Syntheses of 2-formyl-, 2,3-diformyl- and 8-formyl-1-azaazulenes

Article abstract of DOI:10.3987/COM-07-S(U)6

2-Styryl-1-azaazulenes were synthesized by two ways: a) Suzuki coupling of 2-bromo-l-azaazulenes with trans-2-phenylvinylboronic acid b) Condensation of 2-methyl-l-azaazulene, being synthesized by Negishi coupling of 2-bromo-1-azaazulene with dimethylzinc, with benzaldehyde.Oxidative cleavage of 2-styryl-1-azaazulenes with OsO₄-KIO₄ gave 2-formyl-1-azaazulenes. 8-Formyl-1-azaazulenes were synthesized by the reaction of l-azaazulenes with 2-1ithio-1,3-dithiane followed by the hydrolysis.

Full text of DOI:10.3987/COM-07-S(U)6

HETEROCYCLES, Vol. 73, 2007
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HETEROCYCLES, Vol. 73, 2007, pp. 325 - 339. © The Japan Institute of Heterocyclic Chemistry
Received, 7th May, 2007, Accepted, 4th June, 2007, Published online, 5th June, 2007. COM-07-S(U)6
SYNTHESES OF 2-FORMYL-, 2,3-DIFORMYL- AND 8-FORMYL-1-
AZAAZULENES†
Kazuya Koizumi,1 Chikara Miyake,1 Tomoyuki Ariyoshi,1 Kenji Umeda,2
Noriko Yamauchi,1 Shoji Tagashira,2* Yoshiko Murakami,2 Hiroyuki Fujii,3
and Noritaka Abe1*
1Applied Molecular Bioscience, Graduate School of Medicine, and Department
of Biology and Chemistry, Faculty of Science, Yamaguchi University, Yoshida,
Yamaguchi 753-8512, Japan
2Graduate School of Science and Engineering, Yamaguchi University, Yoshida,
Yamaguchi 753-8512, Japan
3Science Research Center, Yamaguchi University, Yamaguchi 753-8512, Japan
Abstract – 2-Styryl-1-azaazulenes were synthesized by two ways: a) Suzuki
coupling of 2-bromo-1-azaazulenes with trans-2-phenylvinylboronic acid b)
Condensation of 2-methyl-1-azaazulene, being synthesized by Negishi coupling
of 2-bromo-1-azaazulene with dimethylzinc, with benzaldehyde. Oxidative
cleavage of 2-styryl-1-azaazulenes with OsO4-KIO4 gave 2-formyl-1-
azaazulenes. 8-Formyl-1-azaazulenes were synthesized by the reaction of 1-
azaazulenes with 2-lithio-1,3-dithiane followed by the hydrolysis.
INTRODUCTION
Formylazulenes are known as useful key products for synthesizing various azulene derivatives and fused
non-alternant aromatics. Formyl-1-azaazulenes are also considered that they have potential versatile
utilities for synthesizing numerous 1-azaazulenes and azaazulene-fused heterocycles, but only 3-formyl-
1-azaazulene derivatives were known.
Although researches for introduction of formyl group on
azulene ring were devoted in azulene chemistry,1-5 Vilsmeier-Haack reaction was only method for
introducing of formyl group at C-3 position of 1-azaazulene ring6 in azaazulene chemistry. In the line of
––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
† Dedicated to late Professor Dr. Ivar Ugi.

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our investigation of azaazulene chemistry,7-9 it is important to exploit the synthetic method of formyl-1-
azaazulenes. It is known that formation of formylazulenes were achieved by oxidation of
methylazulene10-12 and by oxidative cleavage of styrylazulene.1 In spite of the synthetic utility, synthetic
studies of methyl-1-azaazulenes6,13,14 and styryl-1-azaazulenes15 were few. We recently reported that
Suzuki coupling for introducing aryl groups onto 1-azaazulene ring16 and Sonogashira-Hagihara coupling
for ethynyl groups onto 1-azaazulene ring17,18 were achieved successfully. Therefore, it is expected that
Negishi coupling for introducing methyl groups onto 1-azaazulene ring and Suzuki coupling for
introducing styryl group onto 1-azaazulene ring would be available methods. In this paper, we wish to
report the synthesis of 2-methyl-1-azaazulene by Negishi coupling and successive formation of 2-styryl-
1-azaazulene, and the synthesis of 2-styryl-1-azaazulene by Suzuki coupling. Furthermore, the
formation of 2-formylazulenes by oxidative cleavage of 2-styrylazulenes is also mentioned.
On the aldehyde synthesis, it is known that the deprotection of 2-substituted 1,3-dithiane is an excellent
method.19-29 We reported that 8-aryl-1-azaazulenes were easily prepared by the reaction of aryl lithium
with 1-azaazulenes.16,30,31 Therefore, it is expected that the reaction of 2-lithio-1,3-dithine32 with 1-
azaazulenes and successive hydrolysis would give 8-formyl-1-azaazulenes. So we examined the
reaction.
RESULTS AND DISCUSSION
Synthesis of 2-methyl- and 2-styryl-1-azaazulenes
Two synthetic reports of 2-methyl-1-azaazulene (2a) were found; where 2a was obtained as blue or
purple syrup but its character was obscure.14,15 Therefore, we examined the synthesis of 2-methyl-1-
azaazulene by Negishi coupling at first. 2-Methyl-1-azaazulene (2a) was obtained as yellow solution by
the treatment of 2-bromo-1-azaazulene (1a) with ZnMe2 in the presence of PdCl2(dppf), but when the
solvent was evaporated, 2a was turned to blue substance. Therefore, 2a was obtained in 88% yield as
picrate, which can be stored at rt. 2-Methyl-1-azaazulene (2a) can be liberated from the picrate of 2a by
passing through alumina column. Similar treatment of 1b and 1c with ZnMe2 in the presence of
PdCl2(dppf) gave picrates of 2b and 2c in 63% and 67% yields, respectively.
R
R
R
R
Ph
X
Me
CHO
N
N
N
N
3a : R = H
4a : R = H
4b : R = Br
4c : R = Me
1a : X = Br, R = H
1b : X = Br, R = Br
1c : X = Br, R = Me
1d : X = Br, R = CHO
2a : R = H
2b : R = Br
2c : R = Me
3b : R = Br
3c : R = Me
3d : R = CHO
4d : R = CHO

