Asymmetric synthesis and characterization of chiral 2,2′-diamino-3, 3′-diethoxycarbonyl-8,8′-diphenyl-1,1′-biazulene

Article abstract of DOI:10.1080/00397910701473374

rac-2,2′-Diamino-3,3′-diethoxycarbonyl-8,8′-diphenyl-1, 1′-biazulene was synthesized from diethyl 2-aminoazulene-1,3-dicarboxylate and was optically resolved into two enantiomers of S-form and R-form. The enantioselective oxidative couplings with two chir

Full text of DOI:10.1080/00397910701473374

Synthetic Communicationsw, 37: 2975–2987, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701473374
Asymmetric Synthesis and Characterization
of Chiral 2,20-Diamino-3,30-
diethoxycarbonyl-8,80-diphenyl-1,10-
biazulene
Arh-Hwang Chen, Hsiu-Hang Yen, Yu-Chen Kuo,
and Wen-Zhang Chen
Department of Chemical and Materials Engineering, Southern Taiwan
University of Technology, Tainan, Taiwan, R.O.C.
Abstract: rac-2,20-Diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene was
synthesized from diethyl 2-aminoazulene-1,3-dicarboxylate and was optically resolved
into two enantiomers of S-form and R-form. The enantioselective oxidative couplings
with two chiral amines [(2)-sparteine and (R)-(þ)-a-methylbenzylamine] and ferric
chloride catalyst, and the asymmetric couplings with two chiral oxovanadium(IV)
complexes of ethyl 2-amino-4-phenylazulene-1-carboxylate, easily yielded chiral 2,20-
diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene. Therefore, the introduction
of two phenyl groups at the 8- and 80-postions of each azulene ring using phenyl
magnesium bromide via an addition–oxidation–decarboxylation mechanism resulted
in 1,10-biazulene forming a chiral C2 axis.
Keywords: asymmetric couplings with chiral oxovanadium(IV) complexes, CD, chiral
1,10-biazulene, enantioselective oxidative couplings
INTRODUCTION
Although azulenoids were found to be a class of nonbenzenoid hydrocarbons
in essential oils more than a century ago, they are still the subject of much
study in the field of organic chemistry. The study of azulenoid chemistry, in
Received in Japan December 27, 2006
Address correspondence to Arh-Hwang Chen, Department of Chemical and
Materials Engineering, Southern Taiwan University of Technology, YungKang City-
Tainan Hsien 710, Taiwan, R.O.C. E-mail: chenah@ms12.hinet.net
2975

2976
A.-H. Chen et al.
particular, has received great interest because of its many important
applications such as in dyestuffs, liquid crystals, and the medical treatment
of inflammation and hypertension.[1] Azuloquinones have antibacterial, anti-
fungal, and antitumor properties, and they likewise play important roles
photosynthesis, the respiratory electron-transport chain, and solid-state elec-
troconductivity.[2] Recently, Tajiri et al. reported that rac-2,20-dimethyl-1,10-
biazulene could be resolved into R(2) and S(þ) forms with the aid of
high-performance liquid chromatography (HPLC) using a (þ)-polytriphenyl-
methyl methacrylate column, but rac-2,20-dimethoxy-1,10-biazulene could
not be resolved.[3] We have found that 3,30-diethylcarbonyl-2,20-dihydroxy-
1,10-biazulene was not resolved using HPLC with a Chiralcel OD column,
but the chemical shift of both 2- and 20-hydroxy protons shifted the down
field of 0.43 ppm from 300 K to 210 K in a low-temperate 1HNMR.[4] To inves-
tigate the chirality of biazulenoids, in this article we discuss the asymmetric
synthesis and characterization of chiral 2,20-diamino-3,30-diethoxycarbonyl-
8,80-diphenyl-1,10-biazulene through the introduction of two phenyl groups
at the 8- and 80-postions of each azulene ring.
RESULTS AND DISCUSSION
To protect the amino group of diethyl 2-aminoazulene-1,3-dicarboxylate (1)
reacted with phenyl magnesium bromide, it was acetylated with acetic
anhydride in the presence of pyridine to give diethyl 2-acetamidoazulene-
1,3-dicarboxylate (2) in a yield of 72%. Diethyl 2-acetamidoazulene-
1,3-dicarboxylate (2) was reacted with phenyl magnesium bromide,
oxidized with o-chloranil, and then heated at 1408C for 30 min to yield
ethyl 2-acetamido-4-phenylazulene-1-carboxylate (3) (20%), diethyl 2-
acetamido-4-phenylazulene-1,3-dicarboxylate (4) (22%),[4c,5] and diethyl
2-aminolazulene-1,3-dicarboxylate (1) (25%) (Scheme 1). After reaction of
diethyl 2-acetamidoazulene-1,3-dicarboxylate (2) with phenyl magnesium
bromide and oxidization with o-chloranil, the reaction mixture was found to
have diethyl 2-acetamido-4-phenylazulene-1,3-dicarboxylate (4), but no
ethyl 2-acetamido-4-phenylazulene-1-carboxylate (3). Diethyl 2-acetamido-
4-phenylazulene-1,3-dicarboxylate (4), however, might be followed with
the intramolecular Friedel–Crafts cyclization to form 7H-naphth[3,2,1-
cd]azulen-7-one derivative by heating in the acidic media.[6a] The formation
of ethyl 2-acetamido-4-phenylazulene-1-carboxylate (3) might be attributed
to the addition of diethyl 2-acetamidoazulene-1,3-dicarboxylate (2) with
phenyl magnesium bromide, and the protonation produced a 4-phenyl-3,4-
dihydroazulene intermediate; then the intermediate followed oxidation and
decarboxylation at the 3-ethoxycarbonyl group, which was more crowded
with a 4-phenyl group than the 1-ethoxycarbonyl group.[6b] The structure of
ethyl 2-acetamido-4-phenylazulene-1-carboxylate (3) was determined using
spin decoupling and nuclear Overhauser effect difference spectrometry.

