.77 (m, 3H), 2.00–2.10 (m, 1H), 5.41 (dd,
4.5.17. N-[3-(4-Methoxyphenyl)-5-fluoro-(3H)-isobenzo-
furanylidene]-tert-octylamine (4q). Isolated in 38% yield
as a colorless oil: H NMR (CDCl ) d 1.02 (s, 9H), 1.44
3
J¼6.8, 4.1 Hz, 1H), 7.26 (d, J¼7.2 Hz, 1H), 7.35–7.39 (m,
1
3
1
1
NMR (THF-d ) d 9.4, 29.5, 30.85, 30.94, 32.4, 32.7, 56.2,
H), 7.42–7.46 (m, 1H), 7.74 (d, J¼7.5 Hz, 1H);
C
(s, 6H), 1.77 (s, 2H), 3.81 (s, 3H), 6.29 (s, 1H), 6.80 (dd,
J¼2.2 Hz, J ¼8.1 Hz, 1H), 6.90 (d, J¼8.6 Hz, 2H), 7.08
8
5
HRMS Calcd for C H NO: M , 273.2093. Found: m/z
7.7, 84.8, 121.9, 124.1, 129.0, 131.4, 134.0, 146.6, 154.9.
H–F
+
(td, J¼8.9, 2.2 Hz, 1H), 7.17 (d, J¼8.6 Hz, 2H), 7.64–7.81
1
8 27
1
3
2
73.2088.
(m, 1H); C NMR (CDCl ) d 30.3, 30.4, 31.8, 32.0, 55.0,
3
5
5.3, 57.5, 83.9, 109.1 (JC–F¼24.4 Hz), 114.16, 114.23,
C–F
4.5.12. N-(3-tert-Butyl-(3H)-isobenzofuranylidene)-tert-
octylamine (4l). Isolated in 40% yield as a colorless oil:
116.4 (JC–F¼23.1 Hz), 125.5 (J ¼9.8 Hz), 128.1, 130.7,
148.1 (J ¼9.8 Hz), 153.3, 160.0, 164.8 (J
C–F
¼
C–F
1
+
H NMR (CDCl ) d 1.00 (s, 9H), 1.03 (s, 9H), 1.45 (s,
3
251.0 Hz). HRMS Calcd for C H FNO : M , 369.2104.
23 28
2
3
H), 1.47 (s, 3H), 1.70 (d, J¼14.4 Hz, 1H), 1.80 (d,
Found: m/z 369.2076.
J¼14.4 Hz, 1H), 5.11 (s, 1H), 7.36–7.43 (m, 3H), 7.75 (d,
1
3
J¼7.3 Hz, 1H); C NMR (CDCl ) d 25.6, 29.9, 30.3,
4.5.18. A mixture of N-[3-(4-methoxyphenyl)-6-methyl-
(3H)-isobenzofuranylidene]-tert-octylamine (4r) and
N-[3-(4-methoxyphenyl)-5-methyl-(3H)-isobenzofuranyl-
3
3
1
1.9, 32.0, 36.2, 55.2, 57.1, 90.6, 122.6, 123.5, 128.2,
30.1, 133.8, 143.6, 154.8. HRMS Calcd for C H NO:
2
0 31
+
0
M , 301.2406. Found: m/z 301.2423.
idene]-tert-octylamine (4 r). Isolated in 58% yield as a yel-
low oil: H NMR (CDCl ) d 1.02 (s, 18H), 1.44 (s, 12H),
1
3
4.5.13. N-[3-(4-Methoxyphenyl)-(3H)-isobenzofuranyl-
idene]-1-adamantylamine (4m). Isolated in 77% yield as
a white powder: mp 122–126 C; H NMR (CDCl3)
d 1.50–1.61 (m, 6H), 1.97 (s, 9H), 3.70 (s, 3H), 6.22 (s,
1.76–1.77 (m, 4H), 2.35 (s, 3H), 2.40 (s, 3H), 3.798 (s,
3H), 3.804 (s, 3H), 6.27 (s, 1H), 6.29 (s, 1H), 6.86–6.91
(m, 5H), 7.00 (d, J¼7.8 Hz, 1H), 7.17–7.25 (s, 6H), 7.60
ꢀ
1
1
3
(s, 1H), 7.67 (d, J¼7.8 Hz, 1H); C NMR (THF-d )
8
1
H), 6.79 (d, J¼8.7 Hz, 2H), 7.00–7.02 (m, 1H), 7.07 (d,
d 21.2, 21.6, 30.96, 31.00, 31.03, 31.07, 32.4, 32.7, 55.4,
56.0, 56.1, 57.7, 57.8, 85.25, 85.35, 114.69, 114.71, 122.7,
123.2, 123.8, 124.1, 128.9, 130.1, 130.7, 132.7, 133.5,
139.1, 142.16, 144.6, 147.6, 154.7, 154.8, 161.0. HRMS
1
3
J¼8.7 Hz, 2H), 7.28–7.32 (m, 2H), 7.74–7.76 (m, 1H); C
NMR (THF-d ) d 31.0, 37.7, 43.7, 54.8, 55.4, 85.5, 114.8,
8
1
22.9, 124.2, 128.8, 129.0, 131.7, 132.6, 133.0, 147.4,
55.5, 161.0. HRMS Calcd for C H NO : M , 373.2042.
+
+
1
Found: m/z 373.2004.
Calcd for C H NO : M , 365.2355. Found: m/z 365.2365.
24 31
2
5
27
2
2
4.5.19. N-[3-(4-Methoxyphenyl)-5,6-dimethyl-(3H)-iso-
benzofuranylidene]-tert-octylamine (4s). Isolated in 61%
yield as a yellow oil: H NMR (CDCl ) d 1.02 (s, 9H),
3
4.5.14. N-[3-(4-Methoxyphenyl)-(3H)-benzo[e]isobenzo-
furanylidene]-1-tert-octylamine (4n). Isolated in 40%
1
1
(
NMR (CDCl ) d 1.06 (s, 9H), 1.54 (s, 6H), 1.88 (s, 2H),
from 1b) or 41% (from 1c) yield as a pale yellow oil: H
1.44 (s, 6H), 1.76 (d, J¼14.5 Hz, 1H), 1.80 (s, J¼14.5 Hz,
1H), 2.25 (s, 3H), 2.30 (s, 3H), 3.80 (s, 3H), 6.26 (s, 1H),
6.86–6.91 (m, 3H), 7.18 (d, J¼8.7 Hz, 2H), 7.57 (s, 1H);
3
3
.81 (s, 3H), 6.38 (s, 1H), 6.89 (d, J¼8.6 Hz, 2H), 7.18 (d,
J¼8.6 Hz, 1H), 7.23 (d, J¼8.6 Hz, 2H), 7.56 (t, J¼6.8 Hz,
H), 7.68 (t, J¼8.4 Hz, 1H), 7.85–7.90 (m, 2H), 9.59 (d,
1
3
C NMR (THF-d ) d 19.7, 20.3, 30.5, 30.6, 31.9, 32.0,
8
1
54.5, 55.2, 57.2, 84.2, 114.0, 122.7, 123.9, 128.1, 129.8,
131.8, 137.3, 140.3, 143.9, 155.0, 159.7. HRMS Calcd for
C H NO : M , 379.2511. Found: m/z 379.2516.
