A simple and efficient synthesis of 2-alkylazulenes

Article abstract of DOI:10.1016/j.tetlet.2004.10.077

The annulation method based on 2H-cyclohepta[b]furan-2-ones was applied for the synthesis of 2-alkylazulenes; 2-R-azulene (R = Et, i-Pr, n-Pr, i-Bu). Tropolone p-toluenesulfonate was used as a starting compound. By the two step synthesis, 1-carboxylic-3-cyanoazulene derivatives were obtained. Treatment of 1-carboxylic-3-cyanoazulene derivatives with aq H₂SO₄ resulted in decarboxylation and elimination of cyano group to give 2-alkylazulenes in good yields.

Full text of DOI:10.1016/j.tetlet.2004.10.077

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9211–9213
A simple and efficient synthesis of 2-alkylazulenes
Naoshi Iwama,a,* Masami Kashimoto,b Hisashi Ohtaki,b
Taku Katob, and Toshihiko Suganoc
aPolymerization Technical Center, Japan Polypropylene Corp., Yokkaichi, Mie 510-0848, Japan
bOrganic Synthesis and Molecular Catalysis Laboratory, Mitsubishi Chemical Group Science and Technology Research Center, Inc.,
Aoba-ku, Yokohama 227-8502, Japan
cResearch and Development Division, Japan Polychem Corp., Yokkaichi, Mie 510-0848, Japan
Received 16 August 2004; revised 13 October 2004; accepted 15 October 2004
Available online 2 November 2004
Abstract—The annulation method based on 2H-cyclohepta[b]furan-2-ones was applied for the synthesis of 2-alkylazulenes; 2-R-azu-
lene (R = Et, i-Pr, n-Pr, i-Bu). Tropolone p-toluenesulfonate was used as a starting compound. By the two step synthesis, 1-carb-
oxylic-3-cyanoazulene derivatives were obtained. Treatment of 1-carboxylic-3-cyanoazulene derivatives with aq H2SO4 resulted
in decarboxylation and elimination of cyano group to give 2-alkylazulenes in good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
thesis of 2-methylazulene (4a), some strategies were re-
ported including ring expansion by diazo acetic acid
ester,5 annulation method based on 2H-cyclo-
hepta[b]furan-2-ones,6 and annulation and dehydrogen-
ation.7 Furthermore, several methods for substitution of
alkyl group at the 2-position of the azulenyl derivatives
were reported previously.8 On the other hand, few meth-
ods for the selective synthesis of 2-alkylazulenes were
reported so far. For example, the synthesis of 2-ethy-
lazulene was reported by annulation based on the enam-
ine method. However, it was obtained as a mixture with
1,2-dimethylazulene and separation was necessary.9 In
this contribution, we report a simple and selective syn-
thesis of 2-alkylazulenes (4b–e) from tropolone as a
starting material.
Much attention has been focused on ansa-metallocene of
group IV transition metals producing isotactic polyprop-
ylene, when activated with methylaluminoxane (MAO)
and other cocatalysts. Many ansa-metallocene have been
developed for improvement of polymerization perform-
ance and ligand system of the metallocene was found to
be important for the polymerization behavior.1 In the
bis-indenyl metallocene system, the substituents at the
2-positions in the indenyl ring are important for poly-
merization behavior.2 Recently, we have reported ansa-
zirconocene bearing the azulenyl rings, Me2Si(2-Me-4-
Ph-4H-Azu)2ZrCl2 to produce isotactic polypropylene.3
In the course of the design for the novel ligand in the bis-
azulenyl metallocene system, we have developed a sim-
ple and efficient synthetic method of 2-substituted
azulenes.
2. Result and discussion
Several approaches to the synthesis of the azulene deriv-
atives were reported earlier, however the yield was not
good and selective synthesis was difficult.4 For the syn-
We applied the annulation method based on 2H-cyclo-
hepta[b]furan-2-ones for the synthesis of 2-alkyl azu-
lenes.6a,10 It was previously reported that 2-methyl-
azulene (4a) was prepared from 2-chlorotropone in
moderate yield.6a,11 Then this method was applied for
the synthesis of 2-ethylazulene (4b) and we used tropo-
lone p-toluenesulfonate (1) as a starting material, as
shown in Scheme 1. Tropolone p-toluenesulfonate (1)
was prepared from tropolone and p-toluenesulfonyl
chloride in quantitative yield by the reported method.12
Keywords: Azulene; Alkylazulene; Tropolone.
