HETEROCYCLES

Paper | Special issue | Vol. 86, No. 2, 2012, pp. 1187-1210
Received, 29th June, 2012, Accepted, 10th August, 2012, Published online, 24th August, 2012.
DOI: 10.3987/COM-12-S(N)74

■ SYNTHESIS OF α-AMINO KETONES AND O-ALKYLOXIMES BY TITANIUM TETRAHALIDE PROMOTED RING-OPENING REACTION OF 2-MONO-SUBSTITUTED AZETIDIN-3-oNES AND THEIR O-ALKYLOXIMES

Shizuka Ariga, Shingo Hata, Daisuke Fukuda, Takafumi Nishi, Iwao Hachiya, and Makoto Shimizu*

Department of Chemistry for Materials, Graduate School of Engineering, Mie University, 1577 Tsu, Mie 514-8507, Japan

Abstract

Synthesis of α-amino ketones and O-alkyloximes has been developed by titanium tetrahalide-promoted ring-opening reactions of 2-mono-substituted azetidin-3-ones and their O-alkyloximes. Regarding the reductive ring-opening reactions of 2-mono-substituted azetidin-3-ones, an appropriate use of TiI4 or TiI4-TiCl4 as a promoter gave α-amino ketones in good yields with high regioselectivities. In TiBr4-promoted ring-opening reactions, while use of 2-mono-substituted azetidin-3-ones as a substrate provided α-amino-α’-bromo ketones generated by the attack of the bromide anion at the less hindered site, those of 2-mono-substituted azetidin-3-one O-alkyloximes proceeded at the more hindered site to give α-amino-α’-bromo ketone O-alkyloximes in good yields.

INTRODUCTION
α-Amino ketones are one of the most important nitrogen-containing compounds because of their use as versatile building blocks and intermediates for the biologically active compound synthesis.1 Several methods for the synthesis of α-amino ketones have been reported.2 We have reported titanium tetraiodide (TiI4)-promoted reductive aldol, Michael, and Mannich-type reactions by the reductive generation of enolates via ring-opening of small-sized heterocyclic compounds such as alkoxyallene oxides 1 or aziridine derivatives 2a-c bearing electron-withdrawing groups (Scheme 1).3 Azetidin-3-ones 3 have not been well studied compared with their 2-one analogues (β-lactams) because azetidin-3-ones 3 do not exist in nature. However, azetidin-3-ones 3 have been used as intermediates for the synthesis of natural products and biologically active compounds containing an azetidine ring because of ready availability from α-amino acids.4,5 We focused on the ring-opening reaction of azetidin-3-ones 3 by titanium tetrahalide for the synthesis of α-amino ketones. Herein we describe synthesis of α-amino ketones 4-6 and O-alkyloximes 8 from 2-mono-substitued azetidin-3-ones 3 by the use of titanium tetrahalide (Scheme 2).6

RESULTS AND DISCUSSION
We examined the ring-opening reaction of several azetidin-3-ones 3 with TiI4.6a Table 1 summarizes the results. The ring-opening reaction of azetidin-3-one 3a using TiI4 proceeded smoothly to give α-amino ketone 4a in 80% yield (entry 1). The ring-opening reactions of several 2-mono-substituted azetidin-3-ones were next examined. The reaction of 2-methyl-azetidin-3-one 3b gave a mixture of α-amino ketones 4b and 5b in high yield with high regioselectivity (entry 2). When azetidin-3-ones 3c (R1 = Et) and 3d (R1 = iPr) were used, both yields and regioselectivities slightly decreased (entries 3 and 4). Although the reaction of 2-isobutyl-3-azetidin-3-one 3e gave α-amino ketones 4e and 5e in high yield, the regioselectivity was moderate (entry 5). The reaction of 2-benzyl-3-azetidin-3-one 3f gave a mixture of α-amino ketones 4f and 5f in good yield with high regioselectivity (entry 6).

In the reductive ring-opening reaction of 2-mono-substituted azetidin-3-ones by TiI4, C-N bond cleavages occurred at the less sterically congested bond to give the α-amino ketone 4 preferentially. On the other hand, C-N bond cleavages of 2,2-disubstituted azetidin-3-ones 9 proceeded at the more substituted bond to afford the ketones 11 as sole products (Scheme 3).

Regarding the different regioselectivity, we proposed two different pathways including an SN2-like process by TiI4 or a one-electron transfer promoted by low-valent titanium species. In the case of 2-mono-substituted azetidin-3-ones 3, the reaction would prefer an SN2-like process rather than one electron transfer, because radical stabilization is more depressed as compared with that of 2,2-disubstited cases. Initially, α-iodoketone 3C is generated via the ring-opening of azetidin-3-ones 3A or 3B attacked by the iodide anion at the less hindered site and subsequently another iodide anion attacks to the iodine to generate the titanium enolate species 3D. Hydrolysis of the enolate 3D with water to quench the reaction gives the α-amino ketone 4 (Scheme 4).

In the case of 2,2-dimethyl-azetidin-3-ones 9a, it seems that an electron-transfer reaction would play a significant role (Scheme 5). Initially, the disproportion of TiI4 gives low-valent titanium species. One- electron transfer to azetidin-3-one at the C-3 position gives a radical intermediate 12A. A ring-opening reaction proceeded via a fragmentation at the N-C(2) or N-C(4) bond. At this point, the fragmentation at the N-C(2) bond was favored because of the electronically more stabilized 2,2-dimethyl substitution. Further reduction of the intermediate leads to the corresponding titanium enolate. Also, the homolysis of the N-C(4) bond gives the less substituted enolate 12C (path A). Alternatively, the homolysis of the N-C(2) bond leads to the more substituted enolate 12E (path B). In path A, the enolate 12C could reverse to the azetidine 9a via a re-cyclization under equilibrium.7 However, path B may not involve such a cyclization because of the steric hindrance. Finally, the more thermodynamically stable enolate 12E would predominate. The enolate 12E is hydrolyzed with water to give the α-amino ketone 11a.
In order to facilitate the ring-opening reaction of 2-mono-substituted azetidin-3-ones at the more substituted bond, several additives were next examined. When a combined use of TiI4 and titanium chloride (TiCl4) or bromide (TiBr4) was undertaken, ring-opening of several 2-mono-substituted azetidin-3-ones 3b-e occurred at the more substituted bond to give the α-amino ketones 5b-e preferentially.6b Table 2 summarizes the results. Although TiI4-TiBr4 promoted ring-opening reaction proceeded to give α-amino ketones with good to high regioselectivities, the yields were not satisfied in some cases (entries 1-4). On the other hand, when the ring-opening reactions were carried out with TiI4-TiCl4 as a promoter, α-amino ketones were obtained in moderate to high yields with higher regioselectivities.

A plausible reaction mechanism is shown in Scheme 6. The disproportion of TiI4 and TiCl4 gives low-valent titanium species. A one-electron transfer to 2-mono-substituted azetidin-3-one 3 at the C-3 position gives a radical intermediate 13. The ring-opening reaction of 13 would proceed via a fragmentation at the N-C(2) bond to give the more substituted titanium enolate 15, which is more stable than the less substituted one, and the subsequent protonation with water to quench the reaction would give the corresponding α-amino ketone 5.

The reductive aldol reaction of the enolate generated in situ was next examined. TiI4-promoted reductive aldol reaction of 2-ethyl-azetidin-3-one 3c with chloral proceeded smoothly in the presence of InCl3 as a Lewis acid additive to give the adduct 16 in 80% yield with moderate diastereoselectivity (Eq. 1).

The role of InCl3 may be explained in terms of the formation of a more reactive enolate 17C from the stable titania cycle 17A. Finally, the indium enolate 17C reacts with chloral to give the aldol adduct 16.