2,20-Diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene
2977
Scheme 1.
Ethyl 2-acetamido-4-phenylazulene-1-carboxylate (3) was deacetylated with
treatment of sulfuric acid in ethanol to give ethyl 2-amino-4-phenylazulene-
1-carboxylate (5) in a yield of 91%. Finally, several mild oxidants such as
Fe3þ, Cu2þ, Cuþ, and Sn4þ salts and cerium ammonium nitrate (CAN)
Table 1. NOE enhancement (%) of ethyl 2-acetamido-4-phenylazulene-1-carboxylate (3)
Chemical shift
of irradiation
CO2CH2-CH3 CO2CH2-CH3 4-Pha 5-H, 7-H 6-H 8-H
d 1.5 (CH2-CH3)
d 4.5 (CH2-CH3)
d 7.6 (6-H)
d 7.8 (3-H)
d 9.3 (8-H)
15.8
8.3
4.3
1.6
10.2
1.6
7.7
12.0
4.0
1.2
16.0
6.6
a20,60-H2 of 4-phenyl group.

2978
A.-H. Chen et al.
were tried for investigation of the oxidative self-coupling of ethyl 2-amino-4-
phenylazulene-1-carboxylate (5). However, only the treatment of ferric
chloride in methanol of ethyl 2-amino-4-phenylazulene-1-carboxylate (5)
was easily coupled to afford rac-2,20-diamino-3,30-diethoxycarbonyl-8,80-
diphenyl-1,10-biazulene (6) in a yield of 56%.
Although the racemic mixtures of 1,10-bi-2-naphthol (BINOL) and its
derivatives can be separated into their enantiomers using the precipitate of
an inclusion complex with N-benzylcinchonidium chloride[7] or reaction
with (1S)-(þ)-camphor-10-sulfonyl chloride[8a] or (2)-menthyl chloroforma-
te,[8b] rac-2,20-diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene (6)
could not form the precipitate of an inclusion complex with N-benzylcinchoni-
dium chloride and failed to afford its diastereomers upon treatment with
(1S)-(þ)-camphor-10-sulfonyl chloride or (2)-menthyl chloroformate for the
resolution of its enantiomers. Fortunately, rac-2,20-diamino-3,30-diethoxycarbo-
nyl-8,80-diphenyl-1,10-biazulene (6) was found to be optically resolved into two
enantiomers of S-form ((S)-6) and R-form ((R)-6) with the retention times of
7.30 and 12.10 min, respectively, using HPLC with a chiralcel OD column, a
UV detector at 320 nm, and an eluent of n-hexane/ethanol (v/v ¼ 90/10) on
a flow rate of 1 mL/min (Scheme 2). The specific rotations of S-form ((S)-6)
and R-form ((R)-6) were measured at 589 nm and 258C in the degrees of
þ1.73 ꢀ 103 (c ¼ 0.027 g/100 mL, MeOH) and 21.86 ꢀ 103 (c ¼ 0.030 g/
100 mL, MeOH), respectively. The chiral exciton coupling of circular
dichroism (CD) was used to assign the absolute stereochemistry of biaryl
compounds.[9] The CD spectra of these two fractions, S-form ((S)-6) and
R-form ((R)-6), measured in MeOH at 258C under a nitrogen atmosphere, are
shown in Fig. 1, A and B curves, respectively. In comparison with the CD
spectra of S- and R-forms of rac-2,20-dimethyl-1,10-biazulene,[3] the first
fraction, S-form ((S)-6), had positive chirality with Cotton effects at 341 nm
(D1 þ23.9) and 318 nm (D1 235.4), respectively (A curve in Fig. 1),
whereas the second fraction, R-form ((R)-6), gave negative chirality with
Cotton effects at 342 nm (D1 228.5) and 318 nm (D1 þ42.9) respectively (B
curve in Fig. 1). Therefore, 1,10- biazulene introduced with two phenyl
groups at the 8- and 80-postions of each azulene ring using phenyl
Scheme 2.