1
3
J¼8.1 Hz, 1H); C NMR (CDCl ) d 30.7, 30.8, 32.0,
3
+
3
1
1
4
2.1, 54.9, 55.3, 57.9, 83.9, 114.1, 119.2, 125.0, 125.4,
2
5
33
2
26.4, 127.9, 128.1, 128.4, 129.0, 131.3, 132.0, 133.5,
45.9, 154.9, 159.9. HRMS Calcd for C H NO : M ,
01.2355. Found: m/z 401.2325.
+
4.5.20. N-[3-(4-Methoxyphenyl)-5,6-propylen-(3H)-iso-
benzofuranylidene]-tert-octylamine (4t). Isolated in 31%
2
7
31
2
1
yield as a colorless oil: H NMR (CDCl ) d 1.03 (s, 9H),
3
4.5.15. N-[3-(4-Methoxyphenyl)-4-methyl-(3H)-isobenzo-
furanylidene]-tert-octylamine (4o). Isolated in 45% yield
as a pale yellow oil: H NMR (CDCl ) d 1.02 (s, 9H), 1.43
3
1.45 (s, 6H), 1.78 (s, 2H), 2.09 (quintet, J¼7.24 Hz, 2H),
2.85 (dd, J¼14.4, 7.1 Hz, 2H), 2.92 (t, J¼7.2 Hz, 2H),
3.80 (s, 3H), 6.27 (s, 1H), 6.89 (d, J¼8.7 Hz, 2H), 6.93 (s,
1
13
(
s, 3H), 1.44 (s, 3H), 1.74 (d, J¼14.2 Hz, 1H), 1.79 (d,
1H), 7.20 (d, J¼8.7 Hz, 2H), 7.64 (s, 1H); C NMR
J¼14.2 Hz, 1H), 2.73 (s, 3H), 3.80 (s, 3H), 6.24 (s, 1H),
(CDCl ) d 25.8, 30.4, 30.6, 31.9, 32.0, 32.2, 32.7, 54.7,
3
1
3
6
.87–6.93 (m, 3H), 7.14–7.26 (m, 4H); C NMR (THF-
d8) d 18.5, 30.5, 30.7, 31.9, 32.0, 54.9, 55.3, 57.6, 83.4,
55.2, 57.2, 84.3, 114.0, 117.5, 118.9, 128.3, 130.3, 131.8,
144.7, 145.3, 148.4, 155.1, 159.7. HRMS Calcd for
C H NO : M , 391.2511. Found: m/z 391.2522.
+
1
1
3
14.0, 119.3, 128.1, 128.9, 130.1, 130.4, 132.1, 137.4,
46.5, 154.3, 159.6. HRMS Calcd for C H NO : M ,
50.2120. Found: m/z 350.2075.
2
6
33
2
+
2
4
31
2
4.5.21. N-[3-(4-Methoxyphenyl)-4,7-dimethoxy-(3H)-iso-
benzofuranylidene]-tert-octylamine (4u). Isolated in 26%
ꢀ
1
4.5.16. N-[3-(4-Methoxyphenyl)-4-methoxy-(3H)-
isobenzofuranylidene]-tert-octylamine (4p). Isolated in
yield as a white powder: mp 122–126 C; H NMR
(CDCl ) d 1.06 (s, 9H), 1.42 (s, 3H), 1.44 (s, 3H), 1.66 (d,
3
1
1
9
6
7
3
6% yield as a colorless oil: H NMR (CDCl ) d 0.99 (s,
3
J¼14.2 Hz, 1H), 1.73 (d, J¼14.2 Hz, 1H), 3.61 (s, 3H),
H), 1.42 (s, 6H), 1.73 (s, 2H), 3.70 (s, 3H), 3.80 (s, 3H),
.36 (s, 1H), 6.82–6.87 (m, 3H), 7.19 (d, J¼8.6 Hz, 2H),
3.79 (s, 3H), 3.87 (s, 3H), 6.27 (s, 1H), 6.79 (s, 2H), 6.83
(d, J¼8.9 Hz, 2H), 7.19 (d, J¼8.9 Hz, 2H); C NMR
1
3
1
3
.36–7.38 (m, 2H); C NMR (CDCl ) d 30.1, 30.4, 31.8,
3
(THF-d ) d 29.3, 29.6, 31.8, 32.0, 55.2, 55.9, 56.3, 57.7,
8
2.0, 54.8, 55.2, 55.5, 57.3, 83.4, 112.3, 113.6, 115.4,
82.3, 112.1, 113.5, 113.8, 120.9, 128.4, 131.0, 136.2,

H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
4801
1
M , 411.2410. Found: m/z 411.2430.
47.9, 150.7, 153.3, 159.3. HRMS Calcd for C H NO :
2
2H), 6.68 (d, J¼10.2 Hz, 2H), 7.10–7.12 (m, 1H), 7.46–
5
33
4
+
13
7.48 (m, 2H), 7.80 (br s, 1H); C NMR (CDCl ) d 30.4,
3
31.8, 32.0, 54.9, 57.9, 82.1, 121.7, 124.7, 128.5, 128.9,
131.6, 132.6, 142.0, 146.4, 151.7, 184.9. HRMS Calcd for
4.5.22. N-(3-Methyl-3-phenyl-(3H)-isobenzofuranyl-
idene)-tert-octylamine (6a). Isolated in 18% yield as a col-
orless oil: H NMR (CDCl ) d 1.01 (s, 9H), 1.49 (s, 3H), 1.50
3
+
C H NO : M , 308.1649. Found: m/z 308.1631.
22
2
0
2
1
(
1
(
1
s, 3H), 1.77 (d, J¼14.4 Hz, 1H), 1.86 (d, J¼14.4 Hz, 1H),
4.5.28. N-[3,3-(1,4-Di-tert-butyl-3-oxo-penta-1,4-dienyl-
ene)-(3H)-isobenzofuranylidene]-tert-octylamine (6g).
Isolated in 51% yield as a pale yellow solid: mp 125–
1
3
.99 (s, 3H), 7.25–7.46 (m, 8H), 7.78 (br s, 1H); C NMR
CDCl ) d 27.7, 30.3, 30.5, 31.9, 32.0, 54.7, 57.4, 114.4,
3
ꢀ
1
21.3, 123.8, 125.1, 127.0, 127.7, 128.1, 128.5, 129.5,
49.9. HRMS Calcd for C H NO: M , 335.2249. Found:
128 C; H NMR (CDCl ) d 1.00 (s, 9H), 1.06 (s, 9H),
3
+
1
m/z 335.2241.
1.16 (s, 9H), 1.48 (s, 3H), 1.51 (s, 3H), 1.67 (d,
J¼14.5 Hz, 1H), 1.91 (d, J¼14.5 Hz, 1H), 6.13 (s, 1H),
2
3 29
6.38 (s, 1H), 6.95–6.99 (m, 1H), 7.39–7.42 (m, 2H), 7.74
(br s, 1H); C NMR (CDCl ) d 28.8, 30.45, 30.50, 30.7,
1
3
4.5.23. N-[3-(4-Chlorophenyl)-3-methyl-(3H)-isobenzo-
furanylidene]-tert-octylamine (6b). Isolated in 33% yield
as a yellow solid: mp 49–52 C; H NMR (CDCl ) d 1.03
3
(
1
1
3
31.9, 32.0, 34.0, 37.1, 55.4, 57.7, 87.4, 120.8, 124.5,
128.7, 129.2, 131.4, 133.0, 142.5, 144.5, 144.6, 152.1,
163.2, 186.7. HRMS Calcd for C H NO : M , 435.3137.
ꢀ
1
+
s, 9H), 1.48 (s, 3H), 1.49 (s, 3H), 1.75 (d, J¼14.2 Hz,
2
9
41
2
H), 1.86 (d, J¼14.2 Hz, 1H), 1.95 (s, 3H), 7.22–7.24 (m,
H), 7.31 (d, J¼8.9 Hz, 2H), 7.36–7.45 (m, 4H), 7.77 (br
Found: m/z 435.3152.