When the reaction of 2-isobutyl-azetidin-3-one 3e with chloral was carried out using TiI4-TiCl4 in the presence of Pd(O2CCF3)2 as a Lewis acid additive, the aldol adduct 18 was obtained in 66% yield with syn-selectivity (eq. 2).

Although the role of Pd(O2CCF3)2 is not yet clear, we presumed that a transmetallation of titanium to palladium would occur to generate the palladium enolate 20, which would react with chloral to give the aldol adduct 18.

When aldehydes other than reactive chloral were used under the each aldol reaction conditions, the desired aldol adducts were obtained in low yield because of less reactivity of the metal enolates generated in situ. We next examined the ring-opening reaction of 2-mono-substituted azetidine-3-one O-alkyloximes to generate aza-enolates, which enhance the nucleophilicity as compared with their parent carbonyl compounds.8 Table 3 summarizes the results. TiI4-promoted ring-opening reaction of 2-mono-substituted azetidin-3-one O-alkyloxime proceeded at the more hindered site. The ring-opening reaction of 7a gave α-amino ketone 5b in 51% yield accompanied by α-amino ketone 4b in 2% yield (entry 1). Although the ring-opening reactions of both azetidin-3-one O-alkyloximes 7b and 7c also proceeded at the more hindered site to give the α-amino ketones, the yields decreased (entries 2 and 3). In every reaction, a mixture of α-amino ketones 4 and 5 was obtained instead of the desired α-amino ketone O-alkyloximes probably due to the reductive cleavage of the N-O bond by TiI4 and subsequnt hydrolysis with water to quench the reaction.

It was of interest that the regioselectivity of the ring-opening reaction of 2-mono-substituted azetidin-3-one O-alkyloximes was different from that of the parent 2-mono-substituted azetidin-3-ones. We next examined the ring-opening reaction of 2-mono-substituted azetidine-3-one O-alkyloximes by TiCl4 and TiBr4 to obtain the desired α-amino ketone O-alkyloximes because their reducing abilities are less than that of TiI4. TiCl4-promoted ring-opening reaction of 2-methyl-azetidin-3-one O-methyloxime 7a proceeded under the several reaction conditions to give a mixture of α-amino ketone O-methyloximes (E)- and (Z)-8a-Cl in high yields with high regioselectivities (entries 1-4). The reaction of 7a with TiBr4 at room temperature for 20 h gave a mixture of α-amino ketone O-methyloximes (E)- and (Z)-8a-Br in 59% yield with the same high regioselectivities as in the case with TiCl4 (entry 5). When the reaction of 7a was carried out at 0 oC to room temperature for 4 h, the yield increased to 93% (entry 6). Use of 1.5 equivalents of TiBr4 gave the best 97% yield (entry 7). TiBr4-promoted ring-opening reactions of 2-isopropylazetidin-3-one O-methyloxime 7d with several E and Z ratios were carried out to give a mixture of α-amino ketone O-methyloximes (E)- and (Z)-8d-Br in good yields. (entries 9-11).

In order to improve the E-Z ratios, we next examined the reaction of the sterically hindered α-amino ketone O-alkyloxime. Table 5 summarizes the results. TiBr4-promoted ring-opening reaction of 2-isopropyl-azetidin-3-one O-tert-butyloxime 7e proceeded to give only the α-amino ketone O-tert-butyloxime (E)-8e-Br in moderate yields regardless of the geometry of 7e. The reaction of 2-isopropylazetidin-3-one O-isopropyloxime 7f also gave the α-amino ketone O-isopropyl oxime 8f-Br in good yield with E selectivity regardless of the geometry of 7f. The yields using 7e were lower than those using 7f because a tert-butyl group is more sensitive to Lewis acidic conditions than an isopropyl group.

From the results in both Tables 4 and 5, TiBr4 activates the tosylamide nitrogen because geometry of the oxime ether did not affect the regioselectivity. An SN2-like reaction occurs at the carbon having a partially positive charge to generate the intermediate 24 (Scheme 9).
The ring-opening reactions of several azetidine-3-ones by TiBr4 were carried out. Table 6 summarizes the results. The ring-opening reactions of several azetidin-3-ones 3 proceeded to give α-amino-α’-bromo ketones 6 in moderate to good yields with high regioselectivities.
Regarding the different regioselectivity between azetidin-3-ones and azetidin-3-one O-alkyloximes in TiBr4-promoted ring-opening reactions, we presume that one of the reasons is the difference of the electron-withdrawing ability between carbonyl and imino groups. A carbonyl group, which is more electron-withdrawing than an imino group, destabilizes the partially positive charge, and therefore, the ring-opening reactions of azetidin-3-ones 3E or 3F proceed by the attack of the bromide anion at the less hindered site to give the α-amino-α’-bromo ketones 6 via the intermediate 3G (Scheme 10).

CONCLUSIONS
Synthesis of α-amino ketones and O-alkyloximes has been developed by titanium tetrahalide-promoted ring-opening reactions of 2-mono-substituted azetidin-3-ones and their O-alkyloximes. In the reductive ring-opening reactions of 2-mono-substituted azetidin-3-ones, an appropriate use of TiI4 or TiI4-TiCl4 as a promoter gave α-amino ketones 4 or 5 in good yields with high regioselectivities. Reductive aldol reactions of enolates with chloral proceeded in the presence of Lewis acid additives such as InCl3 and Pd(O2CCF3)2 to give the aldol adducts in good yields. In TiBr4-promoted ring-opening reactions, while use of 2-mono-substituted azetidin-3-ones as a substrate gave α-amino-α’-bromo ketones 6 generated by the attack of the bromide anion at the less hindered site, the reaction of 2-mono-substituted azetidin-3-one O-alkyloximes 7 proceeded at the more hindered site to give α-amino-α’-bromo ketone O-alkyloximes 8 in good yields.

EXPERIMENTAL
General. Infrared spectra were recorded on a JASCO FT/IR-460 Plus spectrometer. 1H NMR spectra were recorded on a JEOL ECX- 400 spectrometer (400 MHz) or a JEOL JNM α- 500 spectrometer (500 MHz) with tetramethylsilane as an internal standard. 13C NMR spectra were recorded on a JEOL ECX- 400 spectrometer (100.5 MHz) or a JEOL JNM α- 500 spectrometer (126 MHz). Chemical sifts are reported in δ units, parts per million from the central peak of CDCl3 (δ 77.0) as an internal reference. High resolution mass spectra (EI) were recorded on a JEOL JMS-700D mass spectrometer. Dichloromethane (CH2Cl2) was pre-dried with P2O5, distilled from CaH2, and stored over molecular sieves 4A. Purification of products was performed by column chromatography on silica gel (Kanto Chemical Co. Inc., Silica Gel 60 N (spherical, neutral)) and/or preparative TLC on silica gel (Merck Kiesel Gel GF254). All reactions were carried out under an argon atmosphere. Various azetidin-3-ones were synthesized according to the previously reported literatures.9-13

Typical procedure (Table 1, entry 1): A solution of N-p-tosyl-azetidin-3-one (3a) (22.5 mg, 0.10 mmol) in CH2Cl2 (1.0 mL) was added to a solution of titanium tetraiodide (166.6 mg, 0.30 mmol) in CH2Cl2 (2.0 mL) at 0 oC. The reaction mixture was allowed to warm to ambient temperature with stirring for 15 h. The reaction was quenched with sat. aq. NaHCO3. The whole mixture was diluted with EtOAc (5.0 mL), followed by the addition of 10% aq. NaHSO3. The mixture was filtered through a Celite pad. The layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC on silica gel (n-hexane/CH2Cl2/Et2O = 2/3/2) to give 1-(tosylamino)propan-2-one (4a) (18.2 mg, 80%).

