A new efficient route to 2-substituted azulenes based on sulfonyl group directed lithiation

Article abstract of DOI:10.1021/jo801166f

(Chemical Equation Presented) Directed lithiation of p-tolyl 1-azulenyl sulfone (1) at the 2-position of the azulenyl group was achieved by using lithium 2,2,6,6-tetramethylpiperidide (LTMP). The azulenyllithium thus generated could be efficiently trapped with various electrophiles to form 2-substituted derivatives 2 in moderate to good yields. p-Tolyl 2-trimethylsilyl-1-azulenyl sulfone (2a) was transformed into cyclic sulfone derivative 3a through the directed lithiation in the p-tolyl group and subsequent intramolecular ring closure at the 8-position. 2-(Phenylsulfanyl)-1-azulenyl p-tolyl sulfone (2b) suffered from desulfonylation to form 2-phenylsulfanylazulene (4). The Suzuki coupling reaction of 2-iodo-1-azulenyl p-tolyl sulfone (2d) with arylboronic acids followed by desulfonylation efficiently gave 2-arylazulenes 10.

Full text of DOI:10.1021/jo801166f

A New Efficient Route to 2-Substituted Azulenes Based on Sulfonyl
§
Group Directed Lithiation
Toshihisa Shibasaki,† Takeo Ooishi,‡ Nobuhiko Yamanouchi,‡ Toshihiro Murafuji,*,†,‡
Kei Kurotobi,‡ and Yoshikazu Sugihara*,‡
Graduate School of Medicine, Yamaguchi UniVersity, Yamaguchi City 753-8512, Japan, and Department
of Chemistry, Faculty of Science, Yamaguchi UniVersity, Yamaguchi City 753-8512, Japan
murafuji@yamaguchi-u.ac.jp
ReceiVed June 5, 2008
Directed lithiation of p-tolyl 1-azulenyl sulfone (1) at the 2-position of the azulenyl group was achieved
by using lithium 2,2,6,6-tetramethylpiperidide (LTMP). The azulenyllithium thus generated could be
efficiently trapped with various electrophiles to form 2-substituted derivatives 2 in moderate to good
yields. p-Tolyl 2-trimethylsilyl-1-azulenyl sulfone (2a) was transformed into cyclic sulfone derivative
3a through the directed lithiation in the p-tolyl group and subsequent intramolecular ring closure at the
8-position. 2-(Phenylsulfanyl)-1-azulenyl p-tolyl sulfone (2b) suffered from desulfonylation to form
2-phenylsulfanylazulene (4). The Suzuki coupling reaction of 2-iodo-1-azulenyl p-tolyl sulfone (2d) with
arylboronic acids followed by desulfonylation efficiently gave 2-arylazulenes 10.
Introduction
the 1- and 3-positions,5 while the seven-membered ring under-
goes preferential nucleophilic addition at the 4- and 8-positions,
which competes with the addition at the 6-position, depending
Azulene derivatives have attracted considerable attention in
the design of biologically active molecules and advanced organic
materials.1,2 A practical method for the preparation of such
compounds is therefore of great interest in synthetic organic
chemistry. We have been interested in developing convenient
synthetic methods for substituted azulenes.3 Despite the excellent
one-pot synthesis of azulene provided by Hafner,4 chemical
transformations to introduce a substituent into the ring skeleton
of azulene have been very limited by its unique reactivity arising
from the polarized π-electron system. In this regard, new azulene
transformation techniques are highly desirable for the future
development of this class of compounds.
(2) (a) Kurotobi, K.; Kim, K. S.; Noh, S. B.; Kim, D.; Osuka, A. Angew.
Chem., Int. Ed. 2006, 45, 3944. (b) Thanh, N. C.; Ikai, M.; Kajioka, T.; Fujikawa,
H.; Taga, Y.; Zhang, Y.; Ogawa, S.; Shimada, H.; Miyahara, Y.; Kuroda, S.;
Oda, M. Tetrahedron 2006, 62, 11227. (c) Oda, M.; Thanh, N. C.; Ikai, M.;
Fujikawa, H.; Nakajima, K.; Kuroda, S. Tetrahedron 2007, 63, 10608. (d) Ito,
S.; Ando, M.; Nomura, A.; Morita, N.; Kabuto, C.; Mukai, H.; Ohta, K.;
Kawakami, J.; Yoshizawa, A.; Tajiri, A. J. Org. Chem. 2005, 70, 3939. (e)
Wakabayashi, S.; Kato, Y.; Mochizuki, K.; Suzuki, R.; Matsumoto, M.; Sugihara,
Y.; Shimizu, M. J. Org. Chem. 2007, 72, 744. (f) Wang, F.; Lai, Y.-H.; Han,
M. Y. Org. Lett. 2003, 5, 4791. (g) Lambert, C.; No¨ll, G.; Zabel, M.; Hampel,
F.; Schma¨lzlin, E.; Bra¨uchle, C.; Meertholz, K. Chem. Eur. J. 2003, 9, 4232.
(h) Pham, W.; Weissleder, R.; Tung, C.-H. Angew. Chem., Int. Ed. 2002, 41,
3659. (i) Lacroix, P. G.; Malfant, I.; Iftime, G.; Razus, A. C.; Nakatani, K.;
Delaire, J. A. Chem. Eur. J. 2000, 6, 2599. (j) Redl, F. X.; Ko¨the, O.; Ro¨ckl,
K.; Bauer, W.; Daub, J. Macromol. Chem. Phys. 2000, 201, 2091.
Owing to the π-electron polarization, the five-membered ring
of azulene suffers from electrophilic substitution exclusively at
(3) For recent synthetic studies on substituted azulenes, see: (a) Kane, J. L.,
Jr.; Shea, K. M.; Crombie, A. L.; Danheiser, R. L. Org. Lett. 2001, 3, 1081. (b)
Crombie, A. L.; Kane, J. L., Jr.; Shea, K. M.; Danheiser, R. L. J. Org. Chem.
2004, 69, 8652. (c) Yokoyama, R.; Ito, S.; Okujima, T.; Kubo, T.; Yasunami,
M.; Tajiri, A.; Morita, N. Tetrahedron 2003, 59, 8191. (d) Shoji, T.; Ito, S.;
Toyota, K.; Yasunami, M.; Morita, N. Tetrahedron Lett. 2007, 48, 4999. (e)
Iwama, N.; Kashimoto, M.; Ohtaki, H.; Kato, T.; Sugano, T. Tetrahedron Lett.
