Cycloaddition sequence

Dienamines undergo 1,4 cycloaddition with sulfenes as well as 1,2 cycloaddition. For example, l-(N,N-diethylamino)butadiene (111), when treated with sulfene (generated from methanesulfonyl chloride and triethyl-amine), produces 1,4 cycloadduct 116 in an 18 % yield and di-1,2-cycloadduct 117 in a 60 % yield (160). Cycloadduct 116 was shown not to be the precursor for 117 by treating 116 with excess sulfene and recovering the starting material unchanged (160). This reaction probably takes place by way of zwitterion 115, which can close in either a 1,4 or 3,4 manner to form cycloadducts 116 and 118, respectively. The 3,4 cycloaddition would then be followed by a 1,2 cycloaddition of a second mole of sulfene to form 117. Cycloadduct 117 must form in the 3,4 cycloaddition followed by a 1,2-cycloaddition sequence rather than the reverse sequence since sulfenes undergo cycloaddition only in the presence of an electron-rich olefinic center (159). Such a center is present as an enamine in 118, but it is not present in 119. 

The thionation-cycloaddition sequence is accompanied by the elimination of dimethylamine from the cycloadduct to afford thiopyrans. Similarly, when the thionation-cycloaddition methodology was applied to enaminoketones 98 and 99, obtained from thiochromanones, tricyclic compounds 100 and 101 were obtained (Figure 2.12). 

A sequential cycloaddition, tandem cycloreversion-cycloaddition process is more efficient than the direct cycloaddition, especially in case of aliphatic aldehydes, where the corresponding ylides are rather unstable. The cycloreversion strategy lowers the concentration of the free ylide in the reaction mixture and avoids side reactions such as self-condensation of this reactive species. In some cases, this tandem cycloreversion-cycloaddition sequence provides improved chemical yields without any loss of diastereoselectivity. For example, compound 476 treated with methyl fumarate, methyl maleate, and methyl acrylate provides acceptable yields of compounds 477-479 (Scheme 80) <2000S1170, 2002S1885>. 

If nitrones have been widely used as 1,3-dipoles in the synthesis of hexahydro-isoxazolo[2,3- ]pyridines, the use of nitroacetates such as 92 in the cycloaddition sequence allows for an efficient access to hexahydro-isoxazolo[2,3-tf] pyridin-7-ones such as 93 after spontaneous dehydration (Scheme 30) <2000JOC499>. 

Another route involves a palladium-copper-catalyzed tandem carbon-carbon formation/cycloaddition sequence (Equation 12) <2005TL8531>. Notably, cycloadditions of azide to the internal alkynes failed under click chemistry reaction conditions <2003DDT1128>. Cyclization under oxidative conditions has been reported from dithioacetal 163 (Equation 13) <1996TL3925>. The formation of 164 as a single diastereoisomer has been explained by stereoelectronic effects. 

Tricyclic lactone systems were synthesized by the analogous intramolecular [4+ 2]-reaction followed by hydration and oxidation of the resulting dihydropyran ring. This isomerization-cycloaddition sequence was successfully applied to the synthesis of (+)-platyphyllide [134]. 

Dehydrobromination of 219 with DBU gave rise to allyl propargyl ethers 220, which underwent a base-catalyzed isomerization-[4 +2]-cycloaddition sequence to afford tricyclic enol ethers 221 [179]. 

The intramolecular cyclization of oximes with alkene substituents to dihydropyrroles in the presence of radical initiator or by heating was also describedThus, oxime 83 underwent a tandem 1,2-prototropy-cycloaddition sequence and gave an unstable cycloadduct 84, which on treatment with NaOH afforded indolizine 85 (equation 36). ... 

The first example of a tether remote functionalization was the synthesis of the tris-64 (Scheme 10.14) [75,78]. For this purpose the computer-aided chemically designed addend 63 was allowed to undergo a successive nucleophilic cyclopropanation/ [4-1-2] cycloaddition sequence yielding the tris-adduct 64 in 60% yield with complete regio selectivity. Subsequent cyclopropanation of the remaining octahedral sites with a large excess of diethyl bromomalonate and DBU afforded the hexakisadduct 65... 

In an extension to this work, this group applied the protocol to the synthesis of (—)-mesembrine (258). The key ylide formation and cycloaddition sequence was performed in xylenes at 250 °C in a sealed tube, furnishing the desired pyrrolidine lactone 259 as a single isomer in excellent yield, and further chemical elaboration yielded the target compound 258. Again it can be postulated that the stereochemical outcome is due to the bulky benzyloxymethyl group lying in an equatorial environment in the transition state (Scheme 3.88). 

Padwa and co-workers (36-38) developed a process concerning a tandem carbene cyclization-cycloaddition sequence that led to the formation of products of greater complexity in a single step (Scheme 4.25). 

The intramolecular nitrile oxide-alkene cycloaddition sequence has been used for the assembly of a great variety of natural products. A target that has received special attention is that of taxol (156), undoubtedly due to its unique structural features, its potent anticancer activity, and its hmited availability from natural sources (318,319). In 1984 Kozikowski et al. found that the treatment of nitro dienone 158 (obtained from the p-benzoquinone derivative 157) with p-chlorophe-nyl isocyanate under Mukaiyama conditions afforded the unexpected eight-mem-bered ring 159, which is related to ring B of taxol (156) (Scheme 6.79). 

