Astruc D. - Modern arene chemistry (2002)(en)
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10.5 Beyond DoM: The Directed Remote Metalation (DreM) of Biaryl Amides and O-Carbamates 353
Scheme 37. Friedel–Crafts/DreM complementarity. Synthesis of protein kinase inhibitors.
Scheme 38. Biaryl O-carbamate DreM. Ring-to-ring carbamoyl transfer.
Synthesis of dibenzo[b,d]pyran-6-ones.
in good yield to give 143, an observation also rationalized by CIPE [61, 62]. Acid-catalyzed cyclization of 144 leads to dibenzo[b,d]pyran-6-ones 145, constituting a new route to this class of heterocycles.
This anionic remote Fries rearrangement provides a general route to highly substituted biaryls 146 which, due to steric e ects, may be di cult to prepare directly by Suzuki– Miyaura cross-coupling, as evidenced in the comparison with the synthesis of dibenzopyranones 147 (Scheme 39) [66]. The e cient acid-catalyzed cyclization to dibenzopyranones shows broad scope both for unusually substituted (148–150, Scheme 40) and various heterocyclic analogues (151–153, Scheme 40) [65, 67].
A rational extension of ortho-tolyl benzamide metalation [68], part of the broadly encompassing lateral metalation protocol [69] that can be DoM-connected, is the DreM equivalent, 154 ! 155 (Scheme 41), which provides a general regioselective route to 9-phenanthrols (156, 157, 158) [70] and may be extended to diaryl nitriles, hydroxylamine ethers, and hydrazones 160, which provide the corresponding 9-amino derivatives 161 of similar generality 162–165 (Scheme 42), as may also be applied in natural product synthesis [71]. Further opportunities for DoM–cross-coupling and reduction/oxidation chemistry (159) have also been demonstrated [70a].
354 10 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry
Scheme 39. Biaryl O-carbamate anionic remote Fries rearrangement. Conquering steric encumbrance in direct Suzuki–Miyaura crosscoupling.
Scheme 40. Dibenzopyranones and heterocyclic analogues by anionic remote Fries rearrangement.
Are the above DreM tactics feasible in tandem? A preliminary but a rmative answer is possible. Thus, the biaryl O-carbamate migration–amide cyclization sequence 166 ! 167 ! 168 (Scheme 43), which conceptually constitutes a reaction of a biaryl 2,20-dianion with a carbonyl dication equivalent (169), has found application in natural product synthesis [65, 72].
A di erent sequential DreM pathway involving O-carbamate ring switch–vinylogous tolyl amide cyclization, 170 ! 171 ! 172 (Scheme 44), a formal bridging of a 2,20-methyl diaryl dicarbanion with a carbonyl dication equivalent (173) has been a rmed in a model study (174 ! 175, Scheme 45) [73] and applied in natural product total synthesis [73, 74].
10.5 Beyond DoM: The Directed Remote Metalation (DreM) of Biaryl Amides and O-Carbamates 355
Scheme 41. Synthesis of 9-phenanthrols by DreM chemistry.
Scheme 42. Synthesis of 9-amino phenanthrenes by DreM.
356 10 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry
Scheme 43. Synthesis of fluorenones by tandem remote metalation–amide DMG translocation.
Scheme 44. Synthesis of 9-phenanthrols by tandem remote metalation–amide DMG ring-to-ring translocation.
10.5.1
Heteroatom-Bridged Biaryl DreM. General Anionic Friedel–Crafts Complements for Several Classes of Heterocycles
The mental insertion of a heteroatom X into the biaryl motif 177 also provokes questions of DreM-mediated chemistry (Scheme 46). In response, treatment of all heteroatom X de-
10.5 Beyond DoM: The Directed Remote Metalation (DreM) of Biaryl Amides and O-Carbamates 357
Scheme 45. Sequential remote metalation amide DMG translocation. A model study.
Scheme 46. Heteroatom-bridged diaryl DreM routes to heterocycles.
