Efficient synthesis and applications of 2-substituted azulene derivatives: Towards highly functionalized carbo- and heterocyclic molecules

Article abstract of DOI:10.1016/j.tetlet.2012.07.040

An efficient synthesis of 2-substituted azulene derivatives (3-6) was accomplished from ethyl 2-oxo-2H-cyclohepta[b]furan-3-carboxylate 1 and its derivative 2, which in turn were prepared from readily available tropolone. Compounds 1 and 2 were utilized to construct densely functionalized benz[a]azulene and azulene-furan frameworks (16-25, 29-34, 37, 38).

Full text of DOI:10.1016/j.tetlet.2012.07.040

Tetrahedron Letters 53 (2012) 5019–5022
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis and applications of 2-substituted azulene derivatives:
towards highly functionalized carbo- and heterocyclic molecules
Chi-Phi Wu a, , Badugu Devendar a, Hui-Chi Su a, Ya-Hui Chang a, Chien-Kuo Ku b,
⇑
⇑
a Department of Chemistry, Chung Yuan Christian University, Chungli 32023, Taiwan
b Department of Applied Physics and Chemistry, Taipei Municipal University of Education, Taipei 10042, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of 2-substituted azulene derivatives (3–6) was accomplished from ethyl 2-oxo-2H-
cyclohepta[b]furan-3-carboxylate 1 and its derivative 2, which in turn were prepared from readily avail-
able tropolone. Compounds 1 and 2 were utilized to construct densely functionalized benz[a]azulene and
azulene-furan frameworks (16–25, 29–34, 37, 38).
Received 23 May 2012
Revised 3 July 2012
Accepted 10 July 2012
Available online 15 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to Professor Chun-Chen Liao on
the occasion of his 70th birthday
Keywords:
Azulenes
Electrophilic substitution reactions
Aldol reactions
Paal–Knorr furan synthesis
Carbo- and heterocyclic molecules
Azulene and benz[a]azulene derivatives constitute the best
known class of typical non-benzenoid polycyclic aromatic hydro-
carbons and have long fascinated chemists with their beautiful
colors from red, blue, purple to green.1 The significance of these
derivatives is demonstrated by the presence of azulene frameworks
in various bioactive natural products such as phorbol,2a gnidilatin,2a
aconitine,2a cephalotaxine,2a frondosin C,2b guanacastepene A, C, E,
N,2c linderazulene,2d and hamigeran C, D.2e Several azulene deriva-
tives, in fact, have been known to exhibit various biological activities
such as non-prostanoid thromboxane A2 receptor antagonists,3a
cytotoxicity,3b anti-neoplastic,3c multi-receptor tyrosine kinase
inhibitors,3d antigastric ulcer,3e photomutagenicity, and photogeno-
toxicity.3f Interestingly, these derivatives also play a key role in cos-
metics, dyes, pigments, co-polymers, and nonlinear optical devices.4
Several research groups have reported fascinating syntheses of
azulene5 and benz[a]azulene derivatives.6 Tung and co-workers
have developed a convenient synthesis of substituted bicyclo-
[5.3.0]azulene derivatives.7a Recently, Iwama et al., have reported
a simple and efficient synthesis of 2-alkylazulenes from tropolone
p-toluenesulfonate.7b Very recently, we have developed highly effi-
cient intramolecular Friedel–Crafts type cyclization on azulene
derivatives, and their applications toward thermal and photochem-
ical reactions.7c
In continuation of our ongoing research program7c,8 on azulene
derivatives of carbo- and heterocylic molecules, we herein report a
highly efficient synthesis of 2-substituted azulene derivatives and
their applications toward the syntheses of benz[a]azulene and
multisubstituted furan derivatives. Therefore, it occurred to us that
the azulene frameworks, derived from tropolone, could, in princi-
ple, serve as potential precursors to provide densely functionalized
benz[a]azulene and furan derivatives via Vilsmeier–Haack, Fri-
edel–Crafts, Michael, aldol, Knoevenagel, and Paal–Knorr reac-
tions.9 To the best of our knowledge, syntheses of benz[a]azulene
and azulene-furan frameworks derived from 2-substituted azulene
derivatives have not been reported in the literature.
