Intramolecular base-induced

The intramolecular base-induced ring transformation of 3-phenacyl-2,4-thiazol-idinediones 105 with sodium hydroxide or triethylamine smoothly proceeds to give 5-aryl-2(3/7)-oxazolones 108 (Fig. 5.27). 

A particularly useful application of the types of reaction described above is the formation of a ring by intramolecular base-induced condensation of a methylisoxazole (or isoxazolium salt) with a conveniently placed carbonyl function. The required starting materials are often conveniently prepared from the 4-chloromethyl derivatives.236 The initial products can undergo various transformations via cleavage of the isoxazole ring. One of the earliest examples, which illustrates the principles well, is shown in Scheme 28. 

The Nuphar quinolizidine alkaloid nupharotuline (181) and its 7-epi analogue (182) have been prepared in a sequence featuring as the key step the intramolecular, base-induced opening of an epoxide intermediate, in turn available from the Beckmann rearrangement product of a cyclopentane derivative (Scheme 30) <80JOC3644). 

The final two stages are very straightforward. Oxidative scission of the C3-C5 double bond in 6 with ozone provides triketone 5 which, without purification, is subjected to a base-induced intramolecular aldol/dehydration reaction. The crystalline product obtained from this two-step sequence (45 % overall yield) was actually an 85 15 mixture of ( )-progesterone and a diastereomeric substance, epimeric at C-17. Two recrystallizations afforded racemic progesterone [( )-(1)] in diastereomerically pure form. 

A sequence of straightforward functional group interconversions leads from 17 back to compound 20 via 18 and 19. In the synthetic direction, a base-induced intramolecular Michael addition reaction could create a new six-membered ring and two stereogenic centers. The transformation of intermediate 20 to 19 would likely be stereoselective substrate structural features inherent in 20 should control the stereochemical course of the intramolecular Michael addition reaction. Retrosynthetic disassembly of 20 by cleavage of the indicated bond provides precursors 21 and 22. In the forward sense, acylation of the nitrogen atom in 22 with the acid chloride 21 could afford amide 20. 

The intramolecular Michael addition11 of a nucleophilic oxygen to an a,/ -unsaturated ester constitutes an attractive alternative strategy for the synthesis of the pyran nucleus, a strategy that could conceivably be applied to the brevetoxin problem (see Scheme 2). For example, treatment of hydroxy a,/ -unsaturated ester 9 with sodium hydride furnishes an alkoxide ion that induces ring formation by attacking the electrophilic //-carbon of the unsaturated ester moiety. This base-induced intramolecular Michael addition reaction is a reversible process, and it ultimately affords the thermodynamically most stable product 10 (92% yield). 

Intramolecular cyclization can yield fluorinated phenoxazines by a Smiles rearrangement (86IZV1855) and 2,3-dihydro-l,4-benzodioxins by a base-induced reaction [81JFC(18)483]. 

Other multi-heteroatom systems. Triheterocycles with a tetrazine as the central ring can be prepared by a base-induced intramolecular condensation reaction of the hydrazone-substituted pyrimidone shown in Equation (79) C1997JCM154, 1997JRM1041>. 

This system was described in one report and has been synthesized by a copper-assisted cycloisomerization of alkynyl imines. The authors proposed the following mechanism at first, 372 could undergo a base-induced propargyl-allenyl isomerization to form 373 next, coordination of copper to the terminal double bond of the allene (intermediate 374) would make it subjected to intramolecular nucleophilic attack to produce a zwitterion 375. The latter would isomerize into the more stable zwitterionic intermediate 376, which would be transformed to the thiazole 377 (Scheme 55) <2001JA2074>. 

Intramolecular [4+2]-cycloaddition reactions, which involve base-induced isomerization of a propargyl ether to an allenyl ether, have been extensively studied. Treatment of 157 with a base caused an intramolecular Diels-Alder reaction of the intermediate allenyl ether to give tricyclic compounds 158 [131]. An asymmetric synthesis of benzofuran lactone 159 was achieved by an analogous procedure [132],... 

Thionyl chloride undergoes a cyclization reaction with ketones. Enoli-zation of the intermediate sulfenyl chloride, followed by the base-induced intramolecular nucleophilic displacement reaction, produces the thietanone... 

Hexane-1,6-diol was found to undergo an oxidation-cyclization process at elevated temperatures (250 °C) in the presence of a Cu-Cr catalyst supported on kieselguhr to yield 2,3,4,5-tetrahydrooxepin (68) (65JOC335). The final stage of the latter reaction involves a dehydration of the hemiacetal 2-hydroxyoxepane (75) as indicated in equation (38). An alternative type of base-induced cyclization (equation 39) involving intramolecular nucleophilic attack has been used in the synthesis of 4-ethoxycarbonyI-2,3,6,7-tetra-hydrooxepin (153) (73JOC1767). 

Few examples have been described of nucleophilic cleavage of carbonate- or carbamate-linked alcohols from insoluble supports. A serine-based linker for phenols releases the phenol upon fluoride-induced intramolecular nucleophilic cleavage of an aryl carbamate (Entry 2, Table 3.36). A linker for oligonucleotides has been described, in which the carbohydrate is bound as a carbonate to resin-bound 2-(2-nitrophen-yl)ethanol, and which is cleaved by base-induced 3-elimination (Entry 3, Table 3.36). Trichloroethyl carbonates, which are susceptible to cleavage by reducing agents such as zinc or phosphines, have been successfully used to link aliphatic alcohols to silica gel (Entry 4, Table 3.36). These carbonates can also be cleaved by acidolysis (Table 3.22). 

In a very significant development, the parent 277-azepine 85 was prepared for the first time (Scheme 10) <1995AGE1469>. A ring construction was adopted involving A-BOC deprotection of 84 followed by treatment with strong base to afford 85 after intramolecular imine formation and base-induced elimination of acetate. While the yield was only 1%, the azepine was sufficiently stable at 25 °C for 48 h to allow for H and 13C NMR spectroscopic characterization. 

In a different type d ring-construction process, base-induced intramolecular cyclization of the ester derived from the acids 242 gave the 1-benzazepines 243 in moderate to excellent yields (Scheme 31). The yields were affected by the nature of the substituent group R1 on nitrogen, with the best yield being obtained with an iV-benzyl derivative (243 R1 =CH2Ph, R2 = Br, R3 = Et) <2004TL9335>. 

A new method for a-phenol annulation involving base-induced cycloaromatization of readily available 4-bis (methylthio)-3-buten-2-one 114 was applied to 3,4-dihydro-l-benzothiepin-5(2//)-one 113 (Scheme 14) <2002JOC5398>. Equimolar quantities of the benzothiepinone 113 and 114 in the presence of sodium hydride were stirred in dimethylformamide (DMF) at 25 °C. Treatment of the reaction mixture with/>-toluenesulfonic acid in refluxing benzene furnished the phenol-annulated dihydrothiepine 116 in 62% yield. The reaction sequence involved formation of conjugate addition-elimination adduct 115, followed by intramolecular aldol condensation and cycloaromatization, affording 116. 

In a related Sequence of reactions, cyclization of 549 with POCl3 and then aqueous workup produced the carbinolamine 552. N-Methylation of 552 with methyl iodide followed by treatment with strong base resulted in an intramolecular Cannizzaro process to deliver the intermediate 553, which was converted to ( )-tazettine (397) by tosylation and base-induced elimination (215). 

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