2,20-Diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene
2979
Figure 1. CD spectra of S-form ((S)-6) (A curve) and R-form ((R)-6) (B curve) of rac-
2,20-diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene (6) in MeOH at 258C.
magnesium bromide via an addition–oxidation–decarboxylation mechanism
resulted in the formation of a chiral C2 axis.
Because of the unsuccessful resolution of rac- 2,20-diamino-3,30-diethox-
ycarbonyl-8,80-diphenyl-1,10-biazulene (6) by forming the precipitate of
inclusion complex or the diastereomers, it was discovered to be formed
using the enantioselective oxidative coupling of ethyl 2-amino-4-phenylazu-
lene-1-carboxylate (5) with chiral amines and metal sources, with or
without oxygen.[10] To demonstrate further utility, two chiral amines, (2)-
sparteine and (R)-(þ)-a-methylbenzylamine, were used as the ligands. As
shown in Table 2, the FeCl3/two chiral amines–mediated oxidative
couplings in methanol with or without oxygen provided some level of enan-
tioselectivity in this reaction, for example, in the reactions of 1/10/15
molar ratio of substrate (5)/(2)-sparteine/FeCl3 and 1/10/15 molar ratio
of substrate(5)/(þ)-PhCH(NH2)Me/FeCl3 in methanol with oxygen to give
the enantiomeric excess of 13.7% and 14.3%, respectively (entries 2 and 8
in Table 2). However, this reaction with these two chiral amines in two
solvents of acetonitrile and dichloromethane with or without oxygen could
not afford this enantioselective oxidative coupling. At the same time, the
CuCl2, CuCl, and CuI catalysts with these two chiral amines in a series of
solvents (methanol, acetonitrile, dichloromethane, and isopropanol) failed in
the enantioselective oxidative coupling reactions.
Recently, in addition to using the metal complexes of chiral amines for
the enantioselective oxidative couplings of 2-naphthols, the oxovanadium(IV)
complexes of chiral Schiff bases were developed for the asymmetric couplings
of 2-naphthols to optically active 1,10-bi-nahthol (BINOL) and its derivatives,
which have been extensively used as chiral auxiliaries and ligands in
asymmetric synthesis.[11] Two oxovanadium(IV) complexes of chiral Schiff
bases, 7 and 8, prepared from 2-hydrox-1-naphhthaldehyde and L-valine or
L-phenylalanine, respectively, with vanadyl sulfate, were further investigated

2980
A.-H. Chen et al.
Table 2. Enantioselective oxidative couplings of ethyl 2-amino-4-phenylazulene-
1-carboxylate (5) with the FeCl3/chiral amine–mediated oxidants
molar ratio of
substrate (5)/
ligand metal
Reaction
condition
Yield
(%)
Entry
Ligand
ee (%)a
1
2
3
4
5
6
7
8
(2)-sparteine 1:3.75:15
(2)-sparteine 1:10:15
(2)-sparteine 1:3.75:15
(2)-sparteine 1:5:15
(2)-sparteine 1:10:15
CH3OH þ O2
CH3OH þ O2
CH3OH þ N2
CH3OH þ N2
CH3OH þ N2
CH3OH þ O2
CH3OH þ O2
CH3OH þ O2
33
21
27
55
12
38
15
19
12.6
13.7
2.5
6.6
8.3
(þ)-PhCH(NH2)Me 1:3.75:15
(þ)-PhCH(NH2)Me 1:5:15
(þ)-PhCH(NH2)Me 1:10:15
3.4
9.5
14.3
aThe enantiomeric excess (ee%) determined by chiral HPLC (Chiralcel OD column)
with an eluent of n-hexane/ethanol (90/10, v/v) and calculated with (%R 2 %S/
%R þ %S) ꢀ 100.
for the asymmetric couplings of ethyl 2-amino-4-phenylazulene-1-carboxy-
late (5). As shown in Table 3, these two chiral oxovanadium(IV)
complexes, 7 and 8, produced enantiomeric excess from 9.9% to 17.9%
with chemical yields from 10% to 80% in two solvents of chloroform and
dichloromethane. However, carbon tetrachloride is not a suitable solvent,
despite its wide use as a solvent in the asymmetric coupling of 2-naphthols
by chiral tridenate oxovanadium(IV) complexes.[11] The asymmetric
couplings, using the chiral oxovanadium(IV) complexes, 7 in two solvents
of chloroform and dichloromethane and 8 in a solvent of chloroform,
showed a high recovery of substrate from 47% to 78% by stirring for 6
days at room temperature. The enantiomeric excess of both oxovanadium(IV)
complexes of chiral Schiff bases, 7 and 8, for the asymmetric couplings of
ethyl 2-amino-4-phenylazulene-1-carboxylate (5) in chloroform and dichloro-
methane solvents was different, one R and the other S, respectively.

