Study of alkylation of deprotonated diphenylacetonitrile with halogeneacetones: X-ray crystal structure of 3,3-diphenyl-5-methyl-5-acetonylpyrrolidin-2-one – a new cyclization product in acetone co-solvent

Alkylation of deprotonated diphenylacetonitrile with halogeneacetones (Cl,Br,I) was studied in N,N -dimethylformamide (DMF). The differences in yields of the alkylation product, 4-oxo-2,2-diphenylvaleronitrile ( I ), are caused by variations in the haloacetones and solvents. The detailed structure of a new cyclization by-product, 3,3-diphenyl-5-methyl-5-acetonylpyrrolidin-2-one ( II ), in acetone co-solvent was established by X-ray analysis.


Introduction
4-Oxo-2,2-diphenylvaleronitrile (I) serves as a precursor and useful key substrate for the synthesis of several drugs 1,2 such as analgetics, antirheumatics, non-peptide neurokinin-3 and angiotensin II receptor antagonists, agents for the treatment of overactive detrusor and novel materials 3,4 with opto-electronic properties, as well as for dyes and fluorescent compounds.The objective of this study was the design of a scaleable process for the synthesis of 4-oxo-2,2diphenylvaleronitrile 1,5,6 (I).
The introduction of an acetonyl moiety into a molecule possessing an activated methylene position is usually effected directly with chloro-or bromoacetone. 5When the direct method is unsatisfactory, alternatively, two-or multistep processes are utilized.1,3-Dibromo-2methoxypropane, 3-bromo-2-(tetrahydropyran-2-yloxy)propene 5 and bromoacetone dimethyl ketal 1 were shown to function as masked acetonyl moieties of considerable utility.Alternatively, two-step processes, involving alkylation with propargyl halogenide 2,6 followed by mercuric or transition metal salt catalyzed hydration of the terminal acetylenic function, or, alkylation with 2,3-dichloropropene and subsequent hydrolysis of the vinylic chloride with concentrated sulfuric acid are often used. 5arious approaches 1,5,6 to the synthesis of 4-oxo-2,2-diphenylvaleronitrile (I) have been explored, but they have all encountered problems, multi-step reactions with masked acetonyl moieties and the overall yield not exceeding 56% .The synthetic details of the direct method for introducing an acetonyl moiety into the molecule (I) with haloacetones have not been published in the literature.
In connection with various synthetic objectives for direct acetonylation of diphenylacetonitrile we utilized the commercially available chloro-and bromoacetones.We prepared iodoacetone in situ utilizing chloro-and bromoacetone and NaI with or without acetone as co-solvent.Potassium tert-butylate or NaH used as bases in DMF both easily deprotonated diphenylacetonitrile.The great reactivity of chloro -and bromoacetone toward nucleophilic species in many cases reduces their usefulness as sources of the acetonyl group.The treatment of diphenyl acetonitrile, deprotonated by potassium tert.-butylate, with chloro-acetone resulted in the formation of only 16% of I (by gas chromatographic analysis).A better yield of up to 70-71% was obtained with bromoacetone and in situ prepared iodoacetone.Utilizing NaH as base in DMF for deprotonation of diphenylacetonitrile has the same effect as potassium tert.-butylate.An interesting new cyclization of iodoacetone, prepared in-situ with acetone as co-solvent from solubilization of NaI, was observed and this new cyclization product was shown to have structure II.

Scheme l
A plausible pathway for the formation of II is depicted in Scheme 2. The key step in the process involves a [2+2] cycloaddition in which the carbonyl group of the haloacetone adds to a potassium or sodium salt of ketene-imine (Ph 2 C=C=N -K + ) to form a four membered 1,3oxazetidíne intermediate.Subsequent ring-opening-ring-closure followed by solvent addition would result in the formation of II -a derivative that could easily be isolated by column chromatography on silica gel.The resulting cyclic γlactam II was obtained in 50 % yield in optically inactive form.
a Only ions with relative intensity above 5 %.

X-ray Analysis
Suitable crystals of II were obtained by slow crystallization from a mixture of methyl tert.-butylether at room temperature.The relevant crystallographic data 11 and structure refinement are given in Table 3.The bond length and bond angles are listed in Table 4.A list of selected torsion angles is given in Table 5.The final positional parameters are summarized in Table 6.A perspective view 12 and the numbering of the atoms are depicted in Figure 1.The hydrogen atoms were refined isotropically in idealized positions riding on the atom to which they are attached.