1-(Tosylamino)propan-2-one (4a):
White solid. Mp 96-97 °C. 1H-NMR (400 MHz, CDCl3) δ = 2.11 (s, 3H), 2.42 (s, 3H), 3.85 (d, J = 4.6 Hz, 2H), 5.31 (t, J = 4.6 Hz, 1H), 7.29-7.32 (m, 2H), 7.72-7.75 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 21.5, 27.1, 52.1, 127.1, 129.8, 136.1, 143.8, 201.0. IR (neat) 3279, 3038, 2970, 1718, 1407, 1363, 1343, 1162, 1103, 1094, 816, 706, 546 cm-1. HRMS (EI): Calculated for C13H19NO3S (M)+ 227.0616, found 227.0613.

3-(Tosylamino)butan-2-one (4b):
White solid. Mp 71-72 °C. 1H-NMR (400 MHz, CDCl3) δ = 1.35 (d, J = 7.3 Hz, 3H), 2.09 (s, 3H), 2.42 (s, 3H), 3.93 (dq, J = 6.2, 7.3 Hz, 1H), 5.52 (d, J = 6.2 Hz, 1H), 7.28-7.31 (m, 2H), 7.70-7.73 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 18.8, 21.5, 26.2, 57.6, 127.1, 129.7, 136.9, 143.7, 205.5. IR (neat) 3276, 2984, 2928, 1717, 1598, 1424, 1335, 1163, 1127, 1092, 816, 667, 551 cm-1. HRMS (EI): Calculated for C9H12NO2S (M-C2H3O)+ 198.0589, found 198.0592.

1-(Tosylamino)butan-2-one (5b):
White solid. Mp 83-84 °C. 1H-NMR (400 MHz, CDCl3) δ = 1.03 (t, J = 7.3 Hz, 3H), 2.37 (q, J = 7.3 Hz, 2H), 2.42 (s, 3H), 3.83 (d, J = 4.6 Hz, 2H), 5.29 (t, J = 4.6 Hz, 1H), 7.29-7.32 (m, 2H), 7.72-7.75 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 7.5, 21.5, 33.4, 51.0, 127.2, 129.8, 136.1, 143.8, 204.0. IR (neat) 3280, 2973, 2922, 1717, 1411, 1328, 1163, 1094, 814, 547 cm-1. HRMS (EI): Calculated for C8H10NO2S (M-C3H5O)+ 184.0432, found 184.0437.

3-(Tosylamino)pentan-2-one (4c):
White solid. Mp 74-75 °C. 1H-NMR (400 MHz, CDCl3) δ = 0.86 (dd, J = 7.3, 7.3 Hz, 3H), 1.62 (ddq, J = 6.9, 7.3, 14.4 Hz, 1H), 1.87 (ddq, J = 4.8, 7.3, 14.4 Hz, 1H), 2.04 (s, 3H), 2.41 (s, 3H), 3.89 (ddd, J = 4.8, 6.6, 6.9 Hz, 1H), 5.47 (d, J = 6.6 Hz, 1H), 7.26-7.30 (m, 2H), 7.69-7.72 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 8.7, 21.5, 25.3, 26.6, 62.8, 127.1, 129.7, 136.8, 143.6, 205.3. IR (neat) 3273, 2972, 2935, 2925, 1715, 1598, 1453, 1422, 1334, 1251, 1163, 1125, 1092, 816, 670 cm-1. HRMS (EI): Calculated for C10H14NO2S (M-C2H3O)+ 212.0745, found 212.0752.

1-(Tosylamino)pentan-2-one (5c):
White solid. Mp 81-82 °C. 1H-NMR (400 MHz, CDCl3) δ = 0.84 (t, J = 7.3 Hz, 3H), 1.55 (tq, J = 7.3, 7.3 Hz, 2H), 2.31 (t, J = 7.3 Hz, 2H), 2.42 (s, 3H), 3.82 (d, J = 4.8 Hz, 2H), 5.30 (t, J = 4.8 Hz, 1H), 7.29-7.32 (m, 2H), 7.72-7.54 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 13.5, 17.1, 21.5, 41.9, 51.4, 127.2, 129.8, 136.1, 143.8, 203.6. IR (neat) 3277, 2956, 2918, 1717, 1597, 1445, 1407, 1321, 1159, 1163, 1088, 810, 668 cm-1. HRMS (EI): Calculated for C8H10NO2S (M-C4H7O)+ 184.0432, found 184.0435.

4-Methyl-3-(tosylamino)pentan-2-one (4d):
White solid. Mp 77-78 °C. 1H-NMR (400 MHz, CDCl3) δ = 0.72 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H), 1.97 (s, 3H), 2.07 (dsept, J = 3.7, 6.9 Hz, 1H), 2.41 (s, 3H), 3.81 (dd, J = 3.7, 8.7 Hz, 1H), 5.35 (d, J = 8.7 Hz, 1H), 7.26-7.29 (m, 2H), 7.67-7.70 (m, 2H). 3C-NMR (100.5 MHz, CDCl3) δ = 16.1, 19.9, 21.5, 27.5, 30.1, 66.9, 127.2, 129.6, 136.7, 143.6, 205.7. IR (neat) 3276, 3055, 2967, 2925, 2870, 1719, 1599, 1451, 1408, 1330, 1251, 1161, 1128, 1093, 1039, 856, 812, 670, 546 cm-1. HRMS (EI): Calculated for C11H16NO2S (M-C2H3O)+ 226.0902, found 226.0893.

4-Methyl-1-(tosylamino)pentan-2-one (5d):
White solid. Mp 63-65 °C. 1H-NMR (500 MHz, CDCl3) δ = 0.82 (d, J = 6.7 Hz, 6H), 2.03 (tsept, J = 6.7, 7.0 Hz, 1H), 2.20 (d, J = 7.0 Hz, 2H), 2.42 (s, 3H), 3.80 (d, J = 4.6 Hz, 2H), 5.35 (t, J = 4.6 Hz, 1H), 7.29-7.31 (m, 2H), 7.72-7.74 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 21.5, 22.3, 24.7, 48.9, 51.8, 127.2, 129.8, 136.0, 143.8, 203.3. IR (neat) 3275, 2956, 2925, 2869, 1716, 1600, 1322, 1161, 1038, 814, 688 cm-1. HRMS (EI): Calculated forC8H10NO2S (M-C5H9O)+ 184.0432, found 184.0434.

5-Methyl-3-(tosylamino)hexan-2-one (4e):
White solid. Mp 59-60 °C. 1H-NMR (400 MHz, CDCl3) δ = 0.87 (d, J = 2.7 Hz, 3H), 0.88 (d, J = 2.7 Hz, 3H), 1.31 (ddd, J = 4.5, 9.7, 14.0 Hz, 1H), 1.42 (ddd, J = 4.0, 9.7, 14.0 Hz, 1H), 1.83 (m, 1H), 2.00 (s, 3H), 2.41 (s, 3H), 3.90 (ddd, J = 4.0, 8.4, 9.7 Hz, 1H), 5.31 (d, J = 8.4 Hz, 1H), 7.27-7.30 (m, 2H), 7.68-7.71 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 21.4, 23.3, 24.5, 26.8, 41.2, 60.7, 127.3, 129.8, 136.8, 143.8, 206.5. IR (neat) 3238, 2957, 2875, 1722, 1597, 1161, 1088, 1039, 821, 664 cm-1. HRMS (EI): Calculated for C12H18NO2S (M-C2H3O)+ 240.1058, found 240.1061.

