The Reaction of Isobenzofulvenes with Heterodienophiles: A Simple Route to 2­Heterobicyclo[2.2.1]heptenes and their Conversion to Indeno[1,2-c]Furans and Thiophens

Ronald N. Warrener,* Peter A. Harrison and Richard A. Russell [1]

Centre for Molecular Architecture, Central Queensland University, Rockhampton, Queensland, 4702, Australia.

Abstract: 8,8-Dimethylisobenzofulvene is generated in situ and trapped with the heterodienophiles thiophosgene, diethyl oxomalonate and tosyl cyanide to produce [4p+2p] cycloadducts; ring-opening and rearrangement reactions of the keto and thione adducts yielded novel indeno[1,2-c]furans and indeno[1,2-c]thiophens while the nitrile adduct could be converted to the related 2­azanorbornan-3-one without change to the bicyclic ring-system. None of these products served as a precursor to 8,8­dimethylisobenzofulvene. Graphical Abstract

1. Introduction

Cram and his group at UCLA have recently described a new technique for the stabilisation of reactive species by encapsulation within calixarene-based hosts [2]. We have conducted much research on the chemistry of isobenzofulvenes and used trapped adducts to evaluate periselective outcomes with various cyclic polyenes [3]. The blue-coloured, monomeric isobenzofulvene has been prepared by a flash vacuum pyrolysis technique and found to be stable up to -100 oC [4] The Cram technology appeared to offer a unique opportunity to stabilise isobenzofulvene systems at room temperature and allow their study by NMR techniques. It soon became apparent that existing thermal or photochemical routes to isobenzofulvenes involved large sized precursors or high temperature conditions unsuitable for encapsulation studies. Accordingly, we sought new small-sized precursors for the photochemical generation of isobenzofulvenes. We have recently conducted a study on the host, guest size compatibility using computation methods, and can now predict the appropriate guest dimensions for successful hemicarcerand formation [5].

We report herein our synthetic studies on the preparation of heteroalicyclic precursors which have the potential to expel small stable molecules and yield isobenzofulvenes.

1.1. Earlier Approaches to the Synthesis of Isobenzofulvenes

Although known to theoreticians for over three decades [6], isobenzofulvene 5 has resisted the wiles of the organic chemist and still remains to be identified as a monomeric species. To date, the only syntheses of the parent isobenzofulvene 5 have elimination processes [4,7], and while it has been possible to produce [4p+2p] cycloadducts when generated in the presence of dienophiles such as N-methyl maleimide, only dimeric products are formed in the absence of trapping agents. Although successful in producing 8-monosubstituted-isobenzofulvenes and 8,8-disubstituted isobenzofulvenes [8], application of the s-tetrazine-induced fragmentation of 7-methylenebenzo-norbornadiene 1 failed to generate the parent isobenzofulvene and only the 1,4-dihydropyridazine 4, formed by rearrangement of the intermediate 1,2-dihydropyridazine 3 (Scheme 1). It is now known that such dihydropyridazine rearrangements can be suppressed in the presence of triethylamine [9] but application of this new finding has not been attempted at this point in time.

Scheme 1

Following the successful isolation of o­xylylene 8 via the matrix photolysis of the diazo compound 7 [10] (Scheme 2), an attempt was made to synthesize the diazo compound 9b, as a photochemical precursor to the 8,8-dimethyl substituted isobenzofulvene 10, with the intention of extending this idea to the generation of the parent compound 5 from 8a.

Scheme 2

This idea, however, was not realised as attempted hydrolysis of the intermediate hydrazide 12 resulted in ring cleavage to yield the substituted indene 13 (Scheme 3) [11]. Clearly this type of rearrangement could not occur in the parent system; further, more recent studies have shown that carbamate esters of this type can be hydrolysed at low temperature using BBr3, however neither of these features has been explored.

Scheme 3

In view of the recent success in generating isoindene 15 via the photochemical bisdecarbonylation of a-diketone 14 [12] and of spirocyclopropylisoindene 17 from irradiation of a­diketone 16 [13] the diketone 19 presented itself as a promising precursor to isobenzofulvene (Scheme 4). However, irradiation of 19 lead to a photoinduced isomerisation and production of the enolone 22 as the sole photoproduct.

Scheme 4

Thus, we turned our attention to the heterocyclic compounds 23-25 (Scheme 5) as possible precursors for isobenzofulvene, and the present study describes some of our synthetic endeavours in their production.

Scheme 5

1.1 Background to the selection of the target molecules 23-25

The use of b­lactones as photochemical precursors to thermally labile systems has been established. The cheletropic loss of carbon dioxide from the b-lactone 26 is now a well developed route to cyclobutadiene 27 [14] (Scheme 6, boxed section), and was used as the precursor in Cram's study which tamed cyclobutadiene [2]. Thus, the selection lactone 23 was justified on this basis. By analogy, it was of considered of interest to investigate the photochemical activity of the related thiolactone 24.

Scheme 6

Although the cheletropic loss of isocyanic acid (HNCO) from b­lactams is not presently known, the photochemical loss of phenyl isocyanate (PhNCO) from the substituted b-lactam 28 has been reported [15] (Scheme 6, route a). In this system, however, photochemical cleavage of the carbonyl-to-nitrogen bond has also been observed [15] resulting in the production of imine 31 together with ketene 32 (Scheme 6, route b).

Because of the synthetic accessibility of 8,8-dimethylisobenzofulvene 10 it was decided to use these as model systems to check the feasibility of these heterocyclic compounds as photochemical precursors to isobenzofulvenes 10. It is well established that 8,8­dimethylisobenzofulvene 10 can be readily produced from 33 by the s­tetrazine route (Scheme 1), which, in the presence of the heterocyclic dienophile was expected to yield the adducts 35, 37, 39 which were to be modified to give the desired carbonyl compound 23-25 respectively (Scheme 1).

Scheme 7

Thiophosgene 34 is an established dienophile and has been reported to form [4p+2p] products with cyclopentadiene 14 [16], spirocyclopropyl cyclopentadiene 15 [17] and 9-methyl anthracene 16 [18]. Such adducts are known to be readily hydrolysed to the corresponding bicyclic thiolactone [19]. In addition, several ketone have been observed to participate in Diels-Alder cycloadditions and their reactivity is increased when electron-withdrawing groups are attached to the carbonyl group, thereby favouring the proposal for the use of diethyl oxomalonate 36 in this role [19]. Ruden and Bonjouklian[20] have proposed the use of diethyl oxomalonate as a synthetic equivalent for carbon dioxide and have reported that the gem-diester groups can be transformed to a ketone using the Curtius reaction. Nitriles are less common as dienophiles and most work to date has utilised sulfonyl cyanides such as 38 owing to their high dienophilicity [21]. Indeed, the role of simple nitriles as cycloaddition reagents has only been reported this year [22]. Facile hydrolysis of tosylcyanide adducts to lactams has also been described [19].

2. Results and Discussion