The directed ortho metalation±transition metal±catalyzed reaction symbiosis in heteroaromatic synthesis*

New developments from our laboratories in Directed ortho (DoM) and remote (DreM) metalation reactions are presented and connections to transition metal catalyzed cross coupling and ole®n metathesis processes are described. As it heads into its seventh decade since the Gilman and Wittig discovery, the Directed ortho metalation (DoM) reaction (Scheme 1) [1] is increasingly poised to the challenges and opportunities in synthetic aromatic chemistry. In the quest to develop new amide-based Directed Metalation Groups (DMGs), we have recently discovered that secondary N-cumyl benzamide 1 (Scheme 2) undergoes smooth deprotonationÐelectrophile quench providing a general route to products 2 which, in contrast to previously developed amide DMGs [1,2] are rapidly hydrolyzed to primary amides 3 which, in turn, are readily manipulated to other useful functionality [3]. Similarly, the corresponding benzenesulfonamide 4 is converted to ortho-substituted products 5 (Scheme 3). Most signi®cantly, the tertiary cumyl aryl O-carbamate 8 is transformed to ortho-TMS derivative 6 and undergoes the anionic Fries rearrangement to 7 in useful yields (Scheme 4). The facile further TFAand TFE-mediated hydrolysis to 10 (via 9) and 11, respectively, opens avenues for mild synthesis and manipulation of phenol and salicylamide derivatives which offer advantage over the previous reactions of the corresponding diethyl carbamate 11. *Lecture presented at the 10th IUPAC Symposium on Organo-Metallic Chemistry Directed Towards Organic Synthesis (OMCOS 10), Versailles, France, 18±22 July 1999, pp. 1381±1547. 2 Corresponding author: E-mail: [email protected] Scheme 1 Directed ortho metalation: the new aromatic chemistry. 1522 B. CHAUDER et al. q 1999 IUPAC, Pure Appl. Chem. 71, 1521±1529 Scheme 2 Evolution of a new amide DMG. Scheme 3 Evolution of a new sulfonamide DMG. Scheme 4 Evolution of a new carbamate DMG. In the last two decades, transition metal-catalyzed cross coupling reactions have had a speci®c impact in the synthetic chemist's approach to the aryl±aryl bond forming process [4]. Work in our group has been focussed on the DoM-cross coupling link, 13 ! 14 ! 15 (Scheme 5) especially in the Suzuki-Miyaura, Corriu-Kumada-Tamao, and Negishi reactions. Aside from extensive studies in solution phase chemistry, [1,2] we have effected solid support Suzuki±Miyaura cross coupling reactions. Of these, the Leznoff acetal linked system 16 (Scheme 6) undergoes coupling with boronic acids 17 and 18 derived from DoM chemistry. These reactions allow cyclization modes leading, respectively, to phenanthridines 19 and dibenzopyranones 20 (via 21) in high yields and purities [5]. The discovery of the Grignard±aryl O-carbamate cross coupling process [6] has prompted systematic studies, including the development of a regiospeci®c route to polysubstituted naphthalenes (Scheme 7). Thus, metalation±carbamoylation of 22 leads to 23 which, upon a second metalation±electrophile quench, produces a variety of 1,2,3trisubstituted naphthalenes 25 [7]. In the appropriate case, 25 undergoes smooth Suzuki-Miyaura cross coupling to give biaryls 24 and, upon further metalation±quench, leads to tetra-substituted naphthalenes 26. The overall concept (27) provides walk-around-the-ring DoM chemistry that may allow also an answer to the peri-metalation question. In an application of the new Grignard-carbamate cross coupling which is connected to the Saegusa-Ito ortho-quinodimethane generation method (Scheme 8), compound 28 undergoes exclusive C-4 deprotonation and, upon electrophile quench, provides 29 [8]. Cross coupling with a commercial Grignard reagent affords 30, demonstrating a new mode for functionalization of the important indole C-5 position. Reduction, quaternization, and a protecting group switch (necessary to avoid complications at the N-TBS in the subsequent reaction) leads to 32, which, upon ̄uoride treatment (Scheme 9) and dienophile trap gives, via the reactive species 33, cycloadducts 34±37. The DoM-cross coupling marriage is also effectively illustrated in the organozinc 38±aryl tri ̄ate 39 union (Scheme 10) to give products 40 exempli®ed in various DMG ̄avors [9]. The salient Complex-Induced Proximity Effect (CIPE) concepts of Beak & Meyers [10] and Klumpp [11] led, as a direct consequence, to the establishment of Directed remote Metalation (DreM)-induced reactions, 42 ! 41 and 43, and 45 ! 44 (Scheme 11) [1,2], While the ̄uorenone (41) forming reaction has been extensively developed for methodology and total synthesis [12], emphasis has been placed more recently on the remote anionic Fries rearrangement (42 ! 43), the tolyl DreM (45 ! 44), and the yet to be fully evaluated competition, 45 ! 46 or 47. Thus, coupling of DoM-derived boronic acids (48) (Scheme 12) with halides or tri ̄ates (49) affords biaryls 50 which, upon LDA treatment followed by acidcatalyzed cyclization lead to products 51, in overall routes which are higher yielding than the more sterically demanding direct cross coupling (52), furnish natural products (53), and, as yet, cannot be forced to double migration modes (54) [13]. Among other natural product synthesis applications, the naphthobenzopyrone 55 (Scheme 13), obtained by O-carbamate DreM, was readily transformed, via Stille product 56 into defucogilvocarcin V 57 [14]. In these processes, the effective use of the carbamate moiety as a carbonyl dication equivalent is demonstrated. As a foray into the synthetic potential of the Directed ortho metalation±transition metal±catalyzed reaction symbiosis 1523 q1999 IUPAC, Pure Appl. Chem. 71, 1521±1529 Scheme 5 The DoM±cross coupling nexus.