Practical Chromatography-Free Synthesis of 2-Iodo-N,N-diiso­propylferrocenecarboxamide and Further Transformations

Abstract

An efficient procedure able to deliver grams of racemic and enantioenriched 2-iodo-N,N-diisopropylferrocenecarboxamide without chromatographic purification was developed. To introduce the halogen, two procedures, one using the nBuLi-TMEDA chelate and one using a lithium amide in the presence of ZnCl2 as in situ trap were developed. Further functionalization by Suzuki–Miyaura and Ullman-type cross-couplings was investigated to access a variety of ferrocene derivatives.

Functionalization of 3‐Iodo‐N,N‐Diisopropylferrocene‐Carboxamide, a Pivotal Substrate to Open the Chemical Space to 1,3‐Disubstituted Ferrocenes

“…The required 2-iodo-N,N-diisopropylferrocenecarboxamide (2) [10] can easily be prepared on a multigram scale by following our chromatography-free approach. [11] As the halogen 'dance' reaction to convert 2 into 1 was previously optimized on a 1 to 2 mmol scale, [9a] a gram-scale synthesis was here required. The reaction on a small scale can be carried out by using a slight excess of LiTMP (TMP = 2,2,6,6-tetramethylpiperidide) in THF (THF = tetrahydrofuran) at À 50°C for 14 h. [9a] However, we found that upon scaling-up, the reaction time could be dramatically reduced, provided that a specific methanol quenching was applied (Scheme 2).…”

“…Previously, we successfully investigated the behavior of 2-iodo-N,N-diisopropylferrocenecarboxamide (2) in Ullmann-type and Suzuki-Miyaura cross-coupling reactions. [11] In spite of the steric hindrance resulting from the bulky carboxamide, good yields were obtained. Because 1,3-disubstituted ferrocenes are less common than their 1,2-isomers, we were interested in evaluating the reactivity of 1 under similar conditions.…”

“…N,N-Diisopropyl-3-(4-methoxyphenyl)ferrocenecarboxamide (11). By following the general procedure B, using 4-methoxyphenylboronic acid (304 mg) and triphenylphosphine (26.2 mg), the title product was obtained after column chromatography (PET-EtOAc, 80:20) as an orange solid (162 mg, 77%).…”

“…The required 2‐iodo‐ N , N ‐diisopropylferrocenecarboxamide ( 2 ) can easily be prepared on a multigram scale by following our chromatography‐free approach . As the halogen ‘dance’ reaction to convert 2 into 1 was previously optimized on a 1 to 2 mmol scale, a gram‐scale synthesis was here required.…”

“…Previously, we successfully investigated the behavior of 2‐iodo‐ N , N ‐diisopropylferrocenecarboxamide ( 2 ) in Ullmann‐type and Suzuki‐Miyaura cross‐coupling reactions . In spite of the steric hindrance resulting from the bulky carboxamide, good yields were obtained.…”