Ethyl 2-oxo-2H-cyclohepta[b]furan-3-carboxylate (1) was pre-
pared from commercially available tropolone in 2 steps.8 Com-
pound 1 was treated with 2-methylfuran in toluene at 190 °C in
a sealed tube for 60 h to obtain ethyl 2-(2-oxopropyl)azulene-1-
carboxylate (3) in 56%,10 similarly ethoxy derivative (4) in 60% iso-
lated yield from their precursor (2). For further generalization,
compounds 1 and 2 were treated with 2,5-dimethoxy-2,5-dihydro-
furan to obtain 2-substituted azulene derivatives 5 (60%) and 6
(80%), respectively. All the products were well characterized with
their spectral data (Scheme 1).
After successful syntheses of 2-substituted azulene derivatives
(3–6), we treated compounds 3–6 with Vilsmeier–Haack formyla-
tion (DMF/POCl3), Friedel–Crafts acylation (acetyl chloride with
AlCl3), and Michael addition reaction (methyl vinyl ketone (MVK)
⇑
Corresponding authors. Tel.: +886 32653333; fax: +886 32653399 (C.-P.W.)
E-mail addresses: chiphi@cycu.edu.tw (C.-P. Wu), kuo@tmue.edu.tw (C.-K. Ku).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.040

5020
C.-P. Wu et al. / Tetrahedron Letters 53 (2012) 5019–5022
CO2Et
CO2Et
O
CO2Et
CO2Et
O
Me
NaOEt
O
OH
OH
EtOH, reflux, 10 min,
80%
Toluene, 190 °C,
sealed tube, 60 h
O
O
CHO
R
16
CO2Et
R
7
R = H, 56%(3)
R = H (1)
CO2Et
R = OEt, 60%(4)
R = OEt (2)
NaOEt
CO2Et
CO2Et
EtOH, reflux, 10 min,
79%
OMe
O
MeO
O
CHO
OEt
8
OEt
O
17
O
O
Toluene, 190 °C,
sealed tube, 40 h
CO2Et
O
R
EtO2C
O
R
NaOEt
R = H (1)
R = H, 60% (5)
R = OEt (2)
EtOH, reflux, 10 min,
65%
R = OEt, 80%(6)
O
OEt
HO
OEt
Scheme 1. Syntheses of 2-substituted azulene derivatives.
18
CO2Et
11
EtO2C
O
in the presence of p-TSA) to provide 3-substituted azulene deriva-
tives (7–15, Scheme 2) in moderate to good yields; all the products
were characterized with their spectral data (IR, 1H, 13C NMR).
Encouraged by these results, 3-substituted azulene derivatives (7,
8, 11, 12, and 15) were further transformed into the desired den-
sely functionalized benz[a]-azulene derivatives (16–20) under var-
ious conditions. The best results were obtained via intramolecular
aldol pathway in the presence of NaOEt in refluxing ethanol
(Scheme 3).11
OMe
NaOEt
OH
EtOH, reflux, 30 min,
57%
O
HO
OEt
OEt
12
19
EtO2C
O
CO2Et
CO2Me
OMe
NaOEt
EtOH, reflux, 30 min,
90%
After developing a simple one-pot methodology for the con-
struction of multifunctionalized benz[a]azulene derivatives with
an aldol condensation, further applications were made on Vilsme-
OEt
OEt
20
15
O
Scheme 3. One-pot synthesis of benzo-fused azulenes from 2-substituted azulene
derivatives via aldol condensation.
a. Vilsmeier-Haack formylation reactions
CO2Et
CO2Et
ier–Haack products (9 and 10), with malononitrile under various
conditions. The optimized results were obtained in the presence
of NaOEt in EtOH under reflux for 1 h to provide diethyl 2-ami-
no-3-cyanobenz[a]azulene-1,10-dicarboxylate (21) in 58% isolated
yield12 via Knoevenagel condensation, aldimine formation, and fur-
ther cyclization. Similarly, 5-ethoxy derivative 22 was obtained in
POCl3
R1
R1
DMF, rt, 1-2 h
O
O
CHO
R
R
7
R = H, R1 = Me, 49%( )
3
R = H, R1 = Me( )
8
4
R = OEt, R1 = Me, 53%( )
R = H, R1 = OMe, 60% (9)
R = OEt, R1 = OMe, 79%(10)
R = OEt, R1 = Me ( )
R = H, R1 = OMe (5)
R = OEt, R1 = OMe (6)
CO2Et
CO2Et
CO2Me
NH2
b. Friedel-Crafts reactions
NC
CN
OMe
CO2Et
O
CO2Et
O
CHO
NaOEt, EtOH, reflux, 1 h
CN
R
R
Cl
AlCl3, CH2Cl2, reflux, 4 h
R1
R1
9
R = H ( )
21
R = H, 58% (
)
R = OEt (10)
O
O
R = OEt, 60% (22)
OEt
OEt
R1 = Me ( )
O
4
CO2Et
11
OEt
NC
R1 = Me, 54%(
)
CO2Et
CO2Me
OH
6
R1 = OMe ( )
12
R1 = OMe, 67%(
)
O
OMe
c. Michael addition reactions
NaOEt, EtOH, reflux,
1 h, 53%
O
CN
CHO
OEt
OEt
23
O
CO2Et
10
CO2Et
CO2Et
CO2Et
EtO
OEt
R1
R1
OH
CO2Et
)
O
O
O
O
OMe
p-TSA, EtOH, rt, 30 min
O
R
R
O
CHO
NaOEt, EtOH, reflux, 1 h
R
R
9
24
R = H, 56% (
R = H ( )
R = H, R1 = Me (3)
R = OEt, R1 = Me(4)
R = H, R1 = Me, 72%(13)
R = OEt, R1 = Me, 63%(14)
R = OEt, R1 = OMe, 63%(
R = OEt (10)
R = OEt, 60% (25)
6
15
)
R = OEt, R1 = OMe ( )
Scheme 4. One-pot synthesis of benz[a]azulenes via Knoevenagel condensation
Scheme 2. Applications of 2-substituted azulene derivatives.
