3-(1-Cyclohexylpyrrolidin-2-ylidene)-3 H -indole and 4-(cyclohexylamino)-1-(1 H -indol-3-yl)butan-1-one – the balance between enaminimine and ring-opened forms

Reaction of indole with the combination 1-cyclohexyl-2-pyrrolidinone and phosphoric trichloride gives the hydrochloride of 3-(1-cyclohexylpyrrolidin-2-ylidene)-3 H -indole. Treatment of this with base at room temperature causes hydrolytic ring opening producing 4-(cyclohexylamino)-1-(1 H -indol-3-yl)butan-1-one but careful low-temperature basification allows the isolation of 3-(1-cyclohexylpyrrolidin-2-ylidene)-3 H -indole itself. The crystal structure of the hydrochloride, as a dihydrate, was determined.


Introduction
The reaction of indole with the Vilsmeier reagent 1 (formed using N,N-dimethylformamide (DMF) and phosphoric trichloride), followed by base, is the classic, and very efficient, method for the 3-formylation of indoles 2 (e.g.→ 2, Scheme 1) and indeed other electron-rich heterocycles. 3Before the alkaline hydrolysis step, the product is a salt, 3-[(dimethylamino)methylene]-3H-indolium chloride (1) to which hydroxide adds then dimethylamine is lost revealing the aldehyde.Ketones can also be obtained in this way, using N,N-dimethylamides of acids other than formic. 4
When 1-cyclohexyl-2-pyrrolidinone (8) was was employed in a standard Vilsmeier process, using 8 as both solvent and reactant (as in the standard sequence with DMF) and after diluting the final reaction mixture with water, a white precipitate was formed and was filtered off (25% yield) leaving a clear aqueous solution.The solid proved to be the hydrochloride of 3-(1cyclohexylpyrrolidin-2-ylidene)-3H-indole (9.HCl) as a dihydrate (X-ray crystallography), the characteristic UV absorption (cf.reference 9), the absence of carbonyl stretching in the IR, and its structure determination by X-ray crystallography (Figures 1 and 2) were definitive.When the clear aqueous solution was made basic by the addition of sodium hydroxide at room temperature, a solid was formed, filtered off (68% yield) and purifiedit proved to be the ketone (10) resulting from ring opening.The principal evidences for this were the conjugated carbonyl stretching at 1624 cm -1 , the 13 C NMR signal for carbonyl carbon at  201.4, the typical 3-acylindole UV absorption, and the observation of an indolic N-hydrogen 1 H NMR signal at 10.25.
The free 3-(1-cyclohexylpyrrolidin-2-ylidene)-3H-indole base (9) could be obtained by very careful neutralization of its hydrochloride salt: this was achieved by dissolving the salt in water, cooling the solution to -5 °C, slow addition of aqueous NaOH precooled to -5 °C till the pH reached 8, all the while with vigorous stirring, then rapid extraction with pre-cooled CHCl3, drying of the extract and evaporation.The overall situation is summarized in Scheme 4.

Scheme 4
The structure of 9.HCl.2H2Odetermined by X-ray analysis (see Figures 1 and 2, and Supplementary Information for details) shows the conjugated system (linked indole and pyrrolidine rings) to be essentially planar, the maximum distances above and below the least squares plane through all the atoms (excluding the cyclohexyl unit except the carbon linked to nitrogen) are 0.470 Å for C13 and 0.497 Å for C11.Additionally one can note the small values of the four possible dihedral angles around the exocyclic double bond, which links the indole and pyrrolidine moieties, at only 11.2°, 13.0°, 15.8° and 17.5°.The extensive conjugation which resonance contributor 11 implies (Figure 3) (and which explains the strongly basic character noted 9 for 5) is reflected in the bond lengths shown on 11.

Figure 3
The cyclohexyl unit is twisted out of the plane of the rest of the molecule, no doubt to minimize adverse steric interactions; the average plane of the cyclohexyl unit is at a torsion angle of 66.93° with respect to the average plane of the rest of the molecule.The nearest hydrogen (the hydrogen on the cyclohexyl carbon attached to nitrogen) to the imine hydrogen is at 2.00 Å.

Experimental Section
General.Melting points were determined on a Philip Harris C4954718 apparatus.Infrared spectra were recorded on a Thermo Nicolet (Nexus 670) Fourier transform (FT) infrared spectrometer, using sodium chloride cells and measured in KBr pellets. 1 H (300 MHz) and 13 C (75.5 MHz) NMR spectra were recorded on a Bruker 300 spectrometer in CDCl3 using TMS as the internal reference.Mass spectra were recorded on an Agilent 6890-N-Network-GC-system.The routine purification of reagents and solutions was carried out by standard laboratory procedures. 15Analytical thin-layer chromatography (TLC) was carried out with Merck silica gel 60 F254 aluminum sheets.Microanalyses were performed on a Leco Analyzer 932.

Figure 1 .
Figure 1.ORTEP representation of 9.HCl.2H2Oshowing the relative location of the water molecules and the chloride anion and the atom numbering system.

Figure 2 .
Figure 2. Viewed along the c axis the crystal packing generates columns of 9.H + H-bonded together by columns of water and chloride.