Intramolecular domino-Knoevenagel-hetero-Diels-Alder reaction with terminal acetylenes

New polycyclic pyrans have been synthesized using new and efficient domino-Knoevenagel-hetero-Diels-Alder reaction between O-propargylated salicylaldehydes with 1,3-indanedione in acetonitrile in the presence of CuI. The products are formed in good yields.


Introduction
The development of a new strategy for the synthesis of complex organic molecules is an important aim in modern organic chemistry.L. F. Tietze introduced the domino-Knoevenagelhetero-Diels-Alder reaction as a powerful sequential transformation. 1 It has been proven that this reaction is a valuable method for the construction of annulated dihydropyrans 2 and has already been used for the synthesis of several natural products. 3he reaction can be performed as a two-component transformation using an aldehyde containing an alkene in the side-chain as a dienophile and a 1,3-dicarbonyl compound.Although the advantages of this useful reaction in the construction of polycyclic ring skeletons has been well documented.But its application to the alkynes as the dienophile has been limited, 4 which is related to the poor reactivity of unactivated alkynes.Only after the discovery of the remarkable catalytic effect of various transition metal complexes, the synthetic potential of alkyne transformation could be exploited. 5Copper-(I) iodide has found widespread applications in synthetic organic chemistry. 6The hetero-Diels-Alder cycloadditions of alkynes containing donor-acceptor substitutes were reported so far, 7 but there is no report for the intramolecular domino Knoevenagel hetero-Diels-Alder reaction with unactivated alkynes.As a continuation of our work on the [4+2] cycloaddition chemistry, herein we report a novel, highly efficient domino Knoevenagel-hetero-Diels-Alder reaction of O-propargylated salicylaldehyde with the 1,3indanedione as 1,3-dicarbonyl compound in the presence of CuI (Scheme 1).

Results and Discussion
The O-propargylated salicylaldehydes 2a-c were prepared An extensive screening of the reaction conditions was performed for the reaction of Opropargylated salicylaldehyde (2c) with indanedione.The reaction was carried out in the presence of cuprous iodide or silver acetate as Lewis acid and diammonium hydrogen phosphate as a base for the Knoevenagel condensation.The results are summarized in Table 2.Under optimized conditions (20 mol.% CuI and 20 mol.% DAHP, refluxing in MeCN) the desired pyran derivative was smoothly formed and isolated in 81% yield (Table 2, entry 2 In the domino Knoevenagel-hetero-Diels-Alder reaction, the desired heterodiene (alkylidene-1,3-dicarbonyl compound) is formed in situ by Knoevenagel condensation of O-propargylated salicylaldehyde with indanedione in the presence of diammonium hydrogen phosphate and undergoes a cycloaddition reaction in refluxing acetonitrile in presence of CuI to give the corresponding pyran ring (Table 3).The structure of the products was assigned on the basis of 1 H-NMR, 13 C-NMR spectroscopic data and also high-resolution mass spectrometry data.Reactions were performed with aldehydes 2a-c (1 mmol), 1,3-indanedione (1.2 mmol, 146 mg), CuI (0.2 equiv.)and (NH 4 ) 2 HPO 4 (0.2 equiv.) in acetonitrile at reflux; a Isolated yields.
1 H-NMR spectra for all products showed an AB quartet for the -OCH 2 group at δ 4.6 and 4.9 ppm with J = 11.5 Hz.The diatropicity of methylene hydrogens is related to oxa-helicene structure of the products.The corresponding signals of the O-CH 2 groups in the 13 C-NMR spectra appeared at 65-66 ppm.
Although we have not yet established the mechanism, a possible pathway for the domino intramolecular Knoevenagel-hetero-Diels-Alder reaction is shown in Scheme 3. The initial step is Knoevenagel condensation between 1,3-indanedione and the aldehydes 2a-c, could be catalyzed by diammonium hydrogen phosphate.It seems that the triple bond was activated with CuI through formation of a π-complex or copper acetylide 9 which provided the proper condition for hetero-Diels-Alder reaction.The exact reaction mechanism is not clear.
ARKAT USA, Inc.In conclusion, we have developed a Cu-catalyzed domino intramolecular Knoevenagelhetero-Diels-Alder reaction which provided an efficient route to tetracyclic pyran derivatives.Further studies to extend the scope of the synthetic utility for this Cu-catalyzed domino intramolecular Knoevenagel-hetero-Diels-Alder reaction with inactivated alkynes are continuing.

Experimental Section
General Procedures.Melting points were determined with an Electrothermal 9100 apparatus and were uncorrected.IR spectra were obtained on an ABB FT-IR (FTLA 2000) spectrometer. 1H NMR and 13 C NMR spectra were run on a Bruker DRX-300 AVANCE at 300 MHz for 1 H-NMR and 75 MHz for 13 C-NMR.CDCl 3 and DMSO-d 6 were used as solvents.High-resolution mass spectra were recorded on JEOL JMS-700 (HR-EI) spectrometer.