Preparation and Stille cross-coupling reaction of the first organotin reagents of azulenes. An efficient Pd(0)-catalyzed synthesis of 6-aryl- and biazulenes

Article abstract of DOI:10.1016/S0040-4039(01)02347-4

The first versatile organometallic reagents of azulenes, 6-(tri-n-butylstannyl)azulenes, have been prepared by a Pd(0)-catalyzed direct stannylation of 6-bromoazulenes with bis(tri-n-butyltin). We demonstrate herein the utility of the reagents in the Stille cross-coupling reaction with aryl and azulenyl halides to afford 6-aryl- and biazulenes in good yield.

Full text of DOI:10.1016/S0040-4039(01)02347-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1261–1264
Preparation and Stille cross-coupling reaction of the first
organotin reagents of azulenes. An efficient Pd(0)-catalyzed
synthesis of 6-aryl- and biazulenes
Tetsuo Okujima, Shunji Ito* and Noboru Morita
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 8 November 2001; revised 3 December 2001; accepted 7 December 2001
Abstract—The first versatile organometallic reagents of azulenes, 6-(tri-n-butylstannyl)azulenes, have been prepared by a
Pd(0)-catalyzed direct stannylation of 6-bromoazulenes with bis(tri-n-butyltin). We demonstrate herein the utility of the reagents
in the Stille cross-coupling reaction with aryl and azulenyl halides to afford 6-aryl- and biazulenes in good yield. © 2002 Elsevier
Science Ltd. All rights reserved.
Palladium-catalyzed cross-coupling reaction has
reagents of azulenes, 6-(tri-n-butylstannyl)azulenes (1a
and 1b) and the successful application to Pd(0)-cata-
lyzed Stille cross-coupling reaction of 1a and 1b with
aryl and azulenyl halides to demonstrate the utility of
the reagents for the carbonꢀcarbon bond formation.
become a widely used method of the carbonꢀcarbon
1
bond formation in modern organic synthesis. Several
applications of the transition metal-catalyzed reaction
in the chemistry of azulenes have also appeared in the
2
literature, e.g. palladium-catalyzed vinylation, aryla-
3
4
tion, and ethynylation of haloazulenes. However, the
lack of an organometallic reagent of the azulene itself
imposes restrictions on the versatile transition metal-
catalyzed reaction because of the synthetic difficulty of
such reagent due to the high reactivity of azulenes to
organolithium and magnesium reagents to produce
The first 6-stannylazulenes (1a and 1b) were synthesized
from 6-bromoazulenes (2a and 2b) via Pd(0)-catalyzed
7
direct stannylation with bis(tri-n-butyltin) (3). The
coupling reaction of diethyl 6-bromoazulene-1,3-dicar-
8
boxylate (2a) with 3 in the presence of a catalytic
amount of Pd(PPh ) in refluxing toluene for 1 day
3
4
5
dihydroazulene derivatives. From the viewpoint of
provided the desired diethyl 6-(tri-n-butylstan-
nyl)azulene-1,3-dicarboxylate (1a) in 69% yield. Like-
wise, 6-(tri-n-butylstannyl)azulene (1b) was prepared
general usage of the transition metal-catalyzed reaction
in the chemistry of azulenes, we focused on the devel-
opment of a versatile organometallic reagent of azule-
nes. The Stille cross-coupling of organotin compounds
with a variety of organic electrophiles, catalyzed by
palladium, provides an efficient method for car-
8
from 6-bromoazulene (2b) with 3 in 49% yield (Scheme
1
). These organotin compounds are stable and are
9
easily characterized by usual spectroscopic analysis.
1
,6
bonꢀcarbon bond formation.
Functionalization of
To demonstrate the transformations using the 6-stannyl-
azulenes (1a and 1b), we conducted the Stille cross-
coupling reaction with aryl and azulenyl halides to
produce 6-aryl- and biazulenes. The results of the reac-
azulene in a seven-membered ring is rather difficult so
far, although 1,3-positions of the system can be easily
functionalized by the electrophilic substitution. There-
fore, we examined the stannylation of azulenes in a
seven-membered ring and the potential of the reagents
for the Stille cross-coupling reaction. Herein we report
the preparation of the first versatile organometallic
Keywords: azulenyl-tin compound; palladium-catalyzed reaction;
Stille reaction; cross-coupling reaction.
*
Corresponding author. Tel.: +81-(0)22-217-7714; fax: +81-(0)22-
17-7714; e-mail: ito@funorg.chem.tohoku.ac.jp
2
Scheme 1.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02347-4

