An efficient one-pot synthesis of dialkyl 8 a -acetylamino-8-oxo-8,8 a - dihydro-2 H -1-oxacyclopenta[ α ]indene-2,3-dicarboxylate derivatives

Ninhydrin reacts with amides in ethanol to produce N -(2-hydroxy-1,3-dioxoindan-2-yl)amide derivatives in nearly quantitative yields. Reaction between these adducts and electron-deficient acetylenic esters in the presence of triphenylphosphine leads to dialkyl 8 a -acetylamino-8-oxo- 8,8 a -dihydro-2 H -1-oxacyclopenta[ α ]indene-2,3-dicarboxylate derivatives in good yields.


Results and Discussion
For the preparation of N-(2-hydroxy-1,3-dioxoindan-2-yl)amide derivatives an amide, such as acetamide, propionamide or benzamide was treated with ninhydrin in ethanol to afford the desired adducts 3a-c in nearly quantitative yileds (Scheme 1).The structures of these products were confirmed by their spectral and analytical data.When di(t-butyl) acetylenedicarboxylate was treated in acetone with triphenylphosphine in the presence of N-(2-hydroxy-1,3-dioxoindan-2-yl)acetamide 3a, di(t-butyl) 8a-acetylamino-8-oxo-8,8a-dihydro-2H-1-oxacyclopenta [α]indene-2,3-dicarboxylate 5a was obtained in 78% yield (Scheme 2).The 1 H NMR spectrum of compound 5a showed four sharp singlets at 1.43, 1.55, 2.20 and 5.82 ppm which are related to two t-butyl groups, methyl group and methine group protons, respectively.A singlet was observed at 6.42 ppm that disappeared after addition of a few drops of D 2 O to CDCl 3 solution of compound 5a.This signal was related to NH proton.The aromatic protons resonated between 7.61 and 8.31 ppm.The 13 C NMR spectrum of compound 5a exhibited nineteen signals in agreement with the proposed structure.The above structural assignments based on NMR spectroscopy were supported by IR spectra.The IR spectrum of compound 5a showed absorption bands at 1744, 1706 and 1667 cm -1 for carbonyl groups.Compound 5a possesses two asymmetric centers and may exist as two diastereomers (Scheme 3).The endo-isomer is expected to suffer from steric crowding of the ester group and thus, we assign the exostereochemistry to product 5a.Similar reaction with the same stereochemistry between ninhydrin, ethanol, dialkyl acetylenedicarboxylate and triphhenylphosphine has been recently reported for the stereoselective synthesis of functionalized 2H-Indeno[2,1-b]furans. 15 The reaction between hydrated ninhydrin with two eq of dialkyl acetylenedicarboxylates and triphenylphosphine was also reported for the diastereoselective synthesis of dihydrofuro[2',3':2,3]indeno[2,1-b]furan derivatives. 16The configuration of the products of this reaction was also reported to be exo.The chemical shift of the methine proton in the 1 H NMR spectrum of compound 5a is very similar to those obtained for the similar compounds reported in these two reports, confirming the exo stereochemistry for it.
The NMR spectra of compounds 5b-d indicated the presence of two diastereomers.Efforts to separate them by chromatography were unsuccessful.The ratio of exo/endo diastereomers could be obtained from the 1 Scheme 3. Two diastereomers of compounds 5.
We also examined the preparation of compounds 5a-d by a one-pot reaction between ninhydrin, amide derivative, acetylenic ester and triphenylphosphine.Thus, the reaction between ninhydrin, acetamide, di(t-butyl) acetylenedicarboxylate and triphenylphosphine afforded compound 5a in 73% yield.As shown in scheme 4 this method was also successful for preparing compounds 5b-d.Yields and exo/endo diastereomer ratios obtained for this method were similar to those for the reaction between N-(2-hydroxy-1,3-dioxoindan-2-yl)amide derivatives and acetylenic esters in the presence of triphenylphosphine.On the basis of the well established chemistry of trivalent phosphorus nucleophiles, 15,16 it is reasonable to assume that compound 5 results from the initial addition of triphenylphosphine to the acetylenic ester and subsequent protonation of the 1:1 adduct by N-(2-hydroxy-1,3dioxoindan-2-yl)amide derivative (Scheme 5).Then the positively charged ion 6 is attacked by the conjugate base of the OH-acid to form phosphorane 7, which undergoes an intramolecular Wittig reaction to produce triphenylphosphine oxide and the product 5.In summary, the present procedure carries the advantage that, not only is the reaction performed under neutral conditions, but also that the starting materials and reagents can be mixed without any activation or modification.The procedure described here provides an acceptable one-pot method for the preparation of dialkyl 8a-acetylamino-8-oxo-8,8a-dihydro-2H-1-oxacyclopenta[α]indene-2,3-dicarboxylate derivatives.

Experimental Section
General Procedures.Melting points were determined with an electrothermal 9100 apparatus.Elemental analyses were performed at the analytical laboratory of the Islamic Azad University, the Science and Research Unit.Mass spectra were recorded on a FINNIGAN-MAT 8430 mass spectrometer operating at an ionization potential of 70 eV.IR spectra were recorded on a Shimadzu IR-470 spectrometer. 1 H and 13 C NMR spectra were recorded on Bruker DRX-500 Avance spectrometer at solution in CDCl 3 using TMS as internal standard.The chemicals used in this work purchased from Fluka (Buchs, Switzerland) and were used without further purification.

General procedure for preparation of compounds 3a-c
To a magnetically stirred solution of ninhydrin 1 (2 mmol) in 20 ml ethanol was added amide 2 (2 mmol).After stirring for 1 hour at room temperature, the solvent was removed under reduced pressure and the residue was washed with cold diethyl ether (2×5 mL) to afford the product 3a-c.

General procedure for preparation of compounds 5a-d by reaction between dialkyl acetylenedicarboxylates, triphenylphosphine and N-(2-hydroxy-1,3-dioxoindan-2-yl)amides
To a magnetically stirred solution of N-(2-hydroxy-1,3-dioxoindan-2-yl)amide 3 (2 mmol) and dialkyl acetylenedicarboxylate 4 (2 mmol) in 10 ml acetone was added a mixture of triphenylphosphine (2 mmol) in 2 ml acetone at room temperature.The reaction mixture was then allowed to stir for 24 h.The solvent was evaporated at reduced pressure and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (4:1) as eluent.The solvent was removed under reduced pressure to afford the product.

General procedure for one-pot preparation of compounds 5a-d by reaction between ninhydrin, amides, dialkyl acetylenedicarboxylates and triphenylphosphine
A solution of ninhydrin 1 (2 mmol), amide 2 (2 mmol) and dialkyl acetylenedicarboxylate 4 (2 mmol) in 10 ml acetone was stirred for 5 min.Then, a mixture of triphenylphosphine (2 mmol) in 2 ml acetone was added at room temperature.The reaction mixture was then allowed to stir for 24 h.The solvent was evaporated at reduced pressure and the residue was purified by silica gel column chromatography using hexane-ethyl acetate (4:1) as eluent.The solvent was removed under reduced pressure to afford the product.