Tandem intermolecular-intramolecular synthesis

Silver carbonate, when used as the base in the dehydrochlorination of hydrazonyl chlorides, has a unique effect in enhancing yields and favoring particular modes of reaction, for example, in the promotion of the tandem intermolecular-intramolecular synthesis of macrocycles 302 discussed in Section 7.3.2.4 (73). Such differences have led to some investigations into the mechanism of its reaction. In this work (74), the hydrazonyl chloride 134 was reacted with 2 M equiv of silver carbonate in the presence of various allylic alcohols. 

The Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

An interesting tandem intermolecular/intramolecular hydroamination reaction of cycloheptatriene with substituted anilines has been developed by Hartwig for the synthesis oftropene derivatives [34]. As shown in Eq. (1.14), the coupling of 30 with 31 provided 32 in 73% yield. The mechanism of this transformation is believed to involve acid-assisted formation of an q -pentadienylpalladium complex 33, which is then captured by the aniline nucleophile to afford the allylpalladium intermediate 34. Intramolecular attack of the aniline nitrogen on the allylpalladium moiety affords the observed heterocycle. 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

He and coworkers showed that a simple phosphine-coordinated AuOTf salt could be used for both cyclohydroamination and intermolecular hydroamination with specifically tosyl-protected amine substrates [255]. The combination of tandem intermolecular and intramolecular hydroamination results in the efficient synthesis of substituted pyrrohdine products (Scheme 15.57). Labehng studies support outer-sphere amine addition, although observations that show sensitivity to amine pKa suggest once again that in sitw-generated acid may not be innocent in this reaction [251]. 

Scheme 15.57 Pyrrolidine synthesis through Au-catalyzed tandem intermolecular and intramolecular hydroamination.

Several reports describe a tandem intermolecular Nicholas/intramolecular Nicholas reaction sequence for the synthesis of cyclic compounds. Green employed this strategy for the synthesis of indolophanetetrayne cobalt complexes. Dimerization of substituted indole 50 with boron trifluoride furnishes target 51 in 55% yield. Green also prepared a cobalt-complexed cycloheptyne via tandem intermolecular Nicholas/intramolecular Nicholas reactions. Boron trifluoride promotes combination of cobalt-alkyne complex 52 with allyltrimethylsilane to first yield intermolecular product 53 and then the desired intramolecular product 54. ... 

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I],... 

A tandem sequence of double [2,3]-sigmatropic rearrangement-six-electron electro-cyclization-4 + 2-cycloaddition has been shown to convert acyclic ene-bis(propargyl alcohols) such as (71), via the corresponding bis-sulfenic ethers such as (72), into anthracene (with an intermolecular final cycloaddition) or phenanthrene or related (with an intramolecular cycloaddition) skeletons. The sequence is illustrated in Scheme 12 for synthesis of a steroid skeleton, estra-l,3,5(10)-trien-17-one (73).81... 

Z-tamoxifen 403 tandem cyclization 290, 295 tandem Heck reaction-anion capture 253-4 tandem Heck reaction-phenoxide capture 253 tandem Heck reactions 251, 252-4 tandem intramolecular Heck-intermolecular Stille cross-coupling 255 taxol 140, 143,243,245 ( )-tazettine 146,234 telomerization 352 telomerization products 343, 345 template effect 140 teraconic anhydride 468 terminal acetylenes, synthesis of 216-20 terminal alkynes 6, 213 terminal 2,2-diorgano-l-aIkcnylboronates 51 terminal diynes 207 ternary complex 444 ternary coupling 177... 

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