Synthesis of N-Phenylpyrrole Carboximides

Several N-phenylpyrrole carboximides were synthesised using acyl isocyanates as intermediates.


Introduction
During a certain stage of our synthetic approach towards potential protein tyrosine kinases inhibitors (see e. g. [1], [2]), compounds of the general structure 1 were required (Figure 1).Acyl isocyanates were used as intermediates for the synthesis of the imides of type 1.One route to this type of compounds consisted in the addition of a C-nucleophile to the isocyanate of a pyrrolecarboxylic acid, whereas in a different approach, an acyl isocyanate was used as the electrophile in a Friedel-Crafts type substitution of a suitable pyrrole derivative.

Results and Discussion
Reaction of N-phenylpyrrole-3-carboxylic acid (2) with thionyl chloride (Scheme 1) gave the acid chloride 3, which was treated with tetrabutylammonium isocyanate in tetrahydrofuran to yield the corresponding acyl isocyanate 4.This sensitive compound could not be isolated, but its formation was easily demonstrated by quenching the reaction with ethanol, whereupon the acylated carbamate 5 was obtained.Reaction of 4 with lithium phenylacetylide gave the imide 6.Using the second approach mentioned, the isocyanate 7, which had been obtained from phenylpropiolamide and oxalyl chloride in dichloromethane, was reacted (Scheme 2) with the suitably protected N-phenylpyrrole 8. Imide 9 was obtained in good yield; deprotection to 6, however, was difficult and could be achieved in only 23%.When unprotected N-phenylpyrrole was treated with the isocyanate 7, substitution took place predominantly in the 2-position of the pyrrole ring, yielding 10.This latter compound cyclised to the oxazinone 11 upon heating.The structure of 11 was obtained from X-ray diffraction [3].Scheme 2. Alternate synthesis of imide 6 and formation of oxazinone 11.

General
Chemicals were purchased from Fluka AG, Aldrich Chemical Company, Inc., Merck GmbH, or Lancaster Synthesis Ltd.Solvents used in reactions were distilled and dried or purchased in absolute quality.Tetrahydrofuran was freshly distilled from Na/K.TLC: Merck silica gel 60 F 254 precoated glass plates.Column chromatography: flash-chromatography procedure of Still et al. [4]; columns with water cooling; Merck Kieselgel 60, 40-63 µm.
Colorless Butyllithium (100 mL, 1.6 M in hexane, 160.0 mmol) was added under Ar to 1-phenyl-1H-pyrrole (5.09 g, 36.0 mmol) and N,N,N',N'-tetramethylethylenediamine (22.5 mL, 160.0 mmol).The mixture was refluxed for 23 h and then cooled to -78°.Trimethylchlorosilane (20.0 mL, 160.0 mmol) was added and the mixture stirred for 6 h at 0° and for 90 min at room temperature.After washing twice with sat.NH 4 Cl solution and then with water, the organic layer was dried (Na 2 SO 4 ), filtered, and the solvent evaporated.The crude product (12.4g of a yellowish oil) was purified in ten portions by chromatography on SiO 2 (150 g, pentane/dichloromethane 12:1) to give 4.85 g (37%) of 8 as a yellowish oil.An analytically pure sample was obtained by kugelrohr distillation (175°/0.13mbar).

Figure 1 .
Figure 1.General structure of target compounds.