Cycloaddition with Furan Derivatives

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. 

Recently, Koizumi et al. reported that the use of high pressures allows exclusion of Lewis acids (which are not compatible with many dienes and/or adducts) in the cycloadditions of acrylates [43]. Thus, methyl 3-alkylsulfinyl acrylate 29 is able to react with cyclopentadiene, furan, and 2-methoxyfuran at 12.6 Kbar (Scheme 14). Both 7r-facial and endo/exo selectivities are very high in reactions with cyclopentadiene (only one adduct was obtained), whereas with furan derivatives the endo/exo selectivity is clearly lower. In reactions with cyclopentadiene it could be established that high pressures do not have a significant influence on the diastereoselectivity. The transformation into (-)-COTC of the major adduct obtained from 2-methoxyfuran was carried out in order to confirm its absolute configuration. 

Enantiomerically enriched products can also be obtained by employing a dienophile bearing a chiral controller group [13]. For example, the use of the camphanate ester derivative (S)-3b (also available in the (R) form) in the cycloaddition with furan gave a 29% yield of diastereomer 4 b after purification, along with other endo and exo isomers, Eq. 2. Saponification afforded the chiral ketone (+)-2. Reactions of 4b and 2 have been reported to occur with high regio-and stereocontrol (vide infra). 

Phenyl vinylsulfonate (16) is an effective dienophile and reacts with furan derivatives, which are known as inert dienes in the Diels-Alder reaction. The sulfonate 16 can be prepared in 85% yield by reaction of / -chlorosulfonyl chloride with phenol in the presence of sodium hydroxide and stored indefinitely at 0°C24. The cycloaddition reaction proceeds at room temperature to give predominantly endo adducts as illustrated in equation ll25. When the reaction was carried out at higher temperature, the yield of the endo adduct and the stereoselectivity decreased due to the retro-Diels-Alder reaction. 

In a somewhat related manner, Dewar furan derivative 48 was generated from 47 and underwent [4 + 2] cycloaddition with furan to provide the expected cycloadduct 49 (Scheme 13.15) [40]. 

The addition of p-quinone to enamines normally produces furan derivatives, especially when the enamine possesses a 3 hydrogen (see Section III. A). 1,2 Cycloaddition is claimed to take place to give a cyclobutane derivative when p-quinone and an enamine with no jS hydrogens are allowed to react at low temperatures (51). However, little evidence is reported to verify this structural assignment, and the actual structure probably is a benzofuranol (52). Reaction of a dienamine (formed in situ) with p-quinone in the presence... 

Diels-Alder reaction of the furan derivative 148 with homochiral bicyclic enone 149 is the key step [56] in the total synthesis of the diterpenes jatropho-lone A and B, 151 and 152, respectively, isolated from Jatropha gossypiifolia L [57], Initial efforts to carry out the cycloaddition between 148 and 149 under thermal or Lewis-acid conditions failed due to diene instability. Application of 5kbar of pressure to a neat 1 1 mixture of diene and dienophile afforded crystalline 150 with the desired regiochemistry (Scheme 5.23). Subsequent aromatization, introduction of the methylene group, oxidation and methylation afforded (-l-)-jatropholones 151 and 152. 

By chance, the existence of the borane complex 330 of 329 was discovered. The liberation of 330 occurred with the best efficiency with sodium bis(trimethylsilyl)-amide from the borane complex 327 of 326. When styrene or furan was used as the solvent, three diastereomeric [2 + 2]-cycloadducts 328 and [4 + 2]-cycloadducts 331, respectively, were obtained in 30and 20% yield (Scheme 6.70) [156]. With no lone pair on the nitrogen atom, 330 cannot be polarized towards a zwitterionic structure, which is why its allene subunit, apart from the inductive effect of the nitrogen atom, resembles that of 1,2-cydohexadiene (6) and hence undergoes cycloaddition with activated alkenes. It is noted that the carbacephalosporin derivative 323 (Scheme 6.69) also does not have a lone pair on the nitrogen atom next to the allene system because of the amide resonance. 

Other examples of the iodonium ylide-based syntheses of furan derivatives involve cycloaddition reactions with alkenes or alkynes. Although the majority of these syntheses involve stable iodonium ylides (86JOC3453 94T11541) (e.g., Eqs. 16 and 17), in some cases the ylides are unstable and are generated in situ (92JOC2135) (e.g., Eq. 18). In the case of alkenes, dihydrofuran derivatives are obtained (Eqs. 16-18). This synthetic route is especially useful for the synthesis of dihydrobenzofuran derivatives that are related to the neolignan family of natural products (Eq. 18). 

