Palladium-catalyzed intramolecular amination

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

Intramolecular palladium-catalyzed cyclization reactions are commonly used to synthesize indazole derivatives . For example, A-Aryl-A-(<9-bromobenzyl)hydrazines 203 participate in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2//-indazoles 204 (Scheme 121) <20000L519>. 

Intramolecular palladium-catalyzed cyclization reactions have also been used to synthesize pyrazole derivatives. iV-Aryl-iV-(o-bromobenzyl)hydrazines 494 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2//-indazoles 495 (Equation 101) <20000L519>. Palladium-catalyzed intramolecular C-N bond formation of iV-acetamino-2-(2-bromo)arylindolines 496, followed by hydrolysis and air oxidation in the presence of aluminium oxide, allowed the preparation of indolo[l,2-3]indazoles 498 via intermediate 497 (Scheme 58) <2002TL3577>. 3-Substituted pyrazoles have been prepared from the intramolecular cyclization of A -tosyl-iV-(l-aryl/ vinyl-1-propyn-3-yl)hydrazine and then exposme of the reaction mixture of the cyclization to potassium /i //-butoxide <1997SL959>. iV-Aryl-iV -(o-bromobenzyl)hydrazines 499 or [A -aryl-A -(t>-bromobenzyl)hydrazinato-A ]-triphenyl-phosphonium bromides 501 participated in a palladium-catalyzed intramolecular amination reaction to give 1-phenyl-l//-indazoles 500 (Scheme 59) <2001TL2937>. 

Palladium-catalyzed cyclization reactions with aryl bromides have been used to synthesize pyrazole derivatives. lV-Aryl-Ar -(o-bromobenzyl)hydrazines 20 or [A-Aryl-N -(o-bromobenzyl)hydrazinato-N ]-triphenylphosphonium bromides 21 participated in palladium-catalyzed intramolecular amination reactions to give l-aryl-l//-indazoles 22 <01TL2937>. Thermal extrusion of sulfur dioxide or carbon dioxide from their respective heterocyclic precursors 23 or 24 generated 1,2-diaza-l, 3-butadicnes 25, which underwent palladium(0)-catalyzed carbonylation to yield 2,3-pyrazol-l(5//)-ones 26 <01OL3651> or [4 + 2) Diels-Alder reactions with Af-phenyldiazamaleimide to afford cycloadducts 27 <01OL3647>. 

Recently, l-aryl-l//-indazoles have been prepared via palladium-catalyzed intramolecular amination of aryl halides. For example, the bromo-aryl-hydrazone cyclized to give the corresponding indazole under the influence of a palladium catalyst in the presence of a base. 

For example (Scheme 13.44), treatment of y-hydroxy olefins with a catalytic amount of PdCl2—(CH3CN)2 and a stoichiometric amount of CUCI2 in methanol under CO leads to intramolecular alkoxylation/carboalkoxylation sequence and formation of substituted tetrahydrofurans 61 [80-83]. Similarly, 4-pentenyl carbamates undergo palladium-catalyzed intramolecular amination/carboalkoxylation to form substituted pyrrolidine derivatives 62 [84,85]. 

Continuing their investigation of tandem cascade reactions toward indole synthesis, Barluenga et al. reported a process combining palladium-catalyzed aza-enolate a-arylation followed by intramolecular N-arylation (Scheme 24.1, disconnection D-7) [51]. The process is outlined in Scheme 24.9 initial palladium-catalyzed aza-enolate arylation generates intermediate imine 23 and then palladium-catalyzed intramolecular amination, presumably via intermediate enamine 24, results in the product indole in excellent 86% yield. An XPhos-derived catalyst facilitated both steps of the cascade, and a wide range of imines could be incorporated. 

In 2012, Chen and coworkers developed the palladium-catalyzed intramolecular amination of C(sp )-H at y and 5 positions to synthesize a series of nitrogen-containing heterocycles [15], including azetidine (Scheme 2.11), pyrrolidines, and indolines. With the optimal conditions, using catalytic Pd(OAc)2, an oxidant (PhI(OAC)2, 2.5 equiv.) and an acid additive (AcOH) in toluene at llO C, Chen tested them on other picolinamide substrates bearing primary y-C(sp )-H bonds surprisingly, the seemingly unfavorable four-membered azetidine was obtained as the major product. It is possible that a Pd(IV) intermediate was formed via PhI(OAC)2 oxidation of the palladacycle intermediate because the subsequent C-N and C-O reductive elimination pathways would lead to the formation of the cyclized and acetoxylated product. It was also noteworthy that no P H elimination product was detected under the aforementioned reaction conditions. 