followed by cyclization.

C.-P. Wu et al. / Tetrahedron Letters 53 (2012) 5019–5022
5021
CO2Et
EtO2C
R
O
CO2Et
O
OEt
O
CO2Et
R1
NC
H
O
OMe
OMe
R1
O
O
OH
CHO
NaOEt
O
R
NC
R
R
OEt
EtO2C MeO
O
R1
EtO2C
R
O
O
OEt
R
-H2O
CN
CO2Et
H CO2Me
CO2Et
CO2Me
Scheme 7. Plausible mechanism for the intramolecular Friedel–Crafts reaction.
O
OH
R
CN
R
CN
OMe
O
Scheme 5. Plausible mechanism for the synthesis of benz[a]azulenes.
CO2Et
CO2Et
OMe
Br
60% yield (Scheme 4). We also extended this standard synthetic
strategy to ethyl 2-cynoacetate, and diethyl malonate to provide
various benz[a]azulene derivatives (23–25) in 53–60% yields
(Scheme 4). Although the yields are not high, this one-pot method-
ology demonstrates the potential in construction of multifunction-
alized benz[a]azulene derivatives. A plausible mechanism for the
formation of benzo-fused azulene derivatives is depicted in
Scheme 5.
Next, we focused our attention toward the intramolecular
Friedel–Crafts reaction pathway to obtain new types of benzo-
fused azulene derivatives. For these studies we selected ethyl
2-(2,6-dioxoheptan-3-yl)azulene-1-carboxylate (26), which was
prepared via the Michael addition of ethyl 2-(2-oxopropyl)azu-
lene-1-carboxylate (3) to MVK with CaH2 in DMF at room temper-
ature for 12 h. With compound 26 in hand, we screened several
acids and solvent systems to find the best result to obtain
ethyl 1-acetyl-4-methyl-1,2-dihydrobenz[a]azulene-10-carboxyl-
ate (29) in 73% isolated yield.13 The subsequent oxidization with
DDQ gave fully aromatized benz[a]azulene derivative 32 in
81%.14 All the products were well characterized with their spectral
O
O
CaH2, DMF, 100°C, 3 h
R
O
R
R = H (3)
R = H, 43% (35)
4
R = OEt ( )
36
R = OEt, 46% (
)
OMe
CO2Et
O
p-TSA, DMF, reflux, 1 h
37
R = H, 67% (
)
R = OEt, 70% (38)
R
Scheme 8. Synthesis of azulene-furan frameworks via Paal–Knorr reaction.
data. We also generalized the reactions with various derivatives in
good to excellent yields (Scheme 6). A plausible mechanism for the
intramolecular Friedel–Crafts reaction of azulene derivatives is
presented in Scheme 7.
Finally, we focused our attention on the construction of
azulene-furan frameworks. For these studies, we selected ethyl 2-
(1-(4-methoxyphenyl)-1,4-dioxopentan-3-yl)azulene-1-carboxylate
(35) which was prepared from compound 3 and 2-bromo-1-(4-
methoxyphenyl)ethanone with CaH2 in DMF at 100 °C for 3 h.
