Scheme 1.1 Stoermer & Kahlert – Unexpected rearrangement via “benzofuryne” ...3 Scheme 1.2 Bachmann & Clarke – Proposal for a diradical intermediate ...4 Scheme 1.3 Lüttringhaus & Sääf – Rearrangements of diphenyl ether...5 Scheme 1.4 Wittig – Proposal for a zwitterionic intermediate...6 Scheme 1.5 Unexpected rearrangements during nucleophilic aromatic substitution ...7 Scheme 1.6 Benseker – Proposed rearrangement during nucleophilic aromatic
Substitution...8 Scheme 1.7 Roberts – Nucleophilic aromatic substitution via a “benzyne” intermediate ...9 Scheme 1.8 Roberts – proposed rearrangement during amination via aziridine 43
or diamine 44...12 Scheme 1.9 Results in support of the aryne model ...13 Scheme 1.10 Microdensitometer tracings showing absorbance by gaseous products
of photolysis of phenyldiazonium-2-carboxylate...14 Scheme 1.11 Infrared spectrum of benzyne...16 Scheme 1.12 Methods for generating benzyne...19 Scheme 1.13 Inductive effects upon regioselectivity in nucleophilic aromatic
substitution reactions...22 Scheme 1.14 a) Competing nucleophilic additions to 3- and 4-substituted arynes
b) Substituent effects on regioselectivity
c) Reactivity factor vs. |σ’| in dimethylamine where represents
3-substituted arynes and represents 4-substituted arynes. ...24
CHAPTER 2
Scheme 2.1 Annulation of benzyne via Diels–Alder cycloaddition with furan...37 Scheme 2.2 Aryne annulation via [4 + 2] cycloaddition ...39 Scheme 2.3 Aryne annulation via [3 + 2] cycloaddition ...41 Scheme 2.4 Aryne annulation via nucleophilic addition and cyclization ...43 Scheme 2.5 Aryne annulation via [2 + 2] cycloaddition ...45 Scheme 2.6 Aryne annulation via insertion into activated σ-bonds ...47 Scheme 2.7 Transition metal-catalyzed aryne annulations...49
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Scheme 2.8 Transition metal-catalyzed [2 + 2 + 2] cycloadditions ...51 Scheme 2.9 a) Proposed indoline synthesis via aryne annulation
b) Bioactive indoline-containing natural products ...53 Scheme 2.10 Orthogonal mechanisms for indoline formation via aryne annulation ...57 Scheme 2.11 Unexpected formation of an isoquinoline through an alternative
aryne annulation...58 Scheme 2.12 Arylation of N-vinyl acetamide ...64 Scheme 2.13 Total synthesis of papaverine ...65 Scheme 2.14 a) Synthesis of isoquinolones via aryne annulation
b) Bioactive isoquinolone- and 3,4-dihydroisoquinolone-containing
natural products...68
CHAPTER 3
Scheme 3.1 Proposed biosynthesis of quinocarcin...188 Scheme 3.2 Williams’ proposed mechanism for superoxide formation via
self-redox disproportionation of quinocarcin...197 Scheme 3.3 Fukuyama’s synthesis of (±)-quinocarcin ...199 Scheme 3.4 Garner’s synthesis of (–)-quinocarcin ...201 Scheme 3.5 Terashima’s synthesis of (–)-quinocarcin...203 Scheme 3.6 Myers’ synthesis of tetrahydroisoquinoline 313...205 Scheme 3.7 Myers’ synthesis of aminonitrile 318...206 Scheme 3.8 Myers’ completion of (–)-quinocarcin ...207 Scheme 3.9 Zhu’s synthesis of (–)-quinocarcin...209 Scheme 3.10 Danishefsky’s synthesis of (±)-quinocarcinol methyl ester...211 Scheme 3.11 Hirata’s approach toward quinocarcin...212 Scheme 3.12 Weinreb’s approach toward quinocarcin...213 Scheme 3.13 Joule’s approach toward quinocarcin ...214 Scheme 3.14 Williams’ synthesis of (±)-quinocarcinamide ...216 Scheme 3.15 McMills’ approach toward quinocarcin...217
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CHAPTER 4
Scheme 4.1 a) Pictet–Spengler condensation b) Regioselective aryne annulation
c) Aryne annulation approach to an isoquinoline intermediate
en route to quinocarcin...229 Scheme 4.2 Retrosynthetic analysis of quinocarcin...230 Scheme 4.3 a) Synthesis of N-methyl oxidopyrazinium iodide 387
b) Dipolar cycloaddition ...231 Scheme 4.4 Reductive opening of N-Boc lactam 389 en route to lemonomycin ...232 Scheme 4.5 Proposed coordination conformations leading to lactam 382 and
N-acyl enamine 380...235 Scheme 4.6 Attempted aryne annulation using N-acyl enamine 380...236 Scheme 4.7 Proposed mechanisms for the formation of isoquinoline 392...237 Scheme 4.8 Synthesis of N-benzyl oxidopyrazinium bromide 401 and
dipolar cycloaddition ...239 Scheme 4.9 Auxiliary-mediated diastereoselective dipolar cycloaddition ...240 Scheme 4.10 Advancement of diazabicycle 405a to N-acyl enamine 407...241 Scheme 4.11 Synthesis of 3-methoxy-2-(trimethylsilyl)phenyl triflate (108)...242 Scheme 4.12 Synthesis of isoquinoline 411 via aryne annulation...242 Scheme 4.13 a) One-step homogeneous reduction of isoquinoline 411
b) Two-step reduction of isoquinoline 411 to tetrahydroisoquinolines