5-Methyl-1-(tosylamino)hexan-2-one (5e):
White solid. Mp 82-83 °C. 1H-NMR (400 MHz, CDCl3) δ = 0.83 (d, J = 6.2 Hz, 6H), 1.42 (m, 3H), 2.32 (t, J = 7.6 Hz, 2H), 2.42 (s, 3H), 3.83 (d, J = 4.5 Hz, 2H), 5.34 (t, J = 4.5 Hz, 1H), 7.29-7.32 (m, 2H), 7.72-7.75 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 22.2, 22.3, 27.6, 32.4, 38.2, 51.3, 127.3, 129.6, 136.1, 143.9, 204.1. IR (neat) 3284, 3067, 2954, 2872, 1719, 1602, 1160, 1064, 813, 679 cm-1. HRMS (EI): Calculated for C13H19NO3S (M)+ 283.1242, found 283.1246.

4-phenyl-3-(tosylamino)butan-2-one (4f):
White semisolid. 1H-NMR (400 MHz, CDCl3) δ = 2.02 (s, 3H), 2.40 (s, 3H), 2.91 (dd, J = 6.4, 14.0 Hz, 1H), 2.98 (dd, J = 6.4, 14.0 Hz, 1H), 4.10 (dt, J = 6.4, 7.3 Hz, 1H), 5.22 (d, J = 7.3 Hz, 1H), 7.01-7.04 (m, 2H), 7.20-7.26 (m, 5H), 7.56-7.59 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 14.5, 20.6, 31.3, 55.6, 120.1, 120.3, 121.8, 122.2, 122.7, 127.9, 129.6, 136.7, 198.8. IR (neat) 3279, 2922, 2852, 1717, 1559, 1453, 1404, 1319, 1159, 1072, 813, 665 cm-1. HRMS (EI): Calculated for C15H16NO2S (M-C2H3O)+ 274.0902, found 274.0913.

4-Phenyl-1-(tosylamino)butan-2-one (5f):
White semisolid. 1H-NMR (400 MHz, CDCl3) δ = 2.42 (s, 3H), 2.66 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 3.78 (d, J = 4.1 Hz, 2H), 5.25 (t, J = 4.1 Hz, 1H), 7.07-7.10 (m, 2H), 7.16-7.28 (m, 5H), 7.69-7.71 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 21.5, 29.4, 41.6, 51.6, 126.5, 127.1, 128.1, 128.6, 129.8, 134.1(?), 139.8, 143.8, 202.8.IR (neat) 3281, 3064, 3031, 2925, 2857, 1718, 1601, 1497, 1449, 1319, 1161, 1091, 815, 696 cm-1. HRMS (EI): Calculated for C13H19NO3S (M)+ 317.1086, found 317.1078.

3-Methyl-1-(tosylamino)butan-2-one (11a):
White solid. Mp 75-76 °C. 1H-NMR (400 MHz, CDCl3) δ = 1.02 (d, J = 7.1 Hz, 6H), 2.41 (s, 3H), 2.52 (sept, J = 7.1 Hz, 1H), 3.88 (d, J = 4.6 Hz, 2H), 5.30 (t, J = 4.6 Hz, 1H), 7.28-7.30 (m, 2H), 7.71-7.73 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 18.0, 21.5, 38.8, 49.4, 127.2, 129.7, 136.1, 143.8, 207.3. IR (neat) 3291, 3042, 2975, 2924, 2869, 1705, 1599, 1405, 1347, 1251, 1166, 1032, 808, 668 cm-1. HRMS (EI): Calculated for C8H10NO2S (M-C4H7O)+ 184.0432, found 184.0423.

1-Cyclohexyl-2 -(tosylamino)ethanone (11b):
White solid; Mp 85-86 °C. 1H-NMR (400 MHz, CDCl3) δ = 1.36 (m, 5H), 1.67 (m, 5H), 2.27 (m, 1H), 2.42 (s, 3H), 3.88 (d, J = 4.2 Hz, 2H), 5.36 (t, J = 4.2 Hz, 1H), 7.25-7.35 (m, 2H), 7.68-7.77 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 21.5, 25.3, 28.1, 48.4, 49.6, 127.2, 129.7, 136.0, 143.7, 206.5. IR (neat) 3285, 3042, 2939, 2921, 1717, 1598, 1455, 1411, 1321, 1167, 817, 710, 667 cm-1. HRMS (EI): Calculated for C8H10NO2S (M-C7H11O)+ 184.0432, found 184.0432.

Typical procedure (Table 2, entry 8): To TiI4 (222 mg, 0.40 mmol) was added TiCl4 (0.04 mL, 0.4 mmol) and CH2Cl2 (1.0 mL) at room temperature. The mixture was cooled to –78 oC and to it was added a solution of (S)-2-isobutyl-N-p-tosylazetidin-3-one (3e) (56.2 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) at –78 oC. The resulting mixture was gradually warmed up to room temperature during 15 h and sat. aq. NaHCO3, EtOAc (5.0 mL), and 10% aq. NaHSO3 were added to quench the reaction. The mixture was filtrated through a Celite pad. The layers were separated and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product. Purification on silica gel TLC (n-hexane/CH2Cl2/Et2O = 5/3/2) gave 5-methyl-1-(tosylamino)hexan-2-one (5e) (88%, 24.9 mg).

Reductive aldol reaction (Eq. 1): A solution of N-p-tosyl-2-ethylazetidin-3-one (3c) (50.6 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) and a solution of chloral (58.8 mg, 0.40 mmol) in CH2Cl2 (1.0 mL) were added to a mixture of titanium tetraiodide (222.2 mg, 0.40 mmol) and indium trichloride (88.4 mg, 0.40 mmol) in CH2Cl2 (1.0 mL) at rt. The reaction mixture was stirred for 15 h. The reaction was quenched with sat. aq. NaHCO3. The whole mixture was diluted with EtOAc (5.0 mL), followed by the addition of 10% aq.NaHSO3. The mixture was filtered through a Celite pad. The layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL x 3).The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC on silica gel (developed once with n-hexane/CH2Cl2/Et2O = 3/3/2) to give 1,1,1-trichloro-2-hydroxy-5- (tosylamino)heptan-4-one (16) (64.2 mg, 80%, dr = 80:20).

1,1,1-Trichloro-2-hydroxy-5-(tosylamino)heptan-4-one (16)-(upper):
White solid. Mp 111-112 °C. 1H-NMR (400 MHz, CDCl3) δ = 0.90 (t, J = 7.3 Hz, 3H), 1.05 (d, J = 6.9 Hz, 3H), 2.13 (dsept, J = 3.7, 6.9 Hz, 1H), 2.39 (s, 3H), 2.57 (ddd, J = 1.8, 1.8, 17.4 Hz, 1H), 2.88 (dd, J = 9.2, 17.4 Hz, 1H), 3.12 (dd, J = 1.8, 4.6 Hz, 1H), 3.83 (dd, J = 3.7, 9.6 Hz, 1H), 4.40 (ddd, J = 1.8, 4.6, 9.2 Hz, 1H), 5.32 (d, J = 9.6 Hz, 1H), 7.26-7.29 (m, 2H), 7.68-7.71 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 16.1, 19.9, 21.5, 29.8, 42.9, 66.4, 78.2, 127.4, 129.8, 136.5, 143.9, 204.9. IR (neat) 3519, 3320, 3046, 2971, 1916, 1715, 1598, 1349, 1164, 1038, 673, 576 cm-1. HRMS (EI): Calculated for C10H14NO2S (M-C4H4Cl3O2)+ 212.0745, found 212.0765.

