Preparation of Functionalized Amides Using Dicarbamoylzincs.

We report a new convenient preparation of dicarbamoylzincs of type (R1 R2 NCO)2 Zn by the treatment of ZnCl2 and formamides R1 R2 NCHO with LiTMP in THF (15 °C, 15 min) or by the reaction of formamides R1 R2 NCHO with TMP2 Zn (25 °C, 16 h). This second method tolerates sensitive groups such as an ester, ketone or nitro function. Reaction of these dicarbamoylzincs with allylic, benzylic, aryl, alkenyl bromides, acid chlorides, aldehydes or enones provided various polyfunctional amides in 47-97 % yields. 13 C NMR characterization of these new carbamoylzinc derivatives is reported.

Continuous Flow Acylation of (Hetero)aryllithiums with Polyfunctional N,N-Dimethylamides and Tetramethylurea in Toluene.

The continuous flow reaction of various aryl or heteroaryl bromides in toluene in the presence of THF (1.0 equiv) with sec-BuLi (1.1 equiv) provided at 25 °C within 40 sec the corresponding aryllithiums which were acylated with various functionalized N,N-dimethylamides including easily enolizable amides at -20 °C within 27 sec, producing highly functionalized ketones in 48-90 % yield (36 examples). This method was well suited for the preparation of α-chiral ketones such as naproxene and ibuprofen derived ketones with 99 % ee. A one-pot stepwise bis-addition of two different lithium organometallics to 1,1,3,3-tetramethyurea (TMU) provided unsymmetrical ketones in 69-79 % yield (9 examples).

Regioselective difunctionalization of pyridines via 3,4-pyridynes.

A new regioselective 3,4-difunctionalization of 3-chloropyridines via 3,4-pyridyne intermediates is reported. Regioselective lithiation of 3-chloro-2-ethoxypyridine and a related 2-thio-derivative followed by treatment with aryl- and alkylmagnesium halides as well as magnesium thiolates at -78 °C produced 3,4-pyridynes during heating to 75 °C. Regioselective addition of the Grignard moiety in position 4 followed by an electrophilic quench in position 3 led to various 2,3,4-trisubstituted pyridines. This method was adapted into a continuous flow set-up. As an application, we have prepared a key intermediate for (±)-paroxetine.

Selective Acylation of Aryl- and Heteroarylmagnesium Reagents with Esters in Continuous Flow.

A selective acylation of readily accessible organomagnesium reagents with commercially available esters proceeds at convenient temperatures and short residence times in continuous flow. Flow conditions allow us to prevent premature collapse of the hemiacetal intermediates despite noncryogenic conditions, thus furnishing ketones in good yields. Throughout, the coordinating ability of the ester and/or Grignard was crucial for the reaction outcome. This was leveraged by the obtention of several bisaryl ketones using 2-hydroxy ester derivatives as substrates.