DOI: 10.1002/adsc.201000114 One-Pot Palladium-Catalyzed Synthesis of Selectively Substituted Phenanthridines by Sequential Aryl-Aryl and Heck Couplings, Aza-Michael and Retro-Mannich Reactions Nicola Della Ca’, a Elena Motti, a Antonio Mega, a and Marta Catellani a, * a Dipartimento di Chimica Organica e Industriale and CIRCC, Università di Parma, V. le G.P. Usberti, 17A, 43124 Parma, Italy Fax: (+ 39)-0521-905-472; e-mail: marta.catellani@unipr.it Received: February 11, 2010; Published online: June 8, 2010 Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/adsc.201000114. Abstract: A catalytic synthesis of selectively substi- tuted phenanthridines is achieved through a reac- tion sequence involving palladium/norbornene-cata- lyzed unsymmetrical aryl-aryl and Heck couplings followed by aza-Michael and retro-Mannich reac- tions. In spite of the many steps involved the method is very simple and allows the formation of selectively substituted phenanthridines under mild conditions in a straightforward one-pot reaction starting from readily available aryl iodides and bro- mides. Keywords: C À C and C À N bond formation; C À H ac- tivation; norbornene; palladium; phenanthridine; sequential reactions Phenanthridines are an important group of natural compounds with a broad range of biological and phar- macological activities. [1] Due to these properties they represent attractive synthetic targets and much atten- tion has been focused to establish simple and efficient methods for their preparation. [2] Palladium-catalyzed sequential reactions have proven very useful since they allow to build up complex structures starting from simple reagents with high selectivity, in one-pot, under mild conditions. [3] We have previously reported a facile and efficient synthesis of selectively substituted 5-arenesulfonyl- 5,6-dihydrophenanthridine derivatives by reaction of an ortho-substituted aryl iodide with a sulfonylated o- bromoaniline and an activated terminal olefin, in the presence of PdACHTUNGTRENNUNG(OAc) 2 and norbornene as catalyst, K 2 CO 3 and NBu 4 Br in MeCN. [4] On replacing the sul- fonylated o-bromoaniline with the trifluoroacetylated one, the reaction became very sluggish leading to poor conversion of both aryl halides. For example o- iodotoluene (1a) reacted with o-bromo-N-trifluoro- ACHTUNGTRENNUNGacetanilide (2a) and methyl acrylate (3a), under our previously reported conditions (Scheme 1), to give the corresponding unprotected 5,6-dihydrophenanthridine 4a in ca.10% yield together with a small amount (ca. 4%) of phenanthridine 5a. While formation of the unprotected dihydrophen- ACHTUNGTRENNUNGanthridine 4a could be anticipated in view of an easy hydrolytic cleavage of the N-trifluoroacetyl group, that of compound 5a was quite unexpected. We hy- pothesized that phenanthridine 5a derived from a retro-Mannich reaction (we thank a referee for sug- gesting the term “retro-Mannich”) taking place on compound 4a. Subjecting compound 4a to the action of a DMF solution of an equimolar amount of potas- sium carbonate at 105 8C led indeed to the formation of compound 5a (70% after 24 h) along with the ex- pected methyl acetate. Using the tert-butyl ester of acrylic acid for a better analysis we were able to es- tablish by GC and GC-MS analysis that tert-butyl ace- tate was formed in an almost equimolar amount to 5a. This means that the retro-Mannich is strongly fa- Scheme 1. Adv. Synth. Catal. 2010, 352, 1451 – 1454  2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1451 COMMUNICATIONS