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327
Bromination of 1a with NBS in the presence of benzoyl peroxide gave 1c, which was consistent with the
Negishi coupling product of 1b, and methyl group was not brominated. The results show that C-2
position of 1-azaazulene ring is more reactive than C-3 on the Negishi coupling, and the result is same
that C-2 position is reactive than C-3 on the Suzuki coupling16 and the Sonogashira coupling18.
Compound 1c could be easily prepared from 6 with POBr3, but the reported synthesis of 6 was rather
troublesome.6 Therefore we examined the synthesis of 6 by another route. We previously showed that
3-iodo-1-azaazulene is reactive on the Suzuki coupling.16 So, it is considered that 3-iodo-1-azaazulen-
2(1H)-one (5) would be reactive to Negishi coupling.
Indeed, 5 underwent the reaction with ZnMe2 in
the presence of PdCl2(dppf) and 6 was obtained in 75% yield together with 7 (9%). Treatment of 6 with
POBr3 at 110 ℃ for 1 h gave 1c in 97% yield.
I
Me
ZnMe2
O
O
O
N
H
N
H
N
H
PdCl2(dppf)
5
7
6
POBr3
Me
Br
N
1c
Next, we examined the synthesis of 2-styryl-1-azaazulenes by the condensation reaction of 2-methyl-1-
azaazulene with benzaldehyde. Treatment 2-methyl-1-azaazulene (2a), liberated from its picrate, with
benzaldehyde in the presence of t-BuOK and 18-crown-6 gave 2-styryl-1-azaazulene (3a) in 64% yield.
Although 3a was obtained, this method is unsatisfied because of instability of 2-methyl-1-azaazulenes.
We next examined the synthesis of 2-styryl-1-azaazulenes by the Suzuki coupling of 2-bromo-1-
azaazulenes. Thus, treatment of 1a with trans-2-phenylvinylboronic acid in the presence of
PdCl2(PPh3)2 and K2CO3 in toluene at 110 ℃ for 5 h gave 3a in 71% yield. Similar treatment of 1b, 1c,
and 1d with trans-2-phenylvinylboronic acid gave 3b (88%), 3c (64% along with 31% of 1c), and 3d
(95%), respectively.
Synthesis of 2-formyl-1-azaazulenes
The Lemieux-Johnson oxidation33 would be effective for oxidative cleavage of the ethylenic linkage of 2-
styryl-1-azaazulenes as well as 2-styrylazulenes.1 Thus, the reaction of 2-styryl-1-azaazulenes (3a-d)
with KIO4 in aq. dioxane in the presence of OsO4 underwent oxidative cleavage and gave the
corresponding 2-formyl-1-azaazulenes (4a-c) in 28-46% yields along with some recovered 3a-c.

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The 2-formyl-1-azaazulenes (4a-c) were slightly unstable and changed into brown substance on heating
or stand for long time at rt. These structures were deduced by there spectroscopic data. Synthesis of
2,3-diformyl-1-azaazulene (4c) by the Vilsmeier-Haack reaction of 4a is undesirable for the instability of
4a. Therefore it is thought that the Lemieux-Johnson oxidation of 3d would be preferred. Indeed,
treatment of 3-formyl-2-styryl-1-azaazulene (3d) with KIO4 in aq. dioxane in the presence of OsO4 gave
2,3-diformyl-1-azaazulene (4d) as stable crystals in 84% yield.
The IR spectra of 2-formyl-1-azaazulenes (4a-c) show absorption owing to carbonyl groups around 1690
cm-1. In the IR spectrum of 4d, two carbonyl signals at 1690 and 1653 cm-1 were appeared. They are
assigned as the former is formyl group at C-2 and the latter is that at C-3. In the 1H NMR spectra of 4a-
c, singlet signals due to the formyl group are appeared at δ 10.54-10.66, together with signals due to the
seven-membered ring protons. In the 1H NMR spectra of 4d, two formyl proton singlets are observed at
δ 10.65 and 10.97; the former is assigned to the formyl proton at C-2 and the latter is that at C-3. These
results would be thought that the conjugation of the formyl group at C-3 with 1-azaazulene ring is
favored and the polarization of the formyl group is larger than 2-formyl group, because the resonance
form of the formyl group at C-2 with 1-azaazulene is a quinoido form.
O
O
H
H
C
C
O
C
H
O
C
N
N
N
N
H
Synthesis of 8-formyl-1-azaazulenes
As similar for 2-formyl-1-azaazulenes, synthesis of 8-formyl-1-azaazulenes was examined. The Suzuki
coupling of 8-bromo-3-phenyl-1-azaazulene (8) with trans-2-phenylvinylboronic acid in the presence of
PdCl2(PPh3)2 and K2CO3 in toluene at 40 ℃ for 8 h gave 9 in 66% yield. The Lemieux-Johnson
1
oxidation of 9 gave only trace amounts of 10. In the H NMR spectrum of 10, a singlet due to the
formyl group is appeared at δ 11.90.
Ph
Ph
Ph
N
N
N
Br
CHO
Ph
10
8
9
Because the Lemieux-Johnson oxidation of 8-formyl-1-azaazulene did not give satisfactory result, we

