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

Article abstract of DOI:10.1080/00397911.2015.1137943

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.

Full text of DOI:10.1080/00397911.2015.1137943

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Efficient and Mild Swern Oxidation Using a New
Sulfoxide and bis(Trichloromethyl)carbonate
Xiaojing Ye, Hongliang Fu, Jiahao Ma & Weihui Zhong
To cite this article: Xiaojing Ye, Hongliang Fu, Jiahao Ma & Weihui Zhong (2016): Efficient and
Mild Swern Oxidation Using a New Sulfoxide and bis(Trichloromethyl)carbonate, Synthetic
Communications, DOI: 10.1080/00397911.2015.1137943
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Date: 12 January 2016, At: 04:56

Efficient and mild Swern oxidation using a new sulfoxide and
bis(trichloromethyl)carbonate
Xiaojing Ye1, Hongliang Fu1, Jiahao Ma1, Weihui Zhong1
1Collaborative Innovation Center of Green Pharmaceutical Engineering, College of
Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P.R. China
Corresponding author: Weihui Zhong, Collaborative Innovation Center for Green
Pharmaceutical Engineering, College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, P. R. China. E-mail: weihuizhong@zjut.edu.cn.
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 condition which afford the corresponding
aldehydes or ketones in good yields. It’s noteworthy that the re-oxidation of the
isolated byproduct sulfide V could be further recycled in Swern oxidation.
KEYWORDS: Swern oxidation, Alcohols, Sulfoxide, Bis(trichloromethyl)carbonate,
Sulfide
INTRODUCTION
1

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 by applying activated DMSO in the oxidation of
various alcohols to produce carbonyls has been successfully developed by Swern et al
since 1976,[2] in particular oxalyl chloride is recognized as the most powerful
“activator”[3] and applied in the preparation of medicinal intermediate.[4a-4e]
Unfortunately, the condition of Swern reaction is relatively harsh which usually
requires the reaction to be performed under lower temperature and the byproduct
dimethyl sulfide is the highly volatile compound with 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-1,3,5-triazine,[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 -30 oC but the generation of dimethyl sulfide was still observed. In 2008, an
on-line reactor was designed to enable a high-temperature semi-continuous process
possible. [11]
2

In this article, we wish to report a new oxidation system which contained 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 at -15 oC for the oxidation of primary aromatic alcohols, as well as -10 oC for
the oxidation of secondary aromatic alcohols. To our delight, the byproduct
4-(2-(2-(methylthio)ethyl)-4-nitrophenyl)morpholine V generated in our system is
odorless which 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 -15 oC (Figure 1), in which the byproduct
methyl(phenethyl)sulfane was still stinking. In order to reduce and eventually
eliminate the reaction odor, the basic group such as morpholine on aromatic cycle was
further introduced which might benefit the isolation of our product and the recovery of
the byproduct.
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 of hair which 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
3

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 the byproduct benzyl chloride
(b) was also detected due to the excess amount of BTC was applied. Moreover，the
excess BTC was used at higher temperature (entries 5, 6), resulting in the formation of
more byproduct benzyl chloride. Furthermore the reaction temperature was increased to
0 oC, only trace amount 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). So we choose -15 oC 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
8-9).
It’s worth pointing out that simple ice salt bath could be used to control the reaction
temperature (about -15 oC), which is thought to be a big advantage compared to the
original Swern oxidation system (usually around -60 oC) or other alternative methods
4

(lower than -30 oC).[7-10] Another improvement of our method is that the byproduct
sulfide V derived from sulfoxide I has no stink odor and it turns out to be less volatile.
It’s worth mentioning that the sulfide V could be recovered by adjusting pH with the
recovery of 90% and re-oxidized with 30% H2O2 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 oC 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 oC or -5 oC,
entries 9-16) to give aromatic ketones. No obvious electronic effect was observed
(entries 2-6 or entry 10, entries 12-14). The oxidations of secondary aliphatic alcohols
could be carried out under -15 oC to afford the desired products (entries 19-20) with
good yields. Unfortunately, the oxidations of primary aliphatic alcohols were still
required to be performed at -30 oC 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 oC. In general, our method is more
efficient for the oxidations of secondary aromatic alcohols above -15oC, which could be
used for the selective oxidation of alcohols.
5

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 the
similar condition, 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 (Figure 2). We suspected the key intermediate C in our method might
be more stable than A therefore the high reaction temperature could be tolerated.
The proposed mechanism was 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 converted from intermediate C. The increase of the reaction temperature
(0 oC, Table 1, entry 7, or higher) resulted that none of the desired product was
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
6