Experimental Section
General Procedures.All reagents -diphenylacetonitrile (99+% Avocado), chloroacetone (96% Acros) potassium tert-butoxide (98+%, Merck), sodium hydride, 60% dispersion in mineral oil, in toluene and DMF soluble bags (Acros), N,N-dimethylformamide (99% Acros) were commercial products and were used without purification.Column chromatography was performed on silica gel 100-200 mesh, Merck.Thin-layer chromatography (TLC, on aluminum plates coated with silica gel 60F 254 , 0.25 mm thickness, Merck) was used for monitoring the reactions, eluant CHCl 3 : methanol (99:1).Melting points were determined on a Kofler hot-stage microscope.NMR spectra were measured at ambient temperature on Varian VXR-300 spectrometer equipped with 5 mm broad-band probe operating at 300 MHz for protons and 75 MHz for carbons, respectively.The 1 H and 13 C chemical shifts were extracted from standard proton and carbon NMR spectra.To achieve unambiguous signal assignment and identification additional NMR experiments were performed: HECTOR (H,C one-bond correlation) 7 , DEPT 8 and long-range INEPT 9 HECTOR and DEPT spectra were recorded with the standard pulse sequences provided by the spectrometer manufacturer.The long-range INEPT experiment was performed according to the literature. 10ass spectra (AEI) were measured with a GC/MS 25 RFA instrument (Kratos Analytical, Manchester), equipped with a direct inlet system at a ionizing electron energy 70 eV, trap current 100 µA at temperature of the ion source 200 C o .The precise measurements of the masses was done at static resolution about 4 000 (10% valley definition) using perfluorokerosene as standard and scan speed 10 s/decade.Crystal and experimental data for compound II are given in Table 3 and hydrogen-bonds for II in Table 4.The structure was solved by direct methods 13 and refined by anisotropic full-matrix least-squares technique. 14Because of the small anomalous scattering power of one nitrogen and two oxygen atoms to twenty carbon atoms, the absolute structure was not determined.A flame dried flask was charged with a solution of diphenylacetonitrile 19.2g (0.1 mole) in 200 mL DMF, and under vigorous stirring 0.12 mol of potassium tert.-butylatepowder was added at 25 °C, while a flow of dry argon was maintained through the apparatus.The resulting mixture was stirred 30 min at 25 °C .A solution of 0.12 mol haloacetone in 50 mL of DMF was added at 20 min and thereafter the reaction temperature rose steadily, but was not allowed to exceed 45 °C.The reaction mixture was stirred at 50 °C for 3-5 h and the solvent was evaporated at the same temperature under reduced pressure.Cold water (200 mL) containing 5g NaCl was added and the product was extracted into CH 2 Cl 3 .The extract was washed well with water, dried over sodium sulfate, and the solvent was removed in vacuo at 40 °C leaving crystalline material, analyzed by gas chromatography.For the yields see Table 5.A flame dried flask was charged with 0.12 mol of a sodium hydride 60% dispersion in mineral oil while a flow of dry argon was maintained through the apparatus.The sodium hydride was freed of the carrier by washing with three portions of 50 mL n-heptane, and then it was layered with 50 mL of dry DMF.