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explored for another method. It is thought that introduction of 1,3-dithian-2-yl group, being a synthetic
equivalent of formyl group, would be an excellent method.19-28 Therefore, the reaction of 2-lithio-1,3-
dithine with 1-azaazulenes and successive hydrolysis was examined.
Reaction of 11a with 2-lithio-1,3-dithiane and successive treatment of MeOH followed by
dehydrogenation with p-chloranil gave 12a in 86% yield. In the similar manner, reactions of 11b and
11c gave 12b and 12c in 98 and 68% yields, respectively. In the 1H NMR spectra of 12a-c, H-7 protons
resonated at low field (δ 8.41-8.42). The phenomena would be attributed to the anisotropy of the sulfur
atom in 1,3-dithianyl group at C-8.
As it is anticipated the instability of 13, mild hydrolytic conditions were desired. Therefore, the
hydrolysis of dithioacetal using chloramine-T27-29 was examined at first. Treatment of 12a with
chloramine-T in aq. MeOH-EtOH for 1 h at rt gave 2-chloro-8-formyl-1-azaazulene (13a) in 12% yield.
Compound 13a was unstable under heating and changed to brown powders upon storage at rt. The IR
spectrum 13a shows absorption owing to carbonyl group at 1695 cm-1. In its 1H NMR spectrum, 1H-
singlet due to the formyl group is appeared at δ 11.65, together with signals due to the seven-membered
ring proton signals. In the reaction 13a was obtained but yield was low. Therefore, we examined the
another methods.
It is known that the hydrolysis of 1,3-dithiane using NBS in the presence of moist DMSO is useful
method for preparation of aldehyde.22,23 Thus treatment of 12a with an equivalent of NBS in the
presence of DMSO in chloroform at rt for 16 h gave 13b in 36% yield. Same product (13b) was
obtained by the reaction of 12b with 0.2 equivalent of NBS in the presence of DMSO in chloroform at rt
for 26 h in 58% yield. When 12a was treated with 0.2 equivalent of NBS, compound (12b) was
obtained in 19% yield together with 12a (72%), and 13a was not obtained at all. Therefore, the
bromination at C-3 of 12a underwent preferentially. We next examined the reaction of 12a with NCS in
the presence of DMSO in chloroform at rt for 15 h, and obtained 13a in 25% yield. Treatment of 12c
with NBS gave 13c in 50% yield.
R
R
R
A) NBS or NCS / DMSO
B) MeI / Me2CO - H2O
1) 1,3-dithiane, BuLi
Cl
Cl
Cl
N
N
N
2) MeOH
3) p-chloranil
CHO
S
S
12a : R = H
12b : R = Br
12c : R = CO2Et
13a : R = H
13b : R = Br
13c : R = CO2Et
11a : R = H
11b : R = Br
11c : R = CO2Et
Recently, as the mild conditions, hydrolysis of 2-substituted 1,3-dithianes using CH3I was reported.24-26

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We next examined the reaction of 12a with CH3I at 30 ℃ for 21 h and obtained 13a in 8% yield along
with 12a (10%). Similar reaction of 12b and 12c with CH3I at 30 ℃ for 48 h gave 13b (50% yield
along with 47% of 12b) and 13c (68% yield along with 25% of 12c), respectively.
CONCLUSION
Syntheses of 2-formyl-1-azaazulenes and 8-formyl-1-azaazulenes were achieved.
2-Formyl-1-
azaazulenes were synthesized by the oxidative cleavage of 2-styryl-1-azaazulenes with OsO4-KIO4. 2-
Styryl-1-azaazulenes were synthesized by two ways: a) Suzuki coupling of 2-bromo-1-azaazulenes with
trans-2-phenylvinylboronic acid b) Condensation of 2-methyl-1-azaazulene, being synthesized by
Negishi coupling of 2-bromo-1-azaazulene with dimethylzinc, with benzaldehyde. 8-Formyl-1-
azaazulenes were synthesized by the reaction of 1-azaazulenes with 2-lithio-1,3-dithiane followed by the
hydrolysis using chloramine-T, NBS (or NCS), or MeI.
ACKNOWLEDGEMENTS
This work was partially supported by a Grant-in-Aid for Scientific Research (No.18510075) to S. T. from
the Japan Society for Promotion of Science (JSPS).
EXPERIMENTAL
Mps are measured using a Yanagimoto micro-melting apparatus and uncorrected. 1H NMR spectra
(including HH-COSY and CH-COSY NMR) were recorded on a Bruker AVANCE 400S (400 MHz) and
13C NMR spectra were recorded on a Bruker AVANCE 400S (100.6 MHz) using deuteriochloroform as a
solvent with tetramethylsilane as an internal standard unless otherwise stated; J values are recorded in Hz.
IR spectra were recorded for KBr pellets on a Nicolet FT-IR AVTAR 370DTGS unless otherwise stated.
Electronic spectra were recorded with JASCO V-570 spectrophotometer using chloroform as a solvent.
MS spectra were taken with on an LC-MS Waters Integrity System. Elemental analyses were taken
with a Perkin Elmer 2400II. Kieselgel 60 and activated alumina C300 were used for column
chromatography and Kieselgel 60G was used for thin-layer chromatography.
Synthesis of 2-methyl-1-azaazulenes
Under argon atmosphere, a mixture of 2-bromo-1-azaazulene (1a) (0.047 g, 0.23 mmol), PdCl2(dppf)
(0.006 g, 0.01 mmol), and 1 M ZnMe2 in heptane (0.40 mL, 0.40 mmol) in THF (10 mL) was heated for 1
h at 80 ℃ in a sealed tube. To the mixture water was added, and the mixture was extracted with
CH2Cl2. The extract was dried over Na2SO4, and evaporated. The residue was chromatographed with
EtOAc-EtOH (10 : 1) to give a yellow solution of 2-methyl-1-azaazulene (2a). The solution was

