Multicomponent reactions of 1,3-disubstituted 5-pyrazolones and formaldehyde in environmentally benign solvent systems and their variations with more fundamental substrates

Article abstract of DOI:10.1039/b924699a

Many multicomponent reactions (MCRs) of 1,3-disubstituted 5-pyrazolones and formaldehyde were developed in environmentally benign solvent systems. Styrenes, vinylferrocene and 2-phenylindoles could easily react, under solvent-free conditions or in glycerol solvent, with 1,3-disubstituted 5-pyrazolones and paraformaldehyde in the absence of any catalyst to afford a variety of complex skeletons in moderate to excellent yields. Particularly, these MCRs are proved to be combinable with the synthesis of 1,3-disubstituted 5-pyrazolones from phenylhydrazines and β-ketone esters in glycerol or a carboxylic acid-functionalized ionic liquid, [MIm-CO₂H]BF ₄. Therefore, some two-step sequential reactions of phenylhydrazines, β-ketone esters, formaldehyde and styrenes or indoles were developed for the first time. All these MCRs were conducted in environmentally benign solvent systems that not only minimize generation of wastes but also simplify the work-up procedure.

Full text of DOI:10.1039/b924699a

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www.rsc.org/greenchem | Green Chemistry
Multicomponent reactions of 1,3-disubstituted 5-pyrazolones and
formaldehyde in environmentally benign solvent systems and their variations
with more fundamental substrates†
Jia-Neng Tan,a Minghao Lia and Yanlong Gu*a,b
Received 24th November 2009, Accepted 5th March 2010
First published as an Advance Article on the web 8th April 2010
DOI: 10.1039/b924699a
Many multicomponent reactions (MCRs) of 1,3-disubstituted 5-pyrazolones and formaldehyde
were developed in environmentally benign solvent systems. Styrenes, vinylferrocene and
2-phenylindoles could easily react, under solvent-free conditions or in glycerol solvent, with
1,3-disubstituted 5-pyrazolones and paraformaldehyde in the absence of any catalyst to afford a
variety of complex skeletons in moderate to excellent yields. Particularly, these MCRs are proved
to be combinable with the synthesis of 1,3-disubstituted 5-pyrazolones from phenylhydrazines and
b-ketone esters in glycerol or a carboxylic acid-functionalized ionic liquid, [MIm-CO2H]BF4.
Therefore, some two-step sequential reactions of phenylhydrazines, b-ketone esters, formaldehyde
and styrenes or indoles were developed for the first time. All these MCRs were conducted in
environmentally benign solvent systems that not only minimize generation of wastes but also
simplify the work-up procedure.
oxo-dienes has been well described, and today this reaction is
Introduction
frequently used for developing new MCRs. However, in MCRs
The study of multicomponent reactions (MCRs) is a promising,
of formaldehyde, hetero-Diels–Alder reaction has been rarely
hot field of chemistry, since they allow complicated molecules
involved. The reasons mainly stem from instability and high
to be created by using one reaction in a fast, efficient and
reactivity of the active methylene compounds generated from
time-saving manner.1 Because of these advantages, developing
formaldehyde. Despite these facts, some promising results have
new MCRs with environmentally benign methods has been
been achieved quite recently. For example, Tietze and co-workers
recognized as one of the most important topics of green
have successfully designed a novel three-component tandem
chemistry.2 In a MCR, a product is assembled according to
Knoevenagel/hetero-Diels–Alder reaction involving nitroace-
a cascade of elementary chemical reactions. The challenge is to
tone, formaldehyde and alkyl vinyl ether for the total synthesis of
conduct a MCR in a suitable way that allows the pre-equilibrated
(+)-D-forosamine.8 We have also reported a three-component re-
elementary reactions to channel into the main product and not
action of 1,3-dicarbonyl compounds, formaldehyde and styrenes
yield side products.3 For this purpose, many efforts have been
devoted to optimization of reaction conditions.
that generates substituted dihydropyran derivatives in fair to
excellent yields using water or glycerol as solvents.9 In these
Formaldehyde is a very active substrate frequently used in
reactions, formation of a methylene intermediate is the key
MCRs.4 Most of MCRs using formaldehyde involve fundamen-
to construct the MCR because it can act as an oxo-diene to
tal reactions such as aldol and Mannich type reactions. In some
react with styrenes through hetero-Diels–Alder cycloaddition.
cases, methylenation of electron-rich carbons with formaldehyde
Interestingly, it was also found that replacing water with an aque-
that generates active methylene compounds (or methides) was
ous solution of acetic acid allows successful use of some other
also observed. The generated methylene compounds could be
substrates, such as 2-naphthol, 2-hydroxy-1,4-naphthoquinone,
used as chemical platforms for the creation of various C–C, C–
4-hydroxycoumarin and 4-hydroxy-6-methyl-2-pyrone, in these
O, C–N bonds, among others.5 Thanks to the great contributions
MCRs.10 All these results indicated that: (i) trapping the active
of Tietze6 and the others,7 hetero-Diels–Alder reaction of
methylene intermediate is a fundamental method for developing
new MCRs of formaldehyde; (ii) although many substrates
might be applicable in these MCRs, in order to maximize the
aInstitute of Physical Chemistry and Industrial Catalysis, School of
reactivity, reaction conditions have to be carefully optimized.