4-Oxo
To this vigorously stirred suspension, a solution of diphenylacetonitrile 19.2g (0.1 mole) in 150 mL DMF was added at 25 °C.Hydrogen evolution commenced and.thereafter.the reaction temperature rose steadily, but was not allowed to exceed 45 °C.When the evolution of gas had become slow (after app.30 min) a solution of 0.12 mol of the in situ prepared iodoacetone in 50 mL DMF (prepared separately from 0.12 mol chloro-or bromoacetone and 18g dried NaI in 50 mL DMF at 15 °C , 30 min) was added over 20 min.The reaction mixture was stirred at 40 °C for 8 h and at the same temperature the solvent was evaporated under reduced pressure.Cold water (200 mL) containing 5g NaCl and Na 2 S 2 O 3 was added and the product was extracted into diethyl ether.The extract was washed well with water, dried over sodium sulfate, and the solvent was removed in vacuo at 40 °C leaving crystalline material, analyzed by gas chromatography.Yield of I see Table 5.
A flame dried flask was charged with a solution of diphenyl acetonitrile 57.2 g (0.3 mole) in 250 mL DMF, and under vigorous stirring 0.3 mol of NaI and 0.33 mol chloroacetone in 50 mL of DMF at 25 °C, were added while a flow of dry argon was maintained through the apparatus.
The resulting mixture was stirred 30 min.A suspension of 0.33 mol of sodium hydride as a 60% dispersion in mineral oil was freed of the carrier by washing with three portions of 50 mL n-heptane, and then it was layered with 50 mL of dry DMF and added during 20 min at 0 °C; thereafter the reaction temperature rose steadily, but was not allowed to exceed 25 °C.The reaction mixture was stirred at 25 °C for 3-5 h and at the same temperature the solvent was evaporated under reduced pressure.Cold water (500 mL) containing 50g NaCl and 50g Na 2 S 2 O 3 was added and the product was extracted into diethyl ether.The extract was washed well with water, dried over sodium sulfate, and the solvent was removed in vacuo at 40 °C leaving crystalline material.4-Oxo-2,2-diphenylvaleronitrile (I) (55 % isolated yield) was purified by column chromatography and recrystallized from n-heptane-toluene, m.p. 105-107 °C.

Figure 1 .
Figure 1.ORTEP plot and atomic numbering of compound II.

Table 1 .
. The observed 1 H-13 C long range correlations (shown in Table 1) are fully consistent with the proposed structure of the molecule.NMR spectral parameters of II.Chemical shifts are shown in δ scale in ppm ISSN 1424-6376Page 295 © ARKAT USA, Inc

Issue in Honor of Prof. Sándor Antus ARKIVOC 2004 (vii) 292-302 ISSN 1424-6376 Page 296
Thus, the elemental composition [C 20 H 21 O 2 N] +. was ascertained from high resolution measurements with 7 ppm precision.The basic decomposition patterns of the molecular ion are depicted in Scheme 3.
a Correlations between the protons indicated in the first column and the carbons indicated in the third column.Mass spectrometry was used extensively as additional confirmation of structural proposals.©ARKAT USA, Inc [ ] ] ] +.+.

Table 3 .
Crystal and experimental data for compound II

Table 5 .
Alkylation of diphenylacetonitrile with X-CH 2 -CO-CH 3 13,2-diphenylvaleronitrile (I) purified by column chromatography and recrystallized from n-heptane-toluene, m.p. 105-107 °C.Lit. 1 m.p. 105-107 °C (n-hexane/ethyl acetate).IR, Mass, 1 H and13C NMR identical to those given in the lit.1b)Potassium tert.-butylate in DMF and NaI in acetone and DMF.A flame dried flask was charged with a solution of diphenyl acetonitrile 19.2g (0.1 mole) in 200 mL DMF, and under vigorous stirring 0.12 mol of potassium tert.-butylatepowder was added at 25 °C, while a flow of dry argon was maintained through the apparatus.The resulting mixture was stirred 30 min at 25 °C.A solution of 0.12 mol in situ prepared iodoacetone in 60 mL acetone and 30 mL DMF was added ( prepared separately from 0.12 mol chloroacetone and 18g dried NaI in 60 mL acetone and 30 mL DMF at 15 °C, 30 min) at 20 min and thereafter the reaction temperature rose steadily, but was not allowed to exceed 40 °C.The reaction mixture was stirred at 40 °C for 8 h and at the same temperature the solvent was evaporated under reduced pressure.Cold water (200 mL) containing 5g NaCl and Na 2 S 2 O 3 was added and the product was extracted into ether.Te extract was washed well with water, dried over sodium sulfate, and the solvent was removed in vacuo at 40 °C leaving crystalline material, analyzed by gas chromatography.Yields of I and II see Table5.
c) Potassium tert.-butylate in DMF and NaI in DMF.The preparation is identical to b) but without acetone as co-solvent for dissolution of NaI in DMF.d) Sodium hydride, 60% dispersion in mineral oil in DMF and NaI in DMF.