molecules Article Regioselectivity in Reactions between Bis(2-benzothiazolyl)ketone and Vinyl GrignardGrignard † Reagents: CC-- versus versus O-alkylation—Part III 1, 1 1 1, 2 Carla Boga 1,** SilviaID , Silvia Bordoni Bordoni , Lucia1, Lucia Casarin Casarin , Gabriele1, Gabriele Micheletti Micheletti * and1,* Magda and Magda Monari Monari 2 1 1 DepartmentDepartment of of Industrial Industrial Chemistry Chemistry ‘Toso ‘Toso Montanari’ Montanari’,, Alma Alma Mater Mater Studiorum–Università Studiorum–Università didi Bologna Bologna Viale DelDel Risorgimento Risorgimento 4, 4, 40136 40136 Bologna, Bologna, Italy; Italy; silvia.bor [email protected]@unibo.it (S.B.); (S.B.); luciac [email protected]@yahoo.it (L.C.) (L.C.) 2 2 DepartmentDepartment of of Chemistry Chemistry ‘Giacomo ‘Giacomo Ciamician’, Ciamician’, Alma Alma Mater Mater Studiorum–Università Studiorum–Università didi Bologna Bologna Via Via Selmi Selmi 2, 2, 4012640126 Bologna, Bologna, Italy; Italy; [email protected] [email protected] * Correspondence:Correspondence: carla [email protected]@unibo.it (C.B.); (C.B.); [email protected] [email protected] (G.M.); (G.M.); Tel.:Tel.: +39-051-209-3616 +39-051-209-3616 (C.B.) (C.B.) † Parts Parts 1 1and and 2 2are are references references 10 10 and and 12, 12, respectively. respectively. Received: 20 December 2017; Accepted: 12 January 2018; Published: 15 January 2018 Abstract: The reaction between bis(2-benzothiazolyl)ketone and vinyl Grignard reagents bearing different substituents on the vinyl moiety gave th thee product derived from attack on the carbonylic carbon- and/or oxygen-atom. oxygen-atom. The The regioselectivity regioselectivity of of the the attack attack depends depends on on th thee kind of substituents bound to thethe vinylicvinylic carboncarbon atomsatoms andand onon theirtheir relativerelative position.position. The reaction between vinylmagnesium bromide and 2-methyl-1-propenylmagnesium2-methyl-1-propenylmagnesium bromide bromide was carried out under different experimental conditions and in the presencepresence of radical scavengers. The results indicate a plausible mechanisticmechanistic pathway pathway involving involving radical radical intermediates intermediates in thein the case case of O -alkylation,of O-alkylation, but a but polar a polarones inones the in case the of case classic of classicC-alkylation. C-alkylation. This agreesThis agrees with with our previous our previous reports reports indicating indicating a key a rolekey playedrole played by the by delocalizationthe delocalization ability ability of the of substituentsthe substituents bound bound to the to carbonylthe carbonyl group group in driving in driving the theregioselectivity regioselectivity of the of vinylmagnesiumthe vinylmagnesium bromide bromide attack attack towards towardsO-alkylation. O-alkylation. Further Further support support of this wasof this obtained was obtained by diffractometric by diffractometric analysis analysis of four of distinct four distinct bis(heteroaryl)ketones. bis(heteroaryl)ketones. Keywords: bis(2-benzothiazolyl)ketone; Grignard Grignard reagents; reagents; vinylmagnesium bromide; C-alkylation; O-alkylation 1. Introduction Traditionally, GrignardGrignard reagents reagents [1 ][1] are are considered considered as potentialas potential anions anions able toable easily to easily react toreact hetero to heterodouble double bonds. bonds. The most The important most important reaction reaction is the nucleophilic is the nucleophilic 1,2-addition 1,2-addition to the carbonylic to the carbonylic carbon carbonatom that atom gives that access gives toaccess a plethora to a plethora of alcohol of alcohol derivatives derivatives (Scheme (Scheme1). 