*
Corresponding author. Tel.: +81 593457137; fax: +81 593457038;
e-mail: iwama.naoshi@mc.japanpp.co.jp
Present address: Pharmaceuticals Research Unit, Mitsubishi Pharma
Corp., Japan.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.077

9212
N. Iwama et al. / Tetrahedron Letters 45 (2004) 9211–9213
Scheme 1. Synthetic route for 2-alkylazulenes (4a–e). (a) RCOCH2CO2Et, NaOEt, EtOH; (b) CNCH2CO2Et, EtONa or DBU, EtOH; (c) aq. H2SO4.
The reaction of 1 and excess of ethyl propionylacetate in
the presence of sodium ethoxide gave 3-propionyl-
2H-cyclohepta[b]furan-2-one (2b) in good yield. In the
reaction with 1equiv of ethyl propionylacetate, unre-
acted 1 was recovered.
Chart 1.
Treatment of 2b with excess of ethyl cyanoacetate ester
in the presence of sodium ethoxide resulted in formation
of azulene ring to give 1-carboxylic-3-cyano-2-ethylazul-
ene (3b) after acidic hydrolysis. Ethyl 3-propionyl-2-
Table 2. Yield of 2 and 3
aminoazulene-1-carboxylate was obtained as one of
R
Base (equiv)
2 (%)
Base (equiv)
3 (%)
the byproduct and could be removed by extraction with
dichloromethane. It was reported previously that ethyl
3-acetyl-2-aminoazulene-1-carboxylate was obtained in
the preparation of 3a.6a
Et
NaOEt (1.2)
NaOEt (2.4)
NaOEt (2.4)
NaOEt (1.2)
61
70
68
77
NaOEt (4)
DBU (3)
DBU (3)
DBU (3)
93
56
i-Pr
n-Pr
i-Bu
Quant.
53
Next, we examined the decarboxylation and elimination
of cyano group of 3b in some conditions. In the synthe-
sis of 2-methylazulene, it was reported that decarboxyl-
ation of 3a with 85% H3PO4 proceeded smoothly to give
5a in high yield,6a and treatment of 3a with 85% H3PO4
under longer reaction time gave 4a in a moderate
yield.6b Furthermore, the reaction of 3a with 75%
H2SO4 resulted in moderate yield of 4a and formation
of 5a and 6a was observed.6a Similarly, in the course
of the reaction with H3PO4 or H2SO4, decarboxyla-
tion of 3b proceeded smoothly and gas evolution was
observed at the early stage of the reaction. In the analy-
sis of the reaction mixture by mass spectra, 1-cyanoazu-
lene (5b) was observed as a main product. Further
reaction resulted in the formation of 1-carbamoylazu-
lene (6b) and subsequent elimination of carbamoyl
group of 6b to give 2-ethylazulene (4b). The yield of
4b and reaction conditions are summarized in Table 1.
In the reaction with H3PO4, the yield of 4b was low
and 5b was recovered (entries 1 and 2), however in the
reaction with 75% H2SO4, the yield of 4b was improved
(entry 4).13 In the shorter reaction time, both 5b and 6b
were observed (entry 6) (Chart 1).
Table 3. Yield of alkylazulenes (4)
Compound
Method
4 (%)a
4b (R = Et)
a
b
c
67
42
80
56
4c (R = i-Pr)
4d (R = n-Pr)
4e (R = i-Bu)
a
(a) 75% H2SO4, 90 and 120°C, (b) 65% H2SO4, 90 and 110°C, (c) 65%
H2SO4, 100 and 120°C.
a Isolated yield after purification by silica gel column chromato-
graphy.
Then, this strategy was extended for the synthesis of
the other 2-alkylazulenes. 2H-Cyclohepta[b]furan-2-one
derivatives (2c–e) were obtained in the reaction with
corresponding b-keto ester in good yields.14 It was
reported that 2a was obtained from 2-chlorotro-
pone.6a,b,15 However these 2H-cyclohepta[b]furan-2-
one derivatives (2b–e) bearing acyl group derived from
tropolone p-toluenesulfonate were novel compounds.
