Substituted furan derivatives

There are several reports scattered in the literature of the retarding effect of simple furan derivatives in the polymerization of a specific monomer. Hardy69, U6 found that furan, 2-furoic acid and its esters, and 5-substituted-2-furoie acids were strong retarders in the radical polymerization of vinyl acetate, but did not act likewise with styrene. He proposed that as a result of the reactions of the free radicals with the furan derivatives, dihydro- and tetrahydrofurans would form, but he did not produce any evidence to support these speculations. Clarke, Howard and Stock-... 

The wide variation in the entropy factors for both the substituted phenyl and heterocyclic compounds and in particular for the methoxyphenyl and furan derivatives was considered to be strong evidence for solvent effects being predominant in determining the activation entropy. Consequently, discussion of the substituent effects in terms of electronic factors alone requires caution in this reaction. Caution is also needed since rates for the substituted phenyl compounds were only determined over a 20 °C range. The significance of entropy factors has also been indicated by the poor correlation of the data of the electrophilic reactivities of the heterocyclic compounds, as derived from protodemercuration, with the data for other electrophilic substitutions and related reactions572. 

Rotational equilibria of 2-carbonyl substituted thiophene and furan derivatives were calculated and show that the 2-substituent favors the anti-isomer in thiophene <96MI199>. NMR shifts of 35 alkyl 3-hydroxythiophene-2-carboxylates and 3-alkylamino-l-(3-thienyloxy)-2-propanols have been compiled and analyzed <96HC17>. 

Replacement of the ethanolamine head group is also well tolerated. Substitution with a cyclopropyl (243) [37], allyl (244) or propargyl group (245) [164] all led to an increase in binding affinity compared to AEA. Replacement of the head group with aromatics is also allowed. The phenyl derivative (246) retains affinity at the CBi receptor [37], whereas the 2-substituted A-methyl pyrrole (247) has a 2-fold improved affinity compared to AEA [167]. Interestingly, the 3-substituted furan derivative (23) that has micromolar affinity for the AEA transporter (see above) does not bind to the CBi receptor, but has good affinity for the CB2 receptor [167]. These results are summarised in Table 6.20. 

These cycloadducts, at their most elementary level, are excellent intermediates for the synthesis of 3-substituted furan derivatives. For example, Kawanisi and coworkers reported a synthesis of perillaketone 174 in which the critical step was a Paterno-BUchi photocycloaddition between furan and 4-methylpentanal in the presence of methanesul-fonic acid (Scheme 39)82. This reaction furnished two initial photoadducts, 172 and 173. The unexpected product 173 presumably arises from a Norrish Type II cleavage of 4-methylpentanal to give acetaldehyde, and subsequent cycloaddition with furan. The desired cycloadduct 172 was then converted uneventfully to 174 via acid-catalyzed aromatization and oxidation. 

The synthesis of benzo[Z>]furan derivatives has become a very active field because these molecules have been recently identified as having a variety of biological activities. For example, they can function as inhibitors of protein tyrosine phosphatase IB with antihyperglycemic properties <00JMC1293>, as well as potent and short-acting p-blockers in the treatment of various cardiovascular diseases . An inexpensive, reusable clay has been utilized to catalyze a facile cyclodehydration under microwave without solvent to form 3-substituted benzo[2>]furans from substituted a-phenoxy acetophenones 104. One of the important features of this procedure is that all the selected cyclodehydration reactions are complete in less than 10 minutes <00SL1273>. 

In contrast to the rich chemistry of alkoxy- and aryloxyallenes, synthetic applications of nitrogen-substituted allenes are much less developed. Lithiation at the C-l position followed by addition of electrophiles can also be applied to nitrogen-containing allenes [10]. Some representative examples with dimethyl sulfide and carbonyl compounds are depicted in Scheme 8.73 [147, 157]. a-Hydroxy-substituted (benzotriazo-le) allenes 272 are accessible in a one-pot procedure described by Katritzky and Verin, who generated allenyl anion 271 and trapped it with carbonyl compounds to furnish products 272 [147]. The subsequent cyclization of 272 leading to dihydro-furan derivative 273 was achieved under similar conditions to those already mentioned for oxygen-substituted allenes. 

