Polystyrene cyclization

The example chosen to illustrate this technique of characterization is a sample of a macrocyclic polystyrene cyclized through an acetal function (M = 6900 and MwIMn = 1.5) and represented here ... 

Carbanions stabilized by phosphorus and acyl substituents have also been frequently used in sophisticated cyclization reactions under mild reaction conditions. Perhaps the most spectacular case is the formation of an ylide from the >S-lactam given below using polymeric Hflnig base (diisopropylaminomethylated polystyrene) for removal of protons. The phosphorus ylide in hot toluene then underwent an intramolecular Wlttig reaction with an acetyl-thio group to yield the extremely acid-sensitive penicillin analogue (a penem I. Ernest, 1979). 

The adaptation of the Bischler-Napieralski reaction to solid-phase synthesis has been described independently by two different groups. Meutermans reported the transformation of Merrifield resin-bound phenylalanine derivatives 32 to dihydroisoquinolines 33 in the presence of POCI3. The products 34 were liberated from the support using mixtures of HF/p-cresol. In contrast, Kunzer conducted solid-phase Bischler-Napieralski reactions on a 2-hydroxyethyl polystyrene support using the aromatic ring of the substrate 35 as a point of attachment to the resin. The cyclized products 36 were cleaved from the support by reaction with i-butylamine or n-pentylamine to afford 37. 

The Pictet-Spengler reaction has been carried out on various solid support materials " and with microwave irradiation activation.Diverse structural analogues of (-)-Saframycin A have been prepared by carrying out the Pictet-Spengler isoquinoline synthesis on substrates attached to a polystyrene support. Amine 20 was condensed with aldehyde 21 followed by cyclization to give predominantly the cis isomer tetrahydroisoquinoline 22 which was further elaborated to (-)-Saframycin A analogues. 

The von Richter cinnoline process was further extended to solid-phase synthesis. The route began from benzylaminomethyl polystyrene and the required diverse o-haloaryl resins represented by 21 were prepared from substituted o-haloanilines. A Pd-mediated cross-coupling reaction with 21 and the alkynes provided the alkynylaryl derivatives represented by alkyne 22. The von Richter cyclization reaction with hydrobromic or hydrochloric acid in acetone/HaO and cleavage from the resin occurred in the same step to furnish the cinnoline derivatives 23 in 47-95% yield and 60-90% purity (no yield reported for each entry). 

A one-pot synthesis of thiohydantoins has been developed using microwave heating [72]. A small subset of p-substituted benzaldehydes, prepared in situ from p-bromobenzaldehyde by microwave-assisted Suzuki or Negishi reactions, was reacted in one pot by reductive amination followed by cyclization with a thioisocyanate catalyzed by polystyrene-bound dimethyl-aminopyridine (PS-DMAP) or triethylamine, all carried out under microwave irradiation, to give the thiohydantoin products in up to 68% isolated yield (Scheme 16). 

To cyclize resin bound diene substrates by RCM in this specific case, the pseudo dilution conditions within the polystyrene matrix may favor ring closure over competing polymerization of the substrate via ADMET... 

Cyclization of 1,6- and -enynes.1 This combination produces an unstable Ni-Cr complex that can catalyze cyclization of enynes. The usefulness is markedly improved by coordination to a cross-linked polystyrene. The polymeric Ni-Cr complex (1) has several advantages over Pd(II) catalysts used previously for this cyclization, particularly the ability to effect cyclization of enynes to both five- and six-membered rings. 

Moreover, during the course of our studies, N- I -(4,4-di-methyl-2,6-dioxocyclohex-1 -ylidene)ethyl]hydroxylamine, Dde-NHOH was also successfully coupled with 2-chlorotrityl chloride polystyrene in excellent efficiency.1 The novel compound Dde-NHOH was prepared, in 51% yield, by reacting 2-acetyldi-medone with hydroxylamine in MeOH THF at 5°C for 3h, followed by recrystallization from ice-cold hexane the major side-product, which increases in quantity over prolonged reaction time, was the predicted cyclized derivative 3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1,2-benzisoxazole. 

Hulme et al. describes the novel use of ethyl glyoxalate in the Ugi-4CR to create ketopiperazines [31]. iV-alkylated/Boc-protected ethylene diamines 60 reacted with an isocyanide 61, a carboxylic acid 62, and ethyl 2-oxoacetate 63 in stoichiometric ratio of 1/1/1/1.25 in methanol. Deprotection and cyclization is completed using TFA and MP-carbonate (a macroporous polystyrene... 