Subsequent reaction of 2c–e with ethyl cyanoacetate
ester in the presence of base gave 1-carboxylic-3-cyano-
azulene derivatives (3c–e) as summarized in Table 2. The
decarboxylation and elimination of cyano group of 3c–e
was conducted in the same reaction conditions, in which
the best yield of 4b was obtained as shown in Table 3.
2-Alkylazulenes bearing primary alkyl chain (4b and
4d) were obtained in higher yields, on the other hand
the yields of those bearing secondary alkyl chain (4c
and 4e) were relatively lower due to the stability of the
resulting azulenes under acidic condition at high temper-
ature. Longer reaction time resulted in the decrease of
the yield of 4.
Table 1. Reaction condition and yield of 4b, 5b, and 6ba
Condition
Reaction time (h)
4b (%)
5b (%)
6b (%)
65% H3PO4
85% H3PO4
50% H2SO4
75% H2SO4
75% H2SO4
75% H2SO4
4
0
12
100
88
96
0
0
0
4
4
4
0
4
84b
100
29
0
2
0.25
0
58
0
13
Reaction temperature: 110°C.
a Yield by GC analysis.
b Unidentified product was observed.

N. Iwama et al. / Tetrahedron Letters 45 (2004) 9211–9213
9213
3. General procedures for the synthesis of 2-alkylazulene
References and notes
1. (a) Ewen, J. A. J. Am. Chem. Soc. 1984, 106, 6355; (b)
Kaminsky, W.; Kulper, K.; Brintzinger, H.-H.; Wild, F.
¨
3.1. Synthesis of 3-propionyl 2H-cyclohepta[b]furan-2-one
(2b)
Angew. Chem., Int. Ed. Engl. 1985, 24, 507; (c) Mo¨hring,
P. C.; Coville, N. J. J. Organomet. Chem. 1994, 479, 1; (d)
Brintzinger, H.-H.; Fischer, D.; Mulhaupt, R.; Rieger, B.;
¨
Waymouth, R. M. Angew. Chem., Int. Ed. Engl. 1995, 34,
1143; (e) Resconi, L.; Cavallo, L.; Fait, A.; Piemontesi, F.
Chem. Rev. 2000, 100, 1253.
Tropolone p-toluenesulfonate (8.07g, 29.2mmol)
and ethyl propionylacetate (6.2mL, 43.8mmol) were sus-
pended in ethanol (30mL). To the mixture was added a
solution of sodium ethoxide, prepared from ethanol
(60mL) and sodium (806mg, 35.1mmol) at 0°C. The
mixture was stirred at room temperature overnight and
at 50°C for 45min. To the resultant mixture was added
cold water and the resulting precipitate was separated
by filtration, washed with cold water, dried at 50°C
under reduced pressure to give 2b (3.62g, 61%). 1H
NMR (400MHz, CDCl3) d 1.18 (t, J = 7Hz, 3H, CH3),
3.07 (q, J = 7Hz, 2H, CH2), 7.30–7.45 (m, 1H), 7.50–
7.60 (m, 2H), 7.65–7.70 (m, 1H), 9.23 (d, J = 12Hz, 1H).
2. Spaleck, W.; Antberg, M.; Rohrmann, J.; Winter, A.;
Bachmann, B.; Kiprof, P.; Behm, J.; Herrmann, W. A.
Angew. Chem., Int. Ed. Engl. 1992, 31, 1347.
3. Iwama, N.; Uchino, H.; Osano, T. Y.; Sugano, T.
Organometallics 2004, 23, 3267.
4. (a) Gordon, M. Chem. Rev. 1952, 50, 127; (b) Zeller, K.-P.
In Methoden der Organischen Chemie (Houben-Weyl);
Kropf, H., Ed.; Georg Thieme: Stuttgart, 1985; Vol. V/2c,
p 127.
5. (a) Plattner, P. A.; Wyss, J. Helv. Chim. Acta 1941, 24,
483; (b) Wada, E.; Nakai, T.; Okawara, M. Chem. Lett.
1976, 1025.
6. (a) Nozoe, T.; Takase, K.; Nakazawa, T.; Fukuda, S.
Tetrahedron 1971, 27, 3357; (b) Alder, R. W.; Wilshire, C.