On the other hand, we also planned alternative completely new approach (Route B) to Nakadomarin A, which involves the spirolactam followed by coupling reaction with furan derivative and subsequent intramolecular electrophilic substitution reaction of an iminium cation generated from an aminal to give highly functionalized tetracyclic core system (Scheme 10.3). 

The propensity of the C5 site towards electrophilic substitution has been exploited to prepare functionalized oligomers by cationic polymerization. Thus monomers like isobutene, s ene, the vinyl ethers, etc. polymerize in the presence of simple furan derivatives such as 2-methyl furan to give essentially short chains (DP between 2 and 100 depending on the specific experimental conditions) with a terminal furan ring as a result of predominant transfer onto the C5 position of the added furan compound (20). 

Scheme 1 Synthesis of trihydroxyalkyl-substituted furans derivatives 3 or 4 from D-pentose and C-furyl glycosides 5 or 6 from D-hexoses...

Additionally, the acid-catalyzed decomposition of substituted tetrahydro-l,2-dioxin-3-ols yielded adequately the substituted furan derivatives <1994JHC1219, 1998S1457>. 

When furan was substituted at C-2 by a pyridine function [e.g., 4 -(2, 6 -dimethyl)pyridyl] high yields (>90%) of the 5-bromo derivatives were... 

The intramolecular addition of hydroxyl groups to triple bonds might be utilised in the formation of furane derivatives. Enynols, having the appropriate double bond geometry, underwent ring closure and subsequent double bond isomerisation in the presence of both palladium and ruthenium catalysts to give substituted furans (3.52.),66... 

A similar autooxidative ring contraction was recognized in the oxidation of 2-substituted 3,4,5,6-tetrachloro-2//-pyrans (144b) to furan derivatives 428, proceeding probably via peroxide 427.32... 

The ring closure of orf/io-substituted phenols is a route to production of benzo[6]furans on an industrial scale. The natural benzo[6 ]furan derivatives karanjin, pongapin, khellin and visnagin have been prepared via the respective o-hydroxyarylacetaldehydes, whilst an extension to the cyclization of o-hydroxybenzyl alkyl ketones has made it possible to synthesize polycyclic benzo[6]furans under the influence of demethylating and dehydrating media. Pterocarpans have been synthesized from suitable isoflavones by this route. 

On condensation of peri-hydroxynaphthaldehydes with the Fischer base (82KGS1501) or with 1,3,3-trimethylisobenzofurylium perchlorate (86DOK639), 2-substituted heterocyclic 2//-naphtho[6c]furan derivatives... 

Dihydrodibenzo[7/]thiepine derivatives 145a-c were prepared as 5-HT2A/2C antagonists as potential dmgs. A series of substituted 2-(aminomethyl)-3,3a,8,12 -tetrahydro-2//-dibenzocyclohepta[l,2-3]furan derivatives were synthesized and the 5-HT2A) 5-HT2C, and Hj receptor affinities were examined <2004BML2765> (see Section 13.03.7.2). 

Afterward, analogous intermediates have been isolated by several authors in the nitration of other furan derivatives bearing electron-withdrawing substituents.119 120 Michels and Hayes119 studied the kinetics of the conversion of the addition intermediate into the final nitro-substituted derivative by the action of several bases. 

The most potent compound of the aryl diyne series (type II) was furan derivative 9 with a Ki value of 7.5 nM. An approximately tenfold decrease of potency was observed when the 1,3-substitution pattern of the head groups of 9 was replaced by 1,4-substitution to give 24 with a K, value of 80 nM. Substitution of the 2,5-furan ring in 9 by the 3,4-thiophene ring gave 25, with a twentyfold loss of tryptase inhibition activity (K, =150 nM). Replacement of the furanyl diyne template with the 1,3-substituted phenyl diyne template 29 was well tolerated (K, = 9 nM), whereas 1,4-substituted head groups resulted in a fourfold loss of activity (27, Ki = 32 nM) compared with 29. Combination of a 1,2-substituted phenyldiyne... 

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