Novel synthesis of 2-thienylcarbonyl-cyclohexane-1,3-dione as building block for indazolones and isoxazolones

Article abstract of DOI:10.1071/CH11015

A new synthetic methodology using ultrasonic treatment was applied to the C-acylation of 1,3-cyclohexanedione with thiophene-2-carbonyl chloride to afford 3-hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one (5). This compound was used as a building block to prepare different bicyclic systems: tetrahydro-4H- indazol-4-ones (7ac and 9a,b,d), and 6,7-dihydrobenzisoxazole (11) by reaction with different hydrazines and hydroxylamine, respectively. Structural elucidation of all compounds was thoroughly achieved by NMR spectroscopy. CSIRO 2011.

Full text of DOI:10.1071/CH11015

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2011, 64, 638–646
www.publish.csiro.au/journals/ajc
Novel Synthesis of 2-thienylcarbonyl-cyclohexane-
1,3-dione as Building Block for Indazolones
and Isoxazolones
A
A B
,
A
Guillermo M. Chans, Elizabeth L. Moyano,
and Gloria I. Yranzo
A
INFIQC Department of Organic Chemistry, Faculty of Chemical Sciences,
]
National University of Co´rdoba, Co´rdoba, Argentina.
Corresponding author. Email: lauramoy@fcq.unc.edu.ar
B
A new synthetic methodology using ultrasonic treatment was applied to the C-acylation of 1,3-cyclohexanedione with
thiophene-2-carbonyl chloride to afford 3-hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one (5). This compound was
used as a building block to prepare different bicyclic systems: tetrahydro-4H-indazol-4-ones (7a–c and 9a,b,d), and 6,7-
dihydrobenzisoxazole (11) by reaction with different hydrazines and hydroxylamine, respectively. Structural elucidation
of all compounds was thoroughly achieved by NMR spectroscopy.
Manuscript received: 7 January 2011.
Manuscript accepted: 14 February 2011.
Introduction
part of a central fused ring system plays an important
role in pharmaceutical and medicinal applications and drug
discovery.[8] The classical bioisosteric equivalence between
benzene and thiophene prompted us to study an alternative way
2-Acyl-cycloalkane-1,3-diones and their derivatives have widely
been known for their widespread biological activity. Particularly,
it has been reported that some derivatives have antityrosinemic
activity, working as inhibitors of 4-hydroxyphenylpiruvate
dioxygenase (4-HPPD) activity in the treatment of a hereditary
disease called tyrosinemia type I.[1] Moreover, many articles
describe herbicide agents containing the b-triketone structure or
its derivatives.[2] In addition, these carbonylic compounds are
also attractive because they can be used as building blocks in the
synthesis of various heterocycles.[3]
A general approachtothe synthesis ofacyl-cycloalkanediones
has been developed.[4] According to this method, the cycloalk-
anediones are converted into the mono-O-enol acyl derivatives
by the reaction of acyl chlorides as precursors and pyridine as
base. In the next step, these enol esters undergo O-C isomeriza-
tion to give the target b-triketones in the presence of Lewis acids
(AlCl3 or ZnCl2). This reaction can also proceed either using
phase-transfer catalysis in the presence of a tertiary amine in an
inert organic solvent or through the interaction of a b-diketone
sodium salt with acyl chlorides or carboxylic anhydrides.[5]
Another method to prepare b-triketones with aromatic and also
non-aromatic side chains involves the isomerization reaction
of the O-acylderivative to the C-acylisomer in the presence of
cyanide ion sources.[6,7]
to synthesize
a thienyl-acylcyclohexanedione compound.
Whereas 2-benzoyl-cycloalkane-1,3-diones are commonly found
in the literature, heteroaroyl-cycloalkane-1,3-diones are scarce
and only few examples of pyridinyl, furanyl, pyrrolyl and thienyl
derivatives can be found.[7,9,10]
In this work we report a new synthetic route to obtain 3-
hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one (5) (Fig. 1),
from thiophene-2-carbonyl chloride (1) and cyclohexane-1,3-
dione (2) using an efficient ‘one pot’ methodology applying
ultrasound irradiation to promote the reaction as a clean, useful
and alternative protocol.
We also describe the synthesis of tetrahydro-4H-indazol-4-
ones (7a–c and 9a,b,d) and 6,7-dihydrobenzisoxazol-4-ones (11
and 12), which were synthesized from 5, through the reaction
with different hydrazines and hydroxylamine, respectively
(Fig. 1). These bicyclic compounds have pharmaceutical
interest, thus, 1,5,6,7-tetrahydro-4H-indazol-4-ones present
analgesic,[11] anti-inflammatory,[12] broncholytic, antibiotic,[13]
and antiviral activity.[14] In addition, 6,7-dihydrobenzisoxazol-
4(5H)-ones have been identified as effective anti-psychotic and
analgesic agents.[15]
Our particular focus here is the synthesis of a thienyl-carbonyl
derivative of cyclohexane-1,3-dione, because the presence of an
heterocyclic system and specifically the sulfur heteroatom could
alter the metabolic effect and perhaps improve the therapeutic
properties of these type of compounds. Even that it is known that
potent HPPD inhibitors have the aryl-acylcyclohexanedione
nucleus, heteroaryl-acylcyclohexanediones are also potential
candidates of active substances. Hence, it is not surprising
that the thiophene structure either as the central ring or as
Results and Discussion
In a first approach, compound 5 was prepared according to the
previous reported protocol.[7,10] Thus, the reaction of thiophene-
2-carbonyl chloride (1) with cyclohexane-1,3-dione (2) gave
the enol ester 3, which was properly isolated from the reaction
mixture by column chromatography in 53% yield (Pathway A,
Scheme 1). In the second step, preparation of 5 was
Ó CSIRO 2011
10.1071/CH11015
0004-9425/11/050638

Synthesis of 2-Acyl-cyclohexane-1,3-dione Derivatives
639
accomplished by the cyanide-catalyzed isomerization of this
enol using triethylamine as a base in acetonitrile. It is believed
that an initial attack of cyanide ion to the O-acylated compound
would promote the cleavage of the enol ester and the subsequent
formation of a cyclohexanedione anion and acyl cyanide (4).
Then, both intermediates may recombine to give the
C-acylated product. Following this route, thienyl derivative 5
was obtained in low yield (28%).