Chemistry and Chemical Engineering, Huazhong University of Science
On the other hand, the derivatives of pyrazolone are an im-
and Technology (HUST), 1037 Luoyu road, Hongshan District, Wuhan,
portant class of antipyretic and analgesic compounds.11 As these
430074, China. E-mail: klgyl@hust.edu.cn; Fax: +86-(0)27-87 54 45 32
bHubei Key Laboratory of Material Chemistry and Service Failure,
Huazhong University of Science and Technology, Wuhan, 430074,
P. R. China
compounds have great potential in pharmaceutical chemistry,
their derivatizations by synthetic methods have gained much
attention recently.12 1,3-Disubstituted 5-pyrazolone is one of the
most important pyrazolone derivatives, and today it is often used
in many fundamental reactions. Particularly, 1,3-disubstituted
† Electronic supplementary information (ESI) available: Experimental
details, spectroscopic data, and 1H and 13C NMR profiles of the products.
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5-pyrazolone was proved to be applicable in the Knoevenagel re-
action when some aromatic aldehydes were used as substrates.13
High reactivities of 1,3-disubstituted 5-pyrazolones gave us
impetus to use 1,3-disubstituted 5-pyrazolone and formaldehyde
as substrates in Tietze’s domino reaction. In this paper, we will
now prove the feasibility and generality of the three-component
reaction of 1,3-disubstituted 5-pyrazolone, formaldehyde and
styrenes, which will result in new polyheterocycles. Particularly,
we will show that this MCR could be carried out under catalyst-
and solvent-free conditions, which significantly simplifies the
work-up procedure and minimizes generation of wastes. Fur-
thermore, the MCR was proved to be combinable with synthesis
of 1,3-disubstituted 5-pyrazolones from phenylhydrazines and
b-ketone esters. Environmentally benign solvents, such as glyc-
erol and a carboxylic acid-functionalized ionic liquid, [MIm-
CO2H]BF4, were adopted in order to improve the reaction yield.
Thus, a stepwise one-pot reaction of phenylhydrazines, b-ketone
esters, styrenes and formaldehyde was developed, for the first
time, in green media. We will also show in this paper that other
substrates, such as vinylferrocene and 2-phenylindoles could
assemble readily in glycerol with 1,3-disubstituted 5-pyrazolone
and formaldehydes to generate some complex products in
moderate yields.
reaction yield, excess amounts of paraformaldehyde and
a-methylstyrene have been used (entries 2 and 3). Under an
optimized ratio, 1a/HCHO/2a = 1.0/1.5/2.0, the reaction
yield was kept nearly unaltered when the reaction time was
decreased from 11 h to 5 h (entry 4). Further decrease of reaction
time to 2 h resulted in an incomplete reaction, and as a result,
only 55% of yield was obtained (entry 5). Further investigation
revealed that the reaction was also affected by temperature, and
in order to achieve a higher yield, the reaction has to be carried
out at 110 ◦C (entry 6). In addition, using paraformaldehyde
as HCHO source was proved to be also crucial for the model
MCR, because only 43% of yield was obtained when formalin
was used (entry 7). From all the results in Table 1, we can
conclude, at this stage, that three-component reaction of
1-phenyl-3-methyl-5-pyrazolone (1a), a-methylstyrene (2a) and
paraformaldehyde proceeded readily without any special effort,
and an optimal yield, 85%, could be obtained under catalyst-
and solvent-free conditions.
In order to understand the mechanism of this MCR, counter
experiments were then carried out under the identical condition
by using different combinations of each two substrates. No prod-
uct was detected in the reactions of 1a + (HCHO)n and 1a + 2a.
