Palladium catalyzed allylation is under stereoelectronic control

Palladium catalyzed allylation of menthone and 4-t -butylcyclohexanone derivatives is shown to be under stereoelectronic control leading to the products of axial allylation. The stereochemical assignment is supported by 1 H NMR experiments and X-Ray crystallography of selected examples.


Introduction
The stereochemistry of palladium catalyzed allylation has been extensively studied in terms of the use of asymmetric ligands to induce chirality1 and the stereochemistry of the allylic starting material. 2We are not aware of previous studies concerning preexisting chirality in carbon nucleophiles in these reactions. 3

Results and Discussion
Recently we had occasion to perform the allylation of formyl isomenthone 1 4 and were pleased to find the expected 5 exclusive C-allylation product 2 was obtained as a single diastereoisomer (Scheme 1).Selective reduction of the aldehyde to alcohol 3 and the subsequent treatment with benzoyl isocyanate gave carbamate 4 which upon treatment with methanolic potassium carbonate yielded a carbamate derivative 5 that was amenable to X-Ray crystallography (Figure 1). 6This unequivocally showed the trans relationship of the allyl and methyl groups, although they were now diequatorial, due to epimerization at the iso-propyl center during methanolysis.A small amount of the diastereomer was also obtained.Hence, it was concluded that the original This selectivity may be attributed to the steric hindrance of one face by the α−methyl group, but it could also be due to stereoelectronic effects which are known to favor axial alkylation and protonation. 7We, therefore, turned to the 4-t-butylcyclohexanone system, which is sterically unbiased and has been widely used in stereoelectronic studies.The 2-formyl, 8 2-carbethoxy 9 and 2-phenylsulfonyl 10 derivatives, 6, 7 and 8 were prepared by literature methods.Allylation was carried out by treatment with allyl acetate in THF in the presence of a catalyst system consisting of Pd(dba) 2 and triphenyl phosphine (Scheme 2).For the formyl compounds, potassium carbonate was an effective base.For the ester and sulfone substrates, this base was ineffective, while tetramethyl guanidine resulted in a sluggish reaction.Potassium t-butoxide was found to be the base of choice.In each case, two isomers were formed, but in unequal amounts (Table ).For the 2-formyl substrate 6, the stereochemistry was unequivocally demonstrated by reduction of the major isomer 9 to the diol 10 with sodium borohydride (Scheme 3).The coupling constants of the methyne proton confirmed that the product was the expected equatorial secondary alcohol. 11onversion of diol 10 to 1,3-dioxane 11 by exchange with benzaldehyde dimethyl acetal, allowed the proof of the stereochemistry through NOESY interactions.In particular the correlation between the three axial protons of the dioxolane ring (δ 3.35, 3.60, 5.55) is consistent only with the structure shown.The same diol was obtained by LiAlH 4 reduction of the major isomer of the allylated β-ketoester 12, thus also providing the stereochemical assignment in this case.Recrystallization from hexane of the major isomer of the allylated ketosulfone 13 yielded crystals, which permitted X-ray determination of their structure. 12This showed that the major allylation product 13 was formed with the same sense of diastereoselectivity, i.e. trans to the t-Bu group.In this case however, the allylation product 13 adopted a distorted boat conformation.All of the major products of the allylation reactions are consistent with the approach of the πallyl palladium intermediate towards the face of the enolate so that a chair like transition state 14 results, rather than the alternative boat (Scheme 4).Scheme 4. The stereoelectronic effect.

Conclusions
Palladium catalyzed allylation of cyclohexanone derivatives has been shown to favor the formation of the axial isomer.This is consistent with previous observations made on simple alkylation and protonation reactions, and shows that the same stereoelectronic principles apply.The selectivity was found to be highly dependant on the activating group -with the formyl group giving the highest stereoselectivity.We anticipate that these results will be useful in synthesis.

Experimental Section
General Procedures.Flash chromatography was carried out on silica gel (230-400 mesh, Merck).Melting points were determined on a Büchi 535.NMR spectra were recorded on a Varian Gemini 2000 or Bruker BZH 200 at 200 MHz ( 1 H) with CDCl 3 as the solvent and residual CHCl 3 or Me 4 Si as the internal reference.IR spectra were recorded on a PE 1760X instrument, either neat or as nujol mulls.MS were recorded on a Finigan GCQ insturment and HRMS on a Finigan Mat 90 instrument.Optical rotation data was recorded on a Jasco P-1020 polarimeter.Elemental analysis was performed at the Instrument Centre of Chulalongkorn  5).Anhydrous potassium carbonate (220 mg, 1.71 mmol) was added to a solution of the N-acyl carbamate 4 (640 mg, 1.71 mmol) in methanol (3.5 mL) at room temperature.The mixture was stirred for four hours, then treated with aqueous ammonium chloride and extracted with dichloromethane.The organic layer was washed with brine, dried (Na 2 SO 4 ) and evaporated.The residue was purified by flash chromatography on silica gel (20 g), eluting with 15 and 20% EtOAc/ hexane to give the carbamate 5 (320 mg, 70%) as a colorless solid, mp 125-127 °C. 1

Table :
Allylation Diastereoselectivity a Separable by flash chromatography.bIncomplete separation by flash chromatography