Astruc D. - Modern arene chemistry (2002)(en)

10.3 Heteroaromatic Directed ortho Metalation (HetDoM) in Methodological Practice 343

Scheme 22. The DoM chemistry of carbinolamine alkoxide DMGs in pyridines.

Scheme 23. The O-carbamate DMG in DoM of pyridines.

quench, 66 ! 67, followed by base hydrolysis, conversion to the 4-chloropyridine, and hydrogenolysis leads to two derivatives 68.

In contrast to the well known metal-halogen exchange of bromo and iodo aromatics, commercially available halopyridines are amenable, for all halogens, to DoM chemistry of considerable synthetic value [9d]. Recent results [9d, 41], have pointed to the additional feature of the ‘‘halogen dance’’ as a tool for the construction of unusually substituted pyridines. Illustrative are the conversion of 69 into 2,3,4-substituted pyridines 70 and, more interestingly, of 71 into the tetrasubstituted 72 bearing all but one of the theoretically possible halogens (Scheme 24) [42].

Among the few quinolines and isoquinolines that have been tested for DoM reactivity [9e], utility is compromised by RLi addition reactions and unusual behavior [9d, 43].

344 10 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry

Scheme 24. Tandem DoM/halogen dance reactions of iodopyridines.

10.4

The DoM–Transition Metal Catalyzed Aryl–Aryl Cross-Coupling Symbiosis

The changing face of synthetic methodology has been fueled by dramatic discoveries of new reactions in transition metal catalyzed processes over the past thirty years. In the area of aryl–aryl bond formation, Corriu–Kumada–Tamao, Suzuki–Miyaura, Negishi, and Stille, in addition to others with preceded and interspersed contributions, have provided the synthetic community with e ective cross-coupling methods for biaryl and higher order aryl ring combination constructs (Scheme 25) [44]. The rational connection of these methods to DoM provides, by metal-metal exchange, latitude for the preparation of substituted biaryls and heterobiaryls whose origins may be based on the versatility of DoM and whose new CaC bond regiochemistry is dictated by a variety of carbonand heteroatom-based DMGs (Scheme 26) [45].

Scheme 25. Transition metal catalyzed cross-coupling reactions for the synthesis of aryl–aryl bonds.

10.4 The DoM--Transition Metal Catalyzed Aryl--Aryl Cross-Coupling Symbiosis 345

Scheme 26. The DoM–cross-coupling nexus.

10.4.1

The Suzuki–Miyaura–DoM Link

The connection of the Suzuki–Miyaura strategy [46] with DoM o ers a dependable and general route for the synthesis of biaryls and heterobiaryls. While mechanistic knowledge is still lacking [46, 47] and reasons for homocoupling and deboronation are not fully understood [48], this process constitutes a dependable replacement for alternative classical methods [49], as was demonstrated early in sequential 73 ! 74 and 2:1 75 þ 76 ! 77 cross-coupling modes (Scheme 27) [50]. Similar processes are increasingly being used for the construction of polyaryls of interest in material science areas [51].

Scheme 27. DoM-initiated sequential and 2:1 Suzuki–Miyaura cross-coupling.

346 10 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry

The Suzuki–Miyaura tactic carried out on solid support (Scheme 28) [52] provides routes to small libraries of condensed heterocycles. Thus, Merrifield resin with the Lezno -linked bromobenzene derivative 78 undergoes cross-coupling under normal solution-phase conditions with boron pinacolate 79 or boronic acid 80, prepared by DoM, to a ord phenanthridines 81 or, via 82 and some manipulation, dibenzopyranones 83 in good yields and with high purities. The Stille solid-support reaction has also been successfully executed [53].

Scheme 28. Solution-phase DoM–initiated Suzuki–Miyaura cross-coupling on solid support.

10.4.2

Aryl O-Carbamate and S-Thiocarbamate–Grignard Cross-Coupling Reactions

The discovery that the most powerful OCONEt2 DMG also acts as a coupling partner with Grignard reagents under nickel-catalyzed conditions [54] opened the doors to new methodology whose potential, 84 ! 85 (Scheme 29) allows, in theory, the construction of contiguous electrophile-nucleophile-electrophile substitution patterns on an aromatic ring, i.e. the charged equivalency 86.

