Intramolecular Boger reactions

Several examples of intramolecular Boger reactions toward the synthesis of pyridine-containing heterocyclic systems were reported by the Taylor group and the Snyder group, For instance, intramolecular cyclization of triazine 219, after loss of nitrogen, afforded 220. Alternatively, triazine 221 generated bicyclic systems 222, which was then oxidized to 223. ... 

Boger and co-workers successfully used the intramolecular Ullmann reaction to prepare 23, an intermediate in their total synthesis of piperazinomycin (4) (Scheme 6). In this case, the C9 center of the piperazine-2,5-dione substrate did not epimerize, and the cyclization proceeded smoothly and in high yield 2 ... 

Scheme 6 Boger Intramolecular Ullmann Reaction with Piperazine-2,5-dionel28 ...

Boger and co-workers have studied the intramolecular Ullmann reaction extensively. Some representative examples are shown in Table 3. For substrates in which the N10 site is not methylated, the reaction is complicated by intramolecular N-acylation of the N10—Cu amide by the C12 carbamate. In some cases, the generation of this byproduct could be suppressed by using freshly dried and degassed solvent with purified CuBr-DMS complex. 10 However, in other cases, the byproduct was still produced and the yield of the desired product suffered accordingly. 27 ... 

Boger and co-workers used the intramolecular SNAr reaction on o-fluoronitro substrate 24 with NaH to prepare 25. Compound 25 was then converted in three steps into phenol 26, the cycloisodityrosine subunit of deoxybouvardin (2) and RA-VII (3) (Scheme 7). 24,25 Small amounts of the C9 epimer were also detected in the cyclization reaction, and when K2C03 was employed as the base, this epimer was formed nearly exclusively. 25 ... 

S CONTENTS Introduction to the Series An Editor s Foreword, Albert Padwa. Preface, Dennis P. Curran. Intramolecular 1,3-Dipolar Cycloaddition Chemistry, Albert Padwa and Allen M. Schoffstall. Stereochemical and Synthetic Studies of the Intramolecular Diels-Alder Reaction, William R. Roush. Thermal Reaction of Cyclopropenone Ketals, Key Mechanistic Features, Scope and Application of the Cycloaddition Reactions of Cyclopropenone Ketals and p - Delocalized Singlet Vinyl Carbenes Three Carbon 1,1-/1,3-Dipoles, Dale L. Boger and Christine E. Brotherton-Pleiss. Index. 

The Diels-Alder reaction with inverse electron demand has been one of the most intensively studied reactions of 1,2,4-triazines. In this reaction 1,2,4-triazines behave as electron-deficient dienes and react with electron-rich dienophiles to give, generally, pyridines (see Houben-Weyl, Vol. E7b, p 471 ff). [4 + 2] Cycloadditions of 1,2,4-triazines have been observed with alkenes, alkynes, strained double bonds, electron-rich double and triple bonds, but in a few cases also with electron-deficient alkynes C—N double and triple bonds can also be used as dienophiles. In addition to intermolecular Diels-Alder reactions, intramolecular [4 + 2] cycloaddition reactions of 1,2,4-triazines have also been studied and used for the synthesis of condensed heterocyclic systems. A review on the intermolecular Diels-Alder reaction was published by Boger and Weinreb 14 Sauer published a review on his studies in 1992,381 and E. C. Taylor published a summary of his own work on intramolecular Diels-Alder reactions in 1988.382... 

A stoichiometric, intramolecular variant of the Buchwald-Hartwig amination was reported by D, L. Boger and J, S. Panek as early as 1984 in the synthesis of lavendamycin.7 They showed that 1.2 equiv of Pd(PPh3)4 could effect the intramolecular cyclization of an amino bromide 1 to the desired heterocycle 2. The absence of an external base to sequester the generated HBr rendered this reaction super-stoichiometric in palladium. 