2,20-Diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene
2981
Table 3. Asymmetric couplings of ethyl 2-amino-4-phenylazulene-1-carboxylate (5)
with chiral oxovanadium(IV) complexes 6 and 7
Molar ratio of
substrate(5)/
catalyst
Yield
(%)
Entry
Catalyst
Solvent
ee (%)a
1
2
7
7
7
7
7
8
8
8
8
8
1:0.5
1:1
CHCl3
CHCl3
CHCl3
CH2Cl2
CH2Cl2
CHCl3
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
43
64
59
14
10
48
80
10
43
20
9.9
14.3
3
1:2
1:1
11.4
4
212.5
211.0
17.9
5
1:2
6
1:0.5
1:1
7
17.9
8
1:0.5
1:1
216.1
215.9
212.2
9
10
1:2
aThe enantiomeric excess (ee%) determined by chiral HPLC (Chiralcel OD column)
with an eluent of n-hexane/ethanol (90/10, v/v) and calculated with (%R 2 %S/
%R þ %S) ꢀ 100.
CONCLUSION
2,20-Diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene (6) was
synthesized from diethyl 2-aminoazulene-1,3-dicarboxylate and was
optically resolved into two enantiomers of S-form ((S)-6) and R-form ((R)-
6). The enantioselective oxidative coupling with two chiral amines, (2)-
sparteine and (R)-(þ)-a-methylbenzylamine, and ferric chloride catalyst,
and the asymmetric couplings with two chiral oxovanadium(IV) complexes,

2982
A.-H. Chen et al.
7 and 8, of ethyl 2-amino-4-phenylazulene-1-carboxylate (5) were shown to
easily produce chiral 2,20-diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-
biazulene, (S)-6 and (R)-6. Therefore, by introducing two phenyl groups at
8- and 80-postions of each azulene ring using phenyl magnesium bromide
via an addition–oxidation–decarboxylation mechanism, 1,10-biazulene
resulted in the formation of a chiral C2 axis. Further studies to address
application of the target as a chiral auxiliary in asymmetric synthesis are
under way.
EXPERIMENTAL
General
The melting points were determined without correction on a Yanagimoto
micromelting-point apparatus. 1H and 13C nuclear magnetic resonance,
(NMR) spectra were measured on a Varian Inova-500 spectrometer. Mass
spectra were determined on a VG Quattro GC/MS/MS DS spectrometer.
Elemental analyses were measured on a Heraeus CHN-O-Rapid Analyzer.
Meanwhile, specific rotations were determined on a Horiba SEPA-300 polari-
meter, and CD spectra were measured on a Jasco J-810 spectropolarimeter.
Lastly, HPLC analyses were performed on a Waters Multisolvent Delivery
System 600E with a Waters Tunable Absorbance Detector 486, equipped
with a SISC chromatography data system.
Synthesis of rea-2,20-diamino-3,30-diethoxycarbonyl-8,80-diphenyl-
1,10-biazulene (6)
Diethyl 2-Acetamidoazulene-1,3-dicarboxylate (2)
A solution of diethyl 2-aminooazulene-1,3-dicarboxylate (1) (27.22 g,
0.094 mol) and acetic anhydride (200 mL) was refluxed in an oil bath at
1408C overnight. The reaction mixture was adjusted with 2N aqueous sodium
hydroxide to pH 5–6 and then was extracted with ethyl acetate. The organic
layer was washed with a saturated sodium bicarbonate solution and a brine
solution and then dried over sodium sulfate. After this, the organic solution
was evaporated to remove the solvent under reduced pressure. The residue
was chromatographed on silica gel and eluted with n-hexane–ethyl acetate (v/
v ¼ 3/1) to give diethyl 2-acetamidoazulene-1,3-dicarboxylate (2) (22.57 g,
1
72%). H NMR (CDCl3, 500 MHz): d 1.38 (t, J ¼ 7.5 Hz, 6H), 2.30 (s, 3H),
4.39 (q, J ¼ 7.5 Hz, 4H), 7.85 (t, J ¼ 10.0 Hz, 2H), 8.06 (t, J ¼ 10.0 Hz, 1H),
9.90 (d, J ¼ 10.0 Hz, 2H), 10.58 (s, 1H); 13C NMR (CDCl3, 125 MHz): 14.32,
26.63, 60.55, 113.21, 130.65, 131.60, 136.06, 137.68, 140.69, 141.42, 141.89,
142.44, 149.03, 163.75, 172.32; MS (EI, m/Z, %): 169 (100.0), 196 (33.7),

