Phenols intramolecular cyclization

In the synthesis of morphine, bis-cyclization of the octahydroisoqtiinolinc precursor 171 by the intramolecular Heck reaction proceeds using palladium trifluoroacetate and 1,2,2,6,6-pentamethylpiperidine (PMP). The insertion of the diene system forms the rr-allylpalladium intermediate 172, which attacks the phenol intramolecularly to form the benzofuran ring (see Section 1.1.1.3). Based on this method, elegant total syntheses of (-)- and (+ )-dihydrocodei-none and (-)- and ( + )-morphine (173) have been achieved[141]. 

When excess amounts of the HHT of phenyl glycinate 42 were used with diphenyl phosphite, the preferred product was the novel cyclic derivative 45 (2). Presumably, ring-opening of the HHT produced intermediate 43 first, which lost an equivalent of glycinate formaldimine to give 44. The proximity of the activated phenyl carboxylate ester to the N-H in 44 presumably promoted intramolecular cyclization to 45 with loss of phenol (2). 

Compound 10 has also been used to quantify double Lewis acid activation by two cobalt (HI) ions [37]. In 12, the RNA analogue 2-hydroxypropyl-phenyl phosphate (HPPP) is coordinated to the dinu-clear cobalt site. It is well known that in this substrate the hydroxypropyl group is an efficient intramolecular nucleophile. Release of phenol by intramolecular cyclization is much faster than the reaction by nucleophilic attack of bridging oxide, as observed in 11. At pH >8, transesterification rate is linearly dependent on hydroxide concentration since OH" acts as an intermolecular base for the deprotonation of the hydroxypropyl group. The second order rate constant for the hydroxide-dependent cleavage is 4 x 105 times larger than the second-order rate constant for the hydroxide-dependent spontaneous transesterification of hy-droxypropyl-phenyl phosphate. 

A few examples of ester prodrugs that are activated by intramolecular reactions have been mentioned in Sect. 8.3.1, 8.5.1, and 8.5.2. Here, we discuss the special case of some carboxylic acid esters of active alcohols or phenols that are released following an intramolecular cyclization-elimination reaction [168], The general reaction scheme of such reactions is shown in Fig. 8.8. 

Activation by intramolecular cyclization is not restricted to nucleophilic attack by acidic and basic N-atoms, but can also be catalyzed by carboxylate groups. This has been demonstrated with hemiester prodrugs of phenol and paracetamol (8.136, R=H and MeCONH, respectively, Fig. 8.12) [174]. In... 

DMSO resulted in an intramolecular ester condensation (Baker Venkataraman-type rearrangement) to give a Cl 5 phenol the cyclization of which furnished the 0-benzyl-protected flavone-C-glycoside. After deprotection, isoembigenin was obtained. 

A novel hypervalent iodine-induced direct intramolecular cyclization of a-(aryl)alkyl-jS-dicarbonyl compounds 33 has been recently reported (Scheme 15) [30]. Both meta- and para-substituted phenol ether derivatives containing acyclic or cyclic 1,3-dicarbonyl moieties at the side chain undergo this reaction in a facile manner affording spirobenzannulated compounds 34 that are of biological importance. 

Oxidations of variously-substituted 4-alkyl- and 4-alkoxyphenols with BAIB or BTIB in alcoholic solvents provide ready access to alkoxy(alkyl)- and dialkoxycyclohexadienones (Scheme 23) [70-72]. Dienone formation is generally attributed to the capture of aryloxyiodane and/or aryloxenium ion intermediates with the alcohol [73]. Related C-0 bond forming oxidations of phenols with BAIB and BTIB, including intramolecular cyclizations leading to spiro-dienones, are summarized in several reviews [1 - 3,74]. 

A Ti(0-r-Pr)4-mediated intramolecular cyclization of the G( )-C,(i)-anti phenolic aldehyde 575 occurs with total diastereocontrol to afford anti-1,3-dimethyl isochroman 576. Cyclization of the C(l)-C(3)-ry phenolic aldehyde 575 does not occur with the same level of diastereoselectivity and syn-, 3-dimethyl isochroman 577 is formed as an inseparable mixture of diastereomers (Scheme 125) <1999J(P1)3039>. 

