Oxidative Dearomatization: Synthesis of Functionalized Bicyclo[2.2.2]octenones, Sigmatropic Shift in Excited State, and Radical-Induced Cleavage of Cyclopropane Ring

Abstract Synthesis of novel bicyclo[2.2.2]octenones endowed with a β,γ-enone system in which γ-carbon is substituted with an electron-withdrawing group from simple aromatics is described. Oxa-di-pi-methane reaction of bicyclo[2.2.2]octenones to functionalized bicyclo[3.3.0]octanes and their transformation to bicyclo[3.2.1]octane framework are also presented. GRAPHICAL ABSTRACT


INTRODUCTION
Rapid creation of structural, functional, and stereochemical complexity is one of the most important aspects of synthesis design and development of methods. Cascade reactions and multicomponent reactions are often employed to achieve this objective. [1] In addition, chemistry of reactive species generated by oxidative dearomatization of phenols has played a very important role in developing methods for efficient generation of molecular complexity and has proved to be a powerful method for synthesis of a diverse array of molecular architecture. [2][3][4] Functionalized bicyclo[2.2.2]octanes such as 1 (Fig. 1) endowed with a b,cenone chromophore are versatile intermediates for the synthesis of a diverse array of molecular architectures and serve as precursors for many complex natural products. [5] This is presumably due to their propensity toward various types of regio-and stereoselective reactions by virtue of their rigid structure and interaction among functional groups. For example, bicyclo[2.2.2]octane of type 1 having a b,c-enone chromophore undergoes two unique photoreactions such as 1,2-acyl shift (oxa-di-p-methane rearrangement) and 1,3-acyl shift upon triplet and singlet excitation respectively, as a consequence of homo-conjugation between carbonyl group and olefinic moiety. [6][7][8][9] In view of this and our continuing interest in synthesis and photoreaction of b,c-enone, we considered exploring the photochemical reaction of bicyclo[2.2.2] octenones of type 2 ( Fig. 1) in which the C = C moiety is also conjugated with ester function in addition to homo-conjugation with the CO group and examine the effect of additional conjugation on the photochemical reaction.
We report herein an efficient synthesis of compounds of type 2 via a tandem oxidative dearomatization of aromatic precursor 5 and cycloaddition with ethyl acrylate, and results of photoreactions of compound 2 to diquinanes such as 3 and radical-induced transformation to bicyclo[3.2.1]octanes 4 (Fig. 1).

RESULTS AND DISCUSSION
Conceptually, the desired bicyclo[2.2.2]octenones of type 2 may be prepared by cycloaddition of cyclohexa-2,4-dienones of type I (Fig. 2) with acrylate. However, cyclohexa-2,4-dienone such as I are not easily accessible as these are keto-tautomer of the corresponding phenols. Therefore, we considered employing 6,6-spiroepoxycyclohexadienones such as 6 that may be generated in situ from the aromatic precursor of type 5 via oxidative dearomatization.
To realize our objective, a simple preparation of o-hydroxymethyl phenols 5a,b was required. The compound 5a was prepared by hydroxymethylation of Figure 1. Biocyclo[2,2,2]octanes, related products, and precursor.

OXIDATIVE DEAROMATIZATION
t-butyl-4-hydroxy benzoate 7a that was readily prepared from p-hydroxybenzoic acid following a reported procedure. [10] Thus, treatment of 7a with aqueous NaOH and HCHO at 55 C [11a] gave monohydroxymethylated compound 5a in moderate yield. The precursor 5b is known in the literature and it was prepared in two steps involving reaction of methyl-4-hydroxy benzoate with phenyl boronic acid followed by treatment with H 2 O 2 . [11b] However, we prepared compound 5b by hydroxymethylation of methyl-4-hydroxybenzoate 7b (Scheme 1). Though the yields of hydroxymethylated products 5a,b are on the low side, the experimental procedure is simple and can be repeated in a routine manner to generate significant quantities.
After having prepared the aromatic precursors 5a,b we set out to explore oxidative dearomatization and cycloaddition. At the outset, however, we were aware that oxidative dearomatization of phenols having an electron-withdrawing group is relatively difficult. Thus, a solution of o-hydroxymethylated ester 5a in acetonitrile containing ethyl acrylate was oxidized with aqueous NaIO 4 following a procedure developed earlier in our group, [12] and the reaction mixture was stirred at ambient temperature for 48 h. Indeed, usual workup and chromatography of the product mixture gave the endo-adduct 9a in good yield (62%) along with the known aldehyde 8a [13] as a minor product. The adduct 9a is formed as a result of in situ generation of spirocyclohexa-2,4-dienone 6a followed by a regio-and stereoselective cycloaddition with ethyl acrylate, in a tandem fashion (Scheme 2).
Structure of adduct 9a was deduced from the following spectral features and further confirmed with the help of a single-crystal structure determination. Thus, IR spectrum of 9a showed characteristic absorption bands at 1732 and 1712 cm À1 Figure 2. Potential precursors.