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331
concentrated in vacuo at rt. Addition of saturated EtOH solution of picric acid (1.0 mL) to the
concentrated solution.of 2a gave a picrate of 2a (0.085 g, 88%). 2-Methyl-1-azaazulene (2a) was
liberated from the picrate of 2a by passing over alumina column. Compound (2a) was rather unstable
and changed to unidentified blue substance on heating.
Picrate of 2a: Yellow needles (from EtOH), mp 198-199 ℃ (lit.,14 green crystals, mp 196-198 ℃);
δH(DMSO-d6) 2.82 (3H, s, CH3), 7.60 (1H, s, H-3), 8.40 (1H, dd, J 10.0 and 9.6, H-5), 8.44 (1H, dd, J
10.0 and 9.6, H-7), 8.56 (2H, s, H-phenyl), 8.59 (1H, t, J 10.0, H-6), 8.94 (1H, d, J 9.6, H-8), and 9.15
(1H, d, J 9.6, H-4). Anal. Calcd for C16H12N4O7: C, 51.62; H, 3.25; N, 15.05. Found: C, 51.74; H,
3.28; N, 15.11.
In a similar manner, picrate of 2b and picrate of 2c were obtained in 63% and 67% yield, respectively.
Picrate of 2b: Yellow needles (from EtOH), mp 189-190 ℃ (decomp); δH(DMSO-d6) 2.81 (3H, s, CH3),
8.52 (2H, dd, J 10.0 and 9.6, H-5,7), 8.56 (2H, s, H-phenyl), 8.69 (1H, dd, J 10.0 and 9.6, H-6), 8.99 (1H,
d, J 9.6, H-8), and 9.00 (1H, d, J 10.0, H-4). Anal. Calcd for C16H11N4O7Br: C, 42.52; H, 2.46; N, 12.42.
Found: C, 42.41; H, 2.55; N, 12.23.
Picrate of 2c: Yellow needles (from EtOH), mp 210-212 ℃ (decomp); δH(DMSO-d6) 2.51 (3H, s, CH3),
2.77 (3H, s, CH3), 8.36 (1H, dd, J 10.0 and 9.6, H-5), 8.38 (1H, dd, J 10.0 and 9.6, H-7), 8.55 (2H, s, H-
phenyl), 8.56 (1H, dd, J 10.0 and 9.6, H-6), 8.94 (1H, d, J 9.6, H-8), and 9.15 (1H, d, J 10.0, H-4). Anal.
Calcd for C17H14N4O7: C, 52.85; H, 3.65; N, 14.50. Found: C, 52.67; H, 3.80; N, 14.42.
Synthesis of 3-methyl-1-azaazulen-2(1H)-one
Under argon atmosphere, a mixture of 2-iodo-1-azaazulen-2(1H)-one (5) (1.380 g, 5.09 mmol),
PdCl2(dppf) (0.030 g, 0.05 mmol), and 1 M ZnMe2 in heptane (7.50 mL, 7.50 mmol) in 1,4-dioxane (30
mL) was heated for 2 h at 110 ℃ in a sealed tube. To the mixture water was added, and the mixture
was extracted with CHCl3. The extract was dried over Na2SO4, and evaporation of the extract gave
yellow crystals (0.713 g) which is a (10 : 1) mixture of 3-methyl-1-azaazulen-2(1H)-one (6) and 3-1-
1
azaazulen-2(1H)-one (7) by H NMR spectra. Chromatography of the mixture with EtOAc-CHCl3 (1 :
1) gave 6 (0.620 g, 77%) and 7 (0.070 g, 9%).
6: Yellow needles (from AcOEt-CH2Cl2), mp 218-220 ℃ (lit.,6 mp 220 ℃); δH 2.17 (3H, s, CH3), 6.83
(1H, dd, J 10.7 and 8.9, H-7), 7.54 (1H, dd, J 10.7 and 9.2, H-6), 7.54 (1H, dd, J 11.0 and 9.2, H-5), 7.09,
(1H, d, J 8.9, H-8), 7.40 (1H, d, J 11.0, H-4), and 11,93 (1H, s, NH); δC 7.8, 112.7, 113.4, 126.9, 128.5,
130.1, 130.9, 140.9, 144.2, and 172.1; νmax / cm-1 1681 (C=O). Anal. Calcd for C10H9NO: C, 75.45; H,
5.70; N, 8.80. Found: C, 75.41; H, 5.75; N, 8.76.

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Synthesis of 2-bromo-3-methyl-1-azaazulene
A mixture of 5 (0.438 g, 2.75 mmol) and POBr3 (1.20 g, 4.18 mmol) was heated at 110 ℃ for 1 h. To
the mixture water was added, and the mixture mixture was neutralized with NaHCO3, then extracted with
CHCl3. The extract was dried over Na2SO4, and the extract was evaporated. Chromatography of the
residue with EtOAc-hexane (1 : 5) gave 1c (0.593 g, 97%).
1c: Yellow needles (from hexane-CH2Cl2), mp 104-106 ℃; δH 2.53, 7.65 (1H, dd, J 10.0 and 9.8, H-5),
7.72 (1H, dd, J 10.0 and 9.6, H-7), 7.88 (1H, dd, J 10.0 and 9.8, H-6), 8.34 (1H, d, J 10.0, H-4), and 8.58
(1H, d, J 9.6, H-8); δC 10.4, 121.9, 128.6, 129.6, 132.9, 135.0, 137.9, 142.9, 149.5, and 156.0; νmax / cm-1
2844 (CH3), 731 (C-Br); λmax nm (log ε) 281 (4.67), 295 (4.37, sh), 319 (3.59), 331 (3.67), 346 (3.62),
361 (3.26), 398 (2.59), 420 (2.68), 493 (3.10), 515 (3.05, sh), and 555 (2.68, sh). Anal. Calcd for
C10H8NBr: C, 54.08; H, 3.63; N, 6.31. Found: C, 54.34; H, 3.55; N, 6.28.
Synthesis of 2-bromo-3-formyl-1-azaazulene
A mixture of 2-formyl-1-azaazulen-2(1H)-one (0.104 g, 0.60 mmol) and POBr3 (0.57 g, 1.98 mmol) was
heated at 110 ℃ for 1 h. To the mixture water was added, and the mixture was neutralized with
NaHCO3, then extracted with CHCl3. The extract was dried over Na2SO4, and the extract was
evaporated. Chromatography of the residue with CHCl3 gave 1d (0.123 g, 87%).
1d: Yellow powders (from hexane-CH2Cl2), mp 166-167 ℃; δH 8.09 (1H, ddd, J 10.0, 9.6 and 0.8, H-5),
8.10 (1H, ddt, J 10.0, 9.8, and 0.8, H-7), 8.20 (1H, ddt, J 10.0, 9.6 and 1.0, H-6), 8.81 (1H, dd, J 9.8 and
1.0,, H-8), 9.79 (1H, dd, J 10.0 and 1.0, H-4), and 10.33 (1H, s, CHO); δC 120.1, 133.4, 135.5, 137.1,
138.5, 141.1, 145.3, 153.1, 159.3, and 187.3; νmax / cm-1 1651 (C=O); λmax nm (log ε) 280 (4.21, sh), 299
(4.58), 330 (3.95), 358 (3.68), 437 (2.96, sh), 448 (2.97), and 481 (2.71, sh). Anal. Calcd for C10H8NBr:
C, 54.08; H, 3.63; N, 6.31. Found: C, 54.23; H, 3.61; N, 6.28.
Reaction of 2-methyl-1-azaazulene with NBS
A mixture of 2-methyl-1-azaazulene (2a), prepared from the picrate of 2a (0.051 g, 0.14 mmol) by
passing through alumina column, NBS (0.037 g, 0.21 mmol) and benzoyl peroxide (0.002 g) in CCl4
(10.0 mL) was stirred for 10 min at 0 ℃, then stirred for 2 h at rt. The mixture was evaporated and the
residue was chromatographed with EtOAc to give a yellow solution of 2b. The solution was
concentrated in vacuo at rt. Addition of saturated picric acid solution in EtOH (1.0 mL) to the
concentrated solution of 2b gave a picrate of 2b (0.0322 g, 52%).
Synthesis of 2-styryl-1-azaazulene from 2-methyl-1-azaazulene

