IMDAF

Intramolecular Diels-Alder reactions of the furan diene (IMDAF) rapid construction of highly functionalized isoquinoline skeletons [65i]... 

The IMDAF (intramolecular Diels-Alder furan) precursors 492 were prepared via Michael addition of nucleophiles possessing an unsaturated tether 491 to furoyl nitroalkene 490. Furyl nitroalkene 490 was prepaperd via the nitroaldol (Flenry) reaction. Compound 492 was heated in appropriate solvent such as toluene, xylene, etc., to provide the IMDAF cycloadducts 65 and 66 (Table 16) <2005JOC2235>. 

Table 16 Michael addition of C-, N-, 0-, and S-centered nucleophiles to furyl nitroalkene and subsequent IMDAF reaction of...

Entry X Y n Step 1 (Michael addition) reagents and conditions Yield of 492 (%) Step 2 IMDAF) solvent and conditions Yield of 65+66 (%) 65 66... 

The intramolecular Diels-Alder reaction of furans, often designated as IMDAF,15 helps to overcome the sluggishness of this heteroaromatic ring system toward [4+21-cycloaddition. Not only do IMDAF reactions allow for the preparation of complex oxygenated polycyclic compounds, but they also often proceed at lower temperatures than their intermolecular counterparts.9 Even more significantly, unactivated rc-bonds are often suitable dienophiles for the internal cycloaddition. Indeed, the submitters discovered that the IMDAF reaction of a series of furanamide derivatives occurred... 

Padwa and co-workers have shown that the amides 55 can be conveniently prepared in high yield by [4 + 2]-cycloaddition of an acetylenic dienophile to the corresponding 2-amino oxazole derivative 54 (Eq. (6)). The reaction was extended to intramolecular reactions (e.g. 56 - 57, Eq. (7)), giving convenient 2-aminofuran precursors for further intramolecular Diels Alder furan (IMDAF) reactions (see Section Il.C.l.e) (99JOC3595, 99TL1645). 

The nitrogen atom of amides and carbamates 155 can be alkylated using standard procedures (Eq. (23)) and this type of transformation has been studied extensively in the context of using the products 156 in IMDAF (see Section Il.C.l.e, Schemes 24-26). 

In 2011, Wipf and Petronijevic reported their synthesis route to ( )-cycloclavine (169) (Scheme 4.4), in which the total synthesis proceeded in 14 steps with 1.25% overall yield (148). One key feature of their approach included the formation of the indole moieties through an allylic alcohol-IMDAF (intramolecular Diels-Alder cycli-zation of furan) reaction (212 to 213) (149,150). Another pivotal step of this route is the synthesis of the cycloclavine indoline core through a stereoselective intramolecular Diels-Alder reaction of a methylenecyclopropane building block (208 to 209). 

Boonsompat J, Padwa A (2011) An IMDAF Cycloaddition Approach Toward the Synthesis of the Lycopodium Alkaloid ( )-Fawcettidine. J Org Chem 76 2753... 

Intramolecular Diels—Alder cycloaddition of furans (IMDAF) for natural product synthesis 13AHC(110)1. 

Intramolecular Diels-Alder reactions involving furan (IMDAF) are useful synthetic tool for the formation of two or more rings with stereo- and regiocontrol in a single reaction step [14], The literature examples of... 

More unusual IMDAF reactions involve 2-vinylfuran as an extra-annular diene in which vinyl and furan C4-C5 double bond act as a diene. This synthetic approach was employed by Harwood in the synthesis toward colletofraga-rone A1 (Scheme 18) [31]. The intramolecular reaction showed that the use of a 2-vinylfuran substrate 73 with the dienophile connected by a tether chain at C-4 of the furan nucleus, formed a single tricyclic adduct 74 with a similar skeleton to that of the tricyclic core of colletofragarones. In this instance, the mildness of the high-pressure conditions permits the cycloadducts to be isolated without subsequent isomerization of the double bond to reform the furan, and in greatly superior yields to the thermal conditions (benzene 80 °C, 24 h, 28%). 

HIMDA intramolecular hetero Diels-Alder reaction IMDAF intramolecular furan Diels-Alder reactions i-Pr isopropyl Me methyl Ms mesityl neoPn neopentyl P pressure Ph phenyl... 

Furans are also useful 4ti components for tandem Ugi condensation/intramolecular Diels-Alder cascade reactions. For example, stirring a methanolic mixture of compounds 131-133 and benzylamine at room temperature gave the Ugi condensation product 134 that underwent a subsequent intramolecular Diels-Alder furan cycloaddition (IMDAF) to furnish 135 in 70-90% yield (Scheme 13.35) [69,70]. This methodology also allowed for a solid-phase synthesis by using an ArgoGel-Rink resin as the amine component, thereby providing cycloadducts 135 (after cleavage from the resin) in 90-95% yields. 

Microwave irradiation was found to be an effective tool for accelerating IMDAF cycloadditions, and the Wipf group used microwave assistance in a Diels-Alder approach to 4-substituted indoles. Thermolysis of 155a in boiling toluene... 

The IMDAF of the 2-amidofuran system occurs quite readily and has been studied in some detail by Padwa et al. [101]. Not only do these IMDAF reactions allow for the preparation of complex polycyclic compounds, they have also been found to proceed at lower temperatures than their bimolecular counterparts. Even more significantly, unactivated 7t-bonds can function as suitable dienophiles for the internal cycloaddition. For example, the IMDAF reaction of furanyl carbamates 235 and 236 was carried out by heating a benzene... 

The IMDAF reaction of 2-amidofurans was subsequently used as a method to synthesize the tetrahydroquinohne core ring system found in a number of alkaloids. Thus, the intramolecular Diels-Alder reaction of 2-amidofuran 266 furnished tetrahydroquinohne 267 in 79% yield thereby demonstrating the efficacy of the method (Scheme 13.60). 

Synthesis of the more complex target dendrobine 288 was also successfully completed by Padwa et al. (Scheme 13.65) [107]. This required an IMDAF reaction between 2-amidofuran 285 and a trisubstituted, unactivated dieneo-phile contained in the tether. When 285 was heated at 165 °C for 15 h, the highly functionalized tricyclic enamide 287 was obtained in 74% yield. Due to the instability of the oxabi-cychc adduct 286 that was formed from the IMDAF reaction, it was not possible to isolate the initial Diels-Alder adduct. 

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