Monocyclic cycloaddition reactions

Scheme 26 Synthesis of sugar-based monocyclic [S-lactams by Staudinger [2+2] cycloaddition reaction...

Reaction of D-phenylalanine ethyl ester with cinnamaldehyde has been reported to give a chiral Schiff base, that underwent an asymmetric Staudinger [2+2] cycloaddition reaction with phthalimidoacetyl chloride to give the monocyclic... 

They have also reported a direct route to optically pure, fused, or bridged tricyclic (3-lactams (III and IV, Fig. 18) as further advances in the intramolecular nitrone-alkene cycloaddition reactions of monocyclic 2-azetidinone-tethered alkenyl-aldehydes [289]. 

Aminothiophenol 37 and 277 formed an isolable adduct 278 (X = S) that on heating was transformed to a mixture of complex 283 (10%) and the demetallated benzothiazepinone 284 (51%) (Scheme 50) <2003CEJ4943>. Similarly, monocyclic 1,4-oxazepinone derivatives of tungsten and chromium have been prepared by a domino [4+2]/[2+2] cycloaddition reaction of 1-alkynyl Fischer carbenes with oxazolines <20050M302>. 

Two examples of synthesis of monocyclic oxathiazepines (via the intramolecular cycloaddition reaction and [3+4] cyclization) were discussed in CHEC-II(1996). No additional information on the synthesis of this class of compounds has appeared since. 

During the present decade, a wide variety of polycyclic carbacephem derivatives have been reported starting from readily available monocyclic /3-lactams, which after transformation in more functionalized compounds and further cyclization yielded different fused carbacephems. Several approaches for the preparation of fused carbacephem derivatives including cycloaddition reactions such as the [2+2], 1,3-dipolar, and Diels-Alder reactions, as well as transition metal-catalyzed reactions such as the Pauson-Khand and ring-closing metathesis (RCM) reactions have been reported in the literature. 

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

Cycloaddition reactions, in particular the Diels-Alder reaction, provide a convenient way to increase the number of fused rings by two with high stereoselectivity if a monocyclic dienophile is used <2004S2665>. An early example of this approach to polycyclic /3-lactams used a diene system that was entirely within a ring (Equation 80) <2000JOC3716>. 

Numerous methods of preparing bicyclic systems from monocyclic precursors have been reported and four general strategies can be identified. These are (i) intermolecular cyclization reactions which do not involve 1,3-dipolar cycloaddition reactions (ii) intermolecular 1,3-dipolar cycloaddition reactions (iii) nonoxidative intramolecular cyclizations and (iv) oxidative intramolecular cyclization reactions. These four general methodologies are now considered. 

An intramolecular nitrile oxide cycloaddition reaction of a 1,3-dioxolane monocyclic precursor provided the construction of the two five-membered rings of the isoxazoline (32), a precursor to prostaglandin F2a (Equation (12)) <84JOC230l>. 

An efficient use of triphosgene, as an acid activator, for the synthesis of substituted 2-azetidinones via ketene-imine cycloaddition reaction using various acids and imines has been achieved <02T2215>. Novel routes to monocyclic (3-lactams 13 and 14 through the photochemical decomposition of oxime oxalate amides <02CC2086> and a-oxoamides <02OL1443> have also been described. 

Nucleosides based upon monocyclic, fused and spirocyclic oxepines have been synthesised via nitrone cycloaddition reactions <07JOC7427>, while oxepine nucleic acids were synthesised from the ring expansion of cyclopropanated glycals <07JACS8259>. 

Monocyclic and some bicyclic l,2-dithiole-3-thiones are known that readily undergo 1,3-dipolar cycloaddition reactions to give cyclic 1,3-dithiole and spiro[l,3]dithiole systems. Due to a great variety of applications, the chemistry of this class of compounds still remains a subject of active research. 

The synthesis of monocyclic 3-amino-P-lactams by the photolytic reaction of imines with pentacarbonyl[(dibenzylamino)carbene]chromium(0) was developed by Hegedus and co-workers [74]. These reactions are closely related to the previously described [2 -h 2]-cycloaddition reactions in that they are thought to involve attack of the imine nitrogen on a photogenerated, metal-bound ketene, followed by ring closure (Scheme 15). In a synthesis of a nocardicin precursor, optically active imine trimer 122 was photolyzed with carbene complex 123 providing a 46% yield of a 1 1 diastereomeric mixture of lactams... 