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333
A mixture of 2-methyl-1-azaazulene (2a), prepared from the picrate of 2a (0.0584 g, 0.15 mmol) by
passing through alumina column, t-BuOK (0.0462 g, 0.41 mmol), 18-crown-6 (0.0967 g, 0.36 mmol),
and benzaldehyde (0.15 mL, 0,15 mmol) in Et2O (5.0 mL) was stirred for 5 min at rt. To the mixture
water was added, and the mixture was extracted with Et2O. The extract was dried over Na2SO4, and
evaporated. Chromatography of the residue with EtOAc gave 2-stylyl-1-azaazulene (0.0219 g, 64%).
3a: Red needles (from hexane-CH2Cl2), mp 139-140 ℃ (lit.,13 mp 139-140 ℃); δH 7.33 (1H, t, J 7.6, H-
p-phenyl), 7.41 (2H, dd, J 7.6 and 7.2, H-m-phenyl), 7.49 (1H, s, H-3), 7.54 (1H, d, J 16.2 Hz, trans-
CH=CH), 7.54-7.58 (1H, m, H-5), 7.67 (2H, d, J 7.2, H-o-phenyl), 7.70-7.74 (2H, m, H-6 and 7), 7.90
(1H, d, J 16.2, trans-CH=CH), 8.42 (1H, d, J 9.6, H-4), and 8.56 (1H, d, J 10.4, H-8); δC 112.8, 123.5,
127.4, 128.7, 128.8, 128.9, 130.0, 134.1, 134.5, 136.2, 136.4, 136.8, 147.7, 159.0, and 166.1; νmax / cm-1
971 (trans-CH=CH). Anal. Calcd for C17H13N: C, 88.28; H, 5.67; N, 6.06. Found: C, 88.30; H, 5.72;
N, 5.98.
Synthesis of 2-styryl-1-azaazulenes from 2-bromo-1-azaazulenes with trans-2-phenylvinylboronic
acid
Under argon atmosphere, a mixture of 2-bromo-1-azaazulene (1b) (0.108 g, 0.52 mmol), PdCl2(PPh3)2
(0.007 g, 0.02 mmol), trans-2-phenylvinylboronic acid (0.112 g, 0.75 mmol), K2CO3 (0.139 g, 1.10
mmol) in toluene (10 mL) was heated for 5 h at 110 ℃ in a sealed tube. To the mixture water was
added, and the mixture was extracted with CHCl3. The extract was dried over Na2SO4, and evaporated.
Chromatography of the residue with CHCl3 gave 2-strlyl-1-azaazulene (3a) (0.085 g, 71%).
In a similar manner, we obtained 3b (88%), 3c (64% along with 31% of 1c), and 3d (95% ).
3b: Red needles (from hexane-CH2Cl2), mp 140-141 ℃; δH 7.36 (1H, t, J 7.2, H-p-phenyl), 7.43 (2H, dd,
J 7.4 and 7.2, H-m-phenyl), 7.60 (1H, d, J 16.0, trans-CH=CH), 7.69 (1H, t, J 10.0, H-5), 7.73 (2H, d, J
7.4, H-o-phenyl), 7.70-7.80 (2H, m, H-6 and 7), 8.20 (1H, d, J 16.0, trans-CH=CH); 8.40 (1H, d, J 10.0,
H-4), and 8.55 (1H, d, J 9.2, H-8); δC 102.9, 120.0, 127.8, 128.9, 129.2, 129.4, 130.5, 133.4, 135.3, 136.6,
137.3, 137.8, 143.9, 157.6, and 161.6; νmax / cm-1 961 (trans-CH=CH); λmax nm (log ε) 258 (4.13), 273
(4.15), 301 (4.40), 308 (4.43, sh), 338 (4.33, sh), 347 (4.50), 382 (4.23, sh), 396 (4.33), 418 (4.28), 515
(3.53, sh), 531 (3.56), and 570 (3.29, sh). Anal. Calcd for C17H12NBr: C, 65.83; H, 3.90; N, 4.52.
Found: C, 65.75; H, 3.82; N, 4.73.
3c: Red micro needles, mp 128-129 ℃; δH 2.56 (3H, s, CH3), 7.30 (1H, t, J 7.4, H-p-phenyl), 7.36 (2H,
dd, J 7.4 and 7.2, H-m-phenyl), 7.44 (1H, dd, J 10.4 and 9.6, H-5), 7.51 (1H, d, J 16.0, trans-CH=CH),
7.68 (2H, d, J 7.4, H-o-phenyl), 7.65-7.75 (2H, m, H-6 and 7), 8.10 (1H, d, J 16.0, trans-CH=CH); 8.25