In order to improve the yield of the expected compound 5,
we modified the above methodology. Thus, a new strategy was
developed, based on the preparation of acylcyanide 4 as a key
intermediate (Pathway B, Scheme 1). In the first part of the
reaction, the acyl chloride 1 was treated with dried potassium
cyanide in anhydrous acetonitrile under ultrasound irradiation at
508C. It has been reported that the presence of a small quantity
of water accelerates the heterogeneous reaction between acyl
chlorides and potassium cyanide in acetonitrile.[16] It has been
assumed that the role of a small amount of water is to attack the
crystal lattice of the solid potassium cyanide. Based on the fact
that ultrasound may play the same role of a small quantity of
water, and taking into account the advantages of heterogeneous
sonochemistry in many organic processes,[17] we applied this
alternative source of irradiation to obtain 4. The reaction was
monitored by TLC to ensure completion. GC-MS analysis of the
crude after 3 h indicated the presence of acylcyanide 4 as the
exclusive product. Compound 4 was pure enough to be used
in the next step without purification. Then, triethylamine and
cyclohexane-1,3-dione were added to the same flask (in situ
procedure) and the mixture was stirred overnight at room
temperature to give 2-thienylcarbonyl-cyclohexanedione (5),
achieving a remarkable yield of 88%. After extraction workup,
5 was satisfactory to be used in the next derivatization step
without additional purification. While this compound has been
prepared in the literature using the conventional methodology,
this ‘one pot’ method was a significant improvement in terms of
yields and simplicity.[10]
Although the first effective drug treatment for tyrosinemia
has been discovered, that is, 3-hydroxy-2-[2-nitro-4-(trifluoro-
methyl)benzoyl]cyclohex-2-en-1-one (NTBC), a triketone-type
compound (Fig. 2), its mode of action, based on HPPD inhibi-
tion, remains unclear. In order to provide insights into this
inhibition, it has been studied in previous works that the
favoured keto-enol form mimics the keto-acid functionality
present in the substrate and is capable of binding strongly to
the ferric ion in the active site.[18] Although 2-acyl-cyclohexane-
1,3-diones have up to eight possible keto-enol and enol-enol
tautomeric forms, recent evidences, which include X-ray struc-
tures[19] and molecular modelling studies,[20] suggest that the
exocyclic carbonyl moiety of NTBC is coplanar and conjugated
with the cyclohexanedione ring system by an intramolecular
hydrogen bond of the hydroxyl hydrogen to the oxygen atom
of C-3 carbonyl group. It is known that if one of the carbonyl
groups in the triketone is modified, the inhibition potency of the
resulting compound decreases substantially and the enol at the
C-3 position is an essential feature for potent 4-HPPD inhibition
in NTBC derivatives.[19] In addition, it was found by theoretical
calculations for NTBC derivatives that the enol with the
R
R
N N
N N
S
S
O
O
7a–c
9a,b,d
7a
7b
7c
9a
R ꢂ Ph
R ꢂ Ph
R ꢂ p-FC6H4
R ꢂ p-OCH3C6H4
1ꢀ
S
O
OH
3
9b
9d
R ꢂ p-FC6H4
R ꢂ Bn
2ꢀ
5ꢀ
4ꢀ
2
1ꢁ
4
NO2
O
O
OH
3ꢀ O
1
5
6
N O
S
N
O
S
5
F3C
O
O
11
12
NTBC
Fig. 1. Thienyl derivatives synthesized in this research.
Fig. 2. Structure of NTBC, an inhibitor of 4-HPPD activity.
O
O
O
O
Kꢄ
O
KCN
S
ꢅ
S
ꢄ
Kꢄ
ꢅO
CN
O
Et3N, CH3CN
O
3
4
O
Et3N
CH2Cl2
O
O
2
Pathway A
S
O
O
O
O
OH
S
Pathway B
S
2
CN
Cl
Et3N, CH3CN
r.t., 18 h
KCN, CH3CN
)))
50ꢃC, 3h
O
4
1
5
Scheme 1.

640
G. M. Chans, E. L. Moyano, and G. I. Yranzo
R
HN
R
HN
R
N N
N
N
H2O
OH
S
OEt
S
ꢄ
S
O
O
O
(i)
7a–c
8a,d
R
NH
R
N N
H
O
H2O
OH
O
S
N
RNHNH2
6a–d
S
S
ꢄ
O
O
O
9a,b
5
(ii)
N
6a R ꢂ Ph
6b R ꢂ p-FC6H4
6c R ꢂ p-OCH3C6H4
6d R ꢂ Bn
Ph
Rꢀ
NH2
O
H2O
S
N N
S
O
O
9d
(iii)
Rꢀ ꢂ Bn
Scheme 2.
endocyclic double bond (between C-2 and C-3 in our case) was
the dominant conformation.[20]
microwave irradiation, promoting the conversion of enamino-
ketones into a variety of indazoles.[23]
In our case, we could confirm the keto-enol structure of 5 by
1H NMR spectroscopy, considering a highly deshielded signal at
17.29 ppm corresponding to the enol hydrogen at C-3 position.
This deshielding is in agreement with the same signal of similar
acylcyclohexenone derivatives.[19,21] The identification of all
carbons was done on the basis of two-dimensional HSQC and
HMBC spectroscopic experiments. The corresponding to the
carbonyl groups were assigned at 187.37 (C-100 HMBC con-
nectivity with H-30) and 194.48 ppm (C-1, HMBC connectivity
with H-5 and H-6).
Compounds 3 and 5 were also tested with a ferric chloride
assay to observe the colorimetric change. Only 5 gave a positive
characteristic purple colour, which suggests this derivative can
bind tightly with enzyme-bound ferric ions via the enol tautomer
of the triketone.[19]
Beyond their importance as herbicidal and anti-tyrosinemic
agents, 2-acyl-cyclohexane-1,3-diones are of significant interest
as potential synthons of natural products and of others of
biologically active heterocycles owing to their high degree of
functionalization and their high reactivity.[4] Among these
heterocycles, both 1,5,6,7-tetrahydroindazol-4-one and 6,7-
dihydrobenzisoxazol-4-one nuclei form part of the skeleton of
many biologically active products with both simple and rather
complex structures. Examples of the first group are antipyretic,
analgesic and antiphlogistic agents[11] and among those of the
second group are antipsychotic agents.[14]
Focussing on the indazole chemistry and the synthetic
approaches to prepare them, we can mention the utilization
of cyclohexanone enamines and appropriate bidentate nucleo-
philes as starting materials, where a wide array of pyrazole and
indazole derivatives could be prepared.[22] These known proce-
dures require complex purification of the final products and also
prove to be unsatisfactory for the synthesis of different analo-
gues. In some cases, these difficulties were overcome with
In particular, the synthesis of the 1,5,6,7-tetrahydro-4H-
indazol-4-one derivatives could also be performed on the most
widely used method for constructing the pyrazole ring from the
condensation of b-dicarbonyl compounds with hydrazines.[24]
Following this simple methodology, we decided to deal with
the synthesis of tetrahydroindazole derivatives 7a–c, in a
more straightforward, mild and broadly applicable approach
(Scheme 2). A stepwise procedure, comprising nucleophilic
addition of hydrazine to the exocyclic carbonyl group (C-100),
followed by intramolecular cyclocondensation was proposed.