2004, 45, 9211. (f) Colby, D. A.; Lash, T. D. J. Org. Chem. 2002, 67, 1031. (g)
Lu, Y.; Lemal, D. M.; Jasinski, J. P. J. Am. Chem. Soc. 2000, 122, 2440. (h)
Payne, A. D.; Wege, D. Org. Biomol. Chem. 2003, 1, 2383.
§ This paper is dedicated to Prof. Victor Snieckus.
† Graduate School of Medicine, Yamaguchi University.
‡ Department of Chemistry, Faculty of Science, Yamaguchi University.
(1) (a) Wakabayashi, H.; Hashiba, K.; Yokoyama, K.; Hashimoto, K.;
Kikuchi, H.; Nishikawa, H.; Kurihara, T.; Satoh, K.; Shioda, S.; Saito, S.; Kusano,
S.; Nakashima, H.; Motohashi, N.; Sakagami, H. Anticancer Res. 2003, 23, 4747.
(b) Becker, D. A.; Ley, J. J.; Echegoyen, L.; Alvarado, R. J. Am. Chem. Soc.
2002, 124, 4678. (c) Nakamura, H.; Sekido, M.; Yamamoto, Y. J. Med. Chem.
1997, 40, 2825. (d) Tomiyama, T.; Yokota, M.; Wakabayashi, S.; Kosakai, K.;
Yanagisawa, T. J. Med. Chem. 1993, 36, 791. (e) Yanagisawa, T.; Kosakai, K.;
Tomiyama, T.; Yasunami, M.; Takase, K. Chem. Pharm. Bull. 1990, 38, 3355.
(4) Hafner, K. Organic Syntheses; Wiley: New York, 1990; Collect. Vol.
VII, p 15.
10.1021/jo801166f CCC: $40.75
Published on Web 09/24/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7971–7977 7971

Shibasaki et al.
SCHEME 1
SCHEME 2
on the nature of the nucleophile.6 It has been reported that the
addition of methyl- and phenyllithiums takes place at the 4-
and 8-positions in the normal fashion6a but bulky tritylsodium
adds to the 6-position.6b Therefore, the introduction of substit-
uents into positions that are less reactive or inert toward these
reactions has always required multistep synthesis including the
construction of the azulene skeleton.7 As part of our efforts,
we have recently reported convenient syntheses of 2- or
6-substituted azulenes.8-10 In particular, it should be emphasized
that azulenyllithium and azulenylmagnesium derivatives could
be successfully generated,8 since they had been considered for
a long time to be incompatible with the highly electrophilic
seven-membered ring of azulene (Scheme 1). This finding
provided an important guide for generating σ-anions of azulene.
Thus, an electron-withdrawing group effectively stabilizes these
anionic species and facilitates the deprotonation or halogensmetal
exchange.11
The sulfonyl group is a powerful directed metalation group
(DMG) featuring strong electron-withdrawing properties. It has
been utilized in the directed ortho lithiation of arenes for the
elaboration of aromatic compounds.12 Furthermore, sulfonyla-
zulenes have attracted much attention in medicines.1 The
versatile application of the sulfonyl group prompted us to apply
this metalation methodology to azulene systems. Herein, we
report a convenient synthetic method of 2-substituted azulenes
based on sulfonyl group directed lithiation.
presence of copper salts (Scheme 2).13 In addition to the proton
at the 2-position of the five-membered ring, 1 possesses the
acidic protons which are in close proximity to the sulfonyl
oxygen atoms at the ortho-position of the tolyl ring and at the
8-position of the positively polarized seven-membered ring. To
understand the site selectivity tendencies in the lithiation of 1,
we initially examined the reaction conditions used for 1,3-
dihaloazulene. When a violet solution of 1 in THF was treated
with LTMP (1.5 equiv) at -70 °C in the same solvent, the color
of the reaction mixture immediately became reddish violet.
Addition of chlorotrimethylsilane after 1 h at this temperature
gave the desired product 2a (5%) and cyclic azulenyl sulfone
3a (2%), together with a 10% recovery of 1 (Scheme 2). The
poor yield of 2a suggests that the lithiated azulene is very
reactive, while the formation of 3a is an indication of the
concomitant ortho-lithiation of the p-tolyl group. A competition
experiment involving 1 and 1,3-dichloroazulene carried out at
-100 °C revealed that trapping with D2O gives deuterated
products of 1 and 1,3-dichloroazulene in 52% and 18% yields,
respectively (Scheme 3). This manifests that the sulfonyl group
acts as a powerful lithiation group toward azulene systems. Next,
to achieve efficient generation of azulenyllithium from 1, we
optimized the reaction conditions. Thus, by carrying out the
lithiation at a lower temperature (-100 °C) and by adding a
diluted solution of chlorotrimethylsilane dropwise at this tem-
perature, the yield of 2a increased dramatically to 50%, while
at the same time only small quantities of 3a were detected
(Scheme 2). The azulenyllithium could be trapped with various
electrophiles to give the corresponding 2-substituted products
2b-e in moderate to good yields. An attempted trapping with
DMF resulted in poor yield of 2f (15%); however, the yield
was improved to 50% by using more electrophilic ethyl formate.
Through these trapping experiments, the 8-position did not suffer
from any substitution reaction, which rules out the possibility
of lithiation in the positively polarized seven-membered ring.
For comparison with the sulfonyl group directed lithiation at
the 2-position, we tried the synthesis of sulfone 5a from 2b
Results and Discussion
As a substrate for the directed lithiation, we chose 1-azulenyl
aryl sulfone 1, which is easily prepared through a coupling
reaction of azulene with sodium p-toluenesulfinate in the
(5) Anderson, A. G., Jr.; Nelson, J. A.; Tazuma, J. J. J. Am. Chem. Soc.
1953, 75, 4980.
(6) (a) Hafner, K.; Weldes, H. Justus Liebigs Ann. Chem. 1957, 606, 90. (b)
McDonald, R. N.; Petty, H. E.; Wolfe, N. L.; Paukstelis, J. V. J. Org. Chem.
1974, 39, 1877.
(7) (a) Nozoe, T.; Seto, S.; Matsumura, S.; Murase, Y. Bull. Chem. Soc.
