SCHOOL OF CHEMISTRY AND LIFE

SCIENCES

SWERN
OXIDATION
Lecturer: Dr. Dao Huy Toan

Student Group
Vũ Tuệ Minh 20211608
Ngô Thị Mai Phương 20211611
Trương Thị Hà Anh 20211586
Phạm Thị Thu Trang 20211618

1
 Table of content

1. Introduction

2. Reaction Mechanism

3. Conditions

4. Examples

2
 1.
Introduction
1. Introduction

The Swern oxidation reaction is a mild oxidation reaction commonly used in organic
chemistry and general organic synthesis that convert a primary alcohol into an aldehyde, and a
secondary alcohol into a ketone.
R1 R1
1. DMSO, TFAA or (COCl)2, solvent
OH O
-1 2. Base (amine Et3N) +1
H H

Primary alcohol Aldehyde

R1 R1
1. DMSO, TFAA or (COCl)2, solvent
OH O
0 2. Base (amine Et3N) +2
R2 R2
Secondary alcohol Ketone

4
2. Reaction
Mechanism
 2. Reaction Mechanism

Reaction mechanism activating DMSO by (COCl)2

Step 1: Activation of DMSO by (COCl)2 - Forming of sulfonium cation
O
Cl O O
Cl CO2
O O Cl Cl Cl
O O Cl O
Cl Cl + CO
S S S O S O S
Cl

Step 2: Reaction with alcohol to form aldehyde or ketone

CH3 H2 Et Et
Cl H3C C N H3C CH2 O
Cl R1 S CH3 -HCl S H S
Et S
S + HO H3C CH3 +
O R1 O R1 O H R1 R2
H3C CH3 H
R2
R2 R2 R1 R2 andehyde or ketone

Kurti, L.; Czako, B. Strategic applications of named reactions in organic synthesis; Academic Press, 2005. 6
 2. Reaction Mechanism

Reaction mechanism activating DMSO by TFAA

Step 1: Activation of DMSO by TFAA

O O
O O CF3CO2
S
O O F3C O CF3 < -30oC H3C O CF3 o H3C CH2
S >-30 C
F3C O CF3
S S O F3C O
H3C CH3 H3C CH3 H3C S CH3 O Pummerer
rearrangement
CH3 O
trifluoroacetoxydime- Side product
thylsulfonium trifluoroacetate

Step 2: Reaction with alcohol to form aldehyde or ketone

Et Et
CH3 H2 N
F3C O H3C C H3C CH2 O
H3C O CF3 R1 S CH3 - CF3COOH S H Et S
S S
+ HO
O O R1 O R1 O H H 3C CH3 +
R1 R2
CH3 O R2 H
R2 R2 R1 R2 andehyde or ketone

Kurti, L.; Czako, B. Strategic applications of named reactions in organic synthesis; Academic Press, 2005. 7
3. Reagents and
Conditions
3. Reagents and Conditions
3.1. Reagents
Oxalyl chloride, Dimethyl sulfoxide (DMSO), and Trifluoroacetic anhydride

O
Cl O O O
S
H3C CH3 O Cl F 3C O CF3
Dimethyl sulfoxide Oxalyl Trifluoroacetic
(DMSO) chloride anhydride

Nucleophil Electrophil
e e

9
 3. Reagents and Conditions
3.1. Reagents
3.1.1. Nucleophile

O O O
S S S
H3C CH3 H3C CH3 H3C CH3

Dimethyl sulfoxide
(DMSO)
Nucleophil
e
Properties: Alternatives:
o DMSO is a versatile solvent - miscible with many organic 6-(methylsulfinyl)hexanoic acid
O-
solvents
S+ COOH
o Dipolar aprotic nature H3C

o Exhibits good thermal stability

o DMSO possesses moderate nucleophilicity
Liu,Y.,Vederas, J.C.(1996).Modification of the Swern Oxidation. The Journal of Organic Chemistry, 61(22), 7856–7859. 10
3. Reagents and Conditions
3.1. Reagents
3.1.2. Electrophile
Properties:
Cl O o Electrophilic carbonyl group
o Exhibits good thermal stability
O Cl o The displacement of chlorine atoms
Oxalyl o Low volatility and stability
chloride