1
3
d, J¼6.5 Hz, 1H); C NMR (CDCl ) d 27.7, 30.3,
4.5.29. N-[3,3-(2,4-Di-tert-butyl-3-oxo-penta-1,4-dienyl-
ene)-(3H)-isobenzofuranylidene]-tert-octylamine (6h).
3
3
1
0.5, 31.9, 32.0, 54.8, 57.4, 88.2, 121.2, 123.9, 126.6,
28.6, 131.0, 131.4, 133.6, 141.8, 149.3, 153.2. HRMS
ꢀ
H NMR (CDCl ) d 1.04 (s, 9H), 1.24 (s, 18H), 1.47 (s,
Isolated in 41% yield as a yellow solid: mp 100–103 C;
+
1
Calcd for C H ClNO: M ꢁMe, 354.1623. Found: m/z
2
2
25
3
3
54.1589.
.5.24. N-{3-Methyl-3-[4-(trifluoromethyl)phenyl]-(3H)-
isobenzofuranylidene}-tert-octylamine (6c). Isolated in
6H), 1.83 (s, 2H), 6.38 (s, 2H), 6.95–6.97 (m, 1H), 7.39–
7.45 (m, 2H), 7.80 (br s, 1H); C NMR (CDCl ) d 29.3,
1
3
3
4
30.5, 31.9, 32.0, 35.0, 54.5, 57.7, 83.6, 121.2, 124.4,
129.2, 131.5, 132.7, 138.2, 143.8, 147.1, 152.7, 186.4.
HRMS Calcd for C H NO : M , 435.3137. Found: m/z
1
+
2
9
1
7
3
2
3
5% yield as a yellow oil: H NMR (THF-d ) d 1.08 (s,
8
29 41
2
H), 1.50 (s, 3H), 1.52 (s, 3H), 1.76 (d, J¼14.2 Hz, 1H),
435.3138.
.88 (d, J¼14.2 Hz, 1H), 2.02 (s, 3H), 7.38–7.49 (m, 3H),
1
3
.67–7.76 (m, 5H); C NMR (THF-d ) d 27.9, 30.8, 31.1,
8
4.5.30. N-[3,3-(1,5-Di-tert-butyl-3-oxo-penta-1,4-dienyl-
ene)-(3H)-isobenzofuranylidene]-tert-octylamine (6 h).
0
Isolated in 11% yield as an orange oil: H NMR (CDCl )
2.4, 32.7, 56.2, 58.0, 89.3, 122.4, 124.5, 126.1 (JC–F
71.6 Hz), 126.3 (JC–F¼4.1 Hz), 126.6, 129.5, 130.4 (JC–F
¼
1
¼
3
2.0 Hz), 132.0, 132.3, 148.9, 150.2, 153.4. HRMS Calcd
d 1.08 (s, 27H), 1.58 (s, 6H), 1. 70 (s, 2H), 6.28 (s, 2H),
6.99 (dd, J¼6.2, 1.8 Hz, 1H), 7.31–7.38 (m, 2H), 7.60–
+
for C H F NO: M , 403.2123. Found: m/z 403.2107.
24 28 3
1
3
7.62 (m, 1H); C NMR (CDCl ) d 30.0, 31.0, 31.8, 32.1,
38.6, 57.7, 57.9, 94.1, 121.4, 123.1, 131.3, 133.8, 145.4,
3
4.5.25. N-[3-Phenyl-3-(trifluoromethyl)-(3H)-isobenzo-
furanylidene]-tert-octylamine (6d). Isolated in 42% yield
as a white solid: mp 72–74 C; H NMR (CDCl ) d 1.03
3
+
151.0, 172.6, 188.0. HRMS Calcd for C H NO : M ,
2
9
41
2
ꢀ
1
435.3137. Found: m/z 435.3152.
(
s, 9H), 1.54 (s, 3H), 1.55 (s, 3H), 1.82 (d, J¼14.4 Hz,
1
7
1
5
1
1
3
H), 1.87 (d, J¼14.4 Hz, 1H), 7.39–7.45 (m, 3H), 7.50–
4.6. Three-component coupling using 3j or 3k
.58 (m, 2H), 7.70–7.76 (m, 3H), 7.82 (br d, J¼7.0 Hz,
1
3
H); C NMR (CDCl ) d 30.42, 30.43, 31.8, 32.1, 55.1,
3
To a THF solution (2.5 mL) of KF (0.087 g, 1.5 mmol), 18-
crown-6 (0.40 g, 1.5 mmol), 2b (0.052 g, 0.38 mmol), and 3j
(or 3k) (0.020 g, 0.15 mmol) was added 1a (0.22 g,
7.9, 87.5 (JC–F¼31.1 Hz), 123.4, 123.8 (J ¼284.3 Hz),
C–F
24.2, 126.4, 128.6, 129.3, 130.2, 131.3, 132.7, 134.5,
40.5, 150.6. HRMS Calcd for C H F NO: M ,
+
ꢀ
0.75 mmol), and the resulting mixture was stirred at 0 C
2
2 23 3
74.1730. Found: m/z 374.1722.
.5.26. N-(3-Benzoyl-3-phenyl-(3H)-isobenzofuranyl-
idene)-tert-octylamine (6e). Isolated in 20% yield as a color-
for 7 h. The mixture was diluted with ethyl acetate, filtered
through a Celite plug, and concentrated. Alumina column
chromatography (25% ethyl acetate/hexane as an eluant, Ac-
tivity III) followed by gel permeation chromatography gave
the corresponding product.
4
1
less oil: H NMR (CDCl ) d 0.85 (s, 9H), 1.38 (s, 3H), 1.48
3
(
1
s, 3H), 1.56 (d, J¼14.4 Hz, 1H), 1.70 (d, J¼14.4 Hz, 1H),
.99 (s, 3H), 7.31–7.64 (m, 11H), 7.74 (br s, 1H), 7.92 (d,
4.6.1. 1,4-Bis(1-tert-octylimino-1,3-dihydro-3-isobenzo-
furanyl)benzene (a mixture of diastereomers) (4v). Iso-
1
3
J¼7.2 Hz, 2H); C NMR (CDCl ) d 30.1, 30.7, 31.6,
3
ꢀ
H NMR (CDCl ) d 1.03 (s, 18H), 1.458 (s, 6H), 1.464 (s,
3
1
1
1.8, 54.5, 57.5, 94.7, 124.1, 125.0, 128.1, 128.5, 129.0,
29.3, 130.2, 130.7, 131.1, 133.1, 134.8, 139.7, 144.9,
51.9, 195.1. HRMS Calcd for C H NO : M , 410.2119.
lated in 38% yield as a yellow powder: mp 147–151 C;
1
3
+
6H), 1.76 (s, 4H), 6.36 (s, 1H), 6.37 (s, 1H), 7.13–7.15 (m,
2H), 7.30 (d, J¼3.6 Hz, 4H), 7.39–7.41 (m, 4H), 7.79–
2
8
28
2
Found: m/z 410.2098.
1
3
7
.81 (m, 2H); C NMR (THF-d ) d 30.27, 30.32, 30.4,
8
4.5.27. N-[3,3-(3-Oxo-penta-1,4-dienylene)-(3H)-isobenzo-
furanylidene]-tert-octylamine (6f). Isolated in 32% yield as
an orange solid: mp 104–105 C; H NMR (CDCl ) d 1.03
3
31.9, 32.0, 54.9, 55.0, 57.4, 84.1, 84.2, 121.9, 123.6,
126.8, 126.9, 128.3, 128.6, 130.9, 131.8, 131.9, 139.8,
145.3, 145.4, 154.0. HRMS Calcd for C H N O :
M ꢁMe, 549.3479. Found: m/z 549.3519.