Thus, 5 was treated with arylhydrazines 6a–c to afford
indazoles 7a–c and with benzylhydrazine 6d to give indazole
9d as the major products in moderate to very good yields
(Scheme 2 and Table 1). This synthetic methodology was
versatile and it permitted the formation of compounds not
previously described in literature (7a–c, 8d and 9a,b,d) in
moderate to good yields.
Many reaction conditions were evaluated, thus, indazoles 7a
and 7c were obtained in good yields when DMF was used as the
solvent, while 7b was obtained with better yield when ethanol
and sodium hydroxide were used. Analyzing the effect of the
hydrazine source in the formation of 7a in ethanol, the use
of hydrochloride salt following by neutralization with NaOAc
improved the yield. However, in DMF reactions, using free
hydrazine quantitative amounts of 7a could be obtained.
A particular situation was observed in the reaction when
benzylhydrazine 6d was used, where the expected indazole 7d
was never formed. Thus, hydrazone 8d was isolated as main
product when the reaction solvent was ethanol and the isomeric
indazole 9d was isolated as main product when DMF was used.
In this case, the double bond geometry of hydrazone 8d was not
established and the two isomers may be present.
Even a little amount of the isomeric indazoles (9a,b) were
obtained in the reactions of 5 with hydrazines 6a,b; using

Synthesis of 2-Acyl-cyclohexane-1,3-dione Derivatives
641
Table 1. Reagents and conditions for the synthesis of indazolones
ConditionsA
Hydrazine
Product yield [%]
7
8
9
6aꢀHCl 6a 6aD
6bꢀ2HCl 6bꢀ2HCl
6cꢀHCl
NaOAc, H2O, EtOH EtOHC DMF
Na2CO3, DMF, H2O NaOH, EtOH
Na2CO3, DMF
38B 26B 87B
28E 40E
41E
o5
–
o5
13E
–
–
24B
6dꢀHCl 6dꢀHCl
EtOH, H2O DMF
–
30E
ARatio of 5:6 equal to 1:1.1.
BYield of isolated products after purification by recrystalization from EtOH/H2O.
COne drop of HCl was added.
DFreshly distilled.
EYield of isolated products after purification by chromatographic column.
benzylhydrazine 6d, the formation of 9d was the most important
reaction.
R
R
In these reactions, hydrazone intermediates i were not isolated
and indazolones 7a–c were directly obtained by intramolecular
cyclization. However, in the reactions when ethanol was used as
solvent, the O-ethylated hydrazones 8a,d were detected by GC-
MS as minor products. The formation of these compounds may
be explained in terms of a nucleophilic attack of the solvent
towards cyclohexanedione carbonyl group in the intermediate i.
It is reported in the literature that the regioselectivity of the
reaction of acylcyclohexanediones and hydrazines leads exclu-
sively to the formation of the 1-aryl isomer like 7.[25] In our case,
the –NH2 group of the hydrazine reacts with the exocyclic
carbonyl group of the 2-thienyl-cyclohexane-1,3-dione 5 with
subsequent intramolecular cyclization of the hydrazones inter-
mediates i, affording tetrahydroindazolones 7a–c as main pro-
ducts.[26] However, in the condensation of 5 with 6a and 6b, the
unexpected formation of isomeric 2-aryl-3-(2-thienyl)-2,5,6,7-
2ꢁ
H
N
N
N
N
7a
5
H
3
7a
5
3
2ꢀ
S
7
6
S
7 H
3a
2ꢀ
3ꢀ
3a
3ꢀ
6
4
O
4
O
7a–c
9a,b
Fig. 3. Atom numbering of indazoles 7a–c and 9a,b.
Table 2. 1H and 13C NMR chemical shifts [ppm] of indazoles 7a c and
]
9a,b,d in CDCl3
Compound
H-30
C-20
C-3
C-3a
C-7a
tetrahydro-4H-indazol-4-ones 9a and 9b was obtained ino5 and
13% yield, respectively. The existence of these compounds
could be rationalized by the reaction of the hydrazine with the
endocyclic cyclohexanedione enol group to form intermediate
ii, followed by cyclization (Scheme 2).
When benzylhydrazine 6d was employed in DMF, 9d was
the only product. In this case, we believe that intermediate iii
is more feasible to form than i, due to a higher nucleophilic
character on the secondary amino group of 6d, which at first
reacts with the exocyclic carbonyl group of 5. This type of
regioselectivity in reactions of benzylhydrazine and carbonylic
compounds was previously observed in the synthesis of
pyrazolo-derivatives.[27]
7a
7b
7c
9a
9b
9d
8.49
8.49
8.48
7.49
7.52
7.51
134.44
134.38
134.68
128.34
128.04
127.79
146.49
146.66
146.29
137.76
137.90
137.42
116.18
116.27
115.93
116.77
116.74
116.86
150.78
150.93
150.87
157.42
157.45
156.89
an inclination with respect to the molecular plane. The cause of
this effect might be the steric hindrance with the phenyl group.
The chemical shifts of the quaternary carbons C-20, C-3, C-3a and
C-7a are representative of these compounds (Table 2).
To corroborate the reactivity of the different carbonyl groups
of 5, charge distributions were calculated via the Hartree Fock
approach using the 6–31þG(d,p) method. It has been found that
the highest positive charge of 5 was localized in the C-100,
indicating that this position was the preferred site of attack of the
nucleophile, as it was experimentally corroborated.
A complete elucidation of the structures was achieved by
spectroscopic techniques of 1-D NMR, 2-D NMR HSQC and
HMBC and NOE experiments. Distinction between the regio-
isomeric indazoles was ascertained on the basis of NOESY, 1H
and 13C NMR experiments. Irradiation of the methylene protons
H-7 of compounds 7a–c mutuallyinduces NOE onthe arylproton
H-200 (Fig. 3). Indeed, the same irradiation on isomers 9a,b,d did
not induce NOE on the aryl proton. Another indication was that
protons H-30 ofcompounds7a–c presented higherchemicalshifts
than compounds 9a,b,d, since in the latter the thienyl group has
Theoretical calculations of geometries of compounds 7a and
9a have been made at the HF/6–31þG(d,p) level of theory and it
was found that in 7a, the distance of protons H-200 and H-7 was
˚
˚
2.5 A, whereas in 9a this distance is increased to 3.87 A. These
results were in agreement with our experimental NMR findings.