Jpn. 1962, 35, 1179. (b) McDonald, R. N.; Richmond, J. M.; Curtis, J. R.; Petty,
H. E.; Hoskins, T. L. J. Org. Chem. 1976, 41, 1811.
(8) Kurotobi, K.; Tabata, H.; Miyauchi, M.; Rahman, A. F. M.; Mustafizur;
Migita, K.; Murafuji, T.; Sugihara, Y.; Shimoyama, H.; Fujimori, K. Synthesis
2003, 30.
(9) Kurotobi, K.; Miyauchi, M.; Takakura, K.; Murafuji, T.; Sugihara, Y.
Eur. J. Org. Chem. 2003, 3663.
(10) (a) Kurotobi, K.; Takakura, K.; Murafuji, T.; Sugihara, Y. Synthesis
2001, 1346. (b) Kurotobi, K.; Tabata, H.; Miyauchi, M.; Murafuji, T.; Sugihara,
Y. Synthesis 2002, 1013.
(11) Recently, azulenylmagnesiums without substituents for their stabilization
are successfully prepared through the halogensmetal exchange of the parent
iodoazulenes with magnesium ate complex. Ito, S.; Kubo, T.; Morita, N.; Matsui,
Y.; Watanabe, T.; Ohta, A.; Fujimori, K.; Murafuji, T.; Sugihara, Y.; Tajiri, A.
Tetrahedron Lett. 2004, 45, 2891.
(12) Iwao, M.; Iihama, T.; Mahalanabis, K. K.; Perrier, H.; Snieckus, V. J.
Org. Chem. 1989, 54, 26.
(13) Nefedov, V. A.; Kryuchkova, L. V. J. Org. Chem. USSR 1997, 13, 1601.
7972 J. Org. Chem. Vol. 73, No. 20, 2008

A New Efficient Route to 2-Substituted Azulenes
SCHEME 3
SCHEME 4
a
1
CHART 1. Assignment of 13C and H Chemical Shifts in CDCl3
a Proton shifts are in parentheses.
and attempted the lithiation at the 1-position (Scheme 4). Thus,
2b was found to undergo desulfonylation14 to give 4 when
treated with Na2S2O4 in the presence of NaHCO3. Oxidation of
4 afforded a mixture of 5a and 5b. The reaction of 5a with
LTMP at -100 °C followed by addition of chlorotrimethylsi-
lane, however, resulted in the formation of 6 along with recovery
of 5a. This result indicates that the ortho-lithiation in the phenyl
group proceeds in preference to the lithiation at the 1-position.
Hence, it can be concluded that the acidity of the ring protons
decreases in the following order: 2-position > ortho-position
>1-position.
Theoretical studies of the deprotonation enthalpies of azulene
have shown that the protons at the 1- and 2-positions are less
acidic than that at the 8-position, their acidities being comparable
to that of the protons in benzene.15 Although our experimental
results with respect to the lithiation of 1 and 5a are not in
agreement with this previous study, the discrepancy may be
accounted for by the following reasons. Thus, the 2-lithiated
species from 1 forms the five-membered chelate ring through
intramolecular oxygenslithium interaction, which is geo-
metrically more favorable than the six-membered ring16 ex-
pected from the 8-lithiated species. Furthermore, the azulene
nucleus is more sensitive to the substituent effects of the
electron-withdrawing sulfonyl group than the benzene nucleus
owing to the low aromatic resonance energy17 of the former
conjugation system, which lowers the π-electron density on the
carbon at the 2-position to enhance the acidity of the attached
proton. The difference in the reactivity toward lithiation between
1 and 5a is attributed to the higher π-electron density of the
ring carbon at the 1-position than at the 2-position owing to
the π-polarization of the azulene nucleus.
The 13C NMR studies of 1 and 5a revealed that the tendency
of the lithiation at the ring carbons corresponds with the order
of their chemical shifts, as the 2-position (δ 138.9) > ortho-
positions (δ 126.5 and 127.6) > 1-position (δ 116.2) (Chart 1).
It is known that the 13C chemical shifts of nonbenzenoid
aromatic ions correlate linearly with the π-electron density
relative to benzene.18 If this empirical rule is applied, the
2-position is more electron-deficient than the ortho-positions
and the 1-position is the most electron-rich. The electron
deficiency at the 2-position may be clearly shown in azulene;
the chemical shift of the carbon signal due to the 2-position
(δ 137.0) is comparable to that due to its electron-deficient
6-position (δ 137.2) and is considerably deshielded compared
(16) (a) Reich, H. J.; Goldenberg, W. S.; Sanders, A. W.; Jantzi, K. L.;
Tzschucke, C. C. J. Am. Chem. Soc. 2003, 125, 3509. (b) Monje, P.; Gran˜a, P.;
Paleo, M. R.; Sardina, F. J. Chem. Eur. J. 2007, 13, 2277.
(17) Dewar, M. J. S.; de Llano, C. J. Am. Chem. Soc. 1969, 91, 789.
(18) Spiesecke, H.; Schneider, W. G. Tetrahedron Lett. 1961, 2, 468.
(19) (a) Dias, F. B.; Pollock, S.; Hedley, G.; Pa˚lsson, L.-O.; Monkman, A.;
Perepichka, I. I.; Perepichka, I. F.; Tavasli, M.; Bryce, M. R. J. Phys. Chem. B
2006, 110, 19329. (b) Tai-Hsiang, H.; Jiann, T. L.; Li-Yin, C.; Yu-Ting, L.;
Chung-Chih, W. AdV. Mater. 2006, 18, 602. (c) Lo, P. K.; Li, K. F.; Wong,
M. S.; Cheah, K. W. J. Org. Chem. 2007, 72, 6672.
(14) Sperandio, D.; Hansen, H.-J. HelV. Chim. Acta 1995, 78, 765.
(15) (a) Meot-Ner (Mautner), M.; Liebman, J. F.; Kafafi, S. A. J. Am. Chem.
Soc. 1988, 110, 5937. (b) Meot-Ner (Mautner), M.; Kafafi, S. A. J. Am. Chem.
Soc. 1988, 110, 6297.
J. Org. Chem. Vol. 73, No. 20, 2008 7973

Shibasaki et al.
