Solvent-free synthesis of azulene derivatives via Passerini reaction by grinding

Article abstract of DOI:10.1016/j.tetlet.2012.11.148

An efficient and convenient approach to the synthesis of azulene derivatives bearing a carboxamide unit based on solvent-free Passerini reaction, using grinding is described. This method provides several advantages such as high efficiency, operational sim

Full text of DOI:10.1016/j.tetlet.2012.11.148

Tetrahedron Letters 54 (2013) 661–664
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solvent-free synthesis of azulene derivatives via Passerini reaction by grinding
⇑
Koichi Sato , Takumi Ozu, Naoko Takenaga
Department of Chemical Science and Technology, Faculty of Bioscience and Applied Chemistry, Hosei University, Kajino-cho 3-7-2, Koganei, Tokyo 184-8584, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and convenient approach to the synthesis of azulene derivatives bearing a carboxamide unit
based on solvent-free Passerini reaction, using grinding is described. This method provides several advan-
tages such as high efficiency, operational simplicity, and mild conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 30 October 2012
Revised 29 November 2012
Accepted 30 November 2012
Available online 7 December 2012
Keywords:
Azulene
Solvent-free
Passerini reaction
Grinding
Azulene derivatives have been widely used in the design of
pharmacologically active compounds and advanced organic mate-
rials because of their numerous applications;1,2 the focus has been
on azulenes containing a nitrogen atom.3 Aminoazulene deriva-
tives have been synthesized via several routes. A general approach
to the preparation of aminoazulenes involves reduction of nitro-
azulene or azuleneazobenzene derivatives which are prepared by
aromatic electrophilic substitution.4 N,N-Acetylazulylamine may
be obtained by Beckmann rearrangement of the oxime of acetyl-
azulene.4a Recently, direct amination or palladium-catalyzed ami-
nation of azulene at the 2-position was reported.5 Even though
these methods have undisputed utility, other practical and more
efficient methods of obtaining aminoazulenes are also needed.
Guaiazulene, 7-isopropyl-1,4-dimethylazulene, is a known ac-
tive component of the essential oil of Guaiacum officinalis L., and
there are a number of reports describing the anti-allergenic- and
anti-inflammatory activities of guaiazulene derivatives.6 For exam-
ple, guaiazulene sodium sulfonate, a hydrophilic derivative, has
found widespread clinical applications as anti-inflammatory and
anti-ulcer agents.7 Over the past few decades, we have been inves-
tigating the development of convenient and safe methods for syn-
introduced using the well-known and attractive Passerini reaction,
which meets the need for practical and efficient library preparation
of bioactive compounds with several structural diversities.10 In this
context, we previously found the Passerini reaction of 3-isocyano-
7-isopropyl-1,4-dimethylazulene (1) with aldehydes and carbox-
ylic acids in organic solvents, which furnished azulene derivatives
bearing a carboxamide chain in moderate yields.11 With the drive
to establish greener synthetic processes, we also attempted the
aqueous Passerini reaction and achieved the synthesis of azulene
derivatives bearing a carboxamide unit in water, using a surfac-
tant.11 Notwithstanding the environmental benefit derived from
the use of aqueous media instead of organic solvents, the surfac-
tant was not recyclable.
In view of the escalating demand for more ecologically friendly
chemical processes in the agrochemical and pharmaceutical indus-
tries, solvent-free reactions are attractive because of their high effi-
ciency, operational simplicity, and lower attendant costs.12
Solvent-free reactions using mechanical grinding have been re-
ported for Grignard reaction, Reformatsky reaction, aldol conden-
sation, Knoevenagel condensation, etc.13 In these solvent-free
reactions, it is known that reactivity is generally increased as a re-
sult of the intimacy of the reagents. Herein, we describe an envi-
ronmentally friendly method for synthesizing azulene derivatives
bearing a carboxamide unit by means of a solvent-free Passerini
reaction.
thesizing azulene derivatives from guaiazulene, which is
a
commercially available and cheap starting material.8 Under the
overarching goal of finding agents that have attractive biological
activities, we have attempted to introduce pharmacologically ac-
tive skeletons into the guaiazulene framework. The
a
-acyloxycarb-
The synthesis of 1 was accomplished from the known 5-isopro-
oxamide group is one such functional motif that is commonly
pyl-3,8-dimethylazulene-1-carbaldehyde 214 using
a two-step
found in pharmacologically active compounds9 and can be readily
conversion sequence (Scheme 1). A solution of 2 and hydroxyl-
amine hydrochloride in ethanol was heated under reflux for 1 h,
followed by transformation into isonitrile 115 by treatment with
2-chloro-1,3-dimethylimidazolium chloride (DMC) and 1,4-diaza-
bicyclo[2.2.2]octane (DABCO).16 The structure of 1 was confirmed
⇑
Corresponding author. Tel.: +81 42 387 6127; fax: +81 42 387 7002.
