Magnesium Bisamide-Mediated Halogen Dance of Bromothiophenes

Abstract

A magnesium bisamide-mediated halogen dance of bromothiophenes is described. The thienylmagnesium species generated in situ is more stable than the corresponding thienyllithium species, which was applied to trap the transient anion species with several electrophiles, such as allyl iodide, phenyl isocyanate, and tributylstannyl chloride. The utility of the magnesium bisamide-mediated halogen dance is useful in the concise synthesis of a medicinally advantageous compound via a one-pot, ester-directed halogen dance/Negishi cross coupling.

Nucleophilic C–H Etherification of Heteroarenes Enabled by Base-Catalyzed Halogen Transfer

“…A control experiment in Scheme c shows that 3-methoxypyridine ( 53 ) does not undergo 4-iodination under these conditions. These results are consistent with halogen transfer and subsequent S N Ar as the operative mechanism for C–H etherification. , Studies on the halogen transfer process, including further development of halogen transfer reagents, are ongoing. , …”

Latent Carbene: Diaminomethylation of Thiophenes

“…Its hydrolysis gave aldehyde 16 a almost in quantitative yield. Compound 16 a is described in the literature [14,15] and can be prepared either from 2,3‐dibromo‐ or 2,5‐dibromothiophenes via the lithiation electrophilic substitution sequence due to halogen scrambling [16] …”

Trapping of Transient Thienyllithiums Generated by Deprotonation of 2,3- or 2,5-Dibromothiophene in a Flow Microreactor

“…10 Our group recently reported the generation of the thienylmagnesium derivative 9 (TMP = 2,2,6,6-tetramethylpiperidinyl) by deprotonation of 2,3-dibromothiophene (1) with Mg(TMP) 2 •2LiCl. 11 Although the thienylmagnesium 9 underwent halogen dance at room temperature, 12 this reaction was sufficiently sluggish at 0 °C to permit trapping of the transient 9 by several electrophiles (Scheme 2B). The recent development of flash chemistry in a flow microreactor 13 prompted us to investigate the direct trapping of thienyllithium 4 with an electrophile (Scheme 2C).…”

“…This proposal is consistent with two factors: (1) deprotonation at the -position is faster than that at the -position, 21 and (2) halogenlithium exchange of the bromo group at the -position and the lithium atom at the -position is slower than that of the bromo group at the -position and lithium atom at the position, probably because -lithium species are generally more stable than -lithium species, according to reports on the reactivity of related Grignard reagents. 12,22 In conclusion, we have developed a method to trap the transient dibrominated thienyllithium species generated by deprotonation of 2,3-dibromothiophene in a flow microreactor. This method permits the direct use of thienyllithium species, without transmetalation, in syntheses of 5-substituted 2,3-dibromothiophene derivatives.…”