Of special interest at present are phenolic compounds bearing suitable substituents which can undergo intramolecular cyclization induced by DIB. For example, whereas 4-hydroxybiphenyls normally gave in methanol the expected quinone ethers, when the aryl group had an o-alkenyl moiety, spiroannulated products resulted, with carbon-carbon bond formation [42] ... 

DIB-induced intramolecular cyclization of phenolic compounds Substrate Product Yield (%) Ref. 

With water, the reaction was carried out in aqueous acetonitrile at 0°C, but the products (p-quinols) were formed in moderate yield better results were obtained with silylated phenols, especially with their tripropylsilyl ethers [13]. For fluorina-tion, pyridinium polyhydrogen fluoride was the source of fluoride this system was effective with a variety of substrates, including a phenolic steroid [15]. As with DIB, intramolecular cyclizations were also performed on several occasions. 

The reaction is considered to involve two mechanistic patterns i.e.,the reactions of arylpalladium intermediates with (a) phenolates at the ortho-positions, this being similar to the a-arylation of ketones (see Sect. 2.2 and Scheme 4), and with (b) thus formed biphenyl-2-ols as in Eq. (56). While the latter proceeds in both DME and xylene, the use of the less polar solvent is essential for the former to occur effectively. However, the intramolecular cyclization of halophenyl-linked phenols is known to occur in DMA [ 122]. It is worth noting that 0-arylation of phenols to give diaryl ethers occurs when bulky phosphine ligands are used (Eq. 60) [26-28]. This may imply that in the aryl(aryloxy)palladium intermediates, reductive elimination to give the ethers is enhanced by the ligands (Scheme 4). 

In the development of the tetrafunctional initiator 24, the spatial shapes of initiator molecules turned out to be crucial for obtaining well-defined initiators [140]. As shown in Scheme 11, 24 is prepared from the corresponding tetrafunctional phenol via a reaction with 2-chloroethyl vinyl ether to attach vinyl ether moieties, followed by addition of trifluoro-acetic acid or hydrogen iodide. In this acid addition, the four vinyl ether groups should be well separated spatially. If the vinyl ether groups are located too close to each other, the treatment with the acid leads to intramolecular cyclization and other side reactions. 

Mostly phenols and phcnolethers are subjected to Mannich reaction, with hctcroaromatic substrates also employed. The first group of compounds has been thoroughly investigated (p. 374 in Ref. 2) mainly as far as intramolecular cyclization with the hydroxy-or alkoxy-activatcd aromatic ring of the tclrahydroisoquinolinc-dcrivcd methyleneim-monium sail is concerned (453, Fig. 171). 

Intramolecular cyclizations are not restricted to attack by a nucleophilic nitrogen (basic amino or acidic amido group). They can also be catalyzed by a nucleophilic oxygen as found in a carboxylate, phenolic, or alcoholic group. Illustration of the catalytic role of a carboxylate group can be found in hemiester prodrugs of phenol (taken as model compound) or paracetamol (Fig. 6 R = H or NHCOCH3, respectively). In addition to enzymatic hydrolysis, three mechanisms of chemical hydrolysis were seen, namely, acid-catalyzed, base-catalyzed, and an intramolecular nucleophilic attack. 

Deoxyschizandrin and its related compound (646 and 647) have a novel dibenzocy-clooctadiene framework, which will be constructed in vivo by oxidative phenol-coupling. Thus, the diarylbutane 648, prepared from ethyl 3,4,5-trimethoxyphenyl ketone, underwent VOFs-mediated oxidation in CH2CI2-TFAA at — 10°C with intramolecular cyclization resulting in the formation of deoxyschizandrin (646) (54%) (Scheme 124). ... 

Amsberry and Borchardt" " have applied Cain s cascade concept to prepare lipophilic polypeptide prodrugs. The amine functionality of the polypeptide is coupled to 2 -acylated derivatives of 3-(2, 5 -dihydroxy-4, 6 -dimeth-ylphenyl)-3,3-dimethylpropionic acid (Figure 36.23). Under simulated physiological conditions the parent amine is regenerated in a two-step process enzymatic hydrolysis of the phenolic ester, followed by a non-enzymatic intramolecular cyclization, leading to the release of the free amine (polypeptide) and a lactone. 

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