As part of our continuing work, dihydrobenzisoxazolone 11
was synthesized from cyclocondensation of 5 with hydroxy-
lamine. There are two general methods for the synthesis
of isoxazoles: (a) the reaction of hydroxylamine with a
three-carbon atoms system, such as a 1,3-diketone or a a,b-
insaturated ketone;[28] and (b) the reaction of a nitrile oxide
with an alkene or alkyne.[29] In order to obtain 3-(2-thienyl)-
6,7-dihydro-benzisoxazol-4-ones (11), we found the first
method more convenient. Thus, 2-acyl-1,3-cyclohexanedione
5 was treated with hydroxylamine hydrochloride in the pre-
sence of base, to give 11 as the main product.

642
G. M. Chans, E. L. Moyano, and G. I. Yranzo
HO
HO
O
NH2OH·HCl
EtOH, Pyr
OH
OH
N
OH
N
OH
S
S
S
ꢄ
Reflux, 2 h
O
O
O
5
10
(iv)
H2O
N
H2O
H2O
N
HO
O
O
N
S
S
O
S
O
O
O
12
Scheme 3.
11
13
2
1
HO
2
1
Table 3. Reaction conditions for the synthesis of benzisoxazolones
1ꢀ
S
O N
1ꢀ
S
N
1ꢀ
S
N O
OH
5
7a
5
3
7a
5
3
2ꢀ
7
5'
4ꢀ
5ꢀ
6
7
5ꢀ
1ꢁ
ConditionsA
Product yieldB [%]
Temperature Reaction time [h] 10 11 12 13
2ꢀ
2ꢀ
3a
4
3a
4
4
6
3ꢀ O
4ꢀ
3ꢀ
6
4ꢀ
3ꢀ
Solvent Base
1
O
3
O
2
H2O
NaOMe
r.t.
24
9
–
31
27 42 10
10
–
–
2
3
10
11
12
EtOH Pyridine
808C
808C
EtOH
–
2
3
–
Fig. 4. Atoms numbering of compounds 10, 11 and 12.
ARatio of 5:NH2OHꢀHCl equal to 1:2.
BYield of isolated products.
Table 4. 13C NMR chemical shifts [ppm] of compounds 10 12 in
]
CDCl3
Using sodium methoxide as base and water as solvent, 11 was
obtained as the only product, but in low yield. When the reaction
was carried out with pyridine in ethanol, the yield of 11 was
increased; nevertheless, oxime 10 and isoxazole 12 were
obtained. Traces of the O-ethylated oxime 13 were identified
by GC-MS analysis when ethanol was used as solvent. The
reaction with hydroxylamine hydrochloride without base
resulted in very low yields. Reaction conditions and the forma-
tion of products are described in Scheme 3 and Table 3. It should
be pointed out that compounds 10, 11, 12 and 13 have not been
previously described in literature.
According to the literature data[30] and the previous results
obtained here in the preparation of tetrahydroindazoles, the
formation of both oximes intermediates iv and 10 as precursors
of isoxazoles 12 and 11, respectively, was expected. Several
attempts to obtain quantitatively benzoisoxazolones 11 and/or
12 were carried out, however they were unsuccessful. Thus, in
the best reaction conditions (EtOH/pyridine), not only were both
regioisomeric isoxazoles were obtained, but the oxime 10 could
be also isolated (Table 3). This finding may reflect the greater
stability of the oxime intermediate compared with the hydrazone
intermediates (i–iii) proposed in the synthesis of tetrahydro-
indazoles. It should be noted that the double bond geometry of
oxime 10 was not determined.
Isoxazole
C-20
C-3
C-3a
C-7a
11
12
128.83
129.20
165.46
154.29
111.86
113.25
166.03
183.47
Oxime
C-20
C-100
C-6
C-5
10
130.41
160.33
108.00
150.51
observed in the mass spectrum of 12. In this case, the base peak
corresponds to the molecular ion and the fused ring cleavage is
the main fragmentation (m/z 149).
The assignment of carbons C-3 and C-7a was accomplished
by comparison of their NMR spectra (Fig. 4, Table 4). The
analysis of the HMBC spectra led us to attribute the signal at
183.47 ppm to the quaternary carbon at position 7a in compound
12, due to an interaction with protons H-7 and H-6. The assign-
ment of C-3 (154.29 ppm) was achieved by correlation with
proton H-30. Although the C¼N bond usually resonates upfield
compared with the C–O single bond in fused isoxazoles,[31]
interestingly, in this case we found the other way around.
Conclusions
In summary, we have established a new efficient methodology
for the synthesis of thienylcarbonyl-cyclohexanedione (5),
using ultrasound irradiation as a novel approach.
In addition, a straightforward synthesis of 1,5,6,7-tetrahydro-
4H-indazol-4-ones (7a,b,c) was developed. Unexpectedly,
isomers 2-phenyl-3-(2-thienyl)-2,5,6,7-tetrahydro-4H-indazol-4-
ones (9a,b,d) were also obtained. Furthermore, benzisoxazolone-
type compounds 11 and 12 were synthesized.
Characterization of compounds 10, 11 and 12 was ascer-
tained by spectroscopic analysis (1H, 13C, COSY, HSQC,
HMBC) and mass spectrometry. Structure elucidation of the
regioisomeric products 11 and 12, achieved by 13C NMR and
mass spectra is also reported. The mass spectrum of 11 showed
dominant ions at m/z 111, which is consistent with the loss of
the thiophene-2-carbonitrile fragment. This pattern was not

Synthesis of 2-Acyl-cyclohexane-1,3-dione Derivatives
643
7.91 (dd, J 3.8, 1.2, 1H, H-30). dC (CDCl3) 21.45 (C-3), 28.54
(C-2), 36.92 (C-4), 117.85 (C-6), 128.39 (C-40), 132.02 (C-20),
134.54 (C-50), 135.48 (C-30), 158.63 (C-1000), 169.75 (C-1),
199.59 (C-5). m/z [%] 113 (5), 112 (6), 111 (100), 83 (7), 69 (3),
57 (2), 42 (3).