Watanabe reports a new method for the direct conversion of o-choroacetaldehyde N,N-disubstituted hydrazones into 1-aminoindole derivatives 93 by palladium-catalyzed intramolecular ring closure of 92 in the presence of P Bu3 or the bisferrocenyl ligand 94 <00AG(E)2501>. When X = Cl, this cyclizative process can be coupled with other Pd-catalyzed processes with nucleophilic reagents (e.g., amines, azoles, aryl boronic acids) so as to furnish indole derivatives with substituents on the carbocyclic ring. 

Several examples of transition metal catalysis for the synthesis of piperidines appeared this year. Palladium catalyzed intramolecular urethane cyclization onto an unactivated allylic alcohol was described as the key step in the stereoselective synthesis of the azasugar 1-deoxymannojirimycin . A new synthetic entry into the 2-azabicyclo[3.3.1]nonane framework was accomplished through a palladium mediated intramolecular coupling of amine tethered vinyl halides and ketone enolates in moderate yields . A palladium catalyzed decarboxylative carbonylation of 5-vinyl... 

Hydroamination of Alkynes The discovery of palladium-catalyzed intramolecular addition of amines to acetylene coupled with the spectacular contribution of Hutchings opened the door for the synthesis of several nitrogen heterocycles. The first study in this field was performed by Utimoto et al., who researched gold catalyzed intramolecular 6-exo-dig hydroamination. Tautomerization of the initial enamines allowed them to obtain imines, which were thermodynamically more stable [111] (Scheme 8.20). 

The palladium-catalyzed intramolecular addition of an amine to an alkene is an efficient route to nitrogen heterocycles. The products often undergo further dehydrogenation under the reaction conditions to form fully aromatic... 

Heterocycles - Aromatic substitution via N-oxides has been reviewed.51 Palladium catalyzed intramolecular addition of amines to olefins has resulted in new syntheses of indoles52-3 and isoquinuclidines.53... 

Very recently, Liu and coworkers reported a palladium-catalyzed intramolecular aerobic oxidative allylic amination of unactivated alkenes [34]. The reaction of 22... 

Palladium Catalysts Pd(11)-catalyzed intramolecular amination of sp2 and sp3 C—H bonds has been demonstrated (Equation 11.41) [80]. It was proposed that a Pd(II)/(IV) catalytic cycle is most likely for this transformation. CuCl2 and AgOAc are used as cooxidants. This method provides practical access to a range of (3-, y. and 8-lactams. 

Intramolecular palladium-catalyzed aryl amination chemistry is used to synthesize benzimidazoles. When NaOH in toluene is used as a base, the reaction rate is very slow. But aqueous reaction conditions (20% water/xylene) led to complete conversion of an amidine to benzimidazole 3 after two hours at reflux [7]. 

More recently, Alper and colleagues described a convenient protocol for the synthesis of substituted benzazepine derivatives (Scheme 2.44) [286]. This protocol is based on the sequential palladium-catalyzed allylic amination and a subsequent intramolecular carbonylation reaction. The substrates were obtained by a Baylis-HiUman reaction. 

The first Pd-catalyzed intramolecular amination of an aryl halide was reported by Boger in 1984. This transformation was stoichiometric in palladium and generated the indole core of lavendamycin. ... 

Reactions with other radical initiators, such as AIBN, were reported as well the desired dihydrobenzofurans could be produced selectively. Besides the cyclization of alkenes mentioned previously, intramolecular cyclization of allenes and allq nes was reported as well. In 1995, Grigg and coworkers developed a palladium-catalyzed cyclization-amination of allenes. They demonstrated that the effect of the base was obvious—different regioselectivities were observed by using K2CO3 and Ag2C03 as bases. The corresponding heterocyclic compounds were isolated in good yields (Scheme 2.42). 

The activation of the C-H bond on aromatic rings was explored as expected. As early as 1982, palladium-catalyzed intramolecular cyclization of diatyl ethers and diaryl amines were mentioned. In the presence of a palladium catalyst, low yields of the desired indole and benzofuran derivatives could be observed (Scheme 2.78). 

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