Catalysis by amberlyst A-21: A greener approach to 4,5,6,7-tetrahydro-1H- indazol-3(2H)-ones via construction of cyclohexanones

Article abstract of DOI:10.1080/00397911.2013.844260

The 4,5,6,7-tetrahydro-1H-indazol-3(2H)-one derivatives have been synthesized in good yields via a two-step method in a single pot. The initial step involved the construction of cyclohexanone ring from aromatic aldehydes and β-ketoester in i-PrOH using an

Full text of DOI:10.1080/00397911.2013.844260

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Catalysis by Amberlyst A-21: A Greener
Approach to 4,5,6,7-Tetrahydro-1H-
indazol-3(2H)-ones via Construction of
Cyclohexanones
Manam Sreenivasa Rao a , Meda Haritha b , Sunder Kumar Kolli c ,
Mandava V. Basaveswara Rao d & Manojit Pal e
a C.R.College, Ganapavaram , Chilakaluripet , Andhra Pradesh ,
India
b Department of Pharmacy , Krishna University , Machilipatnam ,
Andhra Pradesh , India
c Department of Chemistry , Acharya Nagarjuna University , Guntur ,
Andhra Pradesh , India
d Department of Chemistry , Krishna University , Nuzvid , Andhra
Pradesh , India
e Dr. Reddy's Institute of Life Sciences, University of Hyderabad
Campus, Gachibowli , Hyderabad , India
Accepted author version posted online: 08 Nov 2013.Published
online: 19 Mar 2014.
To cite this article: Manam Sreenivasa Rao , Meda Haritha , Sunder Kumar Kolli , Mandava V.
Basaveswara Rao & Manojit Pal (2014) Catalysis by Amberlyst A-21: A Greener Approach to 4,5,6,7-
Tetrahydro-1H-indazol-3(2H)-ones via Construction of Cyclohexanones, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:8, 1076-1083, DOI:
10.1080/00397911.2013.844260
To link to this article: http://dx.doi.org/10.1080/00397911.2013.844260
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Synthetic Communications®, 44: 1076–1083, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2013.844260
CATALYSIS BY AMBERLYST A-21: A GREENER
APPROACH TO 4,5,6,7-TETRAHYDRO-1H-INDAZOL-
3(2H)-ONES VIA CONSTRUCTION OF CYCLOHEXANONES
Manam Sreenivasa Rao,1 Meda Haritha,2 Sunder Kumar Kolli,3
Mandava V. Basaveswara Rao,4 and Manojit Pal5
1C.R.College, Ganapavaram, Chilakaluripet, Andhra Pradesh, India
2Department of Pharmacy, Krishna University, Machilipatnam,
Andhra Pradesh, India
3Department of Chemistry, Acharya Nagarjuna University, Guntur,
Andhra Pradesh, India
4Department of Chemistry, Krishna University, Nuzvid, Andhra Pradesh,
India
5Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract The 4,5,6,7-tetrahydro-1H-indazol-3(2H)-one derivatives have been synthesized
in good yields via a two-step method in a single pot. The initial step involved the construction
of cyclohexanone ring from aromatic aldehydes and β-ketoester in i-PrOH using an inexpen-
sive and reusable catalyst (i.e., Amberlyst A-21) under mild reaction conditions. The utility
of this catalyst has been demonstrated in synthesizing a range of cyclohexanone derivatives.
The catalyst can be recovered and recycled, which makes this procedure simple, convenient,
economically viable, and environmental friendly.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Amberlyst A-21; catalysis; cyclohexanone; indazole
Received July 19, 2013.
Address correspondence to Manojit Pal, Dr. Reddy’s Institute of Life Sciences, University
of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh, India. E-mail: manojit-
pal@rediffmail.com or Mandava V. Basaveswara Rao, Department of Chemistry, Krishna University,
Dr. MRAR PG Centre, Nuzvid-521201, Andhra Pradesh, India. E-mail: professormandava@gmail.com
1076

