Synthesis of methyl 2-methylazulene-3-carboxylate in the presence of molecular sieves and reaction with N-bromosuccinimide

Article abstract of DOI:10.1080/00397910701818453

The preparation of methyl 2-methylazulene-1-carboxylate (1) was carried out in the presence of molecular sieves to obtain a good yield. The product was subjected to bromination under different reaction conditions to obtain methyl 1-bromo-2-methylazulene-1-carboxylate (2) and methyl 1-bromo-2-(bromomethyl) azulene-1-carboxylate (3). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701818453

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Synthesis of Methyl
2‐Methylazulene‐3‐carboxylate in the
Presence of Molecular Sieves and Reaction
with N‐Bromosuccinimide
Dao‐Lin Wang a , Jiao Xu a , Zheng Gu a , Shan Han a & Kimiaki Imafuku b
a College of Chemistry and Chemical Engineering, Liaoning Key Laboratory
of Apple Chemistry , Bohai University , Jinzhou, China
b Faculty of Science, Department of Chemistry , Kumamoto University,
Kurokami , Kumamoto, Japan
Published online: 22 Feb 2008.
To cite this article: Dao‐Lin Wang , Jiao Xu , Zheng Gu , Shan Han & Kimiaki Imafuku (2008) Synthesis
of Methyl 2‐Methylazulene‐3‐carboxylate in the Presence of Molecular Sieves and Reaction with
N‐Bromosuccinimide, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:6, 991-996, DOI: 10.1080/00397910701818453
To link to this article: http://dx.doi.org/10.1080/00397910701818453
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Synthetic Communicationsw, 38: 991–996, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701818453
Synthesis of Methyl 2-Methylazulene-3-
carboxylate in the Presence of Molecular
Sieves and Reaction with
N-Bromosuccinimide
Dao-Lin Wang,1 Jiao Xu,1 Zheng Gu,1 Shan Han,1
and Kimiaki Imafuku2
1College of Chemistry and Chemical Engineering, Liaoning Key
Laboratory of Apple Chemistry, Bohai University, Jinzhou, China
2Faculty of Science, Department of Chemistry, Kumamoto University,
Kurokami, Kumamoto, Japan
Abstract: The preparation of methyl 2-methylazulene-1-carboxylate (1) was carried
out in the presence of molecular sieves to obtain a good yield. The product was
subjected to bromination under different reaction conditions to obtain methyl
1-bromo-2-methylazulene-1-carboxylate (2) and methyl 1-bromo-2-(bromomethyl)
azulene-1-carboxylate (3).
Keywords: bromination, 2-methylazulene, molecular sieves
INTRODUCTION
In many synthetic methods for azulenes, the reaction of 2H-cyclohepta[b]furan-
2-one with enamines is an efficacious way of preparaing 1-substituted azulenes
in good yield[1]; however, it was not as effective 2-substituted azulenes. The
enamines can be conveniently prepared in high yield by the reaction of appro-
priate ketones and amines in the presence of molecular sieves.[2]
Address correspondence to Dao-Lin Wang, Faculty of Chemistry and Chemical
Engineering, Bohai University, No. 19, Science and Technology Road, High-Tech
Development District, Jinzhou 121001, China. E-mail: wangdaolin@sina.com
991

