Intramolecular cyclizations of N -acyliminium ions with pyridine rings

The reaction of N -Acyliminium ions with several activated pyridines resulted in an intramolecular cyclization to provide novel heterocycles. The reaction exhibited a regiochemical preference for cyclization para to the electron donating substitutent.


Introduction
The use of electron rich aromatic rings for cationic π-cyclizations 1 has emerged as a powerful method for the construction of novel heterocycles and natural products. 2These cyclizations have been utilized as the key carbon-carbon bond forming reaction in the synthesis of several alkaloids, including the tetrahydroisoquinoline, β-carboline, and lycopodium classes.atom is that electrophilic heteroaromatic substitution of the π-deficient heterocycle is exceptionally difficult.Thus, nitration, sulfonation, and halogenation of pyridine requires drastic conditions and yields of the expected 3-substituted products are very low.11   In this paper, the intramolecular cationic π-cyclization of pyridines of type 1 with tethered N-acyliminium ions is described.

Results and Discussion
Preparation of lactam 7 was accomplished in four steps in good overall yield starting from the appropriate hydroxy pyridine derivative (Scheme 1).Commercially available 2-hydroxy-6methyl pyridine (3) was protected with MeI in the presence of Ag 2 CO 3 to furnish 2-methoxy-6methyl pyridine (4) in quantitative yield.Deprotonation of 4 with n-BuLi at -78 o C followed by quenching with paraformaldehyde afforded the primary alcohol 5 in 60% yield.Incorporation of the phthalimide functionality was accomplished by nucleophilic substitution using Mitsunobu conditions to provide 6 in 90% yield. 13Reduction of 6 to lactams 7 and 8 was carried out using super hydride (Li(Et) 3 BH) at -78 o C. 14 Our initial attempts to cyclize lactam 7 or 8 using a variety of Lewis acid conditions  (BF 3 .OEt 2 , TiCl 4 , ZnCl 2 , SnCl 4 , BF 3 .2AcOH,etc:) were unsuccessful resulting only in recovered starting material or decomposition products.Cationic π-cyclization was ultimately successful when protic acids such as p-TsOH or CSA were used.For example, when lactam 7 was heated in benzene in the presence of a catalytic amount of p-toluenesulfonic acid, the desired tetracyclic lactam 9 was obtained in 70 % yield.The same product was isolated in 55% yield when α-ethoxy amide 8 was treated under the above conditions.In order to probe the regiochemical preference of the reaction, lactam 14 was synthesized in a manner similar to that described above (Scheme 2).2-Hydroxy-4-methyl-pyridine (10) was converted to the methoxy derivative and then transformed into the phthalimide derivative 13 in 40 % overall yield.Reduction with super hydride provided lactam 14 in 90 % yield.Treatment of 14 with a catalytic amount of p-TsOH in benzene at reflux afforded a 3.5:1 mixture of regioisomers in 68 % isolated yield in addition to a dark polymer.Silica gel chromatography of the mixture furnished tetracyclic lactam 15 as the major product arising from electrophilic aromatic substitution para to the electron donating methoxy substituent.The minor product 16 arises from attack of the N-acyliminium ion ortho to the methoxy substituent on the pyridine ring.
Still another example involves the cyclization of lactam 18. 2-(6-Methoxy-pyridin-2yl)ethanol (5) was converted under Mitsunobu conditions to the succinimide derivative in 70 % yield (Scheme 3).Reduction of 17 to 18 followed by acid catalyzed cyclization led to the tricyclic lactam 19 in only 30% yield.All attempts to improve the yield of the cyclization were unsuccessful.The low yield of 19 is presumably related to proton loss from the N-acyliminium Page 38 © ARKAT USA, Inc ion followed by some alternate pathway.Clearly, the best results are obtained when a αhydrogen is not present on the N-acyliminium ion precursor.

Scheme 3
The next phase of our investigation involved an attempted cyclization of an electron rich pyridine ring with a N-acyliminium ion generated from an isomünchnone cycloadduct.Earlier studies in our laboratory showed that 1,3-oxazolium-4-oxides (isomünchnones) 21 can be generated by the rhodium(II)-catalyzed cyclization of a suitable diazo imide 20 (Scheme 4). 15his type of mesoionic ylide corresponds to the cyclic equivalent of a carbonyl ylide and was found to readily undergo [4+2]-cyclo-addition with suitable dipolarophiles. 16 Formation of the isomünchnone cycloadduct proceeds by initial generation of a rhodium carbenoid species, followed by an intramole-cular cyclization onto the neighboring carbonyl oxygen to form the mesoionic ylide 21.
uniquely functionalized cycloadducts contain a "masked" N-acyliminium ion which is generated by its treatment with a Lewis or protic acid.18   By incorporating an internal nucleophile on the tether, annulation of the original cycloadduct 22 allows for the construction of a more complex nitrogen heterocyclic system . 19 In order to test the above concept it was necessary to prepare a suitable isomünchnone cycloadduct (i.e.34 or 35) by first constructing the obligatory diazo imide.The synthesis began with commercially available hept-6-enoic acid (26) or citronellic (27) acid (Scheme 5).Treatment of these acids with 1,1-carbonyldiimidazole followed by reaction with 2-(6-methoxypyridin-2-yl)ethyl amine (25) afforded the corresponding amides 28 and 29 in good yield.Amine 25 was prepared by treating imide 13 with hydrazine hydrate in refluxing ethanol.The above amides were subjected to N-malonylacylation and the resulting imido esters 30 and 31 were then treated with mesyl azide in the presence of triethylamine to provide diazo imides 32 and 33.

Scheme 5
Formation of the isomünchnone dipole proceeded smoothly when these diazo imides were treated with rhodium(II) perfluorobutyrate in CH 2 Cl 2 at 25 °C.After the initial generation of the rhodium carbenoid, intramolecular cyclization onto the substituted hex-7-enoic acyl carbonyl oxygen occurred to produce the mesoionic oxazolium ylide which underwent 1,3-dipolar cycloaddition across the pendant olefinic π-bond.In both cases, the reaction provided the expected cycloadducts 34 (92%) and 35 (82%) as single diastereomers resulting from endo cycloaddition with respect to the dipole.Assignment of the stereochemistry of the cycloadducts was based on a comparison of NMR signals with related substrates synthesized in this laboratory whose structures had been confirmed by X-ray crystallography.18   In all cases, the antistereochemistry between the oxa-bridge and the angular proton (H a ) was obtained.
Unfortunately, all of our attempts to trap the N-acyliminium ion derived from both cycloadducts 34 and 35 using the electron rich pyridine in a Pictet-Spengler type cyclization were unsuccessful.In the case of cycloadduct 34, the 2-oxohexahydroquinolone 36 was isolated as the sole product in 92% yield.
In summary, we have shown that, in certain cases, the pyridine nucleus can be utilized as a suitable nucleophilic partner in cationic π-cyclizations.Although unactivated pyridine rings do not cyclize well, pyridines containing an electron donating substituent cyclize in good yield.The results presented herein demonstrate the potential of using such cyclizations for the synthesis of novel heterocycles and pyridine and pyridone containing natural products.

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.