Pd/C-mediated synthesis of α-pyrone fused with a five-membered nitrogen heteroaryl ring: A new route to pyrano[4,3-c]pyrazol-4(1H)-ones

Article abstract of DOI:10.3762/bjoc.5.64

Pd/C-mediated alkynylation of 5-iodo-pyrazole-4-carboxylic acid, involving the first regioselective construction of α-pyrone ring on a pyrazol moiety via tandem coupling-cyclization process, has been developed to afford pyrano[4,3-c]pyrazol-4(1H)-one in a

Full text of DOI:10.3762/bjoc.5.64

Pd/C-mediated synthesis of α-pyrone fused with a
five-membered nitrogen heteroaryl ring: A new route
to pyrano[4,3-c]pyrazol-4(1H)-ones
Dhilli Rao Gorja1, Venkateswara Rao Batchu2, Ashok Ettam2
and Manojit Pal*3,4
Preliminary Communication
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 64.
1Institute of Science and Technology, JNT University, Kukatpally,
Hyderabad 500072, India, 2Dr. Reddy’s Laboratories Ltd, Bollaram
Road, Miyapur, Hyderabad 500049, India, 3New Drug Discovery,
R&D Center, Matrix Laboratories Ltd, Anrich Industrial Estate,
Bollaram, Jinnaram Mandal, Medak District, Andra Pradesh 502 325,
India and 4present address: Institute of Life Sciences, University of
Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra
Pradesh, India
doi:10.3762/bjoc.5.64
Received: 11 September 2009
Accepted: 22 October 2009
Published: 11 November 2009
Associate Editor: I. Marek
© 2009 Gorja et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Manojit Pal* - manojitpal@rediffmail.com
* Corresponding author
Keywords:
C–C bond; catalysis; palladium; pyrazole; pyrone
Abstract
Pd/C-mediated alkynylation of 5-iodo-pyrazole-4-carboxylic acid, involving the first regioselective construction of α-pyrone ring
on a pyrazol moiety via tandem coupling–cyclization process, has been developed to afford pyrano[4,3-c]pyrazol-4(1H)-one in a
single pot.
Introduction
α-Pyrones [1,2] (or 2H-pyran-2-one) and their benzo deriva- the pyrazole and the pyrone moiety would be responsible for
tives, e.g. isocoumarins [3], have shown a wide range of phar- enhanced anabolic activity of the individual parent compounds.
macological activities [4-6] such as antifungal, antimicrobial, Because of our longstanding interest in the synthesis of pyrone
phytotoxic and other effects. On the other hand α-pyrones fused derivatives of potential pharmacological interest we decided to
with a five-membered heteroaryl ring, e.g. thienopyranones, explore the synthesis of α-pyrones fused with a pyrazole ring,
have shown anticancer properties in vitro [7]. Recently, incor- e.g. pyrano[4,3-c]pyrazol-4(1H)-one B (Figure 1).
poration of another five-membered ring, e.g. pyrazole pyrone
moieties in a single molecule (A, Figure 1) has been reported to Synthesis of compound B could be achieved by either of the
provide polycyclic azaheteroaromatics with a steroid-like skel- following strategies: construction of the six-membered ring
eton [8]. This initiative was based on the assumption that both followed by five-membered one or vice versa. However, only
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Beilstein Journal of Organic Chemistry 2009, 5, No. 64.
Figure 1: Polycyclic azaheteroaromatics (A) and pyrano[4,3-c]pyrazol-4(1H)-ones (B).
one method has been reported so far that falls to the first Results and Discussion
category. It involves the reaction of methyl 2-cyano-3,3- The starting material required for our synthesis, 5-iodo-1-
dimethylthioacrylate with 1-tetralone and subsequently with methyl-1H-pyrazole-4-carboxylic acid (1), was prepared from
hydrazine [8]. Though a number of methods are known for the commercially available ethyl 5-amino-1-methyl-1H-pyrazole-4-
synthesis of isocoumarins by constructing the pyrone ring carboxylate [20] (4) via a two-step process as shown in
[9-17] (the second strategy) none has been reported for the class Scheme 2. Thus Sandmeyer type reaction of amine 4 to intro-
of compounds represented by B. One of the common methods duce the iodo group on the pyrazole ring followed by hydro-
used for the construction of a pyrone ring fused with benzene or lysis of the ester 5 yielded the desired acid 1.