992
D.-L. Wang et al.
Table 1. Catalysis with molecular sieves in the preparation of 2-methylazulene
Entry
Molecular sieve
None
Time (h)
Product yield (%)
1
2
3
4
5
6
7
8
9
72
24
48
48
72
18
24
48
72
46
75
78
73
63
76
79
76
55
˚
4 A 0.6 g/mmol
˚
4 A 0.6 g/mmol
˚
4 A 0.3 g/mmol
˚
4 A 0.1 g/mmol
˚
4 A 1.2 g/mmol
˚
3 A 0.6 g/mmol
˚
3 A 0.3 g/mmol
˚
3 A 0.1 g/mmol
Molecular sieves simultaneously serve as dehydrating agent and catalyst
that can be simply removed at the end of the reaction by filtration. Further, in
some instances, the distillate has been dried effectively with molecular
sieves.[3] Therefore, in the absence of molecular sieves, the reaction rate of
ketone and amine is quite slow. To integrate enamine formation with
azulene synthesis in onepot, the preparation of methyl 2-methylazulene-1-car-
boxylate (1) was carried out in the presence of molecular sieves. Good yields
were obtained while reducing reaction time. The results are shown in Table 1.
2H-Cyclohepta[b]furan-2-one was treated with acetone and diethylamine,
which are precursors to enamine, in the absence of molecular sieves under
refluxing for 72 h. It afforded azulene (1) only in 46% yield[4] (entry 1). The
yield of 1 increased when the reaction was carried out using molecular sieves
˚
sized 3 A or 4 A) (entries 2, 3, 4, and 8). The yield of 1 was optimized to
˚
˚
79% using 0.6 g/mmol of 3 A molecular sieves (entry 7). The reactions using
a small amount of molecular sieves resulted in low yields (entries 5 and 9).
˚
When 1.2 g/mmol of 4 A molecular sieves were used, the reaction time
reduced to 18 h, and azulene (1) was obtained in a good yield (entry 6).
Bromination of Methyl 2-Methylazulene-3-carboxylate with
N-Bromosuccinimide (NBS)
Electrophilic substitution of an aromatic ring using NBS has been observed,[5]
although the results are highly variable in terms both of products and yields. In
the absence of a metal chloride catalyst, bromination of benzene and toluene
with NBS does not occur. However, in polynuclear aromatic hydrocarbons,
the reaction was observed without catalyst.[6]
Halogenation of azulenes with N-halosuccinimide has been described
by Anderson’s group. The reaction of strongly nucleophilic compounds
with NBS are generally considered to be ionic. It was presumed that the
bromination of azulenes would involve substitution at the 1-position.[7]

Methyl 2-Methylazulene-3-carboxylate
993
Table 2. Bromination of 2-methylazulene with NBS
Yield (%)
Entry
Molar ratio
Solvent
Reaction condition
2
3
1
2
3
4
1:1.2
1:2.2
1:1
C6H6
C6H6
CCl4
CCl4
Rt, 1 h
97
11
86
—
—
86
7
Reflux, 24 h
BOP, reflux, 1 h
BOP, reflux, 12 h
1:2.2
83
Reaction of 2-methylazulene (1) with NBS in a molar ratio of 1:1.2 at
room temperature in benzene for 1 h gave 1-bromo-2-methylazulene (2) in
excellent yield (Table 2, Entry 1). The reaction in a molar ratio of 1:2.2
under refluxing for 24 h in benzene afforded 2 in 11% yield and 1-bromo-
2-(bromomethyl)azulene (3) in 86% yield, respectively (entry 2). On the
other hand, reaction of an equimolar amount of 2-methylazulene (1) and
NBS in refluxing carbon tetrachloride in the presence of the radical
initiator, benzoyl peroxide (BOP), for 1 h gave 1-bromo-2-methylazulene
(2) in excellent yields and a small amount of 1-bromo-2-(bromomethyl)azu-
lene (3) (entry 3). The reaction of 1 in a similar condition in carbon tetrachlor-
ide only afforded methyl 1-bromo-2-(bromomethyl)-azulene-3-carboxylate
(3) in 83% yield (entry 4). These results showed the bromination of 2-methy-
lazulenes with NBS in the presence or absence of the radical initiator (BOP) at
the 1-position of azulene priority afforded the corresponding 1-bromo-2-
methylazulenes, whereas bromination at the 2-methyl group was not
observed (Schemes 1 and 2).
Scheme 1.
Scheme 2.

994
D.-L. Wang et al.
Scheme 3.
In the radical bromination process, 1-bromo-2-methylazulene (2) was
heated in refluxing benzene in the presence of benzoyl peroxide to provide
1-bromo-2-bromomethyl-azulenes (3) in 86% yield (Scheme 3).
In conclusion, we have found one new method for the preparation of
methyl 2-methylazulene with improved yields in the presence of molecular
sieves and have investigated the bromination using NBS. The bromination
of 2-methylazulene derivatives with NBS in electrophilic aromatic substi-
tution and under the radical conditions also were investigated.
EXPERIMENTAL
All melting points were determined with a Yanaco MP JP-3 apparatus and
are uncorrected. The IR spectra were measured on a Jasco A-102 IR
spectrophotometer. The NMR spectra were recorded with a Jeol JNM-EX
300 spectrometer (300 MHz for 1H and 75.5 MHz for 13C). Elemental
analyses were performed at the Center for Instrumental Analysis, Beijing
University.
Preparation of Methyl 2-Methylazulene-3-carboxylate (1) in the
Presence of Molecular Sieves
˚
Molecular sieves (3 A, 3.0 g) were added to a mixed solution of methyl 2-
oxo-2H-cyclohepta[b]furan-3-carboxylate (1.02 g, 5.0 mmol), acetone (20 ml),
and diethylamine (7 ml). The reaction mixture was heated under refluxing for
24 h. The mixture were cooled to room temperature. The molecular sieves
were filtered off and washed with solvent. The solvent was removed from the
filtrate. The residue was poured into water (50 ml) and extracted with benzene
(3 Â 20 ml). The benzene layer was washed with water and with brine, then
dried over sodium sulfate. After removal of the solvent, the residue was chro-
matographed on a silica-gel column with benzene as eluent to give 1 (790 mg,
79%) as purple prisms, mp 45–468C (hexane) (lit.[6] 45–468C).

