I(n)organocatalysis: Neutral multidentate halogen‐bond donors (halogen‐based Lewis acids) catalyze the reaction of 1‐chloroisochroman with ketene silyl acetals. The organocatalytic activity is linked to the presence (and number as well as orientation) of iodine substituents. As hidden acid catalysis can be ruled out with high probability, this case constitutes strong evidence for halogen‐bond based organocatalysis. TBS=tert‐butyldimethylsilyl.

Today on both laboratory and industrial scale a very prominent strategy for the enantioselective synthesis of secondary aromatic alcohols is based on a transformation of (a substituted) benzene into (a substituted) acetophenone, for example, by using Friedel-Crafts-type chemistry, and subsequent enantioselective reduction.[1] In contrast, the highly attractive alternative of a direct asymmetric transformation of non-activated alkenes, such as styrene, into the corresponding secondary alcohols still represents a "dream reaction" for organic chemists. [2,3,4] The reaction concept of such a formal hydration process is shown in Scheme 1.So far to the best of our knowledge a reliable, broadly applicable and efficient chiral catalyst suitable for such a direct transformation has not been found. [2,3] In the following we report a "chemoenzymatic catalytic system" (instead of a single catalyst molecule), which enables exactly this desired direct one-pot transformation of (substituted) styrene(s) into the corresponding (substituted) phenylethan-1-ol(s) in a highly enantioselective fashion, thus fulfilling the prerequisites for the challenging process described above and in Scheme 1. The key feature of this "catalytic system", which works in an aqueous reaction medium, is the combination of a palladium component and an enzyme component. This formal hydration process is based on a chemoenzymatic one-pot, two-step process in water comprising a Wacker-Tsuji oxidation and subsequent enantioselective reduction of the in situ-formed (substituted) acetophenone under formation of (the substituted) phenylethan-1-ol (Scheme 2). Thus, this process formally corresponds to the unknown reaction type of an asymmetric hydration of a non-activated alkene.The first focus was on the development of a Wacker-type oxidation [5] in aqueous reaction medium, which would enable a subsequent combination with an in situ enantioselective reduction process. After screening a range of Wacker-type oxidations of styrene and analyzing carefully the side-and trace-product spectra as well as the biocompatibility with the metal catalyst components, we found a method developed by Tsuji as most suitable for our purpose.[6] When using the original reaction conditions [6] such as PdCl 2 as a palladium catalyst, benzoquinone as oxidation reagent, and DMF/water (7:1 (v/v)), however, a low conversion of only 34 % and 80 % selectivity for acetophenone was observed. Subsequently, we conducted a solvent optimization (for details, see Supporting Information) and we were pleased to find that when using a mixture of methanol and water (7:1 (v/v)) the desired acetophenone (2 a) was formed with > 99 % conversion and 90 % selectivity (Scheme 3, route A, [Eq. (1)]). As side products O-methylphenylethan-1-ol (3 %), phenylacetaldehyde dimethyl acetal (2 %), methyl phenylacetate (3 %), and traces of racemic phenylethan-1-ol (1 %) are formed. Notably, this process runs at a high substrate concentration of 1.3 m of styrene (1 a Scheme 2. One-pot process corresponding to a formal h...

I(n)organokatalyse: Neutrale mehrzähnige Halogenbrückendonoren (Halogen‐basierte Lewis‐Säuren) katalysieren die Reaktion von 1‐Chlorisochroman mit Ketensilylacetalen. Die organokatalytische Aktivität hängt von der Gegenwart (sowie Anzahl und relativen Orientierung) der Iodsubstituenten ab. Da versteckte Säurekatalyse mit hoher Wahrscheinlichkeit ausgeschlossen werden kann, liegen im untersuchten Fall starke Hinweise auf Halogenbrücken‐basierte Organokatalyse vor. TBB=tert‐Butyldimethylsilyl.

Under optimized conditions, 3-substituted thiophenes (EWG = COOEt, PO(OEt)(2)) undergo a facile and regioselective oxidative coupling reaction at carbon atom C4. The reactions were performed with various aryl boronic acids as nucleophiles in the presence of silver oxide (2.0 equiv), cesium trifluoroacetate (tfa) (1.0 equiv), benzoquinone (BQ) (0.5 equiv), and catalytic amounts of Pd(tfa)(2) (10 mol %) employing trifluoroacetic acid (TFA) as the solvent.

A total number of 15 different 3,4-diarylthiophenes were synthesized, which bear a chlorine atom in ortho-position of one of the aryl substituents. One aryl group was introduced by an oxidative cross-coupling reaction, involving a CH activation at C4(3) of the thiophene core. The other aryl group was in most cases introduced by a Suzuki cross-coupling reaction, which succeeded the oxidative cross-coupling step. Photocyclization reactions of the 3,4-diarylthiophenes were performed in a solvent mixture of benzene and acetonitrile (50:50 v/v) at λ=254 nm and proceeded to the title compounds in yields of 60-82 %. The selectivity of the photocyclization was determined at the ortho-chloro-substituted aryl ring by the position of the chlorine substituent. At the other ring, a single regioisomer was observed for phenyl and para-substituted phenyl groups. For 2-naphthyl and ortho-substituted phenyl rings a clear preference was observed in favor of a major regioisomer, while meta-substitution in the phenyl ring led to a about 1:1 mixture of 5- and 7-substituted phenanthro[9,10-c]thiophenes. Mechanistically, the photocyclization is likely to occur as a photochemically allowed, conrotatory [(4n+2)π] process accompanied by elimination of HCl. It was shown for two phenanthro[9,10-c]thiophene products that they can be readily brominated in positions C1 and C3 (74-77 %), which in turn allows for further functionalization at these positions, for example, in the course of halogen-metal exchange and polymerization reactions.