J. Chem. Soc., Perkin Trans. 2 1975, 1464; (c) Nozoe, T.;
Seto, S.; Matsunami, S. Bull. Chem. Soc. Jpn. 1962, 35,
1990; (d) Yasunami, M.; Takase, K. Japan Patent Appli-
cation 62/207232, 1987 (Takasago Perfumery); Chem.
Abstr. 1987, 108, 221338.
7. (a) Herz, W. J. Am. Chem. Soc. 1956, 78, 1485; (b) Jacob,
T. M.; Vatakencherry, P. A.; Dev, S. Tetrahedron 1964,
20, 2815.
8. (a) Kato, N.; Fukazawa, Y.; Ito, S. Tetrahedron Lett.
1976, 2045; (b) Balschukat, D.; Dehmlow, E. V. Chem.
Ber. 1986, 119, 2272, and references cited therein.
9. (a) Yasunami, M.; Chen, A.; Yang, P. W.; Takase, K.
Chem. Lett. 1980, 579; (b) Takase, K.; Yasunami, M. J.
Synth. Org. Chem., Jpn. 1981, 39, 1172.
10. Nozoe, T.; Takase, K.; Kato, M.; Nogi, T. Tetrahedron
1971, 27, 6023.
11. Acetyl 2H-cyclohepta[b]furan-2-one (2a) was also pre-
pared from tropolone p-toluenesulfonate (1) in a good
yield in our laboratory.
3.2. Synthesis of 1-cyano-2-ethylazulene-3-carboxylic
acid (3b)
To a suspension of 2b (3.62g, 17.9mmol) and 2equiv of
cyanoacetic acid ethyl ester (3.8mL, 35.8mol) in ethanol
(50mL) was added a solution of sodium ethoxide, pre-
pared from ethanol (80mL) and sodium (1.65g,
71.7mmol) at 0°C. The mixture was stirred at room tem-
perature overnight, the resultant mixture was concen-
trated. To the mixture was added cold water (200mL)
and extracted with dichloromethane. After the organic
phase was separated, to the aqueous solution was added
aqueous hydrochloric acid (1mol/L). The resulting pre-
cipitate was separated by filtration, washed with cold
water, dried at 50°C under reduced pressure to give 3b
1
(3.73g, 93%). H NMR (400MHz, CDCl3) d 1.45 (t,
J = 7Hz, 3H, CH3), 3.47 (q, J = 7Hz, 2H, CH2), 7.78–
7.88 (m, 2H), 8.01 (t, J = 10Hz, 1H), 8.71 (d,
J = 10Hz, 1H), 9.78 (d, J = 10Hz, 1H).
3.3. Synthesis of 2-ethylazulene (4b)
12. Doering, W. E.; Hiskey, C. F. J. Am. Chem. Soc. 1952, 74,
5688.
To a 75% aqueous solution of sulfuric acid (30mL)
was added 3b (3.7g, 16.4mmol) gradually and the
mixture was heated at 90°C for 2h and at 120°C for
further 2h. The obtained mixture was cooled, poured into
an aqueous solution of sodium hydroxide (35g), and
extracted with hexane–ethyl acetate. The extract was
washed with water, concentrated, and purified by silica
gel column chromatography (eluent: hexane) to give 4b
13. Similar reaction with aq H2SO4 for the synthesis of 2-
methylazulene (4a) was reported in Ref. 6a and following
patent: Takuma, Y.; Okamoto, K.; Mizuho, Y.; Mura-
kami, T.; Iwama. N. Japan Patent Application 11/005755,
1999 (Mitsubishi Chemical Corp.); Chem. Abstr. 1999,
130, 124834.
14. b-Oxo ester for the synthesis of 2e was prepared from acid
chloride and potassium ethyl malonate in 72% yield. See:
Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J.
Synthesis 1993, 290, b-Oxo esters for 2b–d were commer-
cially available.
1
as a violet crystal (1.71g, 67%). H NMR (400MHz,
CDCl3) d 1.43 (t, J = 7Hz, 3H, CH3), 3.05 (q, J = 7Hz,
2H, CH2), 7.16 (t, J = 10Hz, 2H), 7.25 (s, 2H), 7.51 (t,
J = 10Hz, 1H), 8.23 (d, J = 10Hz, 2H).
15. Seto, S. Sci. Repts. Tohoku Univ., Ser. I 1953, 37, 367.
Chem. Abstr. 1953, 49, 8234.