Polystyrene sulfonic acid catalyzed greener synthesis of hydrazones in aqueous medium using microwaves

Article abstract of DOI:10.1016/j.tetlet.2007.06.038

An environmentally benign aqueous protocol for the synthesis of cyclic, bi-cyclic, and heterocyclic hydrazones using polystyrene sulfonic acid (PSSA) as a catalyst has been developed; the simple reaction proceeds efficiently in water in the absence of any

Full text of DOI:10.1016/j.tetlet.2007.06.038

Tetrahedron Letters 48 (2007) 5649–5652
Polystyrene sulfonic acid catalyzed greener synthesis
of hydrazones in aqueous medium using microwaves
Vivek Polshettiwar and Rajender S. Varma*
Sustainable Technology Division, National Risk Management Research Laboratory,
US Environmental Protection Agency, 26 W. Martin Luther King Dr., MS 443, Cincinnati, OH 45268, USA
Received 30 May 2007; accepted 6 June 2007
Available online 9 June 2007
Abstract—An environmentally benign aqueous protocol for the synthesis of cyclic, bi-cyclic, and heterocyclic hydrazones using
polystyrene sulfonic acid (PSSA) as a catalyst has been developed; the simple reaction proceeds efficiently in water in the absence
of any organic solvent under microwave irradiation and involves basic filtration as the product isolation step.
Ó 2007 Elsevier Ltd. All rights reserved.
Hydrazones and their derivatives constitute an impor-
tant class of compounds in organic chemistry. These
compounds have interesting biological properties,1 such
as, anti-inflammatory,3 analgesic,4 and antipyretic5 as
well as chelating properties towards various metal ions.2
Savini et al. evaluated heterocyclic hydrazones for anti-
cancer, anti-HIV, and antimicrobial activity.6 Recently
hydrazones have also been found useful as anti-malaria
drugs7 and as inhibitors of macrophage migration inhib-
itory factor (MIF) tautomerase activity.8 The synthetic
efforts for this class of compounds are very well studied
and generally entail the reaction of carbonyl compounds
with hydrazine hydrate in organic solvents.9 Some
examples on supported reactions using silica gel/sodium
hydroxide10 and solvent-free synthesis of heterocyclic
hydrazones under microwave irradiation conditions
are also known.11
ous cyclic, bi-cyclic, and heterocyclic hydrazones in
aqueous medium (Scheme 1).
We explored the condensation of acetophenone with
phenyl hydrazine in water under microwave (MW) irra-
diation conditions. After screening a range of usual
inorganic and organic acids and exploring their scope
at various temperatures, we found that polystyrene sul-
fonic acid (PSSA) was the most efficient catalyst for
hydrazone synthesis in water at 100 °C. Using these
optimized reaction conditions,14 the efficiency of this
aqueous approach was studied for the syntheses of a
wide variety of hydrazones, and the results are summa-
rized in Table 1.
All the described reactions proceeded expeditiously and
delivered excellent yields; the friendly isolation proce-
dure simply involved the filtration of the precipitated
hydrazones. Aromatic ketones were reacted with phenyl
hydrazine (a) and 4-methyl phenyl hydrazine (b) (entries
1–4) to give hydrazone in excellent yields. 5-Bromoinda-
none also reacted well with both (a) and (b) (entries 5
and 6), preserving the bromo-functionality, which can
be elaborated further in synthetic sequences. Aliphatic
ketones were equally suitable substrates (entries 7–10).
From an environmental view point, it is desirable to use
water instead of organic solvents as a reaction medium,
since water is environmentally benign.12 In addition to
the limited aqueous solubility of most organic com-
pounds, a significant drawback of using water as a sol-
vent is its ability to act as both a nucleophile and as
an acid, making it incompatible with various organic
transformations. In continuation of our green chemistry
program,13 we decided to explore the synthesis of vari-
The results of the syntheses of hydrazones from the
corresponding aldehydes are summarized in Table 2.
The general reaction worked well for both aromatic (en-
tries 1–4) as well as aliphatic aldehydes (entries 5 and 6).
Piperonal also reacted with these hydrazines to yield
hydrazones bearing dioxane moiety (entries 7 and 8),
Keywords: Hydrazones; Polystyrene sulfonic acid; Aqueous medium;
Microwave irradiation; Green chemistry.
*
Corresponding author. Tel.: +1 513 487 2701; fax: +1 513 569
7677; e-mail: varma.rajender@epa.gov
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.038