1,1,1-Trichloro-2-hydroxy-5-(tosylamino)heptan-4-one (16)-(lower):
White solid. Mp 111-112 °C. 1H-NMR (400 MHz, CDCl3) δ = 0.90 (dd, J = 7.3, 7.3 Hz, 3H), 1.58 (ddq, J = 6.9, 7.3, 14.6 Hz, 1H), 1.87 (ddq, J = 4.6, 7.3, 14.6 Hz, 1H), 2.40 (s, 3H), 2.72 (ddd, J = 1.2, 2.3, 17.6 Hz, 1H), 2.88 (dd, J = 8.7, 17.6 Hz, 1H), 3.11 (dd, J = 1.2, 4.6 Hz, 1H), 3.93 (ddd, J = 4.6, 6.9, 8.0 Hz, 1H), 4.47 (ddd, J = 2.3, 4.6, 8.7 Hz, 1H), 5.35 (d, J = 8.0 Hz, 1H), 7.27-7.31 (m, 2H), 7.70-7.73 (m, 2H). 13C-NMR (100.5 MHz, CDCl3) δ = 9.1, 21.5, 25.0, 42.2, 62.6, 78.3, 102.1, 127.3, 129.8, 136.7, 143.9, 204.8. IR (neat) 3471, 3255, 2969, 2928, 2885, 1719, 1598, 1293, 1167, 1091, 808, 664 cm-1. HRMS (EI): Calculated for C10H14NO2S (M-C4H4Cl3O2)+ 212.0745, found 212.0765.

Reductive aldol reaction (Eq. 2): To a mixture of TiI4 (111 mg, 0.20 mmol), TiCl4 (0.02 mL, 0.2 mmol), and Pd(O2CCF3)2 (33.2 mg, 0.10 mmol) was added CH2Cl2 (1.0 mL) at rt. The mixture was cooled to 0 oC and to it was added successively a solution of (S)-2-isobutyl-N-p-tosylazetidin-3-one (3e) (28.1 mg, 0.10 mmol) in CH2Cl2 (1.0 mL) and that of chloral (29.4 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) at 0 oC. The resulting mixture was gradually warmed up to room temperature during 15 h and sat. aq. NaHCO3, EtOAc (5.0 mL), and 10% aq. NaHSO3 were added successively to quench the reaction. The mixture was filtrated through a Celite pad. The layers were separated and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product. Purification on silica gel TLC (n-hexane/CH2Cl2/Et2O = 2/3/2, twice) gave (R*)-3-((R*)-2,2,2-trichloro-1-hydroxyethyl)-5-methyl- 1-(tosylamino)hexan-2-one (18) (28.5 mg, 66%).

(R*)-3-((R*)-2,2,2-trichloro-1-hydroxyethyl)-5-methyl-1-(tosylamino)hexan-2-one (18):
White solid. Mp 99-100 °C. 1H NMR (400 MHz, CDCl3): δ = 0.88 (d, J = 6.4 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 1.31-1.37 (m, 1H), 1.40-1.50 (m, 1H), 1.58-1.65 (m, 1H), 2.43 (s, 3H), 3.31 (ddd, J = 1.7, 6.3, 8.0 Hz, 1H), 3.98 (dd, J = 4.4, 20.0 Hz, 1H), 4.04 (dd, J = 4.4, 20.0 Hz, 1H), 4.11 (dd, J = 1.7, 9.0 Hz, 1H), 4.79 (d, J = 9.0 Hz, 1H), 5.28 (t, J = 4.4, Hz, 1H), 7.29-7.31 (m, 2H), 7.72-7.74 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 21.5, 21.9, 22.5, 25.4, 40.0, 44.8, 52.8, 85.2, 102.4, 127.3, 129.8, 135.9, 144.1, 209.0. IR (KBr): 3478, 3278, 2933, 2870, 1703, 1321, 1166, 1096, 934, 809, 782, 662, 588 cm-1. HRMS (EI): Calculated for C16H22Cl3NO4S (M)+ 429.0335, found 429.0346.

Typical procedure for the synthesis of azetidin-3-one O-alkyloximes: Pyridine (1.0 mL) was added to a solution of 2-methyl-1-tosylazetidin-3-one (3b) (837.5 mg, 3.5 mmol), O-methylhydroxylamine hydrochloride (584.6 mg, 7.0 mmol) and Na2SO4 (994.0 mg, 7.0 mmol) in CH2Cl2 (2.0 mL) at ambient temperature. The reaction mixture was stirring for 24 h. The reaction was quenched with H2O. The whole mixture was diluted with EtOAc (15.0 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified flash column chromatography (n-hexane/CH2Cl2/Et2O = 4/3/2) to give 2-methyl-1-tosylazetidine-3-one O-methyloxime (7a) (911.0 mg, 97%, E:Z = 31:69).

2-Methyl-1-tosylazetidin-3-one O-methyloxime (7a):
97%, E:Z = 31:69. White solid. Mp 52-53 °C. 1H NMR (400 MHz, CDCl3): δ = 1.49 (d, J = 6.4 Hz, 2.07 H), 1.55 (d, J = 6.4 Hz, 0.93 H), 2.44 (s, 3H), 3.75 (s, 0.93 H), 3.77 (s, 2.07H), 4.23-4.27 (m, 1H), 4.41 (dd, J = 3.1, 13.7 Hz, 0.31H), 4.47 (dd, J = 3.7, 14.7 Hz, 0.69H), 4.66-4.73 (m, 1H), 7.34-7.36 (m, 2H), 7.71-7.74 (m, 2H). 13C NMR (126 MHz, CDCl3): δ = 18.1, 18.8, 21.6, 56.2, 56.7, 62.2, 62.3, 68.7, 69.3, 128.3, 128.4, 130.0, 131.9, 144.6, 148.7, 149.5. IR (neat): 2979, 2937, 2904, 2819, 1596, 1445, 1349, 1165, 1094, 1056, 1025, 977, 881, 818, 760, 710, 675, 626 cm-1. HRMS (EI): Calculated for C12H16N2O3S (M)+ 268.0882, found 268.0870.

2-Ethyl-1-tosylazetidin-3-one O-methyloxime (7b):
98%, E:Z = 33:67. White solid. Mp 86-87 °C. 1H NMR (400 MHz, CDCl3): δ = 1.00-1.04 (m, 3H), 1.83-1.90 (m, 2H), 2.44 (s, 3H), 3.75 (s, 0.99 H), 3.77 (s, 2.01H), 4.24-4.28 (m, 1H), 4.41 (dd, J = 3.7, 14.2 Hz, 0.33H), 4.43 (dd, J = 3.7, 15.1 Hz, 0.67H), 4.59-4.64 (m, 0.67H), 4.72-4.76 (m, 0.33H), 7.34-7.36 (m, 2H), 7.71-7.73 (m, 2H). 13C NMR (126 MHz, CDCl3): δ = 8.6, 8.7, 21.6, 24.4, 26.2, 56.6, 56.9, 62.2, 62.3, 73.8, 74.6, 128.3, 128.3, 129.9, 132.0, 144.5, 147.5, 148.9. IR (neat): cm-1 2971, 2939, 2879, 2820, 1597, 1458, 1350, 1165, 1094, 1037, 885, 817, 711, 674, 619, 581. HRMS (EI): Calculated for C13H18N2O3S (M)+ 282.1038, found 282.1032.