Compound 35 was further treated with p-TSA in DMF under reflux
for 1 h to provide ethyl 2-(5-(4-methoxy-phenyl)-2-methyl furan-
3-yl)azulene-1-carboxylate (37) in 67%, isolated yield.15 Similarly,
ethoxy derivative 38 was obtained in 70% (Scheme 8) via Paal–Knorr
reaction.
O
CO2Et
O
CO2Et
R1
R1
O
CaH2, DMF, rt, 12 h
O
R
R
In summary, we have successfully synthesized 2-substituted
azulene derivatives (3–6) from ethyl 2-oxo-2H-cyclohepta[b]-fur-
an-3-carboxylate 1 and its derivative 2. These derivatives were
effectively applied in the syntheses of densely functionalized
benz[a]azulene and multisubstituted azulene-furan derivatives
by using aldol, Knoevenagel, intramolecular Friedel–Crafts, and
Paal–Knorr reactions. Utilization of these methodologies for the
syntheses of biologically important heterocyclic molecules is in
progress.
R = H; R1 = Me, 49% (26)
R = H; R1 = Me (3)
27
R = OEt; R1 = Me, 53%(
)
4
R = OEt; R1 = Me ( )
28
R = OEt; R1 = OMe, 45%(
)
6
R = OEt; R1 = OMe ( )
p-TSA, DMF
reflux, 1 h
R1
R1
EtO2C
O
EtO2C
O
DDQ
Acknowledgments
Toluene, reflux, 3 h
R
We gratefully acknowledge Professor Chun-Chen Liao for help-
ful discussions. The financial support is from the CYCU distinctive
research area project as grant CYCU-99-CR-CH and National
Science Council (NSC) of Taiwan (Grant No.: NSC 100-2119-M-
033-001). B.D. thanks NSC of Taiwan (Grant No.: NSC 100-2811-
M-033-008) for a postdoctoral fellowship.
R = H; R1
29
)
R = H, R1 Me, 81%(32)
= Me, 73% (
=
R = OEt; R1
R = OEt; R1
R = OEt; R1
33
= Me, 50%(30)
= Me,73% (
)
R = OEt; R1 = OMe, 78%(
34
=
OMe, 58%(31)
)
Scheme 6. Synthesis of benz[a]azulenes from 2-substituted azulene derivatives via
intramolecular Friedel–Crafts reaction.

5022
C.-P. Wu et al. / Tetrahedron Letters 53 (2012) 5019–5022
7.70 (t, 1H, J = 10.0 Hz), 8.29 (d, 1H, J = 10.0 Hz), 9.53 (d, 1H, J = 10.0 Hz); 13C
NMR (CDCl3, 75 MHZ): d 14.4, 29.8, 46.5, 59.7, 114.8, 120.4, 127.1, 127.8, 137.1,
137.2, 138.3, 141.6, 143.0, 148.6, 165.5, 205.8; IR (KBr): 1702, 1670, 1420,
1402, 1220, 1058 cmÀ1
Supplementary data
m
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.
040.
.
11. General procedure for the preparation of 16: To a solution of ethyl 3- formyl-2-
(2-oxopropyl)azulene-1-carboxylate 7 (1 mmol, 0.284 g) in EtOH (3 mL) at
room temperature was added NaOEt (1.2 mmol, 0.081 g). The mixture was
heated at 100 °C under reflux for 10 min. Then the reaction mixture was
allowed to cool to room temperature, diluted with water (10 mL), and
extracted with EtOAc. The combined organic layer was dried over MgSO4,
concentrated, and chromatographed on silica gel column chromatography
(hexane/EtOAc = 1:1) to afford the compound 16 (0.212 g) as solids (mp: 218–
219 °C) in 80% yield. 1H NMR (CDCl3, 300 MHZ): d 1.44 (t, 3H, J = 7.1 Hz), 4.40
(q, 2H, J = 7.1 Hz), 6.99 (dd, 1H, J = 2.18, 8.6 Hz), 7.58–7.66 (m, 3H), 7.82 (s, 1H),
8.44 (d, 1H, J = 8.6 Hz), 8.86 (dd, 1H, J = 1.0, 8.5 Hz), 9.05 (d, 1H, J = 10.0 Hz),
10.18 (s, 1H); 13C NMR (CDCl3, 75 MHZ): d 14.5, 59.3, 106.0, 109.6, 113.5, 123.1,
123.2, 129.6, 130.1, 130.4, 134.5, 136.1, 141.2, 143.0, 144.3, 160.1, 165.6; IR
References and notes
1. (a) Hafner, K.; Lindner, H. J.; Wassem, W. Heterocycles 1978, 11, 387–399; (b)
Nozoe, T.; Takeshita, H. Bull. Chem. Soc. Jpn. 1996, 69, 1149–1178; (c) Chen, S. L.;
Klein, R.; Hafner, K. Eur. J. Org. Chem. 1998, 423–433; (d) Salman, H.; Abraham,
Y.; Tal, S.; Meltzman, S.; Kapon, M.; Tessler, N.; Speiser, S.; Eichen, Y. Eur. J. Org.