35810 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry
rivatives 177, without ortho protection, with excess LDA provides routes to thioxanthones, xanthones, acridones, and dibenzophosphorinones 178, while the application of very similar conditions to diaryl sulfone and diaryl phosphite systems 177, X ¼ SO2 and X ¼ P(O)Ph, with appropriate protection PG ¼ OMe, SiR3, results in ring-to-ring carbamoyl migration and, via 176, anionic ring-closure to more highly functionalized dibenzophosphorinones and thioxanthones 179, e.g. 180 and 181 [75]. A plethora of heterocycles in all series are thus readily derived with useful and unusual features: following phenol protection, the thioxanthone 180 undergoes ipso-iododesilylation to give a derivative poised for coupling chemistry; the new heterocycle azathioxanthone 182 is available; azaxanthones, for example 183 and 184, are rapidly prepared from readily available starting materials; consistently, Friedel– Crafts complementarity is observed for product xanthones 185 and acridones 186 obtained from precursors bearing DMGs ortho to the incipient anionic site; in the P-heteroatom series, preferred phosphorinone over fluorenone (187) and double DreM cyclization (188) pathways are observed. The availability of precursors by DoM (diaryl sulfones, diaryl phosphites) and DoM–Buchwald–Hartwig and Ullmann Pd-catalyzed coupling reactions (diaryl amines, diaryl ethers) reinforces the convenience of the synthetic pathways to these heterocycles, including natural products [47, 75b, 75c], e.g. 9-deoxyjacarubein (189).
In the diaryl amine series 191 (Scheme 47), additional, synthetically valuable, anionic
pathways provide routes to anthranilates 190, oxindoles 192, and dibenzazepinones 194. Although not explored in terms of its scope [75c], the lateral metalation–cyclization, 191 ! 192, is extensively precedented [69] but harbors intriguing potential for subsequent DreM chemistry. The rearrangement 191 ! 190 is an N ! ortho C anionic Fries equivalent of the aryl O-carbamate migration (Scheme 3E) [75c] and after N-methylation, 190 may be transformed into 1,2,3-trisubstituted systems 193 [76]. In another appealing manifestation of CIPE, the e cient conversion of 191 into dibenzazepinone 194 has been applied in an effective synthesis of the antiepileptic drug oxcarbazepine (Trileptal9) 195 [77] and may also be
Scheme 47. Anionic pathways to oxindoles, anthranilates, and dibenzazepinones.
10.6 Interfacing DoM with Emerging Synthetic Methods 359
extended regioselectively, with one exception (196 ! 197c þ 198), to the formation of dibenzthiepinone dioxide 197a and dibenzophosphorinone 197b (Scheme 48) [75b–d]. The complementarity to Friedel–Crafts technology (e.g. 199) is thus also established for these tricyclics, some of which have long-standing biological interest.
Scheme 48. Synthesis of dibenzthiepinone dioxide, dibenzoxepinone, and dibenzphosphorinone.
10.6
Interfacing DoM with Emerging Synthetic Methods
In the last quarter-century, the practice and art of organic synthesis has been revolutionized by the discovery of transition metal catalyzed organic transformations, ‘‘at a rate that would make the discoverer of islands in the St. Lawrence Seaway envious’’ [78]. Aside from the demonstrated DoMaAraAr cross-coupling connection above and the initial promise of acylative, 200 ! 201 (Scheme 49) [79] and carbonylative, 202 ! 203 ! 204 or Suzuki–Miyaura, 203 ! 205 (Scheme 50) [80] coupling, the establishment of potential DoM links to the literature-visible, already reliable, but not yet mature Heck, Sonogashira, and Grubbs metatheses will undoubtedly reap benefits for synthetic aromatic and heteroaromatic chemistry.
Scheme 49. DoM–acylative Negishi cross-coupling of aryl O-carbamates.