2-Isobutyl-1-tosylazetidin-3-one O-methyloxime (7c):
96%, E:Z = 30:70. White solid. Mp 84-85 °C. 1H NMR (400 MHz, CDCl3): δ = 0.90-0.96 (m, 6H), 1.69-1.82 (m, 2H), 1.86-2.00 (m, 1H), 2.44 (s, 3H), 3.75 (s, 0.90H), 3.76 (s, 2.10H), 4.27 (dd, J = 1.8, 15.1 Hz, 0.70H), 4.29 (dd, J = 1.4, 14.2 Hz, 0.30H), 4.42 (dd, J = 3.7, 14.2 Hz, 0.30H), 4.29 (dd, J = 3.7, 15.1 Hz, 0.70H), 4.64-4.69 (m, 0.70H), 4.71-4.74 (m, 0.30H), 7.35-7.37 (m, 2H), 7.71-7.73 (m, 2H). 13C NMR (126 MHz, CDCl3): δ = 21.6, 22.5, 22.7, 23.1, 24.2, 24.3, 40.6, 42.5, 56.6, 56.8, 62.3, 71.4, 72.3, 128.3, 128.4, 129.9, 131.9, 132.1, 144.5, 144.5, 148.5, 149.6. IR (neat): cm-1 2958, 2871, 2819, 1596, 1559, 1465, 1352, 1165, 1093, 1038, 886, 817, 710, 677, 617, 577. HRMS (EI): Calculated for C15H22N2O3S (M)+ 310.1351, found 310.1339.

The yield of 7d was 84%. (E)-7d was 15%. (Z)-7d was 69%. E:Z = 18:82.
(E)-2-Isopropyl-1-tosylazetidin-3-one O-methyloxime [(E)-7d]:
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 1.03 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 7.3 Hz, 3H), 2.22-2.29 (m, 1H), 2.44 (s, 3H), 3.75 (s, 3H), 4.29 (dd, J = 1.3, 14.2 Hz, 1H), 4.34 (dd, J = 3.2, 14.2 Hz, 1H), 4.64-4.66 (m, 1H), 7.34-7.36 (m, 2H), 7.71-7.73 (m, 2H). 13C NMR (126 MHz, CDCl3): δ = 17.6, 18.2, 21.6, 30.2, 57.1, 62.2, 79.5, 128.3, 129.9, 132.4, 144.4, 147.2. IR (neat): 2966, 2937, 2898, 2876, 2819, 1598, 1463, 1351, 1165, 1093, 1046, 880, 818, 711, 676, 626, 600 cm-1. HRMS (EI): Calculated for C14H20N2O3S (M)+ 296.1195, found 296.1196.

(Z)-2-Isopropyl-1-tosylazetidin-3-one O-methyloxime [(Z)-7d]:
White solid. Mp 54-55 °C. 1H NMR (400 MHz, CDCl3): δ = 1.00 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 2.02-2.10 (m, 1H), 2.41 (s, 3H), 3.74 (s, 3H), 4.26 (dd, J = 1.4, 15.1 Hz, 1H), 4.36 (dd, J = 3.7, 15.1 Hz, 1H), 4.48-4.50 (m, 1H), 7.32-7.34 (m, 2H), 7.69-7.71 (m, 2H). 13C NMR (126 MHz, CDCl3): δ = 16.9, 18.0, 21.5, 31.5, 57.0, 62.2, 77.9, 128.3, 129.9, 132.2, 144.4, 148.3. IR (neat): 2966, 2938, 2901, 2877, 2819, 1598, 1495, 1466, 1389, 1351, 1165, 1094, 1046, 882, 817, 711, 690, 661, 597 cm-1. HRMS (EI): Calculated for C14H20N2O3S (M)+ 296.1195, found 296.1189.

The yield of 7e was 98%. (E)-7e was 27%. (Z)-7e was 71%. E:Z = 28:72.
(E)-2-Isopropyl-1-tosylazetidin-3-one O-tert-butyloxime [(E)-7e]:
White solid. Mp 106-107 °C. δ = 1.03 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 1.17 (s, 9H), 2.21-2.29 (m, 1H), 2.44 (s, 3H), 4.30 (dd, J = 1.9, 14.2 Hz, 1H), 4.35 (dd, J = 3.2, 15.1 Hz, 1H), 4.63-4.65 (m, 1H), 7.34-7.36 (m, 2H), 7.72-7.74 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 17.8, 18.0, 21.6, 27.3, 30.3, 57.4, 79.3, 79.7, 128.3, 129.9, 132.6, 144.2, 145.3. IR (neat): 2974, 2928, 2873, 1559, 1507, 1455, 1367, 1348, 1188, 1163, 1100, 1033, 945, 818, 710, 677, 612 cm-1. HRMS (EI): Calculated for C17H26N2O3S (M)+ 338.1664, found 338.1663.

(Z)-2-Isopropyl-1-tosylazetidin-3-one O-tert-butyloxime [(Z)-7e]:
White solid. Mp 73-74 °C. 1H NMR (400 MHz, CDCl3): δ = 1.00 (d, J = 6.9 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H), 1.17 (s, 9H), 2.03-2.14 (m, 1H), 2.43 (s, 3H), 4.26 (dd, J = 1.0, 14.6 Hz, 1H), 4.37 (dd, J = 3.2, 14.6 Hz, 1H), 4.53-4.55 (m, 1H), 7.33-7.35 (m, 2H), 7.72-7.74 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 16.8, 18.2, 21.6, 27.2, 31.5, 57.3, 78.1, 79.0, 128.3, 129.8, 132.5, 144.2, 146.5. IR (neat): 2973, 2929, 2876, 1560, 1507, 1458, 1354, 1164, 1094, 1021, 952, 815, 710, 680, 600 cm-1. HRMS (EI): Calculated for C17H26N2O3S (M)+ 338.1664, found 338.1655.

The yield of 7f was 94%. (E)-7f was 21%. (Z)-7f was 73%. E:Z = 22:78.
(E)-2-Isopropyl-1-tosylazetidin-3-one O-isopropyloxime [(E)-7f]:
White solid. Mp 56-57 °C. 1H NMR (400 MHz, CDCl3): δ = 1.03 (d, J = 5.0 Hz, 3H), 1.05 (d, J = 5.0 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H), 2.22-2.30 (m, 1H), 2.44 (s, 3H), 4.19 (sept, J = 6.4 Hz, 1H), 4.29 (dd, J = 1.8, 14.2 Hz, 1H), 4.35 (dd, J = 3.7, 14.2 Hz, 1H), 4.63-4.65 (m, 1H), 7.34-7.36 (m, 2H), 7.72-7.74 (m, 2H). 13C NMR (126 MHz, CDCl3): δ = 17.8, 18.0, 21.3, 21.5, 21.6, 30.2, 57.3, 76.2, 79.6, 128.3, 129.9, 132.5, 144.3, 146.1. IR (neat): 2972, 2932, 2875, 1598, 1455, 1352, 1166, 1118, 1093, 1016, 970, 816, 710, 674, 660, 616 cm-1. HRMS (EI): Calculated for C16H24N2O3S (M)+ 324.1508, found 324.1505.

(Z)-2-Isopropyl-1-tosylazetidin-3-one O-isopropyloxime [(Z)-7f]:
White solid. Mp 68-69 °C. 1H NMR (400 MHz, CDCl3): δ = 1.01 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 1.10 (d, J = 6.4 Hz, 3H), 1.13 (d, J = 6.0 Hz, 3H), 2.03-2.13 (m, 1H), 2.42 (s, 3H), 4.19 (sept, J = 6.4 Hz, 1H), 4.27 (dd, J = 1.8, 15.1 Hz, 1H), 4.36 (dd, J = 3.7, 15.1 Hz, 1H), 4.50-4.53 (m, 1H), 7.32-7.34 (m, 2H), 7.70-7.72 (m, 2H). 13C NMR (126 MHz, CDCl3): δ = 16.9, 18.1, 21.2, 21.4, 21.5, 31.5, 57.3, 75.9, 78.0, 128.3, 129.8, 132.4, 144.3, 147.4. IR (neat): 2973, 2931, 2876, 1599, 1496, 1467, 1350, 1164, 1115, 1018, 966, 891, 849, 817, 710, 685, 660, 600 cm-1. HRMS (EI): Calculated for C16H24N2O3S (M)+ 324.1508, found 324.1499.