Chem. 2005, 2207–2212.
2. (a) Marson, C. M.; Pink, J. H.; Hall, D. and back references cited therein. J. Org.
Chem. 2003, 68, 792–798; (b) Li, X.; Kyne, R. E.; Ovaska, T. V. Org. Lett. 2006, 8,
5153–5156; (c) Limura, S.; Overman, L. E.; Paulini, R.; Zakarain, A. J. Am. Chem.
Soc. 2006, 128, 13095–13101; (d) Manzo, E.; Ciavatta, M. L.; Lopez Gresa, M. P.;
Gavagnin, M.; Villani, G.; Naik, C. G.; Cimino, G. Tetrahedron Lett. 2007, 48,
2569–2571; (e) Madu, C. E.; Lovely, C. J. Org. Lett. 2007, 9, 4697–4700.
3. (a) Tomiyama, T.; Yokota, M.; Wakabayashi, S.; Kosakai, K.; Yanagisawa, T. J.
Med. Chem. 1993, 36, 791–800; (b) Nakamura, H.; Sekido, M.; Yamamoto, Y. J.
Med. Chem. 1997, 40, 2825–2830; (c) Hong, B.-C.; Jiang, Y.-F.; Kumar, E. S.
Bioorg. Med. Chem. Lett. 2001, 11, 1981–1984; (d) Chen, C.-H.; Lee, O.; Yao, C.-
N.; Chaung, M.-Y.; Chang, Y.-L.; Chang, M.-H.; Wen, Y.-F.; Yang, W.-H.; Ko, C.-
H.; Chou, N.-T.; Lin, M.-W.; Lai, C.-P.; Sun, C.-Y.; Wang, L.-M.; Chen, Y.-C.; Hseu,
T.-H.; Chang, C.-N.; Hsu, H.-C.; Lin, H.-C.; Chang, Y.-L.; Shih, Y.-C.; Chou, S.-H.;
Hsu, Y.-L.; Tseng, H.-W.; Liu, C.-P.; Tu, C.-M.; Hu, T.-L.; Tsai, Y.-J.; Chen, T.-S.;
Lin, C.-L.; Chiou, S.-J.; Liu, C.-C.; Hwang, C.-S. Bioorg. Med. Chem. Lett. 2010, 20,
6129–6132; (e) Zhang, L.-Y.; Yang, F.; Shi, W.-Q.; Zhang, P.; Li, Y.; Yin, S.-F.
Bioorg. Med. Chem. Lett. 2011, 21, 5722–5725; (f) Struwe, M.; Csato, M.; Singer,
T.; Gocke, E. Mutat. Res. 2011, 723, 129–133.
4. (a) Asato, A. E.; Liu, R. S. H. Tetrahedron Lett. 1996, 37, 419–422; (b) Yamaguchi,
H.; Sato, S.; Yasunam, M.; Sato, T.; Yoshinobu, M. Spec. Chimica Acta. 1997, 53,
2471–2473; (c) Bggio-Pasqua, M.; Bearpark, M. J.; Hunt, P. A.; Robb, M. A. J. Am.
Chem. Soc. 2002, 124, 1456–1470; (d) Wang, F.; Lai, Y.-H. Macromolecules 2003,
36, 536–538; (e) Wang, F.; Lai, Y.-H.; Kocherginsky, N. M.; Kosteski, Y. Y. Org.
Lett. 2003, 5, 995–998; (f) Wang, F.; Lai, Y. H.; Han, M. Y. Org. Lett. 2003, 5,
4791–4794; (g) Zielinski, T.; Kedziorek, M.; Jurczak, J. Tetrahedron Lett. 2005,
46, 6231–6234; (h) Zhang, C.; Liang, H.; Tu, G.; Zhao, Y. Fitoterapia 2010, 81,
849–851; (i) Essaidi, Z.; Niziol, J.; Sahraoui, B. Opt. Mater. 2011, 33, 1387–1390;
(j) Noll, G.; Daub, J.; Lutz, M.; Rurack, K. J. Org. Chem. 2011, 76, 4859–4873. 5.