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(1H, d, J 9.6, H-4), and 8.55 (1H, d, J 10.0, H-8); δC 9.3, 120.7, 121.3, 127.4, 127.5, 128.6, 128.8, 129.3,
131.9, 134.0, 135.8, 136.0, 137.2, 144.9, 158.2, and 163.1; νmax / cm-1 (neat) 975 (trans-CH=CH); λmax nm
(log ε) 274 (3.91, sh), 300 (4.01), 355 (4.33), 388 (3.92, sh), 475 (3.83, sh), 497 (3.93), and 525 (3.73, sh).
Anal. Calcd for C18H15N: C, 88.13; H, 6.16; N, 5.71. Found: C, 88.25; H, 6.22; N, 5.60.
3d: Brownish orange plates (from hexane-AcOEt), mp 134-135 ℃; δH 7.39 (1H, dd, J 7.8 and 1.4, H-p-
phenyl), 7.45 (2H, dd, J 7.8 and 7.1, H-m-phenyl), 7.75 (2H, dd, J 7.1 and 1.4 H-o-phenyl), 7.90-8.01,
(3H, m, H-5, 6, and 7), 7.97 (1H, d, J 15.8, trans-CH=CH), 8.27 (1H, d, J 15.8, trans-CH=CH), 8.71 (1H,
dm, J 10.4, H-8), 9.51 (1H, dd, J 10.0 and 2.0, H-4), and 10.71 (1H, s, CHO); δC 118.9, 119.7, 127.9,
128.9, 129.5, 133.9, 134.1, 135.8, 136.1, 137.0, 138.8, 139.9, 147.3, 160.9, 168.0, and 185.5; νmax / cm-1
1655 (C=O) and 1638 (trans-PhCH=HCAz) and 983 (trans-CH=CH); λmax nm (log ε) 283 (4.31, sh), 293
(4.33, sh), 329 (4.49), 391 (4.31, sh), 405 (4.33), 455 (3.85, sh), 472 (3.90), and 522 (2.70, sh). Anal.
Calcd for C18H13NO: C, 83.37; H, 5.05; N, 5.40. Found: C, 83.32; H, 4.98; N, 5.57.
Synthesis of 2-formyl-1-azaazulenes
General Procedure: To a mixture of 2-styryl-1-azaazulenes and OsO4 (1-2% by weight) in aq dioxane
(dioxane : H2O = 7 : 3), an aliquot of KIO4 (2-4 molar equivalents) was added for 30 min at rt under
stirring. After stirring for 4 h, the mixture was filtered through a pad of celite. The celite was washed
with water and CHCl3. Combined filtrate was extracted with CHCl3. The extract was dried over
Na2SO4, and evaporated. Chromatography of the residue with EtOAc gave 2-formyl-1-azaazulenes.
2-Formyl-1-azaazulene (4a). 2-Styryl-1-azaazulene (3a) (0.1035 g, 0.447 mmol)) was treated
according to the general procedure to give 4a (0.020g, 28%) as red purple powders (from hexane-CH2Cl2),
mp 96-101 ℃; δH 7.78 (1H, dd, J 10.0 and 9.6, H-5), 7.92 (1H, t, J 10.0, H-7), 7.92 (1H, s, H-3), 8.10
(1H, t, J 10.0, H-6), 8.83 (1H, d, J 9.6, H-4), 8.95 (1H, d, J 10.0, H-8), and 10.54 (1H, s, CHO); δC 114.3,
129.6, 130.4, 141.2, 141.3, 141.5, 147.2, 157.9, 160.6, and 191.0; νmax / cm-1 1690 (C=O); m/z 157 (M+).
2,4-DNP of 4a: brown powders (from hexane-CH2Cl2), mp 244-246 ℃. Anal. Calcd for C16H11N5O4: C,
56.98; H, 3.29; N, 20.76. Found: C, 56.84; H, 2.46; N, 20.99.
3-Bromo-2-formyl-1-azaazulene (4b). 3-Bromo-2-styryl-1-azaazulene (3b) (0.0544 g, 0.16 mmol)
was treated according to the general procedure for 9 h to give 3b (0.010 g, 37%) and 4b (0.0189 g, 46%)
as red needles (from hexane-CH2Cl2), mp 111-112 ℃; δH 7.89 (1H, t, J 10.0, H-5), 7.95 (1H, t, J 10.0, H-
7), 8.16 (1H, t, J 10.0, H-6), 8.85 (1H, dd J 10.0, H-4), 8.92 (1H, d, J 10.0, H-8), and 10.60 (1H, s, CHO);
δC 103.7, 130.0, 131.0, 140.3, 142.6, 142.9, 144.7, 154.1, 156.7, and 189.0; νmax / cm-1 1693 (C=O); λmax
nm (log ε) 290 (4.55), 296 (4.54, sh), 330 (3.84), 346 (3.84), 369 (3.21, sh), 458 (2.74, sh), 518 (2.93, sh),
553, (2.95), and 600 (2.72, sh). Anal. Calcd for C10H6NOBr: C, 50.88; H, 2.56; N, 5.93. Found: C,