E-mail address: sato@hosei.ac.jp (K. Sato).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.148

662
K. Sato et al. / Tetrahedron Letters 54 (2013) 661–664
the solid phase, and the combined reagents were mixed in a mortar
and ground with a pestle. The reaction proceeded smoothly to
completion within 20 min to furnish the corresponding Passerini
product 5a in 81% yield (Table 1, entry 1). In the presence of THF
solvent, 5a was obtained in 45% yield and 55% of 1 was recovered
even after 18 h (entry 2). In addition to the simplicity and cleanli-
ness of the procedure, the solvent-free reaction proceeded much
more rapidly than the solution-phase counterpart. The use of other
organic solvents was also ineffective and resulted in lower yields.
The aqueous conditions, which we previously successfully used,
were also revisited: the aqueous Passerini reaction using CTAB as
a surfactant gave 5a in 72% yield (entry 3).
All of the starting materials used in this solvent-free reaction
were initially in the solid state. However, as the reaction pro-
ceeded, it was observed that the mixture which was initially par-
ticulate liquefied, and eventually solidified to generate the
Passerini product. The reaction temperature was monitored to en-
sure that the temperature of this system did not rise to the melting
points of the reagents as a result of mixing. In the course of the
grinding reaction, the temperature increased by 4–5 °C as a result
a
b
NC
CHO
1
2
Scheme 1. Preparation of 3-isocyano-7-isopropyl-1,4-dimethylazulene, 1.
Reagents and conditions; (a) NH2OHÁHCl (3.0 equiv), EtOH, NaOH aq, reflux, 1 h;
(b) 2-Chloro-1,3-dimethylimidazolium chloride (1.0 equiv), 1,4-diazabicy-
clo[2.2.2]octane (2.0 equiv), CH2Cl2, rt, 2 h, 88% for two steps.
by spectral and elemental analyses.17 Isonitrile 1 occurs as dark-
green needles that are stable for months when refrigerated and
protected from light. No isomerization of isonitrile 1 into the nitrile
form was observed. Notably, 1 does not have the objectionable
odor typical of isonitriles, making it more amenable as a reagent
for solvent-free grinding reactions.
Isonitrile 1 (1.0 equiv) was combined with 2.0 equiv of p-chlo-
robenzaldehyde (3a) and 2.0 equiv of decanoic acid (4a), all in
Table 1
Comparison of yields from solvent-free Passerini reaction with those under other conditions
Cl
CHO
Conditions
CH3(CH2)8COOH
1
O
r.t.
HN
O
C9H19
Cl
O
3a
4a
5a
Entry
Solvent
Time
Yield (%)
1
None
THF
H2O
20 min
18 h
20 h
81
2
45 (54)b
3a
72 (16)
b
a
Reaction was performed using 0.5 equiv of cetyltrimethylammonium bromide [CTAB, (C16H33N(CH3)3Br)] as a surfactant.
Yield in parentheses is recovery of 3-isocyano-7-isopropyl-1,4-dimethylazulene, 1.
b
Table 2
Scope and limitations of solvent-free Passerini reaction
X
CHO
Solvent-free
RCOOH
O
O
grinding
r.t.
HN
NC
R
X
O
3
4
5
1
Entry
X
R
Mpa (°C)
Product
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Cl (3a)
Br (3b)
Cl (3a)
Cl (3a)
Br (3b)
Cl (3a)
Cl (3a)
Cl (3a)
Br (3b)
Cl (3a)
Cl (3a)
Br (3b)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
CH3(CH2)8 (4a)
30–32
48
62–63
121–124
121–124
164
140–143
154–158
154–158
239–243
144–149
140–144
239–243
103
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
20
15
20
20
20
7
5
7
7
10
5
5
5
15
5
20
81
71
CH3(CH2)10 (4b)
CH3(CH2)14 (4c)
C6H5 (4d)
C6H5 (4d)
1-Naphthyl (4e)
o-ClC6H4 (4f)
m-ClC6H4 (4g)
m-ClC6H4 (4g)
p-ClC6H4 (4h)
o-NO2C6H4 (4i)
m-NO2C6H4 (4j)
p-NO2C6H4 (4k)
o-MeOC6H4 (4l)
m-MeOC6H4 (4m)
p-MeOC6H4 (4n)
51 (35)b
91
84
82
79
73
84
29 (69)b
52
51
45 (29)b
78
107
184
72
35 (48)b
a
Melting points of carboxylic acids, 4.