Experimental
General
All chemicals were of reagent grade and were used without
further purification. All solvents were distilled. Melting points
were determined in open capillary tubes and are uncorrected.
FT-IR spectra were obtained with a Nicolet 55XC-FTIR. Mass
spectra were measured at an ionizing voltage of 70 eV. All
1H, 19F and 13C NMR spectra were recorded at 400.16, 376.48
and 100.56 MHz, respectively (Bruker Avance II, BBI probe, Z-
gradient spectrometer). Chemical shifts (d) are reported in ppm
values and coupling constants (J) in Hz. The internal standard
was TMS. 13C assignments were confirmed by 2D HSQC and
HMBC experiments.
3-Hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-one 5
Yellow crystals. Yield 88.5% (0.6766 g). nmax(KBr)/cmꢁ1 3092,
2952, 2925, 2861, 1666, 1555, 1406, 1351, 1255, 721. dH
(CDCl3) 2.05 (quintuplet, J 6.2, 2H, H-3), 2.57 (t, J 6.2, 2H, H-
2), 2.72 (t, J 6.2, 2H, H-4), 7.11 (dd, J 5.0, 4.0, 1H, H-40), 7.70
(dd, J 5.0, 1.1, 1H, H-50), 8.08 (dd, J 4.0, 1.1, 1H, H-30), 17.28 (s,
1H, OH-5). dC (CDCl3) 19.02 (C-3), 32.97 (C-4), 38.45 (C-2),
112.78 (C-6), 127.63 (C-40), 135.49 (C-50), 136.38 (C-30),
141.07 (C-20), 187.37 (C-100), 194.48 (C-1), 196.44 (C-5). m/z
[%] 223 (12), 222 [M]þ (62), 221 (89), 194 (15), 166 (57), 138
(31), 111 (100), 84 (19), 83 (11), 69 (16), 42 (11). m/z (HR-EI)
calcd. for C11H10O3S 222.0351 [M]þꢂ; found 222.0361.
Preparative thin-layer chromatography was carried out with
Merck silica gel plates (60 DGF254) and column chromato-
graphy with Merck silica gel (70–230 mesh).
Computational Methods
All geometries and energy calculations were performed at the
HF/6–31þG(d,p) level of theory by using the Gaussian 03[32]
suite of programs. All stationary points were confirmed as true
minima by harmonic vibrational frequency calculations at the
same computational level.
Synthesis of 3-(2-Thienyl)-1,5,6,7-tetrahydro-4H-indazol-
4-ones 7a,c
A mixture of 3-hydroxy-2-(2-thienylcarbonyl)cyclohex-2-en-1-
one 5 (0.318 g, 1.436 mmol) and the corresponding hydrazine in
DMF (3 mL) was heated to reflux for 5 h. The reaction progress
was monitored by TLC. Water was added dropwise to the
mixture; after cooling, the precipitate was collected by filtration.
The mother liquor was further purified by extraction with ether
(3 ꢃ 10 mL), the combined organic extracts were dried with
anhydrous MgSO4 and evaporated. The residue (7c) was pur-
ified by column chromatography with ether as eluent and then
recrystallized from acetone/water.
Synthesis of 3-Oxocyclohex-1-en-1-yl Thiophene-
2-carboxylate 3 and 3-Hydroxy-2-(2-thienylcarbonyl)
cyclohex-2-en-1-one 5 (Pathway A)
Thiophene-2-carbonyl chloride 1 (0.304 g, 2.0 mmol) was added
dropwise to a cooled (ꢁ108C) stirred solution of cyclohexane-
1,3-dione 2 (0.300 g, 2.7 mmol) and triethylamine (0.35 mL) in
anhydrous CH2Cl2 (12 mL). The mixture is left for 10 min at
ꢁ108C and then for another 12 h at room temperature.
A solution of 3 (0.250 g, 1.126 mmol), triethylamine
(0.34 mL), potassium cyanide (1.1mg, 16.9mmol, 1.5% mol) in
acetonitrile (2.8mL) was stirred for 12 h at room temperature.
The solution was concentrated under reduced pressure and
the residue was partitioned between ethyl acetate and 1 M HCl.
The triketone 5 was then extracted from the organic layer into
aqueous sodium bicarbonate. Neutralization and extraction with
ether gave, after drying and concentration, the crude product that
was chromatographed.[15]
1-Phenyl-3-(2-thienyl)-1,5,6,7-tetrahydro-4H-indazol-
4-one 7a
Pale yellow solid, mp 146.8–147.58C. Yield 87.0% (0.3674 g).
n
max(KBr)/cmꢁ1 3092, 3071, 2941, 2923, 2846, 1665, 1497,
1468, 948, 698 cmꢁ1. MS: m/z [%] 295 (20), 294 [M]þ (100),
267 (12), 266 (61), 265 (52), 133 (13), 89 (10), 77 (30), 51 (9). dH
(CDCl3) 2.17 (quintuplet, J 6.2, 2H, H-6), 2.63 (t, J 6.2, 2H, H-
5), 2.97 (t, J 6.2, 2H, H-7), 7.12 (dd, J 5.0, 3.7, 1H, H-40), 7.33
(dd, J 5.0, 1.0, 1H, H-50), 7.43 (tt, J 7.0, 1.7, 1H, H-400), 7.52–
7.59 (m, 2H, H-200 and H-600), 7.52–7.59 (m, 2H, H-300 and H-500),
8.49 (dd, J 3.7, 1.0, 1H, H-30). dC (CDCl3) 23.23 (C-6), 23.82 (C-
7), 38.98 (C-5), 116.18 (C-3a), 124.19 (C-300,500), 126.55 (C-50),
127.62 (C-40), 128.43 (C-400), 129.41 (C-200,600), 129.91 (C-30),
134.44 (C-20), 138.41 (C-100), 146.49 (C-3), 150.78 (C-7a),
192.65 (C-4). m/z (HR-EI) calcd. for C17H14N2OS 294.0827
[M]þꢂ; found 294.0822.
