The Junjappa-Ila (JI)-Heteroaromatic Annulation: A New General α-Oxoketene Dithioacetals Mediated Inverse Method for the Synthesis of Benzo/Condensed Heterocycles and Related Heteroaromatization Processes

H. Ila, *hila@iitk.ac.in; H. Junjappa, *; P.K. Mohanta    Department of Chemistry, Indian Institute of Technology, Kanpur-208 016, India, Fax: 91-0512-597436, 91-0512-590260

1.1 INTRODUCTION

The classical methods for the synthesis of five and six membered benzoheterocycles generally involve a sequential construction of heterocyclic component over the preconstructed regiospecifically substituted benzene ring. This conventional benzoheterocyclic chemistry has been extensively investigated and still continues to be an active area of research. The required substitution pattern in the benzene ring of these heterocycles is generally achieved by subjecting the aromatic compounds to a series of stepwise electrophilic or nucleophilic substitution reactions. These efforts have evolved into elegant heteroaromatic chemistry from which a vast range of benzo-fused heterocycle compounds has emerged. However the synthesis of highly substituted benzene derivatives demands multistep reaction sequences which face difficulties of ortho, meta and para orientation resulting in the formation of isomeric mixtures and consequently poor yields of target molecules which negates the abundance of fossil resources. Some of these limitations are so prominently rigid that many of the substitution patterns still remain unexplored.

Modern methods for the synthesis of substituted aromatic compounds involve highly convergent annulation routes in which the aromatic system is assembled from acyclic precursors in a single step. Particularly noteworthy aromatic annulation reactions developed in recent years include methods based on Diels Alder chemistry, Robinson annelation <76S777> and transition metal mediated Fischer carbene complexes <91COS(5)1065>. However these annulation methods have found limited applications for benzoheterocycle synthesis i.e. construction of a benzene ring on to preconstructed heterocycles and the only transformations of potential general scope which fall under this category are [4 + 2] cycloaddition of heterocyclic o-quinodimethanes <99CRV3199> or benzoannulation with Fischer type heteroaryl carbene complexes.

Recently [3 + 3] benzoannulation reactions <99T8263> have become the subject of intense investigation primarily due to easy availability of three component synthons and high degree of regiocontrol observed in these reactions. Among many other variations of this category, [3 + 3] benzoannulation of α-oxoketene dithioacetals with allyl anions and its hetero variants developed in our laboratory (1984) have emerged as versatile general methods for the construction of a wide range of substituted aromatic and heteroaromatic compounds which we now call “The Junjappa-Ila (JI) aromatic and heteroaromatic annulation”. The JI aromatic annulation has been reviewed <90T5423; 94MI35; 99T8263; 01JOM(624)34> but the present review covers only the JI heteroaromatic annulations.

1.2 SYNTHESIS OF BENZOHETEROCYCLES: INVERSE APPROACH

1.2.1 Allyl Anions Derived from Five and Six Membered Heterocycles (1,3-Binucleophilic Components)

In principle, a wide variety of five and six membered heterocycles bearing a ring C–C double bond with an exocyclic methyl group can be used as allyl anion precursors for benzoheterocycles. The required heterocycles can either be bought or they can be prepared by reported procedures. Theoretically possible anions from various five or six membered heterocycles are depicted in Scheme 1 (Type I-V). Thus the heteroallyl anions 1a-b (Type-I), 2a-b (Type-II) and 3a-b (Type-III) can be generally prepared either by Grignard reaction or by metallation. The reaction of 1a-b and 2a-b with 6 generally yields the corresponding carbinol dithioacetals 7a-b and 9a-b in nearly quantitative yields following the expected 1,2-addition mode. These carbinol acetals can be cycloaromatized in the presence of Lewis acid to yield the corresponding benzoheterocycles 8a-b and 10a-b in high yields. However, when ring atom X = > C = O, the allyl anions 3a-b may react with 6 to afford the intermediates 11a-b involving 1,4-addition-elimination sequence (Type-III) and follow direct insitu cycloaromatization (or acid assisted) to afford the corresponding angularly substituted and fused benzoheterocycles 12a-b in high yields. In the Type IV and Type-V category, the exocyclic methyl group carries an electron withdrawing group (EWG, CN or SChPh) in place of one of the hydrogen atoms and the corresponding anions 4a-b and 5a-b are generally derived under mild basic conditions which on reaction with 6 afford the corresponding 1,4-addition-elimination adducts 13a-b and 15a-b in excellent yields. These intermediates undergo facile acid assisted cyclization to afford the corresponding angularly substituted and fused benzoheterocycles 14a-b and 16a-b respectively in high yields.

The synthetic strategies depicted in the Scheme 1 provide an overall view of the scope and potential of JI-heteroaromatic annulation protocol to yield benzoheterocycles with full regiocontrol on all the four positions of the newly formed benzene ring.

1.2.2 The α-Oxoketene Dithioacetals: (1,3-Biselectrophilic Components)

The α-oxoketene dithioacetals 6 (6.1-6.43) employed in this work as three carbon 1,3-biselectrophilic components have been drawn from various active methylene ketones and are described in the Table-1. The corresponding a-oxoketene N,S- and O,S-acetals (17.1-17.15) which are usually derived from a-oxoketene dithioacetals are described in Table-2. These examples are only a representative groups to demonstrate the general application of the new JI-heteroaromatic annulation methodology