ꢀ
1
37 45 2 2
+
(
s, 9H), 1.44 (s, 6H), 1.76 (s, 2H), 6.33 (d, J¼10.2 Hz,

4802
H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
4.6.2. 1,3-Bis(1-tert-octylimino-1,3-dihydro-3-isobenzo-
furanyl)benzene (a mixture of diastereomers) (4w). Iso-
lated in 35% yield as a white powder: mp 71–74 C; H
Anal. Calcd for C H F N O S: C, 66.40; H, 6.13; N,
30 33 3 2 2
5.16. Found: C, 66.50; H, 6.19; N, 5.15.
ꢀ
NMR (CDCl ) d 0.99 (s, 18H, minor), 1.04 (s, 18H, major),
1
4.7.4. N-[3-(2,4-Dimethylphenyl)-2-tosylisoindolinyl-
idene]-tert-octylamine (8d). Isolated in 66% yield as a
3
1
(
.39–1.41 (m, 12H, minor), 1.47–1.48 (m, 12H, major), 1.75
br s, 4H, minor), 1.77 (br s, 4H, major), 6.34 (br s, 2H),
.08–7.15 (m, 2H), 7.24–7.25 (m, 3H), 7.34–7.42 (m, 7H),
ꢀ
1
colorless solid: mp 150–153 C; H NMR (CDCl ) d 0.87
3
7
7
3
1
1
1
8
(s, 9H), 1.46 (s, 3H), 1.48 (s, 3H), 1.78 (d, J¼14.5 Hz,
1H), 1.99 (d, J¼14.5 Hz, 1H), 2.32 (s, 3H), 2.37 (s, 3H),
2.53 (br s, 3H), 6.53 (br s, 1H), 6.74 (br s, 1H), 6.88 (br s,
1H), 7.03 (br s, 1H), 7.06–7.12 (m, 3H), 7.34–7.38 (m,
1
3
.81–7.82 (m, 2H); C NMR (CDCl ) d 30.2, 30.3, 30.4,
3
1.8, 31.9, 31.995, 32.044, 55.0, 55.1, 57.4, 57.5, 84.3,
21.9, 123.7, 124.5, 124.8, 126.5, 126.8, 128.3, 128.7,
29.2, 129.3, 131.76, 131.84, 140.07, 141.12, 145.26,
45.34, 152.3, 154.2. Anal. Calcd for C H N O : C,
1
3
2H), 7.50 (d, J¼8.4 Hz, 2H). 7.99–8.02 (m, 1H);
C
NMR (CDCl ) d 19.3, 21.0, 21.4, 31.4, 31.6, 31.9, 53.6,
3
8
48
2
2
3
0.81; H, 8.57; N, 4.96. Found: C, 80.59; H, 8.28; N, 5.21.
57.8, 59.9, 124.2, 126.9, 127.5, 127.7, 128.1, 128.9, 131.0,
1
31.7, 135.7, 137.2, 137.7, 142.8, 146.7, 147.2. Anal. Calcd
for C H N O S: C, 74.06; H, 7.62; N, 5.57. Found: C,
4.7. Three-component coupling of arynes, isocyanides,
and sulfonylimines: a general procedure
3
1 38 2 2
74.05; H, 7.69; N, 5.36.
To a THF solution (2.0 mL) of KF (0.070 g, 1.20 mmol), 18-
crown-6 (0.32 g, 1.20 mmol), an isocyanide (0.30 mmol)
and a sulfonylimine (0.60 mmol) was added an aryne precur-
sor (0.60 mmol), and the resulting mixture was stirred at
room temperature. The mixture was diluted with ethyl ace-
tate, filtered through a Celite plug, and concentrated. Silica
gel column chromatography (17% ethyl acetate/hexane as
an eluant) followed by gel permeation chromatography
gave the corresponding product.
4.7.5. N-[3-(2,4,6-Trimethylphenyl)-2-tosylisoindolinyl-
idene]-tert-octylamine (8e). Isolated in 68% yield as a white
solid: mp 147–149 C; H NMR (CDCl ) d 0.97 (s, 9H),
ꢀ
1
3
1.428 (s, 3H), 1.435 (s, 3H), 1.52 (s, 3H), 1.90 (s, 2H),
2.30 (s, 3H), 2.38 (s, 3H), 2.75 (s, 3H), 6.65 (s, 1H), 6.79
(s, 1H), 7.00 (s, 1H), 7.06–7.08 (m, 1H), 7.13 (d,
J¼8.4 Hz, 2H), 7.35–7.40 (m, 2H), 7.54 (d, J¼8.4 Hz,
1
3
2H), 7.99–8.03 (m, 1H); C NMR (CDCl ) d 18.7, 20.9,
3
21.0, 31.5, 30.7, 31.7, 31.8, 54.0, 57.9, 59.9, 123.7, 127.3,
1
27.4, 128.1, 128.7, 128.8, 129.5, 130.9, 131.1, 132.8,
4
.7.1. N-(3-Phenyl-2-tosylisoindolinylidene)-tert-octyl-
amine (8a). Isolated in 64% yield as a colorless needle:
137.0, 137.27, 137.28, 137.8, 142.8, 145.5, 147.2. Anal.
Calcd for C H N O S: C, 74.38; H, 7.80; N, 5.42. Found:
C, 74.17; H, 8.06; N, 5.28.
3
2 40 2 2
ꢀ
1
mp 131–133 C; H NMR (CDCl ) d 0.87 (s, 9H), 1.48 (s,
3
6
2
7
H), 1.75 (d, J¼14.5 Hz, 1H), 2.03 (d, J¼14.5 Hz, 1H),
.36 (s, 3H), 6.28 (s, 1H), 7.10 (d, J¼8.2 Hz, 2H), 7.12–
.15 (m, 1H), 7.23–7.25 (m, 2H), 7.32–7.41 (m, 5H), 7.48
4.7.6. N-[3-(1-Naphthyl)-2-tosylisoindolinylidene]-tert-
octylamine (8f). Isolated in 59% yield as a pale orange solid:
mp 145–149 C; H NMR (CDCl ) d 0.94 (s, 9H), 1.53 (s,
3
1
3
ꢀ
1
(d, J¼8.2 Hz, 2H), 8.01–8.05 (m, 1H); C NMR (CDCl3)
d 21.4, 31.3, 31.6, 31.8, 53.4, 57.8, 64.1, 124.6, 127.5,
6H), 1.82 (d, J¼14.8 Hz, 1H), 2.08 (d, J¼14.8 Hz, 1H),
1
1
27.7, 127.9, 128.2, 128.3, 128.5, 128.8, 130.9, 137.7,
40.7, 142.9, 146.4, 146.7. Anal. Calcd for C H N O S:
2.35 (s, 3H), 7.12–7.53 (m, 12H), 7.82 (d, J¼8.0 Hz, 1H),
1
3
7.91 (d, J¼7.5 Hz, 1H), 8.06 (d, J¼8.0 Hz, 1H); C NMR
2
9 34 2 2
C, 73.38; H, 7.22; N, 5.90. Found: C, 73.51; H, 7.19; N, 5.84.
(CDCl ) d 21.4, 31.3, 31.6, 31.8, 31.9, 53.6, 57.9, 59.2,
3
1
14.3, 123.1, 123.9, 125.3, 125.6, 125.9, 126.4, 127.1,
4.7.2. N-[3-(4-Methoxyphenyl)-2-tosylisoindolinylidene]-
tert-octylamine (8b). Isolated in 61% yield as a pale yellow
solid: mp 144–146 C; H NMR (CDCl ) d 0.84 (s, 9H), 1.45
3
127.7, 127.9, 128.1, 128.9, 130.8, 130.9, 134.1, 137.4,
142.9, 146.8, 147.2. Anal. Calcd for C H N O S: C,
75.54; H, 6.92; N, 5.34. Found: C, 75.53; H, 6.91; N, 5.38.