In the case of 1a + (HCHO)n, a product, (II) (see Scheme 1), was
observed. These results suggest that the concomitant presence
of 1a, 2a and paraformaldehyde in the same reaction pot is
necessary for the selective formation of 3a. Tietze and others
have developed an intramolecular domino Knoevenagel/hetero-
Diels–Alder reaction using 1-phenyl-3-methyl-5-pyrazolone as
one of the substrates.14 Two-component hetero-Diels–Alder
reactions of 1,3-diphenyl-4-arylidene-5-pyrazolone and alkyl
vinyl ether or 2,3-dimethylbutadiene have also been reported and
used for synthesis of heterocyclic compounds.15 Our previous
investigations have demonstrated that styrenes are capable of
trapping a o-quinone methide that was generated in situ from
formaldehyde and a suitable electron-rich carbon-containing
compound. On the basis of these reported results, we suspect
here that the model reaction might proceed through a tandem
Knoevenagel/hetero-Diels–Alder reaction (Scheme 1). Forma-
tion of intermediate (I) is the key to initiate the MCR. There
are two possibilities to trap the intermediate (I): (i) with a-
methylstyrene through a hetero-Diels–Alder reaction; and (ii)
with the next 1-phenyl-3-methyl-5-pyrazolone molecule through
a Michael reaction. In our experiments, products from both reac-
tion pathways could be observed. Fortunately, formation of the
Results and discussion
Initially, the three-component reaction between 1-phenyl-
3-methyl-5-pyrazolone (1a), a-methylstyrene (2a) and
paraformaldehyde was investigated under catalyst- and
solvent-free conditions. Although both 1-phenyl-3-methyl-
5-pyrazolone and paraformaldehyde are solid, because the
reaction was conducted at 110 ◦C, the model reaction could,
in fact, be performed in liquid state. At the end of reaction, a
red viscous mixture was obtained. By isolation with preparative
TLC, a pale yellow solid that was identified as 1,4,5,6-
tetrahydro-3,6-dimethyl-1,6-phenylpyrano[2,3-c]pyrazole
(3a), was obtained. As shown in Table 1, under a ratio of
1a/HCHO/2a = 1.0/1.0/1.0, 3a was obtained in 58% yield
after 11 h of reaction (entry 1). In order to improve the
Table 1 Three-component reaction of 1a, 2a and HCHO under
solvent-free conditiona
Entry
Ratio of 1a/HCHO/2a
Time/h
Yield (%)
1
2
3
4
1.0/1.0/1.0
1.0/1.0/2.0
1.0/1.5/2.0
1.0/1.5/2.0
1.0/1.5.2.0
1.0/1.5/2.0
1.0/1.5/2.0
11
11
11
5
2
11
11
58d
78
86
85e
55
74
43
5
6b
7c
a 1a:◦0.5 mmol paraformaldehyde was used as source of HCHO, 110 ◦C.
b 90 C. c Fformalin (37 wt%) was used instead of paraformaldehyde. d
A
side product (II) was also isolated in 15% yield with respect to 1a. e Only
Scheme 1 Plausible reaction pathway of three-component reaction of
1a, paraformaldehyde and 2a.
trace amount of (II) was isolated.
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Table 2 Substrate scopes for three-component reactions of 1,3-
disubstituted 5-pyrazolones, a-methylstyrene and formaldehydea
side product (II, obtained from tandem Knoevenagel/Michael
reaction) could be significantly inhibited by using excess amount
of a-methylstyrene (Table 1, entris 1 and 4). It should be noted
that hetero-Diels–Alder reaction could theoretically generate
two regioisomers. However, only one product was obtained in
our hand. This high regioselectivity deserves further investiga-
tion, and we are now working on this line.
Literature information about the skeleton of 3a shows that
it is an important structure as its fragment is often involved
in pharmaceutical synthesis.16 However, synthesis of this kind
of compound is generally not easy, because either expensive
chemicals or multi-step reactions were used (see ESI†).17 Our
method presents an effective and a straightforward way to access
such compounds. From the viewpoint of green chemistry, the
model reaction in Table 1 can be considered as an ideal tool
for green synthesis because of the fact that (i) the high atom-
economy of the reaction, the only by-product is water; (ii)
catalyst- and solvent-free conditions that minimizes generation
of wastes. All these aspects make the model MCR highly
attractive to green organic synthesis.
Entry
1
1,3-Disubstituted 5-pyrazolone
Product
Yield (%)
88
1b
3b
2
3
1c
3c
3d
91
85
1d
4
1e
3e
93
Having these results in hand, we then investigated the scope
and limitations of the model MCR. As shown in Table 2,
many 1,3-disubstituted 5-pyrazolones could react readily with
paraformaldehyde and a-methylstyrene, and good to excellent
yields were obtained under solvent-free conditions. In particular,
high yields were obtained with 3-tert-butyl- or 3-aryl-substituted
1-aryl-5-pyrazolones. Aryl groups in N1-position of the pyra-
zolone play a key role in facilitating the reaction because of
the fact that replacing the aryl groups with alkyl group, for
example tert-butyl (1w), results in a decrease of the reaction
yield (43%, entry 22). In order to improve the reaction of 1w,
another styrene, 4-fluoro-a-methylstyrene (2g), was then used,
and in this case, a good yield, 70%, was obtained. Limitation
of this MCR was observed in the reaction of unsubstituted 1-
H-pyrazolone, 1x, with which no desired product was detected
(entry 24).
