Preparation of azulenyllithium and magnesium reagents utilizing halogen-metal exchange reaction of several iodoazulenes with organolithium or magnesium ate complex

Article abstract of DOI:10.1016/j.tetlet.2004.02.059

Preparation of several azulenyllithium and magnesium reagents was achieved by the halogen-metal exchange reaction of iodoazulenes with n-butyllithium or lithium tri(n-butyl)magnesate at low temperature and the synthetic application of the reagents was explored.

Full text of DOI:10.1016/j.tetlet.2004.02.059

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2891–2894
Preparation of azulenyllithium and magnesium reagents utilizing
halogen–metal exchange reaction of several iodoazulenes with
organolithium or magnesium ate complex
a,
Shunji Ito, Takahiro Kubo, Noboru Morita, Yoshitaka Matsui,
b
b
c
*
c
Toshiyuki Watanabe, Akira Ohta, Kunihide Fujimori, Toshihiro Murafuji,
c
c,
*
d
d,
*
a
Yoshikazu Sugihara and Akio Tajiri
a
Department of Materials Science, Faculty of Science and Technology, Hirosaki University, Hirosaki 036-8561, Japan
b
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
c
Department of Chemistry, Faculty of Science, Shinshu University, Matsumoto 390-8621, Japan
d
Department of Chemistry, Faculty of Science, Yamaguchi University, Yamaguchi 753-8512, Japan
Received 14 January 2004; revised 10 February 2004; accepted 13 February 2004
Abstract—Preparation of several azulenyllithium and magnesium reagents was achieved by the halogen–metal exchange reaction of
iodoazulenes with n-butyllithium or lithium tri(n-butyl)magnesate at low temperature and the synthetic application of the reagents
was explored.
Ó 2004 Published by Elsevier Ltd.
n
Organolithium and magnesium reagents are of great
importance as synthetic tools. There are numerous
( Bu
a facile halogen–magnesium exchange reaction with
3
MgLi), which has been recently reported to induce
1
5
reports for the preparation of various organolithium
2
various aryl halides. Herein, we report the preparation
and magnesium reagents in the literature. However,
little attention has been paid to the development of such
of several azulenyllithium and magnesium reagents,
which should be of great importance as synthetic tools
for the functionalization of azulene.
3
reagents in the chemistry of azulene, although the
reagents tolerate the reaction with a wide range of
electrophiles. Recently, the direct deprotonation and
iodine–metal exchange reaction of 1,3-dihalo- and
Preparation of 6-iodoazulene (3) was achieved by the
halogen–halogen exchange reaction of diethyl
6-bromoazulene-1,3-dicarboxylate (1) followed by
decarboxylation via diethyl 6-iodoazulene-1,3-dicarb-
2
the corresponding 2-azulenyllithium and magnesium
-iodo-1,3-dihaloazulenes has been reported to generate
4
6
n
reagents with 1,3-dihalo substituents.
oxylate (2). Initially, 3 was treated with BuLi in ether
at )100 °C and the subsequent addition of DMF to the
reaction mixture afforded 6-azulenecarbaldehyde (5a)
7
However, the halogen–metal exchange reaction with a
metallic reagent is still unexplored in azulene itself. With
the aim of developing a new facile method for the
functionalization of azulene, we investigated the iodine–
metal exchange reaction of iodoazulenes using n-butyl-
in 32% yield as the sole product (Scheme 1) (Table 1,
entry 1). The reaction showed neither recovery of the
starting 3 nor the formation of parent azulene. The
reaction of azulene derivatives with organolithium or
magnesium reagents exhibits facile carbometalation
reaction to produce 4- or 6-substituted 4H- or 6H-
n
lithium ( BuLi) and lithium tri(n-butyl)magnesate
3
dihydroazulenides. Thus, the relatively low yield of the
expected 5a should be attributed to the result on the
iodine–lithium exchange reaction following the inter-
molecular carbolithiation reaction of the expected
Keywords: Azulene; Organolithium; Organomagesium ate complex;
Halogen–metal exchange reaction; Nucleophilic reaction.
6-azulenyllithium intermediate (4a) to exhibit the
decomposition of the reagent under the reaction condi-
*
Corresponding authors. Tel.: +81-172-39-3568; fax: +81-172-39-35-
1; e-mail: ito@cc.hirosaki-u.ac.jp
8
4
tions. In contrast, the magnesate reagent exhibited a
0
040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.02.059

