Preparation and cycloaddition chemistry of 1-amino substituted isobenzofurans

A new strategy for the synthesis of the core skeleton of the benzophenanthridine alkaloid corynoline has been developed which is based on an intramolecular [4+2]-cycloaddition of an amino substituted isobenzofuran derivative.


Introduction
Isobenzofurans represent versatile intermediates for organic synthesis and have attracted a great deal of attention for the high reactivity they exhibit. 1,2The isobenzofuran nucleus contains 10πelectrons and is traditionally grouped with other Hückel aromatic species such as naphthalene and isoindole.However, this molecule exhibits greater reactivity than these related compounds.Highly reactive at the 1-and 3-positions, the isobenzofuran ring readily participates in various transformations that allow for the regeneration of the aromaticity of the benzene ring.The most important of these reactions is the Diels-Alder reaction. 3,4Most isobenzofurans are transient species; only those with exocyclic conjugation are stable enough to be isolated and characterized. 5Since these heteroaromatic ring systems are highly reactive as Diels-Alder dienes, they are commonly generated in the presence of a dienophilic trap.[10] Our interest in preparing various benzo[c]phenanthridinium salts (2) as antitumor agents 11 as well as the benzophenanthridine alkaloid corynoline (4) 12 led us to explore their syntheses via the intramolecular Diels-Alder reaction of an amino substituted isobenzofuran 13 as illustrated in Scheme 1.The [4+2]-cycloaddition reaction should lead to a Diels-Alder cycloadduct that would eventually be converted to the desired systems (i.e. 2 and 4).In this paper, we describe the synthesis of several 1-amino substituted isobenzofurans by the deprotonation of cyclic imidate salts and a study of their subsequent [4+2]-cycloaddition behavior.

Results and Discussion
AM1 calculations indicate that the placement of an electron donating heteroatom at the 1position of isobenzofuran raises the HOMO level and decreases the HOMO-LUMO gap in a "normal electron demand" Diels-Alder reaction.These predictions suggest that 1-(dialkylamino) substituted isobenzofuran should be more reactive than the parent system and show higher regio and stereoselectivity. 14Before starting our planned synthesis of corynoline (4), we decided to first investigate the inter-and intramolecular Diels-Alder behavior of several simpler aminoisobenzofurans in order to probe the viability of our approach.Of the three reported methods for generating 1-amino isobenzofurans, 8 we first chose to explore the metal-induced decomposition of a 2-diazomethyl benzamide derivative such as 11.This approach toward amino-substituted isobenzofurans is an extension of some earlier work carried out by Ibata and Hamaguchi 15 as well as Contreras and MacLean. 16As outlined in Scheme 2, these amino substituted isobenzofurans (i.e. 6) were generated by a metal catalyzed cyclization of the o-diazomethyl substituted benzamide 5.

Scheme 2
Preparation of the desired diazomethyl benzamide 11 required the initial synthesis of 2hydrazonomethyl-N-(2-isopropenylbenzyl)-N-methylbenzamide (10).This hydrazone could be prepared in good overall yield from mono-methyl phthalate (7) by treating the corresponding acid chloride with 2-(isopropenylbenzyl)methylamine (8).Conversion of the ester functionality to the aldehyde followed by treatment with hydrazine hydrate gave hydrazone 10 in 70% overall yield (Scheme 3).Unfortunately, oxidation of hydrazone 10 led to extensive decomposition producing a myriad of products and we ultimately had to abandon this approach.Our attempts at oxidation involved changing the oxidant (NiO 2 , Pb(OAc) 4 , MnO 4 , Ag 2 O, and HgO), the solvent, the base and the dehydrating agent.Sonication also failed to produce a sample of the desired diazo compound 11.

Scheme 3
At this point in time, we decided to prepare a representative amino isobenzofuran using an alternative method which involves a base-induced 1,4-elimination of a cyclic precursor such as an iminium salt. 17We were able to generate iminium salt 13 by allowing N-benzyl-2-bromomethyl-N-methylbenzamide (12) to stand for 10 min at ambient temperature (Scheme 4).The solid that precipitated was insoluble in ether and the structure was assigned on the basis of 1 H and 13 C NMR and IR spectroscopy.When 13 was treated with 2,2,6,6-tetramethylpiperidine in the presence of N-methylmaleimide, naphthalene 15 was obtained in 90% yield as a crystalline solid.We tried several additional bases and found that diazobicycloundecane (DBU) nicely promoted the formation of product 15 in excellent yield.Treatment of salt 13 with methyl acrylate and base also gave rise to a cycloadduct (i.e.16) in 68% yield (Scheme 5).We were not able to detect the presumed isobenzofuran intermediate 14 by carrying out the reaction in the absence of a trapping agent.The only material that was obtained corresponded to a dark oil which resisted all of our efforts at purification.