Table 3 shows the results of different styrenes in the
model MCR. All styrene derivatives react readily with 1a
and formaldehyde under solvent-free conditions affording the
desired pyrano[2,3-c]pyrazoles 3x–3ae in moderate to excellent
yields (54–89% yield, Table 3, entries 1–7). Styrenes with methyl
group in a-position (2g and 2h) afforded better yields than those
without substituents (entries 5 and 7). Not only styrenes, but also
vinylferrocene can be used in this MCR. For example, 3-tert-
butyl substituted 1-aryl-5-pyrazolones, 1c and 1j, could react
readily with vinylferrocene and paraformaldehyde to afford the
corresponding ferrocene-containing heterocycles, 3af and 3ag,
in moderate yields (Scheme 2). It should be noted that skeleton
of the obtained ferrocene-containing product has never been
reported before, indicating great ability of our MCR for creation
of molecular complexity.
5
6
1f
3f
95
55
1g
3g
7
8
9
1h
1i
1j
3h
3i
3j
85
62
92
10
11
12
1k
3k
3l
82
65
87
1l
1m
3m
It is well known that 1,3-disubstituted 5-pyrazolone could
be prepared by condensation between hydrazines and b-ketone
esters.18 The reaction was normally carried out in an alcoholic
solvent under mild conditions with or without assistance of
acidic or basic catalyst. Easy synthesis of 1,3-disubstituted
5-pyrazolone and high efficiency of the model MCR encouraged
us to combine both the condensation and the model MCR
in a one-pot procedure. However, heating a mixture composed of
13
1n
3n
70
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Table 2 (Contd.)
Table 3 Three-component reactions between 1a, HCHO and different
styrenesa
Entry
14
1,3-Disubstituted 5-pyrazolone
Product
Yield (%)
69
1o
3o
Entry
Alkene
Product
Yield (%)
15
16
1p
3p
3q
82
70
1
2
3
4
5
6
7
2b
2c
2d
2e
2f
2g
2h
3y
3z
3aa
3ab
3ac
3ad
3ae
66
71
52
58
54
89
69
1q
a 1a: 0.5 mmol, alkene, 1.0 mmol; paraformaldehyde: 0.75 mmol; 110 ◦C,
5 h.
17b
18b
1r
3r
3s
57
51
1s
19b
1t
3t
62
Scheme
2 Three-component reaction of 1,3-disubstituted 5-
pyrazolone, vinylferrocene and paraformaldehyde (ratio of pyra-
zolone/2i/(HCHO)n = 1.0/2.0/1.5).
20b
21b
22
1u
3u
3v
63
71
43
70
of the fact that the use of an alcoholic solvent is beneficial
for the condensation between phenylhydrazine and b-ketone
ester, we then tried the two-step sequential reaction in glycerol
that has been proposed as a promising, green, renewable and
bio-compatible medium for organic synthesis by us19 and
the others.20 As shown in Table 4, although direct mixing
all the four components is unsuccessful for construction of
3e, a one-pot two-step reaction sequence can be realized in
glycerol by a stepwise manner (entries 2 and 3). The desired
product, 3e, could be prepared by the following procedures:
(i) heating phenylhydrazine and ethyl benzoylacetate in
glycerol that generates 1,3-diphenyl-5-pyrazolone smoothly,
the reaction time in this step was marked as t1, and (ii) mixing
paraformaldehyde and a-methylstyrene together with the
reaction solution, and keeping the system react under the
former condition to the desired reaction time, t2. Monitoring
the progress of reaction with TLC revealed that suitable
reaction time should be t1 = 4 h and t2 = 10 h. The sequential
reaction was also affected by temperature and solvent amount,
and the optimal condition is 110 ◦C and 2.5 g glycerol for
a reaction in 0.5 mmol scale (entries 4 and 5). Under this
optimized condition, many b-ketone esters and styrenes were
used in the one-pot sequential reaction, and the desired
pyrano[2,3-c]pyrazoles were obtained in moderate to good
yields by using glycerol as solvent (entries 6–14). A less-reactive
arylhydrazine, 2,4,6-trichlorophenylhydrazine (4b), was also
1v
1w
3w
3x
23c
1w
24
1x
—
0
a 1,3-Disubstituted 5-pyrazolone: 0.5 mmol, a-methylstyrene: 1.0 mmol,
paraformaldehyde: 0.75 mmol, reaction time: 5 h, temperature: 110 ◦C.
b Reaction time: 11 h. c 4-Fluoro-a-methylstyrene was used.