Typical procedure (Table 5, entry 4)
A solution of (Z)-2-isopropyl-1-tosylazetidin-3-one O-isopropyloxime [(Z)-7f] (32.4 mg, 0.10 mmol) in CH2Cl2 (1.0 mL) was added to a solution of titanium tetrabromide (55.1 mg, 0.15 mmol) in CH2Cl2 (1.0 mL) at 0oC. The reaction mixture was allowed to warm to ambient temperature with stirring for 5 h. The reaction was quenched with sat. aq. NaHCO3. The whole mixture was diluted with EtOAc (5.0 mL). The mixture was filtered through a Celite pad. The layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC on silica gel (n-hexane/CH2Cl2/Et2O = 4/3/2) to give the mixture of (Z)- and (E)-3-bromo-4-methyl- 1-(tosylamino)pentan-2-ones [(E)- and (Z)-8f-Br] (31.2 mg, 77%, E/Z = 97:3).

(E)-3-Chloro-1-(tosylamino)butan-2-one O-methyloxime [(E)-8a-Cl]:
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 1.59 (d, J = 6.9 Hz, 3H), 2.43 (s, 3H), 3.67 (dd, J = 6.4, 15.1 Hz, 1H), 3.85 (s, 3H), 3.92 (dd, J = 7.3, 15.1 Hz, 1H), 4.62 (q, J = 6.9 Hz, 1H), 5.19-5.22 (m, 1H), 7.31-7.33 (m, 2H), 7.73-7.76 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 21.3, 21.5, 38.4, 55.8, 62.5, 127.1, 129.8, 136.5, 143.8, 154.2. IR (neat): 3289, 2981, 2939, 2901, 2873, 2820, 1598, 1494, 1443, 1331, 1219, 1162, 1093, 1042, 997, 907, 815, 667 cm-1. HRMS (EI): Calculated for C12H17ClN2O3S (M)+ 304.0648, found 304.0644.

(Z)-3-Chloro-1-(tosylamino)butan-2-one O-methyloxime [(Z)-8a-Cl]:
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 1.42 (d, J = 6.9 Hz, 3H), 2.42 (s, 3H), 3.81 (s, 3H), 3.87 (dd, J = 6.0, 16.5 Hz, 1H), 3.94 (dd, J = 4.6, 16.5 Hz, 1H), 5.12-5.14 (m, 1H), 5.23 (q, J = 6.9 Hz, 1H), 7.29-7.31 (m, 2H), 7.74-7.77 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 21.5, 21.7, 41.4, 47.9, 62.5, 127.3, 129.7, 136.4, 143.7, 152.3. IR (neat): 3287, 2979, 2938, 2901, 2873, 2823, 1598, 1493, 1444, 1332, 1229, 1163, 1094, 1043, 909, 814, 666 cm-1. HRMS (EI): Calculated for C12H17ClN2O3S (M)+ 304.0648, found 304.0655.

(E)-3-Bromo-1-(tosylamino)butan-2-one O-methyloxime [(E)-8a-Br]:
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 1.76 (d, J = 6.9 Hz, 3H), 2.44 (s, 3H), 3.67 (dd, J = 6.4, 15.1 Hz, 1H), 3.86 (s, 3H), 3.96 (dd, J = 7.4, 15.1 Hz, 1H), 4.71 (q, J = 6.9 Hz, 1H), 5.27-5.30 (m, 1H), 7.32-7.34 (m, 2H), 7.74-7.76 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 21.5, 21.9, 39.2, 46.2, 62.5, 127.1, 129.8, 136.5, 143.8, 154.7. IR (neat): 3290, 2977, 2938, 2821, 1598, 1494, 1442, 1331, 1162, 1092, 1041, 991, 815, 669 cm-1. HRMS (EI): Calculated for C12H17BrN2O3S (M)+ 348.0143, found 348.0131.

(Z)-3-Bromo-1-(tosylamino)butan-2-one O-methyloxime [(Z)-8a-Br]:
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 1.65 (d, J = 6.9 Hz, 3H), 2.43 (s, 3H), 3.83 (s, 3H), 3.89 (dd, J = 5.9, 16.5 Hz, 1H), 3.99 (dd, J = 5.0, 16.5 Hz, 1H), 5.11-5.14 (m, 1H), 5.26 (q, J = 6.9 Hz, 1H), 7.30-7.32 (m, 2H), 7.76-7.78 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 21.5, 22.0, 35.3, 41.6, 62.6, 127.3, 129.7, 136.4, 143.6, 152.0. IR (neat): 3286, 2972, 2937, 2867, 2821, 1598, 1442, 1332, 1162, 1093, 1598, 1442, 1332, 1162, 1093, 1047, 910, 813, 666 cm-1. HRMS (EI): Calculated for C12H17BrN2O3S (M)+ 348.0143, found 348.0129.

(E)-3-Bromo-4-methyl-1-(tosylamino)pentan-2-one O-methyloxime [(E)-8d-Br]:
White solid. Mp 107-108 °C. 1H NMR (400 MHz, CDCl3): δ = 0.96 (d, J = 6.9 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H), 2.11-2.20 (m, 1H), 2.44 (s, 3H), 3.65 (dd, J = 5.5, 14.2 Hz, 1H), 3.82-3.88 [m, 4H, including a singlet of OCH3 at δ = 3.85 (3H)], 4.25 (d, J = 9.6 Hz, 1H), 5.24-5.27 (m, 1H), 7.32-7.34 (m, 2H), 7.75-7.78 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 20.6, 21.3, 21.5, 32.6, 39.0, 60.6, 62.6, 127.2, 129.8, 136.4, 143.8, 153.9. IR (neat): 3272, 2968, 2937, 2871, 2822, 1595, 1493, 1457, 1410, 1334, 1210, 1164, 1094, 1047, 998, 908, 865, 835, 819, 663, 607 cm-1. HRMS (EI): Calculated for C14H21BrN2O3S (M-Br)+ 297.1273, found 297.1261.

(Z)-1-Bromo-4-methyl-3-(tosylamino)pentan-2-one O-methyloxime [(Z)-8d-Br]:
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 0.81 (d, J = 6.4 Hz, 3H), 1.07 (d, J = 6.4 Hz, 3H), 1.89-1.99 (m, 1H), 2.43 (s, 3H), 3.82 (dd, J = 5.9, 16.4 Hz, 1H), 3.82 (s, 3H), 4.04 (dd, J = 4.5, 16.4 Hz, 1H), 4.88 (d, J = 10.0 Hz, 1H), 5.19-5.21 (m, 1H), 7.29-7.31 (m, 2H), 7.76-7.78 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 19.5, 21.1, 21.5, 32.3, 42.1, 49.2, 62.5, 127.3, 129.7, 136.4, 143.6, 151.3. IR (neat): 3287, 2967, 2936, 2873, 2821, 1598, 1494, 1460, 1334, 1162, 1093, 1050, 910, 868, 815, 706, 668 cm-1. HRMS (EI): Calculated for C14H21N2O3S (M-Br)+ 297.1273, found 297.1273.