Scheme 5
We were curious to know whether the nature of the leaving group at the benzylic carbon would influence the cyclization reaction.With this in mind, we prepared mesylate 17.Instead of spontaneously cyclizing to form the salt as was encountered with bromide 12, mesylate 17 had to be heated at reflux in THF for 1 h in order for the cyclization to occur.However, the yield of the resulting mesylate salt 18 was high (78%) and the base induced cycloaddition proceeded in excellent yield to give 19 (Scheme 6).We also examined the base promoted reaction of the related 4-pentenyl substituted iminium salt 20 using similar conditions.Under no circumstances, however, were we able to detect any of the expected tetrahydrobenzo[b]quinoline 21 which would have been produced from an intramolecular Diels-Alder reaction of a transient isobenzofuran followed by elimination of water.Treatment of 20 with tetramethylpiperidine in the presence of N-methylmaleimide did give rise to naphthalene 23 in 89% yield (Scheme 7).Evidently, the π-bond present on the tethered alkene is not sufficiently activated to allow the intramolecular [4+2]-cycloaddition to occur.Use of a dienophile with a much lower lying LUMO is seemingly necessary in order for the [4+2]-cycloaddition of amino-isobenzofuran 22 to occur.At this stage of our investigations, we decided to turn our attention toward a study of the intramolecular [4+2]-cycloaddition of an amino substituted isobenzofuran that contained a more activated π-bond.Attachment of an aryl group on an olefinic π-bond is known to lower its LUMO energy level thereby facilitating [4+2]-cycloaddition chemistry.With an eventual synthesis of corynoline (4) in mind, we set out to prepare 2-bromomethyl-N-methyl-N-(2vinylbenzyl)benzamide (27).Our intention was to convert 27 into the corresponding iminium salt 28 which should give rise to the desired amino substituted isobenzofuran 29 upon treatment with base.A subsequent Diels-Alder reaction across the styryl activated π-bond was expected to lead to the skeletal framework of corynoline (4).A sample of bromide 27 was easily prepared according to the sequence of reactions outlined in Scheme 8. Once formed, bromide 27 slowly underwent cyclization upon standing to furnish the desired salt 28 in good yield.In this case, tetramethylpiperidine was not particularly useful for the generation of the desired amino isobenzofuran 29.Consequently, the less nucleophilic DBU was employed as the base.When the bromide salt 28 was heated at reflux with DBU, alcohol 31 was formed in 54% yield together with 5-methyl-5,6-dihydro-benzo[c]phenanthridine (32) in 15% yield.We suspect that both products are derived from cycloadduct 30 which undergoes spontaneous ring opening to give 31 and this is followed by a subsequent dehydration to give 32.
In summary, a new strategy for the synthesis of the core skeleton of the benzophenanthridine alkaloid corynoline (4) has been developed which is based on an intramolecular [4+2]cycloaddition of an amino substituted isobenzofuran derivative.This approach is particularly attractive as the starting 2-bromomethylbenzamide can be prepared efficiently on a large-scale, and the cyclization/cycloaddition sequence proceeds in good yield.We are currently investigating the application of the methodology toward corynoline (4) and related alkaloids.

Experimental Section
General Procedures.Melting points are uncorrected.Mass spectra were determined at an ionizing voltage of 70eV.Unless otherwise noted, all reactions were performed in flame dried glassware under an atmosphere of dry argon.Solutions were evaporated under reduced pressure with a rotary evaporator and the residue was chromatographed on a silica gel column using an ethyl acetate/hexane mixture as the eluent unless specified otherwise.All solids were recrystallized from ethyl acetate/hexane for analytical data.

N-(2-Isopropenylbenzyl)-N-methylphthalamic acid methyl ester (9).
To a solution containing 4.6 g (26 mmol) of mono-methyl phthalate (7) in 45 mL of CH 2 Cl 2 was added 2 drops of DMF followed by 4.5 mL (52 mmol) of oxalyl chloride at rt.The reaction was stirred for 2 h and was concentrated under reduced pressure.To the residue was added 45 mL of CH 2 Cl 2 , 6.3 g (51 mmol) of DMAP, and 4.1 g (26 mmol) of amine 8, and the mixture was stirred at rt for 18 h.A saturated NaHCO 3 solution was added and the mixture was extracted with CH 2 Cl 2 .Silica gel chromatography of the crude reaction mixture afforded 6.5 g (79%) of 9 as a white solid which consisted of a mixture of rotamers: mp 95-97 °C; IR (CH 2 Cl 2 ) 2947, 1723, 1637, and 1267 cm -1 ;

2-Formyl-N-(2-isopropenylbenzyl)-N-methylbenzamide.
To a solution containing 0.17 g (0.6 mmol) of the above alcohol in 40 mL of CHCl 3 was added 1.2 g (14 mmol) of MnO 2 and the mixture was stirred at rt for 24 h.The reaction mixture was filtered through Celite and the solid was washed with CHCl 3 and EtOH.The solvent was removed under reduced pressure affording 0.17 g (99%) of the titled compound as a colorless oil which consisted of a mixture of rotamers; IR (neat) 3060, 2968, 2854, 2747, 1694, 1630, and 1061 cm -1 ; 1

4-(Benzylmethylamino)-2-methylbenzo[f]isoindole-1,3-dione (15).
To a solution of 0.08 g (0.7 mmol) of N-methylmaleimide and 0.1 mL (0.8 mmol) of 2,2,6,6-tetramethyl-piperidine in 30 mL of THF at reflux was added 0.2 g (0.6 mmol) of salt 13 in 1 mL CH 2 Cl 2 .After stirring for 20 min, the suspension was allowed to cool to rt and was filtered through a pad of silica gel.The solvent was removed under reduced pressure and chromatography on silica gel gave 0.  16).To a solution of 2 mL (18 mmol) of methyl acrylate and 0.3 mL (1.5 mmol) of 2,2,6,6tetramethylpiperidine in 6 mL THF at reflux was added 0.4 g (1.3 mmol) of salt 13 in 1 mL of CH 2 Cl 2 .After stirring for 30 min, the suspension was allowed to cool to rt and was filtered through a pad of silica gel.The solvent was removed under reduced pressure and chromatography on silica gel gave 0.