CATALYSIS BY AMBERLYST A-21
1077
INTRODUCTION
The development of methodologies that involve the use of inexpensive and
reusable catalysts under mild and environmentally friendly reaction conditions is
one of the major goals in green and sustainable chemistry. Methodologies leading to
various carbocyclic/heterocyclic structures are in high demand for both academic and
industrial applications.
The 4,5,6,7-tetrahydro-1H-indazole framework (A, Fig. 1) has attracted consider-
able interest in the area of medicinal chemistry and drug discovery because of its promis-
ing pharmacological properties (e.g., antitumor,[1] antimicrobial,[2] nitric oxide synthase
inhibitory,[3] dopaminergic,[4] HMG-CoA reductase inhibitory,[5] cholesterol lowering,[6]
mitotic motor protein modulatory,[7] and Rho-kinase inhibitory[8] activities). Additionally,
evaluation of a series of 1-aryl-4,5,6,7-tetrahydro-1H-indazole-5-carboxylic acids-
for their anti-inflammatory activities led to the identification of 1-phenyl-4,5,6,7-
tetrahydro-1H-indazole-5-carboxylic acid (B, Fig. 1) that showed high activities in vivo
with ED50 value of 3.5 mg/kg in the carrageenan edema test,[9] Similarly, 2-methyl-
3-methylamino-4,5,6,7-tetrahydroindazole (C, Fig. 1) has showed anti-inflammatory
and analgesic activities.[10] Notably, compared to A its derivative D, 4,5,6,7-tetrahydro-
1H-indazol-3(2H)-one (Fig. 1), has not been explored for the identification of
biologically active new chemical entities (NCE). These observations and our interest in
4,5,6,7-tetrahydro-1H-indazol-3(2H)-ones prompted us to devote our efforts toward the
generation of small molecules based on scaffold D. Herein, we report our results on the
synthesis of these drug-like molecules via a two-step method in a single pot (Scheme 1).
RESULTS AND DISCUSSION
Our strategy was based on the construction of the cyclohexanone ring under
clean conditions followed by the formation of fused indazole ring. We explored the use
of Amberlyst A-21 as an inexpensive and readily available catalyst for the first step. The
resin-bound (or heterogeneous) catalysts are gaining increased interest among modern
organic chemists as the use of homogenous catalysts often involved their cumbersome
separationfromtheproductsandsubsequentdisposalaswellastoxicities. Additionally,
resin-bound catalysts are easy to handle and recover and also provide enhanced safety
for potentially explosive reagents. Amberlyst A-21 is a weakly basic, macroreticular
Figure 1. 4,5,6,7-Tetrahydro-1H-indazole and its bioactive derivatives.
Scheme 1. Generation of a library of small molecules based on scaffold D.

1078
M. S. RAO ET AL.
ion-exchange resin with alkyl amine functionality (it is bonded to the macroreticular
structure of ion exchange resin). We performed a systematic study on the reaction of
4-bromobenzaldehyde (1a) and ethyl acetoacetate (2a) in the presence of Amberlyst
A-21 under various conditions (Table 1). While the use of macroreticular weak base
polymeric catalyst (Amberlyst A-21) in various chemical transformations has been
reported in the literature,[11–15] its use in the construction of cyclohexanone ring has
not been explored extensively earlier. On the other hand synthesis of cyclohexanone 3
has been carried out earlier via the condensation of an aldehyde with β-keto esters or
1,3-diketone in the presence of a base such as piperidine,[16,17] pyrrolidine,[18] and mor-
pholine[19] or a strong base (e.g., NaOMe).[20] The Amberlyst A-21–mediated reaction
of 1a with 2a was carried out initially in i-PrOH at 80°C in the presence of 5% w/w
catalyst (entry 1, Table 1) when the desired product 3a was isolated only in 23% yield
after 15h. Though the increase in catalyst loading increased the product yield signifi-
cantly (entries 2 and 3, Table 1) the best result was obtained when 20% w/w Amberlyst
A-21 was used (entry 4, Table 1). The product 3a was isolated in 90% yield in this case
and was obtained by filtering the reaction mixture followed by washing the solid resin
with warm i-PrOH (55–60°C) (to elute all the organic compounds from the resin)
and then reducing the volume of combined filtrate via evaporation to give the crystal-
line product on cooling. Notably, further increase in catalyst loading did not improve
the yield of 3a (entry 5, Table 1). Similarly, the increase in reaction temperature or time
did not improve the product yield. The use of other solvents [e.g., 1,4-dioxane, tetrahy-
drofuran (THF), dimethylformamide (DMF), toluene, EtOAc, and MeCN] was also
Table 1. Amberlyst A-21–mediated reaction of 1a with 2aa
Amount
(w/w)
T (°C);
t (h)
Entry
Solvent
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
1,4-Dioxane
THF
Yield (%)b
1
2
3
4
5
6
7
8
9
5%
10%
15%
20%
25%
20%
20%
20%
20%
20%
20%
80; 15
80; 15
80; 15
80; 15
80; 15
80; 15
65; 24
100; 24
110; 24
80; 24
80; 24
23
45
67
90 (85, 83, 80)c
87
65
30
43
56
30
19
DMF
Toluene
EtOAc
MeCN
10
11
aAll the reactions were carried out by using 4-bromo benzaldehyde (1a), ethyl
acetoacetate (2a), and Amberlyst A-21 in a solvent (10mL) under open air.
bIsolated yields.
cCatalyst was reused for additional three runs and figures within parentheses
indicate the corresponding yield for each run.