phenylhydrazine (4a), paraformaldehyde, ethyl benzoylacetate
(5a) and a-methylstyrene (2a) generates a messy product
without predominant selectivity (Table 4, entry 1). In view
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Table 4 Two-step sequential reactions of arylhydrazines, HCHO, b-ketone esters and styrenesa
Entry
Arylhydrazine
b-Ketone ester
Solvent
t1/h
Alkene
t2/h
Product
Yield (%)
1b
2b
3
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4a
4b
5a
5a
5a
5a
5a
5b
5c
5d
5e
5f
5a
5a
5a
5a
5a
5e
5f
solvent-free
glycerol
glycerol
glycerol
glycerol
glycerol
glycerol
glycerol
glycerol
glycerol
glycerol
glycerol
glycerol
—
—
4
6
4
4
4
4
4
4
4
4
4
4
4
4
4
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2h
2g
2a
2a
2a
2a
2a
—
—
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
messy mixture
messy mixture
3e
3e
—
—
78
59
70
67
69
69
73
75
48
59
47
75
48
53
56
75
55
4c
5b
6
7
8
9
10
11
12
13
14
15
16
17
18e
19e
3e
3a
3d
3b
3c
3f
3ah
3ai
3aj
3ak
3u
3t
3v
3e
3v
glycerol
[MIm-CO2H]BF4
[MIm-CO2H]BF4
[MIm-CO2H]BF4
glycerol
5a
5f
4
4
[MIm-CO2H]BF4
a Arylhydrazine: 0.5 mmol, b-ketone ester: 0.55 mmol, glycerol: 2.5 g, paraformaldehyde: 0.75 mmol, alkene: 1.0 mmol. b All the four components of
the reaction were added in the beginning of the reaction. c 85 ◦C. d 1.5 g glycerol was used. e Reused in the second run.
used in this reaction. And in order to improve the reaction
yield, a carboxylic acid group-functionalized ionic liquid, [MIm-
CO2H]BF4, was used instead of glycerol solvent. As shown in
Table 4, the desired products were obtained in moderate yields
(entries 15–17). It should be noted that both glycerol and the
ionic liquid are immiscible with non-polar organic solvents.
Therefore, the products could be easily isolated by extraction.
And the recycled glycerol and [MIm-CO2H]BF4 could be reused
in the next run after a simple treatment under vacuum (entries 18
and 19). This property makes the one-pot stepwised reaction not
only efficient to the synthesis of target heterocyclic compounds
but also very attractive from the viewpoint of green chemistry.
Good reactivity of 1,3-disubstituted 5-pyrazolone prompts
us to further explore MCRs by using this unique heterocyclic
compound and formaldehyde as substrates. The next reaction we
developed is a one-pot three-component reaction of indoles, 1,3-
disubstituted 5-pyrazolones and paraformaldehyde. As shown
in Scheme 3, 1,3-diaryl-5-pyrazolones could easily react with 1-
alkyl-2-phenylindoles and formaldehyde in glycerol to form 1,3-
diaryl-2-[(1-alkyl-2-phenylindol-3-yl)methyl]-5-pyrazolone der-
avitives, 7a, 7b and 7c, in moderate yields. Literature information
about the product showed that skeleton of the products has been
proven to be active for sedation of mice.21 Only a few methods are
available for the synthesis of this kind of molecule.22 However,
either chemicals are not available or toxic reagents were used
in the reported methods.23 Our MCR thus offers an effective
and environmentally benign way for the synthesis of these useful
pyrazole derivatives. The MCR might proceed through a tandem
Knoevenagel/Michael reaction pathway. This hypothesis can be
supported by the fact that Michael reaction of 2-phenylindole
and a,b-unsaturated carbonyl compounds could be performed
in glycerol under catalyst-free conditions.19a Importantly, this
three-component reaction can also be extended to a two-step
sequential reaction in glycerol using phenylhydrazine (4a) and
b-ketone ester, 5f , as substrates (Scheme 3). This not only
maximizes the synthetic efficiency but also offers a new and
distinct example to promoting glycerol as reaction media.
Conclusion
Combination of 1,3-disubstituted 5-pyrazolones and formalde-
hyde was proved to be a useful platform for organic synthesis.
Many substrates, such as styrenes, vinylferrocene and indoles
could react readily with 1,3-disubstituted 5-pyrazolones and
formaldehyde in the absence of any catalyst to afford the cor-
responding three-component adducts in moderate to excellent
yields. Particularly, these MCRs are proved to be combinable
with synthesis of 1,3-disubstituted 5-pyrazolones from phenyl-
hydrazines and b-ketone esters in glycerol or a carboxylic acid
group-functionalized ionic liquid, [MIm-CO2H]BF4. Therefore,
some one-pot stepwise sequential reactions of phenylhydrazines,
b-ketone esters, formaldehyde and styrenes or indoles were
developed for the first time. These sequential MCRs not only
open a straightforward way to synthesize the target compounds,
but also maximize the synthetic efficiency significantly. Be-
cause these MCRs were conducted either under solvent-free
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other 1,3-disubstituted 5-pyrazolones, procedures for the other
reactions and physicochemical data of the products are available
in ESI.