Using rw-chloroalkenes (e.g., 42) in 1,3-dipolar cycloaddition reactions, Pearson et al. described the synthesis of several alkaloids [20-22]. The reaction proceeds by an intramolecular cycloaddition of an azide onto an alkene, producing an intermediate triazohne. Fragmentation of the triazoUne and rearrangement to a monocyclic imine occurs, which is internally N-alkylated by the alkyl chloride, resulting in iminium ion 43. Reduction with sodium borohydride leads to the racemic lycorane (44). 

Most examples of the Bradsher cycloaddition reaction have utilized fused polycyclic aromatics as the cationic aza-diene fragment. Falck and co-workers have reported that one can carry out this reaction using monocyclic quaternary aza-aromatics. The application of this methodology was illustrated using the A -(2,4-dinitrophenyl) salt of A, A -diethylnicotin-amide 3 and ethyl nicotinate 4 in conjunction with enol ethers. The reaction proceeded at room temperature to generate adducts 5. This was the result of the exo-addition at the C2-C5 positions of the pyridyl ring. The resultant iminium ion was then trapped by the methanolic solvent. 

Recently, Delpiccolo and Mata have also explored the asymmetric synthesis of monocyclic 3,4-substituted (3-lactams (Scheme 3.15). They employed the same Staudinger-type cycloaddition reaction with the chiral glycine derivative, 4(5)-phenyloxazolidylacetyl chloride (72). The oxazolidinone moiety functioned effectively as a chiral auxiliary, and a small library of optically active p-lactams 75 were obtained following cleavage with 10% TFA/DCM and subsequent conversion to the methyl esters (diastereoselec-tivity ranged from 8/1 to >25/1). 

Cycloaddition Reactions of Monocyclic Thiophens. - Reaction of 2,5-dimethoxythiophen with phenyltriazolinedione in methanol gave (104) and (105) in high yield. At -15°C, (106) was isolated, which at higher temperatures hydrolyzed to (104) and (105). ... 

This reaction can also be used for the synthesis of substituted 1-benzoxepins with one modification instead of the 4/T-benzopyran the 2/7-isomer must be used. 2-[Diazo(phosphoryl)meth-yl]-2//-benzopyrans decompose in the presence of ))3-allylpalladium chloride dimer with elimination of nitrogen to give 1-benzoxepins 2.192 In some cases, the reaction takes a different course and gives 2-methylene-2//-benzopyrans 3.192 In this respect, the bicyclic system behaves differently to the monocyclic diazo(pyranyl)methane. The 2-isomers of the latter structure could not be isolated and gave l//-l,2-diazepines.190 The 4//-benzopyrans do not form benzoxepins but undergo an intramolecular [2+1] cycloaddition to 3,4-dihydro-2,3,4-metheno-2//-ben-... 

The synthesis of monocyclic thiepins from thiophene and dimethyl acetylenedicarboxylate is often accompanied by the loss of sulfur. In particular, in cases where room temperature is required for efficient rates of cycloaddition and rearrangement76 (see Section 2.1.3.3.), the desulfurization reaction proceeds rather quickly with the consequence that thiepin formation can be monitored by low temperature HNMR spectroscopy, but the products cannot be isolated.76 - 78 However, in the case of thiepin 1 where R1 = R2 = C02Me and R3 = H, refluxing toluene is necessary for the extrusion of sulfur.78... 

Reinhoudt et al.53) have reported the first synthesis of a monocyclic thiepin stabilized by electronic effects of the substituents. This synthesis utilizes the idea described in Section 2.3.3. 3-Methyl-4-pyrrolidinothiophene (85a) was treated in deuteriochloroform at —30 °C with dimethyl acetylenedicarboxylate. H-NMR monitoring of the reaction indicated that a [2 + 2]cycloaddition proceeded slowly at this temperature giving the 2-thiabicyclo[3.2.0]heptadiene (86a) which rearranged via ring opening of the cyclobutene moiety to the 4-pyrrolydinylthiepin (87a). At the... 

Asymmetric induction is possible in the two-step [3-1-2] cycloaddition by starting the sequence with an asymmetric cyclopropanation (Scheme 14.15) [106]. The Rh2(S-DOSP)4-catalyzed reactions gave the desired vinylcyclopropanes 126 with high enan-tioselectivities [106]. Partial or complete racemization occurred in the vinylcyclopro-pane rearrangement of monocyclic vinylcyclopropanes, but the fused vinylcyclopropanes 128-133 rearrange to form 134-139 with virtually no racemization. 

An alternative way to make such monocyclic products is to take an advantage of intramolecular reaction with substrates bearing removable functional group after the cycloaddition is performed. 

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