2892
S. Ito et al. / Tetrahedron Letters 45 (2004) 2891–2894
COOEt
COOEt
nBuLi or nBu MgLi
1
00% H PO4
DMF
3
3
X
I
M
OHC
ether, –100˚C
1
2
: X = Br
: X = I
3
4a: M = Li
4b: M = Mg Bu Li
5a
KI, CuI, DMF
n
2
Scheme 1.
a
Table 1. Iodine–metal exchange reaction of iodoazulenes and the reaction with DMF
b
c
Entry
Substrate
Reagent
Temperature (°C)
R
Product
Yield (%)
Reference
n
1
2
3
4
5
6
3
3
BuLi
)100
)100
)100
)80
)80
)60
CHO
CHO
CHO
CHO
CHO
CHO
5a
5a
32
90
89
99
82
95
7
11
12
n
Bu
3
MgLi
BuLi
Bu MgLi
BuLi
Bu MgLi
n
n
n
n
6
8a
6
3
8a
10
10
12a
12a
3
a
b
c
n
n
The reaction of 3 (1 mmol), 6 (1 mmol), and 10 (1 mmol) with BuLi (1.2 mmol) or Bu
3
MgLi (1.2 mmol) was carried out in ether (20 mL) for 30 min.
The reaction was quenched by adding DMF (0.4–1 mL).
n
Magnesium reagent was prepared by mixing BuMgCl (0.84 or 0.90 M solution in THF) and BuLi (1.6 M solution in hexane) in a 1:2 ratio in ether
n
(10 mL) at 0 °C.
All yields are isolated yields.
clean iodine–magnesium exchange reaction to afford
-azulenylmagnesium reagent (4b), which reacted with
1-azulenylmetal reagents 11a and 11b reacted with DMF
to give 1-azulenecarbaldehyde 12a in high yields
(Scheme 3) (entries 5 and 6).
12
6
DMF to give 5a in high yield (entry 2). The slow car-
bometalation characteristic of the magnesium reagents
should be considered to be important for success of the
The synthetic application to the functionalization of
azulene was explored utilizing the azulenylmagnesium
reagents (4b, 7b, and 11b) due to the clean conversion of
the metalation step in all three substrates. The results on
the reaction with several electrophiles are summarized in
Table 2. The reaction of 4b, 7b, and 11b with deuterium
9
halogen–metal exchange reaction of 3.
In contrast to the results on the reaction of 3, satisfactory
results were obtained when the metalation of 2-iodo-
10
n
azulene (6) with BuLi was conducted in ether at
100 °C. Subsequent reaction with DMF at the same
temperature, followed by warming the mixture to room
13
14
)
oxide gave 6-, 2-, and 1-dueterioazulenes (5b, 8b, and
12b) in 90—98% yields with high deuteration ratio
(Table 2, entries 1–3), which provides the criterion of the
11
temperature, gave 2-azulenecarbaldehyde (8a) in 89%
yield as the sole product (Scheme 2) (entry 3). The iodine–
high efficiency of the iodine–magnesium exchange
n
n
magnesium exchange reaction of 6 utilizing Bu MgLi is
3
reaction in iodoazulenes with Bu MgLi. Under similar
3
also efficient for the preparation of 2-azulenylmetal re-
agent (7b) (entry 4). Treatment of the reagent 7b with
DMF also afforded the expected 8a in 99% yield.
conditions, the reaction of 4b and 7b with chlorodi-
phenylphosphine also afforded the desired coupling
product 5c and 8c in high yields (entries 4 and 5).
The relatively low yield of the reaction of 11b with
chlorodiphenylphosphine to afford 1-azulenylphosphine
12c should be attributed to the instability of the
product with electron-rich phosphine owing to the
substitution with the 1-azulenyl group (entry 6)
1-Iodoazulene 10 prepared by the iodination of 9 was
also tolerated in the halogen–metal exchange reaction
n
n
with both BuLi and Bu MgLi, and the intermediary
3
(
Schemes 4–6).
n
A typical example: To a solution of BuMgCl (1.3 mL, 0.90 M
n
solution in THF) in ether (10 mL) was added BuLi (1.5 mL, 1.6 M
solution in hexane) at 0 °C, and the mixture was stirred for 10 min.
After the mixture was cooled at )100 °C, a solution of 6-iodoazulene
Boronate reagents represent an important class of syn-
thetic intermediates for the transition-metal catalyzed
cross-coupling reaction.
2
catalyzed cross-coupling reaction of 6 and the Ir-cata-
lyzed direct introduction reaction of azulene with
bis(pinacolato)diboron in 42% and 70% yields, respec-
tively. The iodine–magnesium exchange of 6 with
n
15
Recently, preparation of
-azulenylboronate (8d) has been reported by the Pd-
(
3) (252 mg, 0.993 mmol) in ether (20 mL) was added dropwise. The
mixture was allowed to react at the temperature for 30 min. To
the cooled mixture was added dropwise DMF (0.35 mL, 4.5 mmol).
The mixture was allowed to warm to room temperature to react for
1
.5 h. The reaction was quenched with water, washed with NH
solution, and dried with MgSO . The solvent was evaporated and the
residue was purified by column chromatography on silica gel with
CH Cl
to afford 5a (140 mg, 90%) as green prisms. Mp 58.0–58.5 °C
methanol) [lit. mp 56 °C].
4
Cl
16
4
3
Bu MgLi followed by an addition of 2-isopropoxy-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane also furnished
the desired boronate 8d (entry 8). 6-Azulenylboronate
2
2
7
(