CATALYSIS BY AMBERLYST A-21
1079
examined but they were found to be less effective (entries 6–11, Table 1). While the
reasons for these observations are not clearly understood, it is known that the reactiv-
ity of polystyrene resin is mainly governed by the accessibility of the reactants to the
catalytic sites via swelling of the resin in solvents. It seemed that the swelling of resin
perhaps was more effective in i-PrOH than any other solvents tested. The recyclability
of the catalyst was examined by recovering it via filtration, washing with i-PrOH and
THF, and reusing it for an additional three runs in the reaction of 1a with 2a. The
product 3a was isolated without significant loss of its yield in these cases (entry 4,
Table 1). Moreover, these reactions were performed under open air and therefore do
not require the use of an inert or anhydrous atmosphere. Nevertheless, the use of
Amberlyst A-21 (20% w/w) in i-PrOH at 80°C was identified as the optimum reaction
conditions for the synthesis of 3a.
With the optimized reaction conditions for the preparation of cyclohexanone
derivative in hand, we then focused on the direct and efficient synthesis of
4,5,6,7-tetrahydro-1H-indazol-3(2H)-ones. Thus, the diethyl-2-(4-bromophenyl)-
4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylate (3a) generated in situ via the
reaction of 1a with 2a was treated with hydrazine hydrate 4 in the same pot at 80°C
for 12h when the corresponding indazole derivative 5a was isolated in good yield
(Scheme 2). The reaction proceeded well under this condition and after completion
of the reaction (confirmed by thin-layer chromatography, TLC) the resin was sepa-
rated by filtration. The filtrate was concentrated under low vacuum to give the crude
product, which was purified by recrystallization from ethanol without any column
chromatography. This allowed us to prepare other indazoles, 6-hydroxy-6-methyl-
4-(4-nitrophenyl)-5-propionyl-4,5,6,7-tetrahydro-1H-indazol-3(2H)-one (5b) and
4-(6-hydroxy-6-methyl-3-oxo-5-propionyl-2,3,4,5,6,7-hexahydro-1H-indazol-4-yl)
benzonitrile (5c), following the same strategy (Scheme 2). Both 5b and 5c were isolated in
good yield, highlighting the utility of this method. It is worth mentioning that worldwide
initiatives against environmental pollution have forced synthetic chemists to opt for the
solvents that are more ecofriendly. Because the organic solvents are considered the great-
est contributors toward environmental waste, the use of environmentally compatible
solvents,suchaswaterori-PrOH,ishighlydesirable.Thusthepresenti-PrOH–basedstrat-
egy represents a greener approach toward 4,5,6,7-tetrahydro-1H-indazol-3(2H)-ones in
Scheme 2. One-pot synthesis of 4-(4-bromophenyl)-6-hydroxy-6-methyl-5-propionyl-4,5,6,7-tetrahydro-
1H-indazol-3(2H)-one (5a), 6-hydroxy-6-methyl-4-(4-nitrophenyl)-5-propionyl-4,5,6,7-tetrahydro-1H-inda-
zol-3(2H)-one (5b), and 4-(6-hydroxy-6-methyl-3-oxo-5-propionyl-2,3,4,5,6,7-hexahydro-1H-indazol-4-yl)
benzonitrile (5c).

1080
M. S. RAO ET AL.
Figure 2. Examples of cyclohexanone derivatives 3 (with yield) synthesized using Amberlyst A-21–
mediated reaction.
a single pot. Because all these reactions were performed under open air, the methodology
is free from the risk of pressure development, often observed in reactions performed in
isolated vessels. The methodology therefore is amenable for scale-up.
To demonstrate the generality and scope of the Amberlyst A-21–mediated syn-
thesis of cyclohexanones we prepared several other derivatives as shown in Fig. 2
using a range of aldehydes 1. Thus 1 was reacted with ethyl acetoacetate (2a) in the
presence of Amberlyst A-21 in i-PrOH at 80°C for 15h under open air. The desired
products 3 were isolated in good yields irrespective of the nature and type of alde-
hydes (e.g., aryl, heteroaryl, or alkyl aldehydes) employed. Once again the potential
utility of these compounds was demonstrated by converting the two representative
compounds 3d and 3f to the corresponding 4,5,6,7-tetrahydro-1H-indazol-3(2H)-
ones separately via the reaction with hydrazine (Scheme 3). However, the reaction
of 3e with hydrazine was not clean, perhaps due to the presence of reactive aldehyde
moiety as an additional functional group.
Scheme 3. Synthesis of ethyl 6-hydroxy-6-methyl-3-oxo-4-p-tolyl-2,3,4,5,6,7-hexahydro-1H-indazole-5-
carboxylate (5d) and ethyl 4-(4-chlorophenyl)-6-hydroxy-6-methyl-3-oxo-2,3,4,5,6,7-hexahydro-1H-indazole-
5-carboxylate (5f).

