Radical cyclization in heterocycle synthesis. Part 14. 1 A simple and effective preparation of cyclic oxime ethers by photochemical radical addition–cyclization of acyclic oxime ethers

The sulfanyl radical addition–cyclization of acyclic oxime ethers containing alkene groups proceeded smoothly under photochemical conditions to give the cyclic oxime ethers


Introduction
Free radical cyclization is an efficient method for synthesis of functionalized cyclic compounds, including biologically active natural products and medicinals. 2 In particular, the radical additioncyclization using N-C multiple bonds as the radical acceptor has been studied extensively by several organic chemists, 3 including our own group 4 for the preparation of cyclic amine derivatives.4f As an extension of our research on the sulfanyl radical addition-cyclization, we now report that the radical reaction of oxime ethers 1 with diphenyl disulfide under photochemical conditions provides direct routes to cyclic oxime ethers 2. Although it is known 6 that the cyclic oxime ethers can be synthesized via radical addition-elimination reactions of bismethanesulfonyl oxime ethers, the reaction requires one to employ as substrate imidate derivatives having a leaving group.In our newly found methods, one can use readily available aldoxime ethers as substrates.

Results and Discussion
We first investigated the radical cyclization of O-methyl- 1 and O-phenyl-oxime ethers 1a,b under photochemical conditions (Scheme 2, Table 1).The substrate 1b was prepared from aminoacetaldehyde dimethyl acetal via tosylation, alkylation, deacetalization, and finally condensation with phenoxyamine, according to the reported procedure.The reaction was carried out under bubbling nitrogen.
A solution of diphenyl disulfide (0.5 equiv.)and the oxime ether 1a in benzene was irradiated with a high-pressure mercury lamp through a Pyrex filter under N 2 bubbling at 5-10°C for 2 h.The solution was concentrated and the resulting residue was purified by column chromatography to give the cyclic oxime ethers 5a (E-5aA:Z-5aB = 1:2) and the cyclic amine 6a (cis:trans = 2:1), both of which have a phenylsulfanylmethyl group (Entry 1).When 1-and 3 equiv.of diphenyl disulfide were used, 5a was obtained in 60% and 74% yields, respectively (Entries 2 and 3).Interestingly, when methanol was used as solvent, the cyclic amine 6a was obtained exclusively without formation of the cyclic oxime ether 5a (Entry 4).The Ophenyloxime ether 1b was subjected to the radical reaction under the photochemical conditions to give the cyclic amine 6b in low yield, in addition to formation of the nitrile 7 which would be formed by elimination of phenol from the substrate 1b (Entry 5).
We next investigated the radical reaction of various types of known oxime ethers 1c-f 1 as shown in Scheme 3 and Table 2.The radical reaction of N-Boc-oxime ether 1c with (PhS) 2 gave a mixture of cyclic oxime ether 5c and amine 6c (entry 1 in Table 2, Scheme 3).The oxime ether 1e with a quaternary carbon was subjected to radical reaction with (PhS) 2 to give the cyclic oxime ether 5e in improved yield (entry 3) while 1d,f gave the cyclic oxime ethers 5d,f in moderate or low yields (entries 2 and 4).The stereo-structures of the cyclic oxime ethers 5a,c-f were established as follows (Figure 1, Table 3).The E/Z-geometries of the oxime ether 5a were determined by 1 H NMR spectroscopy.Karabatsos's group 7 reported that the oxime ethers which exhibit their hydrogen signals at lower field for the group on the same side as the N-OR group have E-geometries, while the oxime ethers showing these at higher field have Z-geometries.In our case, the signals for the hydrogen at the 4-position of the E-isomer, 5aA (δ 3.20), appeared at lower field compared with that of the Z-isomer 5aB (δ 2.97).Similarly, the stereo-structures of 5c-f were established from their spectroscopic data.The cyclic amines 6a,c-f were identical with authentic samples 1 prepared by the radical cyclization of the same substrates 1a,c-f as used under the thermal conditions.The stereo-structure of 6b was deduced by NOESY of the 1 H NMR spectrum.In order to clarify the reaction pathway, we next investigated the radical reactions of 1a,g and 6a under various reaction conditions (Schemes 4 and 5, Tables 4 and 5).The sulfonamide 1a was treated with 0.5 equiv. of (PhS) 2 through bubbling O 2 under the photochemical conditions to give a mixture of the cyclic oxime ether 5a and the cyclic amine 6a (entry 1, Table 4).This is similar to the result of the reaction using bubbling N 2 , as shown in Table 1, Entry 1. Furthermore, the radical reaction of 1a in the absence of (PhS) 2 gave neither the cyclic oxime ether 5a nor the cyclic amine 6a; the oxime ether 1a was recovered (Entry 2).Since 1a in the absence of (PhS) 2 did not give the azetidine derivative 8a photochemically, which would be expected from its photochemical [2+2]-cycloaddition reaction, the cyclic compounds 5a and 6a could not be formed via [2+2]-cycloaddition followed by ring-opening reaction with attack of the phenylsulfanyl radical.Next, the conversion of the cyclic amine 6a into the cyclic oxime ether 5a was examined under our reaction conditions (Table 5).The radical reaction of cyclic amine 6a, under nitrogen, both in the presence and absence of (PhS) 2 , gave the cyclic oxime ether 5a, in 29% and 5% yields, respectively.Under similar the reaction conditions, but with the solution of 6a treated with bubbling O 2 , 5a was formed in 4% yield.These results suggest that 6a is almost certainly not converted into 5a by the reaction with O 2 , but by the phenylsulfanyl radical.Furthermore, when the oxime ether 1g having no alkenyl group was subjected to the radical reaction with (PhS) 2 , no cyclic compound 5g was found, and 1g was recovered (Scheme 5).This result suggests that the radical reaction is initiated by addition of the phenylsulfanyl radical to the olefin in 1a.Therefore, we propose the plausible reaction pathway shown in Scheme 6.The phenylsulfanyl radical formed from (PhS) 2 under the photochemical conditions would attack the olefin in the substrate 1.The radical A then undergoes a 5-exo-trig cyclization to form the aminyl radical B. In the formation of oxime ether 5, either the phenylsulfanyl radical or the dissolved O 2 in solvent would attack the hydrogen at the 3-position of radical B to afford the cyclic oxime ether 5, which is also partially formed from the cyclic amine 6 under the photochemical conditions, by the action of the phenylsulfanyl radical.On the other hand, 6 is obtained by trapping radical B with thiophenol formed in situ.Furthermore, the fact that the cyclic amine 6a was isolated exclusively, without the formation of cyclic oxime ether 5a, in the radical reaction using methanol as solvent (Entry 4, Table 1) suggests that the aminyl radical B can be trapped with methanol to afford the cyclic amine 6 in preference to the cyclic oxime ether 5.

