Highly Regioselective Preparation of Heteroaryl–Magnesium Reagents by Using a Br/Mg Exchange

Abstract

Disubstituted thienyl-, furyl- and pyridylmagnesium derivatives are regioselectively prepared from a Br/Mg exchange of the corresponding dibromo compounds by using either iPrMgCl⋅LiCl or hindered arylmagnesium reagents, such as isitylmagnesium bromide⋅lithium chloride (isityl = 2,4,6-triisopropyl-phenyl) complexed with a diamine ligand, in difficult cases. The selective functionalisations of these heterocyclic scaffolds by using Negishi cross-coupling reactions, acylations or addition to aldehydes were readily achieved.

One‐Pot Halogen Dance/Negishi Coupling of Dibromothiophenes for Regiocontrolled Synthesis of Multiply Arylated Thiophenes

“…These results are complementary to those reported by Knochel (Scheme ) . They achieved regioselective magnesiation of tribromothiophene 8 using a combination of hindered Grignard reagent 9 and diamino ether 10 .…”

“…These results are complementary to those reported by Knochel (Scheme 4). [16] They achieved regioselective magnesiation of tribromothiophene 8 using ac ombination of hindered Scheme2.Initial attemptst oi ntroduce anisyl groupb yM urahashi coupling. Table 1.…”

Preparation of Functionalized Lithium, Magnesium, Aluminum, Zinc, Manganese­, and Indium Organometallics from Functionalized Organic Halides

“…Subsequent transmetalation with zinc chloride and Negishi cross-coupling afforded the trisubstituted pyridine 383 in 74% yield. 129 In the case of dibromothiophenes or -furans bearing an alkyl substituent at position 3, the regioselectivity of the bromine-magnesium exchange reaction is poor with the use of isopropylmagnesium chloride-lithium chloride complex. However, with a sterically hindered Grignard reagent such as 384, the exchange reaction rate was lower and a longer reaction time was required (16 hours instead of 1 hour), but it led to increased regioselectivity.…”

Review. Regioselective Functionalization of Pyridines using a Directed Metalation or a Halogen/Metal Exchange

“…Thus, the treatment of 87 with iPrMgCl·LiCl at −78 • C and heating of the reaction mixture to 25 • C for 1 h produces an intermediate pyridyne 88 which, after trapping with an excess of furan, produces the bicyclic product 89 in 85 % yield (Scheme 22) [66]. The homogeneous nature of the Br/Mg-exchange allows to tune the reaction by changing various parameters, and impressive regioselectivities can be achieved for the functionalization of various 3,5-dibromopyridines [67]. Thus, the reaction of the dibromopyridine 90 with iPrMgCl·LiCl at −55 • C is complete within 1 h leading to the pyridylmagnesium reagent 91 with a regioselectivity better than 27 : 1.…”

“…After 2 h of reaction time at −25 • C, the exchange is complete and the resulting Grignard reagent 94 is obtained. Transmetalation with ZnCl 2 followed by Pd-catalyzed cross-coupling with 4-iodobenzonitrile produces the pyridine 95 in 60 % isolated yield (Scheme 23) [67].…”