The Intramolecular Radical Cation Induced Diels-Alder Reaction in the Diene- Diene Format

Two 1,3,8,10-undecatetraenes were synthesized to test the viability of the intramolecular radical cation induced Diels-Alder reaction in the diene - diene format. Cyclization was successful only for the substituted tetraene with the lower oxidation potential. The major hexahydroindene product possessed a trans ring juncture demonstrating a selectivity for the endo stereochemistry.

Although a [4+1] cycloaddition pathway is symmetry allowed [10], the reaction appears virtually insensitive to symmetry considerations and the products of both [4+1] and [3+2] pathways have been observed [11].Calculation of a minimum energy reaction pathway for the [3+2] cycloaddition using MINDO/3 revealed the likelihood that the reaction proceeds by a non-synchronous "bis-allylic" pathway [12].The reaction shows a strong preference for formation of products having an endo stereochemical disposition.Most importantly, the radical cation induced reaction adds a new dimension to the synthetic utility of the Diels-Alder reaction since it is effective with substrates that are not amenable to reaction under neutral thermal conditions.
Bauld has categorized the starting materials that are known to participate in the radical cation Diels-Alder reaction into three groups: diene -styrene, diene -electron rich alkene, and diene -diene [13].To date, Bauld has reported examples of intramolecular radical cation induced Diels-Alder reactions using the diene -styrene and dieneelectron rich alkene formats [14,15].Hertel et al. [16] have described a copper(I) catalyzed photo-induced cycloaddition of several bis-diene ethers which gave rise to some Diels-Alder [4+2] products as well as mixtures of [2+2], [4+4] and rearranged products.Herein we report our success with a radical cation initiated intramolecular Diels-Alder reaction in the diene -diene format.
Methods of initiation of radical cation reactions include anodic oxidation [17], photoinduced electron transfer (PET) [18], and introduction of a stable radical cation salt.This last method is particularly convenient, and the substance tris( p -bromophenyl)aminium hexachloroantimonate, (1), has become widely used for this purpose [19].One limitation in its use is its low potential for oxidation of substrates (for the neutral amine, E ox = 1.05 V vs SCE) [20] which restricts its effectiveness as an initiator to substrates that have oxidation potentials close to or less than this value.
(1 ) "TBA" In selecting substrates with which to study the radical cation induced Diels-Alder reaction, the intramolecular arrangement of diene and dienophile reactants is attractive because of the facility with which bicyclic systems can be constructed.Gassman and coworkers [21,22] have previously observed protic acid catalyzed formation of Diels-Alder adducts from tetraenes such as (2).Treatment of (2) with the radical cation initiator (1) also induced the formation of Diels-Alder adducts, but this outcome was completely prevented by the inclusion of the hindered base, 2,6-di-t-butyl pyridine, in the reaction mixture.This result indicated that product formation in this example was due to the formation of catalytic amounts of hydrogen ion, and not the result of a radical cation mediated process.Lack of initiation by (1) in the presence of base has subsequently become one of several mechanistic criteria used to ensure that a reaction is truly proceeding by a radical cation pathway [13].
For our investigation of the radical cation induced Diels-Alder reaction in the diene -diene format, (3) was selected because of its optimal placement of a substituted electron rich diene together with an unhindered diene.In addition, Gorman and Gassman [22] have shown that this compound does not give Diels-Alder products under protic conditions.Compound (4), which lacks stabilizing methyl substituents, was included for comparison.