SCHEME 5
SCHEME 6
SCHEME 7
1
to that due to the electron-rich 1-position (δ 118.0). The H
NMR spectra of 1 and 5a showed that a similar tendency is
observed in the chemical shifts, as the 2-position (δ 8.3) > ortho-
positions (δ 7.9 and 8.1) > 1-position (δ 7.7) (Chart 1). These
spectroscopic findings seem to provide a measure about the
acidity of the ring proton.
Recently, much attention has been focused on derivatives
bearing an electron-deficient dibenzothiophene-S,S-dioxide moi-
ety, owing to their electroluminescent,19a photoluminescent,19b
and nonlinear optical properties.19c Although many examples
have been reported for the synthesis of this class of compounds,
analogous derivatives bearing an azulene skeleton, such as 3a,
have not appeared due to the lack of synthetic methods.
Furthermore, azulene-fused heterocycles have attracted much
attention from the viewpoint of their reactivity and structural
characteristics.3g,h The unique electronic structure of nonalter-
nant azulene, whose conjugation provides molecules with some
useful physical properties,2 led us to try the preferential synthesis
of 3a. Thus, the lithiation of 2a with LTMP proceeds in the
p-tolyl group to give 3a directly as the main product (Scheme
5). Compound 3b was easily converted to 3a by deprotection
of the silyl group with TBAF.
Sulfonamide 7 underwent sulfonyl group directed lithiation
with LTMP at -70 °C to give the corresponding 2-substituted
products 8 after trapping with electrophiles (Scheme 6). Unlike
the lithiated derivative of 1, that of 7 was stable even at -70
°C, suggesting that the stabilizing effect of the sulfonylamide
group is stronger than that of the sulfonyl group.
Next, the synthetic utility of 2d and 2e was examined by
Suzuki coupling (Scheme 7).20 Recently, aryl-substituted azu-
lenes have attracted much attention from the viewpoint of
organic light-emitting devices such as hole-injecting materials.2b
When 2d was allowed to react with phenylboronic acid in the
presence of Pd(dppf)Cl2, BINAP, and Cs2CO3, 9a was obtained
in high yield. On the other hand, a similar coupling reaction of
2e with iodobenzene also gave 9a, but the yield was lower than
that in the reaction of 2d owing to the concomitant formation
of 1. Comparison of the reactivity between 2d and 2e reveals
(20) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
7974 J. Org. Chem. Vol. 73, No. 20, 2008

A New Efficient Route to 2-Substituted Azulenes
of chlorotrimethylsilane (1 mmol) in THF (5 mL) and the resulting
solution was stirred for 5 h during which time the temperature was
gradually raised to ambient. The reaction was quenched with brine
(10 mL) and the mixture was extracted with ether (3 × 7 mL).
The combined extracts were dried over anhydrous sodium sulfate
and evaporated to leave a residue, which was chromatographed on
silica gel with hexanesAcOEt (3:1) to give 2a.
that the sulfonyl group facilitates the cross-coupling reaction
in 2d; however, it brings about the unfavorable deborylation in
2e. Desulfonylation14 of 9a under reduction conditions pro-
ceeded smoothly to give the corresponding 2-substituted azulene
10a in high yield. Encouraged by this result, we applied the
efficient transformation of 2d to the synthesis of biazulene 10b.
The importance of biaryls as components in liquid crystals and
other novel materials is well established.21 Furthermore, oli-
goazulenes have attracted enormous attention in recent years
due to their utility as advanced materials.22 Thus, the coupling
reaction of 2d with azulene-2-boronic acid23 afforded 9b, which
was successfully converted into 10b.
In summary, we have established a new method to introduce
a substituent into the 2-position of an azulene skeleton based
on sulfonyl group directed lithiation. Contrary to the previous
theoretical study, the lithiation of 1 reveals that the ring proton
at the 2-position is easily deprotonated compared to those at
the 1-, 8-, and ortho-positions to afford substituted products 2.
The azulene analogue of dibenzothiophene-S,S-dioxide 3a is
selectively synthesized from 2a by protection of the reactive
2-position with a trimethylsilyl group. Furthermore, the syn-
theses of 2-substituted azulenes 4 and 10 are achieved via
desulfonylation. The present methods tolerate easy access to
these useful derivatives that are difficult or impossible for their
syntheses by conventional methods.
p-Tolyl 2-(trimethylsilyl)-1-azulenyl sulfone (2a): 50%; violet
1
powder; mp 130 °C; H NMR (400 MHz, CDCl3) δ 0.50 (9H, s),
2.33 (3H, s), 7.18 (2H, d, J ) 8.2 Hz), 7.48 (1H, t, J ) 10.0 Hz),
7.49 (1H, t, J ) 10.0 Hz), 7.54 (1H, s), 7.69 (2H, d, J ) 8.2 Hz),
7.82 (1H, t, J ) 10.0 Hz), 8.46 (1H, d, J ) 10.0 Hz), 9.18 (1H, d,
J ) 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 0.5, 21.4, 126.0,
126.4, 127.3, 127.6 (2×), 129.3, 136.3, 138.8, 139.9, 140.0, 142.2,
142.5, 143.8, 155.8; IR (KBr) 1407, 1315, 1294, 1247, 1185, 1138,
1082, 842, 670, 539 cm-1. Anal. Calcd for C20H22O2SSi: C, 67.75;
H, 6.25. Found: C, 67.45; H, 6.24.
2-(Phenylsulfanyl)-1-azulenyl p-tolyl sulfone (2b): 80%; red
powder; mp 162-163 °C; 1H NMR (400 MHz, CDCl3) δ 2.35 (3H,
s), 6.42 (1H, s), 7.26 (2H, d, J ) 8.0 Hz), 7.32 (1H, t, J ) 9.8 Hz),
7.50 (4H, m), 7.62 (3H, m), 7.91 (1H, d, J ) 9.8 Hz), 8.04 (2H, d,
J ) 8.0 Hz), 9.29 (1H, d, J ) 9.9 Hz); 13C NMR (100 MHz, CDCl3)
δ 21.5, 115.2, 118.0, 126.4, 128.5, 129.1, 129.5, 129.6, 129.8, 131.5,
132.9, 135.1, 135.3, 137.1, 140.0, 141.0, 142.3, 143.3, 153.3; IR
(KBr) 1403, 1346, 1284, 1144, 1084, 795, 671, 539 cm-1. Anal.