Synthesis of 3-Hydroxy-2-(2-thienylcarbonyl)cyclohex-
2-en-1-one 5 (Pathway B)
A mixture of thiophene-2-carbonyl chloride 1 (0.500 g,
3.400 mmol), potassium cyanide (dried at 1508C under reduced
pressure and powdered; 0.245 g, 3.75 mmol), and acetonitrile
(5 mL) is placed in a 100-mL round-bottom flask, which is
immersed in a laboratory ultrasonic cleaner (TestLab, 80 W,
40 KHz) thermostated at 508C. After ultrasonic treatment for
3 h, anhydrous Et3N (1 mL) and cyclohexane-1,3-dione
(0.420 g, 3.750 mmol) were added and the mixture was stirred at
room temperature overnight. The isolation methodology used
was identical to Pathway A, nevertheless, no further purification
was needed. Spectral data agrees with literature.[10]
1-(4-Methoxyphenyl)-3-(2-thienyl)-1,5,6,7-tetrahydro-
4H-indazol-4-one 7c
Pale brown solid, mp 160.7–162.68C dec. Yield 41.1%
(0.0609 g). dH (CDCl3) 2.15 (quintuplet, J 6.2, 2H, H-6), 2.61 (t,
J 6.2, 2H, H-5), 2.90 (t, J 6.2, 2H, H-7), 3.86 (s, 3H, H-1000), 7.00
(m, 2H, H-300,500), 7.11 (dd, J 5.0, 3.7, 1H, H-40), 7.31 (dd, J 5.0,
1.0, 1H, H-50), 7.43 (m, 2H, H-200,600), 8.48 (dd, J 3.7, 1.0, 1H, H-
30). dC (CDCl3) 23.29 (C-6), 23.68 (C-7), 39.10 (C-5), 55.77 (C-
1000), 114.63 (C-300,500), 115.93 (C-3a), 125.86 (C-200,600), 126.53
(C-50), 127.71 (C-40), 129.89 (C-30), 131.59 (C-100), 134.68 (C-
20), 146.29 (C-3), 150.87 (C-7a), 159.71 (C-400), 192.71 (C-4).
m/z [%] 325 (29), 324 [M]þ (100), 323 (47), 297 (10), 296 (50),
3-Oxocyclohex-1-en-1-yl Thiophene-2-carboxylate 3
White crystals, mp 41–448C. Yield 55.7% (0.335 g). nmax(KBr)/
cmꢁ1 3092, 2951, 2886, 2866, 1733, 1674, 1410, 1249, 1123,
735. dH (CDCl3) 2.12 (quintuplet, J 6.2, 2H, H-3), 2.46 (t, J 6.2,
2H, H-2), 2.68 (t, J 6.2, 1.1, 2H, H-4), 6.06 (t, J 1.1, 1H, H-6),
7.17 (dd, J 5.0, 3.8, 1H, H-40), 7.69 (dd, J 5.0, 1.2, 1H, H-50),

644
G. M. Chans, E. L. Moyano, and G. I. Yranzo
216 (10), 135 (26), 133 (12), 107 (29), 77 (15). m/z (HR-EI)
calcd. for C18H16N2O2S 324.0932 [M]þꢂ; found 324.0936.
(JCF 22.9, C-300,500), 116.74 (C-3a), 127.03 (C-40), 128.04 (C-20),
128.42 (JCF 9.2, C-200,600), 129.17 (C-50), 132.12 (C-30), 135.44
(JCF 3.0, C-100), 137.90 (C-3), 157.45 (C-7a), 162.63 (JCF 250.0,
C-400), 193.86 (C-4). dF (CDCl3) ꢁ111.43 (ddd, J 12.3, 8.0, 4.3,
F-400). m/z [%] 313 (20), 312 [M]þ (100), 311 (66), 285 (11), 284
(63), 204 (16), 133 (54), 123 (18), 95 (40), 89 (13), 75 (13).
m/z (HR-EI) calcd. for C17H13FN2OS 312.0733 [M]þꢂ; found
312.0743.
Synthesis of 1-(4-Fluorophenyl)-3-(2-thienyl)-
1,5,6,7-tetrahydro-4H-indazol-4-one 7b
Compound 5 (0.105 g, 0.475 mmol) was dissolved in ethanol
(2 mL) and 4-fluorophenylhydrazine hydrochloride 6d (0.080 g,
0.493 mmol) and NaOH (0.022 g, 0.552 mmol) were added.
The reaction mixture was heated at reflux temperature for 6 h.
The residue was evaporated to dryness under reduced pressure,
dissolved with CHCl3 (10 mL) and extracted with HCl (0.1 M,
3 ꢃ 10 mL). The organic layer was dried (MgSO4), filtered and
evaporated. The solid residue obtained was purified by column
chromatography with CHCl3/Hexane/EtOH (3.5:0.1:0.05) as
eluent.
2-Benzyl-3-(2-thienyl)-2,5,6,7-tetrahydro-4H-indazol-
4-one 9d
Pale yellow solid, mp 166.3–168.28C dec. Yield 29.9%
(0.0430 g). dH (CDCl3) 2.15 (quintuplet, J 6.2, 2H, H-6), 2.52 (t,
J 6.2, 2H, H-5), 2.89 (t, J 6.2, 2H, H-7), 5.35 (s, 2H, H-1000), 7.09–
7.11 (m, 2H, H-200,600), 7.10 (dd, J 5.0, 3.7, 1H, H-40), 7.25 (dd, J
3.7, 1.0, 1H, H-50), 7.25–7.33 (m, 2H, H-300 and H-500), 7.25–
7.33 (m, 1H, H-400), 7.51 (dd, J 5.0, 1.0, 1H, H-30). dC (CDCl3)
23.46 (C-6), 23.46 (C-7), 39.67 (C-5), 53.34 (C-1000), 116.86
(C-3a), 126.96 (C-200,600), 127.17 (C-40), 127.79 (C-20), 127.88
(C-50), 128.78 (C-300,500), 128.85 (C-400), 130.61 (C-30),
136.38 (C-100), 137.42 (C-3), 156.89 (C-7a), 193.66 (C-4). m/z
[%] 309 (22), 308 [M]þ (100), 307 (27), 280 (16), 279 (25), 231
(17), 217 (12), 189 (28), 133 (27), 91 (77), 89 (19), 65 (19).
m/z (HR-EI) calcd. for C18H16N2OS 308.0983 [M]þꢂ; found
308.0983.
