Formamides as Lewis Base Catalysts in S_N Reactions—Efficient Transformation of Alcohols into Chlorides, Amines, and Ethers

Abstract

A simple formamide catalyst facilitates the efficient transformation of alcohols into alkyl chlorides with benzoyl chloride as the sole reagent. These nucleophilic substitutions proceed through iminium-activated alcohols as intermediates. The novel method, which can be even performed under solvent-free conditions, is distinguished by an excellent functional group tolerance, scalability (>100 g) and waste-balance (E-factor down to 2). Chiral substrates are converted with excellent levels of stereochemical inversion (99 %→≥95 % ee). In a practical one-pot procedure, the primary formed chlorides can be further transformed into amines, azides, ethers, sulfides, and nitriles. The value of the method was demonstrated in straightforward syntheses of the drugs rac-Clopidogrel and S-Fendiline.

A General Catalytic Method for Highly Cost‐ and Atom‐Efficient Nucleophilic Substitutions

“…The evaluation of other Lewis bases as catalysts for the transformation of model substrate 1 2 into 2 2 showed that any deviation from the original FPyr scaffold results in diminished catalytic activities, which are indicated by the yield of 2 2 (Table , entries 8–11; see also Scheme S4 in the Supporting Information). In fact, structural variations of the catalyst have a stronger deteriorative effect on the yield of 2 2 in comparison of TCT to BzCl, which is underpinned by the lower yield of 2 2 when DMF is applied (Table , entry 8). While methylformamide (MF) still furnishes 2 2 as major product, simple formamide (F) and dimethylacetamide (DMA) provide 2 2 only as a side product in traces (Table , entries 9–11).…”

“…Only when DMSO was applied as solvent the quantity of TCT could be lowered to 55 mol %. Recently, we discovered that formamides such as DMF and N ‐formylpyrrolidine (FPyr) are potent catalysts for the preparation of alkyl halides of type 2 from alcohols 1 with application of benzoyl chloride (BzCl) as sole reagent (Scheme C ) …”

Optically Active 1‐Deuterio‐1‐phenylethane – Preparation and Proof of Enantiopurity

“…[13] Compound (R)-2a could be obtained with 77 % yield and 95 % ee, as was established by GLC on a chiral phase. For the preparation of optically active (1-chloroethyl)benzene (2a) we relied on a recent report by Huy et al, who developed excellent reaction conditions for the stereoselective nucleophilic displacement of a secondary alcohol function to the respective chloro compound with inversion of configuration.…”

“…First of all, we followed a recently published protocol [13] for the stereospecific preparation of α-chloroethylbenzene (R)-2a from (S)- It′s preparation from optically active 1-phenylethanol (1) by twofold nucleophilic displacement via α-chloroor bromoethylbenzene (2a or 2b) was reported before in the literature.…”

“…Following the procedure of Huy et al, [13] benzoyl chloride (30.0 mmol, 4.22 g, 1.5 equiv.) was added at 0°C (ice/water bath) to a solution of 1-phenylethanol (S)-1 (20.0 mmol, 2.44 g, 1.0 equiv.)…”