Calcd for C23H18O2S2: C, 70.74; H, 4.65. Found: C, 70.64; H, 4.61.
2-(Pentamethyldisilyl)-1-azulenyl p-tolyl sulfone (2c): 68%;
1
violet powder; mp 140-142 °C; H NMR (400 MHz, CDCl3) δ
0.11 (9H, s), 0.53 (6H, s), 2.33 (3H, s), 7.18 (2H, d, J ) 8.3 Hz),
7.46 (3H, m), 7.68 (2H, d, J ) 8.3 Hz), 7.79 (1H, t, J ) 9.8 Hz),
8.43 (1H, d, J ) 9.5 Hz), 9.05 (1H, d, J ) 10.0 Hz); 13C NMR
(100 MHz, CDCl3) δ -1.6, -1.2, 21.3, 126.0 (2×), 127.1, 127.5,
127.6, 129.3, 135.5, 138.1, 139.5, 139.6, 142.2, 142.5, 143.8, 156.7;
Experimental Section
Sulfonylation of Azulene. To a suspension of copper hydroxide
(10 mmol) in water (20 mL) prepared from copper sulfate
pentahydrate (10 mmol) and sodium hydroxide (20 mmol) was
added at room temperature azulene (20 mmol) in CH3CN (30 mL),
p-toluenesulfinic acid sodium salt (20 mmol) (commercially avail-
able from Tokyo Chemical Industry Co., Ltd.) in water (20 mL),
and copper sulfate pentahydrate (40 mmol) in water. The resulting
mixture was stirred at 40 °C for 4 h. The reaction mixture was
extracted with ether (3 × 10 mL) and the solvent was evaporated
to leave a residue, which was purified by column chromatography
on silica gel with hexane-AcOEt (5:1) to give 1.
IR (KBr) 1406, 1285, 1242, 1133, 1084, 834, 672, 537 cm-1
.
2-Iodo-1-azulenyl p-tolyl sulfone (2d): 70%; dark red powder;
mp 159-160 °C; 1H NMR (400 MHz, CDCl3) δ 2.35 (3H, s), 7.23
(2H, d, J ) 8.5 Hz), 7.53 (1H, t, J ) 9.8 Hz), 7.60 (1H, s), 7.64
(1H, t, J ) 10.1 Hz), 7.92 (2H, d, J ) 8.5 Hz), 7.92 (1H, t, J ) 9.3
Hz), 8.35 (1H, d, J ) 9.7 Hz), 9.77 (1H, d, J ) 10.2 Hz); 13C
NMR (100 MHz, DMSO-d6) δ 20.9, 122.6, 126.3, 128.4, 129.6,
129.7, 129.8, 135.8, 138.3, 138.4, 139.2, 140.3, 141.4, 143.3, 143.4;
IR (KBr) 1390, 1344, 1298, 1144, 1085, 668, 601, 536 cm-1. Anal.
Calcd for C17H13IO2S: C, 50.01; H, 3.21. Found: C, 49.55; H, 2.92.
1-(p-Tolylsulfonyl)azulene-2-boronic acid (2e): 73%; violet
powder; mp 170-172 °C; 1H NMR (400 MHz, acetone-d6) δ 2.31
(3H, s), 7.31 (2H, d, J ) 8.0 Hz), 7.65 (1H, t, J ) 9.6 Hz), 7.74
(1H, t, J ) 10.2 Hz), 7.79 (1H, s), 7.88 (2H, s), 7.92 (2H, d, J )
8.4 Hz), 8.04 (1H, t, J ) 9.6 Hz), 8.69 (1H, d, J ) 9.6 Hz), 9.48
(1H, d, J ) 10.4 Hz); 13C NMR (100 MHz, CDCl3) δ 21.1, 121.5,
126.2, 126.9, 128.0, 128.3, 129.8, 135.6, 137.3, 139.4, 140.4, 141.4,
143.1, 144.2; one carbon signal was too weak to be assigned; IR
(KBr) 1453, 1416, 1348, 1328, 1275, 1129, 1080, 744, 665, 562
cm-1. Anal. Calcd for C17H15BO4S: C, 62.60; H, 4.64. Found: C,
63.03; H, 4.83.
2-Formyl-1-azulenyl p-tolyl sulfone (2f): 50%; green powder;
mp 211 °C; 1H NMR (400 MHz, CDCl3) δ 2.35 (3H, s), 7.24 (2H,
d, J ) 8.1 Hz), 7.57 (1H, t, J ) 9.7 Hz), 7.70 (1H, t, J ) 10.1 Hz),
7.81 (1H, s), 7.83 (2H, d, J ) 8.1 Hz), 8.00 (1H, t, J ) 9.9 Hz),
8.64 (1H, d, J ) 9.8 Hz), 9.75 (1H, d, J ) 9.8 Hz), 11.05 (1H, s);
13C NMR (100 MHz, CDCl3) δ 21.4. 118.9, 122.6, 126.2, 128.7,
129.3, 129.9, 139.4, 140.7, 141.2, 142.1, 142.7, 143.3, 143.7, 144.1,
190.4; IR (KBr) 1664, 1592, 1574, 1412, 1385, 1314, 1288, 1139,
1051 cm-1. Anal. Calcd for C18H14O3S: C, 69.66; H, 4.55. Found:
C, 69.91; H, 4.97.
1-Azulenyl p-tolyl sulfone (1): 84%; reddish violet powder; mp
1
144 °C; H NMR (400 MHz, CDCl3) δ 2.24 (3H, s), 7.22 (2H, d,
J ) 8.2 Hz), 7.33 (1H, d, J ) 4.2 Hz), 7.50 (1H, t, J ) 10.0 Hz),
7.59 (1H, t, J ) 10.0 Hz), 7.86 (1H, t, J ) 10.0 Hz), 7.87 (2H, d,
J ) 8.2 Hz), 8.32 (1H, d, J ) 4.2 Hz), 8.49 (1H, d, J ) 10.0 Hz),
9.33 (1H, d, J ) 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 21.4,
117.4, 124.1, 126.5, 127.5, 127.7, 129.6, 136.6, 137.2, 138.9, 139.5,
139.9, 141.3, 143.0, 144.2; IR (KBr) 1579, 1395, 1290, 1136, 740
cm-1. Anal. Calcd for C17H14O2S: C, 72.31; H, 5.00. Found: C,
72.35; H, 5.07.
