Carbonyl cycloaddition with aldehydes

Trapping reactions of benzoylmethyleneoxophosphorane 39 a with carbonyl compounds dispel any remaining doubts as to the existence of acylated phosphenes. Unlike the diphenylmethyleneoxophosphorane 9, whose P/C double bond participates in cycloadditions, compound 39 a acts as a hetero-1,3-diene and undergoes [4 + 2]-cycloaddition with aldehydes and ketones 10 I7,35> it may again be assumed that the reaction is a two-step process involving 55 as intermediate. 

The carbonyl ylide generated from metal carbene can also add to C=0 or C=N bonds. The [2 + 3]-cycloaddition of carbonyl ylide with G=0 bond has been used by Hodgson and co-workers in their study toward the synthesis of zaragozic acid as shown in Scheme n 27a,27d Recently, a three-component reaction approach to syn-a-hydroxy-f3-amino ester based on the trapping of the carbonyl ylide by imine has been reported.The reaction of carbonyl ylide with aldehyde or ketone generally gives l,3-dioxolanes. Hu and co-workers have reported a remarkable chemoselective Rh2(OAc)4-catalyzed reaction of phenyl diazoacetate with a mixture of electron-rich and electron-deficient aryl aldehydes. The Rh(ii) carbene intermediate reacts selectively with electron-rich aldehyde 95 to give a carbonyl ylide, which was chemospecifically trapped by the electron-deficient aldehyde 96 to afford 1,3-dioxolane in a one-pot reaction (Equation (12)). 

Diels-Alder cycloadditions of carbonyl compounds with aldehydes and ketones provide a powerful method for synthesis of 5,6-dihydropyrans, which are useful synthons for a variety of purposes. This methodology was slow to develop since early work indicated that simple carbonyl compounds react poorly with most alkyl and aryl substituted 1,3-dienes. However, with the understanding that [4 + 2] cycloadditions are facilitated by Lewis acid catalysts and high pressure, along with the recent availability of highly reactive oxygenated dienes, this chemistry has been increasingly exploited in total synthesis. 

Cycloaddition of COj with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiocheraistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /3-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

Chiral salen chromium and cobalt complexes have been shown by Jacobsen et al. to catalyze an enantioselective cycloaddition reaction of carbonyl compounds with dienes [22]. The cycloaddition reaction of different aldehydes 1 containing aromatic, aliphatic, and conjugated substituents with Danishefsky s diene 2a catalyzed by the chiral salen-chromium(III) complexes 14a,b proceeds in up to 98% yield and with moderate to high ee (Scheme 4.14). It was found that the presence of oven-dried powdered 4 A molecular sieves led to increased yield and enantioselectivity. The lowest ee (62% ee, catalyst 14b) was obtained for hexanal and the highest (93% ee, catalyst 14a) was obtained for cyclohexyl aldehyde. The mechanism of the cycloaddition reaction was investigated in terms of a traditional cycloaddition, or formation of the cycloaddition product via a Mukaiyama aldol-reaction path. In the presence of the chiral salen-chromium(III) catalyst system NMR spectroscopy of the crude reaction mixture of the reaction of benzaldehyde with Danishefsky s diene revealed the exclusive presence of the cycloaddition-pathway product. The Mukaiyama aldol condensation product was prepared independently and subjected to the conditions of the chiral salen-chromium(III)-catalyzed reactions. No detectable cycloaddition product could be observed. These results point towards a [2-i-4]-cydoaddition mechanism. 

The major developments of catalytic enantioselective cycloaddition reactions of carbonyl compounds with conjugated dienes have been presented. A variety of chiral catalysts is available for the different types of carbonyl compound. For unactivated aldehydes chiral catalysts such as BINOL-aluminum(III), BINOL-tita-nium(IV), acyloxylborane(III), and tridentate Schiff base chromium(III) complexes can catalyze highly diastereo- and enantioselective cycloaddition reactions. The mechanism of these reactions can be a stepwise pathway via a Mukaiyama aldol intermediate or a concerted mechanism. For a-dicarbonyl compounds, which can coordinate to the chiral catalyst in a bidentate fashion, the chiral BOX-copper(II)... 

The existence of ketenes was established over a hundred years ago, and, in recent years, asymmetric synthesis based on [2 + 2] cycloadditions of ketenes with carbonyl compounds to form chiral p-lactones has been achieved with high yields and high stereoselectivities. In 1994, Miyano et al. reported the use of Ca-symmetric bis(sulfonamides) as ligands of trialkylaluminum complexes to promote the asymmetric [2 + 2] cycloaddition of ketenes with aldehydes. The corresponding oxetanones were obtained in good yields and enantioselectivities... 

There are two important rhodium-catalyzed transformations that are broadly used in domino processes as the primary step. The first route is the formation of keto carbenoids by treatment of diazo keto compounds with Rh11 salts. This is then followed by the generation of a 1,3-dipole by an intramolecular cyclization of the keto carbenoid onto an oxygen atom of a neighboring keto group and an inter- or intramolecular 1,3-dipolar cycloaddition. A noteworthy point here is that the insertion can also take place onto carbonyl groups of aldehydes, esters, and amides. Moreover, cycloadditions of Rh-carbenes and ring chain isomerizations will also be discussed in this section. 