with other heteroaryl moieties is Sonogashira-type coupling
followed by electrophilic or transition metal mediated cycliza- Our study started with the reaction of iodo acid 1 with a
tion of the resulting alkyne (possessing a carboxylate or an terminal alkyne, e.g. 1-hexyne (2a) and the results are summar-
equivalent group in proximity to the triple bond). Thus, isocou- ized in Table 1. Due to our earlier success in the use of 10% Pd/
marins have been prepared by reacting o-iodobenzoic acid with C-PPh3-CuI as a catalyst system [21] for coupling-cyclization
terminal alkynes in the presence of a Pd-catalyst [14-16]. reactions we decided to conduct the initial reaction of 1 (1.0
Recently, we have reported synthesis of thienopyranones equiv) with 2a (2.0 equiv) in the presence of same catalysts in
following a similar strategy [7,18]. On the other hand construc- ethanol using Et3N as a base. The reaction proceeded smoothly
tion of a pyridine ring on a pyrazole moiety has been described affording the desired product 3a in 72% yield (Entry 1, Table 1)
under Ni or Pd catalysis [19]. Herein we report the first and no isomeric compound, i.e. 1-methyl-6-pentylidene-1H-
construction of an α-pyrone ring on a pyrazol moiety leading to furo[3,4-c]pyrazol-4(6H)-one, was isolated. The reaction was
the synthesis of 6-substituted pyrano[4,3-c]pyrazol-4(1H)-one 3 carried out for 16 h and increase of reaction time did not
under Pd/C-Cu catalysis (Scheme 1).
improve the product yield (Entry 2, Table 1). Product forma-
tion was almost suppressed in the absence of PPh3 (Entry 3,
Table 1). The use of other catalysts, e.g. PdCl2(PPh3)2,
Pd(PPh3)4 or Pd(OAc)2-PPh3, afforded the product 3a in
inferior yield (Entries 4-6, Table 1). Ethanol was found to be
the best solvent in our study as the use of other solvents, e.g.
1,4-dioxane or DMF, decreased the product yield (Entries 7 and
8, Table 1). Finally, the use of fewer equiv of 2a also decreased
the product yield significantly (Entry 9, Table 1) perhaps due to
the evaporation of 2a under the conditions employed.
Scheme 1: Pd/C-mediated synthesis of 6-substituted pyrano[4,3-
c]pyrazol-4(1H)-ones 3.
Scheme 2: Preparation of 5-iodo-1-methyl-1H-pyrazole-4-carboxylic acid (1).
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Beilstein Journal of Organic Chemistry 2009, 5, No. 64.
Table 1: Effect of reaction conditions on the Pd-catalyzed coupling of 5-iodo-1-methyl-1H-pyrazole-4-carboxylic acid (1) with 1-hexyne (2a).a
Entry
Catalyst
Solvent; time
Yield (%)b
1.
2.
3.
4.
5.
6.
7.
8.
9.
10% Pd/C-PPh3
10% Pd/C-PPh3
10% Pd/C
EtOH; 16h
EtOH; 24h
EtOH; 16h
EtOH; 16h
EtOH; 16h
EtOH; 16h
1,4-Dioxane; 16h
DMF; 16h
72c
70c
13
PdCl2(PPh3)2
Pd(PPh3)4
51
55
Pd(OAc)2-PPh3
10% Pd/C-PPh3
10% Pd/C-PPh3
10% Pd/C-PPh3
48c
59c
61c
55c,d
EtOH; 16h
aReaction conditions: 1 (1.0 equiv), terminal alkyne 2a (2.0 equiv), Pd-catalyst (0.05 equiv) or Pd/C (0.035 equiv), CuI (0.06 equiv), Et3N (5.0 equiv) in a
solvent at 70–80 °C under N2.
bIsolated yield.
cPPh3 used: 0.3 equiv.
d1.5 equiv of 2a was used.