Scheme 6
In conclusion, we have developed a method for the preparation of cyclic oxime ethers by phenylsulfanyl radical-mediated reaction of acyclic oxime ethers under photochemical conditions.

(E/Z)-4-Methyl-N-[2-(phenoxyimino)ethyl]-N-(2-propenyl)benzenesulfonamide (1b).
To a solution of 2-aminoacetaldehyde dimethyl acetal (3.15 g, 0.03 mol) in CH 2 Cl 2 (50 mL) were added Et 3 N (4.05 g, 0.04 mol) and then TsCl (7.63 g, 0.04 mol) in CH 2 Cl 2 under a nitrogen atmosphere at 0°C.After being stirred at room temperature for 2 h, the reaction mixture was diluted with water and extracted with CHCl 3 .The organic phase was dried over MgSO 4 and concentrated under reduced pressure to give the crude tosylate.To a suspension of the crude tosylate and K 2 CO 3 (5.6 g, 0.04 mol) in acetone (55 mL) was added 3-bromo-1-propene (4.05 g, 0.03 mol) under a nitrogen atmosphere.After being heated at reflux for 5h, the reaction mixture was diluted with water and extracted with CHCl 3 .The organic phase was dried over MgSO 4 and concentrated under reduced pressure.Purification of the residue by MPCC (hexane/AcOEt 5:1) afforded N-(2,2-dimethoxy-ethyl)-4-methyl-N-(2-propenyl)-benzenesulfonamide (4.32 g, 46%) as a pale yellow oil.To a solution of the acetal (1.26 g, 4.2 mmol) in acetone (50 mL) was added 2M-HCl (25 mL) under a nitrogen atmosphere at room temperature.After being stirred a further 1 h, the reaction mixture was extracted with CHCl 3 .The organic phase was dried over MgSO 4 and concentrated under reduced pressure to give the crude aldehyde as yellow oil.To a solution of the crude aldehyde in CH 2 Cl 2 (80 mL) was added AcONa (685 mg, 8.3 mmol) and PhONH 2 8 (458 mg, 4.2 mmol) at room temperature under a nitrogen atmosphere.After being stirred at room temperature for 2.5 h, the reaction mixture was diluted with water and extracted with CH 2 Cl 2 .The organic phase was washed with water and dried over Na 2 SO 4 and concentrated under reduced pressure.The residue was purified by FCC (hexane/AcOEt 1:1) to afford the oxime ether 1b (577 mg, 40%) as a pale yellow oil and a 3:2 mixture of Eand Zisomers; IR (CHCl 3 ) 1645 (C=N), 1354, 1161 (NSO 2 ) cm -1 ; 1

Radical reaction of oxime ethers 1c-f under the photochemical conditions (Table 2)
According to the procedure given for the radical reaction of 1a, a solution of oxime ether 1c-f (0.7 mmol) and (PhS) 2 (2.1 mmol) in benzene (120 mL) was irradiated for 2 h, then concentrated under reduced pressure and the residue was purified by MCC (hexane/AcOEt 5:1) to afford 5c-f and 6c-f as shown in Table 2.The spectral data of cis-and trans-6c-f were identical with those reported in the literature. 1 4, entry 1).According to the procedure given for radical reaction of 1a, a solution of oxime ether 1a (198 mg, 0.7 mmol) and (PhS) 2 (76.3 mg, 0.35 mmol) in benzene (120 mL) was stirred through O 2 bubbling at 0°C for 10 min.The reaction mixture was irradiated under atmosphere for 2 h, then concentrated under reduced pressure and the residue was purified by MCC (hexane/AcOEt 5:1) to afford 5a and 6a as shown in Table 4, Entry 1.

Conversion of cyclic amine 6a into cyclic oxime ether (5a).
According to the procedure given for radical reaction of 1a, a solution of the cyclic methoxyamine 6a (274 mg, 0.7 mmol) and (PhS) 2 (458 mg, 2.1 mmol) in benzene (120 mL) was irradiated for 2 h, then concentrated under reduced pressure and the residue was purified by MCC (hexane/AcOEt 5:1) to afford 5a and 6a as shown in Table 5, Entry 1.