When these cycloaddition reactions are carried out with alkynes, furan derivatives are formed. lodonium ylide 5, for instance, on photochemical reaction with alkynes 43, gives benzofurans 44 (86JOC3453) (Eq. 19). In a similar way, the iodonium ylide derived from 2-hydroxy-1,4-naphthoquinone undergoes a cycloaddition reaction with phenylacety-lene to yield benzofuran 45 (Scheme 16) (89LA167). 

The sesquiterpene skeleton has also been assembled by the intramolecular nitrile oxide cycloaddition sequence. Oxime 238 (obtained from epoxy silyl ether 237), on treatment with sodium hypochlorite gave isoxazoline 239, which was sequentially hydrolyzed and then subjected to the reductive hydrolysis conditions-cyclization sequence to give the furan derivative 240 (330) (Scheme 6.93). In three additional steps, compound 240 was converted to 241. This structure contains the C11-C21 segment of the furanoterpene ent-242, that could be obtained after several more steps (330). 

Cycloadditions of dienes with oxyallyl offer the opportunity to prepare seven-membeted ring systems. This reaction has also proved to be of importance in Ae furan series. A few examples may illustrate the value of this methodology. A tandem Pummerer rearrangement and intramolecular [4-i3]-cycloaddition with a fiiran derivative has been reported <99TL545>. For a similar reaction see <99T13999>. 

An interesting one-pot, five-component domino process using an intermolecular Diels-Alder reaction of furans with AT-phenylmaleimide as its final step has been used to construct the central core of indolo[2,3- ]carbazoles (Equation 86) <2002AGE4291>. Thus, aminooxazoles produced from an Ugi three-component reaction undergo acylation/intramolecular Diels-Alder/retro-Diels-Alder cycloreversion with pentafluorophenyl arylprop-2-ynoates to give furan derivatives. Subsequent Diels-Alder cycloaddition at elevated temperatures with A -phenylmaleimide produces carbazoles in good yields (Table 5). 

In this section we refer to types of addition to the carbonyl group, which by their very nature lead to C4-elongation. Examples are found in the addition of furan derivatives and [4+2] cycloaddition. We have recently described [39] the stereoselective addition of 2-furyl-lithium 26 to N,N-diprotected alaninals. For example, the reaction of 26 with alaninal 25 led to a mixture of diastereoisomers syn-21 and anti-28, with predominance of the latter isomer (Scheme 10). A similar method was used in the synthesis of methyl a-D-lincosaminide (see Sec. III.F). 

Furan, which can be considered an 1,4-oxygenated 1,3-butadiene, usually does not react readily with normal dienophiles. However, with 2-acetoxyacrylonitrile (15 R = OAc) and in the presence of zinc iodide, furan enters into cycloaddition to form derivatives of 7-oxabicyclo[2.2.1]hept-5-ene 16 in very good yield [35](Scheme 7). 

The AuCl-catalysed 4 + 2-cycloaddition of benzyne with o-alkynyl(oxo)benzenes produced anthracene derivatives having a ketone in the 9-position, in good to high yields under mild conditions.118 Hypervalent iodine compounds, [5-acyl-2-(trimethyl-silyl)]iodonium triflates, readily yielded acylbenzynes which could be trapped with furan.119 Both DMAD and benzyne reacted with borabenzene to yield substituted borabarrelenes and borabenzobarrelenes, respectively.120... 

The cyclic /J-dicarbonyl iodonium ylides can undergo [3 + 2] cycloaddition reactions with various substrates under catalytic or photochemical conditions, presumably via a stepwise mechanism [153-156]. In a recent example, iodonium ylide 211, derived from dimedone, undergoes dirhodium(II) catalyzed thermal [3+ 2]-cycloaddition with acetylenes 212 to form the corresponding furans 213 (Scheme 75). Under photochemical conditions ylide 211 reacts with various alkenes 214 to form dihydrofuran derivatives 215 [156]. 

Nair, V., Nandakumar, M.V., Anilkumar, G.N., Maliakal, D., Vairamani, M., Prabhakar, S., and Rath, N.P. (2000) Cycloaddition of 2-oxo-2H-cydohepta[b] furan derivatives with arylacetylenes and di-Jt-methane rearrangement of... 

As an extension of this work, photoinduced [2+2]-cycloadditions of 1-acetylisatin (13) with cyclic enolethers (furan, benzofuran, 2-phenylfuran, 8-methoxypsoralen), and acyclic enolethers (//-butyl vinyl ether and vinyl acetate) were investigated which afforded the spiro-oxetanes in high yields (82-96%) and with high regio- and diastereoselectivity (Sch. 4) [19]. Treatment of the furan-derived oxetane 15 with acid resulted in oxetane ring opening and yielded the 3-(furan-3-yl)indole derivative 16. 

---