A facile entry into a novel class of dispiroheterocycles through 1,3-dipolar cycloaddition

The cycloaddition reaction of non-stabilized azomethine ylides, generated through decarboxylation and deprotonation, with ( E )-2-arylidene-1-tetralones as dipolarophile has been investigated. A high degree of regioselectivity has been observed in the synthesis of a new class of functionalised dispiroheterocyclic compounds bearing a tetralone, acenapthenequinone and oxindole framework.


Introduction
][6] Although highly substituted spiropyrrolidines are known, there seems to be no report on the synthesis of dispiro substituted pyrrolidine heterocycles.1,3-Dipolar cycloaddition provides a way for the synthesis of many dispiroheterocycles through the cycloaddition reaction of nonstabilised azomethine ylides with the olefinic dipolarophiles.Highly substituted pyrrolidines have attracted much interest as they contribute the central structural element of many alkaloids and pharmacological active compounds. 7,8s a part of our study 9,10 on the synthesis of novel dispiropyrrolidinyl derivatives we have examined the 1,3-dipolar cycloaddition reaction of E-2-arylidene-1-tetralones with the azomethine ylide generated through a decarboxylation and deprotonation method.

Scheme 1
The dispiroheterocyclic ring structures of products 4a-e were confirmed by IR, 1 H/ 13 C NMR and mass spectral studies.The IR spectrum of 4a showed two peaks corresponding to tetralone and acenapthenequinone ring carbonyls at 1670.9 and 1714.2 cm -1 , respectively.The NMR spectrum of the cycloadduct 4a exhibited a doublet of doublets at δ 5.17 due to the C-4 benzylic proton of the pyrrolidine ring.The regiochemical outcome of the Azomethine ylide cycloaddition with conformationally restricted s-cis enone, 2-arylidene-1-tetralones 3a-e is probably attributed to the involvement of the anti-ylide 11 in the transistion state where the exoorientation of the dipolarophile to W-periphery of the ylide prevents the formation of syn-ylide which is not observed due to the unfavorable steric repulsions between the carbonyl oxygen of the acenaphthequinone ring and tetralone-1-one ring systems.Further, the regiochemistry of the cycloadduct 4a was established by the coupling pattern in its 1 H NMR spectrum.Also, the 13 C NMR showed two signals at δ 69.9 ppm and δ 71.2 ppm due to the spiro carbon atoms and peaks at δ 192.7 ppm, δ 199.6 ppm due to the tetralone and acenaphthequinone ring carbonyls, respectively.Identical results were observed for the other derivatives irrespective of the nature of the substituents present in the arylidene moiety of the tetralone as indicated in Table 1.

Deprotonation method
In this method the non-stabilized azomethine ylide generated by treating benzylamine 7 with isatin 6, is reacted with 2-arylidene-1-tetralones to afford a series of dispiropyrrolidinyl oxindoles in acetonitrile at ambient temperature.Condensation of benzylamine with isatin could give rise to two configurationally distinct azomethine ylides, 8a and 8b the transition state leading to the azomethine ylide 8a is favoured over 8b due to the developing steric interaction between the carbonyl moiety and the phenyl group. 12Thus, 8a preferentially interacts with dipolarophile.The azomethine ylide 8a so generated readily reacts with 2-arylidene-1-tetralones to give a series of novel dispirooxindole derivatives in a regioselective manner.The above reaction gave single dispiropyrrolidinyl oxindole heterocycles in all cases, as evidenced by TLC and spectral analyses.

Scheme 2
The structures of the products 9a-e were confirmed by IR, 1 H/ 13 C NMR and mass spectral studies.The IR spectrum of 9a shows a peak at 1686.3 cm -1 for the tetralone carbonyl which is 10 cm -1 greater than benzylidene tetralone, which indicates the loss of conjugation.The peak at 1718.5 cm -1 confirms the presence of the oxindole moiety.The 1 H NMR spectrum of 9a shows a multiplet in the region δ 2.44-2.76 for the tetralone ring methylene protons.The N-CH proton of the pyrrolidine moiety resonates as a doublet at δ 4.91 (J = 9.7 Hz) while the NH proton of the pyrrolidine ring appears as a singlet at δ 8.3.The benzylic proton H a exhibits a peak at δ 5.63 as a doublet (J = 9.7 Hz).The 13 C NMR shows signals at δ 192.5 and 178.2 for tetralone and oxindole ring carbonyls, respectively, which confirms the structure of the products.Identical results were observed for the other derivatives irrespective of the nature of the substituents present in the arylidene moiety of the tetralone-1-one, as indicated in Table 2.
In summary, we have studied the reactivity of s-cis restricted tetralones with two different azomethine ylides generated through decarboxylative and deprotonation methods.These studies showed that, in most cases, the azomethine cycloadditions are highly regioselective, giving good yields of novel dispiroheterocycles.These methods provide easy access to various dispiroheterocyclic frameworks, which frequently occur in alkaloids.The starting (E)-2-arylidene-1-tetralones (3a-e) were prepared according to a literature procedure 12,13 .
General procedure for the synthesis of dispiroheterocycles 4a-e and 8a-e Decarboxylative method A solution of (E) 2-arylidene-1-tetralone 3a-e (1 mmol), acenapthenequinone 1 (1 mmol) and sarcosine 2 (1 mmol) in 20 mL of aqueous methanol was refluxed until the disappearance of starting material as evidenced by TLC.The solvent is removed under reduced pressure and the crude product is purified by column chromatography using petroleum ether:ethyl acetate (9:1) as eluent.

Deprotonation method
A solution of (E) 2-arylidene-1-tetralone (1 mmol), isatin (1 mmol) and benzylamine (2 mmol) in 20 mL of dry acetonitrile was refluxed until the disappearance of the starting material as monitored by TLC.The solvent was then evaporated under reduced pressure and the residue was separated by column chromatography with petroleum ether-ethyl acetate (8:2) as eluent.