Efficient and mild swern oxidation using a new sulfoxide and bis(trichloromethyl)carbonate

ABSTRACT A new type of sulfoxide, 4-(2-(2-(methylsulfinyl) ethyl)-4-nitrophenyl)- morpholine (I), was designed and prepared in good yield. Upon the combination of I and bis(trichloromethyl)carbonate, the Swern oxidation of primary and secondary alcohols was significantly promoted under mild conditions, which afforded the corresponding aldehydes or ketones in good yields. It is noteworthy that the reoxidation of the isolated by-product sulfide V could be further recycled in Swern oxidation. GRAPHICAL ABSTRACT


Introduction
The oxidation of alcohols to the corresponding aldehydes or ketones is one of the most fundamental and important reactions widely used in the laboratories for manufacturing and productivity. [1] The method for applying activated dimethylsulfoxide (DMSO) in the oxidation of various alcohols to produce carbonyls has been successfully developed by Swern et al., [2] and in particular oxalyl chloride is recognized as the most powerful activator [3] and is applied in the preparation of medicinal intermediates. [4a-4e] Unfortunately, the conditions of the Swern reaction are relatively harsh and usually require the reaction to be performed under lower temperature. The by-product dimethyl sulfide is a highly volatile compound with a foul smell. Lots of efforts have been contributed to develop modified reagents to overcome these drawbacks. Several research groups endeavored to develop the odorless Swern oxidation system by using a modified sulfoxide to replace DMSO, although the low reaction temperature was still required. [5a-5e] Upon switching the activated reagents from oxalyl chloride to other reagents such as 2,4,6-trichloro-1,3,5triazine, [6] dichlorotriphenylphosphorane, [7] trichloro(methyl)-silane, [8] 1,1-dichlorocycloheptatriene, [9] and 4-methylbenzene-1-sulfonyl chloride, [10] the reaction temperature could be slightly raised to À 30 °C but the generation of dimethyl sulfide was still observed. In 2008, an online reactor was designed to enable a high-temperature semicontinuous process possible. [11] In this article, we report a new oxidation system containing a new type of sulfoxide, 4-(2-(2-(methylsulfinyl)ethyl)-4-nitrophenyl)morpholine I (Scheme 1), and bis(trichloromethyl) carbonate (BTC) as the activator. The reaction temperature could be increased to −15 °C for the oxidation of primary aromatic alcohols, as well as to À 10 °C for the oxidation of secondary aromatic alcohols. To our delight, the by-product 4-(2-(2-(methylthio)ethyl)-4nitrophenyl)morpholine V generated in our system is odorless and could be easily recovered and recycled.

Results and discussion
Initially, (2-(methylsulfinyl)ethyl)benzene was designed and prepared for the oxidation of benzyl alcohols at À 15 °C (Fig. 1), in which the by-product methyl(phenethyl)sulfane was still stinky. To reduce and eventually eliminate the reaction odor, a basic group such as morpholine on aromatic cycle was further introduced which might benefit the isolation of our product and the recovery of the by-product.  A new type of sulfoxide, 4-(2-(2-(methylsulfinyl)ethyl)-4-nitrophenyl)morpholine I, was designed and prepared from 2-(2-chloro-5-nitrophenyl)ethanol II by several steps (Scheme 1). The starting material II is a dye intermediate that has been prepared in our previous project. After the substitution from morpholine to generate III, the intermediate IV was then achieved through the subsequent chloration using BTC. Treatment of IV with 20% sodium methyl mercaptide aqueous solution, followed by 30% hydrogen peroxide, gave the target sulfoxide I in 76% yield.
The sulfoxide I was combined with BTC to afford a novel Swern oxidation system, which was tested in the oxidation of benzyl alcohol as a model substrate to screen the optimized condition towards the loading of I and BTC at various temperatures (Table 1).
In entry 1, not only benzaldehyde (a) could be formed but also the by-product benzyl chloride (b) was detected due to the excess amount of BTC was applied. Moreover, the excess BTC was used at higher temperature (entries 5 and 6), resulting in the formation of more by-product benzyl chloride. Furthermore the reaction temperature was increased to 0 °C, and only trace amounts of product a and byproduct b were detected due to the fast decomposition of the generated sulfonium salt and sulfoxide I was almost recovered (entry 7). We choose À 15 °C as the optimum reaction temperature and the ratio of alcohol, sulfoxide I, and BTC was recognized as 1:1.8:0.6 or 1:1.5:0.5 (entries 8 and 9).
It is worth pointing out that a simple ice salt bath could be used to control the reaction temperature (about À 15 °C), which is thought to be a big advantage compared to the original Swern oxidation system (usually around À 60 °C) or other alternative methods (lower than À 30 °C). [7][8][9][10] Another improvement of our method is that the by-product sulfide V derived from sulfoxide I has no stinky odor and turns out to be less volatile. The sulfide V could be recovered by adjusting pH with the recovery of 90% and reoxidized with 30% H 2 O 2 aqueous solution to produce sulfoxide I with excellent yield (94%), which could be reused for the oxidation of substrates in the next round. The scope of this new oxidation method was studied under the optimum condition ( Table 2). The oxidations of the primary aromatic alcohols were carried out at −15 °C to give aromatic aldehydes with good yields (entries 1-8), while the oxidations of secondary aromatic alcohols were carried out at a slightly higher temperature (−10 °C or −5 °C, entries 9-16) to give aromatic ketones. No obvious electronic effect was observed (entries 2-6, 10, 12-14). The oxidations of secondary aliphatic alcohols could be carried out under −15 °C to afford the desired products (entries 19 and 20) with good yields. Unfortunately, the oxidations of primary aliphatic alcohols were still required to be performed at −30 °C and gave the corresponding aldehyde in moderate yields (entry 18). As for long alkyl chain alcohol (entry 17), it was difficult to isolate a pure product due to the formation of byproduct at −30 °C. In general, our method is more efficient for the oxidations of secondary aromatic alcohols above −15 °C, which could be used for the selective oxidation of alcohols. The selective oxidation of alcohols was observed when we treated 1-phenylethanol and benzyl alcohol with the sulfoxide I and BTC. 1-Phenylethanol was transformed into acetophenone while more than 95% benzyl alcohol was recovered (Scheme 2). Under similar conditions, benzyl alcohol was selectively transformed into benzaldehyde in the presence of 4-phenylbutan-1-ol (Scheme 2).
According to the mechanism of the original Swern oxidation, the alkoxysulfonium salt A was the key intermediate and formed as a precursor of the carbonyl compound once alcohol was added (Fig. 2). We suspected the key intermediate C in our method might be more stable than A and therefore the high reaction temperature could be tolerated.
The proposed mechanism is outlined in Scheme 3. Treatment of sulfoxide I with BTC gave an intermediate B, which was then reacted with alcohols to form the key intermediate C, with the emission of carbon dioxide and hydrogen chloride. However, the gas emission was not obvious before the base was added under lower temperature. A plausible equilibrium between B and C was proposed in which B is sufficiently stable to be further    Table 1, entry 7, or higher) resulted in none of the desired product being detected, possibly due to the decomposition of intermediate B to recover the sulfoxide I. On the other hand, once triethylamine was added at lower temperature, the equilibrium status between B and C was broken and the intermediate D could be formed, which was then transformed into the carbonyl compounds and the sulfide V.

