Solvent-free, one-pot synthesis of pyrano[2,3-c]pyrazole derivatives in the presence of KF·2H2O by grinding

Article abstract of DOI:10.1080/00397910500212809

A solvent-free, one-pot process for the preparation of 4H-pyrans in the presence of KF · 2H₂O by grinding was achieved. Its advantages are easy workup, mild reaction conditions, high yields, and environmental friendliness. Copyright Taylor & Fr

Full text of DOI:10.1080/00397910500212809

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Solvent‐Free,
One‐Pot Synthesis of
Pyrano[2,3‐c]pyrazole
Derivatives in the Presence of
KF·2H2O by Grinding
Zhongjiao Ren a , Weiguo Cao a b , Weiqi Tong a &
Zhu Jin a
a Department of Chemistry , Shanghai University ,
Shanghai, China
b State Key Laboratory of Organometallic
Chemistry , Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences , Shanghai, China
Published online: 18 Aug 2006.
To cite this article: Zhongjiao Ren , Weiguo Cao , Weiqi Tong & Zhu Jin (2005)
Solvent‐Free, One‐Pot Synthesis of Pyrano[2,3‐c]pyrazole Derivatives in the Presence
of KF·2H2O by Grinding, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:19, 2509-2513
To link to this article: http://dx.doi.org/10.1080/00397910500212809
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Synthetic Communicationsw, 35: 2509–2513, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500212809
Solvent-Free, One-Pot Synthesis of
Pyrano[2,3-c]pyrazole Derivatives in the
.
Presence of KF 2H2O by Grinding
Zhongjiao Ren
Department of Chemistry, Shanghai University, Shanghai, China
Weiguo Cao
Department of Chemistry, Shanghai University, Shanghai, China and
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
Weiqi Tong and Zhu Jin
Department of Chemistry, Shanghai University, Shanghai, China
Abstract: A solvent-free, one-pot process for the preparation of 4H-pyrans in the
.
presence of KF 2H2O by grinding was achieved. Its advantages are easy workup,
mild reaction conditions, high yields, and environmental friendliness.
Keywords: grinding, 4H-pyran, one-pot synthesis, potassium fluoride dihydrate,
solvent-free
Improving the efficiency of organic synthesis, lowering the consumption of
chemicals, and constructing complex molecules from simple and available
starting materials are fundamental goals in organic synthesis. Performing
multistep reactions in one pot is an efficient way to achieve these goals.
Until now, much effort has been devoted to the development of a one-pot
methodology.[1]
Revised in Japan March 28, 2005
Address correspondence to Zhongjiao Ren, Department of Chemistry, Shanghai Uni-
versity, Shanghai 200444, China. Fax: þ86-21-6613-4856; E-mail: renrui198229@ hot-
mail.com
2509

2510
Z. Ren et al.
Recently, great strides have been made in solvent-free reactions using
grinding condition because of their high efficiency, operational simplicity,
low cost, and environmentally benign processes. Numerous successful
reactions widely used in a variety of organic syntheses have been reported,
such as the Grignard reaction,[2] Knoevenagel condensation,[3] Aldol conden-
sation,[4] Dieckmann condensation,[5] Reforrmatsky reaction,[6] reduction,[7]
rearrangement reaction,[8] cyclopropanation reaction,[9] and other
reactions,[10] but the synthesis of heterocyclic compounds by solvent-free,
one-pot methods using grinding conditions has rarely been reported.
The compounds possessing 4H-pyran frameworks have shown biological
and pharmacological properties.[11] As a result, several methods for synthesis
4H-pyran derivatives have been reported.[12]
In continuation of our research of solvent-free reactions using grinding
conditions, here we report a solvent-free, one-pot method for preparation of
.
4H-pyran derivatives in the presence of KF 2H2O with grinding.
In the initial experiment, the mixture of 4-methoxybenzaldehy (1a),
malononitrile (2), 3-methyl-2-phenyl-2-pyrazolin-5-one (3), and K2CO3 was
ground. After the starting materials were consumed, the expected 4H-pyran
(4a) was obtained in 72% yield, but some deep color by-products were produced,
thus reducing the yield and increasing the difficulty of the separation and purifi-
cation. We thought that these side reactions resulted from K2CO3.
.
We have reported that KF 2H2O is a more efficient base than K2CO3 in
the cycloproparation of olefine with arsonium salt in DME.[13] The main
.
advantages of the process using KF 2H2O as base are that the reaction is
carried out under essentially neutral conditions, thus reducing the possibility
of many unwanted side reactions [14]and in that it is unnecessary to keep
unhydrous reaction conditions, compared with using KF as base. Until now,
.
using KF 2H2O as efficient, clean base remains relatively uninvestigated.
.
To expand the application of KF 2H2O in organic synthesis, the reaction of
.
preparing 4H-pyran in the presence of KF 2H2O was tested. When the
.
reaction was carried out in the presence of KF 2H2O at the same conditions,
the yield of 4a was 82% and the deep color by-products were not found. The
results of the experiment are shown in Table 1.
In summary, a solvent-free, one-pot process for the preparation of
.
4H-pyrans in the presence of KF 2H2O using grinding was achieved.
Scheme 1.

