Facile synthesis of guaiazulene-heterocycle hybrids via multicomponent reactions involving formation of zwitterionic intermediates

Article abstract of DOI:10.3987/COM-13-12680

The synthesis of a series of guaiazulene-heterocycle hybrids via zwitterionic intermediates was performed. The multicomponent reactions of 3-isocyano-7-isopropyl-1,4-dimethylazulene 1, dimethyl acetylenedicarboxylate 2, and a third reactant 3 (cyclic CH-acids, phenols, aldehydes or amines) proceeded to afford heterocyclic guaiazulene derivatives 4.

Full text of DOI:10.3987/COM-13-12680

HETEROCYCLES, Vol. 87, No. 4, 2013
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HETEROCYCLES, Vol. 87, No. 4, 2013, pp. 807 - 814. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 12th February, 2013, Accepted, 26th February, 2013, Published online, 7th March, 2013
DOI: 10.3987/COM-13-12680
FACILE SYNTHESIS OF GUAIAZULENE-HETEROCYCLE HYBRIDS
VIA MULTICOMPONENT REACTIONS INVOLVING FORMATION OF
ZWITTERIONIC INTERMEDIATES
Koichi Sato,* Erina Yokoo, and Naoko Takenaga
Department of Chemical Science and Technology, Faculty of Bioscience and
Applied Chemistry, Hosei University, Kajinocho 3-7-2, Koganei, Tokyo,
184-8584, Japan
*Corresponding author. Tel.: +81-42-387-6127; fax: +81-42-387-7002; e-mail:
sato@hosei.ac.jp (K. Sato)
Abstract – The synthesis of a series of guaiazulene-heterocycle hybrids via
zwitterionic intermediates was performed. The multicomponent reactions of
3-isocyano-7-isopropyl-1,4-dimethylazulene 1, dimethyl acetylenedicarboxylate 2,
and a third reactant 3 (cyclic CH-acids, phenols, aldehydes or amines) proceeded
to afford heterocyclic guaiazulene derivatives 4.
Azulene derivatives are widely used in the design of pharmaceutically active compounds and advanced
organic materials because of their numerous applications.1,2 In particular, azulenes bearing a heterocycle
have attracted much attention because of their promising properties.3 Therefore, efficient and facile
approaches to introducing heterocycles into the azulene skeletons have been extensively explored.4 A
general approach to the preparation of heteroarylazulene derivatives involves transition-metal-catalyzed
coupling reactions with haloazulenes or azulenyl-metal reagents.3,4f-4g Though this method is versatile and
reliable and is widely used, but it sometimes requires synthetically difficult starting materials. Imafuku
and coworkers stepwise introduced a pyridine ring into azulenes via the prepared azulene derivatives
bearing an , -unsaturated ketone in a side chain.4h Recently Shoji and coworkers established an
efficient and unique strategy using triflates of N-containing heteroarenes, and succeeded in preparing
various heteroarylazulenes.4i-4p Although these methods are undoubtedly useful, most of these studies did
not use guaiazulene, which is a practical and cheap starting material for synthesizing azulene nucleus.
Guaiazulene (7-isopropyl-1,4-dimethylazulene), derived from an abundant sesquiterepene, is a known

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HETEROCYCLES, Vol. 87, No. 4, 2013
active component of the essential oil of Guaiacum officinalis L., and many reports have described the
anti-allergenic- and anti-inflammatory activities of guaiazulene derivatives.5 For example, guaiazulene
sodium sulfonate, a hydrophilic guaiazulene derivative, has found widespread clinical applications as
anti-inflammatory and anti-ulcer agents.6 Since the past few decades, we have been investigating the
development of convenient and safe methods for synthesizing azulene derivatives from guaiazulene,
which is a commercially available and cheap starting material.7 In order to find agents that have attractive
biological activities, we have attempted to introduce pharmacologically active skeletons into the
guaiazulene framework. However, the use of guaiazulene as a starting material puts additional limitations
on the reactive positions because of the occupied 1,4,7-substituted positions, which could cause steric
hindrance in various reactions. At the same time, such investigations are worthwhile in view of the
increasing demand for more practical processes in the pharmaceutical industry. For example, Yin and
coworkers recently reported that a simple modified guaiazulene derivative possessed excellent in vivo
anti-gastric ulcer activity.8 In this paper, we describe a simple approach to prepare of guaiazulene
derivatives bearing a heterocycle.
Multicomponent reactions (MCRs),9 especially isocyanide based MCRs (IMCRs),10 meet the need for
practical and efficient preparation of libraries of structurally diverse compounds. It has been shown that
the addition of isocyanide to dimethyl acetylenedicarboxylate (DMAD, 2) generates reactive zwitterionic
species, which can be captured by a third component to form diverse heterocyclic scaffolds.10c We
investigate several IMCRs of 2 with 3-isocyano-7-isopropyl-1,4-dimethylazulene 1,7d which is readily
prepared in two steps.
In a pilot experiment, 1, 2, and 4-hydroxy-2H-chromen-2-one 3a were stirred in several different organic
solvents at room temperature (Table 1).11 The reaction proceeded smoothly in dichloromethane and
afforded the desired guaiazulene-heterocycle hybrid 4a in 72% yield (Entry 1). Acetonitrile and
tetrahydrofuran as solvents also gave 4a in moderate yields (Entries 2 and 3), but the use of ethanol was
ineffective and resulted in a lower yield (Entry 4).
Table 1. Solvent screening
OH
O
CO2Me
solvent
rt
O
O
HN
O
O
CO2Me
NC
MeO2C
CO2Me
1
2
3a
4a