2,20-Diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene
2983
287 (35.6), 329 (M, 10.6), 330 (M þ 1, 2.5). Anal. found: C, 65.47%; H, 5.76%;
N, 4.15%; calcd. for C18H19NO5: C, 65.64%; H, 5.81%; N, 4.25%.
Ethyl 2-Acetamido-4-phenylazulene-1-carboxylate (3)
Under a nitrogen atmosphere, a solution of diethyl 2-acetamidoazulene-
1,3-dicarboxylate (2) (1.64 g, 5.00 mmol) in a dry diethyl ether (260 mL) on
an ice bath was added to an ether solution of phenyl magnesium bromide
(25 mL of 1.0 M solution, 25.0 mmol); this was stirred continuously for
10 min on an ice bath and for another 10 min at room temperature. The
reaction mixture was cooled on an ice bath, methanol (20 mL), was added
and it was then stirred for 10 min. The reaction mixture was then poured
into 6N HCl (10 mL) and then extracted with diethyl ether. The extract was
washed with a saturated sodium bicarbonate solution, dried over anhydrous
magnesium sulfate, and then evaporated under reduced pressure to remove
the solvent. The residue was dissolved in dry benzene (20 mL), o-chloranil
(2.54 g, 10.0 mmol) was added, and then it was refluxed in an oil bath
overnight. The reaction mixture was evaporated to remove benzene under
reduced pressure. Then the residue was heated in an oil bath at 1408C for
30 min. The reaction mixture was dissolved in benzene and flowed through
a column of alumina to remove excess o-chloranil. The benzene elution was
evaporated to remove benzene under reduced pressure. The residue was chro-
matographed again on silica gel and eluted with n-hexane–ethyl acetate (v/
v ¼ 5/1) to give ethyl 2-acetamido-4-phenylazulene-1-carboxylate (3)
(327 mg, 20%), diethyl 2-acetamido-4-phenylazulene-1,3-dicarboxylate (4)
(456 mg, 22%), and diethyl 2-aminolazulene-1,3-dicarboxylate (1) (366 mg,
25%). Ethyl 2-acetamido-4-phenylazulene-1-carboxylate (3): 1H NMR
(CDCl3, 500 MHz): 1.54 (t, J ¼ 7.0 Hz, 3H), 2.25 (s, 3H), 4.53
(q, J ¼ 7.0 Hz, 2H), 7.43–7.54 (m, 7H), 7.63 (t, J ¼ 9.5 Hz, 1H), 7.84
(s, 1H), 9.37 (d, J ¼ 9.5 Hz, 1H), 10.92 (s, 1H); 13C NMR (CDCl3,
125 MHz): 14.60, 24.93, 60.38, 102.43, 109.66, 127.72, 128.52, 128.41,
128.98, 131.39, 134.49, 134.88, 140.39, 142.65, 143.33, 149.14, 149.61,
167.47, 168.69; MS (EI, m/Z, %): 189 (100.0), 217 (66.1), 245 (60.9), 272
(72.5), 287 (18.7), 333 (M, 30.0), 334 (M þ 1, 6.7). Anal. found: C, 75.47%;
H, 5.80%; N, 4.15%; calcd. for C21H19NO3: C, 75.66%; H, 5.74%; N, 4.20%.
Ethyl 2-Amino-4-phenylazulene-1-carboxylate (5)
A solution of ethyl 2-acetamido-4-phenylazulene-1-carboxylate (3) (50 mg,
0.15 mmol) and 6N sulfuric acid (2 mL) in ethanol (10 mL) was refluxed for
40 min. Water (10 mL) was added to the reaction mixture and extracted with
ethyl acetate; the mixture was washed with a saturated sodium bicarbonate
solution and a brine solution and then dried over sodium sulfate. The
ethyl acetate solution was evaporated to remove the solvent under reduced
pressure. The residue was chromatographed on silica gel and eluted with

