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

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6 J. E. R. Sadig, M. C. Willis REVIEW The Hsung research group employed related cascade processes for the synthesis of 2-aminoindoles. 41 Scheme 12 shows an example in which ynamide 30 was combined with p-toluamine to deliver indole 31 in 85% yield. An XPhos-derived palladium catalyst was found to be optimal, and a variety of 2-carbamate-substituted indoles were prepared in good yields. The ynamide substrates were prepared, in a separate operation, by a copper-catalyzed amidation of the corresponding bromo-alkynes. 30 Br Scheme 12 Ackermann and colleagues were able to extend their original methodology to a three-component system, featuring the in situ formation of the key o-alkynylhaloarenes. 38a,e The process involved the initial combination of an ochloroiodobenzene with an alkyne in the presence of a mixed palladium/copper catalyst system (Scheme 13); after two hours the required nitrogen nucleophile was introduced along with additional base, resulting in arylamination followed by a 5-endo ring closure. A variety of 1,2-disubstituted indoles were obtained in good yields. A possible limitation of the method is the poor commercial availability of alternative o-chloroiodobenzene derivatives. Scheme 13 O N O Pd2(dba) 3 (2.5 mol%) XPhos (5 mol%) Cs2CO3 + Ph toluene, 110 °C H2N p-Tol Cy2P i-Pr i-Pr XPhos (32) N N p-Tol Ph 31, 85% The Barluenga research group developed a successful cascade process, based on palladium-catalyzed aza-enolate a-arylation followed by intramolecular N-arylation, for the synthesis of a variety of indole derivatives. 42 The process is outlined in Scheme 14: Initial palladium-catalyzed aza-enolate arylation joins N-phenylimine 33 with 1,2-dibromobenzene, to provide imine 34. Palladium-catalyzed intramolecular amination, presumably via enamine intermediate 35, then delivers the expected indole in an excel- i-Pr 29 I i) Pd(OAc) 2 (10 mol%) CuI (10 mol%), (10 mol%) Cs2CO3 Cl toluene, 105 °C H + Ph ii) KOt-Bu H2N p-Tol Ph 65% Cl Ph N p-Tol Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York O O lent 86% yield. The same XPhos-derived catalyst proved optimal for both steps of the cascade. A wide range of imine derivatives could be incorporated. The use of mixed halogen systems, such as 1-bromo-2-iodobenzenes, allowed the regioselective synthesis of substituted indoles by exploiting the greater reactivity of the aryl iodide substituent. The authors were also able to show that mixed halide/sulfonate substrates were efficient reaction components, with both triflate and nonaflate systems being successfully employed. The ability to generate the required sulfonate derivatives from the parent o-chlorophenols significantly widened the scope of the process and allowed unusual substitution patterns to be accessed, such as the 2,4,6-trisubstituted example 36. 42b Although an N-aryl or N-alkyl substituent was a requirement of the imine components, the authors demonstrated that N-tert-butylsubstituted indoles could be deprotected under a variety of conditions. For example, the N-H indole derived from Ntert-butylindole 37 was obtained in 97% yield for the indole formation and deprotection (AlCl 3) sequence. The group also reported a three-component variant of the methodology, in which an initial palladium-catalyzed alkenyl halide amination was used to prepare the imine reaction components. Scheme 14 33 86% Br + Br Me N Ph Ph Pd2(dba)3 (2 mol%) XPhos (32) (4 mol%) NaOt-Bu, dioxane 110 °C N Ph N 86% Ph Br Ph N 2.2 Carbazoles Ph Br Ph HN 34 35 OMe Catalytic amination chemistry has a number of applications in carbazole synthesis. Nozaki was one of the first to exploit cascade amination processes for the preparation of a wide range of carbazole architectures. 43 An example of the general process developed by the Nozaki research group is shown in Scheme 15; the key heterocycle-forming reaction is a coupling between a nitrogen nucleophile and a doubly activated biphenyl. In this particular example, ditriflate 37 was coupled with tert-butylcarbamate using a XantPhos-derived catalyst to deliver carbazole 38 in 70% yield. 43b Deprotection of the Boc group from carbazole 38 revealed the natural product mukinone. The same group has exploited their methodology in the synthesis of heteroacenes, 43d,e chiral carbazole variants, 43a as well as Ph Ph 36, 74% N Ph Ph N 37, 91% Me Ph Me Me (from Cl/ONf substrate) (from I/Cl substrate) Cl