In this context, to tempt the synthetic practitioner’s palate, a general Grubbs ring-closing metathesis (RCM) retrosynthetic analysis may be envisaged for aromatic ring-annelated targets 206 (Scheme 51), which cascades, via 207, to simple ortho-lithiated species 208. Such starting points o er diverse DMG potential to be either directly or, with modification, incorporated into 206 and the tactic may lend itself to consideration of synergistic e ects of double-DMG containing precursors 209.
360 10 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry
Scheme 50. DoM–amidocarbonylation and Suzuki–Miyaura cross-coupling connections.
Scheme 51. DoM–Grubbs ring-closing metathesis connections.
Towards these ends, aside from the demonstration of use of the DoM–RCM strategy in natural product synthesis [81], prototype sequences leading to benzazocinone 213 (Scheme 52), macrocyclic ether sulfonamide 217 (Scheme 53), and thiaazepine 222 (Scheme 54) have been accomplished [82]. Thus, in the first series, 210 is subjected to DoM–transmetalation, which allows e cient allylation of the incipient Grignard reagent to give 211. N-Allylation to 212 followed by RCM using the popular Grubbs Ru-carbene catalyst a ords 213. In the second sequence, para-tolyl sulfonamide 214 metalation followed by the boronation–oxidation sequence to introduce an OHþ synthetic equivalent leads to 215, which, by double allylation to give 216 and RCM a ords the new heterocyclic system 217. In the third but undoubtedly not last series, Sonogashira coupling of the DoM-derived sulfonamide 218 furnishes 219, which, after desilylation (220) and allylation gives 221. Grubbs metathesis of 221, constitut-
10.6 Interfacing DoM with Emerging Synthetic Methods 361
Scheme 52. Benzoazocinone ring system via DoM–Grubbs ring-closing metathesis (RCM) connections.
Scheme 53. Macrocyclic sulfonamide via DoM–RCM.
ing an example of the still relatively unexplored ene–yne RCM, gives 222 in modest yield. The ease with which simple ring systems (213), classical syntheses of which appear not to have been described, and bizarre systems (217) are available, and the fact that some derived products are obviously useful for venerable follow-up reactions (222), o ers invitations for further methodological studies, which may lead to opportunities that are greater than their individual sum.
362 10 The Directed ortho Metalation Reaction -- A Point of Departure for New Synthetic Aromatic Chemistry
Scheme 54. Benzthiazepine dioxide via DoM–RCM.
10.7
Closing Comments
Although the DoM strategy has undergone remarkable development and unexpected industrial application since the systematic work of Hauser [83], it continues in unbridled evolution. This account has attempted to show a) the value of the ortho-lithiated DMG species for the regiospecific preparation of polysubstituted aromatics and heteroaromatics, b) the transition metal catalyzed cross-coupling–DoM symbiosis, c) with the availability of biaryls, the extension of DoM to the DreM tactic with the ensuing benefits for the construction of condensed aromatics, and d) the early indications of DoM links to other modern methodologies of synthetic significance. The decision to concentrate on methods and processes prevented discussion of total syntheses endeavors in which the DoM–DreM–cross-coupling trio plays, to various extents, a key role (Scheme 55). While convenience and reasonable temperatures in large-scale DoM remain to be established, mechanistic insight is advancing [10, 62a], new DMGs are being uncovered and, perhaps most significantly, reactions of other aryl metals species (B, Zn, Mg, Sn), derived by transmetalation from Li and with potential for catalytic processes, appear to be rapidly growing [84]. Although written prognosis is dangerous [85], DoM chemistry continues to o er routes to polysubstituted aromatics and heteroaromatics which, at times, are complementary, at other times, highly advantageous, and often unique compared to classical and previous methodologies. There is no defined rubric for organic synthesis and the DoM-derived chemistry waiting to be discovered will be as useful as the eye and experience of the practitioner.
Acknowledgements
Since the transition from the University of Waterloo to Queen’s (350 km ¼ 219 miles), synthetic chemistry according to DoM continues apace in our laboratories due to a group of lively and dedicated students and postdoctoral fellows. They make going to the lab each day