HETEROCYCLES, Vol. 87, No. 4, 2013
809
Entry
1
Solvent
Time
22 h
Yield (%)
72
CH2Cl2
2
3
4
MeCN
THF
24 h
24 h
23 h
62
66
19
EtOH
To explore the scope of IMCR of 1 and 2, we extended it to include a third reactant as shown in Table 2.
The use of 2-hydroxynaphthalene-1,4-dione 3b gave the desired 4H-benzo[g]chromene-3,4-dicarboxylate
derivative 4b (Entry 2). Phenols 3c and 3d afforded the
corresponding guaiazulene-chromene hybrids 4c and 4d in
moderate yields (Entries 3 and 4). Once we had ascertained that the
reactive zwitterionic intermediate generated by 1 and 2 (Figure 1)
N
could be trapped by a third component, other IMCRs were also
examined. The use of aldehydes12 3e-3i afforded the desired furan
MeO2C
CO2Me
hybrids 4e-4i in 50-64% yields (Entries 5-9), while the treatment of
amines13 3j and 3k gave the corresponding 1,2-dihydropyridine
hybrids 4j and 4k in 20% and 38% yields respectively (Entries 10
Figure 1. zwitterionic intermediate
and 11). It seemed that the reactivity of sterically demanding isocyanide 1 was fairly different from that
of simple alkylisocyanides; steric repulsion between 4-methyl group of azulene ring and methyl
carboxylate of 1,2-dihydropyridine ring presumably resulted in low yields.14
Table 2. Synthesis of guaiazulene-heterocycle hybrids 4a
CO2Me
CH2Cl2
3
rt
HN Heterocycles
NC
CO2Me
2
4
1
Entry
1
3
Time (h)
22
Product 4
Yield (%)b
72
OH
O
O
O
O
HN
O
CO2Me
MeO2C
3a
4a

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HETEROCYCLES, Vol. 87, No. 4, 2013
O
O
O
2
20
51
OH
O
O
HN
CO2Me
MeO2C
3b
4b
OH
3
4
20
20
57
55
O
O
HN
O
CO2Me
MeO2C
4c
3c
O
O
MeO
OH
O
OMe
CO2Me
HN
MeO2C
3d
3e
4d
5
20
60
CHO
O
HN
CO2Me
MeO2C
4e
Cl
CHO
6
7
8
20
20
20
63
52
50
O
Cl
HN
CO2Me
MeO2C
3f
4f
CHO
Br
O
Br
HN
CO2Me
3g
MeO2C
4g
CO2H
CHO
O
HO2C
HN
CO2Me
MeO2C
3h
4h