Having prepared the pyranopyrazol-4-one 3a successfully we were well characterized by spectral (NMR, IR and MS) data.
decided to explore the scope and generality of this reaction in The appearance of a vinylic signal in the region δ 6.3–6.8 in the
the synthesis of other analogues especially varying the 1H NMR spectrum and a carbonyl absorption in the region
substituent at C-6. Accordingly, a variety of commercially 1720–1730 cm−1 in the IR spectrum confirmed the presence of
available terminal alkynes were reacted with the iodo acid 1 a pyrone ring in compound 3. This was further supported by the
(Table 2) under the optimized conditions as presented in Entry 1 C=O signal in the region 160–170 ppm in the 13C NMR
of Table 1. As evident from Table 2, all the terminal alkynes spectrum.
participated well in this coupling-cyclization reaction affording
the desired products in moderate to good yields. Various Mechanistically, the reaction proceeds via a C–C bond forming
substituents such as alkyl, hydroxyalkyl or aryl groups present reaction between the halide 1 and the terminal alkyne 2 in the
in the terminal alkyne were well tolerated. The use of presence of Pd(0) generated in situ. The resulting alkyne Z
arylalkynes (Entries 7 and 8, Table 2) however led to the (Scheme 3) thus formed subsequently undergoes 6-endo-dig
moderate yields of product as this class of alkynes is known to ring closure in an intramolecular fashion to give the desired
undergo rapid dimerization. Deiodination of 1 as a side reac- product 3. A favorable geometry associated with the formation
tion was also observed in these cases. All the products isolated of the 5-6 ring over the 5-5 ring did not allow the intermediate
Scheme 3: Mechanism of ring closure of intermediate alkyne Z.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 64.
Table 2: Pd/C-mediated synthesis of 6-substituted pyrano[4,3-c]pyrazol-4(1H)-onesa (3).
Entry
1.
Alkyne 2 (R =)
Time (h)
16
Products (3)
Yield (%)b
72
n-butyl
3a
3b
3c
2.
3.
n-pentyl
n-hexyl
18
16
68
67
4.
–CH(OH)CH3
12
3d
65
5.
6.
–C(OH)Me2
–(CH2)3OH
12
16
3e
3f
72
60
7.
8.
–C6H5
12
12
3g
3h
54
50
–C6H4CH3-p
aReaction conditions: 1 (1.0 equiv), terminal alkyne 2 (2.0 equiv), 10% Pd/C (0.035 equiv), PPh3 (0.3 equiv), CuI (0.06 equiv), Et3N (5.0 equiv) in a
solvent at 70–80 °C under N2.
bIsolated yield.
alkyne Z to undergo a 5-exo-dig ring closure though it is Conclusions
favoured by Baldwin’s rules. Unlike 3-iodo thiophene-2- In conclusion, we have developed a new, straightforward and
carboxylic acid [18] the coupling of 1 with terminal alkynes 2 general method for the regioselective synthesis of novel
in the presence of PdCl2(PPh3)2 and CuI did not provide the 6-substituted pyrano[4,3-c]pyrazol-4(1H)-ones under Pd/C-Cu
7-alkynyl substituted derivative of 3 possibly due to the “peri” catalysis, preparation of which would be difficult via other
effect caused by the N-1 methyl group of the pyrazole ring.
methods. The reaction proceeds via tandem C-C and C-O bond
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Beilstein Journal of Organic Chemistry 2009, 5, No. 64.
19.Heller, S. T.; Natarajan, S. R. Org. Lett. 2007, 9, 4947.
formation between the 5-iodopyrazole-4-carboxylic acid and a
terminal alkyne in the same pot. Being an integral part of many
drugs or bioactive molecules, the pyrazole framework plays an
important role in pharmaceutical research. We therefore believe
that the present methodology and the product pyranopyrazol-4-
one being a potential synthon for more complex heterocycles
may find wide applications in organic synthesis, especially in
medicinal chemistry.
doi:10.1021/ol701784w
20.Schmidt, P.; Eichenberger, K.; Wilhelm, M.; Druey, J. Helv. Chim. Acta
1959, 42, 349. doi:10.1002/hlca.19590420132
21.Pal, M. Synlett 2009, 2896. doi:10.1055/s-0029-1218021
For an account.
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General procedure for the preparation of 3 and spectral data
for selected compounds.
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