Thia Diels-Alder Reactions

The stereoselectivity of hetero Diels-Alder reactions of thioaldehydes and cyclopentadiene has thoroughly been investigated by Vedejs and his coworkers [404]. In general, these cycloadditions proceed only with moderate endo selec-tivities for high endo-selectivities, very bulky thioaldehydes are necessary. This 

In a more recent study, Koizumi et al. employed terpene derivatives as chiral auxiliaries attached to thioaldehydes [405], but these heterodienophiles gave only moderate diastereoselectivities in reactions with cyclopentadiene. Mazzan-ti et al. have investigated the hetero Diels-Alder reaction of thioketones bearing an asymmetric silicon atom directly attached to the thiocarbonyl moiety which induced diastereoselectivities up to 50% de [406]. 

Due to the high reactivity and high sensitivity of thioaldehydes, Lewis acid catalysis has not been applied to thia Diels-Alder reactions. However, Heim-garten et al. clearly demonstrated the suitability of Lewis acids to make less reactive thiocarbonyl compounds, e. g. thiazole thiones, react as heterodieno-philes in hetero Diels-Alder reactions [412]. 

Similarly to the homologous 1-oxa-1,3-butadienes, 1-thia-1,3-butadienes are known to be very suitable and reactive substrates for hetero Diels-Alder reactions. However, in contrast to the oxa-1,3-butadienes which in general act as electron-deficient component in such cycloadditions, thia-1,3-butadienes predominantly undergo normal electron demand Diels-Alder reactions with electron-deficient dienophiles. Nevertheless, also some reactions of thia-1,3-butadienes involving electron-rich dienophiles have been described [412,413], Thia-1,3-butadienes considerably tend to dimerize due to their high reactivity in hetero Diels-Alder reactions [414]. 

Enaminothiones such as 5-10 bearing an electron-donating dialkylamino moiety have been extensively used as thia-1,3-butadienes [415-417]. In a typical procedure, 5-10 cycloadded to the oxoglutaconic acid derivative 5-11 in the absence of any catalyst under very mild conditions. Subsequent elimination of dimethylamine yields the thiopyran 5-12 (Fig. 5-3) [418]. 

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Finally, a thia Diels-Alder reaction representing a less common cycloaddition type in natural product synthesis shall be discussed. Thus, Vedejs et al. have included such a cycloaddition into an elegant strategy aimed at the synthesis of macrocyclic [ll]-cytochalasans such as zygosporin E 7-76 [536-538]. Thus, release of the thioaldehyde 7-73 from its phenacyl sulfide precursor in the presence of the silyloxydiene 7-74 yielded 7-75 as 2 1 mixture with its C20 epimer. Fortunately, equilibration of this mixture raised the ratio up to 10 1. Several subsequent steps yielded the tetracyclic intermediate 7-77 cleavage of its thioether moiety then liberated the 11-membered macrocycle present e.g. in zygosporin E 7-76 (Fig. 7-16). 

A review of the asymmetric thia-Diels-Alder reactions of chiral dithioesters with dienes has been published. The asymmetric organocatalytic thio-Diels-Alder reac- 0 tion of thiocarbonyls with a-methylene carbonyl dienes produced dihydrothiopyrans in high yields and high to excellent selectivities. The inverse-electron-demand 0 hetero-Diels-Alder cycloadditions of norbomene (106) with 5-benzylidene-2-arylimino-3-aryl-thiazolidine-4-thiones (107) at 25 °C produced cycloadducts (108)... 

Dithioesters bearing a chiral auxiliary have been used in asymmetric thia-Diels-Alder reactions with acyclic 1,3-dienes to produce cycloadducts with a diastereomeric excess of 90%. A Cu(II)bis(oxazoline)/dithioesters complex has been proposed to rationalize the chiral induction ... 

One of the features of Diels-Alder reactions with most alkyl and aryl nitriles that has made them rather unattractive as dienophiles is the requirement of very high reaction temperatures Again, only when electron-withdrawing substituents are directly bonded to the nitnle function do [4+2] cycloaddition reactions occur at reasonably low temperatures [ 48, 231, 232] A high yield [4+2] cycloaddition was observed on reaction of 4,4-bis(trifluoromethyl) 1 thia-3-aza-l,3-butadienes with trifluoroacetonitrile at 150 °C [225]... 

Thia-1,3-butadienes have been successfully employed in intramolecular hetero Diels-Alder reactions [414, 424, 425]. More recently, some interesting varieties of such intramolecular cycloadditions which allow the efficient construction of sulfur containing polycyles have been worked out by Saito s group. 

The use of Lewis acids in order to catalyze hetero Diels-Alder reactions of thia-1,3-butadienes is not widespread, but recent investigations stemming from Saito et al. reveal a remarkable acceleration of these transformations in the presence of A1C13 or EtAlCl2 [428]. In a first study concerning asymmetric hetero Diels-Alder reactions of thia-1,3-butadienes, Saito et al. found Lewis acids to have a beneficial effect on the induced diastereoselectivities. Thus, the thioketone 5-17, generated in situ by thermal cycloreversion from its dimer, underwent a completely endo-selective cycloaddition upon treatment with (-)-dimenthyl... 