Methyl 2-Methylazulene-3-carboxylate
995
Bromination of Methyl 2-Methylazulene-3-carboxylate (1) with NBS
N-bromosuccinimide (106 mg, 0.6 mmol) was added to a solution of methyl
2-methylazulene-3-carboxylate (1) (0.5 mmol) in benzene (20 ml). After
stirring for 1 h at room temperature, cold water (20 ml) was added to the
mixture. The combined organic layer and extracts were washed with water
and dried over sodium sulfate. The evaporation residue was chromatographed
on a silica-gel column with benzene as eluent. The blue fraction was collected
and afforded 1-bromo-2-methylazulenes 2.
Methyl 1-Bromo-2-methylazulene-3-carboxylate (2)
1
Blue crystals (benzene); mp 88–898C IR (KBr): n 1694 (C55O) cm21; H
NMR (CDCl3): d 2.77 (3H, s, CH3), 3.95 (3H, s, COOCH3), 7.38 (1H, dd,
J ¼ 9.9, 9.6 Hz, 5- or 7-H), 7.42 (1H, dd, J ¼ 10.2, 9.9 Hz, 7- or 5-H), 7.64
(1H, t, J ¼ 9.9 Hz, 6-H), 8.31 (1H, d, J ¼ 9.9 Hz, 8-H), 9.36 (1H, d,
J ¼ 9.9 Hz, 4-H); 13C NMR (CDCl3): 17.1 (CH3), 51.0 (COOCH3), 108.6
(55C, ), 114.4 (55C, ), 127.2 (55CH-), 128.1 (55CH-), 135.4 (55CH-),
136.6 (55CH-), 138.3 (55CH-), 140.6 (55C, ), 151.1 (55C, ), 165.7
(COOCH3). Anal. calcd. for C13H11BrO2: C, 55.94; H, 3.97%. Found: C,
56.19; H, 3.94%.
Bromination of Methyl 1-Bromo-2-methylazulene-3-carboxylate (2)
with NBS
A solution of 1-bromo-2-methylazulenes (2) (0.5 mmol) in benzene (30 ml)
containing finely powdered N-bromosuccinimide (1 mmol) and dibenzoyl
peroxide (10 mg) was refluxed for 1 h. After the reaction mixture had been
cooled, it was diluted with water and then extracted with dichloromethane.
The extract was dried over sodium sulfate and evaporated in vacuo to leave
a residue that was chromatographed on a silica-gel column with benzene as
eluent to give 1-bromo-2-(bromomethyl)azulenes (3).
Methyl 1-Bromo-2-(bromomethyl)azulene-3-carboxylate (3)
Dark violet crystals (benzene); mp 99–1018C; IR (KBr): n 1679 (C55O)
1
cm21; H NMR (CDCl3): d 4.02 (3H, s, COOCH3), 5.17 (2H, s, CH2Br),
7.48 (1H, dd, J ¼ 11.1, 9.9 Hz, 5 or 7-H), 7.52 (1H, dd, J ¼ 11.1, 10.2 Hz,
7- or 5-H), 7.77 (1H, t, J ¼ 9.9 Hz, 6-H), 8.46 (1H, d, J ¼ 9.0 Hz, 8-H),
9.52 (1H, d, J ¼ 9.9 Hz, 4-H); 13C NMR (CDCl3): 26.4 (CH2Br), 51.5
(COOCH3), 108.1 (55C, ), 113.3 (55C, ), 127.9 (55CH-), 128.8 (55CH-),
137.8 (55CH-), 138.8 (55C, ), 139.0 (55CH-), 140.5 (55CH-), 140.7

996
D.-L. Wang et al.
(55C, ), 146.9 (55C, ), 164.9 (COOCH3). Anal. Calcd. for C13H10Br2O2: C,
43.61; H, 2.81%. Found: C, 43.52; H, 2.81%.
ACKNOWLEDGMENT
The authors gratefully acknowledge the financial support of this work by the
Ministry of Education of Liaoning Province of China (No. 2005021).
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