2984
A.-H. Chen et al.
n-hexane–ethyl acetate (v/v ¼ 3/1) to give ethyl 2-amino-4-phenylazulene-1-
carboxylate (5) (40 mg, 91%). 1H NMR (CDCl3, 500 MHz): 1.48
(t, J ¼ 7.0 Hz, 3H), 4.63 (q, J ¼ 7.0 Hz, 2H), 5.40 (br, 2H), 7.22–7.51
(m, 9H), 9.04 (d, J ¼ 9.0 Hz, 1H); 13C NMR (CDCl3, 125 MHz): 14.70, 59.71,
108.62, 127.27, 127.49, 127.73, 128.16, 128.33, 128.47, 128.88, 129.38,
130.18, 130.98, 135.84, 136.30, 143.69, 166.57; MS (EI, m/Z, %): 217 (49.3),
245 (100.0), 291 (M, 86.2), 292 (M þ 1, 18.1). Anal. found: C, 78.02%; H,
5.60%; N, 4.55%; calcd. for C19H17NO2: C, 78.33%; H, 5.88%; N, 4.81%.
Typical Coupling Reaction of Ethyl 2-Amino-4-phenylazulene-
1-carboxylate (5)
A solution of ethyl 2-amino-4-phenylazulene-1-carboxylate (5) (286 mg,
0.96 mmol) and ferric chloride (796 mg, 4.90 mmol) in methanol was
stirred at room temperature overnight. The reaction mixture was evaporated
to remove the solvent under reduced pressure. The residue was extracted
with ethyl acetate, washed with a brine solution, dried over sodium sulfate,
and evaporated to remove the solvent under reduced pressure. The residue
was chromatographed on silica gel and eluted with n-hexane–ethyl
acetate (v/v ¼ 5/1) to give rac-2,20-diamino-3,30-diethoxycarbonyl-8,80-
1
diphenyl-1,10-biazulene (6) (133 mg, 54%). H NMR (CDCl3, 500 MHz):
1.50 (t, J ¼ 7.0 Hz, 6H), 4.49 (q, J ¼ 7.0 Hz, 4H), 4.80 (br, 4H), 6.53–6.60
(m, 8H), 6.86 (d, J ¼ 7.5 Hz, 2H), 6.91 (d, J ¼ 9.0 Hz, 2H), 7.17–7.26
(m, 4H), 8.75 (d, J ¼ 10.5 Hz, 2H); 13C NMR (CDCl3, 125 MHz): 14.83,
59.42, 97.89, 110.55, 125.22, 125.32, 125.89, 126.32, 127.71, 129.83,
133.55, 141.06, 143.27, 144.21, 145.71, 158.07, 166.53; MS (EI, m/Z, %):
411 (60.7), 445 (13.0), 472 (13.8), 506 (10.2), 538 (12.1), 580 (M, 100.0),
582 (M þ 1, 35.5). Anal. found: C, 78.32%; H, 5.70%; N, 4.68%; calcd. for
C38H32N2O4: C, 78.60%; H, 5.55%; N, 4.82%.
Typical Enantioselective Oxidative Couplings of Ethyl 2-Amino-
4-phenylazulene-1-carboxylate (5) with the FeCl3/Chiral
Amine–Mediated Oxidants
Under an oxygen atmosphere, (2)-sparteine (64.2 mg, 0.274 mmol) was added
to a 3-mL methanol solution of ferric chloride (296.4 mg, 1.09 mmol), and the
mixture was stirred for 10 min at room temperature. A 3-mL methanol solution
of ethyl 2-amino-4-phenylazulene-1-carboxylate (5) (21.3 mg, 0.073 mmol)
was added to the mixture. This was then stirred for 24 h at room temperature.
The reaction mixture was poured in 10 mL of water and then extracted with
ethyl acetate. The extract was washed with a brine solution and dried over
anhydrous magnesium sulfate, and then the solvent was evaporated under
reduced pressure. The residue was separated on a thin-layer chromatography