5. (a) Abe, N. Bull. Chem. Soc. Jpn. 1991, 64, 2393–2397; (b) Pham, W.; Weissleder,
R.; Tung, C.-H. Tetrahedron Lett. 2003, 44, 3975–3978; (c) Ito, S.; Okujima, T.;
Kabuto, C.; Morita, N. Tetrahedron 2003, 59, 4651–4659; (d) Ito, S.; Kubo, T.;
Morita, N.; Matsui, Y.; Watanabe, T.; Ohta, A.; Fujimori, K.; Murafuji, T.;
Sugihara, Y.; Tajiri, A. Tetrahedron Lett. 2004, 45, 2891–2894.
(KBr):
m
3200, 1620, 1588, 1420, 1350, 1290, 1120 cmÀ1; LC–MS (m/z): 266
(100), 254 (26.0), 238 (29.1), 225 (11.9), 210 (11.6), 197 (24.9), 181 (34.8), 152
(27.3), 139 (12.6), 126 (11.1).
12. General procedure for the preparation of 21: To a stirred solution of ethyl 3-
formyl-2-(methoxy carbonylmethyl)azulene-1-carboxylate 9 (1 mmol, 0.3 g)
in EtOH (3 mL) were added malononitrile (1.5 mmol, 0.1 mL), and NaOEt
(1.2 mmol, 0.081 g) at room temperature. The mixture was heated at 100 °C
under reflux for 1 h. Then the reaction mixture was allowed to cool to room
temperature, diluted with water (10 mL), and extracted with EtOAc. The
combined organic layer was dried over anhydrous MgSO4, filtered, and
stripped off the solvent to give crude product 21, which was isolated by
silica gel column chromatography (hexane/EtOAc = 1:1) to afford compound
21 (0.202 g) as solids (mp: 180–181 °C) in 58% yield. 1H NMR (CDCl3, 300
MHZ): d 1.36 (t, 3H, J = 7.1 Hz), 1.38 (s, 3H), 4.38 (q, 2H, J = 7.2 Hz), 6.40 (s, 2H),
7.39–7.57 (m, 3H), 8.39 (dd, 1H, J = 8.4, 10.0 Hz), 8.46 (s, 1H), 8.87 (dd, 1H,
J = 0.9, 11.2 Hz); 13C NMR (CDCl3, 75 MHz): d 14.3, 51.5, 60.8, 94.3, 103.7, 117.8,
121.5, 129.9, 130.0, 130.1, 131.1, 134.4, 136.7, 139.6, 140.2, 142.8, 145.4, 150.7,
166.5, 168.6; IR (KBr):
m
3400, 2200, 1680, 1610, 1420, 1160 cmÀ1; LC–MS (m/
z): 348 (18.10), 319 (13.95), 288 (10.39), 270 (16.32), 244 (15.43), 190 (12.46),
188 (62.31), 135 (18.99), 111 (24.63), 100 (27.30), 59 (100).
13. General procedure for the preparation of 29: To a solution of ethyl 2-(2, 6-
dioxoheptan-3-yl)azulene-1-carboxylate 26 (1 mmol, 0.326 g) in DMF (3 mL) at
room temperature was added p-TSA (2 mmol, 0.344 g) the mixture was heated
at 170 °C under reflux for 1 h. Then the reaction mixture was allowed to cool to
room temperature, diluted with water (10 mL), and extracted with EtOAc. The
combined organic layer was dried over MgSO4, concentrated, and
chromatographed on silica gel column chromatography (hexane/EtOAc = 4:1)
to afford compound 29 (0.225 g) as a viscous liquid in 73% yield. 1H NMR (CDCl3,
300 MHZ): d 1.38 (t, 3H, J = 7.2 Hz), 1.95 (s, 3H), 2.40 (s, 3H), 2.49-2.59 (m, 1H),
2.83 (dd, 1H, J = 6.6, 16.8 Hz), 4.38 (q, 2H, J = 7.2 Hz), 4.59 (dd, 1H, J = 1.7, 8.1 Hz),
5.66 (brs, 1H), 7.23 (t, 1H, J = 10.0 Hz), 7.34 (t, 1H, J = 10.0 Hz), 7.58 (t, 1H,
J = 10.0 Hz), 8.72 (d, 1H, J = 10.0 Hz), 9.45 (d, 1H, J = 10.0 Hz); 13C NMR (CDCl3,
75 MHz): d 14.5, 22.7, 26.7, 28.9, 48.4, 60.1, 113.9, 122.9, 126.0, 126.4, 127.9,
6. (a) Wentrup, C.; Becker, J. J. Am. Chem. Soc. 1984, 106, 3705–3706; (b) Cresp, T.
