From 2- to 3-Substituted Ferrocene Carboxamides or How to Apply Halogen “Dance” to the Ferrocene Series

Abstract

Two methods were compared to convert ferrocene into N,N-diisopropylferrocenecarboxamide, N,N-diethylferrocenecarboxamide, N,N-dimethylferrocenecarboxamide and (4-morpholinocarbonyl)ferrocene, namely deprotometalation followed by trapping using dialkylcarbamoyl chlorides and amide formation from the intermediate carboxylic acid. The four ferrocenecarboxamides were functionalized at C 2 ; in the case of the less hindered and more sensitive amides, recourse to a mixed lithium-zinc 2,2,6,6-tetramethylpiperidinobased base allowed to achieve the reactions. Halogen migration using lithium amides was next optimized. Whereas it appeared impossible to isolate the less hindered 3-iodoferrocenecarboxamides, 3-iodo-N,N-diisopropylferrocenecarboxamide proved stable and was converted to new 1,3-disubstituted ferrocenes by Suzuki coupling or amide reduction. DFT calculations were used to rationalize the results obtained.

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

“…Although we previously demonstrated the usefulness of 2 to access original 3-iodo-N,N-diisopropylferrocenecarboxamide through a halogen 'dance' reaction, 13,17 the functionalization of the former was not extensively studied. In 2014, Kumar has reported an original example of a tBuOK-mediated sp 3 C-H bond functionalization to access lactams in 96% yield from (±)-2.…”

“…Analytical data analogous to those reported previously. 13 νmax (film)/cm − The reaction mixture was cooled to between -85 and -80 °C (external temperature) in an acetone/liquid nitrogen bath. nBuLi (1.4 M, 100 mL, 140 mmol, 1.50 equiv) was then introduced dropwise by cannula, keeping the temperature of the bath between -85 and -80 °C.…”

“…1 H NMR (300 MHz, CDCl3): δ (ppm) 7.86 (dd, J = 1.3, 3.8 Hz, 1H, ArCH), 7.59 (dd, J = 1.3, 5.0 Hz, 1H, ArCH), 7.11 (dd, J = 3.8, 5.0 Hz, 1H, ArCH), 4.66 (dd, J = 1.5, 2.6 Hz, 1H, FcCH), 4.11 (dd, J = 1.5, 2.6 Hz, 1H, FcCH), 4.04 (br s, 1H, CH), 3.99 (t, J = 2.6 Hz, 1H, FcCH), 3.38 (br s, 1H, CH), 1.44 (br s, 6H, 2 x CH3), 1.02 (br s, 6H, 2 x CH3). 13 N,N-Diisopropyl-2-(3,4-methylenedioxycinnamoyl…”

“…In the frame of our ongoing research program dedicated to the synthesis of original ferrocene derivatives, 13 we required large quantities of 2-iodo-N,N-diisopropylferrocenecarboxamide (2) in both racemic and enantioenriched forms. Although already reported in the literature, the protocols relying on chromatographic purification were not compatible with the scale required here.…”

“…NMR (300 MHz, CDCl3): δ (ppm) 8.10 (dd, J = 5.5, 8.9 Hz, 2H, 2 x ArCH), 7.11 (t, J = 8.6 Hz, 2H, 2 x ArCH), 4.64 (dd, J = 1.5, 2.6 Hz, 1H, FcCH), 4.38 (s, 5H, Cp), 4.12 (dd, J = 1.5, 2.7 Hz, 1H, FcCH), 4.06 (br s, 1H, CH), 4.00 (t, J = 2.7 Hz, 1H, FcCH), 3.36 (br s, 1H, CH), 1.45 (br s, 3H, CH3), 1.37 (br s, 3H, CH3), 1.05 (br s, 3H, CH3), 0.99 (br s, 3H, CH3) 13. C NMR (75.4 MHz, CDCl3): δ (ppm) 166.2 (d, J = 254.7 Hz, ArC-F), 165.8 (s, C=Oamide), 164.4 (s, C=Oester), 132.7 (d, J = 9.4 Hz, 2 x ArCH), 126.0 (d, J = 2.8 Hz, ArC), 115.9 (d, J = 22.2 Hz, 2 x ArCH), 115.2 (s; FcC-O), 80.1 (s, FcC), 71.4 (s, Cp), 62.8 (s, FcCH), 62.1 (s, FcCH), 61.1 (s, FcCH), 50.7 (s, CH), 46.1 (s, CH), 20.8 (s, 4 x CH3).…”