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The transposition of Sandmeyer chlorination from a batch to a safe continuous-flow process was investigated. Our initial approach was to develop a cascade method using flow chemistry which involved the generation of a diazonium salt and its quenching with copper chloride. To achieve this safe continuous process diazotation, a chemometric approach (Simplex method) was used and extrapolated to establish a fully continuous-flow method. The reaction scope was also examined via the synthesis of several (het)aryl chlorides. Validation and scale-up of the process were also performed. A higher productivity was obtained with increased safety.

Efficient Transposition of the Sandmeyer Reaction from Batch to Continuous Process

Joseph D’Attoma^†, Titi Camara^‡, Pierre Louis Brun^‡, Yves Robin^‡, Stéphane Bostyn^*§, Frédéric Buron^*† , and Sylvain Routier^*†

^† Institut de Chimie Organique et Analytique, Univ Orleans, UMR CNRS 7311, Rue de Chartres, BP 6759, 45067 CEDEX 2 Orléans, France

^‡ ISOCHEM, 4 Rue Marc Sangnier, BP 16729, 45300 Pithiviers, France

^§ Institut de Combustion, Aérothermique, Réactivité, et Environnement (ICARE), 1c, Avenue de la Recherche Scientifique, 45071 CEDEX 2 Orléans, France

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00318, http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00318

*E-mail: frederic.buron@univ-orleans.fr., *E-mail: sylvain.routier@univ-orleans.fr., *E-mail: stephane.bostyn@univ-orleans.fr.

¹H NMR (250 MHz, Chloroform-d) δ 7.65 (dd, J = 2.1, 0.6 Hz, 1H, H_ar), 7.42 (dd, J = 8.7, 0.6 Hz, 1H, H_ar), 7.32 (dd, J = 8.7, 2.0 Hz, 1H, H_ar).

2,5-Dichloro-1,3-benzoxazole (33)

1H NMR PREDICT

13 C NMR PREDICT

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