The reactions of A -BOC-protected a-amino acids 424 and diazomethane in the presence of iV-methylmorpholine-polystyrene and isobutyl chloroformate resulted in formation of diazoketones 425, which, on treatment with indium(lll) triflate, were cyclized to 4-substituted-tetrahydro-l,3-oxazine-2,5-diones 426 in high overall yields (Scheme 82) <2006TL7969>. 

Intramolecular Dieckmann cyclization of polystyrene-bound pimelates has been used to prepare (l-keto esters (Entry 4, Table 3.41). Oxidative cleavage reactions leading to the formation of aldehydes include the ozonolysis of resin-bound alkenes, the periodate-mediated cleavage of 1,2-diols, and the oxidation of Wang resin derived ethers (Entries 5-7, Table 3.41). 

The reaction of suitably functionalized alkenes with polystyrene-bound selenyl bromide can lead to cyclization of the alkene by C-C, C-O, or C-N bond formation with simultaneous attachment to the support. The cyclic product can then be released from... 

Figure 9.2. Oxidative cyclization of alkenes with polystyrene-bound selenyl bromide [8,9,12-14].

Isothioureas can be prepared on insoluble supports by S-alkylation or S-arylation of thioureas (Entry 7, Table 14.6). Further methods for the preparation of isothioureas on insoluble supports include the N-alkylation of polystyrene-bound, A/,/V -di(alkoxy-carbonyl)isothioureas with aliphatic alcohols by Mitsunobu reaction (Entry 7, Table 14.6) and the addition of thiols to resin-bound carbodiimides [7]. Resin-bound dithio-carbamates, which can easily be prepared from Merrifield resin, carbon disulfide, and amines [76], react with phosgene to yield chlorothioformamidines, which can be converted into isothioureas by treatment with amines (Entry 8, Table 14.6). The conversion of support-bound a-amino acids into thioureas can be accompanied by the release of thiohydantoins into solution (see Section 15.9). The rate of this cyclization depends, however, on the type of linker used and on the nucleophilicity of the intermediate thiourea. 

Dihydropyrroles have recently become readily available by ring-closing metathesis. For this purpose, N-acylated or N-sulfonylated bis(allyl)amines are treated with catalytic amounts of a ruthenium carbene complex, whereupon cyclization to the dihydropyrrole occurs (Entries 6 and 7, Table 15.3 [30,31]). Catalysis by carbene complexes is most efficient in aprotic, non-nucleophilic solvents, and can also be conducted on hydrophobic supports such as cross-linked polystyrene. Free amines or other soft nucleophiles might, however, compete with the alkene for electrophilic attack by the catalyst, and should therefore be avoided. 

Halocinnolines can be prepared by treatment of polystyrene-bound (2-alkynyl-phenyl)triazenes with hydrogen chloride or hydrogen bromide (Entry 6, Table 15.27). This reaction involves the initial release of 2-alkynylphenyldiazonium salts into solution, which then cyclize to the halocinnolines. The corresponding 4-hydroxycinnolines are obtained as by-products in variable amounts. Hydrogen fluoride or hydrogen iodide do not lead to the formation of cinnolines [324]. 

Solid-phase syntheses of triazines (Table 15.32) include the cyclocondensation of polystyrene-bound isothiuronium salts with /V-(cyano)iminodithiocarbonates and the cyclization with simultaneous cleavage from the support of derivatives of a-amino acid hydrazides (Table 15.32). (Benzylthio)triazines, such as those listed in Table 15.32 (Entries 1 and 2), have been cleaved from a support by oxidation to sulfoxides or sul-fones with N-benzenesulfonyl-3-phenyloxaziridine, followed by nucleophilic cleavage with primary or secondary aliphatic amines or with electron-rich anilines (see Section 3.8). 

Benzazepinones can be prepared on cross-linked polystyrene by intramolecular Heck reaction (Entry 6, Table 15.35). In the presence of sodium formate, the intramolecular Heck reaction of iodoarenes with alkynes yields methylene benzazepinones (Entry 7, Table 15.35). Surprisingly, when this reaction was performed in solution, the main product (65% yield) was a dehalogenated, non-cyclized benzamide. In the synthesis on cross-linked polystyrene, however, this product was not observed [419]. 

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