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

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12 J. E. R. Sadig, M. C. Willis REVIEW via intermediate 77. For certain substrates it was necessary to add acid to achieve complete conversion into the aromatic system. The bis(ene)hydrazides could be isolated, or more conveniently used directly in the next step of the sequence with no purification. The overall method represents a modified Piloty–Robinson reaction. The final pyrrole synthesis considered here comprises a copper-catalyzed cascade alkenyl amidation/hydroamination sequence. The process is essentially a pyrroleforming version of the indole synthesis described in Scheme 11. In this approach, described by Buchwald and co-workers, haloenynes such as 78 replace the alkynylhaloarenes used for indole synthesis, and, when combined with tert-butyl carbamate and a copper(I) iodide/diamine catalyst, provide the corresponding pyrroles in good yields (Scheme 35). 87 A broad range of di- and trisubstituted pyrroles were prepared, and although the study focused on the use of iodoenynes, it was also possible to employ bromoenynes. A brief mechanistic study established that the reactions likely proceed via initial intermolecular aryl carbon–nitrogen bond formation followed by a 5-endo-dig intramolecular hydroamination. Pent 78 OTIPS I + t-BuO NH2 Scheme 35 O 2.6 Pyrazoles 25 CuI (5 mol%) (20 mol%) OTIPS Cs2CO3 THF, 80 °C Pent N Boc 83% Buchwald and co-workers utilized haloenyne substrates in a tandem copper-catalyzed pyrazole synthesis. 87 For example, combination of iodoenyne 78 with bis(Boc)hydrazine using a copper(I) iodide/diamine catalyst provided pyrazole 79 in 78% yield after Boc-deprotection with trifluoroacetic acid (Scheme 36). As in the related pyrrole syntheses, a good range of di- and trisubstituted aromatics were prepared. The mechanism was again established as proceeding via intermolecular aryl carbon–nitrogen bond formation followed by intramolecular hydroamination, although the cyclizations were in this case 5-exo-dig processes. Cho and Patel reported a pyrazole synthesis based on the palladium-catalyzed combination of b-bromovinyl aldehydes with hydrazines. 88 For example, treatment of Pent 25 78 (i) CuI (5 mol%) (20 mol%) Pent I + H N Boc NH Boc OTIPS Cs2CO3 THF, 80 °C ii) TFA, CH2Cl2, r.t. Scheme 36 N N H 79, 78% Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York OTIPS bromo-enal 80 with phenylhydrazine in the presence of a dppf-derived catalyst yielded pyrazole 81 in 77% (Scheme 37). Both cyclic and acyclic substrates could be employed, although no ketone-derived substrates were reported. Haddad and co-workers developed a pyrazole synthesis in which aryl benzophenone hydrazones, prepared by the palladium-catalyzed coupling of benzophenone hydrazone with aryl halides, were treated with a range of 1,3-bifunctional substrates under acidic conditions. 89 1,3- Diketones, keto esters and ester/acid chlorides could be combined with the hydrazones to provide a range of substituted pyrazole products. 80 O H + Br Scheme 37 H2N Pd(OAc) 2 (5 mol%) dppf (12) (7.5 mol%) NH NaOt-Bu, toluene Ph 125 °C N N Ph 81, 77% 2.7 Oxazoles Buchwald and co-workers utilized copper-catalyzed alkenyl iodide amidation reactions as the key step in a route to oxazoles. 90 For example, enamides such as 82 could be treated with iodine and base to provide the expected trisubstituted oxazoles in good yields (Scheme 38). The required enamides were prepared from the corresponding alkenyl bromides using a copper(I) iodide/diamine-catalyzed coupling with the appropriate amide; both aryl and alkyl amides could be used. Depending on the substitution pattern of the oxazole product, certain examples required the addition of p-toluenesulfonic acid to achieve complete conversion into the aromatic molecule. Attempts to prepare mono- and disubstituted oxazoles using this method resulted in complex reaction mixtures, and an alternative process, based on the use of 1,2-dihaloalkene substrates, was developed. Ph Br + O Ph H2N Ph Scheme 38 Ph Ph H N 82 O 2.8 Quinolones i) CuI (5 mol%) (20 mol%) 25 Cs2CO3, THF, 80 °C ii) I2, DBU r.t. to 80 °C Ph Ph Ph Manley and Bilodeau used palladium-catalyzed intermolecular aryl halide amidation followed by an in situ aldol condensation to prepare 2-quinolones. 91 In this way o-bromobenzaldehydes were combined with a range of enolizable amides to deliver the quinolone products. Scheme 39 I H N O Ph Ph Ph N O 77% Ph
REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 13 illustrates the combination of the parent aldehyde (83) with phenylacetamide using a XantPhos-derived catalyst in combination with cesium carbonate as base. A variety of substituted amides could be employed, as could ketonebased substrates, allowing the synthesis of 4-substituted products such as quinolone 84. Pyridine derivatives could also be employed, thus providing a route to naphthyridinones. Ester- and nitrile-substituted aryl bromides were also examined and allowed access to hydroxy- and aminosubstituted products, respectively. For a small number of amide coupling partners, the researchers were able to employ a copper(I) iodide/diamine catalyst system. 83 Scheme 39 O O H + H2N Br N H 94% O N Ph Pd 2(dba)3 (1 mol%) XantPhos (2) (3 mol%) Cs2CO3 toluene, 100 °C N H 84, 55% N H 94% Huang et al. utilized the related o-acetylbromoarenes as substrates in a palladium-catalyzed synthesis of 4-quinolones. The simplest version of the process employed formamide as the nitrogen nucleophile and, when coupled with bromide 85, delivered quinolone product 86 in 77% yield (Scheme 40). 92 The reactions proceeded via initial palladium-catalyzed amidation followed by a base-promoted intramolecular condensation step. A XantPhosderived catalyst in combination with cesium carbonate as base was optimal for the amidation step, and the addition of sodium tert-butoxide as a second base was found to be necessary to achieve high yields for the combined process. As can be seen from the examples presented in Scheme 40, a range of substituted amides could be employed, including lactams, which allowed the synthesis of N-fused products such as quinolone 87. The Buchwald research group reported a related process based on coppercatalyzed amidation, although in their case it was neces- MeO N H Scheme 40 85 O Ph Ph O Me Br H O Pd2(dba) 3 (1 mol%) XantPhos (2) (2.5 mol%) + 2N H Cs2CO3, dioxane 100 °C, 2–48 h then NaOt-Bu, 100 °C MeO O N H O N N H 75% Ph O Ph O O N H 86, 77% S 82% 91% 87, 85% Me O N sary to isolate the initial amidation products before cyclization. 93 A tandem Heck/intramolecular amidation strategy was reported by Cacchi and co-workers as a route to 4-aryl-2quinolones. 94 Using molten tetrabutylammonium acetate/ tetrabutylammonium bromide as the reaction medium and a simple palladium(II) acetate catalyst, the combination of o-bromophenylacrylamides (88) and aryl iodides provided the quinolone products in moderate to good yields (Scheme 41). Although only a single acrylamide substrate was employed, a good range of aryl iodide coupling partners could be incorporated. A brief mechanistic investigation supported the Heck followed by intramolecular amidation pathway. 88 + Br Scheme 41 Willis and co-workers exploited 2-(2-haloalkenyl)aryl halide substrates, previously employed in indole syntheses (see Scheme 8), in the preparation of 2-quinolones. 95 A cascade palladium-catalyzed carbonylation/intramolecular amidation sequence was employed to access a range of quinolone products. For example, combination of the simple dibromide 89 and p-methoxybenzylamine under a balloon pressure of carbon monoxide delivered quinolone 90 in 80% yield (Scheme 42). Although all of the products shown in Scheme 42 were obtained using a dppp-derived catalyst, the researchers found that ligand variation was needed for particular substrate/amine combinations. In addition, purging the reaction of carbon monoxide was shown to benefit the efficiency of certain amidation reactions. By delaying the introduction of the carbon monoxide and running the reaction in a two-stage process, it was also possible access the regioisomeric isoquinolone products, although in these cases competing indole formation was problematic. O Scheme 42 O I NH 2 + H2N Br Br 89 Pd(OAc)2 (5 mol%) n-Bu4NOAc, n-Bu4NBr 120 °C CO (balloon) Pd2(dba)3 (3 mol%) dppp (6 mol%) Cs2CO3, toluene 100 °C OMe N H 75% Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York O N O PMB 90, 80% O N O MeO N O N N O Oct O Oct Oct 69% 65% 73%
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