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.
CONCLUSION
A novel Swern oxidation system, derived from the new type of sulfoxide
4-(2-(2-(methylsulfinyl)ethyl)-4-nitrophenyl)morpholine (I) with bis(trichloromethyl)
carbonate, displays good reactivity towards the oxidation of aromatic alcohols to
achieve the corresponding carbonyl compounds in good yields under mild condition.
Moreover, the inodorous byproduct 4-(2-(2-(methylthio)ethyl)nitrophenyl)morpholine (V)
could be easily isolated, re-oxidized and reused in Swern oxidation.
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 uncorrected. Optical ratations were determined by using an
AUTOPOL V Polarimeter. 1H NMR and 13C NMR spectra were recorded on a Varian-400
MHz spectrometer at 400 and 100 MHz for solution in CDCl3 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. Less solution mass spectra were obtained
with a Trace DSQ mass spectrometer in ESI mode. High resolution mass spectra were
acquired with an Agilent 6210 TOF mass spectrometer.
7

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 CH3SNa (9.07 g, 25.9 mmol) was added dropwise over 0.5 h at rt. The flask
was heated to 60oC and the reaction was monitored by TLC until completed. A 30%
aqueous solution of H2O2 (3.15 g, 27.8 mmol) was added dropwise over 0.5 h at rt. and
then the reaction mixture was heated to 30oC in an O2 atmosphere. After stirred for 1h,
the reaction was completed. EtOH was recovered by vacuum distillation, the mixture was
extracted with EtOAc (15 mL x 2), decanted, and washed with brine. After drying over
Na2SO4 and concentration, the crude was purified by flash chromatography (SiO2;
CH2Cl2). 4-(2-(2-(methylsulfinyl)ethyl)-4-nitrophenyl)morpholine I was acquired, an
orange red liquid (4.20 g, 76%).
I: 1H NMR (400 MHz, CDCl3): δ 7.99 (dd, J1 8.8 Hz, J2 2.4 Hz, 1H), 7.84 (m, 1H), 6.27
(d, J 8.8 Hz, 1H), 3.94 – 3.84 (m, 2H), 3.79 – 3.66 (m, 4H), 3.51 – 3.38 (m, 2H), 3.07 (t,
J 8.4 Hz, 2H), 2.97 – 2.80 (m, 2H), 2.58 (s, 3H ). 13C NMR (100 MHz, CDCl3): δ 156.8,
137.7, 129.5, 126.3, 120.5, 103.3, 68.8, 63.6, 54.8, 53.0, 46.9, 39.3, 27.2. LRMS (ESI+):
m/z = 299.3 [M+H]+, 321.3 [M+Na]+. HRMS (ESI): calcd. for C13H18N2O4S [M+Na]+
321.0893; found 321.0879.
Typical Procedure For The Oxidation Of Alcohols
8

A solution of BTC (0.41 g, 1.39 mmol) in dry CH2Cl2( 5 mL) was cooled in ice salt bath
under an atmosphere of N2, A solution of I (1.24 g, 4.17 mmol) in dry CH2Cl2( 5 mL) was
added dropwise for 0.5 h, at -15oC. Stirring was continued for 0.5 h, a solution of benzyl
alcohol (0.3 g, 2.78 mmol) in dry CH2Cl2(5 mL) was added dropwise for 0.5 h, at -15oC.
After stirred for 0.5 h, Et3N (0.84 g, 8.34 mmol) was added slowly while the temperature
should be controlled below -15oC. 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 x 2), decanted.
The product was acquired after organic layer was concentrate and purified by flash
chromatography (SiO2; 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 Co-Product
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 CH2Cl2 (15
mL x 2), decanted, and washed with brine. The byproduct
4-(2-(2-(methylthio)-ethyl)-4-nitrophenyl)-morpholine V was recovered after
concentration (90%). Treated V with 30% aqueous solution of H2O2 at r.t. and then the
reaction mixture was heated to 30oC in an O2 atmosphere. After stirred for 1h, the
reaction was completed. EtOH was recovered by vacuum distillation, the mixture was
9

extracted with EtOAc (15 mL x 2), decanted, and washed with brine. After drying over
Na2SO4 and concentration, the crude was purified by flash chromatography (SiO2;
CH2Cl2), (94%).
V: 1H NMR (400 MHz, CDCl3): δ 7.98 (dd, J1 8.8 Hz, J2 2.4 Hz, 1H), 7.82 (d, J 2.4 Hz,
1H), 6.26 (d, J 8.8 Hz, 1H), 3.76 (t, J 8.4 Hz, 2H), 3.69 – 3.60 (m, 4H), 3.43 (t, J 5.2 Hz,
2H), 3.06 (t, J 8.4 Hz, 2H), 2.65 (t, J 6.4 Hz, 2H), 2.11 (s, 3H). LRMS (ESI+): m/z =
283.0 [M+H]+.
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%.
ACKNOWLEDGEMENTS
We thank the National Natural Science Foundation of China (No. 21276238) for financial
support.
REFERENCES
[1] Daisuke, T.; Masayuki, T.; Katsuhiko, M.; Togo, H. Tetrahedron 2012, 68,
6849-6855.
[2] Omura, K.; Sharma, A. K.; Swern, D. J. Org. Chem. 1976, 41, 957-962.
10