1
262
T. Okujima et al. / Tetrahedron Letters 43 (2002) 1261–1264
a
Table 1. Stille cross-coupling reaction of 1a with 4a and 4b
Entry
X
Catalyst
Ligand
Additive
Solvent
Yield (%)b
5
6
7a
8a
1a
1
2
3
4
5
6
7
8
Br
I
Br
Br
I
I
Br
Br
Pd(PPh3)4
Pd(PPh3)4
Pd (dba)
Toluene
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
16
8
52
30
–
–
–
–
17
17
12
25
14
8
4
4
5
2
11
5
6
6
0
11
0
PtBu3
PtBu3
PtBu3
PtBu3
BINAP
BINAP
45
74
11
61
13
35
2
3
3
3
3
3
3
Pd (dba)
CsF
CsF
CsF
0
2
Pd (dba)
61
22
0
2
Pd (dba)
2
c
c
Pd (dba)
26
5
2
2
2
Pd (dba)
2
0
a
Reactions of 1a (0.2 mmol) with 4a or 4b (0.6 mmol) were carried out at reflux temperature for 24 h by using 10 mol% Pd(0) catalyst, ligand
Pd/P=1:2), and 2.2 equiv. of CsF in 20 ml of the solvent.
All yields are isolated yields.
(
b
c
BINAP: 2,2%-bis(diphenylphosphino)-1,1%-binaphthyl.
tion of 1a with 4-bromo- and 4-iodotoluenes (4a and
coupled product 9a in high yield (entry 1). Under
similar conditions, the reaction of 1a with 4-bromoace-
tophenone also afforded the desired coupling product
9b in good yield (entry 2). In the case of the reaction of
1a with electron-rich bromide, 4-bromoanisole, the
reaction also proceeded smoothly under our reaction
conditions to give the cross-coupling product 9c (entry
3).
4
b) are summarized in Table 1. In our initial experi-
ments, 1a proved to be inefficient in the cross-coupling
reaction under typical conditions for the reaction with
1
0
aryl halides. The reaction of 1a with 4a in the pres-
ence of Pd(PPh ) catalyst produced the desired diethyl
3
4
6
-(4-tolyl)azulene-1,3-dicarboxylate (5) in 16% yield
together with a significant amount of undesired diethyl
1
1
12
(
6-phenyl- and azulene)-1,3-dicarboxylate (6 and 7a )
and tetraethyl 6,6%-biazulene-1,1%,3,3%-tetracarboxylate
8a) (entry 1) (Chart 1). Using 4b instead of 4a
The fluoride-activation strategy was also effective for
the catalytic protocol of 1b with 4a. The reaction of 1b
with 4a afforded the desired cross-coupling product
(
increased the recovery of 1a (entry 2). As seen from
Table 1, the choice of the catalytic system was very
important for the success of the reaction of 1a. Substi-
tution of the Pd(PPh ) catalyst with Pd (dba) /PtBu
3
,14
9
4
d
under similar Pd(0)-catalyzed conditions (entries
and 5). On the whole, 1b also reacted rapidly with a
variety of aryl bromides including an electron-rich one
under Pd(0)-catalyzed conditions, and generally the iso-
lated yields of the cross-coupling product were above
60% (entries 6–8).
3
4
2
3
3
in the catalytic protocol resulted in a significant
increase of the desired cross-coupling product 5a (entry
1
3
3
). A fluoride-activation strategy, which was utilized
for the activation of the organotin compound, was
effective for this Stille cross-coupling reaction. The
addition of CsF in the catalytic protocol increased the
desired coupling product 5 up to 74% yield (entry 4).
While good conversions were obtained by using 4a, the
use of 4b was unfavorable under the reaction condi-
tions, which decreased the conversion ratio of the cata-
lytic reaction significantly (entries 5 and 6). The use of
BINAP as a ligand did not afford satisfactory results
either in the presence or absence of CsF (entries 7 and
8).
To test the generality, the cross-coupling reaction with
several aryl bromides was conducted under the reaction
conditions. The results of the cross-coupling reaction of
1
a and 1b with aryl bromides are summarized in Table
2
. The electron-deficient aryl bromide, 4-bromoni-
trobenzene was efficiently reacted with 1a to afford the
Chart 1.