Yield in parentheses is recovery of 3-isocyano-7-isopropyl-1,4-dimethylazulene, 1.
b

K. Sato et al. / Tetrahedron Letters 54 (2013) 661–664
663
5. Yokoyama, R.; Ito, S.; Okujima, T.; Kubo, T.; Yasunami, M.; Tajiri, A.; Morita, N.
Tetrahedron 2003, 59, 8191.
6. Yamazaki, H.; Irono, S.; Uchida, A.; Ohno, H.; Saito, N.; Kondo, K.; Jinzenji, K.;
Yamamoto, T. Nippon Yakurigaku Zasshi 1958, 54, 362.
7. Okabe, S.; Takeuchi, K.; Honda, K.; Ishikawa, M.; Takagi, K. Oyo Yakuri 1975, 9,
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8. (a) Sato, K.; Yamaguchi, M.; Ogura, I. Nippon Kagaku Kaishi 1982, 1199; (b) Sato,
K.; Arifuku, N.; Takigawa, T. Abstracts of papers, The 45th Symposium on the
Chemistry of Terpenes, Essential Oils, and Aromatics, October 2001, p 162.; (c)
Sato, K.; Nakagawa, K.; Ozu, T. Abstracts of papers, The 90th Annual Meeting of
the Chemical Society of Japan, Osaka, March 2010, 2PB-068.
of frictional heat. However, as anticipated, the temperature re-
mained below 29 °C, which is lower than the melting points of
the reagents (1: 56 °C, 3a: 46 °C, 4a: 32 °C). It is postulated that this
solvent-free reaction based on the grinding of several solids to-
gether involves the formation of a liquid phase prior to reaction,
that is, formation of a eutectic melt of uniform distribution in
which the reacting components, being in close proximity, are
poised to react.
The scope of this solvent-free system was explored, using sev-
eral types of carboxylic acids. Selected examples are summarized
in Table 2.18 The melting points of the carboxylic acids 4a–4n are
also shown in the table (The melting points of 3a and 3b are
46 °C and 57 °C, respectively). All reactions were completed within
20 min. The aliphatic carboxylic acids 4a–c generally afforded the
corresponding compounds 5a–c in good to moderate yields (en-
tries 1–3). The yields of 5c were lower than the yields of 5a and
5b obtained using decanoic acid 4a and lauric acid 4b. This seemed
to be mainly the result of inefficient mixing because of the high
melting point of palmitic acid 4c. Various aromatic carboxylic acids
4d–n were also tolerated in the reaction (entries 4–16). Although
both electron rich and electron deficient carboxylic acids could
be used, reactions using carboxylic acids with high melting points,
especially para-substituted benzoic acids 4h, 4k, and 4n did not
proceed to completion, with consequently low yields (entries 10,
13, and 16).
In summary, the facile and green synthesis of azulene deriva-
tives bearing a carboxamide unit was demonstrated: these prod-
ucts may be useful intermediates for the development of
biologically active agents containing the azulene skeleton. The syn-
thetic merits of the present technique include high efficiency (high
yields and short reaction times), simple work-up, and mild condi-
tions (reactions were carried out under ambient conditions).19 The
facile and efficient synthesis of other azulene derivatives under
solvent-free conditions is now in progress in our laboratory.
9. Doming, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. references cited
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10. (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126; (b) Banfi, L.; Riva, R. Org. React.
2005, 65, 1–140.
11. Unpublished results.
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Kishigami, S.; Toda, F. J. Org. Chem. 1991, 56, 4333; (e) Schmeyers, T.; Toda, F.;
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14. Hafner, K.; Bernhard, C. Angew. Chem. 1957, 69, 533. 5-isopropyl-3,8-
dimethylazulene-1-carbaldehyde 2: violet needles, mp: 82–83 °C. 1H NMR
(CDCl3) d: 1.37 (6H, d, J = 6.8 Hz), 2.57 (3H, s), 3.13 (3H, s), 3.14 (1H, sept,
J = 6.8 Hz), 7.41 (1H, d, J = 10.8 Hz), 7.56 (1H, dd, J = 2.0, 10.8 Hz), 8.21 (1H, s),
8.27 (1H, d, J = 2.0 Hz), 10.62 (1H, s).