Interaction of a carbonyl group with an electrophilic metal carbene would be expected to lead to a carbonyl ylide. In fact, such compounds have been isolated in recent years 14) the strategy comprises intramolecular generation of a carbonyl ylide whose substituent pattern guarantees efficient stabilization of the dipolar electronic structure. The highly reactive 1,3-dipolar species are usually characterized by [3 + 2] cycloaddition to alkynes and activated alkenes. Furthermore, cycloaddition to ketones and aldehydes has been reported for l-methoxy-2-benzopyrylium-4-olate 286, which was generated by Cu(acac)2-catalyzed decomposition of o-methoxycarbonyl-m-diazoacetophenone 285 2681... 

The mode of reaction of titanacydobutenes with carbonyl compounds is largely dependent on steric factors (Scheme 14.31) [72]. Ketones and aldehydes tend to insert into the titanium—alkyl bond of 2,3-diphenyltitanacydobutene, and homoallylic alcohols 70 are obtained by hydrolysis of the adducts 71 [65a,73]. On the contrary, when dialkyl-substi-tuted titanacydobutenes are employed, the reaction with aldehydes preferentially proceeds through insertion into the titanium—vinyl bond. Thermal decomposition of the adducts 72 affords conjugated dienes 73 with E-stereoselectivity as a result of a concerted retro [4+2] cycloaddition [72]. 

Isonitrile complexes, having a similar electronic structure to carbonyl complexes, can also react with nucleophiles. Amino-substituted carbene complexes can be prepared in this way (Figure 2.6) [109-112]. Complexes of acceptor-substituted isonitriles can undergo 1,3-dipolar cycloaddition reactions with aldehydes, electron-poor olefins [113], isocyanates [114,115], carbon disulfide [115], etc., to yield heterocycloalkylidene complexes (Figure 2.6). 

An interesting entry to functionalized dihydropyrans has been intensively studied by Tietze in the 1990s using a three-component domino-Knoevenagel Hetero-Diels-Alder sequence. The overall transformation involves the transient formation of an activated heterodienophile by condensation of simple aldehydes with 1,3-dicarbonyls such as barbituric acids [127], Meldrum s acid [128], or activated carbonyls. In situ cycloaddition with electron-rich alkenes furnished the expected functionalized dihydropyrans. Two recent examples concern the reactivity of 1,4-benzoquinones and pyrazolones as 1,3-dicarbonyl equivalents under microwave irradiation. In the first case, a new three-component catalyst-free efficient one-pot transformation was proposed for the synthesis of pyrano-1,4-benzoquinone scaffolds [129]. In this synthetic method, 2,5-dihydroxy-3-undecyl-1,4-benzoquinone, paraformaldehyde, and alkenes were suspended in ethanol and placed under microwave irradiations to lead regioselectively the corresponding pyrano-l,4-benzoquinone derivatives (Scheme 38). The total regioselectivity was... 

Epoxide 96 was prepared such that photolytic conversion to the carbonyl ylide could be followed by an intramolecular cycloaddition with the tethered pendant olefin. However, photolysis of epoxide 96 led only to the formation of the regio-isomer 97 and the aldehyde 98 with no evidence of the corresponding cycloadduct. It was presumed that 97 arose from the ylide by thermal recyclization to the epoxide while 98 could form through the loss of a carbene from the ylide. The failure of the tethered alkene to undergo cycloaddition may have resulted from a poor trajectory for the cycloaddition. An extended analogue (99) allowed greater flexibility for the dipolarophile to adopt any number of conformations. Photolysis of epoxide 99 did lead to formation of the macrocyclic adduct 100, albeit in modest yields. 

One novel and interesting method of generating a silacarbonyl ylide occurred through the addition of a carbonyl species with a silylene formed under photolytic conditions. Komatsu and co-workers (177) found that photolysis of trisilane (315) in solution with a bulky carbonyl species led initially to the formation of a silacarbonyl ylide followed by a dipolar cycloaddition of an olefinic or carbonyl substrate. Reaction of simple, nonbulky aldehydes led to only moderate yields of cycloadduct, the siladioxolane. One lone ketone example was given, but the cycloadduct from the reaction was prepared in very low yield (Scheme 4.89). 

Reactions of the same carbonyl ylide intermediate with aldehydes are even more fruitful. The Rh2(OAc)2 catalyzed reaction proceeds at room temperature in the presence of 2 mol% of the catalyst, but the diastereoselectivity is disappointingly low (endo/exo = 49 51, Scheme 11.56). However, when 10 mol% of the cocatalyst Yb(OTf)3 is added, the reaction becomes highly exo-selective (endo/ exo = 3 97) (198). Suga has extended this Lewis acid catalyzed carbonyl ylide cycloaddition reaction to catalyzed asymmetric versions. The chiral cocatalyst employed is ytterbium(III) tris(5)-1,1 -binaphthyl-2,2 -diyl phosphonate, Yb[(S) BNP]3 (10 mol%). In the reaction of methyl o-(diazoacetyl)benzoate with benzyloxyacetaldehyde in the presence of Rh2(OAc)2 (2 mol%) at room temperature with the chiral Yb catalyst, the diastereoselectivity is low (endo/exo = 57 43) and the enantiopurity of the endo-cycloadduct is 52% ee. 