Acknowledgements
The authors thank for National Natural Science Fundation of
China for the financial support (20903042). The authors are also
grateful for Ms. Ping Liang and all the other stuff members in
the Analytical and Testing Center of HUST, for their supportive
and constant contributions to our works. The Program for
new Century Excellent Talents in the University of China and
Chutian Scholar Program of the Hubei provincial government
are also acknowledged.
Notes and references
1 (a) W. Bannwarth, E. Felder, Combinatorial Chemistry, Wiley-VCH,
Weinheim, 2000; (b) J. Zhu, H. Bienayme´, Multicomponent reactions,
Wiley-VCH, Weinheim, 2005; (c) A. Do¨mling, Chem. Rev., 2006, 106,
17–89; (d) G. Balme, E. Bossharth and N. Monteiro, Eur. J. Org.
Chem., 2003, 4101–4111; (e) R. V. A. Orru and M. De Greef,
Synthesis, 2003, 1471–1499; (f) H. Bienayme´, C. Hulme, G. Oddon
and P. Schmitt, Chem.–Eur. J., 2000, 6, 3321–3329; (g) G. Vasuki and
K. Kumaravel, Tetrahedron Lett., 2008, 49, 5636–5638.
2 (a) K. Kumaravel and G. Vasuki, Green Chem., 2009, 11, 1945; (b)
G.-W. Wang and C.-B. Miao, Green Chem., 2006, 8, 1080–1085;
(c) S. L. Jain, S. Singhal and B. Sain, Green Chem., 2007, 9, 740–
741; (d) G. Zhao, T. Jiang, H. Gao, B. Han, J. Huang and D. Sun,
Green Chem., 2004, 6, 75–77; (e) K. Kumaravel and G. Vasuki, Curr.
Org. Chem., 2009, 13, 1820–1841.
Scheme
3
Multicomponent reactions of 1-alkyl-2-phenylindoles,
paraformaldehdye and 1,3-diaryl 5-pyrazolones and their variation with
more fundamental substrates (for the three-component reaction, ratio
of 6a/7a/HCHO = 1.0/1.0/1.0; for the two-step sequential reaction,
ratio of 4a/5f /6a/HCHO = 1.0/1.1/1.0/1.5)
conditions or in green media, including glycerol and ionic
liquid, the reaction systems possess many properties of green
chemistry, such as simple work-up procedure, recyclable solvent
and minimization of waste. In view of the fact that pyrazole
derivatives have been widely used in pharmaceutical industry,
our method might be useful for synthesis of biologically active
compounds, and the investigation is underway in our group.
3 (a) J. D. Sunderhaus and S. F. Martin, Chem.–Eur. J., 2009, 15, 1300;
(b) D. Tejedor and F. Garcia-Tellado, Chem. Soc. Rev., 2007, 36, 484–
491; (c) R. V. A. Orru and M. De Greef, Synthesis, 2003, 1471–1499;
(d) V. Nair, C. Rajesh, A.U. Vinod, S. Bindu, A. R. Sreekanth, J. S.
Methen and L. Balagopal, Acc. Chem. Res., 2003, 36, 899–907; (e) A.
Do¨mling and I. Ugi, Angew. Chem., Int. Ed., 2000, 39, 3168–3210.
4 (a) Y. Ohta, S. Oishi, N. Fujii and H. Ohno, Chem. Commun., 2008,
835–837; (b) E. R. Bonfield and C.-J. Li, Adv. Synth. Catal., 2008, 350,
370–374; (c) A. Zanobini, A. Brandi and A. de Meijere, Eur. J. Org.
Chem., 2006, 1251–1255; (d) G. M. Mahandru, A. R. L. Skauge, S. K.
Chowdhury, K. K. D. Amarasinghe, M. J. Heeg and J. Montgomery,
J. Am. Chem. Soc., 2003, 125, 13481–13485; (e) M. Ihara, K. Makita,
Y. Tokunaga and K. Fukumoto, J. Org. Chem., 1994, 59, 6008–6013;
(f) L. E. Kaim, M. Gizolme and L. Grimaud, Synlett, 2007, 227–
230; (g) D. Basavaiah, D. S. Sharada and A. Veerendhar, Tetrahedron
Lett., 2004, 45, 3081–3083; (h) Q. Zhu, H. Jiang, J. Li, M. Zhang, X.
Wang and C. Qi, Tetrahedron, 2009, 65, 4604–4613; (i) H. Cao, X.
Wang, H. Jiang, Q. Zhu, M. Zhang and H. Liu, Chem.–Eur. J., 2008,
14, 11623–11633; (j) Y. Ma, M. Wang, D. Li, B. Bekturhun, J. Liu
and Q. Liu, J. Org. Chem., 2009, 74, 3116–3121; (k) R. Scheffelaar,
N. R. A. Klein, M. Paravidino, M. Lutz, A. L. Spek, A. W. Ehlers,
F. J. J. de Kanter, M. B. Groen, R. V. A. Orru and E. Ruijter, J. Org.
Chem., 2009, 74, 660–668; (l) N. G. Kozlov and A. P. Kadutskii,
Tetrahedron Lett., 2008, 49, 4560–4562; (m) M. Zhang, H. Jiang, H.