CATALYSIS BY AMBERLYST A-21
1081
Scheme 4. Proposed reaction mechanism.
Based on the fact that Amberlyst A-21 is a weakly basic, macroreticular resin
with alkyl amine functionality, a plausible mechanism for the present two-step
method in a single pot is shown in Scheme 4. The reaction seemed to proceed via
a Knoevenagel condensation of 1 with 2 in the initial step. The resin facilitates the
generation of carbanion E-1 from 2 possessing an active methylene group. The reac-
tion of E-1 with the aldehyde 1 affords the Knoevenagel product (E-2), which on
Michael type addition by the carbanion E-1 affords E-3. An intramolecular aldol type
condensation of E-3 mediated by the resin provides the cyclohexanone derivatives 3.
The reaction of hydrazine 4 with 3 in the same pot affords the 4,5,6,7-tetrahydro-
1H-indazol-3(2H)-one derivatives (5).
CONCLUSIONS
In conclusion, 4,5,6,7-tetrahydro-1H-indazol-3(2H)-one derivatives have been
synthesized in good yields via a two-step method in a single pot. The initial step
involved the construction of cyclohexanone ring from aromatic aldehydes and
β-ketoester in i-PrOH using inexpensive and reusable catalyst (i.e., Amberlyst A-21)
under mild reaction conditions. The utility of this catalyst has been demonstrated in
synthesizing a range of cyclohexanone derivatives. The catalyst can be recovered and
recycled, which makes this procedure simple, convenient, economically viable, and
environmentally friendly. The present Amberlyst A-21–catalyzed method therefore
has potential for the generation of library of small molecules useful for synthetic and
medicinal applications.
EXPERIMENTAL
Preparation of Diethyl 4′-Bromo-5-methyl-3-oxo-
1,2,3,4-tetrahydro-[1,1′-biphenyl]-2,6-dicarboxylate (3a)
Amberlyst A-21 (20%w/w) was added to a solution of ethyl acetoacetate 2a
(2.2mmol) and 4-bromobenzaldehyde 1a (1.0mmol) in i-PrOH (10 ml) and the mix-
ture was stirred at 80°C for 15h. After completion of the reaction as indicated by

1082
M. S. RAO ET AL.
thin-layer chromatography, (TLC), the mixture was cooled to room temperature.
The resin was separated by filtration and washed with warm i-PrOH (55–60°C) to
elute all the contaminated organic compounds from the resin. The combined filtrate
was concentrated under low vacuum to reduce its volume and then cooled to give the
desired product 3a as a white solid; mp 150–151°C; 1H NMR (DMSO-d6, 400MHz)
δ 7.48 (d, J=8.0Hz,2H), 7.27 (d, J=8.0Hz,2H), 4.97 (s, OH), 3.97–3.79 (m, 6H), 3.29
(d, J=8.0Hz,1H), 2.92 (d, J=16.0Hz,1H), 2.34 (d, J=16.0Hz,1H), 0.96 (s,3H), 0.88
(t, J=8.0Hz,3H), 0.87 (t, J=8.0Hz,3H); 13C NMR (CDCl3, 100MHz): δ 200.7,
173.5, 167.4, 137.3, 131.7, 129.7, 121.6, 72.9, 62.2, 61.1, 60.9, 56.7, 52.6, 44.5, 28.5,
13.9, 13.6; IR (KBr): 3433, 1736, 1598, 1364, 1174, 775 cm−1; HRMS (ESI): calcd. for
C19H24O6Br (M+H)+ 427.0756; found 427.0736; MS (ESI): m/z ([M+H]+): 427.1
General Procedure for the Preparation of Compounds 5a–c
Amberlyst A-21 (20%w/w) was added to a solution of ethyl acetoacetate 2a
(2.2mmol) and aldehyde 1 (1.0mmol) in ethanol (10ml), and the mixture was stirred
at 80 °C for 15h to ensure the completion of the reaction (monitored by TLC). The
reaction mass was cooled to room temperature, and hydrazine hydrate 4 (1.0mmol)
was added. The mixture was stirred at 80°C for another 12h. After completion of
the reaction (confirmed by TLC) the resin was separated by filtration. The filtrate
was concentrated under low vacuum to give the crude product, which was purified by
recrystallization from ethanol to afford the pure product 5a–c.
Recovery of the Catalyst
The recovered Amberlyst A-21 resin, obtained by filtering off the reaction prod-
uct, was washed successively with THF (5 mL) and EtOH (5mL) three times and
dried at 100°C for 2h. The efficiency of the catalyst was not changed significantly
after using it three additional times in the model reaction, shown in Table 1.
ACKNOWLEDGMENT
The authors thank the management of Dr. Reddy’s Institute of Life Sciences for
continuous support and encouragement.
SUPPORTING INFORMATION
Full experimental details, and spectral data can be found via the Supple-
mentary Content section of this article’s Web page.
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