3
3 36 2 2
ꢀ
1
(
s, 3H), 1.46 (s, 3H), 1.72 (d, J¼14.5 Hz, 1H), 2.02 (d,
J¼14.5 Hz, 1H), 2.35 (s, 3H), 3.82 (s, 3H), 6.25 (s, 1H),
4.7.7. N-[3-(2-Thienyl)-2-tosylisoindolinylidene]-tert-
octylamine (8g). Isolated in 64% yield as a pale yellow
6
2
.86 (d, J¼8.2 Hz, 2H), 7.09–7.15 (m, 5H), 7.36–7.41 (m,
1
3
ꢀ
1
H), 7.47 (d, J¼7.5 Hz, 2H), 8.00–8.02 (m, 1H);
C
needle: mp 142–144 C; H NMR (CDCl ) d 0.79, (s, 9H),
3
NMR (CDCl ) d 21.4, 31.3, 31.6, 31.8, 31.9, 53.4, 55.2,
3
1.437 (s, 3H), 1.444 (s, 3H), 1.67 (d, J¼14.5 Hz, 1H), 2.03
(d, J¼14.5 Hz, 1H), 2.34 (s, 3H), 6.62 (s, 1H), 6.99–7.01
(m, 1H), 7.11 (d, J¼8.2 Hz, 2H), 7.23–7.30 (m, 3H), 7.40–
7.45 (m, 2H), 7.48 (d, J¼8.2 Hz, 2H), 7.99–8.01 (m, 1H);
5
1
7.7, 63.6, 113.9, 124.6, 127.5, 127.6, 128.2, 128.3, 128.8,
29.0, 130.9, 132.8, 137.8, 142.8, 146.3, 147.0, 159.3.
Anal. Calcd for C H N O S: C, 71.40; H, 7.19; N, 5.55.
0 36 2 3
Found: C, 71.52; H, 7.14; N, 5.47.
3
1
3
C NMR (CDCl ) d 21.4, 31.3, 31.6, 31.8, 32.0, 53.3,
3
5
7.8, 59.1, 124.7, 125.8, 126.5, 127.4, 127.6, 127.7, 128.1,
4.7.3. N-{3-[4-(Trifluoromethyl)phenyl]-2-tosyl-
isoindolinylidene}-tert-octylamine (8c). Isolated in 44%
128.3, 128.6, 130.9, 137.7, 142.8, 144.3, 145.5, 146.0.
Anal. Calcd for C H N O S : C, 67.46; H, 6.71; N, 5.83.
Found: C, 67.66; H, 6.74; N, 5.80.
2
7 32 2 2 2
ꢀ
1
yield as a colorless solid: mp 142–144 C; H NMR
CDCl ) d 0.86 (s, 9H), 1.46 (s, 3H), 1.47 (s, 3H), 1.74 (d,
(
3
J¼14.5 Hz, 1H), 2.02 (d, J¼14.5 Hz, 1H), 2.37 (s, 3H),
4.7.8. N-(3-Phenyl-2-tosylisoindolinylidene)-tert-butyl-
amine (8h). Isolated in 55% yield as a white solid: mp
165–167 C; H NMR (CDCl ) d 1.45 (s, 9H), 2.36 (s,
3
6
.32 (s, 1H), 7.10–7.14 (m, 3H), 7.37–7.43 (m, 4H), 7.51
ꢀ
1
(
d, J¼8.2 Hz, 2H), 7.60 (d, J¼8.2 Hz, 2H), 8.02–8.05 (m,
1
3
1
5
4
H); C NMR (CDCl ) d 21.4, 31.2, 31.6, 31.9, 53.4,
3
3H), 6.26 (s, 1H), 7.11 (d, J¼8.2 Hz, 2H), 7.14–7.16 (m,
7.9, 63.6, 124.0 (JC–F¼271.3 Hz), 124.5, 125.6 (J
¼
1H), 7.23–7.25 (m, 2H), 7.29–7.32 (m, 3H), 7.36–7.39 (m,
2H), 7.55 (d, J¼8.2 Hz, 2H), 7.97–7.99 (m, 1H);
C–F
1
3
.1 Hz), 127.5, 127.8, 128.1, 128.3, 128.4, 128.7, 130.2
C
NMR (CDCl ) d 21.5, 30.4, 53.5, 64.6, 124.5, 127.0,
(
JC–F¼31.7 Hz), 131.2, 137.4, 143.3, 145.0, 145.8, 146.1.
3

H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
4803
1
1
27.4, 127.7, 127.87, 127.92, 128.2, 128.6, 128.9, 131.0,
37.3, 140.6, 143.0, 146.6, 147.4. Anal. Calcd for
J¼7.2 Hz, 1H), 2.94 (t, J¼7.2 Hz, 2H), 3.81 (s, 3H), 6.17
(s, 1H), 6.85 (d, J¼7.4 Hz, 2H), 6.93 (s, 1H), 7.05 (d,
J¼7.4 Hz, 2H), 7.15 (d, J¼6.6 Hz, 2H), 7.46 (d, J¼6.6 Hz,
C H N O S : C, 71.74; H, 6.26; N, 6.69. Found: C,
2
7
7 32 2 2 2
1
3
1.67; H, 622; N, 6.72.
2H), 7.80 (s, 1H); C NMR (CDCl ) d 21.4, 25.5, 31.2,
3
31.6, 31.8, 32.6, 53.3, 55.2, 57.5, 63.4, 113.8, 120.1,
4.7.9. N-(3-Phenyl-2-tosylisoindolinylidene)-1-adaman-
tylamine (8i). Isolated in 35% yield as a colorless needle:
mp 174–178 C; H NMR (CDCl ) d 1.75 (br s, 6H), 2.06
3
123.1, 125.8, 128.1, 128.7, 128.9, 133.4, 138.0, 142.6,
144.3, 145.8, 146.6, 148.2, 159.1. Anal. Calcd for
C H N O S: C, 72.76; H, 7.40; N, 5.14. Found: C,
ꢀ
br s, 6H), 2.16 (br s, 3H), 2.37 (s, 3H), 6.25 (s, 1H), 7.09–
1
33 40 2 3
(
72.65; H, 7.55; N, 5.18.
7
7
1
6
1
.14 (m, 3H), 7.21–7.25 (m, 2H), 7.29–7.33 (m, 3H),
.36–7.40 (m, 2H), 7.51 (d, J¼8.2 Hz, 2H), 8.08–8.10 (m,
4.7.14. N-[3-(4-Methoxyphenyl)-2-tosyl-cyclohexano-
[f]isoindolinylidene]-tert-octylamine (8n). Isolated in
68% yield as a white solid: mp 155–158 C; H NMR
1
3
H); C NMR (CDCl ) d 21.5, 29.7, 36.5, 42.2, 54.5,
3
ꢀ
1
4.4, 124.4, 127.5, 127.7, 127.8, 127.9, 128.1, 128.3,
28.5, 128.9, 130.9, 137.3, 140.6, 142.9, 146.6, 146.8.
(CDCl ) d 0.87 (s, 9H), 1.43 (s, 6H), 1.70 (d, J¼14.6 Hz,
3
Anal. Calcd for C H N O S: C, 74.97; H, 6.49; N, 5.64.
3
Found: C, 74.49; H, 6.52; N, 5.75.