In 1988, Boger and co-worker found that the intramolecular free-radical cyclization reactions of acyl radicals generated from selenol esters proceeded efficiently, suppressing competing reduction and decarbonylation (Eq. 47) [98]. 

There were a few isolated examples of coupling reactions that form C—and C—S bonds.f Tunney and Stille had reported the Pd-catalyzed formation of the C—P bonds in aromatic phosphines, and several groups had reported the formation of C—S bonds in sulfides using catalysts based on both palladium and nickel. In addition there were suggestions that simple procedures for C—bond formation could be developed and that palladium complexes could act as catalysts for C—N bond-forming cross-coupling processes. For example, Boger and co-workers used stoichiometric amounts of palladium to form aromatic C—N bonds in a /3-carbolide natural product by an intramolecular process (Eq. 1). Perhaps more closely related to the work discussed in detail here. 

Scheme 3. Use of 1,2,4,5-tetrazine 8 in an inverse-electron-demand Diels-Alder reaction followed by an intramolecular 1,2-diazine/alkyne cycloaddition in Boger s total synthesis of (-i-)-CC-1065 (15).

Boger and coworkers reported the first total synthesis of chloropeptin II and later its transformation into chloropeptin I (2009JA16036). The key step to this total synthesis was macrocycHzation of peptide 31 by an intramolecular Larock indole heteroannulation. This intramolecular reaction between a substituted 2-bromoaniline with a removable terminal alkyne substituent afforded simultaneous regioselective indole ring formation and macrocycli-zation. The TES substituent of the alkyne dictates indole cyclization regio-selectivity (Scheme 20). 

On the contrary, while working in the synthesis of the alkaloid ru-brolone, Boger and Zhu (91TL7643) have found 0-alkyl a,/3-unsaturated oximes 98 to participate as effective 4ir components of an intramolecular Diels-Alder reaction with an electron-deficient dienophile. Thus, 98 was prepared from butane-1,4-diol and heated in triisopropylbenzene to furnish 2-pyrindine derivatives 99 by virtue of in situ elimination of alcohol (Scheme 25). 

The first example of intramolecular Pd-mediated N-arylation was reported by Boger, who employed this reaction for constmction of the aromatic core of lavendamydn methyl ester. See ... 

Nitrogen-containing heterocycles are also available via intramolecular hetero Diels-Alder reactions. Williams employed an aza diene to prepare a complex polycyclic synthetic intermediate in his synthesis of versicolamide B. Boger reported a tandem intramolecular hetero Diels-Alder/l,3-dipolar cycloaddition sequence for the synthesis of vindorosine. Cycloaddition precursor 137 undergoes an inverse electron demand Diels-Alder reaction to yield 138. This compound decomposes via a retro dipolar cycloaddition to generate nitrogen gas and a 1,3-dipole that completes the cascade by reacting with the indole alkene to afford 139. Seven more steps enable the completion of vindorosine. ... 

The propagation steps of these chain reactions are given in Scheme 12, which represents a plausible mechanistic rationalization of the results. That is, Bu Sn radical, initially generated by photolysis of ditin, reacts with alkyl halide to form an alkyl radical that attacks the allyl sulfide (Sh2 process) to give the desired product and thiyl radical. The displacement reaction from ditin gives the Bu Sn radical, thus completing the cycle of this chain reaction. An intramolecular version of this process (equation (43)) has been introduced by Ueno et ai [89a] and later applied by Boger and Wysocki as a key step in multistep synthesis of some natural products [89b]. 

In 1980s, Boger et al. reported pioneering work on carbazole synthesis by using palladium-mediated intramolecular N-arylation. The reaction of 4-(2-bromophenyl)pyridin-3-ylamines 6 in the presence of stoichiometric palladium complex gave P-carboline 7 (Scheme 23.3) [6]. This synthetic strategy was applied to the syntheses of other carbazole derivatives, 8 and 9, which were the synthetic intermediates for neuropeptide Y Y1 antagonists and clausenamine A, respectively (Scheme 23.3) [7]. 

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