2,20-Diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene
2985
(TLC) plate of silica gel with a developing solvent of n-hexane/toluene
(v/v ¼ 1/20) to give rac-2,20-diamino-3,30-diethoxycarbonyl-8,80-diphenyl-
1,10-biazulene (6) (5.4 mg, 25%). The enantiomeric excess (ee) was deter-
mined by the chiral HPLC method (Chiralcel OD column, 4.6 cm
ID ꢀ 25 cm) with an eluent of n-hexane/ethanol (90/10, v/v).
Typical Asymmetric Couplings of Ethyl 2-Amino-4-phenylazulene-
1-carboxylate (5) with Chiral Oxovanadium(IV) Complexes
In a 50-mL, two-necked, round-bottomed flask, L-phenylalanine (2.0 g,
12.1 mmol) and NaOAc (1.98 g, 24.2 mmol) were placed in 20 mL of
degassed H2O. After completely dissolving the reaction mixture by stirring
at 608C, the reaction mixture was added dropwise to a solution of
2-hydroxy-1-naphthaldehyde (2.08 g, 12.1 mmol) in 10 mL of degassed
EtOH. The reaction mixture became slightly yellow in color by heating at
808C for 10 min and was gradually cooled to ambient temperature for 2 h.
A solution of vanadyl sulfate hydrate (1.97 g, 12.1 mmol) in 15 mL of
degassed water was added to the resultant Schiff base. The reaction mixture
was stirred for 2 h and then concentrated to half of the original solvent
volume. The precipitate of vanadyl complex (8) was collected by filtration
to provide 3.02 g of 8 (65%) as a dark green solid.
Under an oxygen atmosphere, vanadyl complex (8) (11.8 mg, 0.03 mmol)
was dissolved in 2 mL of anhydrous CH2Cl2, and the solution was stirred for
15 min at room temperature. Ethyl 2-amino-4-phenylazulene-1-carboxylate
(5) (9.0 mg, 0.03 mmol) and methanol (3 mL) were added to the solution,
and the reaction mixture was stirred for 6 days at room temperature. The
reaction mixture was evaporated to remove the solvent under reduced
pressure. The residue was extracted with ethyl acetate, washed with a brine
solution, dried over sodium sulfate, and evaporated to remove the solvent
under reduced pressure. The residue was chromatographed on silica gel
and eluted with ethyl acetate–toluene (v/v ¼ 1/20) to give rac-2,20-
diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene (6) (3.8 mg,
43%). The enantiomeric excess (ee) was determined by the chiral HPLC
method (Chiralcel OD column, 4.6 cm ID ꢀ 25 cm) with an eluent of
n-hexane/ethanol (90/10, v/v).
ACKNOWLEDGMENT
This study was financially supported by the National Science Council of the
Republic of China (NSC93-2113-M-218-003). We thank L. S. Chang of
National Sun Yat-Sen University for circular dichroism (CD) measurement.

2986
A.-H. Chen et al.
REFERENCES
1. (a) Loyd, D. Non-Benzenoid Conjugated Carbocyclic Compounds; Elsevier:
New York, 1984, pp. 351–377; (b) Zeller, K. P. Methoden der Organishen
Chemie (Houben-Weyl), Bd.5, 2c; Carbocyclische p-Elektronen-Systeme;
Kropf, H. (Ed.); Georg Thieme Verlag: New York, 1985, pp. 127–417;
(c) Brettle, R.; Dunmur, S.; Estdale, S.; Marson, C. M. Synthesis, linear
dichroism and mesogenic properties of substituted azulenes. J. Mater. Chem.
1993, 3, 327–332; (d) Asato, A. E.; Liu, R. S. H. Azulene-containing donor–
acceptor compounds as second-order nonlinear chrophores. Tetrahedron Lett.
1996, 37, 419–422; (e) Estadle, S. E.; Brettle, R.; Dumnmur, D. A.;
Marson, C. M. The azulene ring as a structural element in liquid crystals.
J. Mater. Chem. 1997, 7, 391–402.
2. (a) Scott, L. T.; Rozeboom, M. D.; Houk, K. N.; Fukunaga, T.; Lindner, H. J.;
Hafner, K. The quinones of azulene: A theoretical prognosis. J. Am. Chem. Soc.
1980, 102, 5169–5176; (b) Waltman, R. J.; Bargon, J. Electrically conducting
polymers: A review of the electropolymerization reaction, of the effects of
chemical structure on polymer film properties and of applications towards technol-
ogy. Can. J. Chem. 1986, 64, 76–95; (c) Nozone, T.; Takeshita, H. Chemistry of
azulenequinones and their analogues. H. Bull. Chem. Soc. Jpn. 1996, 69,
1149–1178.
3. Tajiri, A.; Fukuda, M.; Hatano, M.; Morita, T.; Takase, K. Resolution, circular
dichroism and absolute configuration of 1,10-biazulenes. Angew. Chem. Int. Ed.
Engl. 1983, 22, 870–871.
4. (a) Chen, A. H.; Nozoe, T. Electromethoxylation of diethyl 2-hydroxyazulene
1,3-dicarboxylate and 2-amino-1,3-dicyanoazulene. Tetrahedron Lett. 1998, 39,
7511–7512; (b) Chen, A. H. Electrochemical methoxylation of 1,2,3-trisubstituted
azulene. J. Chin. Chem. Soc. 1999, 46, 35–39; (c) Chen, A. H.; Chiu, S. C.;
Kuo, Y. C. Arylation of diethyl 2-chloroazulene-1,3-dicarboxylate with Grignard
reagent. Synth Commun. 2003, 33, 2701–2707.
5. Morita, T.; Abe, N.; Takase, K. Reactions of diethyl azulene-1,3-dicarboxylate
derivatives and 1-azaazulene derivatives with Grignard reagents, and alkyl- and
aryllithium. J. Chem. Soc., Perkin Trans. 1, 2000, 3063–3070.
6. (a) Abe, N.; Fujii, H.; Takase, K.; Morita, T. Synthesis and some properties of
7H-naphth[3,2,1-cd]azulene-7-ones and related compounds. J. Chem. Soc.,
Perkin Trans. 1, 2001, 1353–1358; (b) Chen, A. H.; Yen, H. H.; Chen, W. Z.;
Hong, Z. X.; Yuan, S. B.; Chen, W. Y. Nucleophilic substitution of diethyl 2-chlor-
oazulene-1,3-dicarboxylate with alkyl lithium. J. Chin. Chem. Soc. 2006, 53,
1531–1538.
7. (a) Hu, Q. S.; Vitharana, D.; Pu, L. An efficient and practical direct resolution of
racemic 1,10-bi-2-naphthol to both of its pure enantiomers. Tetrahedron:
Asymmetry, 1995; 6, 2113–2126; (b) Cai, D.; Hughes, D. L.; Verhoeven, T. R.;
Reider, P. J. Simple and efficient resolution of 1,10-bi-2-naphthol. Tetrahedron
Lett. 1995, 36, 7991–7994; (c) Wang, Y.; Sun, J.; Ding, K. Practical method
and novel mechanism for optical resolution of BINOL by molecular complexation
with N-benzylcinchoninium chloride. Tetrahedron 2000, 56, 4447–4451.
8. (a) Chow, H. F.; Wan, C. W.; Ng, M. K. A versatile method for the resolution and
absolute configuration assignment of substituted 1,10-bi-2-naphthols. J. Org. Chem.
1996, 61, 8712–8714; (b) Fabbri, D.; Delogu, G. Widely application method of res-
olution of binaphthyls: Preparation of enantiomerically pure 1,10-binaphthalene-2,20-

