Arylation of diethyl 2-chloroazulene-1,3-dicarboxylate with Grignard reagent

Article abstract of DOI:10.1081/SCC-120021993

Reaction of diethyl 2-chloroazulene-1,3-dicarboxylate (2) with phenyl magnesium bromide, followed by oxidation with o-chloranil, gave diethyl 2-chloro-4-phenylazulene-1,3-dicarboxylate (3), diethyl 2-chloro-5-phenylazulene-1,3-dicarboxylate (4) and diethy

Full text of DOI:10.1081/SCC-120021993

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Arylation of Diethyl 2-Chloroazulene- 1,3-dicarboxylate
with Grignard Reagent
Arh-Hwang Chen a , Shu-Ching Chiu a & Yu-Chen Kuo a
a Department of Chemistry , National Kaohsiung Normal University , Kaohsiung, Taiwan,
R.O.C.
Published online: 17 Aug 2006.
To cite this article: Arh-Hwang Chen , Shu-Ching Chiu & Yu-Chen Kuo (2003) Arylation of Diethyl 2-Chloroazulene- 1,3-
dicarboxylate with Grignard Reagent, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:15, 2701-2707, DOI: 10.1081/SCC-120021993
To link to this article: http://dx.doi.org/10.1081/SCC-120021993
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 15, pp. 2701–2707, 2003
Arylation of Diethyl 2-Chloroazulene-
1,3-dicarboxylate with Grignard Reagent
*
Arh-Hwang Chen, Shu-Ching Chiu, and Yu-Chen Kuo
Department of Chemistry, National Kaohsiung Normal
University, Kaohsiung, Taiwan, R.O.C.
ABSTRACT
Reaction of diethyl 2-chloroazulene-1,3-dicarboxylate (2) with
phenyl magnesium bromide, followed by oxidation with o-chloranil,
gave diethyl 2-chloro-4-phenylazulene-1,3-dicarboxylate (3), diethyl
2-chloro-5-phenylazulene-1,3-dicarboxylate (4) and diethyl 6-phenyl-
azulene-1,3-dicarboxylate (5).
Key Words: Azulenoids; Arylation; Nucleophilic substitution;
Oxidation.
*Correspondence: Arh-Hwang Chen, Department of Chemistry, National
Kaohsiung Normal University, Kaohsiung 802, Taiwan, R.O.C.; Fax: þ886-7-
3360342; E-mail: chenah@ms12.hinet.net.
2701
DOI: 10.1081/SCC-120021993
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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2702
Chen, Chiu, and Kuo
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 many investigations in the field of organic chemistry.
These compounds find application in the preparation of dyes, in liquid
crystals and in the medical treatment of inflammation and hyperten-
sion.[1,2] Recently, azuloquinones have been found to have antibacterial,
antifungal and antitumor activities and to play an important role in the
photosynthesis and in the respiratory electron transport chain as well as
in solid state electroconductivity.[3–5] Nucleophilic substitution to
introduce alkyl and aryl substituents in azulenes preferentially occurs at
the 4- or 8-positions. If these positions are already occupied, and/or
sterically hindered nucleophiles are used, substitution occurs at the
6-position.[1,2] The reaction of 2-alkoxy- or 2-halo-1,3-disubstituted azu-
lenes with alkoxides, amine, sulfides and Grignard reagents leads to the
replacement of the alkoxy or halogen substituents with the nucleo-
philes.[6–8] Recently, Dr. Takase et al. reported that 2-chloro-1,3-disub-
stituted azulenes with Grignard reagents or organic lithiumallowed alkyl
or phenyl substitution at the 4- and 6-positions.[9] In our continuous
study on the synthetic application of azulenoids,[10–13] we reported
herein a novel arylation of diethyl 2-chloroazulene-1,3-dicarboxylate
with the Grignard reagent phenyl magnesium bromide.
Diethyl 2-aminoazulene-1,3-dicarboxylate (1) was prepared accord-
ing to the literature,[12,13] identified by using spectroscopy and then
chlorinated at the 2-position via treatment with hydrogen chloride
and isoamyl nitrite to give diethyl 2-chloroazulene-1,3-dicarboxylate
(2)[14] (Sch. 1). 2-Chloroazulene (2) was treated with phenyl magnesium
bromide and then oxidized with o-chloranil to give diethyl 2-chloro-4-
phenylazulene-1,3-dicarboxylate (3), diethyl 2-chloro-5-phenylazulene-
1,3-dicarboxylate (4) and diethyl 6-phenylazulene-1,3-dicarboxylate
(5), as shown in Sch. 2. The position of phenyl group in diethyl 2-
chloro-5-phenylazulene-1,3-dicarboxylate (4) was determined by using
spin decoupling and nuclear Overhauser effect difference spectrometry
(NOE effect see Table 1). This finding showed that arylation of
Scheme 1.