Experimental
All starting materials were commercially available except II and were used without further purification. Melting points were determined on a Büchi B-540 capillary melting-point apparatus and are uncorrected. Optical rotations were determined by using an AUTOPOL V Polarimeter. 1 H NMR and 13 C NMR spectra were recorded on a Varian 400-MHz spectrometer at 400 and 100 MHz for solution in CDCl 3 with tetramethylsilane (TMS, δ 0) as an internal standard. The chemical shifts (δ) were reported in ppm and coupling constants J were expressed in hertz. Low-resolution mass spectra (LRMS) were obtained with a Trace DSQ mass spectrometer in electrospray ionization (ESI) mode. High-resolution mass spectra (HRMS) were acquired with an Agilent 6210 TOF mass spectrometer.

Typical procedure for the preparation of I
A solution of IV (5.0 g, 18.5 mmol) in EtOH (10 mL) was stirred, and a 20% aqueous solution of CH 3 SNa (9.07 g, 25.9 mmol) was added dropwise over 0.5 h at rt. The flask was heated to 60 °C and the reaction was monitored by thin-layer chromatography (TLC) until completed. A 30% aqueous solution of H 2 O 2 (3.15 g, 27.8 mmol) was added dropwise over 0.5 h at rt and then the reaction mixture was heated to 30 °C in an O 2 atmosphere. After stirring for 1 h, the reaction was completed. EtOH was recovered by vacuum distillation, and the mixture was extracted with EtOAc (15 mL � 2), decanted, and washed with brine. After drying over Na 2 SO 4 and concentration, the crude was purified by flash chromatography (SiO 2 ; CH 2 Cl 2 ). 4-(2-(2-(Methylsulfinyl)ethyl)-4-nitrophenyl)morpholine I was acquired as an orange-red liquid (4.20 g, 76%).

Typical procedure for the oxidation of alcohols
A solution of BTC (0.41 g, 1.39 mmol) in dry CH 2 Cl 2 (5 mL) was cooled in an ice-salt bath under an atmosphere of N 2 . A solution of I (1.24 g, 4.17 mmol) in dry CH 2 Cl 2 (5 mL) was added dropwise for 0.5 h, at −15 °C. Stirring was continued for 0.5 h, and a solution of benzyl alcohol (0.3 g, 2.78 mmol) in dry CH 2 Cl 2 (5 mL) was added dropwise for 0.5 h, at −15 °C. After stirring for 0.5 h, Et 3 N (0.84 g, 8.34 mmol) was added slowly while the temperature should be controlled below −15 °C. When the reaction was completed, 10% HCl solution in water was added dropwise until the pH of the reaction solution reached 2 under ice bath. The mixture was extracted with n-hexane or petroleum ether (10 mL � 2), decanted. The product was acquired after organic layer was concentrated and purified by flash chromatography (SiO 2 ; n-hexane). (0.27 g, 92%). The water layer was used for the recovery of V and the excess I.

Typical procedure for the recovery and re-oxidized of coproduct 4-(2-(2-(methylthio)ethyl)-4-nitrophenyl)morpholine V
An aqueous solution of 25% NaOH was added dropwise in the water layer from the oxidation procedure until the pH reached 12. The mixture was extracted with CH 2 Cl 2 (15 mL � 2), decanted, and washed with brine. The by-product 4-(2-(2-(methylthio)ethyl)-4-nitrophenyl)-morpholine V was recovered after concentration (90%). Compound V was treated with 30% aqueous solution of H 2 O 2 at rt, and then the reaction mixture was heated to 30 °C in an O 2 atmosphere. After stirring for 1 h, the reaction was completed. EtOH was recovered by vacuum distillation, and the mixture was extracted with EtOAc (15 mL � 2), decanted, and washed with brine. After drying over Na 2 SO 4 and concentration, the crude was purified by flash chromatography (SiO 2 ; CH 2 Cl 2 ), (94%).

Typical procedure for the reuse of I
The procedure was the same as the typical procedure for the oxidation of alcohols. The yield of benzaldehyde was 90%.

Funding
We thank the National Natural Science Foundation of China (No. 21276238) for financial support.