General Procedure for Directed Lithiation of 1 or 4 and
Trapping with Electrophiles. A typical example is exemplified
by the reaction with chlorotrimethylsilane. To a solution of 1
(1 mmol) in THF (5 mL) at -100 °C was added a solution of
lithium 2,2,6,6-tetramethylpiperidide (1.2 mmol) prepared from
2,2,6,6-tetramethylpiperidine (1.2 mmol) and BuLi (1.2 mmol) in
THF (5 mL) at -70 °C. The color of the solution immediately
turned from violet to reddish violet showing the generation of an
intermediate. To this solution thus obtained was added a solution
(21) Liquid crystalline behavior of azulenylbenzene derivative, see: Ito, S.;
Ando, M.; Nomura, A.; Morita, N.; Kabuto, C.; Mukai, H.; Ohta, K.; Kawakami,
J.; Yoshizawa, A.; Tajiri, A. J. Org. Chem. 2005, 70, 3939.
(22) (a) Wang, F.; Lai, Y.-H.; Kocherginsky, N. M.; Kosteski, Y. Y. Org.
Lett. 2003, 5, 995. (b) Dias, J. R. J. Phys. Org. Chem. 2007, 20, 395.
(23) Azulene-2-boronic acid was newly synthesized from its pinacol ester9
by transesterification with phenylboronic acid. To read about the transesterifi-
cation method, see: (a) Belfaitah, A.; Isly, M.; Carboni, B. Tetrahedron Lett.
2004, 45, 1969.
10-Methyl-7-thianaphtho[3,2,1-cd]azulene-7,7-dioxide (3a):
48%; blue powder; mp 250-251 °C; 1H NMR (400 MHz, CDCl3)
δ 2.54 (3H, s), 7.46 (1H, d, J ) 4.4 Hz), 7.54 (1H, d, J ) 8.0 Hz),
7.61 (1H, t, J ) 10.0 Hz), 8.00 (1H, t, J ) 10.0 Hz), 8.17 (1H, s),
8.30 (1H, d, J ) 8.0 Hz), 8.40 (1H, d, J ) 4.4 Hz), 8.45 (1H, d,
J. Org. Chem. Vol. 73, No. 20, 2008 7975

Shibasaki et al.
IR (KBr) 1577, 1463, 1404, 1346, 1241, 1181, 834, 693, 530 cm-1
Anal. Calcd for C17H25NO2SSi: C, 60.85; H, 7.51; N, 4.17. Found:
C, 60.49; H, 7.50; N, 4.05.
J ) 10.0 Hz), 8.58 (1H, d, J ) 10.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.9, 120.4, 124.6, 124.7, 127.9, 128.2, 130.6, 131.8,
132.9, 133.0, 136.1, 137.7, 138.4, 139.7, 142.2, 145.0; one carbon
signal was too weak to be assigned; IR (KBr) 1385, 1270, 1258,
1202, 1132, 797, 610, 540 cm-1. Anal. Calcd for C17H12O2S: C,
72.83; H, 4.31. Found: C, 72.99; H, 4.39.
.
1-(N,N-Diethylaminosulfonyl)-2-phenylsulfanylazulene (8b):
1
69%; reddish violet powder; mp 125 °C; H NMR (400 MHz,
CDCl3) δ 1.11 (6H, t, J ) 7.1 Hz), 3.43 (4H, q, J ) 7.1 Hz), 6.44
(1H, s), 7.29 (1H, t, J ) 10.3 Hz), 7.43 (4H, m), 7.59 (1H, t, J )
9.7 Hz), 7.66 (2H, m), 7.93 (1H, d, J ) 9.9 Hz), 9.11 (1H, d, J )
2-Trimethylsilyl-10-methyl-7-thianaphtho[3,2,1-cd]azulene-
1
7,7-dioxide (3b): 12%; dark blue powder; mp 253-255 °C; H
10.0 Hz); 13
C NMR (100 MHz, CDCl3) δ 13.6, 41.0, 114.6, 117.9,
127.8, 128.2, 129.5, 129.7, 131.6, 133.1, 134.8, 135.2, 136.8, 139.5,
141.3, 152.5; IR (KBr) 1405, 1320, 1291, 1137, 694, 618 cm-1
NMR (400 MHz, CDCl3) δ 0.58 (9H, s), 2.56 (3H, s), 7.55 (1H, d,
J ) 7.8 Hz), 7.60 (1H, s), 7.61 (1H, t, J ) 9.6 Hz), 7.98 (1H, t, J
) 10.3 Hz), 8.14 (1H, s), 8.31 (1H, d, J ) 8.0 Hz), 8.43 (1H, d, J
) 10.7 Hz), 8.54 (1H, d, J ) 8.9 Hz); 13C NMR (100 MHz, CDCl3)
δ 0.0, 21.9, 124.5, 124.6, 125.4, 127.9, 128.2, 128.6, 131.7, 132.3,
133.3, 135.9, 137.5, 138.6, 139.0, 141.9, 145.0, 152.1. Anal. Calcd
for C20H20O2SSi: C, 68.14; H, 5.72. Found: C, 68.29; H, 5.99.
2-Phenylsulfanylazulene (4): 40%; violet crystals; mp 50 °C;
1H NMR (400 MHz, CDCl3) δ 7.04 (2H, s), 7.14 (2H, t, J ) 9.9
Hz), 7.44 (4H, m), 7.65 (2H, m), 8.04 (2H, t, J ) 10.3 Hz); 13C
NMR (100 MHz, CDCl3) δ 115.0, 124.2, 128.5, 129.4, 133.0, 133.3,
133.6, 135.1, 140.5, 148.1.
.
Anal. Calcd for C20H21NO2S2: C, 64.66; H, 5.70; N, 3.77. Found:
C, 64.66; H, 5.56; N, 3.66.