Liu and Q. Zhu, Org. Lett., 2007, 9, 4111–4113; (n) H. Bradley, G.
Fitzpatrick, W. K. Glass, H. Kunz and P. V. Murphy, Org. Lett., 2001,
3, 2629–2632.
Experimental section
All reactions were conducted in a 10 mL V-type flask equipped
with triangle magnetic stirring. In a typical reaction, 1-phenyl-
3-methyl-5-pyrazolone (1a, 87.0 mg, 0.50 mmol) was mixed with
a-methylstyrene (2a, 118.0 mg, 1.00 mmol) and paraformalde-
hyde (45.0 mg, 0.75 mmol) under air. The mixture was stirred for
5.0 h at 110 ◦C. After reaction, the mixture was mixed with ethyl
acetate (3 mL), and then subjected to isolation with preparative
TLC using a mixed solution of ethyl acetate and petroleum ether
as eluting solvent (normally, the ratio of ethyl acetate/petroleum
ether is 1/10). Product: 1,4,5,6-tetrahydro-3,6-dimethyl-1,6-
diphenyl-pyrano[2,3-c]pyrazole (3a): pale yellow liquid, yield =
1
85%, H NMR (CDCl3): 1.56 (s, 3H), 1.86-1.95 (m, 1H), 2.02
5 (a) G. Appendino, G. Cravotto, L. Toma, R. Annunziata and G.
Palmisano, J. Org. Chem., 1994, 59, 5556–5564; (b) V. Nair, P. M.
Treesa, C. N. Jayan, N. P. Rath, M. Vairamani and S. Prabhakar,
Tetrahedron, 2001, 57, 7711–7717; (c) A. Kumar and R. A. Maurya,
Tetrahedron Lett., 2008, 49, 5471–5474; (d) A. Kumar, S. Sharma and
R. A. Maurya, Tetrahedron Lett., 2009, 50, 5937.
6 (a) L. F. Tietze, Chem. Rev., 1996, 96, 115–136; (b) L. F. Tietze and G.
Kettschau, Top. Curr. Chem., 1997, 189, 1–120; (c) L. F. Tietze and
U. Beifuss, in Comprehensive Organic Synthesis, B. M. Trost, Ed.,
Pergamon Press, Oxford, 1991, Vol. 2, p. 341.
(s, 3H), 2.03-2.11 (s, 1H), 2.17 (dt, Ja = 5.2 Hz, Jb = 13.6 Hz,
1H), 2.30 (dt, Ja = 4.8 Hz, Jb = 14.4 Hz, 1H), 7.03-7.12 (m,
1H), 7.15 (t, J = 7.2 Hz, 2H), 7.20 (d, J = 7.6 Hz, 2H), 7.29
(t, J = 7.6 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H); 13C NMR: 12.8,
15.7, 28.8, 33.5, 83.8, 95.8, 119.8, 124.6, 125.0, 127.3, 128.6,
129.1, 139.3, 144.2, 146.5, 150.1; IR (cm-1): 3061, 2978, 2925,
2855, 1605, 1507, 1445, 1393, 1375, 1328, 1266, 1158, 1120, 1102,
1070, 1029, 1004, 900, 866, 758, 697, 658; HRMS (ESI): calcd for
C20H20N2O, [M + H+]: 305.3936; found: 305.3987. Synthesis of
7 (a) L. F. Tietze and U. Beifuss, Angew. Chem., Int. Ed. Engl., 1993,
32, 131–163; (b) L. F. Tietze, J. Heterocycl. Chem., 1990, 27, 47–69;
This journal is
The Royal Society of Chemistry 2010
Green Chem., 2010, 12, 908–914 | 913
©

View Article Online
(c) D. L. Boger and S. M. Weinreb, Hetero Diels–Alder Methodology
in Organic Chemistry, Academic, San Diego, 1987.
8 L. F. Tietze and N. B. S. Dietz, Org. Lett., 2009, 11, 2948–2950.
9 (a) Y. Gu, R. De Sousa, G. Frapper, C. Bachmann, J. Barrault and
F. Je´roˆme, Green Chem., 2009, 11, 1968–1972; (b) M. Li, C. Chen, F.
He and Y. Gu, Adv. Synth. Catal., 2010, 352, 519–530.
16 (a) K. H. Huang, J. Mangette, T. Barta, P. Hughes, S. E. Hall, J. Veal,
PCT Int. Appl. 2008, WO 2008024978; (b) D. M. Bradley, K. M.
Thewlis, S. E. Ward, PCT Int. Appl. 2008, WO 2008148832; (c) K. V.