5650
V. Polshettiwar, R. S. Varma / Tetrahedron Letters 48 (2007) 5649–5652
R
O
O
N
H
O
N
H
H
PSSA/H2O
1000C, MW
HN
H2N
R
R
O
O
R-H, CH3, Cl
N
N
H
O
Scheme 1. Hydrazone synthesis of furaldehyde and flavanone in water.
Table 1. PSSA catalyzed hydrazone synthesis from ketones in aqueous medium
Entry
Ketone
Hydrazine
Product
Yielda (%)
90
O
HN
N
1
H2N
NH
(a)
O
N
NH
HN
H2N
2
3
88
91
(b)
N
NH
O
O
(a)
(b)
N
NH
4
90
O
N
5
6
(a)
(b)
90
88
NH
Br
Br
Br
O
N
NH
Br
O
NH
N
7
8
(a)
(b)
87
88
O
NH
N
O
N
N
9
(a)
(b)
89
86
H
O
N
N
H
10
a Yields were determined by GC. All the compounds are known in the literature and were characterized by GC–MS and NMR.
which may be useful for the synthesis of derivatives con-
taining a dioxane system.
In view of the exceptional biological properties of
heterocyclic and bi-cyclic hydrazones,1 we extended this

V. Polshettiwar, R. S. Varma / Tetrahedron Letters 48 (2007) 5649–5652
Table 2. PSSA catalyzed syntheses of hydrazones from aldehydes in aqueous medium
5651
Entry
Aldehyde
Hydrazine
Product
Yielda (%)
H
Cl
Cl
HN
H2N
N
1
92
91
91
H
O
NH
(a)
Cl
H
N
HN
H2N
NH
2
3
H
O
(b)
Cl
H
H
O
N
(a)
(b)
F
F
NH
F
F
H
O
4
90
HN
N
H
O
H
NH
N
5
6
(a)
(b)
87
86
H
O
H
NH
N
H
O
O
O
O
O
O
O
H
7
8
(a)
(b)
92
92
HN
N
H
H
O
O
O
H
HN
N
a Yields were determined by GC. All the compounds are known in the literature and were characterized by GC–MS and NMR.
Table 3. PSSA catalyzed synthesis of heterocyclic and bi-cyclic hydrazones in aqueous medium
Entry
Aldehyde/ketone
Hydrazine
Product
Yielda (%)
86
O
HN
O
1
H
N
H2N
(a)
O
O
N
N
O
HN
H2N
H
N
2
84
(b)
O
O
3
4
(a)
(b)
N
85
85
O
H
N
H
O
O
H
O
O
H
N
N
H
H
Cl
Cl
O
5
6
84
O
H
H2N
H2N
N
N
H
N
H
O
O
(c)
H
H
N
O
O
H
N
N
H
85
H
(d)
(continued on next page)