1-(N,N-Diethylaminosulfonyl)azulene-2-boronic acid (8c):
1
60%; dark violet powder; mp 134-135 °C; H NMR (400 MHz,
CDCl3) δ 1.04 (6H, t, J ) 7.2 Hz), 3.23 (4H, q, J ) 7.2 Hz), 7.14
(2H, s), 7.49 (1H, t, J ) 9.7 Hz), 7.56 (1H, t, J ) 10.1 Hz), 7.89
(1H, t, J ) 9.9 Hz), 7.92 (1H, s), 8.53 (1H, t, J ) 9.1 Hz), 9.47
(1H, d, J ) 10.2 Hz); 13C NMR (100 MHz, acetone-d6) δ 14.0,
41.8, 125.8, 127.4, 128.3, 128.4, 138.4, 140.0, 141.1, 141.9, 143.8;
one carbon signal was too weak to be assigned; IR (KBr) 1577,
1450, 1392, 1322, 1260, 1121, 1063, 730, 688, 555 cm-1. Anal.
Calcd for C14H18BNO4S: C, 54.74; H, 5.91; N, 4.56. Found: C,
54.95; H, 6.20; N, 4.32.
2-Azulenyl phenyl sulfone (5a): 44%; blue powder; mp 167
1
°C; H NMR (400 MHz, CDCl3) δ 7.29 (2H, t, J ) 9.9 Hz), 7.52
(3H, m), 7.66 (2H, s), 7.76 (1H, t, J ) 10.0 Hz), 8.06 (2H, d, J )
7.5 Hz), 8.45 (2H, d, J ) 9.6 Hz); 13C NMR (100 MHz, CDCl3) δ
116.3, 125.2, 127.7, 129.2, 133.1, 139.7, 141.7, 141.9, 142.3, 146.4;
IR (KBr) 1580, 1475, 1313, 1148, 802, 726, 636, 599 cm-1. Anal.
Calcd for C16H12O2S: C, 71.62; H, 4.51. Found: 71.64; H, 4.80.
2-Azulenyl phenyl sulfoxide (5b): 21%; blue solid; mp 92-93
General Procedure of the Coupling Reaction. Phenylboronic
acid (0.2 mmol), 2d (0.1mmol), Pd(dppf)Cl2 (0.01mmol), cesium
carbonate (1 mmol), and (R)-BINAP (0.01 mmol) were dissolved
in toluene (7 mL) and the resulting mixture was refluxed for 1 h.
The reaction was quenched at room temperature with brine (10
mL) and the mixture was extracted with ether (3 × 7 mL). The
combined extracts were dried over anhydrous sodium sulfate and
evaporated to leave a residue, which was chromatographed on silica
gel with hexanesAcOEt (5:1) to give 9.
2-Phenyl-1-azulenyl p-tolyl sulfone (9a): 90%; violet powder;
mp 132 °C; 1H NMR (400 MHz, CDCl3) δ 2.28 (3H, s), 7.02 (2H,
d, J ) 8.1 Hz), 7.23 (1H, s), 7.38 (7H, m), 7.52 (1H, t, J ) 9.7
Hz), 7.67 (1H, t, J ) 10.0 Hz), 7.87 (1H, t, J ) 9.8 Hz), 8.44 (1H,
d, J ) 9.6 Hz), 9.84 (1H, d, J ) 10.1 Hz); 13C NMR (100 MHz,
CDCl3) δ 21.3, 120.3, 120.5, 126.3, 127.2, 127.8, 127.9, 128.5,
128.9, 130.2, 136.1, 137.4, 138.6, 139.4, 139.6, 141.3, 142.2, 142.6,
153.1; IR (KBr) 1448, 1411, 1328, 1280, 1136, 770, 731, 659, 571
cm-1. Anal. Calcd for C23H18O2S: C, 77.07; H, 5.06. Found: C,
77.19; H, 5.29.
1
°C; H NMR (400 MHz, CDCl3) δ 7.25 (2H, t, J ) 9.8 Hz), 7.47
(3H, m), 7.49 (2H, s), 7.67 (1H, t, J ) 9.8 Hz), 7.76 (2H, d, J )
7.4 Hz), 8.36 (2H, d, J ) 9.7 Hz); 13C NMR (CDCl3) δ 113.9,
124.5, 124.8, 129.1, 130.8, 139.1, 139.5, 139.8, 145.4, 152.4; IR
(KBr) 1578, 1392, 1086, 1045, 807, 748, 688, 489 cm-1. Anal.
Calcd for C16H12OS: C, 76.16; H, 4.79. Found: C, 75.90; H, 4.71.
2-Azulenyl 2-trimethylsilylphenyl sulfone (6): 10%, blue oil;
1H NMR (CDCl3) δ 0.43 (9H, s), 7.28 (2H, t, J ) 9.9 Hz), 7.49
(1H, t, J ) 7.5 Hz), 7.54 (2H, s), 7.55 (1H, t, J ) 7.4 Hz), 7.74
(1H, t, J ) 9.9 Hz), 7.81 (1H, d, J ) 7.4 Hz), 8.02 (1H, d, J ) 7.8
Hz), 8.42 (2H, d, J ) 9.7 Hz); 13C NMR (100 MHz, CDCl3) δ
1.41, 116.0, 125.0, 129.4, 130.5, 132.0, 136.5, 139.5, 140.6, 141.3,
141.6, 146.5, 147.7. Anal. Calcd for C19H20O2SSi: C, 67.02; H,
5.92. Found: C, 67.44; H, 6.08.
Preparation of N,N-Diethyl 1-Azulenylsulfonamide (7). To a
solution of azulene (5 mmol) in dioxane (20 mL) was added
SO3 ·pyridine complex (3 mmol) and the mixture was stirred for
12 h at room temperature. After addition of triethylamine (3 mmol)
and 2,4,6-trichloro-1,3,5-triazine (3 mmol) at 0 °C, the resulting
solution was stirred for 10 min at this temperature. Then, diethy-
lamine (10 mmol) was added at 0 °C and the mixture was stirred
for 10 min at this temperature. The reaction mixture was evaporated
to leave a residue, which was purified by column chromatography
on silica gel with hexanesAcOEt (3:1) to give 7.