Scheme 29. O-Carbamate DoM–cross-coupling connection.

10.4 The DoM--Transition Metal Catalyzed Aryl--Aryl Cross-Coupling Symbiosis 347

Even in the brief methodological studies so far undertaken (Scheme 30) [54], steric and electronic e ects (A and B) and a rapid route to benzyl silanes using commercially available Grignards have been established.

Scheme 30. Nickel-catalyzed cross-coupling of O-aryl carbamates and triflates with Grignards; electronic and steric e ects.

Of perhaps greater value is the utility of this carbamate variation of the Corriu–Kumada– Tamao reaction in the formulation of substitution patterns on simple aromatics that cannot be purchased nor easily constructed. In a demonstration of this point, the naphthyl O- carbamate 87 (Scheme 31) [54, 55] is converted into 88, which, when subjected to a second DoM and various electrophile quenches, leads to 90. The latter may be elaborated in two directions: by nickel-catalyzed coupling with RMgX reagents (R ¼ Ar, vinyl, Me, TMSCH2) [56] to 1,2,3-substituted naphthalenes 89 or, by taking advantage of the b-hydride donor properties of iPrMgCl, into the 2,3-substituted derivatives 91. With the proviso that the E substituent is unreactive or protected from RMgX attack, the conceptual framework (92) may be of further value in simpler condensed aromatic and heteroaromatic molecules.

The methodological exploration of O-carbamate–Grignard cross-coupling in heterocyclic systems may also prove profitable, as suggested by the initial work on the indole 5-O- carbamate 93 (Scheme 32) [57]. Thus, the intermediate amide 94 obtained by standard DoM chemistry, when subjected to coupling with an excess of the commercially available TMSCH2MgX reagent, provides 95 in reasonable yield. Further conversion leads, via 96, to 97, a precursor of the indolo 4,5-quinodimethide intermediate 98, which undergoes cycloaddition with a variety of dienophiles to give new annelated products 99.

A logical progression of O-carbamate DoM chemistry, to metalate S-thiocarbamates 103, E ¼ H, proved unsuccessful, but turning attention to the corresponding O-thiocarbamates

348 10 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry

Scheme 31. Nickel-catalyzed O-aryl carbamate Grignard cross-coupling; regiospecific access to 1,2,3- and 2,3-substituted naphthalenes.

Scheme 32. Indole 5-O-carbamate–Grignard cross-coupling; annelation via indole 4,5-quinodimethide.

10.4 The DoM--Transition Metal Catalyzed Aryl--Aryl Cross-Coupling Symbiosis 349

Scheme 33. DoM of aryl O-thiocarbamate. Link to the Newman–Kwart rearrangement and consequent S-thiocarbamate cross-coupling.

100 and using 2 equivalents of alkyllithium (obligatory) resulted in the development of this new DMG not only per se (101) but also, via Newman–Kwart rearrangement (102), as a precursor to the S-thiocarbamates 103 (Scheme 33). Systems 103, upon hydrolysis, lead to orthosubstituted thiophenols 104 that are not easily accessible by electrophilic substitution reactions [55, 58]. While the O-thiocarbamate 100 could not be persuaded to cross-couple with RMgX reagents, the S-thiocarbamate 105 successfully undergoes coupling with Grignards to give 106. The further development of this O-thiocarbamate–S-thiocarbamate connection may lead to its advantageous use in overcoming the poor DMG qualities of other sulfur groups (SH, SR), the cross-coupling chemistry of which has already been defined by the extensive work of Wenkert [59].