(E)-3-Bromo-4-methyl-1-(tosylamino)pentan-2-one O-tert-butyloxime [(E)-8e-Br]:
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 0.95 (d, J = 6.4 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H), 1.24 (s, 9H), 2.10-2.19 (m, 1H), 2.44 (s, 3H), 3.61 (dd, J = 5.5, 13.7 Hz, 1H), 3.84 (dd, J = 7.8, 13.7 Hz, 1H), 4.30 (d, J = 9.1 Hz, 1H) 5.27-5.30 (m, 1H), 7.32-7.34 (m, 2H), 7.74-7.77 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 20.5, 21.3, 21.5, 27.4, 32.5, 39.4, 61.5, 80.5, 127.2, 129.8, 136.3, 143.7, 152.2. IR (neat): 3289, 2977, 2930, 2873, 1597, 1453, 1411, 1388, 1366, 1331, 1261, 1164, 1118, 1093, 975, 858, 813, 667 cm-1. HRMS (EI): Calculated for C13H19N2O3S (M-C4H8Br)+ 283.1116, found 283.1107.

(E)-3-Bromo-4-methyl-1-(tosylamino)pentan-2-one O-isopropyloxime [(E)-8f-Br]:
White solid. Mp 59-60 °C. 1H NMR (400 MHz, CDCl3): δ = 0.94 (d, J = 6.9 Hz, 3H), 1.11 (d, J = 6.4 Hz, 3H), 1.18 (d, J = 6.4 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H), 2.07-2.18 (m, 1H), 2.43 (s, 3H), 3.61 (dd, J = 5.0, 13.7 Hz, 1H), 3.82 (dd, J = 8.3, 13.7 Hz, 1H), 4.25-4.34 (m, 2H), 5.25 (dd, J = 5.0, 8.2 Hz, 1H), 7.31-7.36 (m, 2H), 7.72-7.76 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 20.6, 21.3, 21.5, 32.5, 39.2, 61.1, 76.9, 127.2, 129.8, 136.2, 143.7, 153.0. IR (neat): 3290, 2975, 2930, 2873, 1456, 1330, 1164, 1118, 1094, 977, 815, 668 cm-1. HRMS (EI): Calculated for C16H25N2O3S (M-Br)+ 325.1586, found 325.1580.

(Z)-3-Bromo-4-methyl-1-(tosylamino)pentan-2-one O-isopropyloxime [(Z)-8f-Br]:
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 0.78 (d, J = 6.9 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 1.17 (d, J = 6.4 Hz, 3H), 1.89-1.98 (m, 1H), 2.40 (s, 3H), 3.80 (dd, J = 5.9, 16. 5 Hz, 1H), 4.03 (dd, J = 4.6, 16. 5 Hz, 1H), 4.26 (sept, J = 6.4 Hz, 1H), 4.89 (d, J = 10.1 Hz, 1H), 5.23-5.26 (m, 1H), 7.27-7.29 (m, 2H), 7.74-7.76 (m, 2H).13C NMR (126 MHz, CDCl3): δ = 19.4, 21.1, 21.4, 21.4, 21.5, 32.5, 42.2, 49.7, 76.8, 127.2, 129.7, 136.4, 143.5, 150.3. IR (neat): 3284, 2974, 2930, 2873, 1598, 1457, 1335, 1163, 1119, 1094, 1006, 872, 814, 669 cm-1. HRMS (EI): Calculated for C16H25N2O3S (M-Br)+ 325.1586, found 325.1592.

Typical procedure (Table 6, entry 4)
A solution of 2-isobutyl-1-tosylazetidin-3-one (3e) (28.1 mg, 0.10 mmol) in CH2Cl2 (1.0 mL) was added to a solution of titanium tetrabromide (73.5 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) at 0 oC. The reaction mixture was allowed to warm to ambient temperature with stirring for 17 h. The reaction was quenched with sat. aq. NaHCO3. The whole mixture was diluted with EtOAc (5.0 mL). The mixture was filtered through a Celite pad. The layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL x 3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by preparative TLC on silica gel (n-hexane/CH2Cl2/Et2O = 4/3/2) to give 1-bromo-5-methyl-3-(tosylamino)hexan-2-one (6e) (32.2 mg, 89%).

1-Bromo-3-(tosylamino)butan-2-one (6b):
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 1.33 (d, J = 6.3 Hz, 3H), 2.41 (s, 3H), 3.90 (d, J = 13.3 Hz, 1H), 3.99 (d, J = 13.3 Hz, 1H), 4.24-4.31 (m, 1H), 5.34 (d, J = 7.4 Hz, 1H), 7.29-7.31 (m, 2H), 7.71-7.73 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 19.0, 21.5, 30.7, 55.1, 127.1, 129.9, 136.5, 144.1, 200.4. IR (neat): 3264, 2930, 1730, 1597, 1495, 1422, 1332, 1160, 1093, 1035, 955, 875, 814, 667 cm-1. HRMS (EI): Calculated for C9H12NO2S (M-C2H2BrO)+ 198.0589, found 198.0586.

1-Bromo-3-(tosylamino)pentan-2-one (6c):
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 7.3 Hz, 3H), 1.52-1.63 (m, 1H), 1.81-1.91 (m, 1H), 2.42 (s, 3H), 3.84 (d, J = 13.2 Hz, 1H), 3.93 (d, J = 13.2 Hz, 1H), 4.18-4.23 (m, 1H), 5.39 (d, J = 8.3 Hz, 1H), 7.29-7.31 (m, 2H), 7.71-7.73 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 9.3, 21.5, 25.8, 31.1, 60.4, 127.2, 129.8, 136.4, 144.0, 200.2. IR (neat): 3276, 2973, 2937, 2879, 1730, 1598, 1494, 1424, 1334, 1163, 1091, 1050, 1009, 908, 813, 773, 670, 570 cm-1. HRMS (EI): Calculated for C12H16BrNO3S (M)+ 333.0034, found 333.0036.

1-Bromo-4-methyl-3-(tosylamino)pentan-2-one (6d):
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 0.74 (d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 2.07-2.15 (m, 1H), 2.41 (s, 3H), 3.78 (d, J = 13.2 Hz, 1H), 3.83 (d, J = 13.2 Hz, 1H), 4.16 (dd, J = 5.1, 9.2 Hz, 1H), 5.36 (d, J = 9.2 Hz, 1H), 7.28-7.30 (m, 2H), 7.69-7.71 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 16.3, 19.7, 21.5, 30.4, 31.7, 64.2, 127.3, 129.7, 136.3, 143.9, 200.2. IR (neat): 3250, 2965, 2931, 2901, 2873, 1742, 1647, 1447, 1394, 1325, 1168, 1092, 1029, 876, 812, 682, 584 cm-1. HRMS (EI): Calculated for C11H16NO2S (M-C2H2BrO)+ 226.0902, found 226.0902.

1-Bromo-5-methyl-3-(tosylamino)hexan-2-one (6e):
Colorless semisolid. 1H NMR (400 MHz, CDCl3): δ = 0.78 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 1.29-1.51 (m, 2H), 1.67-1.76 (m, 1H), 2.40 (s, 3H), 3.85 (d, J = 13.2 Hz, 1H), 3.94 (d, J = 13.2 Hz, 1H), 4.16-4.22 (m, 1H), 5.40 (d, J = 8.7 Hz, 1H), 7.27-7.29 (m, 2H), 7.70-7.72 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ = 21.0, 21.5, 23.0, 24.4, 31.4, 41.3, 57.9, 127.3, 129.8, 136.2, 144.0, 201.0. IR (neat): 3281, 2959, 2871, 1732, 1598, 1494, 1421, 1335, 1162, 1092, 961, 926, 815, 706, 669 cm-1. HRMS (EI): Calculated for C12H18NO2S (M-C2H2BrO)+ 240.1058, found 240.1052.

ACKNOWLEDGEMENTS
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, of the Japanese Government, and grants from the Japan Science and Technology Agency are also gratefully acknowledge.

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