Pyrano[2,3-c]pyrazole Derivatives
2511
.
Table 1. Synthesis of 4H-pyrans in the presence of KF 2H2O with grinding
Reaction
time (h)
Product
Ar
Base
Yield (%)
4a
4a
4b
4b
4c
4d
4d
4e
4f
4-CH3OC6H4
4-CH3OC6H4
4-ClC6H4
K2CO3
.
KF 2H2O
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
72
84
82
93
93
71
87
83
76
86
K2CO3
.
4-ClC6H4
KF 2H2O
.
KF 2H2O
4-NO2C6H4
3-NO2C6H4
3-NO2C6H4
2,4-Cl2C6H3
3,4-OCH2O C6H3
2,4-(CH3O)2C6H3
K2CO3
.
KF 2H2O
.
KF 2H2O
.
KF 2H2O
.
KF 2H2O
4g
Its advantages are easy workup, mild reaction conditions, high yields, and
environmental friendliness.
EXPERIMENTAL
The potassium fluoride dihydrate and other reagents were obtained from a
commercial source and used without purification in the preparation of 4H-
pyrans. Melting points are uncorrected. Melting points were determined on
WRS-1 digital melting-point apparatus made by Shanghai Physical Instrument
Factory (SPOIF), China. IR spectra were measured in KBr on a PE-580B spec-
trometer. 1H NMR spectra were recorded at a Bruker AM-300, using CDCl3 or
DMSO as solvent and TMS as internal reference. Elemental analyses were
measured on a Foss Heraeus CHN-O-RAPID elemental-analysis instrument.
General Procedure for Preparing Pyrano[2,3-c]pyrazole
Derivatives
A mixture of aldehyde (1) (2 mmol), malononitrile (2) (132 mg, 2 mmol),
.
3-methyl-2-phenyl-2-pyrazolin-5-one (3) (384 mg, 2 mmol), and KF 2H2O
(188 mg, 2 mmol) is ground at room temperature with the glass mortar and
pestle. The reaction is monitored by TLC. The precipitate is collected by
suction filtration and washed with water. The product is recrystallized from
a mixture of ethanol and dried under room temperature.
4a. Mp. 169–1708C (lit.[15] 173–1758C). 1H NMR (CDCl3) d: 1.90
(s, 3H, CH3); 3.80 (s, 3H, CH3O); 4.62 (s, 3H); 6.86–6.89 (d, 2H); 7.17
(d, J ¼ 8.8 Hz, 2H); 7.26–7.34 (tri, 1H); 7.43–7.49 (tri, 2H); 7.66
(d, J ¼ 8.8 Hz, 2H). IR (n, cm21): 3392, 3322, 3204, 2192, 1661, 1596.

2512
Z. Ren et al.
1
4b. Mp. 178–1798C (lit.[15] 178–1798C). H NMR (CDCl3) d: 1.99
(s, 3H, CH3); 4.65 (s, 1H); 4.71 (s, 2H, NH2); 7.20 (d, J ¼ 8.5 Hz, 2H);
7.31–7.34 (m, 3H); 7.44–7.49 (tri, 2H); 7.64 (d, J ¼ 8.3 Hz, 2H). IR (n,
cm21): 3439, 3068, 2254, 1614, 1595.
4c. Mp. 194–1958C (lit.[15] 192–1948C). 1H NMR (CDCl3) d: 1.89 (s, 3H,
CH3); 4.80 (s, 1H); 4.85 (s, 2H, NH2); 7.32–7.37 (tri, 1H); 7.43–7.50 (m, 4H);
7.65 (d, J ¼ 8.3 Hz, 2H); 8.23 (d, J ¼ 8.5 Hz, 2H). IR (n, cm21): 3391, 3317,
3199, 2195,1651, 1592.
4d. Mp. 182–1838C (lit.[15] 188–1898C). 1HNMR (CDCl3) d: 1.89 (s, 3H,
CH3), 480 (s, 1H); 482 (s, 2H, NH2); 7.35–7.37 (tri, 1H); 7.46–7.51 (tri, 2H);
7.54–7.59 (m, 1H); 7.65–7.68 (d, 3H); 8.10–8.12 (tri, 1H); 8.17–8.20 (d, 1H).
IR (n, cm21): 3438, 3300, 3191, 2195, 1651, 1592.
4e. Mp. 188–1898C (lit.[15] 182–1848C). 1H NMR (CDCl3) d: 1.90 (s, 3H,
CH3); 4.74 (s, 2H, NH2); 5.26 (s, 1H); 7.13–7.16 (d, 1H); 7.23–7.26 (m, 2H);
7.33–7.35 (tri, 1H), 7.43–7.50 (m, 2H); 7.63–7.65 (d, 2H). IR (n, cm21):
3458, 3325, 3196, 2198, 1660, 1583.
1
4f. Mp. 174–1758C (lit.[15] 174–1768C). H NMR (DMSO-d6) d: 1.81
(s, 3H, CH3); 4.61 (s, 1H); 5.98–6.01 (d, 2H, CH2); 6.74–6.78 (m, 2H);
6.85–6.88 (d, 1H): 7.16 (s, 2H, NH2); 7.28–7.33 (tri, 1H); 7.46–7.51 (tri, 2H);
7.76–7.79 (d, 2H). IR (n, cm21): 3441, 2225, 1614, 1570.
1
4g. Mp. 178–1798C. H NMR (DMSO-d6) d: 1.99 (s, 3H, CH3); 3.75
(s, 3H, CH3O); 3.78 (s, 3H, CH3O); 4.92 (s, 1H); 6.48–6.51 (d, 1H); 6.57–
6.58 (d, 1H); 6.96–6.99 (d, 1H); 7.06 (s, 2H, NH2); 7.28–7.33 (tri, 1H);
7.48–7.50 (tri, 2H); 7.76–7.79 (m, 2H). IR (n, cm21): 3411, 3321, 3202,
2199, 1660, 1588. Anal. calculated for C22H20N4O3: C, 68.03; H, 5.19;
N, 14.42. Found: C, 67.91; H, 5.08; N, 14.56.
ACKNOWLEDGMENT
Thanks are due to the National Natural Science Foundation of China for
financial support.
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