HETEROCYCLES, Vol. 87, No. 4, 2013
811
9
20
64
20
CHO
O
HN
CO2Me
MeO2C
3i
3j
4i
10 c
24
22
NH2
CO2Me
CO2Me
Cl
HN
Cl
N
MeO2C
CO2Me
4j
11 c
38
NH2
CO2Me
CO2Me
MeO
HN
N
MeO2C
3k
MeO2C
OMe
4k
a Reactions were performed with 1.0 equiv of isocyanide 1, 2.0 equiv of 2, and 2.0 equiv of 3 , unless otherwise noted.
b Isolated yields after purification.
c 3.0 equiv of 2 were used.
In summary, we successfully synthesized a series of guaiazulene derivatives bearing a heterocycle via
IMCRs involving the reactive zwitterionic intermediate generated by readily available 1 and 2. The merits
of this procedure include operational simplicity and mild condition (reactions were carried out at room
temperature). These products may be useful intermediates to develop biologically active agents
containing an azulene nucleus. The practical synthesis of other guaiazulene derivatives is in progress in
our laboratory.
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15. General procedure for the synthesis of guaiazulene-chromene hybrids 4a-4e: (Table 2, entry 1) To a
mixture of 3a (0.40 mmol) and 2 (0.40 mmol) in CH2Cl2 (3 mL), a solution of 1 (0.20 mmol) in
CH2Cl2 (3 mL) was dropwise added over a 10-min period, and the mixture was stirred at room
temperature for 20 h. After completion of the reaction, the resultant mixture was extracted with
CH2Cl2, dried (Na2SO4), and concentrated. The residue was purified using silica gel column
o
chromatography (hexane-acetone as eluent) to give 4a as green needles (72%). Mp 187.7 C.
1H-NMR (CDCl3) δ: 1.37 (6H, d, J = 6.8 Hz), 2.68 (3H, s), 2.92 (3H, s), 3.06 (1H, sept, J = 6.8 Hz),
3.75 (3H, s), 3.82 (3H,s), 4.84 (1H, s), 6.83 (1H, d, J = 10.4 Hz), 7.01-7.08 (2H, m), 7.30-7.33 (2H,
m), 7.47-7.52 (1H, m), 7.57 (1H, s), 8.15 (1H, d, J = 2.4 Hz), 10.65 (NH, s). MS m/z: 527(M+),
100.0% (Calcd for C31H29NO7 (M+): 527.5751). Found: 527.1944.

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16. General procedure for the synthesis of guaiazulene-furan hybrids 4f-4j: (Table 2, entry 6): To a
mixture of 3f (0.40 mmol) and 2 (0.40 mmol) in CH2Cl2 (3 mL), a solution of 1 (0.20 mmol) in
CH2Cl2 (3 mL) was dropwise added over a 10-min period, and the mixture was stirred at room
temperature for 20 h. After completion of the reaction, the resultant mixture was extracted with
CH2Cl2, dried (Na2SO4), and concentrated. The residue was purified using silica gel column
o
chromatography (hexane-acetone as eluent) to give 4f as green needles (60%). Mp 128.8 C.
1H-NMR (CDCl3) δ: 1.33 (6H, d, J = 6.8 Hz), 2.66 (3H, s), 2.98 (1H, sept, J = 6.8 Hz), 3.01 (3H, s),
3.85 (3H, s), 3.94 (3H, s), 6.71 (1H, d, J = 10.4 Hz), 7.22 (2H, d, J = 10.0 Hz), 7.32-7.36 (2H, m),
7.52 (2H, d, J = 7.6 Hz), 7.80 (1H, s), 8.03 (1H, d, J = 2.0 Hz), 9.28 (NH, s). MS m/z: 471 (M+),
100.0% (Calcd for C29H29NO5 (M+): 471.7699). Found: 471.2046.
17. General procedure for the synthesis of guaiazulene-1,2-dihydropyridine hybrids 4k-4l: (Table 2,
entry 11) To a mixture of 3l (0.40 mmol) and 2 (0.60 mmol) in CH2Cl2 (3 mL), a solution of 1 (0.20
mmol) in CH2Cl2 (3 mL) was dropwise added over a 10-min period, and the mixture was stirred at
room temperature for 20 h. After completion of the reaction, the resultant mixture was extracted with
CH2Cl2, dried (Na2SO4), and concentrated. The residue was purified using silica gel column
1
chromatography (hexane-ether as eluent) to give 4l as red brown powder (38%). H-NMR (CDCl3)
δ: 1.30 (6H, d, J = 6.8 Hz), 2.53 (3H, s), 2.94 (1H, sept, J = 6.8 Hz), 3.04 (3H, s), 3.64 (6H, s), 3.80
(6H, s), 3.83 (3H, s), 3.93 (1H, s), 5.50 (NH, s), 6.65 (1H, d, J = 10.0 Hz), 6.89 (4H, d, J = 8.8 Hz),
7.14 (1H, d, J = 8.4 Hz), 7.40 (1H, s), 7.87 (1H, d, J = 2.0 Hz). MS m/z: 630 (M+), 100.0% (Calcd
for C35H38ClN2O9 (M+): 630.9125). Found: 630.2577.