Dearomatization-Aromatization Sequence

Transition-Metal-Mediated Aromatic Ring Construction, First Edition. Edited by Ken Tanaka. 2013 John Wiley Sons, Inc. Published 2013 by John Wiley Sons, Inc. 

This chapter deals with advances in the synthetic application of the transition-metal-catalyzed reactions of arynes or o-QDMs, except for the cycloaddition of arynes, which was described in earlier chapters. Because arynes and o-QDMs, which can be regarded as dearomatized reactive intermediates, are utilized for the construction of aromatic skeletons via the reactions discussed herein, this chapter is entitled Dearomatization-Aromatization Sequence.  

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A variety of catalytic transformations for constructing aromatic skeletons by use of arynes and o-QDMs have been developed based on the dearomatization/aromatization sequence, leading to the direct formation of benzo-annulated structures and multisub-stituted arenes of structural diversity. Because precise control of the high reactivity... 

Since arynes and o-QDMs can be regarded as reactive equivalents of alkynes and 1,3-dienes, which have rich chemistry in catalytic transformations, there would be a number of unexploited reactions with arynes and o-QDMs, which further enhance the versatility of the dearomatization/aromatization sequence. 

Reaction of nucleophiles with the polarized N=C bond of azines proceeds via dearomatization and formation of the corresponding 1,2-adduct. With alkyllithiums, for example, it is possible to isolate the dihydro products by careful neutralization of the reaction mixtures these are, in general, rather unstable, however, and can easily be reoxidized to the fully aromatic compounds (Scheme 4). The dihydro adducts formed in these direct nucleophilic addition reactions can also be utilized for the introduction of substituent groups /3 to the heteroatom. Thus, reaction of (35) with one of a number of electrophiles, followed by oxidation of the intermediate dihydro product, constitutes a simple and, in many cases, effective method for the introduction of substituent groups at both the 2- and 5-positions of the pyridine ring (Scheme 4). Use of LAH in this sequence, of course, results in the formation of 3-substituted pyridines. 

Norethindrone 31a, the gestagenic component in the combination pill, is smoothly accessible from estrone-methylether by partial synthesis [71]. The reaction sequence begins with a dearomatization (Birch reduction) and ends with an ethynylation (Scheme 1-10), necessary for the oral applicability. Technical production of estrone 24 (or estradiol) from inexpensive steroids such as diosgenin or cholesterol by partial synthesis is also feasible. Pyrolytic aromatization (Inhoffen at Schering AG) assists the transition from the steroid to the 19-nor-steroid class (such as from androsta-1,4-dien-l 7/i-ol-3-one 32 to estradiol 33 [72]). 

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