2,20-Diamino-3,30-diethoxycarbonyl-8,80-diphenyl-1,10-biazulene
2987
diol, 1,1-binaphthalene-2,20-dithiol, 20-mercapto-1, 10-binaphthalen-2-ol and 1,10-
binaphthalene-8,80-diol. J. Org. Chem. 1995, 60, 6599–6601.
9. Hagen, R.; Nakanishi, K. Circular Dichroism Spectroscopy-Exciton Coupling in
Organic Stereochemistry; University Science Books, Oxford University Press:
Mill Valley, CA, 1983; pp. 190–219.
10. (a) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S. I.; Noji, M.; Koga, K.
Enantioselective synthesis of binaphthol derivatives by odidative coupling of
naphthol derivatives catalyzed by chiral diamine copper complexes. J. Org.
Chem. 1999, 64, 2264–2271; (b) Li, X.; Yang, J.; Kozlowski, M. C. Enantioselec-
tive oxidation biaryl coupling reactions catalyzed by 1,5-diazadecalin metal
complexes. Org. Lett. 2001, 3, 1137–1140; (c) Li, X.; Hewgley, B.;
Mulrooney, C. A.; Yang, J.; Kozlowski, M. C. Enantioselective oxidation biaryl
coupling reactions catalyzed by 1,5-diazadecalin metal complexes: Efficient
formation of chiral functionalized BINOL derivatives. J. Org. Chem. 2003, 68,
5500–5511.
11. (a) Chu, C. Y.; Hwang, D. R.; Wang, S. K.; Uang, B. J. Chiral oxovanadium
complex catalyzed enantioselective oxidative coupling of 2-naphthols. Chem.
Commun. 2001, 980–981; (b) Hon, S. W.; Li, C. H.; Kuo, J. H.; Barhate, N. B.;
Liu, Y. H.; Chen, C. T. Catalytic asymmetric coupling of 2-naphthols by chiral tri-
dentate oxovanadium(IV) complexes. Org. Lett. 2001, 3, 869–872; (c) Luo, Z.;
Liu, Q.; Gong, L.; Cui, X.; Mi, A.; Jiang, Y. The rational design of novel chiral
oxovanadium(IV) complexes for highly enantioselective oxidative coupling of
2-naphthols. Chem. Commun. 2002, 914–915; (d) Barhate, N. B.; Chen, C. T.
Catalytic asymmetric oxidative coupling of 2-naphthols by tridentate N-ketopini-
dene-based vanadyl dicarboxylates. Org. Lett. 2002, 4, 2529–2532; (e) Somei, H.;
Asano, Y.; Yoshida, T.; Takizawa, S.; Yamataka, H.; Sasai, H. Dual activation in a
homolytic coupling reaction promoted by an enantioselective dinuclear vanadium
(IV) catalyst. Tetrahedron Lett. 2004, 45, 1841–1844.