M.; Wege, D. Tetrahedron 1986, 42, 6713–6718; (c) Sperandio, D.; Hansen, H.-J.
Helv. Chimica Acta 1995, 78, 765–771; (d) Yamamura, K.; Yamane, T.;
Hashimoto, M.; Miyake, H.; Nakatsuji, S.-I Tetrahedron Lett. 1996, 37, 4965–
4966; (e) Cioslowski, J.; Schimeczek, M.; Piskorz, P.; Moncrieff, D. J. Am. Chem.
Soc. 1999, 121, 3773–3778; (f) Morita, N.; Yokoyama, R.; Asao, T.; Kurita, M.;
Kikuchi, S.; Ito, S. J. Organomet. Chem. 2002, 642, 80–90; (g) Okazaki, T.; Laali, K.
K. Org. Biomol. Chem. 2003, 1, 3078–3093; (h) Kimura, T.; Takahashi, T.;
Nishiura, M.; Yamamura, K. Org. Lett. 2006, 8, 3137–3139.
7. (a) Pham, W.; Weissleder, R.; Tung, C.-H. Tetrahedron Lett. 2002, 43, 19–20; (b)
Iwama, N.; Kashimoto, M.; Ohtaki, H.; Kato, T.; Sugano, T. Tetrahedron Lett.
2004, 45, 9211–9213; (c) Wu, C.-P.; Devulapally, R.; Li, T.-C.; Ku, C.-K.; Chung,
H.-C. Tetrahedron Lett. 2010, 51, 4819–4822.
131.0, 135.9, 136.6, 137.1, 138.7, 142.5, 151.0, 165.5, 208.8; IR (KBr):
m 2925,
1686, 1573, 1430, 1260, 1192, 1092, 1031, 799 cmÀ1; GC–MS (m/z): 308 (M+,
24), 265 (63), 236 (38), 219 (100), 192 (56), 178 (47), 95 (87), 81 (47).
14. General procedure for the preparation of 32: To a solution of ethyl 1- acetyl-4-
methyl-1,2-dihydrobenz[a]azulene-10-carboxylate 29 (1 mmol, 0.308 g) in
toluene (3 mL) at room temperature was added DDQ (2 mmol, 0.454 g). The
mixture was heated at 120 °C under reflux for 3 h. Then the reaction mixture
was allowed to cool to room temperature, diluted with water (10 mL), and
extracted with EtOAc. The combined organic layer was dried over MgSO4,
concentrated, and chromatographed on silica gel column chromatography
(hexane/EtOAc = 2:1) to afford compound 32 (0.248 g) as a solid (mp: 115–
116 °C) in 81% yield. 1H NMR (CDCl3, 300 MHZ): d 1.37 (t, 3H, J = 7.2 Hz), 2.65 (s,
3H), 2.99 (s, 3H), 4.42 (q, 2H, J = 7.2 Hz), 7.23 (dd, 1H, J = 0.6, 9.6 Hz), 7.25 (ddd,
1H, J = 1.1, 11.0, 11.0 Hz), 7.29 (dd, 1H, J = 0.6, 7.5 Hz), 7.46 (dd, 1H, J = 9.6,
11.0 Hz), 7.82 (d, 1H, J = 7.5 Hz), 8.74 (d, 1H, J = 9.6 Hz), 8.90 (d, 1H,
J = 11.0 Hz); 13C NMR (CDCl3, 75 MHz): d 14.3, 23.5, 29.0, 60.3, 116.4, 125.5,
128.0, 128.3, 128.5, 128.7, 131.5, 135.0, 135.2, 136.9, 137.2, 138.2, 141.4, 142.1,
8. Wu, C.-P.; Cheng, L.-Y.; Wen, Y.-S.; Hsiao, C.-D. J. Chin. Chem. Soc. 1997, 44, 265–
269.
9. (a) Kametani, T.; Kigasawa, K.; Hiiragi, M.; Ishimaru, H.; Uryu, T.; Haga, S. J.
Chem. Soc., Perkin Trans. 1 1973, 471–472; (b) Takayasu, T.; Nitta, M. J. Chem.
Soc., Perkin Trans. 1 1997, 3255–3260; (c) Takayasu, T.; Nitta, M. J. Chem. Soc.,
Perkin Trans. 1 1997, 3537–3542; (d) Katritzky, A. R.; Arend, M. J. Org. Chem.
