An improved synthesis of 2-substituted-3-furoic acids leading to an intramolecular Diels–Alder reaction between a dienophile and furan diene both containing an electron withdrawing group

Yu, Shuyuan; Beese, G.; Keay, Brian A.

doi:10.1039/p19920002729

Cited by 18 publications

(3 citation statements)

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“…In the case of phosphonopyrrolidines 6 , the isomers might originate from three diverse structural properties: endo - or exo -annulation, amide rotamers, or configuration of the C 2 -center. Most studies using similar substrates show exclusive formation of the exo -adduct when the reaction is performed under thermodynamic control. ,,,,, Endo -fused, kinetic products are normally formed under high-pressure-mediated conditions . Nevertheless, it is reasonable to suggest the appearance of an endo -fused isomer next to the exo -fused isomer based on the results of Tromp and co-workers .…”

Section: Resultsmentioning

confidence: 99%

“…Furans can undergo Diels−Alder reactions as the 4π diene components despite their aromaticity and hence expected decrease in reactivity, both inter- and intramolecularly . Furthermore, the IMDAF reaction (intramolecular Diels−Alder reaction of furan) is particularly attractive as two or more rings can be constructed in a single step with high regio- and stereocontrol, providing a convenient entry into polycyclic targets including natural products like prostaglandins , and terpenoids . The 7-oxabicyclo[2.2.1]heptane skeleton, formed here, is present in biologically active natural products, but moreover, the 7-oxanorbornanes and their unsaturated derivatives can undergo a variety of reactions making them quite useful synthetic intermediates in the synthesis of natural products and analogues …”

Section: Introductionmentioning

confidence: 99%

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Synthesis of Tricyclic Phosphonopyrrolidines via IMDAF: Experimental and Theoretical Investigation of the Observed Stereoselectivity

et al. 2008

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During the synthesis of tricyclic phosphonopyrrolidines via intramolecular Diels-Alder reactions of 1-acylamino(furan-2-yl)methyl phosphonates, two isomers are formed in most cases. The presence of a short three-atom tether together with spectroscopic data, including difference NOE, revealed that the cycloaddition occurred exo, but the phosphonate substituent on the tether had an exo or endo orientation. This was confirmed via X-ray analysis. A thermodynamic preference for the product with the phosphonate function in the endo position was observed experimentally and was confirmed theoretically. Density functional theory methods and several high-level post Hartree-Fock procedures were used to rationalize the observed isomer ratio of the IMDAF-reactions. This was done for two different types of reagents: with the activating carbonyl group in the tether or as a substituent on the tether. For the first type of molecules there is a large steric hindrance of the bulky tether substituents that disfavors the exo-isomer. In the latter case, there was a very small energy difference between the transition states causing a mixture of epimers being formed.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of Tricyclic Phosphonopyrrolidines via IMDAF: Experimental and Theoretical Investigation of the Observed Stereoselectivity

et al. 2008

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“…Subsequent treatment of acid 55 with 2 equivs of BuLi (THF, −20 °C, 1 h) resulted in lithiation at the methyl group. Deuteration with MeOD afforded furoic acid 58 (85%) and ketone 57 (8%) . These results indicate that BuLi can be used directly on some furoic acids to direct lithiation; however, the presence of ketone 57 indicates that some side reactions at higher temperatures may occur (Scheme ).…”

Section: C-4 Lithiation Of 2-(tert-butyldimethylsilyl)-3-furoic Acid ...mentioning

confidence: 96%

Regioselective Preparation of 2,4-, 3,4-, and 2,3,4-Substituted Furan Rings. 2.¹ Regioselective Lithiation of 2-Silylated-3-substituted Furan Rings

Bures

Nieman

et al. 1997

J. Org. Chem.

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A new method for the preparation of 3,4-and 2,5-disubstituted furan rings is described. A variety of 2-silylated-3-(hydroxymethyl)furans and 2-silylated-3-furoic acids lithiate exclusively at C-4 when treated with 2.2 equivs of BuLi. The resulting dianions were quenched with a variety of electrophiles to provide 2-silylated-3-(hydroxymethyl)-4-substituted furans and 2-silylated-4-substituted 3-furoic acids in good to excellent yields. Removal of the silyl group (n-Bu 4 NF) provided a variety of 4-substituted-3-(hydroxymethyl)furans and methyl 4-substituted-3-furoates, respectively. The latter esters were prepared due to difficulties encountered in isolating 4-substituted-3-furoic acids. The site of lithiation was altered by protecting the 3-hydroxyl group with a triethylsilane. Lithiation of 2-silylated-3-(((triethylsilyl)oxy)methyl)furan with 1.2 equivs of BuLi followed by the addition of electrophiles provided 2-silylated-3-(((triethylsilyl)oxy)methyl)-5-substituted furan rings. Subsequent removal of both silyl groups provided 2,4-disubstituted furan rings in moderate to good yields. A rationale is provided to explain why protection of the hydroxyl group at C-3 leads to a change in lithiation from the C-4 to the C-5 position of the furan ring. In addition, an explanation for the observed effect of adding HMPA or LiCl to the solution during the lithiation of 2-(tertbutyldimethylsilyl)-3-(hydroxymethyl)furan is provided.In the preceding paper, 1 the difficulty in preparing 3,4and 2,4-disubstituted furan rings due to the preference for furan rings to lithiate 2 and add electrophiles 3 in the C-2 or C-5 positions was discussed. New synthetic routes toward the preparation of furan rings which contain groups in the 3 and/or 4 positions are useful, since many natural products incorporate furan rings with either a 3,4-or 2,4-disubstituted or 2,3,4-trisubstituted pattern. 4 This paper describes a full account of our work in this area.Some previous reports on the preparation of 3,4disubstituted furans have involved using Diels-Alder/ retro-Diels-Alder chemistry, 5 chemical modifications of 3,4-furandicarboxylic acid, 6 and the synthetic modification of acyclic precursors. 7 An alternative approach to the preparation of 3,4-disubstituted furans is the direct lithiation of substituted furan rings. The C-4 lithiation of a 3-substituted furan, however, has not been successful

