Ring-Expansion Reaction of Oximes with Aluminum Reductants

The ring-expansion reactions of heterocyclic ketoximes and carbocyclic ketoximes with several reductants such as AlHCl2, AlH3 (alane), LiAlH4, LiAlH(OtBu)3, and (MeOCH2CH2O)2AlH2Na (Red-Al) were examined. Among reductants, AlHCl2 (LiAlH4:AlCl3 = 1:3) in cyclopentyl methyl ether (CPME) has been found to be a suitable reagent for the reaction, and the rearranged cyclic secondary amines were obtained in good to excellent yields.


Introduction
The development of novel synthetic method of constructing basic heterocyclic skeletons is an important research topic from the viewpoint of both synthetic chemistry and medicinal chemistry. Specifically, the fundamental skeletons containing a nitrogen functionality attached to an aromatic ring are of great importance because they are often used as the core structures of medicines or clinical candidates. In this research area, we have recently reported the synthesis of five-to eight-membered bicyclic or tricyclic fused heterocycles containing nitrogen attached to an aromatic ring by the reductive ring expansion reaction of cyclic ketoximes or hydroxylamines using diisobutylaluminum hydride [DIBALH: ( i Bu) 2 AlH] [1][2][3][4][5][6]. We also carried out mechanistic studies to prove the intermediacy of the corresponding hydroxylamines and to obtain mechanistic information about the ring expansion on the basis of DFT calculations [3].
However, we have not yet performed systematic examinations of suitable reductants and solvents for the reductive ring expansion reaction. A similar reaction using borane was in fact reported by Ortiz-Marciales et al. The reductive ring expansion of O-silylated oximes proceeded using borane in the presence of boron trifluoride [7]. In this report, we disclose our recent results on the reductive ring-expansion reactions of oximes with a variety of aluminum reductants.

Results and Discussion
We selected five reductants, i.e., lithium aluminum hydride (LiAlH 4 ) [8,9], aluminum hydride (AlH 3 ; alane) [9][10][11], sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al; Vitride) [12], dichloroaluminum hydride (AlHCl 2 ) [9][10][11]13], lithium tri-tert-butoxyaluminum hydride [LiAlH(O t Bu) 3 ], and compared their reactivities using the oxime 1a as the test substrate (Table 1). When 1a was treated with six mol equiv. of LiAlH 4 , the desired ring expansion product, 2,3,4,5tetrahydrobenzo[b] [1,4]thiazepine (2a) was obtained in only 29% yield and was associated with substantial amounts of the primary amine 3a [14], which should be generated by the C=N and N-O reduction of the oxime (Entry 1). Reaction with Red-Al gave similar results providing a mixture of 2a (31%) and 3a (18%) (Entry 2). LiAlH(O t Bu) 3 , on the other hand, was considerably less reactive and produced no product (Entry 3). Next, we examined AlH 3 and AlHCl 2 , which possess Lewis acidic character. When 1a was treated with six mol equiv. of AlH 3 in Et 2 O, a result parallel to those of LiAlH 4 and Red-Al was obtained. Thus, a mixture of 2a and 3a in 46% and in 47% yield, respectively, was isolated (Entry 4). Interestingly, however, the treatment of the ketoxime 1a with six mol equiv. of AlHCl 2 , which was prepared as a suspension in Et 2 O, afforded 2a in 72% yield associated with only a small amount of the primary amine 3a (6%) (Entry 5). The smooth ring expansion after 1,2-reduction may be attributed to the Lewis acidity of AlHCl 2 etc., which should coordinate with the oxygen of the hydroxylamine A to promote a rearrangement process via intermediate B (Scheme 1) [3]. Having found that AlHCl 2 is a suitable reductant to promote the ring expansion reaction, we then investigated this generality along with solvent effects. As to reaction solvents, several solvents such as Et 2 O, i Pr 2 O, THF, cyclopentyl methyl ether (CPME) [15,16] and mixed solvents were examined. Among them, the use of CPME was found to suppress the formation of undesired 3a to provide 2a in 76% yield (Entry 6). CPME is an alternative to conventional ethereal solvents, such as THF and diethyl ether, due to a higher solubility for substrates, the superior handling, and safety for a large-scale production [15]. Scheme 1. Proposed mechanisms of reductive ring expansion reaction of ketoximes with the aluminum reagent.