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50.74; H, 2.66; N, 5.83.
2-Formyl-3-methyl-1-azaazulene (4c). 3-Methyl-2-styryl-1-azaazulene (3c) (0.0519 g, 0.21 mmol)
was treated according to the general procedure to give 3c (0.176 g, 34%) and 4c (0.0105 g, 29%) as
purple needles (from hexane-CH2Cl2), mp 101-106 ℃; δH 2.84 (3H, s, CH3), 7.72 (1H, dd, J 10.0 and 9.6,
H-5), 7.80 (1H, dd, J 10.0 and 9.6, H-7), 8.03 (1H, t, J 10.0, H-6), 8.68 (1H, d, J 9.6, H-4), 8.83 (1H, d, J
9.6, H-8), and 10.66 (1H, s, CHO); δC 9.7, 125.4, 128.1, 129.6, 138.7, 140.8, 141.5, 145.8, 156.3, 157.0
and 192.5; νmax / cm-1 1688 (C=O); λmax nm (log ε) 265 (4.12, sh), 280 (4.23), 304 (3.97, sh), 347 (3.96),
363 (3.98), 379 (3.85, sh), 468 (2.95), 526 (2.88, sh), and 586 (2.63, sh).
2,3-Diformyl-1-azaazulene (4d). 3-Formyl-2-styryl-1-azaazulene (3d) (0.1549 g, 0.60 mmol) was
treated according to the general procedure for 6 h to give 4d (93.2mg, 84%) as red needles (from hexane-
AcOEt), mp 144-145 ℃; δH 8.13 (1H, t, J 10.0, H-5), 8.15 (1H, t, J 10.0, H-7), 8.31 (1H, t, J 10 and, H-
6), 9.08 (1H, d, J 9.6, H-8), 10.0 (1H, d, J 10.0, H-4), 10,65 (1H, s, CHO), and 10.97 (1H, s, CHO); δC
122.6, 133.6, 134.9, 143.1, 143.7, 143.8, 146.0, 159.2, 161.1, 188.6, and 192.0; νmax / cm-1 1690 and 1653
(C=O); λmax nm (log ε) 278 (4.36, sh), 294 (4.52), 335 (3.98), 351 (3.74, sh), 466 (3.00, sh), 494 (3.90),
and 525 (2.90, sh). Anal. Calcd for C11H7NO2: C, 71.35; H, 3.81; N, 7.56. Found: C, 71.42; H, 3.88; N,
7.43.
Synthesis of 3-phenyl-8-styryl-1-azaazulene from 8-bromo-3-phenyl-1-azaazulene with trans-2-
phenylvinylboronic acid
Under argon atmosphere, a mixture of 8-bromo-3-phenyl-1-azaazulene (8) (0.284 g, 1.00 mmol),
PdCl2(PPh3)2 (0.007 g, 0.02 mmol), trans-2-phenylvinylboronic acid (0.222 g, 1.50 mmol), K2CO3 (0.189
g, 1.50 mmol) in toluene (10 mL) was heated for 8 h at 40 ℃ in a sealed tube. To the mixture water
was added, and the mixture was extracted with CHCl3. The extract was dried over Na2SO4, and
evaporated. Chromatography of the residue with CHCl3 gave 3-phenyl-8-stylyl-1-azaazulene (9) (0.204
g, 66%).
9: Purple oil; δH 7.34-7.45 (3H, m, H-m,p-phenyl)), 7.46 (1H, t, J 10.0, H-5), 7.49-7.54 (3H, m, H-m,p-
phenyl), 7.59-7.62 (2H, m, H-o-phenyl), 7.60 (1H, d, J 16.4, trans-CH=CH), 7.77 (2H, d, J 7.2,H-o-
phenyl)), 7.84 (1H, t, J 10.0, H-6), 8.18 (1H, d, J 10.0, H-7), 8.63 (1H, d, J 10.0, H-4), 8.82 (1H, s, H-2),
and 8.98 (1H, d, J 16.4, trans-CH=CH); δC 125.9, 127.0, 127.2, 127.8, 127.9, 128.8, 129.0, 129.1, 129.5,
129.7, 134.6, 134.9, 136.2, 136.9, 137.1, 141.4, 144.5, 154.3, and 155.0; νmax / cm-1 (neat) 969 (trans-
CH=CH). Anal. Calcd for C23H17N: C, 89.87; H, 5.57; N, 4.56. Found: C, 89.77; H, 5.59; N, 4.46.
Reaction of 2-chloro-1-azaazulene with 2-lithio-1,3-dithiane
Under argon atmosphere, 1.5 M butyl lithium (3.40 mL, 5.50 mmol) was added to the solution of 1,3-

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dithiane (0.656 g, 5.50 mmol) in dry THF (30 mL) at –80 ℃, then the mixture was stirred for 1 h. To
the mixture 2-chloro-1-azaazulene (11a) (0.600 g, 3.65 mmol) in dry THF (30 mL) was added at –80 ℃,
and temperature was raised to –20 ℃ under stirring for 1.5 h, then MeOH (2 mL) was added. After the
mixture was warm to rt, tetrachloro-p-benzoquinone (1.300 g, 5.50 mmol) was added to the mixture and
the mixture was stirred for 24 h. To the mixture was added water, and the mixture was extracted with
CHCl3, then the extract was dried over Na2SO4, and evaporated. The residue was chromatographed on
silica gel column with CHCl3 to give 2-chloro-8-(1,3-dithian-2-yl)-1-azaazulene (12a) (0.892 g, 86%).
In a similar manner, 12b and 12c were obtained in 98% and 68% yield, respectively.
12a: Orange needles (from hexane-CH2Cl2), mp 169-170 ℃; δH 2,07 (1H, dtt, J 14.2, 12.6, and 3.6, ax-
CHCH2S), 2.30 (1H, dtt, J 14.2, 2.4, and 2.4, eq-CHCH2S), 2.99 (2H, ddd, J 14.4, 3.6, and 2.0, SCH2),
3.36 (2H, ddd, J 14.8, 12.6, and 2.4, SCH2), 7.01 (1H, s, SCHS), 7.31 (1H, s, H-3), 7.63, (1H, t, J 9.6, H-
5), 7.91, (1H, dd, J 10.8 and 9.6, H-6), 8.25 (1H, d, J 10.8, H-4), and 8.42 (1H, d, J 9.6, H-7); δC 25.2,
31.9, 48.5, 113.7, 129.8, 131.3, 137.7, 145.6, 147.1, 152.3, and 156.6; m/z (rel intensity) 283 (M+, 12),
281 (M+, 76), 209 (45), 207 (100), 177 (26), 163 (26), 128 (25), and 106 (33); λmax nm (log ε) 275 (4.52),
294 (4.27, sh), 327 (3.73), 340 (3.67), 448, (3.03, sh), 471 (3.16), and 520 (2.83, sh). Anal. Calcd for
C13H12NClS2: C, 55.40; H, 4.29; N, 4.97. Found: C, 55.63; H, 4.35; N, 4.84.
12b: Red powders (from hexane-CH2Cl2), mp 190 ℃ (decomp); δH 2,06 (1H, dtt, J 14.8, 3.6, and 2.0,
eq- CHCH2S), 2.29 (1H, dtt, J 14.4, 12.4, and 2.0, ax-CHCH2S), 2.97 (2H, ddd, J 14.4, 3.6, and 2.4,
SCH2), 3.32 (2H, ddd, J 14.8, 12.4, and 2.4, SCH2), 7.03 (1H, s, SCHS), 7.72, (1H, dd, J 10.4 and 9.6, H-
5), 7.96, (1H, t, J 9.6, H-6), 8.27 (1H, d, J 10.4, H-4), and 8.41 (1H, d, J 9.6, H-7); δC 25.2, 31.9, 47.9,
101.4, 130.2, 131.9, 134.8, 138.9, 143.1, 146.8, 151.1, and 155.5; λmax nm (log ε) 288 (4.55), 298 (4.50,
sh), 335 (3.72), 350 (3.61, sh), 365 (3.42, sh), 495, (3.12), 507 (3.11, sh), and 552 (2.79, sh). Anal.
Calcd for C13H11NBrClS2: C, 43.29; H, 3.07; N, 3.88. Found: C, 43.33; H, 3.01; N, 3.92.
12c: Yellow powders (from hexane-CH2Cl2), mp 171-172 ℃; δH 1.48 (3H, t, J 7.2, CH3), 2,04 (1H, dtt, J
13.4, 3.6, and 2.0, eq-CHCH2S), 2.28 (1H, dtt, J 14.4, 12.4, and 2.0, ax- CHCH2S), 2.97 (2H, ddd, J 14.4,
3.6, and 2.0, SCH2), 3.31 (2H, ddd, J 13.4, 12.4, and 2.0, SCH2), 7.05 (1H, s, SCHS), 7.89, (1H, t, J 10.0,
H-5), 8.05, (1H, dd, J 10.8 and 10.0, H-6), 8.41 (1H, d, J 10.8, H-7), and 9.58 (1H, d, J 10.0, H-4); δC
14.4, 25.1, 32.0, 48.5, 60.7, 113.0, 133.1, 134.1, 137.1, 139.5, 147.0, 147.9, 153.4, 158.1, and 163.3; λmax
nm (log ε) 288 (4.48, sh), 295 (4.55), 316 (4.16), 335 (3.94, sh), 353 (3.79, sh), 488, (3.14, sh), 497 (3.03),
and 520 (3.03, sh). Anal. Calcd for C16H16NO2ClS2: C, 54.34; H, 4.56; N, 3.96. Found: C, 54.44; H,
4.51; N, 4.06.