S. Ito et al. / Tetrahedron Letters 45 (2004) 2891–2894
nBuLi or nBu
ether, –80˚C
2893
3
MgLi
DMF
I
M
CHO
6
7a: M = Li
8a
n
7
b: M = Mg Bu Li
2
Scheme 2.
t-Bu
t-Bu
t-Bu
t-Bu
nBuLi or nBu MgLi
NIS
3
DMF
t-Bu
t-Bu
t-Bu
t-Bu
ether, –60˚C
I
M
CHO
9
10
11a: M = Li
12a
n
1
1b: M = Mg Bu Li
2
Scheme 3.
a
Table 2. Reaction of azulenymagnesium reagents with electrophiles
b
Entry
Substrate
Electrophile
R
Product
Yield (%)
Reference
c
1
2
3
4
5
6
3
6
D
D
D
2
2
2
O
O
O
D
5b
8b
91 (99)
90 (90)
98 (100)
13
14
c
D
c
10
3
D
12b
5c
Ph
Ph
Ph
2
2
2
PCl
PPh
PPh
PPh
2
2
2
83
81
6
10
PCl
PCl
8c
12c
d
52
e
7
8
9
3
6
5d
8d
55
O
O
O
O
O
B
B
53
90
16
10
12d
10
11
12
13
14
3
6
Bu
Bu
3
SnCl
SnCl
SnBu
SnBu
Allyl
Allyl
Allyl
3
5e
8e
82
91
17
17
3
3
f
3
Allyl bromide
Allyl bromide
Allyl bromide
5f
54
g
6
10
8f
12e
57
83
a
n
The reaction of 3 (1 mmol), 6 (1 mmol), and 10 (1 mmol) with Bu
3
MgLi (1.2–1.5 mmol) was carried out in ether (20 mL) for 30 min. The reaction
was quenched by adding D O (0.1–1 mL) or other electrophiles (4.5 mmol) in ether (5 mL).
2
b
c
d
e
f
All yields are isolated yields. All the reactions reported here did not show any recovery of the starting iodoazulenes.
1
Deuteration ratio, which was shown in the parentheses, was determined by H NMR spectra.
Azulene was also obtained in 7% yields.
Azulene was also obtained in 8% yields.
6-Butylazulene was also obtained in 8% yields.
g
2-Butylazulene was also obtained in 6% yields.
5
d was also obtained by a similar reaction of 3 (entry 7).
-Azulenylboronate 12d was also prepared by the reac-
azulene at the 2-position is hampered by the inefficiency
of the preparation of 2-(tri-n-butylstannyl)azulene (8e)
under the direct stannylation conditions. However, the
1
tion of 10 in high yield (entry 9).
à
iodine–magnesium exchange reaction of iodoazulenes 3
n
We have recently reported the preparation of 6-(tri-n-
butylstannyl)azulene (5e) and its 1,3-diethoxycarbonyl
derivative utilizing Pd-catalyzed direct stannylation of
the corresponding 6-bromoazulenes. The reagents are
applied to the Pd(0)-catalyzed Stille cross-coupling
and 6 with Bu
n
3
MgLi followed by an addition of
3
Bu SnCl furnished the desired 5e and 8e in high yields
§
(entries 10 and 11).
17
reaction with aryl, acyl, and/or azulenyl halides. The
extension of the methodology to the functionalization of
§
Compound 8e prepared by this reaction showed facile hydrolysis to
give azulene by column chromatographic purification utilizing silica
gel, although 6-(tri-n-butylstannyl) derivative 5e was stable under the
conditions. Isolation of 8e was possible to use column chromato-
à
Azulenylboronate 12d showed facile hydrolysis to give 9 in 79% yield.
Isolation of 12d was achieved by using column chromatography on
â
Bio-Beads S-X3 with CH
2
Cl
2
.
2 3
graphy on Al O .