T. Okujima et al. / Tetrahedron Letters 43 (2002) 1261–1264
1263
a
Table 2. Stille cross-coupling reaction of 1a and 1b with aryl bromides
Entry
Reagent
R
Time (h)
Products (yield/%)b
1
2
3
4
1a
1a
1a
1b
1b
1b
1b
1b
NO2
COMe
OMe
Me
2
2
2
24
24
2
9a (85)
9b (65)
9c (65)
9d (58)
9d (27)
9e (83)
9f (67)
9g (63)
7a (5)
7a (4)
7a (5)
7b (10)
7b (18)
7b (5)
7b (0)
7b (6)
8a (10)
8a (5)
8a (3)
8b (31)
8b (32)
1b (5)
1b (1)
1b (8)
c
5
Me
6
7
8
NO2
COMe
OMe
4
6
a
Reaction conditions: 1a (0.2 mmol) or 1b (0.3 mmol), aryl bromides (0.6 and 0.9 mmol, respectively), Pd (dba) (10 mol%), PtBu3 (40 mol%),
2
3
CsF (2.2 equiv.), dioxane (20 and 30 ml, respectively), refluxed under an Ar atmosphere.
All yields are isolated yields.
The reaction was carried out without an addition of CsF.
b
c
To demonstrate the scope of this procedure, attempts
were made for the preparation of 6,6%- and 2,6%-biazule-
nes using the cross-coupling reaction of 1a with 6- and
stannylazulenes were effective in the Stille cross-cou-
pling reaction to afford 6-aryl- and biazulenes. This
initial study shows the potential utility of the new
transition metal-catalyzed reaction for the difficult
functionalization of azulenes in a seven-membered ring.
Investigation into the scope and application of the
methodology is currently under way in our
laboratories.
2
-azulenyl bromides. Preparation of biazulenes has
been achieved by homo-coupling reaction of azulenyl
halides or stepwise reaction to prepare the two azu-
1
5
1
6
lene rings. However, selective synthesis of unsymmet-
rical biazulenes is significantly difficult so far because of
the restriction of the synthetic methods. We then
applied our new 6-stannylazulene 1a to the selective
synthesis of biazulenes including unsymmetrical ones.
Under the analogous conditions of the reaction with
aryl bromides, 1a reacted smoothly with 6-bromoazule-
nes (2a and 2b) to afford 6,6%-biazulenes (8a and 10) in
References
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8 and 45% yields, respectively. Similarly, the present
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1
5b
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2
,6%-biazulene 11. The reaction of 1a with 2-bromo-
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1
3
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1
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the Pd(0)-catalyzed direct stannylation of 6-bromoazu-
lenes (2a and 2b), and their application in Pd(0)-cata-
lyzed Stille cross-coupling reaction with aryl and
azulenyl halides was investigated. In fact, our new
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1
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−
1
wmax 1694 (CꢁO) cm ; UV–vis (CH Cl ): u
(log m) 235
Trans. 1 2000, 3063–3070.
2
2
max
1
(
4.52), 275 (4.44), 311 (4.65), 377 (4.06), 502 (2.88) nm; H
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3
7
6
1
.96 (d, J=10.0 Hz, 2H), 4.44 (q, J=7.1 Hz, 4H), 1.58 (m,
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2
2
max
3
32 (3.70), 339 (3.67), 347 (3.83), 575 (2.51), 620 (2.44), 682
1
(2.01) nm; H NMR (CDCl ): l 8.22 (d, J=9.3 Hz, 2H),
3
7
.88 (t, J=3.8 Hz, 1H), 7.36 (d, J=3.8 Hz, 2H), 7.35 (d,
J=9.3 Hz, 2H), 1.57 (m, 6H), 1.35 (tq, J=7.3, 7.3 Hz, 6H),
.14 (m, 6H), 0.89 (t, J=7.3 Hz, 9H).
1
1
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