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Synthesis of 2-chloro-8-formyl-1-azaazulenes (13) by hydrolysis of 12
a) Hydrolysis using chloramine-T. To the mixed solution (90 mL) of EtOH : 85% aq CH3OH (1 : 2) of
2-chloro-8-(1,3-dithian-2-yl)-1-azaazulene (12a) was added chloramine-T (0.704 g, 2.50 mmol) in 85%
aq CH3OH (20 mL), and the mixture was stirred for 1 h at rt. To the mixture, 2M NaOH solution (20
mL), and the mixture was extracted with CHCl3. The extract was dried over Na2SO4, and evaporated.
The residue was chromatographed with CHCl3 gave 13a (0.034 g, 12%).
b) General method of hydrolysis using NBS. A mixture of 12b (0.120 g, 0.30 mmol), NBS (0.012 g,
0.07 mmol), and DMSO (0.12 mL, 1.65 mmol) in CHCl3 (15 mL) was stirred for 26 h at rt, then poured
into water (30 mL). The mixture was extracted with CHCl3, and the extract was dried over Na2SO4, and
evaporated. The residue was chromatographed with CHCl3 gave 13b (0.052 g, 58%).
c) Hydrolysis using NCS. A mixture of 12a (0.142 g, 0.50 mmol), NCS (0.013 g, 0.10 mmol), and
DMSO (0.18 mL, 2.50 mmol) in CHCl3 (15 mL) was stirred for 26 h at rt, then poured into water (30
mL). The mixture was extracted with CHCl3, and the extract was dried over Na2SO4, and evaporated.
The residue was chromatographed with CHCl3 gave 13a (0.028 g, 25%).
d) General method using CH3I. To the solution of 12b was added MeI (4.8 mL, 76 mmol) in Me2CO-
H2O (100 : 0.05, 12.6 mL), and the mixture was stirred for 48 h at 30 ℃, then poured into water (30 mL).
The mixture was extracted with CHCl3, and the extract was dried over Na2SO4, and evaporated. The
residue was chlromatographed with CHCl3 gave 13b (0.135 g, 50%) and 12b (0.168 g, 47%).
13a: Orange needles (from hexane-CH2Cl2), mp 100-105 ℃ (decomp); δH 7.35 (1H, s, H-3), 7.82 (1H,
dd, J 9.8 and 9.7, H-5), 8.04 (1H, dd, J 10.0 and 9.7, H-6), 8.34 (1H, d, J 9.8, H-4), 8.55 (1H, d, J 10.0,
H-7), and 11.65 (1H, s, CHO); νmax / cm-1 1695 (C=O).
13b: Orange needles (from hexane-CH2Cl2), mp 190-193 ℃ (decomp); δH 7.91 (1H, dd, J 10.0 and 9.6,
H-5), 8.10 (1H, t, J 10.0, H-6), 8.36 (1H, d, J 9.6, H-4), 8.52 (1H, d, J 10.0, H-7), and 11.63 (1H, s,
CHO); δC 110.0, 127.5, 128.8, 132.3, 134.9, 136.9, 138.7, 145.8, 159.2, and 193.0; νmax / cm-1 1690
(C=O); λmax nm (log ε) 255 (4.12, sh), 290 (4.44, sh), 296 (4.49), 318 (4.17), 343 (3.89, sh), 374 (3.25,
sh), 539 (3.18), 546, (3.17, sh), and 605 (2.87, sh). Anal. Calcd for C10H5NOBrCl: C, 44.40; H, 1.86; N,
5.18. Found: C, 44.51; H, 2.12; N, 5.06.
13c: Orange needles (from hexane-CH2Cl2), mp 105-109 ℃ (decomp); δH 1.51, (3H, t, J 7.2, CH3), 4.53
(2H, q, J 7.2, OCH2), 8.11 (1H, dd, J 10.4 and 9.6, H-5), 8.21 (1H, dd, J 10.0 and 9.6, H-6), 8.51 (1H, d, J
10.0, H-7), 9.69 (1H, d, J 10.4, H-4), and 11.63 (1H, s, CHO); δC 14.4, 61.0, 112.1, 130.3, 135.0, 135.5,
137.6, 139.3, 156.6, 161.0, 163.0, and 193.2; νmax / cm-1 1697 (C=O); λmax nm (log ε) 288 (4.48, sh), 295
(4.55), 316 (4.16), 335 (3.94, sh), 353 (3.79, sh), 488, (3.14, sh), 497 (3.15), and 520 (3.03, sh). Anal.
Calcd for C13H10NO3Cl: C, 59.22; H, 3.82; N, 5.31. Found: C, 59.28; H, 3.98; N, 5.22.

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