Synthesis by Cycloaddition

Synthesis by Cycloaddition.—Further details have been given of high-pressure Diels-Alder addition of maleic anhydride to thiophen, and we note the formation of Diels-Alder adducts from 2//-thiopyran, of the dimer (132), and of the adduct (133).  

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The Kametani group further investigated quinazolone synthesis by cycloaddition of iminoketene with imines based on the concept of retro mass spectral synthesis and applied it to the total syntheses of deoxyvasicinone (24),... 

Synthesis by Cycloaddition. Earlier reports have shown that acylnitroso-com-pounds add efficiently to dienes. Now a full paper describes the oxidation of hydroxamic acids to give acylnitroso-compounds which can act both as dienophiles or as hetero-dienes with respect to cyclopentadiene. Heating the bridged oxazine adducts causes partial rearrangement to dioxazines (Scheme 1). 

Synthesis.—By Cycloaddition. The Noyori cycloaddition of halogeno-ketones to furans is now sufficiently well established to provide a firm base for the successful synthesis of C-nucleosides. For example, the ketone (109) has been prepared ... 

Pyrone synthesis by cycloaddition of CO2 to terminal alkynes (1-hexyne, 1-propyne) has also been investigated. This process can be catalytically promoted, albeit with low yield and selectivity, by Co [74] and Rh [75] complexes. Rh(dppe) (Ti -BPh4), in acetonitrile, at 390 K, catalyzed the formation of 4,6-dimethyl-2-pyrone from 1-propyne and CO2 (1 MPa) with a TON of 50 [75]. The Rh-catalyzed reaction has been proposed to proceed through a mechanism (Scheme 5.15) not involving an oxametallacycle intermediate species. The CO2 insertion into the Rh-C(sp )-o-bond of a Rh-alkenyl intermediate, obtained upon propyne dimerization, affords a linear unsaturated carboxylate which is converted into the pyrone. 

The current paradigm for B syntheses came from the first report in 1957 of a synthesis of pyridines by cycloaddition reactions of oxazoles (36) (Fig. 5). This was adapted for production of pyridoxine shordy thereafter. Intensive research by Ajinomoto, BASF, Daiichi, Merck, Roche, Takeda, and other companies has resulted in numerous pubHcations and patents describing variations. These routes are convergent, shorter, and of reasonably high throughput. 

In a more recent and improved approach to cyclopropa-radicicol (228) [ 110], also outlined in Scheme 48, the synthesis was achieved via ynolide 231 which was transformed to the stable cobalt complex 232. RCM of 232 mediated by catalyst C led to cyclization product 233 as a 2 1 mixture of isomers in 57% yield. Oxidative removal of cobalt from this mixture followed by cycloaddition of the resulting cycloalkyne 234 with the cyclic diene 235 led to the benzofused macrolactone 236, which was converted to cyclopropa-radicicol (228). 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

Inverse electron-demand Diels-Alder reaction of (E)-2-oxo-l-phenylsulfo-nyl-3-alkenes 81 with enolethers, catalyzed by a chiral titanium-based catalyst, afforded substituted dihydro pyranes (Equation 3.27) in excellent yields and with moderate to high levels of enantioselection [81]. The enantioselectivity is dependent on the bulkiness of the Ri group of the dienophile, and the best result was obtained when Ri was an isopropyl group. Better reaction yields and enantioselectivity [82, 83] were attained in the synthesis of substituted chiral pyranes by cycloaddition of heterodienes 82 with cyclic and acyclic enolethers, catalyzed by C2-symmetric chiral Cu(II) complexes 83 (Scheme 3.16). 

An interesting example of accelerating a reaction when high pressure is applied is the synthesis of a series of highly functionalized 4a,5,8,8a-tetrahy-dro-l,4-naphthalenediones 10 by cycloaddition of p-benzoquinone (8) with a variety of electron-poor dienic esters 9 at room temperature (Equation 5.2) reported by Dauben and Baker [6]. Using conventional methods, these heat-sensitive cycloadducts are difficult to synthesize free of the isomeric hydroquin-ones. When the reactions were carried out under thermal conditions, the primary cycloadducts were mostly converted into the corresponding hydroqui-nones. 

The different ratios of 52/53 produced by cycloadditions performed at atmospheric and high pressure, and the forma tion of the unusual trans adducts 53, have been explained by the facts that (i) Diels-Alder reactions under atmospheric pressure are thermodynamically controlled, and (ii) the anti-endo adducts 52 are converted into the short-lived syn-endo adducts 54 which tautomerize (via a dienol or its aluminum complexes) to 53. The formation of trans compounds 53 by induced post-cycloaddition isomerization makes the method more flexible and therefore more useful in organic synthesis. 

More functionalized 5,6-dihydro-2H-pyran-derivatives 71 and 72 have been prepared [26] by cycloaddition of 1 -methoxy-3-trialkylsilyloxy-1,3-butadienes 69 with t-butylglyoxylate (70) (Scheme 5.6). Whereas thermal reactions did not occur in good yields because of the decomposition of the cycloadducts, application of pressure (10 kbar) allowed milder conditions to be used, which markedly improved the reaction yields. The use of high pressure also gives preferentially en Jo-adduct allowing a stereocontrolled synthesis of a variety of substituted 5,6-dihydro-2H-pyran-derivatives, which are difficult to prepare by other procedures. 

Two new pyridone derivatives (14) and (15) have been prepared by cycloaddition of saccharin pseudochloride (16 R = Cl) with Danishefsky s diene and by treatment of (16 R = Me) with ciimamoyl chloride. The synthesis of two more ting expanded derivatives (17) and (18) via cycloaddition to benzisothiazoles was also described <96T3339>. 

The synthesis of 2-azacycl[3.2.2]azine (imidazo[2.1.5-c /]-indolizine), 334, by Paudler et al. <1975JOC1210> (Scheme 97) is apparently the only successful synthesis to date, and is in effect a variant of the Vilsmeier-Haack-Arnold method of Scheme 90. All attempts to synthesize the ring system by cycloadditions to imidazo[l,5- ]pyridine have been unsuccessful. 

The process has been applied to the synthesis of a A9-19-nor-10-azatesto-sterone 378 by cycloaddition of nitrile oxide 377 to MCP followed by thermal rearrangement of the adduct (Scheme 52) [94]. 

A synthesis of highly-substituted tetracenes was developed starting from isoindole (benzo[c]pyrrole) <06OL273>. For example, treatment of dibromonaphthalene 87 with phenyllithium in the presence of isoindole 86 followed by deamination of the intermediate cycloadduct provided tetracene 88. Separately, the synthesis and cycloaddition chemistry of oxadisilole-fused isoindoles was investigated <06SL2510>. 

An example of asymmetric synthesis involving cycloaddition of an azide to dimethyl acetylenedicarboxylate is depicted in Scheme 172. Thus, asymmetric auxiliary 1042 reacts with styrene and sodium azide to generate azide 1043 in 90% yield and 94% diastereomeric purity. The following reaction (Scheme 172) with dimethyl acetylenedicarboxylate converts azide 1043 into triazole 1044 in 75% yield. Finally, the bond with selenium is cleaved by treatment with triphenyltin hydride and AIBN to furnish triazole 1045 in 80% yield and preserved optical purity (94%) <2003AGE3131>. 

Synthesis of Five-membered Cyclic Nitronates by Cycloaddition Reactions... 

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