Results and Discussion
The reactants chosen for the present study were prepared according to Scheme I. Thus, glutaraldehyde was treated with stabilized ylide (5) to give diester (6) in 90% yield.Reduction with diisobutylaluminum hydride (DIBAL-H) afforded dialcohol (7), and oxidation with pyridinium dichromate (PDC) gave the dialdehyde, (8).Treatment of (8) with methylene phosphonium ylide in dry THF at -78 °C gave (4) as a colorless oil after flash chromatography.Treatment of (8) with a mixture of methylene and isopropylidene ylides afforded (3 ) in 27% yield after purification by preparative gas liquid chromatography.
The oxidation potentials of compounds (3) (E ox =1.20 V) and (4 ) (E ox =1.61 V) were determined in acetonitrile by cyclic voltammetry versus a standard calomel electrode using ferrocene as internal standard.Attempts to induce radical cation initiated reactions were conducted in dry CH 2 Cl 2 at 0 °C.A solution of (1) in the same solvent was added at once to a solution of the tetraene and samples were withdrawn periodically for glc analysis.
Compound (3) reacted rapidly with (1) producing one major and one minor product in an 8.5 to 1 ratio in a combined 70% yield (glc) (Scheme 2).Purification by preparative HPLC (reversed phase, 90% acetonitrile -water) afforded the purified components in 57% combined isolated yield.A variety of reaction conditions was investigated.At -78 °C no reaction occurred.At higher temperatures, (-23 °C, 0 °C and 22 °C), the reaction was typically complete within 3 minutes using 3 to 50 mol % of (1).Rapid addition of the reactant (3 ) to 20 mol % TBA afforded the highest combined yield (77%) by glc.The relative proportions of the products were the same in all cases.In acetonitrile solvent, lower yields (40-60%) were obtained and a larger proportion of (1) (35-50%) was required for complete consumption of the starting material.Support for a radical cation mediated mechanism was provided by the observation that the reaction was unimpaired by inclusion of 2,6-di-t-butylpyridine.The cis ring juncture of the minor product (9) was verified using 1 H-NMR spectroscopy and a series of decoupling experiments; a coupling constant of J = 7.25 Hz was found for the cis ring juncture hydrogens.For the major isomer (10), nuclear magnetic resonance spectra ( 1 H-NMR, 13 C-NMR, COSY, HETCOR, NOESY) and decoupling experiments were consistent with the proposed structure (10) but were unable to verify the trans ring juncture.Conversion of (10) to a bis(dichlorocarbene) adduct using chloroform, KOH and a phase transfer catalyst, followed by slow crystallization from acetonitrile produced crystals of the tetrachloro adduct (11), which by X-ray crystallography confirmed the trans ring juncture.

Cl
Cl Cl (11) As expected, based on the differences in oxidation potential, the initiator (1) failed to induce Diels-Alder adduct formation with compound (4); no reaction had occurred after stirring for 24 hours at room temperature.In an attempt to expose (4) to more vigorous conditions, this compound was irradiated at 300nm in acetonitrile solution in the presence of the sensitizer 1,4-dicyano-2,3,5,6tetraethylbenzene (E ox =1.96 V) [23].In addition to conspicuous amounts of polymer, two soluble products were isolated by preparative gas liquid chromatography and were identified as ( 12) and ( 13) in 8% and 13% yield respectively (Scheme 3).Since these compounds are exactly those that would be predicted to result from an excited state reaction, the irradiation experiment was repeated with the sensitizer omitted.The same products were obtained, thereby indicating that a radical cation process was not involved in their formation, and that compound (4) does not convert to a Diels-Alder adduct under radical cation conditions.

Conclusion
To summarize, tetraenes (3 ) and (4) have been synthesized and have been exposed to reaction conditions expected to generate radical cation intermediates.Successful cyclization of (3) demonstrates the viability of the diene -diene format for the intramolecular radical cation initiated Diels-Alder reaction.In keeping with previous observations [14], a high endo to exo stereoselectivity (8.5:1) was observed.The contrast in reactivity of (3) versus (4) clearly demonstrates the importance of having at least one easily oxidized diene in the reactant.

General
All nuclear magnetic resonance (NMR) spectra ( 1 H-NMR, 13 C-NMR) were recorded on an IBM NR/200 FT, IBM NR/300 FT or a Varian Unity 500 Nuclear Magnetic Resonance Spectrometer.Infrared spectra were recorded using a Mattson Polaris FT-IR spectrometer.Analytical GC was performed on a Hewlett Packard Model 5890A capillary gas chromatograph equipped with a 25 m x 0.2 mm HP-5 (0.33 micrometer cross-linked 5% Ph-Me silicone) column and a Hewlett Packard 3390A Reporting Integrator.Mass spectral analyses were performed on a Hewlett Packard 5995 Gas Chromatograph-Mass Spectrometer.Preparative gas chromatography was done using a Varian Aerograph Model 900 with a Fisher Recordall Series 5000 chart recorder.Preparative HPLC was accomplished using a Waters Model 6000A Solvent Delivery System with a 5 micron Lichrosorb RP-18 reversed phase 250 x 10 mm column, a Waters Model R401 differential refractometer detector and an Omniscribe D5000 strip chart recorder.