10.4.3

The DoM–Negishi Cross-Coupling Connection

A most important advantage of organozinc over organomagnesium reagents is the compatibility of the former with a variety of functional groups: CHO, COR, CN, NO2, CO2R, CONR2. Thus, the DoM–Negishi cross-coupling reaction with aryl triflates, 107 þ 108 ! 109, provides a rich array of aromatic and heteroaromatic products (Scheme 34) [60]. The selected cases illustrate unreactivity of O-carbamates, thus providing opportunity for tuning in the RMgX cross-coupling partner subsequent to the triflate-RZnX coupling (111a); the preparation of a number of products which are predisposed for further DoM chemistry (e.g. 111a, 112a); compatibility of the ester functionality (112c), and the di culty of ortho-N-

350 10 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry

Scheme 34. The DoM–Negishi cross-coupling connection.

Boc organozinc coupling (113) presumably due to stability of the incipient ortho-zinc intermediate.

10.4.4

DoM–Derived Cross-Coupling Reactions. Synthetic Comparison of Boron, Zinc, and Magnesium Coupling Partners

The literature explosion of new methodologies demand comparisons for the purpose of application and further exploitation. For the Suzuki–Miyaura, Corriu–Kumada, and Negishi processes, qualitative comparison of synthetic value (Scheme 35) [60b] suggests synthetic advantage of the Suzuki–Miyaura and Negishi processes. Thus, in a prototype study, 114 þ 115 ! 116, even outside of the context of DoM chemistry, the coupling of triflates bearing esters (117), N-Boc (118), and nitro (119) groups fail with Grignard partners and give modest yields with fluoro (120) and O-carbamate (121) aromatics. On the other hand, arylzincs and arylboronic acids provide good to excellent yields of biaryls with two exceptions:

10.5 Beyond DoM: The Directed Remote Metalation (DreM) of Biaryl Amides and O-Carbamates 351

Scheme 35. Qualitative comparison of the Suzuki–Miyaura, Corriu–Kumada, and Negishi processes.

in Negishi couplings, the triflate from N-Boc aniline fails (118), possibly due to the presence of acidic NaH in the coupling partner, and that derived from the nitrobenzene derivative (119) is modestly successful, probably due to the incompatibility of zinc reagents with nitro groups; in the case of Suzuki–Miyaura coupling of triflate of a benzoate (117), the use of Cs2CO3 rather than Na2CO3 avoids ester hydrolysis, an apparently detrimental aspect in obtaining good yields in this coupling reaction.

10.5

Beyond DoM: The Directed Remote Metalation (DreM) of Biaryl Amides and O-Carbamates – New Methodologies for Condensed Aromatics and Heteroaromatics

The Complex-Induced Proximity E ect (CIPE), suggested over 15 years ago [61, 62] to rationalize significant e ects of strong coordination of donor substituents with organometallic reagents in enhancement of acidity at remote, non-thermodynamic sites, was the concept responsible for the discovery of DreM reactivity in biaryl amides (Scheme 36). A general reaction was developed in which biaryl amide 123, upon treatment with LDA, in spite of availability of ortho hydrogens, G1 ¼ H, underwent deprotonation on the alternate ring to generate a species (124) that could not be trapped by external electrophiles, but led to fluo-

352 10 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry

Scheme 36. Biaryl amide DreM. Versatile anionic Friedel–Crafts complements for assemblage of fluorenones and azafluorenones.

renone 125 (Scheme 36) [62, 63]. The scope of the reaction (129–137), its regioselectivity dictated by DMGs, and its complementarity to the classical Friedel–Crafts reaction on a small scale (126 127 ! 128) and in industrial practice for the preparation of protein kinase inhibitors 138 ! 139 ! 140 (Scheme 37) [64] are indicative of the further potential of this DreM process. The ready availability of precursor biaryls via Suzuki–Miyaura chemistry is a further advantage of this ‘‘beyond DoM’’ reaction.

The similarly and equally accessible biaryl O-carbamate 142 (Scheme 38) requires ortho substitution (PG ¼ OMe) or protection (PG ¼ SiEt3) to avoid anionic ortho Fries rearrangement (141) and to launch a DreM pathway leading to 144 using LDA under vigorous conditions [65]. For PG ¼ TMS, carbamoyl migration to the incipient a-silylmethyl anion occurs