Intramolecular 3+21 cycloaddition alkylation

A synthesis of 2-alkyl-2,3-dihydro-y-pyrones (187) from methoxybutenyne and aldehydes has been described (83TL4551). The condensation of lithiomethoxy-butenyne (184) with aldehydes at -78°C leads to the secondary alcohols 185, which form the dihydropyrones 187 via hydration of the acetylenic bond and hydrolysis of the methoxyethenyl group to the ketoenol 186 (0°C, p-TSA, THF, H2O or 30% HCIO4, 20 min) folowed by intramolecular cycloaddition. 

Treatment of 6-arylidenehydrazino-3-alkyl-5-nitrouracils 510 with etha-nolic KOH caused a benzylic acid type of rearrangement to give 511, which were alkylated to give 512, whose cyclization with diethyl azodicar-boxylate gave (80H1295) 513 by intramolecular cycloaddition through valence isomerization and then aromatization with diethyl azodicarboxylate (Scheme 107). 

The synthetic utility of o-quinodimethane generated by cheletropic elimination of S02 has been amply demonstrated by Oppolzer and Nicolaou, who have conducted an intramolecular cycloaddition coupled with the alkylation of 1,3-dihydrobenzo[c]thiophene 2,2-dioxide122. When 1,3-dihydro-l-(4-pentenyl)benzo[c]thiophene 2,2-dioxide (201) prepared from 1,3-dihydrobenzo[c]thiophene 2,2-dioxide and 4-pentenyl bromide is heated in di-n-butyl... 

The synthetic utility of o-quinodimethane generated by cheletropic elimination of SO2 has been amply demonstrated by Oppolzer and Nicolaou, who have conducted an intramolecular cycloaddition coupled with the alkylation... 

The synthesis of longifolene in Scheme 13.30 commenced with a Birch reduction and tandem alkylation of methyl 2-methoxybenzoate (see Section 5.6.1.2). Step C is an intramolecular cycloaddition of a diazoalkane that is generated from an aziridinoimine intermediate. 

In contrast, substrates 149 all furnished [4 + 3]-cycloadducts 150 and 151 in yields ranging from 10-79% (Scheme 34)68. In all cases, exclusive approach of the furan from the zwitterion face opposite the epoxide ring was seen. In most cases, the exo diastereomer 151 was the major product or was formed to the exclusion of the endo diastereomer 150. The contrasting diastereoselectivity seen in inter- and intramolecular cycloadditions may result from unfavorable nonbonding interactions in the endo transition state between the tether atoms and the alkyl groups at C-2 and C-5. 

A diastereoselective synthesis of bis(3,5)pyrazolophanes was accomplished by sequential inter- and intramolecular cycloadditions of homochiral nitrilimine intermediates . A-Alkyl pyrazolidine-3,5-diones were synthesized in a three-step sequence from dialkyl malonates <00JHC1209>. Methyl acetoacetate was employed as the initial substrate to 3-carboxamido-4-pyrazolecatboxylic acid derivatives <00JHC175>. Vilsmeier type reagent 33 reacted with imines 34 to afford enaminoimine hydrochlorides 35, which were transformed to pyrazoles 36 upon addition of hydrazine <0OJHC13O9>. 

A 1,3-dipolar cycloaddition of the nonstabilized azomethine ylide 6 is the key step in a three-component reaction. The azomethine ylides were generated from (2-azaallyl)stannanes or (2-azaallyl)silanes 5 through an intramolecular iV-alkylation/demetallation cascade. The ylides underwent cycloaddition reactions with dipolarophiles yielding indolizidine derivatives 7-9 <2004JOC1919> (Scheme 1). 

An intramolecular cycloaddition occurred, when 2-alkylidene-l,3-dithianes having a hydroxy group at an appropriate distant position (3- or 4-atoms) were treated with trifluoromethyl iodide in the presence of SO2. A radical mechanism with 2-alkyl-2-iodo-l,3-dithianes as intermediates is suggested (Equation 37) <1997JOC9107>. 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

The combination of the geometrical preference of the tether and the stereochemical preference of the dipolarophile substituent can be seen in the intramolecular cycloadditions of alkyl nitronates, (Scheme 2.6) (99). When the tether is restricted to two atoms, only the endo approach of the tether is observed in up to a 100 1 ratio, independent of the configuration of the disubstituted dipolarophile. However, in the case of a three-atom linker, there exists a matched and mismatched case with respect to the observed stereoselectivities. With a (Z)-configured dipolarophile, only the exo isomer was observed since the ester moiety also approaches on the exo to the nitronate. However, with an ( )-configured dipolarophile, the ester group is forced to approach in an endo manner to accommodate an exo approach of the tether, thus leading to lower selectivity. 

Sha et al. (45) reported an intramolecular cycloaddition of an alkyl azide with an enone in an approach to a cephalotaxine analogue (Scheme 9.45). Treatment of the bromide 205 with NaN3 in refluxing methanol enabled the isolation of compounds 213 and 214 in 24 and 63% yields, respectively. The azide intermediate 206 underwent 1,3-dipolar cycloaddition to produce the unstable triazoline 207. On thermolysis of 207 coupled with rearrangement and extrusion of nitrogen, compounds 213 and 214 were formed. The lactam 214 was subsequently converted to the tert-butoxycarbonyl (t-Boc)-protected sprrocyclic amine 215. The exocyclic double bond in compound 215 was cleaved by ozonolysis to give the spirocyclic ketone 216, which was used for the synthesis of the cephalotaxine analogue 217. 

Although the first attempts at asymmetric azomethine ylide cycloadditions were reported by Padwa s group (92), the acyclic azomethine ylides chosen, bearing an a-chiral alkyl substituent on the nitrogen, showed poor diastereoselectivities (93,94). When the chiral center is fixed in a cyclic structure (95) or when chirality is introduced in an intramolecular cycloaddition system (96-98), high selectivities have been accomplished. There are only a few examples known of asymmetric cycloadditions of achiral azomethine ylides to chiral dipolarophiles where cyclic azomethine ylides (99,100) or cyclic chiral dipolarophiles (94) were used. 

The synthesis of (+)-estrone methyl ether (36) illustrates the enantioselective construction of a polycyclic target by the use of chiral auxiliary control to establish the first cyclic stereogenic center [14], In this case, the specific design of the naphthyldiazoester 32 directed Rh-mediated intramolecular C-H insertion selectively toward one of the two diastereotopic C-H bonds on the target methylene. The new ternary center so created then biased the formation of the adjacent quaternary center in the course of the alkylation. The chiral skew in the product cyclo-pentanone (35) controlled the relative and absolute course of the intramolecular cycloaddition, to give the steroid (+)-estrone methyl ether (36). 

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