Indazole regioselectivity

Metal-promoted approaches have been investigated for the preparation of indazoles. A copper(II) oxide-catalyzed regioselective synthesis of 1-alkyl- and 1-aryi-1 //-indazoles 25 from ortho-halogenated alkanoylphenones, benzophenones, and arylcarboxylic acids 24 with hydrazines in the presence of potassium carbonate has been developed <07OL525>. A... 

Products 6 were formed by a concerted [3+2] cycloaddition via a helical TS of type 47 however, it was unexpected that the cycloaddition should show this regioselectivity rather than that shown in structure 48. The only example to show the expected regioselectivity was the case of 46e in which the formation of 6e was observed (28%) and the major product was the indazole 49 (59%) (Scheme 11). It is worthy to mention that diazo compounds in which the cyclopentene was not present are stable at 25 °C and gave compounds of type 18 as the main products. The presence of the cyclopentene ring serves in some way to expedite the cycloaddition reaction through the TS 47 <2000J(P1)1139>. 

Tetrasubstituted pyrazoles 589 were synthesized regioselectively in good yields from the reaction of Baylis-Hillman adducts 588 with various hydrazine hydrochlorides in 1,2-dichloroethane (Equation 120) <2003TL6737>. Baylis-Hillman adducts 591, derived from aldehydes and 2-cyclohexen-l-one 590, reacted with hydrazines to give pyrazoles 592, which could be dehydrogenated to 277-indazoles 593 (Scheme 74) <2005TL5387>. 

Terzidis MA, Tsoleridis CA et al (2008) Synthesis of chromeno[2,3-b]carbazole and chro-meno[3,2-f]indazole derivatives. A new class of indole- and pyrazole-fused polycyclic compounds using o-quinodimethane chemistry. A reactivity and regioselectivity computational study. ARKIVOC 132-157... 

This reaction has been modified by using quinone mono-ketals to control the regioselectivity. In addition, an aza-Nenitzescu reaction involving the condensation between quinones and hydrazones has been developed for the synthesis of indazole derivatives. ... 

Indazoles were prepared by many different methods. Indazoles 41 were synthesized from nitroaromatics 39 and N-tosylhydrazones 40 with bases (14CC5061). A rhodium(III)-catalyzed oxidative olefination of 1,2-di-substi-tuted arylhydrazines with alkenes via sp C-H bond aaivation followed by an intramolecular aza-Michael reaction yielded indazoles (140L2494). Copper-catalyzed C-H amidation with aromatic imines 42 with tosyl azide provided a route to 3-substituted indazoles 43 (14OL4702). 4,5,6,7-Tetrahydro-lH-inda-zol-3-(2fJ)-one derivatives were prepared in two-step one-pot process (14SC1076). A regioselective synthesis of 2H-indazoles 45 was achieved using... 

Wang et al. [49] developed a highly regioselective Povarov reaction of an aromatic aldehyde, l//-indazol-5-amine, and methyl 3-oxobutanoate catalyzed by iodine. This novel reaction selectively gave 3/f-pyrazolo[4,3-y]quinolin-9-yl acetates 20, rather than 3//-pyrazolo[4,3-/jquinoline-8-carboxylate derivatives. Further, they [50] also extended the reaction using tetrahydropy ran-4-one instead of methyl-3 -oxobutanoate for the synthesis of 7-aiylpyrano[3,4-c]pyrazolo[3,4-/]quinoline derivatives 21 (Scheme 10.16). 

Incorporation of a fluorine at C-3 can be achieved by treatment of a preformed 3H)-indazole with electrophilic fluorinating reagents. In the context of a medicinal chemistry programme, scientists at GSK carried out the fluorination of 4-nitro-6-bromo-(7//)-mdazole (120) with Selectfluor in a mixture of acetonitrile and acetic acid (Scheme 39). Best yields (64 %) were observed when the reaction mixture was submitted to microwave irradiation [65]. The scope of this synthetic transformation is somewhat limited, since the regioselectivity is controlled by the presence of two electron withdrawing groups on the phenyl ring. 

The C-2 selective oxidative C-H coupling of unactivated pyridines with heterocycles was achieved in the presence of Pd(OAc)2, phenanthroline as the ligand, a silver oxidant, and pivalic acid (eq 145). Moderate to good yields were obtained when heteroarenes, such as thiophenes, indoles, furans, indazoles, or xanthines, were coupled to p3uidine (or p3razine, quinoline, pyrimidine). Virtually no homo-coupling or other regioselective (C-3 or C-4) products were observed in the reaction. 

Halland et al. showed that the same o-alkynylhaloarene substrates used successfully by others to access indoles (Scheme 24.1, disconnection D-3) could be used to access 2//-indazole products (Scheme 24.19) [90]. The reaction proceeded via an initial regioselective intermolecular palladium-catalyzed amination using a mono-substituted hydrazine to generate an N,N -disubstituted hydrazine. Intramolecular hydroamination then forms a dihydroindazole intermediate such as 42. Isomerization to the aromatic 2//-indazole products occurred spontaneously under the reaction conditions. A variety of examples were reported, and good functional group tolerance was observed. 

Lavis and Ellman reported an efficient method for the preparation of Af-aryl-2//-indazoles 18 by Rh(III)-catalyzed C-H bond addition of azobenzenes to aldehydes without external oxidant (Eq. (5.18)) [13]. In this reaction, the regioselective activation of azobenzenes can be controlled either by electronic or by steric effects, and the azo moiety serves as a nucleophile to trap the initial aldehyde addition product. A wide range of aldehydes and azobenzenes participate in the reaction to afford differently substituted indazoles. An interesting feature of this reaction... 

Based on the early work of Ohta et a/., " heterocycles like pyrroles, pyrazoles, " thiophenes, flirans, oxazoles, indoles, imidazoles, thiazoles, triazoles, and indazoles can be arylated under palladium-catalysis very efficiently (Scheme 5-136). " " Even the 3-selective fourfold arylation of porphyrins is made possible. " Challenges of this reaction are regioselectivity, tum-over number and mild reactions conditions. A combination with an alkene relay to give a (intermolecular or intramolecular) domino Heck arylation is also possible. " " Thus, this arylation reaction is a potent terminator in domino reactions (Scheme 5-202). 

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