O O Properties:
o Acylating agent
F 3C O CF3 o The trifluoromethyl group is electron-withdrawing

Trifluoroacetic → enhances the electrophilicity of the carbonyl carbon

anhydride o Stable under typical reaction conditions

Omura, K., Sharma, A. K., & Swern, D. (1976). The Journal of Organic Chemistry, 41(6), 957–962. 11
 3. Reagents and Conditions
3.1. Reagents
3.1.2. Electrophile CH3
Cl
THF S
H3C N N H3C O
S O Cl
H3C Cl N Cl -30 C, 30 min N N
Alternative:
Cl N Cl
Cyanuric
Cl
chloride R
OH
N N
R' -30 C, 30 min
Cl N Cl

OH
H3C H3C
R S CH3 TEA R
N N O S
O H3C
Cl N Cl R' -30 C, 30 min R'
Cl

De Luca, L., Giacomelli, G., Porcheddu, A. (2001). A Mild and Efficient Alternative to the Classical Swern Oxidation.
12
The Journal of Organic Chemistry, 66(23), 7907–7909.
3. Reagents and Conditions
3.2. Reaction
3.2.1. Solvent
Conditions
H
Cl H O
Cl O
Dichloromethan Tetrahydrofura Diethyl
e (DCM) n (THF) ether
Fp = -97°C Fp = - Fp (Et2O)
= -116.3°C
108.5°C

Aprotic Low freezing

point
Inert Common

13
3. Reagents and Conditions
3.2. Reaction
3.2.2. Temperature
Conditions
When TFAA is used, the intermediate is unstable
above -30°C
Side reaction:
O Pummerer rearrangement
O O O S
H S S S S S
O CF3 O CF3 O CF3 O CF3 F3C O
CF3CO2
O

When oxalyl chloride is used, the intermediate is unstable

above -60°C (usually conducted at -78 °C -> cryogenic
condition)
Side reaction: Decomposition of chloro(dimethyl)sulfonium ion
OH
Cl O S
R1 R2
S S S
R1 R2

Kurti, L.; Czako, B. Strategic applications of named reactions in organic synthesis; Academic Press, 2005. 14
3. Reagents and Conditions
3.2. Reaction
3.2.3. Procedure
Conditions
• DMSO reacts with TFAA or oxalyl chloride violently, therefore the typical procedure
begins as followed
Low temperature
Slow addition Slow addition
DMSO + TFAA/OC
of alcohol of tertiary
amine
• The efficiency of the oxidation is not influenced by the steric hindrance of the
substrate,OTBS
for example OTBS
DMSO, TFAA; PhO2S
(COCl)2, DMSO; PhO2S
S OH Et3N, -30C S O
Et3N, -78C H
HO O H
OMe OMe y. 92% S
y. 90% S

• The active species chlorosulfonium salt is unstable towards water, therefore the reaction must be
kept anhydrous.
• The reaction also generates a toxic gas (CO) and a foul odorant (Me2S), thus should be carried
out under ventilated fume hoods.

Smith, A. B., III; Wan, Z. J. J. Org. Chem. 2000, 65, Braish, T. F.; Saddler, J. C.; Fuchs, P. L. J. Org. Chem. 1988, 53, 15
3738 3647.
4. Examples
4. Examples
Synthesis of (+)-deoxyneodolabelline (D.R. Williams)
H3C H3C
H H

H H
O O
CH3 CH3
H3C HO H
H H3 C OH H3C H3C
HO OH H H
(COCl)2
A B DMSO, DCM
H H
Et3N O + O
H3C H3 C
H H -78oC CH3 CH3
H3C HO
H HO O H3 C O
O H
O
CH3 CH3 (+)-4,5-Deoxyneodolabelline epi-4,5-deoxyneodolabelline
H3C HO 8%
HO H OH H3C H OH
65%

C D

Mixture of 4 diastereomers (A:B:C:D = 8:2:1:1)