1-(4-Fluorophenyl)-3-(2-thienyl)-1,5,6,7-tetrahydro-
4H-indazol-4-one 7b
Pale yellow solid. Yield 39.4% (0.0553 g). dH (CDCl3) 2.17
(quintuplet, J 6.3, 2H, H-6), 2.62 (t, J 6.3, 2H, H-5), 2.93 (t, J 6.3,
2H, H-7), 7.12 (dd, J 5.1, 3.7, 1H, H-40), 7.18–7.23 (m, 2H, H-300
and H-500), 7.33 (dd, J 5.1, 1.1, 1H, H-50), 7.50–7.54 (m, 2H, H-
200,600), 8.49 (dd, J 3.7, 1.1, 1H, H-30). dC (CDCl3) 23.27 (C-6),
23.77 (C-7), 39.03 (C-5), 116.27 (C-3a), 116.50 (JCF 22.9, C-
300,500), 126.24 (JCF 8.8, C-200,600), 126.75 (C-50), 127.77 (C-40),
130.13 (C-30), 134.38 (C-20), 134.64 (JCF 3.2, C-100), 146.66
(C-3), 150.93 (C-7a), 162.32 (JCF 248.7, C-400), 192.62 (C-4). dF
(CDCl3) ꢁ112.27 (ddd, J 12.4, 7.9, 4.8, F-400). m/z [%] 313 (20),
312 [M]þ (100), 285 (13), 284 (62), 283 (53), 133 (20), 95 (26),
89 (11), 75 (9). m/z (HR-EI) calcd. for C17H13FN2OS 312.0733
[M]þꢂ; found 312.0734.
Synthesis of 3-(2-Thienyl)-6,7-dihydro-1,2-benzisoxazol-
4(5H)-one 12
To a solution of 5 (0.100 g, 0.450 mmol) in ethanol (3 mL),
hydroxylamine hydrochloride (0.344 g, 0.495 mmol) and pyr-
idine (0.1 mL) were added. The mixture was heated to reflux
in a water bath for 6 h. The solvent was evaporated to dryness,
and the residue was dissolved with water, extracted with ethyl
acetate and dried with anhydrous MgSO4. The residue was
purified by thin-layer chromatography with CHCl3/hexane/
EtOH (3:1:0.05) as eluent.[33]
2-[(Benzylhydrazono)(2-thienyl)methyl]-
3-ethoxycyclohex-2-en-1-one 8d
Brown solid. Yield 24.3% (0.0432 g). m/z [%] 354 [M]þ (15),
309 (11), 268 (12), 267 (67), 254 (12), 217 (12), 189 (12), 163
(15), 91 (100), 65 (9). m/z (HR-EI) calcd. for C20H22N2O2S
354.1402 [M]þꢂ; found 354.1392.
3-Hydroxy-2-[(hydroxyimino)(2-thienyl)methyl]cyclohex-
2-en-1-one 10
2-Phenyl-3-(2-thienyl)-2,5,6,7-tetrahydro-4H-indazol-
4-one 9a
Pale yellow solid, mp 1898C dec. Yield 26.9% (0.0287 g).
max(KBr)/cmꢁ1 3085, 3063, 2916, 2873, 1716, 1628, 1591,
n
Yellow solid. Yield o5% (0.007 g). dH (CDCl3) 2.20 (quintu-
plet, J 6.3, 2H, H-6), 2.59 (t, J 6.3, 2H, H-5), 2.96 (t, J 6.3, 2H, H-
7), 6.99 (dd, J 5.0, 3.7, 1H, H-40), 7.31–7.33 (m, 2H, H-200 and H-
600), 7.38 (dd, J 5.0, 1.2, 1H, H-50), 7.37–7.41 (m, 2H, H-300 and
H-500), 7.37–7.41 (m, 1H, H-400), 7.49 (dd, J 3.7, 1.2, 1H, H-30).
dC (CDCl3) 23.44 (C-6), 23.66 (C-7), 40.07 (C-5), 116.77 (C-
3a), 126.55 (C-200,600), 126.93 (C-40), 128.34 (C-20), 129.05
(C-50), 129.05 (C-100), 129.31 (C-300,500), 132.02 (C-30), 137.76
(C-3), 139.44 (C-400), 157.42 (C-7a), 193.93 (C-4). m/z [%] 295
(20), 294 [M]þ (100), 293 (67), 267 (10), 266 (65), 186 (11),
133 (36), 105 (23), 77 (50), 51 (11). m/z (HR-EI) calcd. for
C17H14N2OS 294.0827 [M]þꢂ; found 294.0825.
1404, 941, 892, 710. dH (CD3CN) 1.90 (quintuplet, J 6.2, 2H, H-
3), 2.75 (t, J 6.2, 2H, H-4), 2.78 (t, J 6.2, 2H, H-2), 7.21 (dd, J 5.0,
3.8, 1H, H-40), 7.67 (dd, J 5.0, 1.1, 1H, H-50), 8.44 (dd, J 3.8, 1.1,
1H, H-30), 9.10 (s, 1H, OH-5). dC (CD3CN) 21.56 (C-3), 22.20
(C-4), 23.58 (C-2), 108.00 (C-6), 128.80 (C-40), 130.41 (C-20),
131.08 (C-50), 131.78 (C-30), 150.51 (C-5), 160.33 (C-100),
163.85 (C-1). m/z [%] 237 [M]þ (1), 235 (15), 234 (100), 233
(33), 217 (27), 120 (25), 111 (76), 110 (12), 83 (17), 45 (14),
41 (16).
3-(2-Thienyl)-6,7-dihydro-2,1-benzisoxazol-4(5H)-one 11
White solid, mp 137–139.58C. Yield 42.4% (0.0418 g).
max(KBr)/cmꢁ1 3111, 3090, 2948, 2912, 2847, 1729, 1676,
2-(4-Fluorophenyl)-3-(2-thienyl)-2,5,6,7-tetrahydro-
4H-indazol-4-one 9b
n
1575, 1480, 1427, 1296, 745. dH (CD3CN) 2.13 (quintuplet, J
6.2, 2H, H-6), 2.56 (t, J 6.2, 2H, H-5), 2.91 (t, J 6.2, 2H, H-7),
7.28 (t, J 5.0, 1H, H-40), 7.81 (d, J 5.0, 1H, H-50), 8.54 (d, J 3.7,
1H, H-30). dC (CD3CN) 21.94 (C-7), 22.89 (C-6), 39.95 (C-5),
111.86 (C-3a), 128.83 (C-20), 129.41 (C-40), 133.53 (C-30),
133.62 (C-50), 165.46 (C-3), 166.03 (C-7a), 193.68 (C-4). m/z
[%] 220 (16), 219 [M]þ (99), 190 (22), 163 (10), 162 (28), 136
Pale yellow solid. Yield 12.8% (0.018 g). dH (CDCl3) 2.19
(quintuplet, J 6.3, 2H, H-6), 2.59 (t, J 6.3, 2H, H-5), 2.94 (t, J 6.3,
2H, H-7), 7.01 (dd, J 5.0, 3.7, 1H, H-40), 7.09 (collapsed dd, J
9.2, 5.0, 2H, H-300,500), 7.31 (dd, J 9.2, 5.0, 2H, H-200 and H-600),
7.39 (dd, J 5.0, 1.1, 1H, H-50), 7.52 (dd, J 3.7, 1.1, 1H, H-30).
dC (CDCl3) 23.36 (C-6), 23.58 (C-7), 40.02 (C-5), 116.32

Synthesis of 2-Acyl-cyclohexane-1,3-dione Derivatives
645
(12), 135 (55), 112 (11), 111 (100), 83 (21), 41 (15). m/z (HR-EI)
calcd. for C11H9NO2S 219.0354 [M]þꢂ; found 219.0352.