1H), 1.73–1.78 (m, 4H), 1.98 (d, J¼14.6 Hz, 1H), 2.64–
2 33 2 2
2.75 (m, 2H), 2.81–2.83 (m, 2H), 3.81 (s, 3H), 6.16 (s,
1
H), 6.80 (s, 1H), 6.86 (d, J¼8.7 Hz, 2H), 7.10 (d,
4.7.10. N-(3-Phenyl-2-tosylisoindolinylidene)cyclohexyl-
amine (8j). Isolated in 23% yield as a colorless needle:
J¼8.2 Hz, 2H), 7.16 (d, J¼8.7 Hz, 2H), 7.47 (d, J¼8.2 Hz,
1
3
2H), 7.69 (s, 1H); C NMR (CDCl ) d 21.4, 22.6, 22.8,
3
ꢀ
1
mp 163–165 C; H NMR (CDCl ) d 1.32–1.44 (m, 3H),
3
1
2
29.5, 29.7, 31.1, 31.6, 31.8, 53.0, 55.2, 57.6, 63.5, 113.8,
124.5, 125.0, 128.1, 128.7, 128.9, 133.4, 136.8, 138.0,
141.0, 142.6, 144.3, 146.7, 159.1. Anal. Calcd for
C H N O S: C, 73.08; H, 7.58; N, 5.01. Found: C,
.51–1.57 (m, 2H), 1.65–1.68 (m, 1H), 1.82–1.84 (m, 4H),
.36 (s, 3H), 4.06–4.11 (m, 1H), 6.25 (s, 1H), 7.08–7.13
(
(
m, 3H), 7.17–7.19 (m, 2H), 7.27–7.30 (m, 3H), 7.34–7.38
m, 2H), 7.58 (d, J¼8.2 Hz, 2H), 7.80 (d, J¼7.0 Hz, 1H);
3
4 42 2 3
73.07; H, 7.54; N, 4.92.
1
3
C NMR (CDCl ) d 21.5, 24.7, 25.8, 34.1, 34.5, 56.7,
3
6
1
1
6
5.9, 114.4, 124.4, 126.2, 127.6, 127.7, 128.0, 128.2,
28.3, 128.6, 128.8, 129.1, 129.3, 131.3, 136.8, 140.3,
43.2, 145.3. Anal. Calcd for C H N O S: C, 72.94; H,
4.7.15. N-[3-(4-Methoxyphenyl)-2-tosyl-benzo[f]isoindol-
inylidene]-tert-octylamine (8o). Isolated in 31% yield as
a yellow solid: mp 171–174 C; H NMR (CDCl ) d 0.88
3
ꢀ
1
2
7
28
2
2
.35; N, 6.30. Found: C, 73.12; H, 6.53; N, 6.05.
(s, 9H), 1.52 (s, 3H), 1.55 (s, 3H), 1.83 (d, J¼14.4 Hz,
1
H), 2.13 (d, J¼14.4 Hz, 1H), 2.36 (s, 3H), 3.82 (s, 3H),
4.7.11. N-(3-Phenyl-2-tosylisoindolinylidene)-n-octyl-
amine (8k). Isolated in 46% yield as a white solid: mp
6.41 (s, 1H), 6.85 (d, J¼8.8 Hz, 2H), 7.10 (d, J¼8.1 Hz,
2H), 7.18 (d, J¼8.8 Hz, 2H), 7.46–7.53 (m, 4H), 7.57 (s,
1H), 7.73–7.76 (m, 1H), 7.93–7.97 (m, 1H), 8.51 (s, 1H);
ꢀ
1
1
1
3
7
7
40–141 C; H NMR (CDCl ) d 0.91 (t, J¼6.8 Hz, 3H),
3
1
3
.31–1.36 (m, 10H), 1.73 (quintet, J¼7.1 Hz, 2H), 2.36 (s,
H), 3.81–3.88 (m, 2H), 6.29 (s, 1H), 7.08–7.15 (m, 3H),
.18–7.21 (m, 2H), 7.27–7.30 (m, 3H), 7.34–7.42 (m, 2H),
C NMR (CDCl ) d 21.5, 31.2, 31.6, 31.9, 53.1, 55.3,
3
58.1, 63.5, 113.9, 123.2, 125.7, 126.4, 127.5, 127.9, 128.3,
128.6, 128.8, 129.1, 129.5, 132.5, 133.8, 134.2, 137.9,
142.8, 142.9, 146.0, 159.3. Anal. Calcd for C H N O S:
1
3
.54 (d, J¼8.2 Hz, 2H), 7.92 (d, J¼7.5 Hz, 1H); C NMR
3
4 38 2 3
(
CDCl ) d 14.1, 21.5, 22.7, 27.5, 29.4, 29.6, 31.9, 32.0,
3
C, 73.61; H, 6.90; N, 5.05. Found: C, 73.51; H, 6.90; N, 5.02.
4
1
9.8, 66.1, 114.4, 124.3, 126.5, 127.6, 128.0, 128.1, 128.3,
28.5, 128.9, 131.4, 136.8, 140.0. 143.3, 145.1, 150.7.
4.7.16. N-[3-(4-Methoxyphenyl)-4,7-dimethyl-2-tosyl-
isoindolinylidene]-tert-octylamine (8p). Isolated in 71%
Anal. Calcd for C H N O S: C, 73.38; H, 7.22; N, 5.90.
2
Found: C, 73.50; H, 7.27; N, 5.95.
9 34 2 2
ꢀ
1
yield as a colorless crystal: mp 148–151 C; H NMR
CDCl ) d 0.68 (s, 9H), 1.43–1.49 (m, 7H), 1.79 (s, 3H),
(
3
4.7.12. N-[3-(4-Methoxyphenyl)-5,6-dimethyl-2-tosyl-
isoindolinylidene]-tert-octylamine (8l). Isolated in 78%
yield as a white solid: mp 154–156 C; H NMR (CDCl )
3
1.92 (d, J¼14.2 Hz, 1H), 2.22 (s, 3H), 2.51 (s, 3H), 3.75
(s, 3H), 5.66 (s, 1H), 6.75–6.77 (m, 3H), 6.85 (d,
J¼7.5 Hz, 1H), 6.96 (d, J¼8.1 Hz, 2H), 6.99 (d, J¼8.7 Hz,
ꢀ
1
1
3
d 0.87 (s, 9H), 1.45 (s, 6H), 1.72 (d, J¼14.4 Hz, 1H), 2.00
2H), 7.45 (d, J¼8.1 Hz, 2H); C NMR (CDCl ) d 17.3,
3
(
3
d, J¼14.4 Hz, 1H), 2.21 (s, 3H), 2.31 (s, 3H), 2.35 (s,
18.2, 21.3, 27.0, 31.4, 31.8, 32.0, 55.2, 59.3, 62.3, 65.0,
113.7, 127.5, 128.6, 129.4, 129.6, 129.7, 130.1, 130.4,
133.2, 133.5, 134.4, 139.7, 143.3, 143.4, 159.2. Anal. Calcd
for C H N O S: C, 72.14; H, 7.57; N, 5.26. Found: C,
H), 3.81 (s, 3H), 6.18 (s, 1H), 6.85–6.88 (m, 3H), 7.10 (d,
J¼7.5 Hz, 2H), 7.16 (d, J¼7.5 Hz, 2H), 7.47 (d, J¼6.8 Hz,
1
3
2
3
1
1
H), 7.76 (s, 1H); C NMR (CDCl ) d 20.0, 20.2, 21.4,
3
32 40 2 3
1.2, 31.5, 31.6, 31.8, 53.1, 55.15, 55.18, 57.5, 63.4,
13.7, 125.0, 125.3, 128.1, 128.2, 128.7, 128.9, 133.2,
36.2, 137.9, 140.5, 142.6, 144.9, 146.7, 159.1. Anal. Calcd
71.95; H, 7.55; N, 5.12.