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Diethyl 2-Chloroazulene-1,3-dicarboxylate
2703
Scheme 2.
Table 1. The NOE effect of 2-chloro-5-phenylazulene-1,3-dicarboxylate (4).
Chemical shift
of irradiation CO2CH2-CH3 CO2CH2-CH3 5-Phc
6-H
7-H
8-H
ꢀ 7.7 (7-H)
6.97%
6.85%
ꢀ 8.2 (6-H)
ꢀ 9.4 (8-H)
ꢀ 9.8 (4-H)
2.26%
5.24%
5.47%
7.46%
0.29%a
0.37%b
0.13%a
0.17%b
a1-CO2CH2CH3.
b3-CO2CH2CH3.
c20,60-H2 of 5-phenyl group.
Table 2. The yields of arylation of diethyl 2-chloroazulene-1,3-dicarboxylate (2).
Yields (%)a
Molar ratios of
Entries substrate to PhMgBr
Solvents Conversion
used
(%)
3
4
5
1
2
3
4
5
6
1:1
Et2O
Et2O
Et2O
THF
THF
THF
74.9
97.3
100.0
24.5
92.7
70.2
6.4
23.6
5.4
3.3 13.8
7.5 32.7
4.7 31.9
8.5 15.5
2.8 13.9
1:2.5
1:3
1:1
9.3
10.7
1:2.5
1:3
5.1 11.9 27.7
aYield based on consumed diethyl 2-chloroazulene-1,3-dicarboxylate (2).
2-chloroazulene (2) with Grignard reagent occurred at the 4- or 8- and
5-positions as well as at the 6-position accompanied with elimination
of the 2-Cl substituent. The yield depended significantly on the molar
ratio of substrate to Grignard reagent and the solvent used (Table 2).

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2704
Chen, Chiu, and Kuo
Scheme 3.
The formation of diethyl 6-phenylazulene-1,3-dicarboxylate (5) from
diethyl 2-chloroazulene-1,3-dicarboxylate (2) was proposed to follow
the addition–elimination mechanism[15,16] (Sch. 3). The reaction of
diethyl 2-chloroazulene-1,3-dicarboxylate (2) with phenyl magnesium
bromide is proposed to lead to a cyclopentadienyl anion (6), which
then is protonated by methanol to produce a 2,6-dihydroazulene inter-
mediate (7). Dehydrochlorination of the 2,6-dihydroazulene inter-
mediate (7) afforded diethyl 6-phenylazulene-1,3-dicarboxylate (5).
EXPERIMENTAL
The melting points were measured without correction on a
Yanagimoto Micromelting Point Apparatus. 1H and 13C nuclear magnetic
resonance spectra were measured on a Varian VXR-300 spectrometer or a
Varian INOVA-500 spectrometer. Mass spectra were determined on a VG
Quattro GC/MS/MS DS spectrometer. High resolution mass spectral were
determined on a VG 70-250S GC/MS spectrometer.
Diethyl 2-Chloroazulene-1,3-dicarboxylate (2)
Dry hydrogen chloride passed through a solution of diethyl 2-amino-
azulene-1,3-dicarboxylate (1) (1.0 g, 3.48 mmol) dissolved in 50 mL of
anhydrous benzene on an ice-bath for 2 h. Isoamyl nitrite (0.48 g,
4.10 mmol) was added to the reaction solution and then the mixture
was stirred at roomtemperature overnight. The reaction solution was
washed with water, dried over anhydrous sodiumsulfate and evaporated.