Recently, the intramolecular nitrile oxide-alkene cycloaddition sequence was used to prepare spiro- w(isoxazolines), which are considered useful as chiral ligands for asymmetric synthesis (321). Reaction of the dibutenyl-dioxime (164) (derived from the diester 163) with sodium hypochlorite afforded a mixture of diastereomeric isoxazolines 165-167 in 74% combined yield (Scheme 6.80) (321). It was discovered that a catalytic amount of the Cu(II) complex 165-Cu(acac)2, where acac = acetylacetonate, significantly accelerated the reaction of diisopropylzinc... 

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). 

The original synthesis of thiomiinchnones (4) (l,3-oxathiohum-5-olates) (53-55), which involves the cyclodehydration of an (5)-acylthioglycolic acid, was used by (jribble and co-workers (56) to generate 2,4-diphenylthiomiinchnone (94) and trap it with 1,5-cyclooctadiene in a tandem 1,3-dipolar cycloaddition sequence to afford sulfide 95 (Scheme 10.16). Apart from this one report, this mesoionic heterocycle has received no attention since the review by Potts (1). 

Figure 9. C4 cycloaddition sequences leading to C60. (Reprinted with permission of VCH Publishers 1992.)...

Methods for the construction of the thieno[2,3-c]pyridine skeleton based on the formally simultaneous formation of both the pyridine and thiophene rings were documented. Under the Pummerer rearrangement conditions, ( -s ul liny lain idc 222 underwent a cascade transformation into 223, which was oxidized to fused lactam 224 in low yield (1999JOC2038). Data on the use of cascade transformations, including the Pummerer rearrangement - cycloaddition sequence, in the synthesis of complex heterocyclic systems were summarized in a review (1997S1353). 

Selenoacylamidines also take part in Diels-Alder reactions yielding 4W-selenopyrans through a cycloaddition-cycloreversion-cycloaddition sequence (95TL237). 5,6-Dihydro-27/-selenopyrans have also been obtained by hetero-Diels-Alder protocol (95JA10922). 

A formal [3+3] cycloaddition reaction of a vinylogous amide was used in the presence of chiral amine salts and yielded the fused piperidine derivative enantioselectively (Equation 146) <2005JOC4248>. A stepwise [3+3] cycloaddition sequence starting from a dianion of 46, transmetallation, and addition of aziridine allowed for the... 

Highly substituted 4-dimethylamino-4/7-thiopyrans result from a cycloaddition-cycloreversion-cycloaddition sequence commencing with the heterodiyne 417 and dimethyl acetylenedicarboxylate (DMAD) <1996J(P2)2623, 1997MI2185>. Activated alkynes cycloadd to 3-aryl-2-cyanothioacrylamides yielding 4-aryl-477-thiopyrans 418 (Scheme 127) <1994J(P1)989>. 

In the context of a coupling-1,3-dipolar cycloaddition sequence, Muller and coworkers [89] developed a consecutive one-pot, three-component process to indolizines. Starting from (hetero)arenecarbonyl chlorides 88 and terminal alkynes 89 under Sonogashira conditions, the expected alkynones were formed (Scheme... 

Cycloadduct 212 was subsequently converted to desacetoxy-4-oxo-6,7-dihy-drovindorosine 211 via intermediate 217 in high overall yield thereby proving the merits of the method. The tandem cyclization-cycloaddition sequence is particularly attractive as four of the stereocenters are formed in one step with a high degree of stereocontrol. 

This new multicomponent cascade reaction can also be performed with a large variety of aryl halides, most favorably iodides (Scheme 7). The yields in this coupling-cycloaddition sequence are particularly high with the parent... 

A study of the mechanism of this catalytic process revealed that the reaction proceeds by two [2-1-2] cycloaddition sequences via a phosphine imine (iminophosphorane) intermediate... 

Multicomponent Synthesis of Heterocycles by Coupling-Cycloaddition Sequences... 

Besides their pronounced Michael reactivity (vide supra and infra) alkynones are perfectly suited as highly polarized and reactive dipolarophiles for (3 + 2)-cycload-ditions giving rise to five-membered heterocycles. Taking into account the mild and catalytic access to ynones, the implementation of coupling-cycloaddition sequences as a three-component approach to five-ring heterocycles lies at hand (Scheme 13). According to this concept the three-component syntheses of isoxa-zoles and indolizines have been realized to date. 

Scheme 15 Mechanistic rationalization of the coupling-cycloaddition sequence to isoxazoles 23...

Willy B, Rominger F, Muller TJJ (2008) Novel microwave-assisted one-pot synthesis of isoxazoles by a three-component coupling-cycloaddition sequence. Synthesis 293-303... 

Rotaru AV, Dmta ID, Oeser T, Muller TJJ (2005) A novel coupling 1,3-dipolar cycloaddition sequence as a three-component approach to highly fluorescent indolizines. Helv Chim Acta 88 1798-1812... 

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