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K. ARORA AND V. SINGH The presence of contiguous keto-epoxide functionality in adducts 9a,b provided opportunity for selective manipulation of the oxirane ring. Thus treatment of 9a with Zn-NH 4 Cl in aqueous methanol at ambient temperature furnished the b-hydroxymethyl ketone 11a (as a mixture of syn-anti isomers) in excellent yield along with minor amounts of 10a (Scheme 3). The compound 10a was formed as a result of deoxygenation of the oxirane ring. Subsequent oxidation of 11a by Jones's reagent followed by decarboxylation of the resulting b-ketoacid furnished the desired chromophoric system 2a. Similarly, adduct 9b was also reduced with Zn-NH 4 Cl, which gave 10b and 11b, the latter as a major product. Oxidation of 11b followed by decarboxylation gave the desired bicyclic compound 2b endowed with a b,c-enone chromophore.
After having prepared bicyclo[2.2.2]octenones 2a,b in which the ene-moiety is also conjugated with ester group in addition to its homoconjugation with the CO group, their photochemical reaction was explored. The photochemical reactions of b,c-enones have stimulated interest for long time, [6] which has increased recently because of its synthetic potential. [7][8][9] As we have mentioned earlier, rigid b,c-enones undergo 1,2-acyl shift (oxa-di-pi-methane reaction) and 1,3-acyl shift upon triplet and singlet (1S) excitation, respectively. Though these two types of reactions are quite characteristic of the excited state, it often controlled by structural features and the presence of functional group in the chromophoric system, in a subtle fashion. [6a,6b] While photoreaction of a number of bicyclo[2.2.2]octanes endowed with b,c-enone chromophore has been examined, [6,7] only a few examples of photoreaction of bicyclo[2.2.2]octenones having an electron-withdrawing substituent at the c-carbon of b,c-enone moiety have been studied. [8a,8b] Keeping this in mind, we first examined the sensitized photoreaction of compound 2a. Thus, a solution of 2a in acetone (both solvent as well as sensitizer) was irradiated in a Pyrex immersion well with a mercury vapor lamp (125 W, Bajaj) for 1 h. Removal of solvent followed by chromatography of photolysate furnished the product 3a in excellent yield, as a result of an efficient 1,2-acyl shift or oxa-dipi-methane rearrangement (Scheme 4). Similar irradiation of substrate 2b also led to a smooth reaction and furnished the diquinane 3b as a result of 1,2-acyl shift.
The structure of both the products was deduced from their spectral features and comparison with spectral data of their precursor. Thus, the IR spectrum of  To explore the possibility of a 1,3-acyl shift, the photoreaction of chromophoric systems 2a,b in an excited singlet (1S) was also examined. Thus, a solution of 2a in benzene was irradiated in a Pyrex immersion well with a mercury vapor lamp for 1 h (Scheme 4). However, no photoreaction was observed and starting material was recovered. Irradiation for extended time period also did not lead to any reaction. The substrate 2b was also found to be unreactive and did not give any 1,3-acyl shift product. While it is difficult to rationalize the unreactivity of 2a,b toward the 1,3-acyl shift upon direct excitation, it may be due to the presence of an electron-withdrawing group at the c-carbon of b,c-enone moiety as similar systems without such groups are known to undergo 1,3-acyl shift upon direct excitation. [6,7] Subsequently, the photoproducts 3a,b were subjected to reductive cleavage of the cyclopropane ring. Thus, initially, tricyclic compound 3a was treated with H 2 = Pd-C both at atmospheric pressure and at 147 psi. However, no reaction was observed. Then, it was treated with Bu 3 SnH-AIBN in refluxing benzene. Chromatography of the reaction mixture gave the compound 4a as a sole product (a single stereoisomer) in excellent yield (93%) a result of highly regio-and stereoselective cleavage of the internal cyclopropane bond. The reaction of 3b with Bu 3 SnH-AIBN also gave the compound 4b containing the bicyclo[3.2.1]octane ring system in excellent yield. Interestingly, products of type 13 that may form as a result of cleavage of peripheral cyclopropane bond were not obtained (Scheme 5).

CONCLUSION
We have described oxidative dearomatization of o-hydroxymethyl phenols having an electron-withdrawing group to spiroepoxycyclohexa-2,4-dienones and their cycloaddition with ethyl acrylate leading to bicyclo[2.2.2]octenones. Manipulation of adducts led to desired chromophoric systems that upon oxa-di-pi-methane reaction gave tricyclic compound having a diquinane framework. Cleavage of the cyclopropane ring of photoproducts gave functionalized bicyclo[3.2.1]octanes.

EXPERIMENTAL
IR spectra were recorded on a Nicolet Impact 400 FT-IR. 1 H NMR and 13 C NMR spectra were recorded on either Brucker 400-MHz or Brucker 500-MHz instruments. The samples were dissolved in CDCl 3 with tetramethylsilane (TMS) as internal standard. High-resolution mass spectrometry (HRMS) were recorded on a Maxis Impact Bruker mass spectrometer. Melting points were determined on a Veego apparatus of Buchi type. All organic extracts were dried over anhydrous Na 2 SO 4 . Reactions were monitored with thin-layer chromatography (TLC), and spots were visualized with I 2 vapor. Column chromatography was performed using SRL=Thomas Baker silica gel (60-120 and 100-200 mesh) with elution using petroleum ether (bp 60-80 C) and EtOAc mixtures.