Mityurina, L. K. Kulikova, M. K. Krasheninnikova and V. G.
Kharchenko, Khim. Farm. Zh., 1981, 15, 34–37; (d) G. Desimoni,
G. Faita, A. Gamba, P. P. Righetti, G. Tacconi and L. Toma,
Tetrahedron, 1990, 46, 2165–2178.
17 (a) G. Heinisch, C. Hollub and W. Holzer, J. Heterocycl. Chem.,
1991, 28, 1047–1050; (b) K. V. Mityurina, V. G. Kharchenko
and L. V. Cherkesova, Khim. Geterotsikl. Soedin., 1982, 317–320;
(c) K. V. Mityurina, V. G. Kharchenko and L. V. Cherkesova, Khimi.
Geterotsikl. Soedin., 1981, 245–248.
18 (a) M. M. Mojtahedi, M. Javadpour and M. S. Abaee, Ultrason.
Sonochem., 2008, 15, 828–832; (b) Z.-X. Wang and H.-L. Qin, Green
Chem., 2004, 6, 90–92; (c) U. Schoen, J. Messinger, N. Merayo, G.
Juszkiewicz and A. Kirschning, Synlett, 2003, 983–986.
19 (a) Y. Gu, J. Barrault and F. Je´roˆme, Adv. Synth. Catal., 2008, 350,
2007–2012; (b) F. He, P. Li, Y. Gu and G. Li, Green Chem., 2009, 11,
1767–1773.
10 Y. Gu, J. Barrault and F. Je´roˆme, Adv. Synth. Catal., 2010, 11, 3269–
3278.
11 (a) The Merck Index 10th edn, M. Windholz, Merck, Rahway, 1983;
(b) A. Kimata, H. Nakagawa, R. Ohyama, T. Fukuuchi, S. Ohta, T.
Suzuki and N. Miyata, J. Med. Chem., 2007, 50, 5053–5056.
12 (a) E. Ceulemans, M. Voets, S. Emmers, K. Uytterhoeven, L. V.
Meervelt and W. Dehaen, Tetrahedron, 2002, 58, 531–544; (b)
T.-S. Jin, R.-Q. Zhao and T.-S. Li, ARKIVOC, 2006, 176–182; (c) J.
Burgress and P. J. Steel, Tetrahedron Lett., 2006, 47, 4107–4108.
13 (a) Y. Hu, P. Wei, H. Zhou, P. K. Ouyang and Z. C. Chen, Chin. Chem.
Lett., 2006, 17, 299–301; (b) G. Desimoni, L. Astolfi, M. Cambieri, A.
Gamber and G. Tacconi, Tetrahedron, 1973, 29, 2627–2634; (c) W. S.
Hamama, Synth. Commun., 2001, 31, 1335–1345.
14 (a) L. F. Tietze, T. Brumby, M. Pretor and G. Remberg, J. Org. Chem.,
1988, 53, 810–820; (b) L. F. Tietze, U. Beifuss, M. Lo¨ko¨s, M. Rischer,
A. Go¨hrt and G. M. Sheldrick, Angew. Chem., Int. Ed. Engl., 1990,
29, 527–529; (c) S. Tiwari, N. Khupse and A. Kumar, J. Org. Chem.,
2008, 73, 9075–9083.
15 (a) G. Desimoni and G. Tacconi, Chem. Rev., 1975, 75, 651–692;
(b) M. Brugnolotti, C. A. Corsico, G. Desimoni, G. Faita, I. A.
Gamba, P. P. Righetti and G. Tacconi, Tetrahedron, 1988, 44, 5229–
5242; (c) M. Abdel-Rahman and H. Abdel-Ghany, Synth. Commun.,
1991, 21, 1281–1291.
20 (a) A. Karam, N. Villandier, M. Delample, C. K. Koerkamp, J.-P.
Douliez, R. Granet, P. Krausz, J. Barrault and F. Je´roˆme, Chem.–
Eur. J., 2008, 14, 10196–10200; (b) A. Wolfson, C. Dlugy and Y.
Shotland, Environ. Chem. Lett., 2007, 5, 67–71; (c) A. Wolfson and
C. Dlugy, Chem. Pap., 2007, 61, 228–232.
21 H. Zinnes, N. A. Lindo, USP 4153711, 1979.
22 (a) X.-L. Li, Y.-M. Wang, B. Tian and J.-B. Meng, Chin. J. Chem.,
1996, 14, 421–427; (b) X. Li, Y. Wang, D. Du, Z. Wen, G. Xiong and
J. Meng, Sci. China, Ser. B: Chem., 1997, 40, 270–277.
23 M. Xia and Y. Lu, Synth. Commun., 2006, 36, 2389–2399.
914 | Green Chem., 2010, 12, 908–914
This journal is
The Royal Society of Chemistry 2010
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