15. As the first isocyanoazulene, 6-isocyanoazulene was synthesized from 6-
aminoazulene. See: Robinson, R. E.; Holovics, T. C.; Deplazes, S. F.; Lushington,
G. H.; Powell, D. R.; Barybin, M. V. J. Am. Chem. Soc. 2003, 125, 4432.
16. 2-chloro-1,3-dimethylimidazolium chloride (DMC) could act as a dehydrating
agent. See: Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984.
17. 3-isocyano-7-isopropyl-1,4-dimethylazulene 1: dark green needles, mp: 56 °C. 1
H
References and notes
NMR (CDCl3) d: 1.31 (6H, d, J = 6.8 Hz), 2.55 (3H, s), 3.00 (1H, sept, J = 6.8 Hz),
3.14 (3H, s), 6.97 (1H, d, J = 10.8 Hz), 7.40 (1H, dd, J = 2.0, 10.8 Hz), 7.51 (1H, d,
J = 2.0 Hz), 8.13 (1H, t, J = 2.0 Hz). Anal. Calcd for C16H17N: C, 86.05; H, 7.67; N,
6.27. Found: C, 85.96; H, 7.74; N, 6.16.
1. (a) Hamajima, R.; Iwano, K.; Okuda, H. Yakugaku Zasshi 1978, 98, 1101; (b)
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18.
A typical procedure of solvent-free Passserini reaction: (Table 2, entry 2): a
mixture of 1 (0.20 mmol), 3b (0.40 mmol), and 4b (0.40 mmol) was thoroughly
mixed in an agate mortar and grinded with a pestle manually until the
completion of the reaction (a mixture which was initially particulate liquefied
and eventually solidified to generate the Passerini product 5). The resultant
material was extracted with chloroform and washed with water, dried
(Na2SO4), and concentrated. The residue was purified by silica gel column
chromatography (hexane/acetone as eluent) to give 5b as blue prisms (71%).
mp: 85 °C. 1H NMR (CDCl3) d: 0.86–0.89 (3H, m), 1.24–1.29 (16H, m), 1.32 (6H,
d, J = 7.2 Hz), 1.69 (2H, quiq, J = 7.6 Hz), 2.50 (2H, t, J = 7.6 Hz), 2.58 (3H, s), 2.84
(3H, s), 2.99 (1H, sept, J = 6.8 Hz), 6.27 (1H, s), 6.72 (1H, d, J = 10.8 Hz), 7.24 (1H,
dd, J = 2.0, 10.8 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.54 (2H, d, J = 8.4 Hz), 7.93 (1H, s),
8.04 (1H, d, J = 2.0 Hz), 8.55 (NH, s). Anal. Calcd for C35H46BrNO3: C, 69.07; H,
7.62; N, 2.30. Found: C, 68.77; H, 7.83; N, 2.22. Compound 5e: blue prisms, mp:
197 °C. 1H NMR (CDCl3) d: 1.31 (6H, d, J = 7.2 Hz), 2.58 (3H, s), 2.74 (3H, s), 2.98
(1H, sept, J = 6.8 Hz), 6.55 (1H, s), 6.67 (1H, d, J = 10.8 Hz), 7.22 (1H, dd, J = 2.0,
10.8 Hz), 7.50–7.58 (6H, m), 7.64–7.67 (1H, m), 7.96 (1H, s), 8.30 (1H, d,
J = 2.0 Hz), 8.15 (2H, dd, J = 1.2, 8.4 Hz), 8.58 (NH, s). Anal. Calcd for
C30H28BrNO3: C, 67.93; H, 5.32; N, 2.64. Found: C, 67.99; H, 5.50; N, 2.59.
Compound 5g: blue prisms, mp: 197 °C. 1H NMR (CDCl3) d: 1.31 (6H, d,
J = 6.8 Hz), 2.58 (3H, s), 2.73(3H, s), 2.98 (1H, sept, J = 6.8 Hz), 6.53 (1H, s), 6.69
(1H, d, J = 10.8 Hz), 7.23 (1H, dd, J = 2.0, 10.4 Hz), 7.37–7.41 (3H, m), 7.51–7.61
(4H, m), 7.85 (1H, s), 7.96 (1H, d, J = 7.6 Hz), 8.04 (1H, d, J = 2.0 Hz), 8.67 (NH, s).
