Friedel-Crafts Cyclization of 1,1-Difluoroalk-1-enes: Synthesis of Benzene-Fused Cyclic Ketones via α-Fluorocarbocations

Abstract

1,1-Difluoroalk-1-enes bearing a phenyl group at the C-3, -4, or -5 position, readily obtained from 2,2,2-trifluoroethyl p-toluenesulfonate, are treated with FSO 3 H·SbF 5 to undergo FriedelCrafts cyclization in (CF 3 ) 2 CHOH. The cyclization takes place via a-fluorocarbocations, followed by spontaneous hydrolysis of the C-F bond to afford bicyclic ketones including a five, six, or sevenmembered ring in good yield.Fluorine possesses a-carbocation stabilizing effect caused by donation of its unshared electron pair to the vacant porbital of the a-carbon, despite its leaving group ability as a fluoride ion (F -) due to its high electronegativity. 1 In contrast to a number of theoretical and mechanistic studies on fluorinated carbocations, 2 their synthetic applications are quite limited. 3 Furthermore, there are few reports on reactions utilizing both of the two properties mentioned above. 4 Recently, we have reported such an example, the fluorine-directed Nazarov cyclization of 2,2-difluorovinyl vinyl ketones, which proceeds via a-fluorocarbocations, generated by silylation of the carbonyl oxygen with TMSOTf, to afford b-fluorocyclopentenones with accompanying loss of a fluoride ion (Scheme 1). 5 Scheme 1The Nazarov cyclization of 2,2-difluorovinyl vinyl ketones Reagents and conditions: i. TMSOTf (1.0 equiv), CH 2 Cl 2 -HFIP (1:1), r.t., 10 min.Our interest in fluorine-containing carbocations prompted us to investigate: (i) the generation of a-fluorocarbocations from simple 1,1-difluoroalk-1-enes without a carbonyl group; and (ii) their reaction with an intramolecular aryl group instead of an alkenyl group. The a-cation-stabilizing effect was expected to direct the reaction of 1,1-difluoroalk-1-enes with a protic acid, so that protonation would preferably occur on the inner carbon of the olefinic part, leading to terminal carbocations rather than tertiary cations. Herein we report the Friedel-Crafts cyclization of 1,1-difluoroalk-1-enes bearing an aryl group 1, which provides a variety of fused bicyclic ketones 2. 6 Initially, the 1,1-difluoroalk-1-enes 1a-h bearing an aryl group at the C-3, -4, or -5 position were designed as the Friedel-Crafts substrates. We have already established a one-pot synthesis of 1,1-difluoroalk-1-enes from commercially available 2,2,2-trifluoroethyl p-toluenesulfonate (3) via boron-mediated alkylation followed by palladium-catalyzed coupling reaction with organohalides (Scheme 2). Monosubstituted difluoroalkenes 1a-d were readily prepared by protonolysis of in situ generated difluorovinylboranes 4 via the corresponding vinylcopper species 5 (Scheme 2, Eq. 1); disubstituted difluoroalkenes 1e-h were prepared by the cross-coupling reaction of vinylcoppers 5 with aryl or benzyl halides in good yield from 3 (Scheme 2, Eq. 2). Both reactions were conducted as a one-pot operation. 7

Metal-free synthesis of indanes by iodine(III)-mediated ring contraction of 1, 2-dihydronaphthalenes

“…The hydroxyl group would attack the C1 position of 15, giving the four-membered ring intermediate 16, 6 which would ring open to form 17. The ring contraction would take place on its conformer (18) giving trans-5n (path a, Scheme 2). The solvent may have some influence in the stereoselectivity of the electrophilic addition of the iodine(III), explaining the formation of cis-1,3-disubstituted indanes.…”

“…The behavior of alkene 1n is slightly different to that observed for other substrates. The reaction of 1n with HTIB in CH 3 CN led mainly to indane 5n and ketone 6n 18 in 26 and 23% yield, respectively. The tetralone 6n is formed by migration of the phenyl group.…”

“…The mixture was stirred for 20 min at room temperature. The product crude was purified by column (0-10% EtOAc in hexane) affording 5n (0.0452 g, 0.191 mmol, 26%), 13 and 6n (0.0414 g, 0.175 mmol, 23%), 18 as yellow oil and as a cis:trans mixture (6:1). 4n (7.00 mg, 0.0321 mmol, 4%) 42 was isolated, as a colorless oil.…”

Domino Friedel–Crafts‐Type Cyclizations of Difluoroalkenes Promoted by the α‐Cation‐Stabilizing Effect of Fluorine: An Efficient Method for Synthesizing Angular PAHs

“…[19] The reaction mixture was allowed to warm to room temperature and stirred for 3 h. Chromatographic purification afforded the indenoindene 5 a, with a 6/ 5/5/6 tetracyclic structure, in 63 % yield, together with an 11 % yield of the 2-benzylindanone 6, which originated from D ( Table 1, entry 1). [7] The formation of 5 a confirmed the successful capture of the second carbocation D. [20] The reaction time was prolonged and the reaction temperature was raised in order to improve the yield of 5 a, but in vain (Table 1, 5,6). TLC analysis showed that 1 a was consumed completely within 10 min at 0 8C.…”

“…[7] Here, fluorine substituents stabilize a-carbocations by donating their unshared electron pairs into the vacant p orbitals of the cationic centers (+M effect, Figure 1). At the same time, fluorine substituents also act as leaving groups (fluoride ion, F À ), because of their high elecAbstract: In order to synthesize polycyclic aromatic hydrocarbons with nonlinear arrangements (angular PAHs), acid-promoted domino cyclizations of 1,1-difluoroalk-1-enes and 1,1-difluoroalka-1,3-dienes were studied.…”