Azomethine ylides undergo a formal [3 + 2] cycloaddition with carbonyl compounds to provide oxazolines. Thioimidates, in particular, are effective as ylide precursors. For example, Kohra and co-workers reported that the thioimidate 260, upon activation with cesium fluoride, reacts with aromatic aldehydes and diaryl-ketones to provide oxazolines 261 in modest to good yields. Aliphatic aldehydes and simple ketones are unreactive (Scheme 8.72). 

For A-(trimethylsilylmethyl)-5-methylisothioureas 262, cycloaddition with carbonyl compounds results in 2-aminooxazolines 263. ° Aliphatic and aromatic aldehydes and ketones can be employed successfully. However, reaction with ketones appears to be poor. Ylide generation with CsF is the method of choice although TBAF and KF have also been used but with lower yields. A polar solvent such as MeCN, DMF, or hexamethylphosphoric triamide (HMPA) is required for a succesful reaction (Scheme 8.73). 

N-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloadditions with carbonyl compounds to give oxetanes. Furan and benzophenone give the oxetane (192). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 193), via an intermediate oxetane which undergoes rearrangement under the reaction conditions (79JOC2949). 

It has been long established that Lewis acid-catalysed [2+2] cycloaddition of ketenes and carbonyl compounds provides access to 2-oxetanones. In the development of this reaction prior to 1996, there has been a specific focus on controlling the stereochemistry of the /3-lactone product and cycloadditions have been achieved between trimethyl-silylketene and aldehydes with up to 90% stereoselectivity, as discussed in CHEC-II(1996) <1996CHEC-II(1)721>. CHEC(1984) and CHEC-II(1996) also discuss examples of the Lewis acid-catalyzed, nonphotolytic [2+2] cycloaddition of electron-rich alkenes with aldehydes or ketones <1984CHEC(7)363, 1996GHEC-II(1)721>. While this method can have some advantages over the photolytic reaction in terms of regioselectivity, no examples of this reaction have been reported in recent years. 

The reaction of benzyne with aromatic aldehydes proceeds via nucleophilic attack of the carbonyl oxygen onto the benzyne to give the zwitterionic intermediate 172 followed by cyclization to the benzoxete intermediate. Cycloreversion then forms an ortho-quinone methide, which undergoes a [4+2] cycloaddition with a second molecule of the benzyne to form the xanthene (Scheme 56) <20040L4049>. 

In addition to participating in [2 + l]-cycloaddition reactions, divalent reactive intermediates can form ylides in the presence of carbonyl or other Lewis basic functionalities.108 These ylides participate in cycloaddition or other pericyclic reactions to furnish products with dramatically increased complexity. While carbenes (or metal carbenoids) are well known to participate in these pericyclic reactions, silylenes, in contrast, were reported to react with aldehydes or ketones to form cyclic siloxanes109,110 or enoxysilanes.111,112 Reaction of silylene with an a,p-unsaturated ester was known to produce an oxasilacyclopentene.109,113,114 By forming a silver silylenoid reactive intermediate, Woerpel and coworkers enabled involvement of divalent silylenes in pericyclic reactions involving silacarbonyl ylides115 to afford synthetically useful products.82,116,117... 

The cycloaddition reaction with diethyl acetylenedicarboxylate tolerated a range of carbonyl compounds (Scheme 7.46). Facile reaction was obtained with aldehydes,... 

In contrast to the carbonyl oxide of Figure 15.47, they do not undergo a cycloaddition with each other. Instead, they undergo a 1,3-dipolar cycloaddition to the C=0 double bond of the concomitantly formed aldehyde(s). The orientation selectivity is such that the trioxolane formed differs from the primary ozonide the 1,2,4-trioxolane products are the so-called secondary ozonides. 

The reactions of silenes with aldehydes and ketones is another area whose synthetic aspects have been particularly well-studied4,6 7 10 12. The favoured reaction pathways for reaction are generally ene-addition (in the case of enolizable ketones and aldehydes) to yield silyl enol ethers and [2 + 2]-cycloaddition to yield 1,2-siloxetanes (equation 44), but other products can also arise in special cases. For example, the reaction of aryldisilane-derived (l-sila)hexatrienes (e.g. 21a-c) with acetone yields mixtures of 1,2-siloxetanes (51a-c) and ene-adducts (52a-c) in which the carbonyl compound rather than the silene has played the role of the enophile (equation 45)47,50 52 98 99. Also, [4 + 2]-cycloadducts are frequently obtained from reaction of silenes with a,/i-unsaturated- or aryl ketones, where the silene acts as a dienophile in a formal Diels-Alder reaction6 29,100-102. 

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