1,3-Dipolar Cycloaddition of Nitrile Imines with Functionalized Acetylenes: Regiocontrolled Sc(OTf)3-Catalyzed Synthesis of 4- and 5-Substituted Pyrazoles

Abstract

S y n t h e s i s o f 4 -a n d 5 -S u b s t i t u t e d P y r a z o l e sAbstract: 1,3-Dipolar cycloaddition of C-aryl-N-aryl-and C-carboxymethyl-N-aryl-nitrile imines with functionalized acetylenes have been studied. Regioisomeric mixtures have been obtained with the 5-substituted pyrazole as the major cycloadduct. Under scandium triflate catalysis a reversal in the regiochemistry was observed, especially in the case of C-carboxymethyl-N-aryl-nitrile imines.Owing to its high synthetic efficiency and high regio-and stereoselectivity, the 1,3-dipolar cycloaddition (1,3-DC) of 1,3-dipoles with p-electronic-deficient systems has emerged as a popular way for obtaining five-membered heterocycles. 1 The synthetic utility of the 1,3-DC reaction stems from the wide scope and from the relevance of numerous targets achievable by this chemistry, 2 since many 1,3-dipolar species are readily available and react with a variety of dipolarophiles. In particular, nitrogen-containing heterocycles have attracted widespread attention in the field of synthetic organic chemistry as well as in medicinal chemistry. 3 Among them, pyrazoles are synthetic targets of utmost importance in the pharmaceutical industry, since such a five-membered heterocyclic moiety represents the core structure of numerous drugs. 4Only two routes of general importance for the assembly of 4-and 5-substituted pyrazoles have been reported so far. The first is the ring closure using hydrazines with bdiketones 5a or a derivative of comparable reactivity and the second is the 1,3-DC of diazoalkanes with unfunctionalised and carboxyalkyl acetylenes. 5b-d The 1,3-DC of nitrile imines in situ generated from hydrazonoyl halides and a base to triple-bond derivatives is a potentially powerful method for the synthesis of the pyrazole ring. However, a deep search in the literature revealed a lack of general investigation about this reaction, in contrast with the impressive number of papers related to the use of alkenes as dipolarophiles. Alkynes have a reduced dipolarophilic activity and react more slowly than alkenes by a power of 10. 1 Simple alkynes such as phenyl acetylene react with diphenyl nitrile imine to give in 72% yield the 1,3,5-triphenyl pyrazole 6 but a 90:10 mixture of 5-and 4-phenyl pyrazoles was obtained with C-phenyl Nmethyl nitrile imine. 7 Moreover, alkynes with electronwithdrawing substituents have a higher propensity to form 4-substituted pyrazoles, and methyl propiolate adds to diphenyl nitrile imine to yield mixtures of 5-and 4-substituted pyrazoles in 78:22 ratio. 8 Recent works 9 reported the regioselective synthesis of 5-substituted 3-dimethoxyphosphonopyrazoles 9a through the 1,3-DC of Cdimethoxyphosphono N-aryl nitrile imines with monosubstituted acetylenes and methyl propiolate with yields in the range 12-40% and computational study for the cycloaddition of nitrilimines to methyl propiolate. 9bWith the aim to extend the scope of nitrile imines cycloaddition and following our interest for the [3+2] cycloaddition of 1,3-dipoles for the synthesis ...

Regiocontrolled Synthesis of Ring‐Fused Thieno[2,3‐c]pyrazoles through 1,3‐Dipolar Cycloaddition of Nitrile Imines with Sulfur‐Based Acetylenes

“…[19] As expected, the amount of the 4-isomer was higher under Sc(OTf) 3 catalysis (Table 1, Entries 1-3), and the 4-isomer increased to 12:88 for 6-6Ј and to 14:86 for 7-7Ј and 8-8Ј due to the possibility of a chelated transition state involving the CO 2 Me group and the sulfonyl group with the scandium catalyst. [19] Disubstituted sulfone 2 gave good yields of cycloadducts (60-65 %) with an higher quantity of the 4-isomer, ratio 11:89 for 9-9Ј, 20:80 for 10-10Ј, and 10:90 for 11-11Ј (Table 1, Entries 4-6), but in this case no significant improvement was observed in the ratio under scandium catalysis in favor of the 4-isomer. Therefore, we believe that this kind of 1,3-DC is substrate-controlled and does not take place under the control of the catalyst.…”

“…This signal was not found in our cycloadducts. [19] Furthermore, NOE experiments confirmed the formation of 5-pyrazole also for compounds 9-11 and 15-17.…”

“…Starting acetylenes 1-4 were readily prepared according to literature procedures (see the Experimental Section), whereas selected hydrazonoyl chlorides 5a-c were obtained as reported by us. [19] Figure 3. Dipolarophiles 1-4 and hydrazonoyl chlorides 5a-c.…”

“…These results are in line with results obtained by us in 1,3-NED (normal electron demand) dipolar cycloadditions of nitrile imines with acetylene derivatives. [19] Scheme 2. 1,3-DC of 3 or 4 with 5a-c.…”

“…We recently developed a method for the regiocontrolled synthesis of pyrazoles based on the 1,3-DC of nitrile imines with functionalized acetylenes. [19] As part of our group's ongoing effort [20] directed towards the preparation of pyrazoles as multikinases inhibitors we decided to investigate the application of our methodology to the regiocontrolled synthesis of thieno[2,3-c]-pyrazoles G, through 1,3-DC of nitrile imines and substituted acetylenes bearing thiol or sulfone groups.…”