General
All the melting points were determined with a Yanaco micro melting point apparatus and are uncorrected. IR spectra were measured with a Shimadzu FTIR-8300 spectrometer. NMR spectra (at 400 MHz for 1 H and 100 MHz for 13 C) were recorded on a JEOL JNM-Al 400 spectrometer with tetramethylsilane (0 ppm) or chloroform (7.24 ppm) as the internal standard. Mass spectra were recorded on JMS-DX303, JMS-700, or JMS-T100GC spectrometers. Elemental analyses were performed with a Yanaco CHN CORDER MT-6. Column chromatography was performed on silica gel 60N (Kanto, 63-210 μm), and flash column chromatography was performed on silica gel 60N (Kanto, 40-60 μm) using the indicated solvents. Reactions and chromatography fractions were monitored by using precoated silica gel 60 F 254 plates (Merck).

General Preparation of AlHCl 2 and AlH 3 in Accordance with the Procedure Reported by
Ashby et al. [10,11] Four mol equiv. of AlHCl 2 (containing one mol equiv. of LiCl) was prepared in Et 2 O or CPME at 0 °C from one mol equiv. of LiAlH 4 , and three mol equiv. of AlCl 3 . Four mol equiv. of AlH 3 (containing three mol equiv. of LiCl) was prepared in Et 2 O from three mol equiv. of LiAlH 4 and one mol equiv. of AlCl 3 .
Reaction of 1a with 6.1 mol equiv. of LiAlH 4 ( Table 1, Entry 1). A flame-dried 10-mL two-necked round-bottomed flask equipped with a magnetic stirring bar was charged with LiAlH 4 (23.2 mg, 610 μmol). The LiAlH 4 in the flask was stirred at 0 °C. To the stirred LiAlH 4 was added dry Et 2 O (1.0 mL). To the suspension was added 1a (18.2 mg, 100 μmol). After stirring for 0.5 h at 0 °C, the reaction mixture was warmed to room temperature, stirred for another 6 h, cooled to 0 °C, and then treated carefully with wet Et 2 O (1 mL) and water (1 mL). The mixture was made basic with 2 M aqueous NaOH (2 mL) and extracted with Et 2 O. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/Et 2 O = 3:1) to afford 2a (4.8 mg, 29 µmol, 29%) and 3a (7.4 mg, 45 µmol, 45%). Reaction of 1a with 6.0 mol equiv. of Red-Al ( Table 1, Entry 2). A two-necked 10-mL round-bottomed flask equipped with a magnetic stirring bar was charged with 1a (18.0 mg, 100 μmol) and dry toluene (1 mL). The solution was cooled to 0 °C. To the solution was added Red-Al (76 μL, ≥65 wt% in toluene, 600 μmol) at 0 °C, and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was heated at 50 °C for 6 h, cooled to 0 °C, and then treated carefully with wet Et 2 O (1 mL) and water (1 mL). The mixture was made basic with 2 M aqueous NaOH (2 mL) and extracted with Et 2 O. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/Et 2 O = 3:1) to afford 2a (5.1 mg, 31 µmol, 31%) and 3a (2.9 mg, 18 µmol, 18%). Orlova and Kucherova reported the reaction of 1a with Red-Al, but they simply noted the reaction in only 12 lines and no details were given [12].

Conclusions
The examination of the reductive ring-expansion reaction of cyclic ketoximes using a variety of aluminum reductants, i.e., LiAlH 4 , LiAlH(O t Bu) 3 , Red-Al, AlHCl 2 , and AlH 3 , revealed that dichloroaluminum hydride (AlHCl 2 ) (LiAlH 4 /AlCl 3 = 1:3) is a suitable reagent for promoting the reaction and affords ring expansion products in good to excellent yields. In addition, it was clarified that CPME could be effective solvent than Et 2 O for the rearrangement of cyclic ketoximes with AlHCl 2 . The finding may lead to further synthetic application of variously substituted heterocyclic compounds and complicated medicine candidates containing a nitrogen functionality attached to an aromatic ring.