[5] M. Barcelo´, E. Ravin˜a, C. F. Masaguer, E. Dom´ınguez, F. M. Areias,
J. Brea, M. I. Loza, Bioorg. Med. Chem. Lett. 2007, 17, 4873.
doi:10.1016/J.BMCL.2007.06.045
[6] (a) J. B. Heather, P. D. Milano, U.S. Patent 4,695,673 1987.
3-(2-Thienyl)-6,7-dihydro-1,2-benzisoxazol-4(5H)-one 12
(b) E. Bay, U.S. Patent 4,774,360 1988.
White solid. Yield 10.2% (0.0108 g). nmax(KBr)/cmꢁ1 3096,
3068, 2959, 2914, 2854, 1720, 1679, 1579, 1456, 1269, 1119,
1068. dH (CD3CN) 2.21 (quintuplet, J 6.4, 2H, H-6), 2.56 (t, J
6.4, 2H, H-5), 3.04 (t, J 6.4, 2H, H-7), 7.19 (dd, J 5.1, 3.7, 1H, H-
40), 7.59 (dd, J 5.1, 1.1, 1H, H-50), 8.45 (dd, J 3.7, 1.1, 1H, H-30).
dC (CD3CN) 21.45 (C-6), 22.82 (C-7), 38.16 (C-5), 113.25 (C-
3a), 127.95 (C-40), 128.51 (C-50), 129.20 (C-20), 132.70 (C-30),
154.29 (C-3), 183.47 (C-7a), 192.59 (C-4). m/z [%] 220 (15),
219 [M]þ (100), 163 (12), 162 (30), 150 (14), 149 (77), 136 (18),
135 (13), 123 (25), 82 (15), 45 (15), 42 (42), 41 (13). m/z (HR-
EI) calcd. for C11H9NO2S 219.0354 [M]þꢂ; found 219.0353.
[7] I. I. Flores Montes, U. Burger, Tetr. Lett. 1996, 37, 1007. doi:10.1016/
0040-4039(95)02362-3
[8] M. Szajda, J. N. Lamin, Thiophenes and their Benzo Derivatives:
Structure, in Comprehensive Heterocyclic Chemistry II (Eds A. R.
Katritzky, C. W. Rees, E. F. V. Scriven) 1996, Vol. 2, pp. 438–490
(Pergamon Press: Oxford).
[9] R. Beaudegnies, A. Edmunds, T. Fraser, R. Halla, T. Hawkesb, G.
Mitchell, J. Schaetzer, S. Wendeborn, J. Wibley, Bioorg. Med. Chem.
2009, 17, 4134. doi:10.1016/J.BMC.2009.03.015
[10] (a) J. E. D. Barton, D. Cartwright, C. G. Carter, J. M. Cox, D. L. Lee,
G. Mitchell, F. H. Walker, F. X. Woolard, Eur. Pat. Appl. EP 283,261
A2 19,880,921 1988.
(b) R. J. Anderson, J. Grina, F. Kuhnen, S. F. Lee, G. W. Luehr,
H. Schneider, K. Seckinger, Ger. Offen. DE 3,902,818 1989.
[11] W. Eberlein, W. Engel, G. Mihm, K. Rudolf, G. Engelhardt,
U.S. Patent 5,468,766 1995.
3-Ethoxy-2-[(hydroxyimino)(2-thienyl)methyl]cyclohex-
2-en-1-one 13
Pale yellow solid. Yield 2.1% (0.0025 g). nmax(KBr)/cmꢁ1 3070,
2952, 2926, 2854, 1724, 1457, 1283, 1118, 1062, 738. dC
(CDCl3) 1.23 (t, J 7.2, 3H), 2.00 (quintuplet, J 7.5, 2H), 2.40 (t, J
7.5, 2H), 2.74 (t, J 7.5, 2H), 4.09 (q, J 7.2, 2H), 7.20 (dd, J 5.1,
3.7, 1H), 7.60 (dd, J 3.7, 1.0, 1H), 7.69 (dd, J 5.1, 1.0, 1H), 10.51
(s, 1H). m/z [%] 265 [M]þ (18), 220 (28), 179 (11), 178 (100),
177 (9), 165 (46), 111 (38), 45 (11), 41 (13). m/z (HR-EI) calcd.
for C13H15NO3S 265.0773 [M]þꢂ; found 265.0771.
[12] (a) O. Rosati, M. Curini, M. C. Marcotulli, A. Macchiarulo, M.
Perfumi, L. Mattioli, F. Rismondo, G. Cravotto, Bioorg. Med. Chem.
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(b) A. Nakhai, J. Bergman, Tetrahedron 2009, 65, 2298.
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(c) H. M. Blatter, R. A. J. Lucas, U.S. Patent 3,657,438 1972.
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doi:10.3987/COM-90-5594
(b) M. E. Le Tourneau, N. P. Peet, U.S. Patent 4,734,430 1988.
(c) M. E. Le Tourneau, N. P. Peet, U.S. Patent 4,734,429 1988.
[14] H. M. Blatter, R. A. Lucas, U.S. Patent 3,691,180 1972.
[15] (a) D. G. Wettlaufer, G. M. Shutske, P. A. Nemoto, U.S. Patent
5,256,672 1993.
Accessory Publication
General procedure for the synthesis of these new compounds
1
and their H, 13C and 2D NMR spectra, are available on the
Journal’s Website.
(b) D. G. Wettlaufer, G. M. Shutske, P. A. Nemoto, U.S. Patent
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Acknowledgements
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This work was financially supported by the National Research Council of
Argentina (CONICET) and the Secretary of Sciences and Technology –
National University of Co´rdoba (SECyT-UNC). G.M.C. thanks CONICET
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Ph.D. Walter J. Pela´ez and Prof. Mar´ıa T. Baumgartner.
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