4.7.17. N-[4,7-Dimethoxy-3-(4-methoxyphenyl)-2-tosyl-
isoindolinylidene]-tert-octylamine (8q). Isolated in 43%
for C H N O S: C, 72.14; H, 7.57; N, 5.26. Found: C,
3
2 40 2 3
ꢀ
1
7
2.15; H, 7.50; N, 5.10.
yield as a colorless solid: mp 145–148 C; H NMR
CDCl ) d 0.89 (s, 9H), 1.40 (s, 3H), 1.48 (s, 3H), 1.53 (d,
(
3
4
[
7
.7.13. N-[3-(4-Methoxyphenyl)-2-tosyl-cyclopentano-
f]isoindolinylidene]-tert-octylamine (8m). Isolated in
5% yield as a white solid: mp 145–150 C; H NMR
J¼14.3 Hz, 1H), 1.95 (d, J¼14.3 Hz, 1H), 2.27 (s, 3H),
3.52 (s, 3H), 3.76 (s, 3H), 3.82 (s, 3H), 5.80 (s, 1H), 6.61
(d, J¼8.6 Hz, 1H), 6.69 (d, J¼8.6 Hz, 1H), 6.77 (d,
J¼8.6 Hz, 2H), 7.00 (d, J¼8.1 Hz, 2H), 7.08 (d, J¼8.6 Hz,
ꢀ
1
(
1
2
CDCl ) d 0.85 (s, 9H), 1.43 (s, 6H), 1.70 (d, J¼14.2 Hz,
3
1
3
H), 1.99 (d, J¼14.2 Hz, 1H), 2.08 (quintet, J¼7.2 Hz,
H), 2.35 (s, 3H), 2.80 (t, J¼7.2 Hz, 1H), 2.86 (t,
2H), 7.50 (d, J¼8.1 Hz, 2H); C NMR (CDCl ) d 21.3,
3
29.7, 31.3, 31.4, 31.8, 55.1, 55.9, 56.3, 57.1, 61.7, 62.8,

4804
H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
1
1
13.3, 113.5, 125.3, 128.0, 128.2, 128.5, 129.1, 130.3, 132.7,
34.6, 140.4, 143.0, 148.5, 149.9, 159.1. Anal. Calcd for
Acknowledgements
C H N O S: C, 68.06; H, 7.14; N, 4.96. Found: C,
3
We thank Central Glass Co. Ltd. for a generous gift of
trifluoromethanesulfonic anhydride. We also thank Dr.
Yoshiaki Nakao and Professor Tamejiro Hiyama (Kyoto
University) for HRMS measurements.
2 40 2 5
6
8.05; H, 7.19; N, 4.80.
4
.7.18. A mixture of N-[3-(4-methoxyphenyl)-6-methyl-2-
tosylisoindolinylidene]-tert-octylamine (8r) and N-[3-(4-
methoxyphenyl)-5-methyl-2-tosylisoindolinylidene]-tert-
0
24–128 C; H NMR (CDCl ) d 0.84 (s, 9H), 0.86 (s, 9H),
octylamine (8 r). Isolated in 76% yield as a white solid: mp
References and notes
ꢀ
1
1
1
3
.44 (s, 6H), 1.46 (s, 6H), 1.69 (d, J¼14.6 Hz, 1H), 1.74 (d,
1. For reviews, see: (a) Hoffmann, R. W. Dehydrobenzene and
Cycloalkynes; Academic: New York, NY, 1967; (b) Pellissier,
H.; Santelli, M. Tetrahedron 2003, 59, 701–730.
J¼14.6 Hz, 1H), 2.00 (d, J¼15.1 Hz, 2H), 2.31 (s, 3H), 2.35
(
s, 6H), 2.41 (s, 3H), 3.81 (s, 3H), 3.82 (s, 3H), 6.20 (s, 2H),
6
7
7
2
5
1
1
1
1
7
.83–6.88 (m, 4H), 6.92 (s, 1H), 7.01 (d, J¼7.6 Hz, 1H),
2. Rondan, N. G.; Domelsmith, L. N.; Houk, K. N.; Bowne, A. T.;
Levin, R. H. Tetrahedron Lett. 1979, 20, 3237–3240.
.08–7.22 (m, 10H), 7.46 (d, J¼8.1 Hz, 4H), 7.80 (s, 1H),
1
3
.88 (d, J¼8.1 Hz, 1H); C NMR (CDCl ) d 21.3, 21.4,
3. For a review on nucleophilic couplings with arynes, see: Kessar,
S. V. Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 483–515.
4. For examples, see: (a) Sato, Y.; Toyooka, T.; Aoyama, T.;
Shirai, H. J. Org. Chem. 1976, 41, 3559–3564; (b)
Nakayama, J.; Takeue, S.; Hoshino, M. Tetrahedron Lett.
1984, 25, 2679–2682; (c) Hayashi, S.; Ishikawa, N. Bull.
Chem. Soc. Jpn. 1972, 45, 642–644.
3
1.6, 31.2, 31.51, 31.54, 31.72, 31.77, 31.79, 31.81, 53.15,
3.18, 55.2, 57.5, 57.7, 63.4, 63.5, 113.8, 124.2, 124.8,
24.9, 127.4, 127.6, 127.8, 128.11, 128.15, 128.71,
28.74, 128.9, 129.0, 131.9, 132.9, 133.0, 137.3, 137.79,
37.83, 141.5, 142.68, 142.70, 144.3, 146.4, 146.5, 147.2,
59.1, 159.2. Anal. Calcd for C H N O S: C, 71.78; H,
3
1 38 2 3
.38; N, 5.40. Found: C, 71.89; H, 7.51; N, 5.22.
5
. N–C s-bond: (a) Yoshida, H.; Shirakawa, E.; Honda, Y.;
Hiyama, T. Angew. Chem., Int. Ed. 2002, 41, 3247–3249; S–
Sn s-bond: (b) Yoshida, H.; Terayama, T.; Ohshita, J.; Kunai,
A. Chem. Commun. 2004, 1980–1981; N–Si s-bond: (c)
Yoshida, H.; Minabe, T.; Ohshita, J.; Kunai, A. Chem.
Commun. 2005, 3454–3456; C–C s-bond: (d) Yoshida, H.;
Watanabe, M.; Ohshita, J.; Kunai, A. Chem. Commun. 2005,
3292–3294; (e) Yoshida, H.; Watanabe, M.; Ohshita, J.;
Kunai, A. Tetrahedron Lett. 2005, 46, 6729–6731; (f)
Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127,
5340–5341; (g) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M.
J. Am. Chem. Soc. 2006, 128, 11752–11753; C–P s-bond: (h)
Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem.
Lett. 2005, 34, 1538–1539.
4
.7.19. N-[4-Methoxy-3-(4-methoxyphenyl)-2-tosyliso-
indolinylidene]-tert-octylamine (8s). Isolated in 57% yield
ꢀ
1
as a colorless crystal: mp 160–164 C; H NMR (CDCl )
3
d 0.84 (s, 9H), 1.43 (s, 3H), 1.44 (s, 3H), 1.74 (d,
J¼14.6 Hz, 1H), 1.99 (d, J¼14.6 Hz, 1H), 2.33 (s, 3H),
3
2
.66 (s, 3H), 3.80 (s, 3H), 6.24 (s, 1H), 6.78 (d, J¼8.6 Hz,
H), 6.86 (d, J¼8.1 Hz, 1H), 7.04 (d, J¼8.4 Hz, 2H), 7.11
(
d, J¼8.6 Hz, 2H), 7.32–7.38 (m, 3H), 7.59 (d, J¼8.1 Hz,
1
3
1
5
1
1
H); C NMR (CDCl ) d 21.4, 31.6, 31.8, 53.5, 55.2,
3
5.6, 57.8, 61.5, 112.7, 113.3, 119.6, 128.1, 128.8, 129.2,
29.3, 129.5, 131.8, 135.1, 137.8, 142.6, 146.1, 154.9,
58.9. Anal. Calcd for C H N O S: C, 69.63; H, 7.16;
3
1 38 2 4
N, 5.24. Found: C, 69.67; H, 7.12; N, 5.18.