1-(p-Tolylsulfonyl)-2,2′-biazulene (9b): 62%; violet powder; mp
1
192-194 °C; H NMR (400 MHz, CDCl3) δ 2.23 (3H, s), 6.96
(2H, d, J ) 8.2 Hz), 7.18 (2H, t, J ) 9.8 Hz), 7.47 (2H, d, J ) 8.3
Hz), 7.53 (1H, s), 7.54 (1H, t, J ) 9.4 Hz), 7.58 (1H, t, J )
9.9 Hz), 7.66 (1H, t, J ) 10.1 Hz), 7.73 (2H, s), 7.82 (1H, t, J )
9.8 Hz), 8.33 (2H, d, J ) 9.4 Hz), 8.46 (1H, d, J ) 9.5 Hz), 9.86
(1H, d, J ) 10.1 Hz); 13C NMR (100 MHz, CDCl3) δ 21.3 120.5,
121.8, 123.4, 126.2, 127.9, 128.8, 129.0, 137.4, 137.5, 137.6, 138.5,
139.2, 139.9, 140.9, 141.5, 142.3, 142.6, 144.4, 148.9; one carbon
signal was too weak to be assigned; IR (KBr) 1439, 1395, 1333,
1285, 1145, 802, 662, 600, 540 cm-1. Anal. Calcd for C27H20O2S:
C, 79.38; H, 4.93. Found: C, 79.10; H, 5.11.
N,N-Diethyl 1-azulenylsulfonamide (7): 40%; dark violet
1
powder; mp 54 °C; H NMR (400 MHz, CDCl3) δ 1.09 (6H, t, J
) 7.0 Hz), 3.27 (4H, q, J ) 7.0 Hz), 7.33 (1H, d, J ) 4.2 Hz),
7.49 (1H, t, J ) 10.0 Hz), 7.55 (1H, t, J ) 10.0 Hz), 7.85 (1H, t,
J ) 10.0 Hz), 8.17 (1H, d, J ) 4.2 Hz), 8.50 (1H, d, J ) 10.0 Hz),
9.29 (1H, d, J ) 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 13.9,
41.5, 116.7, 122.8, 126.6, 126.8, 136.5, 136.6, 138.0, 139.1, 139.6,
143.0; IR (KBr) 1399, 1330, 1299, 1200, 1017, 943, 780, 697, 524
cm-1. Anal. Calcd for C14H17NO2S: C, 63.85; H, 6.51; N, 5.32.
Found: C, 63.96; H, 6.51; N, 5.19.
General Procedure of Desulfonylation. To a solution of 9
(1 mmol) in 1-methyl-2-pyrrolidone was added at room temperature
a solution containing sodium hydrogen carbonate (6 mmol) and
sodium dithionite (3 mmol) in distilled water (7 mL). The resulting
mixture was stirred at 90 °C for 12 h. The reaction mixture was
extracted with ether (3 × 10 mL) and the solvent was evaporated
to leave a residue, which was purified by column chromatography
on silica gel with hexanesAcOEt (5:1) to give 10.
1-(N,N-Diethylaminosulfonyl)-2-trimethylsilylazulene (8a):
1
74%; dark violet powder; mp 77-78 °C; H NMR (400 MHz,
2-Phenylazulene (10a): 98%; reddish violet powder; mp 228
°C (lit.24 mp 234 °C); 1H NMR (400 MHz, CDCl3) δ 7.17 (2H, t,
J ) 9.8 Hz), 7.36 (1H, t, J ) 7.4 Hz), 7.48 (2H, t, J ) 7.8 Hz),
CDCl3) δ 0.47 (9H, s), 1.04 (6H, t, J ) 7.1 Hz), 3.30 (4H, q, J )
7.1 Hz), 7.46 (1H, t, J ) 7.2 Hz), 7.48 (1H, s), 7.50 (1H, t, J ) 7.7
Hz), 7.82 (1H, t, J ) 9.9 Hz), 8.44 (1H, d, J ) 9.5 Hz), 9.00 (1H,
d, J ) 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 0.2, 13.1, 40.1,
125.5, 126.6, 127.0, 127.2, 136.1, 138.3, 138.5, 139.7, 143.2, 155.8;
(24) Nozoe, T.; Takase, K.; Fukuda, S. Bull. Chem. Soc. Jpn. 1971, 44, 2210.
7976 J. Org. Chem. Vol. 73, No. 20, 2008

A New Efficient Route to 2-Substituted Azulenes
7.52 (1H, t, J ) 9.8 Hz), 7.69 (2H, s), 7.98 (2H, d, J ) 7.2 Hz),
8.30 (2H, d, J ) 9.6 Hz).
146.1. Anal. Calcd for C10H9BO2: C, 69.84; H, 5.27. Found: C,
70.11; H, 5.48.
2,2′-Biazulene (10b): 85%; green powder; mp >300 °C (lit.25
mp >300 °C); 1H NMR (500 MHz, DMSO-d6) δ 7.21 (4H, t, J )
10.0 Hz), 7.58 (2H, t, J ) 10.0 Hz), 8.37 (4H, d, J ) 10.0 Hz),
7.94 (4H, s).
Azulene-2-boronic Acid. To a solution of azulene-2-boronic acid
pinacol ester9 (1.0 mmol) in ethanol (7 mL) was added phenylbo-
ronic acid (1.2 mmol) followed by a diluted aqueous solution of
hydrochloric acid (5 mL, pH 3) at room temperature, then the
mixture was stirred for 5 h. After concentration of the reaction
mixture, an aqueous solution of potassium hydroxide (10%, 10 mL)
was added and the resulting mixture was washed with ether (3 ×
10 mL). The water layer was acidified with a diluted aqueous
solution of hydrochloric acid (10 mL) and extracted with ether
(3 × 10 mL). The organic layer was dried with Na2SO4 and the
solvent was evaporated to give the crude product. Purification by
recrystallization from hexanesAcOEt (5:1) afforded the pure
product.
Acknowledgment. Support from the Japan Society for the
Promotion of Science (Grant-in-Aid for Scientific Research, No.
19550043) is gratefully acknowledged.
1
Supporting Information Available: Copies of H and 13C
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
Blue solids; yield 58%; mp 256-259 °C dec; H NMR (500
JO801166F
MHz, DMSO-d6) δ 7.13 (2H, t, J ) 9.7 Hz), 7.61 (1H, t, J ) 9.9
Hz), 7.72 (2H, s), 8.20 (2H, br s), 8.35 (2H, d, J ) 9.5 Hz); 13C
NMR (100 MHz, DMSO-d6) δ 122.9, 125.2, 137.8, 138.7, 140.5,
(25) Ito, S.; Okujima, T.; Morita, N. Perkin Trans. 1 2002, 1896.
J. Org. Chem. Vol. 73, No. 20, 2008 7977