Lewis Acid-Promoted Friedel−Crafts Alkylation Reactions with α-Ketophosphate Electrophiles

Abstract

The BF 3 ·OEt 2 -promoted nucleophilic substitution of α-aryl-α-ketophosphates to afford α,α-diaryl ketone products is described. Electron-rich α-ketophosphates perform best, with electron-neutral and electron-poor substrates also tolerated. The reaction is tolerant of a range of aromatic, heteroaromatic and non-aromatic nucleophiles, with yields ranging from 44-84%. Enantioenriched starting material yields racemic product, suggesting an S N 1 pathway via an acylcarbenium ion.α-Aryl carbonyl compounds have garnered considerable attention as synthetic targets, most notably in the chemical production of non-steroidal anti-inflammatory drugs (NSAIDs). Common drugs such as naproxen, ibuprofen, fluribiprofen, and dichlofenac all contain this moiety. 1 The Pd(0)-catalyzed α-arylation of ketones, pioneered concurrently by Buchwald, Hartwig and Miura in 1997, has served as the premier route to these products.2 , 3 In recent years, this methodology has been expanded to include esters, amides, aldehydes, and lactones as carbonyl coupling partners in the presence of an aryl halide or triflate and a Bronsted base. , 5The aforementioned transition metal-catalyzed routes take advantage of the conventional reactivity patterns of nucleophilic ketone enolates and electrophilic Pd(II) intermediates to arrive at α-arylated carbonyls. We wanted to observe whether formation of an Ar-C α bond was possible through polarity reversal, or umpolung methodology 6 , with Friedel-Crafts alkylation occuring at an electrophilic α-carbon (Figure 1). Such a route could be envisioned from a substrate with a sufficient nucleofuge in place adjacent to the carbonyl functionality ( Figure 2).An umpolung α-alkylation route has precedent. In 2004, Ready and Malosh described the copper-catalyzed cross-coupling of primary and secondary organozinc halides with α-chloroketones, providing α-branched ketones in high yields with inversion of configuration at the α-carbon. 7 In 2008, Breit and Studte described a zinc-catalyzed stereospecific sp 3 -sp 3 crosscoupling reaction involving alkyl Grignard reagents and α-hydroxy ester triflates. 8 The umpolung alkylation route becomes especially attractive if the needed functionality (i.e. jsj@unc.edu . Supporting Information Available: Experimental procedures, spectroscopic and analytical data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript nucleofuge) can be directly installed in conjunction with another synthetic operation. In this context, we noted a potential connection to our previous work demonstrating that cyanidecatalyzed additions of acyl phosphonates to aldehydes provide α-keto phosphate products (Figure 2). 9,10 Acyl phosphonates are easily prepared in one step via the Michaelis-Arbuzov reaction, rendering them a convenient acyl donor. The "phospha-benzoin" reaction forms a C-C bond and installs a potential nucleofuge in a concomitant fashion. In p...

Friedel–Crafts alkylation of sodium salicylate with 4-tert butylbenzyl chloride performed in aqueous dispersions of mesoporous oxides

“…In general, the correlation between catalyst efficiency and catalyst acidity seemed to be stronger for Lewis acidity than for Brønstedt acidity. A good correlation between Lewis acid strength and efficiency as a catalyst for Friedel-Crafts alkylation has been reported before [1,[32][33][34][35][36].…”

Base‐Catalyzed Direct Aldolization of α‐Alkyl‐α‐Hydroxy Trialkyl Phosphonoacetates

“…The OPO 3 R 2 groups in benzylic phosphates are viable leaving groups in acid-promoted Friedel-Crafts alkylations. [21] Upon treatment of (AE)-3 a (d.r. 2:1) and anisole with TfOH, the ahydroxy ester 11 was isolated in 91 % yield as a single diastereomer.…”

“…The –OPO 3 R 2 groups in benzylic phosphates are viable nucleofuges in acid-promoted Friedel-Crafts alkylations. [21] Upon treatment of (±)- 3a (dr 2:1) and anisole with TfOH, the α-hydroxy ester 11 was isolated in 91% yield as a single diastereomer. Heteroatom and heteroaromatic nucleophiles were also employed in this Friedel-Crafts alkylation in good to excellent yields (Scheme 3), [22] providing stereogenic β-diaryl glycolates in a single step with pronounced stereoconvergency.…”

Azidotrimethylsilane

“…It is considered a very convenient and safer replacement for hydrazoic acid as an azide source in many reactions. 1 It has been used for the synthesis of aryl 1,2,3-triazoles, [2][3][4][5] tetrazoles, 6,7 functionalized bicyclic triazoles, 8 azides, [9][10][11][12][13][14][15] and N-tetrazolated diamine derivative. 16 In addition, azidotrimethylsilane has been employed for the preparation of proline-derived chiral aminotriazole ligands.…”