5652
V. Polshettiwar, R. S. Varma / Tetrahedron Letters 48 (2007) 5649–5652
Table 3 (continued)
Entry
Aldehyde/ketone
Hydrazine
Product
Yielda (%)
88
O
N
(a)
N
H
7
8
O
O
O
N
N
H
(b)
(c)
(d)
87
88
88
Cl
9
N
N
N
H
N
H
10
a Yields were determined by GC. All the compounds are known in the literature and were characterized by GC–MS and NMR.
6. Savini, L.; Massarelli, P.; Travagli, V.; Pellerano, C.;
Novellino, E.; Cosentino, S.; Pisano, M. B. Eur. J. Med.
Chem. 2004, 39, 113.
aqueous protocol for their synthesis and the results are
described in Table 3.
7. Melnyk, P.; Leroux, V.; Sergheraert, C.; Grellier, P.
Bioorg. Med. Chem. Lett. 2006, 16, 31.
8. Dabideen, D. R.; Cheng, K. F.; Aljabari, B.; Miller, E. J.;
Pavlov, V. A.; Al-Abed, Y. J. Med. Chem. 2007, 50,
1993.
Phenyl hydrazine (a) and 4-methyl phenyl hydrazine (b)
reacted efficiently with flavanone (entries 1 and 2) to
yield the respective hydrazone in high yield. Hydrazines
(a), (b), (c) and (d) also react with furaldehyde (entries
3–6) and bi-cyclic ketones (entries 7–10).
9. (a) Banik, B. K.; Barakat, K. J.; Wagle, W. R.; Manhas, M.
S.; Bose, A. K. J. Org. Chem. 1999, 64, 5746; (b) Gadhwal,
S.; Baruah, M.; Sandhu, J. S. Synlett 1999, 1573.
10. Hajipour, A. R.; Mohammadpoor-Baltork, I.; Bigdeli, M.
J. Chem. Res. (S) 1999, 570.
11. (a) Jes˘elnik, M.; Varma, R. S.; Polanc, S.; Koc˘evar, M.
Chem. Commun. 2001, 1716; (b) Jes˘elnik, M.; Varma, R.
S.; Polanc, S.; Koc˘evar, M. Green. Chem. 2002, 4, 35.
12. (a) Li, C.-J.; Chen, L. Chem. Soc. Rev. 2006, 5, 68;
(b) Varma, R. S. Org. Chem. Highlights 2007, February
1, Clean Chemical Synthesis in Water, Feb. 1, 2007,
URL: http://www.organic-chemistry.org/Highlights/2007/
01February.shtm.
Thus, we have demonstrated an efficient and general
MW protocol for the synthesis of hydrazones from
cyclic, bi-cyclic, and heterocyclic carbonyl compounds
using PSSA as a catalyst in aqueous medium. The
simple product isolation via filtration precludes the use
of a organic solvent thus culminating in an environ-
mentally benign aqueous protocol for the synthesis of
hydrazones.
13. (a) Varma, R. S. In Green Chemistry: Challenging
Perspectives; Tundo, P., Anastas, P. T., Eds.; Oxford
University Press: Oxford, 2000; p 221; (b) Kumar, D.;
Chandra Sekhar, K. V. G.; Dhillon, H.; Rao, V. S.;
Varma, R. S. Green Chem. 2004, 6, 156; (c) Ju, Y.; Varma,
R. S. Org. Lett. 2005, 7, 2409; (d) Yang, X.-F.; Wang, M.;
Varma, R. S.; Li, C. -J. Org. Lett. 2003, 5, 657; (e) Varma,
R. S.; Kumar, D. Tetrahedron Lett. 1999, 40, 7665; (f)
Wei, W.; Keh, C. C. K.; Li, C.- J.; Varma, R. S. Clean
Technol. Environ. Policy 2005, 7, 62; (g) Ju, Y.; Varma, R.
S. J. Org. Chem. 2006, 71, 135; (h) Ju, Y.; Varma, R. S.
Org. Lett. 2005, 7, 2409; (i) Ju, Y.; Kumar, D.; Varma, R.
S. J. Org. Chem. 2006, 71, 6697.
14. Typical experimental procedure: All the reactions were
carried out in CEM discover MW reactor. Typically, the
carbonyl compound (1 mmol) and hydrazine (1.2 mmol)
were dissolved in 20% PSSA solution in water (three times
the weight of ketone/aldehyde). This homogeneous reac-
tion mixture was then exposed to microwaves at 100 °C in
a closed system for 8 min and 5 min for ketone and
aldehyde, respectively. After completion of the reaction,
products were isolated with simple filtration (1–2 mL of
water was added to facilitate easy filtration) and washed
with methanol to afford pure hydrazones.
Acknowledgment
V.P. is a postgraduate research participant at the Na-
tional Risk Management Research Laboratory adminis-
tered by the Oak Ridge Institute for Science and
Education.
References and notes
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