In contrast to 1-thia-l,3-butadienes, the use of 2-thia-1,3-butadienes in hetero Diels-Alder reactions has only sparingly been studied. First work concerning the stereochemical course of intramolecular cycloadditions involving 2-thia-butadienes has been carried out by Beifuss et al. very recently [438]. The catio-... 

In addition to the mentioned oxa-, aza- and thia- 1,3-butadienes and the hitherto discussed dienophiles, a multitude of polyhetero dienes and -dienophiles have been employed in recent hetero Diels-Alder reactions. The array of heteroatoms amenable for such cycloadditions is by no means restricted to oxygen, nitrogen and sulfur since there exist numerous reactions involving less common heteroatoms such as phosphorus, silicon or selenium. 

Hetero Diels-Alder reactions of l-thia-3-aza-l,3-butadienes have also attracted theoretical interest resulting in a study dealing with kinetic and thermodynamic parameters of such cycloadditions [444]. 

N-Acylimines which may react as l-oxa-3-aza-l,3-butadienes represent a class of heterodienes which exhibit a close relationship to l-thia-3-aza-l,3-butadienes [13]. A very impressive application of such an l-oxa-3-aza-l,3-butadiene has been worked out by Swindell et al.[445]. The asymmetric hetero Diels-Alder reaction described therein opens a very elegant approach to the A-ring side chain of taxol. This synthesis takes advantage of the bulky chiral auxiliary attached to the dienophile 6-5 which upon cycloaddition with the l-oxa-3-aza-1,3-butadiene 6-4 yielded the 1,3-oxazine derivative 6-6. Subsequent hydrolysis, hydrogenolysis and transesterification gave the methyl ester of the taxol A-ring side chain 6-7 in good endo and excellent zr-facial selectivity (Fig. 6-2). 

In contrast to the thorough studies of the Diels-Alder reactions of oxa- and aza-butadienes, the [4 + 2] cycloaddition reactions of 1-thia-1,3-butadienes have not been studied extensively.Although the general participation of thiabutadienes in LUMOdiene-controlled [4 + 2] cycloaddition reactions has been recognized and experimentally verified, most investigations have detailed their 4rr participation in HOMOdiene-controlled reactions with typical electron-deficient dienophiles. In such instances, the complementary C-2 or C-4 addition of electron-donating substituents to the 1-thia-1,3-butadiene increases the rate and regioselectivity of its Ait participation in HOMOdiene-controlled Diels-Alder reactions. With notable exceptions, the LUMOdiene-controlled Diels-Alder reactions provide the expected 2-substituted 3,4-dihydro-2//-thiopyrans and, unlike simple 1-oxa-1,3-butadienes, the HOMOdiene-controlled Diels-... 

Alder reactions of 1-thia-1,3-butadienes with electron-deficient or conjugated dienophiles provide 3-sub-stituted 3,4-dihydro-2ff-thiopyrans (equation 6). Representative Diels-Alder reactions of 1-thia-1,3-butadienes are presented in Table 7 and hetero-l-thiabutadienes that have been demonstrated to participate in [4 + 2] cycloaddition reactions are summarized in Figure 4. ... 

The 4-oxa-l-thia-l,3-butadienes, the acyl sulfines 25 and acyl sulfenes 26, which have been shown to be capable of 4ir participation in selected Diels-Alder reactions, have been summarized in the preceding section. It... 

The aza-l-thia-1,3-butadienes are the most widely recognized and thoroughly investigated hetero-l-thiabutadienes capable of 4w Diels-Alder participation. A single report has detailed the [4 + 2] cycloaddition of the selected 4-aza-l-thia-l,3-butadiene 28 as the 47t component of a Diels-Alder reaction [Eq. (20)].55... 

A wide range of 3-aza-l-thia-l,3-butadiene systems has been extensively investigated as Att components of Diels-Alder reactions. The work with each of these systems is summarized in Chapter 9 and includes the 477-Diels-Alder reactions of appropriately substituted TV-thioacylimines (e.g., 29, Chapter 9, Section 3),47-56 thioacyl isocyanates (e.g., 30, Chapter 9, Section 3),5758 thioacyl isothiocyanates (e.g., 31, Chapter 9, Section 3),5759 and TV-thioacyl dithioimidocarbonates (e.g., 32).2223 Examples of... 

The reaction of vinylfurans with DAD usually affords intractable mixtures however, furan itself undergoes cycloaddition readily, provided suitable reaction conditions are employed to avoid decomposition of the reactive products. Oxazole derivatives readily participate in [4 + 2] cycloadditions with DAD. 7 asymmetric Diels-Alder reaction between DAD and pyridazin-3-ones facilitated by Baker s Yeast has been reported with ee s in the range of 9.1-62.7%. The reactions of a number of acyclic heterodienes with DAD have also been reported recently, including 2-aza-l,3-dienes, a,p-unsaturated thioketones, and l-thia-3-aza-1,3-dienes. The quinodimethane derivatives of a number of heterocycles have been used in cycloadditions with DAD (eq 9). ... 

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