1998, 63, 9989–9991; (e) Yamamura, K.; Kusuhara, N.; Kondou, A.; Hashimoto,
M. Tetrahedron 2002, 58, 7653–7661; (f) Mahata, P. K.; Venkatesh, C.; Kumar, U.
K. S.; Ila, H.; Junjappa, H. J. Org. Chem. 2003, 68, 3966–3975; (g) Kreuzer, T.;
Metz, P. Eur. J. Org. Chem. 2008, 572–579; (h) Damodiran, M.; Selavam, N. P.;
Perumal, P. T. Tetrahedron Lett. 2009, 50, 5474–5478; (i) Quiroga, J.; Diaz, Y.;
Insuasty, B.; Abonia, R.; Nogueras, M.; Cobo, J. Tetrahedron Lett. 2010, 51, 2928–
2930; (j) Kumar, A. S.; Nagarajan, R. Org. Lett. 2011, 13, 1398–1401; (k) Huang,
Y.-Y.; Keneko, K.; Takayama, H.; Kimura, M.; Wong, F.-F. Tetrahedron Lett. 2011,
52, 3786–3792.
10. General procedure for the preparation of 3: To a stirred solution of ethyl 2-oxo-
2H-cyclohepta[b]furan-3-carboxylate 1 (1 mmol, 0.218 g) in toluene (3 mL)
was added 2-methylfuran (2 mL), and the mixture was refluxed at 190 °C for
60 h. The mixture was allowed to cool to room temperature, diluted with water
(10 mL), and extracted with EtOAc. The combined organic layer was dried over
anhydrous MgSO4, filtered, and stripped off the solvent to give a crude product,
which was purified by silica gel column chromatography (hexane/EtOAc = 9:1)
to afford the compound 3 (0.143 g) as solids (mp: 51-52 °C) in 56% yield. 1H
NMR (CDCl3, 300 MHZ): d 1.40 (t, 3H, J = 7.2 Hz), 2.19 (s, 3H), 4.29 (s, 2H), 4.39
(q, 2H, J = 7.2 Hz), 7.12 (s, 1H), 7.37 (t, 1H, J = 10.0 Hz), 7.48 (t, 1H, J = 10.0 Hz),
166.7, 201.5; IR (KBr):
m 2970, 1698, 1681, 1455, 1403, 1254, 1197, 1085, 1033,
798; GC–MS (m/z): 306 (M+, 100), 261 (70), 234 (26), 189 (42), 178 (20).
15. General procedure for the preparation of 37: To a solution of ethyl 2-(1- (4-
methoxyphenyl)-1,4-dioxopentan-3-yl)azulene-1-carboxylate 35 (1 mmol,
0.404 g) in DMF (3 mL) at room temperature was added p-TSA (2 mmol,
0.344 g). The mixture was heated at 170 °C under reflux for 1 h. Then the
reaction mixture was allowed to cool to room temperature, diluted with water
(10 mL), and extracted with EtOAc. The combined organic layer was dried over
MgSO4, concentrated, and chromatographed on silica gel column
chromatography (hexane/EtOAc = 3:1) to afford compound 37 (0.259 g) as a
viscous liquid in 67% yield. 1H NMR (CDCl3, 300 MHZ): d 1.26 (t, 3H, J = 7.2 Hz),
2.48 (s, 3H), 3.81 (s, 3H), 4.35 (q, 2H, J = 7.2 Hz), 6.70 (s, 1H), 6.92 (d, 2H,
J = 6.9 Hz), 7.24 (s, 1H), 7.37 (t, 1H, J = 10.0 Hz), 7.51 (t, 1H, J = 10.0 Hz), 7.59 (d,
2H, J = 6.9 Hz), 7.64 (t, 1H, J = 10.0 Hz), 8.31 (d, 1H, J = 10.0 Hz), 9.40 (d, 1H,
J = 10.0 Hz); 13C NMR (CDCl3, 75 MzH): d 13.1, 14.3, 55.2, 60.0, 107.1, 114.1,
115.1, 119.2, 119.8, 124.7, 126.8, 127.7, 136.5, 136.7, 137.7, 141.9, 142.6, 145.6,
149.1, 151.1, 158.7, 166.1; IR (KBr):
m 2900, 1687, 1608, 1502, 1417, 1248,
1205, 1031, 805; GC–MS (m/z): 386 (M+, 100), 340 (29), 325 (28), 313 (13), 135
(66).