415a and 415b...246 Scheme 4.14 Models for diastereoselective reduction of isoquinoline 411...247 Scheme 4.15 Completion of (–)-quinocarcin ...249 Scheme 4.16 Retrosynthetic analysis of jorumycin...250 Scheme 4.17 Proposal for the synthesis of jorumycin via bis-isoquinoline 430...252 Scheme 4.18 Retrosynthetic analysis of ecteinascidin 743...253
APPENDIX 2
Scheme A2.1 Synthesis of the N-acyl enamine ...283 Scheme A2.2 Synthesis of 3-methoxy-2-(trimethylsilyl)phenyl triflate ...283 Scheme A2.3 Aryne annulation and completion of (–)-quinocarcin ...283
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APPENDIX 4
Scheme A4.1 Cyanocycline A and naphthyridinomycin...317 Scheme A4.2 Retrosynthetic analysis of cyanocycline A ...320 Scheme A4.3 Synthesis of silyl ether 438...321 Scheme A4.4 Oxidative amination of styrene 438...322 Scheme A4.5 Synthesis of oxazoline 437...323 Scheme A4.6 Synthesis of benzylic ketone 457 via aldehyde 454...324 Scheme A4.7 Reductive amination of a model benzylic ketone...325 Scheme A4.8 Proposed Petasis three-component coupling reaction ...326 Scheme A4.9 Petasis three-component coupling via iminium boronate 466...326 Scheme A4.10 a) Evaluating the Petasis reaction with aryl boronic acid 462
and amine 460
b) Evaluating the Petasis reaction with amido aldehyde 474...327 Scheme A4.11 Proposed advancement of benzylic amine 436...329 Scheme A4.12 Proposed completion of cyanocycline A...330
CHAPTER 5
Scheme 5.1 Discovery of the aryne acyl-alkylation reaction...365 Scheme 5.2 Total synthesis of (+)-amurensinine...372 Scheme 5.3 Total synthesis of (–)-curvularin...375 Scheme 5.4 a) Synthesis of β-ketoester 547
b) Synthesis of ortho-silyl aryl triflate 550...376 Scheme 5.5 a) Model acyl-alkylation using ortho-silyl aryl triflate 71
b) Aryne acyl-alkylation and strategy for the completion of
integrastatins A and B...377 Scheme 5.6 a) Bentley’s synthesis of 3-hydroxyisoquinolines and 2-hydroxy-1,4-
naphthoquinones from 2-acylhomoveratric esters
b) Selected previous syntheses of functionalized isoquinoline and
naphthoquinone motifs via transition metal-catalyzed cross coupling...379 Scheme 5.7 Aryne acyl-alkylation followed by condensation with ammonia
or intramolecular condensation and aerobic oxidation ...380 Scheme 5.8 a) Synthesis of 1,3-diarylisoquinoline 578
b) Synthesis of QUINAP ...385
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Scheme 5.9 Synthesis of 2-hydroxy-1,4-naphthoquinones via one-pot aryne
acyl-alkylation, intramolecular condensation, and aerobic oxidation...386
CHAPTER 6
Scheme 6.1 Laurent & Gerhardt – Synthesis of α-aminobenzonitrile...511 Scheme 6.2 a) Linear synthesis of a product containing four components
b) One-step synthesis via four-component reaction
c) Multicomponent reaction approach to library synthesis...512 Scheme 6.3 Benzyne as a relay species in multicomponent reactions...513 Scheme 6.4 Meyers – Synthesis of 2,3-disubstituted benzoic acid derivatives...514 Scheme 6.5 Three-component synthesis of phenanthridines (601) and xanthenes (605)
using two aryne equivalents...515 Scheme 6.6 Three-component synthesis of nitrogen-containing products using three
distinct components ...517 Scheme 6.7 Transition metal-catalyzed three-component aryne reactions ...520 Scheme 6.8 Four-component synthesis of anthracenamines (635) and isoquinolines
(642) using multiple aryne equivalents ...522 Scheme 6.9 a) Three-component synthesis of alcohols 648a and 648b en route to
ent-clavilactone B
b) Four-component synthesis of tricycle 634 en route to
dehydroaltenuene B ...524 Scheme 6.10 Passerini three-component synthesis of α-acyloxyamides ...525 Scheme 6.11 Proposed benzyne analogue of the Passerini three-component coupling ...526 Scheme 6.12 Attempted three-component coupling of benzyne, tert-butyl isocyanide,
and carboxylate salts ...527 Scheme 6.13 Revised approach to the synthesis of ortho-ketobenzamides via
three-component coupling of arynes, isocyanides, and esters...528 Scheme 6.14 a) Attempted three-component coupling of benzyne, tert-butyl isocyanide,
and ethyl acetate
b) Three-component coupling of benzyne, tert-butyl isocyanide, and
phenyl acetate ...529 Scheme 6.15 a) Potential equilibration between iminoisobenzofuran and isoindolinone
isomers
b) X-ray crystal structure of phenoxy iminoisobenzofuran 683p...533 Scheme 6.16 Two-step synthesis of dibenzoketocaprolactams ...535 Scheme 6.17 a) Proposed three-component coupling of arynes, isocyanides, and a
two-carbon relay species
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b) Three-component coupling of benzyne, tert-butyl isocyanide, and
methyl propiolate ...537 Scheme 6.18 a) Hydrolysis of iminoindenone 698a
b) Indenone-derived natural products ...539 Scheme 6.19 Three-component coupling of benzyne, tert-butyl isocyanide, and
quinones ...540