tert -Butoxide-Mediated Protodeformylative Decarbonylation of  -Quaternary Homobenzaldehydes

tert -Butoxide mediates the Haller–Bauer-type (protode-formylative) decarbonylation of readily accessed  -quaternary homo-benzaldehydes and related compounds at room temperature, generating cumene products. Both geminal dialkyl and geminal diaryl substituents are tolerated. gem -Dimethyls are sufficient for decarbon-ylation of polycyclic arenyl substrates whereas monocyclic aromatic ho-mobenzaldehydes require cyclic gem -dialkyls or gem -diaryls for significant decarbonylation.

The decarbonylation of aldehydes is an important C-C bond-cleaving reaction in synthesis and in nature. 1,2Chemosynthetic decarbonylations mediated by stoichiometric rhodium complexes were first developed by Tsuji and Wilkinson 3 and are notable for their application in natural products total synthesis; 4 flow-type and catalytic variants have been developed to lower the cost. 5Haller and Bauer popularized the base-mediated debenzoylation of aromatic ketones in the early 1900s; 6 a room-temperature Haller-Bauer-type tert-butoxide-mediated protodebenzoylation was used as the third step to achieve formal protodeformylation of non-enolizable aldehydes (Scheme 1A). 7Recently, Madsen and co-workers studied the mechanism of Haller-Bauer-type decarbonylations of enolizable aldehydes (Scheme 1B) as well as non-enolizable aldehyde substrates like 2,6-dichlorobenzaldehyde (not shown). 8Similar conditions are known to be capable of deformylating certain non-enolizable aldehydes like triphenylacetaldehyde 9 despite benzaldehydes being especially sensitive to hydroxide-mediated Cannizzaro-type disproportionation into the alcohol and carboxylic acid. 102][13] Of the single-pot approaches (specifically Wilkinson and Haller-Bauer-type), a mild and general decarbonylation of -quaternary aldehydes has not been described.Herein, we show that a wide variety of readily accessed -quaternary

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homobenzaldehydes are deformylated at ambient temperature using tert-butoxide in THF to afford isopropyl arene (cumene) derivatives (Scheme 1C). 14Mechanistically, this presumably occurs via stabilized anion B generated from tert-butoxide adduct A. 15 The impetus for developing this method stemmed from our interest in alkene functionalization reactions of -quaternary homobenzylstyrenes and related compounds, 16 whereby we occasionally observed competing decarbonylation of -quaternary homobenzaldehydes during Wittig olefination if excess tert-butoxide was present.We sought to optimize this reaction using the homonaphthaldehyde substrate shown in Table 1. 17Excitingly, the use of 1.6 equivalents of KOt-Bu afforded complete substrate conversion and good yield at ambient temperature upon aqueous workup (entry 1).Evaluation of solvent effects showed that DMF was also well tolerated (entry 2) whereas HOt-Bu did not allow appreciable reaction (not shown). 18The reaction must be performed air-free (entry 3), and the yield decreased somewhat when molecular sieves were employed (entry 4).Adding TEMPO inhibited substrate conversion somewhat (entry 5).NaOt-Bu was similarly effective as KOt-Bu (entry 6), whereas the use of lithium diisopropyl amide (LDA) resulted in complex decomposition (entry 7).Potassium hydroxide afforded no reaction in THF, with or without HOt-Bu present as additive (entries 8 and 9, respectively).Taken together, none of these data refute the canonical mechanism shown in Scheme 1C. 19It should be noted that product formation can take place prior to workup via quench by adventitious water, but excess water in the reaction will lead to competing detrimental Cannizzaro disproportionation.
In terms of breadth of scope, phenyl analogues (1a-c) afford lower yield than the optimized naphthyl substrate (Scheme 2A).In particular, cumene (2a) was only produced in 11% NMR yield; the yield improved significantly by substitution with a para-phenyl group, thereby accessing 2d in 67% yield.In revision, the para-trifluoromethyl analogue was prepared and protodeformylated to afford a modest 20% yield of the corresponding cumene by 1 H NMR analysis. 20Strained cyclic gem-dialkyl-containing substrates like -cyclopropyl (1e) and -cyclobutyl (1f) afford just 9% and 24% yield of their respective methine products, whereas cyclopentyl (1g) and cyclohexyl (1h) substrates were decarbonylated in useful yield (44% and 76%, respectively).Other monoarenyl substrates evaluated include tetralin 1i and triphenylacetaldehyde 1j, both of which afforded decarbonylation products in good yield (61% and 79%, respectively).tert-Butanol was a common byproduct after workup, potentially arising from hydrolysis of the implied tert-butylformate byproduct of C-C bond cleavage of intermediate A in Scheme 1C.
Fused bicyclic and tricyclic substrates afforded generally excellent decarbonylation yields (Scheme 2B and C), presumably because the extended conjugation in these com-pounds affords a relatively stabilized benzylic anion.Among bicyclic arenes (Scheme 2B), cyclopentane-containing product 4a was accessed with double the yield of the analogous monocyclic arene 2g.A 1.0 mmol scale reaction of 1naphthyl substrate 3b afforded the highest decarbonylation yield that we observed in the study (93% yield of 4b).2-Naphthyl and 4-benzofuranyl analogues (4c and 4d) were also accessed in good yield.In contrast, 3-benzofuranyl analogue 4e was not prepared efficiently and a significant amount of dearomatized product 7 was formed (Scheme 3).A number of benzyl-protected 4-substituted indole analogues (3f-j) were also decarbonylated efficiently, as were a number of benzothiophenyl substrates (3k-n), with the exception of the 3-substituted analogue 3o, which may be prone to dearomatization as observed for 3e.
In conclusion, we have developed a tert-butoxide-mediated protodeformylative decarbonylation of -quaternary homobenzaldehydes. 21,22The method enables efficient access to a variety of cumenes.Efforts to expand the scope and better understand the mechanism are ongoing in our lab.

Table 1
Optimization of Aldehyde Decarbonylation a Reactions were conducted on 0.1 mmol scale in solvent (1.1 mL) under an atmosphere of N 2 unless otherwise noted.Conversions and yields were determined by 1 H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard (n.d.= not detected).Base and HOt-Bu (1.6 equiv) sonicated for 5 minutes.Evaluation of the generality of the protodeformylation of -quaternary homobenzaldehydes.aReactions were conducted with 0.2 mmol of aldehyde unless otherwise noted, and yields refer to isolated yields unless otherwise noted.bYieldwas determined by 1 H NMR analysis using 1,3,5trimethoxybenzene as an internal standard.cProductis volatile under high vacuum.d Reaction was executed on 1.0 mmol scale of 3b.Dearomative protodeformylation predominates in the case of benzofuran 3e.
a c Solid KOt-Bu and DMF as solvent.dReactionwas conducted open to air.e 100% w/w of molecular sieves.f