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Lateral Lithiation Reactions Promoted by Heteroatomic Substituents

Clark¹,

Jahangir²

1995

Organic Reactions

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Heteroatom‐facilitated lithiation reactions have assumed an increasingly important role in the elaboration of carbocyclic aromatic and heteroaromatic systems in the 40 years subsequent to the seminal review on metalation with organolithium reagents by Gilman and Morton. Of particular note has been the development of methodology for the lateral lithiation of alkyl‐substituted aromatic systems promoted by an extensive array of heteroatomic substituents. These lithiations involve deprotonation at a benzylic (side chain) position that is lateral to, or flanked by, a heteroatom‐containing substituent (G); this substituent facilitates lithiation relative to the parent system in which G is not present. The derived lithiated species have great synthetic utility for functionalization of benzylic sites, for chain extensions, and for the synthesis of fused carbocyclic and heterocyclic systems via annelation processes. This chapter summarizes the significant amount of work reported on heteroatom‐facilitated lateral lithiations and the synthetic applications thereof. The survey covers the substituents that promote these reactions, and the methods of formation, stability, reactivity, and synthetic utility of the lithiated species. Coverage is limited to examples in which the R 1 group in the representative equation is hydrogen (toluene derivatives), alkyl, or aryl. Examples that would be better classified as alpha ‐lithiations are not covered, for example, where R 1 is an anion‐stabilizing group such as cyano, carboxy, and so on. Rare examples of lithiations of alkyl groups that are meta or para to the facilitating group G are included in the chapter, although these are not, strictly speaking, lateral lithiations. Also included are a limited number of older lateral metalations that were originally effected with sodium or potassium bases but would now be more conveniently carried out with lithium dialkylamide bases. The aromatic nucleus may be carbocyclic or heterocyclic, but lateral lithiations of heterocycles lacking the heteroatomic substituent are not covered. For example, lithiation of nicotinamides (Eq. 2) are included; however, lithiations of picolines, and other heterocyclic systems, are considered beyond the scope of this chapter. The relationship of lateral lithiation reactions to heteroatom‐facilitated ortho lithiations is obvious and the two fields have developed, for the most part, in concert. With several notable exceptions, the same heteroatomic substituents (G) promote both types of lithiations. A number of reviews cover various aspects of ortho lithiation reactions, including the comprehensive chapter in Organic Reactions by Gschwend and Rodriguez that surveyed the literature to 1979. In the present chapter, the relationship of lateral lithiation and ortho lithiation reactions is discussed within the contexts of mechanism, reactivity, and synthetic utility. In addition, the sequential use of these two lithiation processes for the synthesis of complex aromatic and heteroaromatic systems is covered.

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An improved synthesis of 2-substituted-3-furoic acids leading to an intramolecular Diels–Alder reaction between a dienophile and furan diene both containing an electron withdrawing group

Cited by 18 publications

References 41 publications

Synthesis of Tricyclic Phosphonopyrrolidines via IMDAF: Experimental and Theoretical Investigation of the Observed Stereoselectivity

Synthesis of Tricyclic Phosphonopyrrolidines via IMDAF: Experimental and Theoretical Investigation of the Observed Stereoselectivity

Regioselective Preparation of 2,4-, 3,4-, and 2,3,4-Substituted Furan Rings. 2.¹ Regioselective Lithiation of 2-Silylated-3-substituted Furan Rings

Lateral Lithiation Reactions Promoted by Heteroatomic Substituents

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An improved synthesis of 2-substituted-3-furoic acids leading to an intramolecular Diels–Alder reaction between a dienophile and furan diene both containing an electron withdrawing group

Cited by 18 publications

References 41 publications

Synthesis of Tricyclic Phosphonopyrrolidines via IMDAF: Experimental and Theoretical Investigation of the Observed Stereoselectivity

Synthesis of Tricyclic Phosphonopyrrolidines via IMDAF: Experimental and Theoretical Investigation of the Observed Stereoselectivity

Regioselective Preparation of 2,4-, 3,4-, and 2,3,4-Substituted Furan Rings. 2.1 Regioselective Lithiation of 2-Silylated-3-substituted Furan Rings

Lateral Lithiation Reactions Promoted by Heteroatomic Substituents

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Regioselective Preparation of 2,4-, 3,4-, and 2,3,4-Substituted Furan Rings. 2.¹ Regioselective Lithiation of 2-Silylated-3-substituted Furan Rings