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Diethyl 2-Chloroazulene-1,3-dicarboxylate
2705
The residue was recrystallized fromethanol to afford 0.982 g (91.1%) of
diethyl 2-chloroazulene-1,3-dicarboxylate (2), m.p. 78–80ꢀC (Lit.[14]
:
77–79ꢀC). H NMR (CDCl3, 300 MHz): ꢀ 1.48 (t, J ¼ 7.2, 6H), 4.50 (q,
J ¼ 7.2, 4H), 7.41 (t, J ¼ 10.2, 2H), 7.93 (t, J ¼ 10.2, 1H), 9.53 (d, J ¼ 10.2,
2H); 13C NMR (CDCl3, 75 MHz): 14.42, 60.71, 77.42, 115.41, 130.88,
138.00, 140.19, 141.69, 164.36; MS (EI, m/Z, %): 69 (100), 233 (27.7),
261 (16.0), 306 (Mþ, 15.4), 308 (M þ 2, 4.9); HRMS: 306.0654 (Mþ),
calcd. 306.0659; Anal.: Found: C: 62.49%, H: 4.94%; calcd. for
C16H15ClO4: C: 62.65%, H: 4.93%.
1
Typical Arylation of Diethyl 2-Chloroazulene-
1,3-dicarboxylate (2)
Under a nitrogen atmosphere, an ether solution of phenyl magne-
sium bromide (0.815 mL of 2.5 M solution, 0.815 mmol) was added to a
cold (ice-salt bath) solution of diethyl 2-chloroazulene-1,3-dicarboxylate
(2) (0.100 g, 0.326 mmol) in a dry diethyl ether (10 mL) and the mixture
was stirred for 30 min with an ice-salt bath cooling and then 30 min at
room temperature. The reaction mixture was cooled (ice-salt bath), to
which was added methanol (2 mL) and then stirred for 30 min. The reac-
tion mixture was poured into 2 M HCl (1.4 mL) and then extracted with
diethyl ether. The extract was washed with a saturated sodiumbicarbo-
nate solution and a brine solution, dried over anhydrous sodiumsulfate
and then evaporated. o-Chloranil (0.16 g, 0.652 mmol) was added to the
residue dissolved in dry benzene (7 mL) and then stirred for 2 days at
room temperature. The reaction solution was passed through a column of
alumina to remove the o-chloranil residue and then evaporated to dry.
The residue was chromatographed on silica gel and eluted with n-hexane–
benzene (v/v ¼ 1/20) to give a mixture of diethyl 2-chloro-5-phenylazu-
lene-1,3-dicarboxylate (4) and diethyl 6-phenylazulene-1,3-dicarboxylate
(5) and a crystal of diethyl 2-chloro-4-phenylazulene-1,3-dicarboxylate
(3) (23.0 mg, 23.6%), m.p. 108–110ꢀC (Lit.[9]: 108–109ꢀC). The above
mixture was separated on a TLC plate (silica gel) with a developing
solvent of n-hexane–benzene (v/v ¼ 1/1) to give diethyl 6-phenylazulene-
1,3-dicarboxylate (5) (31.9 mg, 32.7%), m.p. 150–152ꢀC and diethyl
2-chloro-5-phenylazulene-1,3-dicarboxylate (4) (7.3 mg, 7.5%), m.p.
108–110ꢀC. 3: H NMR (CDCl3, 500 MHz): ꢀ 1.12 (t, J ¼ 7.0, 3H), 1.47
1
(t, J ¼ 7.0. 3H), 3.57 (q, J ¼ 7.0, 2H), 4.49 (q, J ¼ 7.0, 2H), 7.44–7.49 (m,
5H), 7.55–7.62 (m. 2H), 7.80–7.84 (m, 1H), 9.67 (dd, J ¼ 1.0, J ¼ 10.0
1H); 13C NMR (CDCl3, 125 MHz): 13.82, 14.36, 60.58, 61.06, 114.04,
121.78, 128.16, 128.59, 128.62, 129.09, 133.87, 135.55, 138.13, 138.29,

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2706
Chen, Chiu, and Kuo
140.75, 141.27, 142.24, 151.56, 164.30, 165.06; MS (EI, m/z, %): 238
(46.8), 309 (70.6), 337 (43.7), 382 (Mþ, 100.0), 384 (M þ 2, 39.3);
HRMS: 382.0974 (Mþ), calcd. 382.0972; Anal.: Found: C: 69.01%, H:
5.03%; calcd. for C22H19ClO4: C: 69.02%, H: 5.00%; 4: 1H NMR
(CDCl3, 500 MHz): ꢀ 1.45–1.50 (m, 6H), 4.46–4.53 (m, 4H), 7.44–7.47
(m, 1H), 7.51–7.54 (m, 2H), 7.70–7.71 (M, 2H), 7.79 (dd, J ¼ 1.0,
J ¼ 10.0, 1H), 7.79 (t, J ¼ 10.0, 1H), 8.15 (dd, J ¼ 1.0, J ¼ 10.0, 1H),
9.48 (dd, J ¼ 1.0, J ¼ 10.0, 1H), 9.89 (d, J ¼ 2.5, 1H); 13C NMR
(CDCl3, 125 MHz): 13.37, 14.42, 60.68, 114.95, 115.79, 128.25, 128.57,
129.12, 130.50, 136.88, 138.69, 140.13, 140.93, 141.61, 143.41, 144.16,
144.74, 164.32, 164.39; MS (EI, m/z %): 309 (64.3), 337 (37.5), 382
(Mþ, 100.0), 384 (M þ 2, 36.2); HRMS: 382.0970 (Mþ), calcd.
1
382.0972; 5: H NMR (CDCl3, 500 MHz): ꢀ 1.47 (t, J ¼ 7.0, 6H), 4.45
(q, J ¼ 7.0, 4H), 7.50–7.56 (m, 3H), 7.69–7.70 (m, 2H), 7.97 (d,
J ¼ 11.0, 2H), 8.83 (s, 1H), 9.82 (d, J ¼ 11.0, 2H); 13C NMR (CDCl3,
125 MHz): 14.58, 60.07, 116.42, 128.79, 128.95, 128.09, 130.90, 138.50,
142.75, 143.22, 143.57, 154.60, 165.10; MS (EI, m/z, %): 275 (76.8), 303
(55.6), 348 (Mþ, 100.0), 349 (M þ 1, 23.1); HRMS: 348.1360 (Mþ), calcd.
348.1362; Anal.: Found: C: 75.89%, H: 5.76%; calcd. for C22H20O4: C:
75.84%, H: 5.79%.
ACKNOWLEDGMENT
This study was financially supported by the National Science Council
of the Republic of China (NSC89-2113-M-017-003).
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Diethyl 2-Chloroazulene-1,3-dicarboxylate
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Received in the USA December 12, 2002

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