[3] Mnacuso, A. J.; Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 2480-2482.
[4] (a) Robl, J. A.; Sulsky, R. B.; Augeri, D. J.; etc. US 6395767. 2002-05-28. (b) Huang,
D. F.; Li, D. M. CN 102101850. 2013-06-12. (c) Liu, J. W.; Wang, Z. P.; Guo, S. X.; etc.
CN 103420951. 2013-12-04. (d) Reznik, S. K.; Leighton, J. L. Chem. Sci. 2013, 4,
1497–1501. (e) Zou, J. F.; Huang, W. S.; Li, L.; Zheng, X.; Zheng, Z. J.; Yang, K. F.; Xu,
L. W. RSC Adv. 2015, 5, 30389–30393.
[5] (a) Liu, Y. Q.; Vederas, J. C. J. Org. Chem. 1996, 61, 7856-7859. (b) Crich, D.;
Neelamkavil, S. J. Am. Chem. Soc. 2001, 123, 7449-7450. (c) Ohsugi, S.; Nishide, K.;
Oono, K. Tetrahedron 2003, 59, 8393-8398. (d) Choi, M. K. W.; Toy, P. H. Tetrahedron
2003, 5, 7171-7176. (e) Tsuchiya, D.; Moriyama, K.; Togo, H. Synlett 2011, 18,
2701-2704.
[6] Luca, L. D.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2001, 66(23), 7907-7909.
[7] Bisai, A.; Chandrasekhar, M.; Singh, V. K. Tetrahedron Lett. 2002, 43, 8355-8357.
[8] Wang, Y.; Wang, C.; Sun, J. Synth. Commun. 2014, 44, 2961-2965.
[9] Nguyen, T. V.; Hall, M. Tetrahedron Lett. 2014, 55, 6895-6898.
[10] Saadati, F.; Yousefi, K. Synth. Commun. 2014, 44, 2818-2825.
[11] McConnell, J. R.; Hitt, J. E.; Daugs, E. D.; Rey, T. A. Org. Process. Res. Dev. 2008,
12, 940-945.
Supplemental data for this article can be accessed on the publisher’s website.
11

Table 1 Optimization of conditions for the oxidation of benzyl alcohol with I in the
presence of bis(trichloromethyl)carbonate
Entry
Temp (oC)
Yield (%) [a]
The mole ratio of Alcohol : I : BTC
a
b
1
-30
-30
-15
-15
-10
-5
1 : 2.1 : 1.1
1 : 2.1 : 0.7
1 : 2.1 : 0.7
1 : 2.1 : 0.4
1 : 2.1 : 0.7
1 : 2.1 : 0.7
1 : 2.1 : 0.7
1 : 1.8 : 0.6
1 : 1.5 : 0.5
1 : 1.2 : 0.4
65
93
91
73
84
36
trace
94
90
74
35
2
trace
trace
trace
15
3
4[b]
5
6
63
7[c]
8
0
trace
trace
trace
trace
-15
-15
-15
9
10[b]
[a]. Yield determined after purification by flash chromatography (SiO2; n-hexane).
[b]. The conversion was less than 80%.
[c]. The sulfoxide I was recovered.
12

Table 2. Swern oxidation of various alcohols using I / BTC [a]
Entry
R1
R2
H
H
H
H
H
Temp(oC)
-15
Products
PhCHO
Yield (%) [b]
91(90)[c]
1
2
3
4
5
6
Ph
4-MeC6H4
4-MeOC6H4
2-ClC6H4
2-NO2C6H4
-15
4-MeC6H4CHO
4-MeOC6H4CHO
2-ClC6H4CHO
2-NO2C6H4CHO
81
-15
80
-15
93
-15
77
-15
76
7
8
-15
-15
70
68
92(89)[d]
9
C6H4
CH3
-10
PhCOCH3
10
11
12
13
14
15
4-MeC6H4
Ph
CH3
Ph
-5
4-MeC6H4COCH3
PhCOPh
80
80
83
81
83
89
-5
4-FC6H4
CH3
CH3
CH3
-10
-10
-10
-10
4-FC6H4COCH3
3,5-(CF3)2C6H3COCH3
4-NO2C6H4COCH3
3,5-(CF3)2C6H3
4-NO2C6H4
16
-10
86
17
18
Ph(CH2)3
H
-15
-15
Ph(CH2)3CHO
trace(30)[e]
25(71)[e]
19
20
-15
-15
70
78
[a]. Reaction conditions: substrates (2.5 mmol), I (3.75 mmol), BTC (1.25 mmol), Et3N (7.5 mmol),
dry CH2Cl2 as solvent (15 mL).
13

[b]. Yield determined after purification by flash chromatography (SiO2; n-hexane).
[c]. The sulfoxide I recovered from co-product V was employed.
[d]. at -5oC.
[e]. at -30oC.
14

Scheme 1. Preparation of 4-(2-(2-(methylsulfinyl)ethyl)-4-nitrophenyl)morpholine I
15

Scheme 2. Selective oxidation of alcohols with I / BTC
16

Scheme 3. A plausible reaction mechanism
17

Figure 1 The sulfoxide we firstly designed and prepared
18

Figure 2 The key intermediates A and C in Swern oxidation
19