1). O OMgX OH + + R''MgX H3O R R' R R" R R" R' R' R, R' = H, alkyl, aryl R'' = alkyl, aryl Scheme 1. Classic pathway of the addition of Grig Grignardnard reagents to carbonyl compounds. Depending on the structure of Grignard reagents, substrates or the nature of solvents, alternative Depending on the structure of Grignard reagents, substrates or the nature of solvents, alternative reactions can take place [2]. For example, benzophenone reacts with cyclohexyl or isobutyl Grignard reactions can take place [2]. For example, benzophenone reacts with cyclohexyl or isobutyl Grignard reagents forming alcohols [3] or bimolecular reduction to pinacol by using neopentylmagnesium reagents forming alcohols [3] or bimolecular reduction to pinacol by using neopentylmagnesium halides; both the classic 1,2-addition and the conjugate addition on the phenyl ring can occur with tert-butyl Grignard reagents. O-alkylation by Grignard reagents [2] to carbonylic oxygen atom is rarely Molecules 2018, 23, 171; doi:doi:10.3390/molecules2301017110.3390/molecules23010171 www.mdpi.com/journal/moleculeswww.mdpi.com/journal/molecules Molecules 2018, 23, 171 2 of 14 halides; both the classic 1,2-addition and the conjugate addition on the phenyl ring can occur with tert-butyl Grignard reagents. O-alkylation by Grignard reagents [2] to carbonylic oxygen atom is rarely Molecules 2018, 23, 171 2 of 14 observed, although it occurred to a minor extent in the case of substrates such as orthoquinones [4], orthoquinolacetatesobserved, although [5 –it7 occurred], 9,10-phenanthraquinone to a minor extent in the [8], case and of benzil substrates [9]. such In our as orthoquinones previous studies, [4], we foundorthoquinolacetates unexpected reactivity [5–7], 9,10-phe of vinylmagnesiumnanthraquinone bromide [8], and (Schemebenzil [9].2 )In and our isoprevious-propenylmagnesium studies, we bromidefound with unexpected di(1,3-benzothiazol-2-yl)ketone reactivity of vinylmagnesium (1) which bromide gave (Scheme an exclusive 2) and attack iso-propenylmagnesium to the oxygen carbonyl atombromide [10]. By reactingwith di(1,3-ben1 and 2-methyl-1-propenylmagnesiumzothiazol-2-yl)ketone (1) which gave bromide, an exclusive mixtures attack of C to-and the Ooxygen-alkylation speciescarbonyl were atom obtained [10]. By in reacting almost equimolar1 and 2-methyl-1-propenylmagnesium amount. Conversely, alkyl, bromide, allyl, mixtures or alkynyl of C- Grignard and O-alkylation species were obtained in almost equimolar amount. Conversely, alkyl, allyl, or alkynyl reagents gave exclusively the expected carbinol [11]. O-alkylation and concomitant C-alkylation [12] Grignard reagents gave exclusively the expected carbinol [11]. O-alkylation and concomitant occurred with azaheteroaryl ketones such as di(thiazol-2-yl)ketone (5) or di(1,3-benzoxazol-2-yl)ketone (8). C-alkylation [12] occurred with azaheteroaryl ketones such as di(thiazol-2-yl)ketone (5) or di(1,3- Conversely,benzoxazol-2-yl)ketone di-[N-methyl-1,3-benzimidazol-2-yl]ketone (8). Conversely, di-[N-methyl-1,3-benzimidazol-2-yl]ketone (11) gave the carbinol as unique (11) gave compound the (see Schemecarbinol2 as). unique compound (see Scheme 2). Scheme 2. C- and O-alkylation reactions between vinylmagnesium bromide and several azaheteroaryl Scheme 2. C- and O-alkylation reactions between vinylmagnesium bromide and several ketones. azaheteroaryl ketones. More recently, we discovered that phenyl lithium and phenyl Grignard reagents also produced Morea mixture recently, of C- weand discovered O-alkylation that species; phenyl the lithium relative andratio phenyl is dependent Grignard on the reagents substituent also producedon the a mixturephenyl of C ring- and [13].O-alkylation species; the relative ratio is dependent on the substituent on the phenyl ring [13]. Based on the above considerations, to verify the influence of the geometry and the nature of substituents bound to vinyl moiety to C- versus O-alkylation selectivity, we planned to run reactions Based on the above considerations, to verify the influence of the geometry and the nature of between 1 and a series of 1-alkenylmagnesium reagents. Further, we designed an investigation of substituents bound to vinyl moiety to C- versus O-alkylation selectivity, we planned to run reactions the crystal structure of the aza-heteroaryl ketones reported in Scheme 2, in order to try to rationalize betweentheir1 differentand a series behaviour of 1-alkenylmagnesium when they react with reagents.vinylmagnesium Further, bromide. we designed an investigation of the crystal structure of the aza-heteroaryl ketones reported in Scheme2, in order to try to rationalize their different behaviour when they react with vinylmagnesium bromide. 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