Palladium- and Copper-Catalyzed Aryl Halide Amination ...

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10 J. E. R. Sadig, M. C. Willis REVIEW Me HN H2N + N Scheme 26 2.4 Indazoles and Indazolones Indazoles have proven to be popular targets for amination chemistry. A number of groups have described the cyclization of appropriately substituted arylhydrazones. Scheme 27 illustrates an intramolecular coupling of bromo-substituted arylhydrazone 57 to deliver 1H-indazole 58 in 85% yield. 72 The DPEPhos-derived catalyst system was effective for a wide range of substrates, although aryl chloride substrates performed poorly. Analogous N-tosylhydrazones were also established as effective indazole precursors, 73a and were utilized in a synthesis of the natural product nigellicine. 73b 3-Amino-1H-indazoles were also prepared by similar palladium-catalyzed cyclizations. 74 Song and Yee demonstrated that appropriately substituted hydrazines are also useful indazole precursors. For example, palladium-catalyzed ring closure using hydrazine 59 delivered the corresponding aromatic 1H-indazole directly in 87% yield, following intramolecular amination and spontaneous aromatization. 75 The mechanism of aromatization was not established. The authors noted the instability of certain hydrazine substrates to long-term storage, and as alternatives established that the corresponding N-triphenylphosphonium bromide salts provided convenient stable precursors that could be cyclized under identical reaction conditions. MeO 57 Scheme 27 Br I Br N O CuI (15 mol%) 25 (30 mol%) Cs2CO3 DMA, 165 °C N N O N H 53% There are a number of reports of halo-substituted hydrazones being formed in situ and then cyclized to yield 1Hindazoles; Scheme 28 presents examples using both palladium and copper catalysis. Cho et al. were able to show that o-bromobenzaldehydes could be combined with phenylhydrazine using a palladium(II) chloride/dppp catalyst system to furnish the corresponding indazoles in good yields (60 → 61). 76 The copper example, reported by Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York Me Me H N Pd(dba)2 (2 mol% N DPEPhos (22) (2 mol%) N Me NH K 3PO 4 toluene, 110 °C MeO Pd(OAc) 2 (5 mol%) dppf (12) (7.5 mol%) Me 58, 85% Br HN NaOt-Bu toluene, 90 59 °C 87% N N Me Pabba et al., required a two-step one-pot approach in which a ten-minute microwave reaction was used to form the hydrazone before a copper(I)/diamine catalyst was added to the system (62 → 63). 77 Del Olmo and co-workers reported a related copper-catalyzed process which also allowed the use of aryl carboxylic acid substrates to deliver 1-hydroxy-1H-indazoles. 78 MeO MeO F Scheme 28 Guillaumet and co-workers reported an intermolecular copper-catalyzed amination method for the preparation of pyrazolopyridines (azaindazoles). 79 3-Cyano-2-chloropyridine was combined with a range of hydrazines using a copper(I) iodide/phenanthroline catalyst to deliver 3-amino-1H-azaindazoles in good yields (Scheme 29). The 3amino products were converted into the corresponding 3iodo derivatives by way of their diazonium salts, and were employed in a range of palladium-catalyzed coupling processes including Stille, Heck and Suzuki reactions. N CN Cl Scheme 29 O 60 O + 62 H + H2N Br H + H2N Br Et H N NH2 NH Ph NH Ph PdCl 2 (2 mol%) dppp (3 mol%) MeO NaOt-Bu toluene, 100 °C i) NMP, 160 °C 10 min, MW ii) CuI (5 mol%) 64 (10 mol%) K2CO 3, 160 °C 10 min, MW NHMe NHMe MeO 61, 65% N N N N The less thermodynamically stable 2H-indazole isomers can also be accessed using amination chemistry. In an approach mirroring their route to the 1H-isomers (see Scheme 27), Song and Yee employed a palladium-catalyzed cyclization of appropriately substituted hydrazines. 80 For example, N-alkyl-N-arylhydrazine 65 was converted into 2-aryl-2H-indazole 66 in 60% yield (Scheme 30). Katayama and co-workers showed that N2– C3-fused examples can also be prepared using similar chemistry. 81 64 CuI (5 mol%) 1,10-phenanthroline (10 mol%) Cs 2CO 3 DMF, 60 °C N N 1,10-phenanthroline F 63, 84% NH 2 N N N 86% Et
REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 11 N Ph MeO Pd(OAc) 2 (5 mol%) MeO dppf (12) (7.5 mol%) NH2 Br NaOt-Bu toluene, 90 °C 65 Scheme 30 Halland, Lindenschmidt and co-workers reported an alternative route to the 2H-indazole isomers employing the same o-alkynylhaloarene substrates used successfully by others to access indoles (see Schemes 11 and 12). The reactions proceeded via an initial regioselective amination reaction using a monosubstituted hydrazine to generate an N,N¢-disubstituted hydrazine, which then underwent intramolecular hydroamination to form a dihydroindazole intermediate (67, Scheme 31). 82 Isomerization from these intermediates to the aromatic 2H-indazoles occurred spontaneously under the reaction conditions of palladium(II) chloride/tri(tert-butyl)phosphine with cesium carbonate in N,N-dimethylformamide. Good functional group tolerance was demonstrated and an extensive range of substituted products was described; three examples are shown in Scheme 31. 67 Scheme 31 Indazolones can be prepared by the copper-catalyzed cyclization of o-halobenzohydrazides. For example, treatment of hydrazide 68 with a copper(I) iodide/proline catalyst system delivered indazolone 69 in 60% yield (Scheme 32). 83 Iodo substrates delivered the most efficient reactions; the bromo and chloro substrates were also shown to deliver the desired products, albeit in reduced yields. Scheme 32 Ph + H2N Cl O I Ph N Ph N H N H H N 2.5 Pyrroles PdCl2 (5 mol%) Pt-Bu3 HBF4 (10 mol%) NH Cs2CO Ph 3 DMF, 110–130 °C . 93% CO2t-Bu N Ph N CuI (10 mol%) L-proline (20 mol%) K 2CO 3, DMSO r.t. to 70 °C 68 69, 60% N Ph N 66, 60% N Ph N 79% OEt The Buchwald and Li research groups both reported cascade copper-catalyzed alkenyl amidation routes to pyr- Ph N Ph N 55% O OEt NH N roles. The Buchwald group utilized a copper(I) iodide/ diamine 25 catalyst system to combine carbamates (and a limited number of amides) with 1,4-diiodo-1,3-dienes to generate highly substituted pyrrole products (70 → 71, Scheme 33). 84 The methodology displayed excellent functional group tolerance and was applied to the synthesis of a wide range of pyrroles, including tetrasubstituted examples. The method was also applicable to the synthesis of heteroarylpyrroles, such as thienopyrrole 72. The Li approach exploited similar diene substrates in combination with a range of amide coupling partners. 45,85 For example, diiododiene 73 was combined with phenylacetamide using a copper(I) iodide/diamine 64 catalyst to deliver the expected pyrrole in 86% yield (Scheme 33). Pr S Bu Bu SiMe3 Pr 70 73 Scheme 33 I O I + H2N Ot-Bu Me Pr CuI (5 mol%) 25 (20 mol%) Cs 2CO 3 THF, 80 °C CuI (20 mol%) 64 (20 mol%) Cs 2CO 3 dioxane, 100 °C Pr N Boc 71, 86% N SiMe3 Pr N SiMe3 N Boc Boc Boc 98% 80% 72, 83% I O + I H2N Ph Buchwald and colleagues reported a complementary stepwise approach to pyrroles also based on copper-catalyzed alkenylation reactions. 86 N,N¢-Di(Boc)-protected alkenylhydrazides 74, themselves prepared by copper-catalyzed alkenylation reactions, were coupled with a second alkenyl iodide to generate bis(ene)hydrazide 75 (Scheme 34). Thermolysis triggered a [3,3] rearrangement to generate bis-imine 76, cyclization of which provided the pyrrole Pr Pr Pr Boc Oct N Boc N N H Boc 74 + Boc N Pr Oct I [3,3] Bu (i) CuI (10 mol%) 1,10-phenanthroline (20 mol%) Cs2CO3, DMF 80 °C, 30 h ii) o-xylene, 140 °C, 30 h iii) p-TsOH, r.t. Boc Boc N N Pr Pr Oct Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York Pr S Bu N Bu O 86% Ph 75 76 77 Scheme 34 Pr Pr Pr Oct N 68% Boc Boc N Pr Oct SiMe3 H NBoc
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