6
. For a review on insertion reactions of arynes into element–ele-
ment s-bonds, see: Pe n˜ a, D.; P ꢀe rez, D.; Guiti ꢀa n, E. Angew.
Chem., Int. Ed. 2006, 45, 3579–3581.
4.7.20. N-[3-(4-Methoxyphenyl)-7-methyl-2-tosylisoin-
dolinylidene]-tert-octylamine (8t). Isolated in 56% yield
ꢀ
1
as a colorless needle: mp 132–135 C; H NMR (CDCl )
3
7. Three-component couplings of arynes were hitherto achieved
using anionic nucleophiles in contrast to the results demon-
strated herein: (a) Meyers, A. I.; Pansegrau, P. D. Tetrahedron
Lett. 1983, 24, 4935–4938; (b) Meyers, A. I.; Pansegrau, P. D.
J. Chem. Soc., Chem. Commun. 1985, 690–691; (c) Tripathy,
S.; LeBlanc, R.; Durst, T. Org. Lett. 1999, 1, 1973–1975.
8. (a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew.
Chem., Int. Ed. 2004, 43, 3935–3938; (b) Yoshida, H.;
Fukushima, H.; Ohshita, J.; Kunai, A. Tetrahedron Lett.
2004, 45, 8659–8662.
d 0.70 (s, 9H), 1.47 (d, J¼14.2 Hz, 1H), 1.50 (s, 6H), 1.94
(
3
d, J¼14.2 Hz, 1H), 2.23 (s, 3H), 2.55 (s, 3H), 3.76 (s,
H), 5.71 (s, 1H), 6.70 (d, J¼7.3 Hz, 1H), 6.77 (d,
J¼8.4 Hz, 2H), 6.93–7.00 (m, 4H), 7.05 (d, J¼8.6 Hz,
1
3
2
2
1
1
H), 7.48 (d, J¼8.6 Hz, 2H); C NMR (CDCl ) d 18.6,
3
1.3, 27.1, 31.5, 31.8, 55.2, 59.3, 62.5, 65.9, 113.7, 121.0,
27.7, 128.8, 129.1, 129.3, 130.0, 131.0, 133.8, 134.6,
36.0, 140.9, 142.7, 143.9, 159.3. HRMS Calcd for
+
C H O N S: M +H, 519.2681. Found: m/z 519.2680.
31 39 3 2
9
. Other three-component couplings using neutral nucleophiles:
(a) Yoshida, H.; Watanabe, M.; Fukushima, H.; Ohshita, J.;
Kunai, A. Org. Lett. 2004, 6, 4049–4051; (b) Yoshida, H.;
Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc.
2006, 128, 11040–11041; (c) Jeganmohan, M.; Cheng, C.-H.
Chem. Commun. 2006, 2454–2456.
4.7.21. N-[3-(4-Methoxyphenyl)-4-methyl-2-tosyliso-
indolinylidene]-tert-octylamine (8 t). Isolated in 18% yield
0
as a colorless needle: mp 162–164 C; H NMR (CDCl )
ꢀ
1
3
d 0.82 (s, 9H), 1.42 (s, 3H), 1.45 (s, 3H), 1.74 (d,
J¼14.6 Hz, 1H), 1.985 (s, 3H), 1.992 (d, J¼14.6 Hz, 1H),
2
2
7
.32 (s, 3H), 3.81 (s, 3H), 6.20 (s, 1H), 6.81 (d, J¼8.9 Hz,
10. Three-component couplings of dimethyl acetylenedicarboxyl-
ate, isocyanides, and electrophiles have been reported: (a)
Nair, V.; Vinod, A. U. Chem. Commun. 2000, 1019–1020;
(b) Nair, V.; Vinod, A. U.; Rajesh, C. J. Org. Chem. 2001,
66, 4427–4429; (c) Nair, V.; Vinod, A. U.; Abhilash, N.;
Menon, R. S.; Santhi, V.; Varma, L. R.; Viji, S.; Mathew, S.;
Srinivas, R. Tetrahedron 2003, 59, 10279–10286; (d) Nair, V.;
H), 7.00–7.09 (m, 4H), 7.18 (d, J¼7.3 Hz, 1H), 7.24–
1
3
.35 (m, 3H), 7.87 (d, J¼7.8 Hz, 1H); C NMR (CDCl )
3
d 18.3, 21.4, 31.6, 31.7, 31.9, 53.5, 55.3, 57.8, 62.8, 113.7,
1
1
25.2, 127.9, 128.1, 128.3, 128.6, 130.2, 131.1, 132.3,
34.1, 137.9, 142.6, 144.9, 146.3, 159.2. HRMS Calcd for
+
C H O N S: M +H, 519.2681. Found: m/z 519.2673.
31 39 3 2

H. Yoshida et al. / Tetrahedron 63 (2007) 4793–4805
4805
Menon, R. S.; Beneesh, P. B.; Sreekumar, V.; Bindu, S. Org.
Lett. 2004, 6, 767–769.
1. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
18. For the reversibility in the addition of nucleophiles to arynes,
see Ref. 3.
19. The three-component coupling of benzyne with 2b and
1
1
ꢀ
1
211–1214.
7a at 0 C proceeded much slower (47 h, 63% yield)
2. Although the three-component coupling product was eluci-
dated to be a single isomer by NMR spectra, we could not de-
termine the exact stereochemistry (E or Z) of the imine unit.
3. Diels–Alder reaction of thiophene with an aryne: Callander,
D. D.; Coe, P. L.; Tatlow, J. C. J. Chem. Soc., Chem.
Commun. 1966, 143–144.
4. Crystallographic data for the structures in this paper have been
deposited with the Cambridge Crystallographic Data Centre as
supplementary publication numbers CCDC 247264. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44
than that with 3a (entry 3 of Table 2), showing lower
reactivity of sulfonylimines in the three-component cou-
pling.
1
1
20. Pe n˜ a, D.; P ꢀe rez, D.; Guiti ꢀa n, E.; Castedo, L. J. Org. Chem.
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1999, 121, 5827–5828.
23. Pe n˜ a, D.; Cobas, A.; P ꢀe rez, D.; Guiti ꢀa n, E. Synthesis 2002,
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(0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
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24. Yoshikawa, E.; Radhakrishnan, K. V.; Yamamoto, Y. J. Am.
Chem. Soc. 2000, 122, 7280–7286.
1
1
6. Preferential nucleophilic attack at a para position of a chlorine
atom also occurred in electrophilic coupling reactions of 4-
chlorobenzyne: (a) Bunnett, J. F.; Pyun, C. J. Org. Chem.
25. Yoshida, H.; Sugiura, S.; Kunai, A. Org. Lett. 2002, 4, 2767–
2769.
26. Ugi, I.; Meyr, R.; Lipinski, M.; Bodesheim, F.; Rosendahl, F.
Org. Synth. 1964, 41, 13–15.
27. Suginome, M.; Fukuda, T.; Nakamura, H.; Ito, Y.
Organometallics 2000, 19, 719–721.
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493–494.
1969, 34, 2035–2037; (b) Bunnett, J. F.; Kim, J. K. J. Am.
Chem. Soc. 1973, 95, 2254–2259.
1
7. Similar regioselectivities were observed in other electrophilic
coupling reactions of these unsymmetrical arynes. See Refs.
5
,9b.