Indenols, synthesis

In recent years several closely related transition metal processes have been reported. For example, both catalytic amounts of Col2(dppe) [133, 134] and NiBr2(dppe) [135] in the presence of Zn metal and acetonitrile will effect this same indenol synthesis from o-haloaryl aldehydes or ketones and alkynes. Similarly, rhodium will catalyze the formation of indenones from simple aroyl chlorides and internal alkynes (Eq. 69) [136]. 

Similar treatment of carbonate roc-20 with Pd(0)/L (2 mol%), BPA (3 mol%), and water in CH2CI2 afforded indenol 21 in 88% yield with 97% ee (Scheme 2.1.4.26) [37]. Indenol 21 and cyclopentenol 9d are useful building blocks for the synthesis of an HlV-protease inhibitor and a chiral catalyst for asymmetric Diels-Alder reactions, respectively [38]. 

Scheme 4. Synthesis of indenols by nucleophilic attack of a vinylic palladium species on a carbonyl (c) 5 mol% Pd(OAc)2, 2equiv. KOAc, lOequiv. EtOH, DMF, 60°C, 24h.

Cascade intermolecular carbopalladations of alkynes followed by intramolecular trapping with electrophiles represent not only a novel type of organic transformation involving vinylpalladium intermediates, but also provide synthetically useful routes toward differently substituted indenols, indanones, indenones, and naphthy-lamines." Although these protocols are restricted to the intramolecular trapping with electrophiles, a wide application of this methodology toward the synthesis of various types of complex carbocychc compounds may be anticipated in the near future. 

Scheme 7.4 Synthesis of indenols and indenones by eilkynylation of qrclometalated compounds [68]...

Reaction of the cyclometallated derivative of phenyl-2-pyridylketone 73 leads to indenol-chelated, palladium-containing derivatives 74. Here, incorporating an electrophilic (CO) function in the starting palladacycle signifies that, following alkyne insertion in the Pd-C bond, an intramolecular attack of the vinyl palladated unit on the metal-bound, activated CO function occurs. This is in sharp contrast to the reaction described in Scheme 9 whereby incorporating a nucleophilic, masked, secondary amine function leads to indole derivatives 40 and to the azepinium synthesis from the metallated benzylpyridine complex 34. Therefore, these reactions are rather sensitive to the nature of other potentially reactive functions within the metallacyclic framework. 

One of the most challenging vitamin D precursors to prepare is (3aJ ,4, 7a, -(Z)-ethylidene-7a-methyloctahydro-1. ff-4-indenol (88). Many possible approaches to this key intermediate were reviewed recently. Since then, ongoing work at Hoffman-LaRoche has produced an updated route starting from Hajos dione 3. One of the key problems in the original approach was the thermal instability of fert-butyl copper hydride used in the reduction of the double bond. Replacement of t-BuCu with dimethylphenylsilyl copper gave a better yield than that obtained with the former reagent. The remaining steps of the synthesis of 88 are shown below. 

Scheme 24 Mechanism for Ru(II) catalysed synthesis of indenol and benzofulvene from arylketones...

The data shown in Table 2 suggest that C-methylation of indenones 1 with trimeth-ylaluminum was an important improvement in the synthesis of indenol derivatives 2 because the yields were higher with respect to those obtained by means of other standard methods. Moreover in most cases, the indenol derivative was used in the following step of the synthesis without any further purification. The introduction of a fluorine atom at the 2-position of the benzofulvene nucleus of BF3c was carried out at the indenol stage. Thus, indenol 2e underwent lithium-halogen exchange with t-BuLi in THF and subsequent fluorination with Af-fluorobenzenesulfonimide (NFSI). 

---