**A Simple and E**ffi**cient Protocol for Proline-Catalysed Asymmetric Aldol Reaction**

#### **Marco Giuseppe Emma, Alice Tamburrini, Ada Martinelli, Marco Lombardo \*, Arianna Quintavalla \* and Claudio Trombini**

Department of Chemistry "G. Ciamician", Alma Mater Studiorum, University of Bologna, Via Selmi 2, 40126 Bologna, Italy; marcogiuseppeemma@hotmail.it (M.G.E.); alice.tamburrini@hotmail.it (A.T.); ada.martinelli2@unibo.it(A.M.);claudio.trombini@unibo.it(C.T.)

**\*** Correspondence: marco.lombardo@unibo.it (M.L.); arianna.quintavalla@unibo.it (A.Q.); Tel.: +39-0512-099-544 (M.L.); +39-0512-099-462 (A.Q.)

Received: 1 May 2020; Accepted: 7 June 2020; Published: 10 June 2020

**Abstract:** The proline-catalysed asymmetric aldol reaction is usually carried out in highly dipolar aprotic solvents (dimethylsulfoxide, dimethylformamide, acetonitrile) where proline presents an acceptable solubility. Protic solvents are generally characterized by poor stereocontrol (e.g., methanol) or poor reactivity (e.g., water). Here, we report that water/methanol mixtures are exceptionally simple and effective reaction media for the intermolecular organocatalytic aldol reaction using the simple proline as the catalyst.

**Keywords:** proline; organocatalysis; asymmetric aldol reaction; methanol/water mixtures; sustainability