REVIEW Palladium- and Copper-Catalyzed Heterocycle Synthesis 7 helicenes. 43b The second example shown in Scheme 15 was reported by Chida and colleagues, and shows that related strategies developed using dibromobiphenyls are also effective in carbazole synthesis. 44a The example shows the preparation of a key intermediate in the synthesis of the natural product murrayazoline. 44b In order to achieve an efficient transformation using the sterically demanding amine 39, it was necessary to employ a high catalyst loading (20 mol%). A copper-catalyzed version of these transformations has also been reported. 45 The cascade coupling of nitrogen nucleophiles with doubly activated bi-aromatics has proven to be a powerful method for carbazole synthesis and has been exploited by several other groups. For example, Samyn and co-workers utilized dibromo-2,2¢-bithiophene substrates to prepare dithienopyrroles, 46 as did the Barlow research group. 47 MeO Me O 37 OMOM Scheme 15 O OMe OTf OTf Pd2(dba)3.CHCl3 (5 mol%) XantPhos (2) (10 mol%) K3PO4 o-xylene, 100 °C Br Pd2(dba) 3 (20 mol%) XPhos (32) (60 mol%) Br H2N + Me Me NaOt-Bu toluene, 130 °C O + t-BuO NH2 39 O MeO2C Bedford et al. developed a cascade sequence based on intermolecular aryl-amination followed by intramolecular direct C–H arylation as a route to carbazole derivatives; several examples are shown in Scheme 16. 48 The process combines o-chloroanilines with aryl bromides using palladium catalysis. Use of the bulky electron-rich tri(tertbutyl)phosphine ligand in combination with palladium(II) acetate was the optimal catalyst system and allowed the preparation of a range of carbazoles in good yields. Significant substitution could be tolerated on the coupling partners, as illustrated by the preparation of the natural product clausine P (40). Ackermann et al. developed a related aryl-amination and direct C–H arylation sequence for carbazole synthesis. 49 In the Ackermann approach, 1,2-dihaloaromatics were combined with anilines to deliver carbazole products (Scheme 17). A combination of palladium(II) acetate and Me N OMe Boc 70% N-Boc mukonine (38) MOMO murrayazoline 59% O O Me N Me F 3C Me Scheme 16 tricyclohexylphosphine was found to be optimal and allowed a wide range of carbazoles to be prepared. Using this catalyst system it was possible to employ inexpensive 1,2-dichloroarenes as coupling partners, as well as heterocyclic derivatives, illustrated by the preparation of pyrazine and pyridine derivatives 41 and 42. The authors exploited the methodology in a synthesis of the natural product murrayafoline A (43). 49b Although less accessible, 1,2-dihaloalkenes could also be employed as substrates, allowing the same cascade sequence to be applied to indole synthesis. + + N H 43% Cl H N N Cl Scheme 17 Ph N Ph 41, 93% Bn NH Cl Br N Pd(OAc)2 (4 mol%) t-Bu3P (5 mol%) NaOt-Bu toluene, reflux OMe Pd(OAc)2 (5 mol%) Cy3P (10 mol%) NaOt-Bu NMP, 130 °C N Ph 42, 93% N 69% Bn Kan and co-workers reported a palladium-catalyzed cascade route to carbazoles based on initial intermolecular Suzuki coupling followed by an intramolecular aryl amination. A small scoping study was described, although a possible limitation is the availability of suitably functionalized boronic acids. 50 Fujii and Ohno have also described a cascade route to carbazoles. In their approach, an intermolecular aryl amination between an aryl triflate and an aniline was used to construct a diphenylamine which then underwent an oxidative coupling to generate a carbazole product. The efficiency of the oxidative step was shown to be dependent on the substitution pattern of the diphenylamine intermediates. 51 N F 3C MeO N H 69% clausine P (40) CF 3 Synthesis 2011, No. 1, 1–22 © Thieme Stuttgart · New York Me Me N Ph 85% OMe N MeO H murrayafoline A (43) 74% from Br/Cl-Ar 72% from Cl/Cl-Ar Me Me
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