Anal. Calcd for C30H27Cl2NO3: C, 69.23; H, 5.23; N, 2.69. Found: C, 69.21; H,
5.34; N, 2.66. Compound 5h: blue prisms, mp: 219 °C. 1H NMR (CDCl3) d: 1.31
(6H, d, J = 6.8 Hz), 2.58 (3H, s), 2.74 (3H, s), 2.98 (1H, sept, J = 6.8 Hz), 6.52 (1H,
s), 6.68 (1H, d, J = 10.8 Hz), 7.22 (1H, dd, J = 2.0, 10.4 Hz), 7.37–7.62 (6H, m),
7.94 (1H, s), 8.02 (1H, s), 8.03 (1H, d, J = 2.0 Hz), 8.10 (1H, t, J = 2.0 Hz), 8.47
(NH, s). Anal. Calcd for C30H27Cl2NO3: C, 69.23; H, 5.23; N, 2.69. Found: C,
69.09; H, 5.36; N, 2.70. Compound 5i: blue prisms, mp: 230 °C. 1H NMR (CDCl3)
d: 1.31 (6H, d, J = 6.8 Hz), 2.58 (3H, s), 2.74 (3H, s), 2.98 (1H, sept, J = 6.8 Hz),
6.51 (1H, s), 6.69 (1H, d, J = 10.8 Hz), 7.46 (1H, t, J = 8.0 Hz), 7.51–7.63 (6H, m),
7.94 (1H, s), 8.02 (1H, s), 8.04 (1H, d, J = 2.0 Hz), 8.11 (1H, s), 8.47 (NH, s). Anal.
Calcd for C30H27BrClNO3: C, 63.79; H, 4.82; N, 2.48. Found: C, 63.90; H, 4.92; N,
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Y.; Ito, S. Tetrahedron Lett. 2012, 53, 1493.
4. (a) Anderson, A. G.; Nelson, J. A.; Tazuma, J. J. J. Am. Chem. Soc. 1953, 75, 4980;
(b) Anderson, A. G., Jr.; Frjtz, C. G.; Scotoni, R., Jr. J. Am. Chem. Soc. 1957, 79,
6511; (c) Anderson, A. G., Jr.; Scotoni, R., Jr.; Cowles, E. J.; Fritz, C. G. J. Org. Chem.
1957, 22, 1193.

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2.50. Compound 5k: blue prisms, mp: 219 °C. 1H NMR (CDCl3) d: 1.31 (6H, d,
(1H, s), 8.25 (NH, s), 8.30–8.35 (4H, m). Anal. Calcd for C30H27ClN2O5: C, 67.86;
H, 5.13; N, 5.28. Found: C, 67.57; H, 5.13; N, 5.19.
J = 7.2 Hz), 2.58 (3H, s), 2.69 (3H, s), 2.99 (1H, sept, J = 6.8 Hz), 6.46 (1H, s),
6.70–6.73 (1H, d, J = 10.8 Hz), 7.22 (1H, m), 7.46 (2H, d, J = 8.4 Hz), 7.57 (2H, d,
J = 8.4 Hz), 7.72–7.75 (2H, m), 7.78 (1H, s), 7.88–7.89 (1H, m), 7.95–7.98 (1H,
m), 8.05 (1H, d, J = 2.0 Hz), 8.03 (NH, s). Anal. Calcd for C30H27BrN2O5: C, 62.62;
H, 4.73; N, 4.87. Found: C, 62.72; H, 4.84; N, 4.86. Compound 5m: blue prisms,
mp: 197 °C. 1H NMR (CDCl3) d: 1.31 (6H, d, J = 6.8 Hz), 2.57 (3H, s), 2.66 (3H, s),
2.98 (1H, sept, J = 7.2 Hz), 6.50 (1H, s), 6.68 (1H, d, J = 10.4 Hz), 7.23 (1H, d,
J = 10.8 Hz), 7.45 (2H, d, J = 8.4 Hz), 7.59 (2H, d, J = 8.4 Hz), 7.89 (1H, s), 8.04
19. Solvent-free Passerini reactions for simple substrates at high temperature or
under microwave irradiation were recently reported. See: (a) Bousquet, T.; Jida,
M.; Soueidan, M.; Deprez-Poulain, R.; Agbossou-Niedercorn, F.; Pelinski, L.
Tetrahedron Lett. 2012, 53, 306; (b) Barreto, A. F.; Vercillo, O. E.; Andrade, C. K. Z.
J. Braz. Chem. Soc. 2011, 22, 462; (c) Koszelewski, D.; Szymanski, W.; Krysiak, J.;
Ostaszewski, R. Synth. Commun. 2008, 38, 1120.