2894
S. Ito et al. / Tetrahedron Letters 45 (2004) 2891–2894
) nBu MgLi, ether, –100
Ministry of Education, Culture, Sports, Science and
Technology, Japan.
1
2
˚C
3
3
R
) Electrophile
5
b—f
References and notes
Scheme 4.
1
2
. (a) Wakefield, B. J. The Chemistry of Organolithium
Compounds; Pergamon: Oxford, 1974; (b) Wakefield, B.
J. Organic Compounds of the Alkali Metals. In Compre-
hensive Organic Chemistry; Jones, D. N., Ed.; Pergamon:
Oxford, 1979; Vol. 3, pp 943–967.
. (a) Wakefield, B. J. Organic Compounds of Group II
Metals. In Comprehensive Organic Chemistry; Jones, D.
N., Ed.; Pergamon: Oxford, 1979; Vol. 3, pp 969–1012; (b)
Grignard Reagents-New Developments; Richey, H. G., Jr.;
Ed.; Wiley: New York, 2000.
1
) nBu MgLi, ether, –80
˚C
3
6
R
2) Electrophile
8b—f
Scheme 5.
3
. Zeller, K.-P. Azulene. In Houben-Weyl; Methoden der
Organischen Chemie, 4th ed.; Georg Thieme: Stuttgart,
1985; Vol. V, Part 2c, pp 127–418.
t-Bu
1
2
) nBu MgLi, ether, –60
˚C
3
1
0
t-Bu
4
. Kurotobi, K.; Tabata, H.; Miyauchi, M.; Mustafizur, A.
F. M. R.; Migita, K.; Murafuji, T.; Sugihara, Y.;
Shimoyama, H.; Fujimori, K. Synthesis 2003, 30–34.
) Electrophile
R
1
2b—e
5. (a) Inoue, A.; Kitagawa, K.; Shinokubo, H.; Oshima, K.
J. Org. Chem. 2001, 66, 4333–4339; (b) Iida, T.; Wada, T.;
Tomimoto, K.; Mase, T. Tetrahedron Lett. 2001, 42, 4841–
Scheme 6.
4
844; (c) Dumouchel, S.; Mongin, F.; Tr ꢀe court, F.;
Qu ꢀe guiner, G. Tetrahedron 2003, 59, 8629–8640.
Finally, we demonstrated the use of the new azulenyl-
magnesium reagents in the synthesis of allylazulenes. As
expected, the reaction of 4b, 7b, and 11b with allyl
bromide afforded the expected allylazulenes 5f, 8f, and
6
7
8
. Morita, T.; Takase, K. Bull. Chem. Soc. Jpn. 1982, 55,
1
144–1152.
. H u€ nig, S.; Hafner, K.; Ort, B.; M u€ ller, M. Liebigs Ann.
Chem. 1986, 1222–1240.
1
2e in good yields (entries 14–16). In the case of the
reaction of 3 and 6 afforded 6- and 2-butylazulenes in
% and 6% yields, respectively, as a side reaction.
. Baily, F.; Carson, M. W. J. Org. Chem. 1998, 63, 9960–
9967.
8
9. Richey, H. G., Jr.; Veale, H. S. Tetrahedron Lett. 1975, 16,
15–618.
6
1
0. (a) Nozoe, T.; Seto, S.; Matsumra, T. Bull. Chem. Soc.
Jpn. 1962, 35, 1990–1998; (b) Ito, S.; Nomura, A.; Morita,
N.; Kabuto, C.; Kobayashi, H.; Maejima, S.; Fujimori,
K.; Yasunami, M. J. Org. Chem. 2002, 67, 7295–7302.
1. Saito, M.; Morita, T.; Takase, K. Bull. Chem. Soc. Jpn.
We have demonstrated that organolithium or magne-
sium ate complex induces facile halogen–magnesium
exchange of iodoazulenes 3, 6, and 10; the only excep-
n
tion was the reaction of 3 with BuLi. The high reac-
1
1
tivity of the azulenylmagnesium reagents 4b, 7b, and 11b
formed by the halogen–metal exchange reaction with a
variety of organic electrophiles, provided an efficient
method for functionalization of azulene. The wide-
spread use of boronate and tin reagents produced by this
reaction also should provide an efficient method for
functionalization of azulene in various metal-catalyzed
C–C bond-forming reactions.
1
980, 53, 3696–3700.
2. Ito, S.; Morita, N.; Asao, T. Bull. Chem. Soc. Jpn. 1995,
8, 1409–1436.
6
13. Berger, S.; Kunzer, H. Tetrahedron 1983, 39, 1327–1329.
14. Alder, R. W.; Wilshire, C. J. Chem. Soc., Perkin Trans. 2
1975, 1464–1468.
1
5. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–
2
1
483; (b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147–
68; (c) Suzuki, A. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; pp 49–97.
1
6. (a) Kurotobi, K.; Tabata, H.; Miyauchi, M.; Murafuji, T.;
Sugihara, Y. Synthesis 2002, 1013–1016; (b) Kurotobi, K.;
Miyauchi, M.; Takakura, K.; Murafuji, T.; Sugihara, Y.
Eur. J. Org. Chem. 2003, 3663–3665.
Acknowledgements
The present work was supported by a Grant-in-Aid for
Scientific Research (No. 14540486 to S.I.) from the
17. Ito, S.; Okujima, T.; Morita, N. J. Chem. Soc., Perkin
Trans. 1 2002, 1896–1905.