The oxidation of a secondary alcohol functionality of a 1,2-diol to the corresponding α-hydroxy

ketone:
- 1,2-diols are known to be unstable under most oxidation conditions, and often glycol cleavage
is observed
- Under the Swern oxidation conditions, the desired α-hydroxy ketone was isolated in a 65% yield
Williams, D. R., Heidebrecht, R. W., Jr. Total Synthesis of (+)-4,5-Deoxyneodolabelline. J. Am. Chem. Soc. 2003, 125, 1843-1850. 17
4. Examples
Synthesis of (+)-asteltoxin (J.K. Cha et al.)
OH O
O
O O
PMBO (COCl)2 (5 equiv) PMBO Me OH O
DMSO (6 equiv) Steps HO Me
Me H Me H
Et3N (10 equiv) OMe
Me Me
-78oC; 95% HO O O O Me
HO O
H
(+)-Asteltoxin

bis(tetrahydrofuran) bis(tetrahydrofuran)
primary alcohol aldehyde

Convergent total synthesis of (+)-asteltoxin:

- HWE olefination of a bis(tetrahydrofuran) aldehyde with an α-pyrone phosphonate.
- Bis(tetrahydrofuran) aldehyde was prepared by the Swern oxidation of the corresponding
bis(tetrahydrofuran) primary alcohol

Eom, K. D., Raman, J. V., Kim, H., Cha, J. K. Total Synthesis of (+)-Asteltoxin. J. Am. Chem. Soc. 2003, 125, 5415-5421. 18
4. Examples
Synthesis of (+)-isovelleral (Thompson & Heathcock)

O
Me
H Me2S
Me steps MeO2C THF, 25oC
Me
MeO2C Me
O
H

H Pd(OAc)2, PPh3,
i. LDA H CO, MeOH. Et3N,
MeO2C ii. PhNTf2 MeO2C DMF

O
H TfO
H

H HO O H
DIBAL,
H
MeO2C (COCl)2, DMSO
PhMe, THF
Et3N, CH2Cl2 O
MeO2C HO -78oC to r.t.
H H H
(+)-isovelleral

Thompson, S. K.; Heathcock, C. H. (1992). "Total synthesis of some marasmane and lactarane sesquiterpenes". J. Org. Chem. 57 (22): 5979– 19
5989. doi:10.1021/jo00048a036.
4. Examples
Synthesis of Ircinal A (S.F. Martin et al.)
CO2Me CO2Me
CO2Me H H
H
H H
H O H N O H2C H N O
HO N O (COCl)2, DMSO Ph3P=CH2 (xs)

O N THF O N
O N Et3N Boc Boc
Boc -78oC; 89% -78 to 0oC; 63%
H H
O CH2
OH

CHO
H

H OH
Steps N

Ircinal A

Martin, S. F., Humphrey, J. M., Ali, A., Hillier, M. C. Enantioselective Total Syntheses of Ircinal A and Related Manzamine Alkaloids. J. Am. 20
Chem. Soc. 1999, 121, 866-867.
REFERENCES
• Kurti, L., & Czako, B. (2005). Strategic applications of named reactions in
organic synthesis. Academic Press.
• Braish, T. F., Saddler, J. C., & Fuchs, P. L. (1988). Seven-ring annulation. A
linch-pin approach to a tetracyclic precursor of the lathrane diterpenes.
Journal of Organic Chemistry, 53(16), 3647–3658.
• Smith, A. B., & Wan, Z. (2000). Total synthesis of the ansamycin antibiotic
(+)-Thiazinotrienomycin e. Journal of Organic Chemistry, 65(12), 3738–3753.
• Swern oxidation. (n.d.).
https://www.organic-chemistry.org/namedreactions/swern-oxidation.shtm
• Mancuso, A. J., Huang, S., & Swern, D. (1978). Oxidation of long-chain and
related alcohols to carbonyls by dimethyl sulfoxide “activated” by oxalyl
chloride. Journal of Organic Chemistry, 43(12), 2480–2482.
• Omura, K., & Swern, D. (1978). Oxidation of alcohols by “activated” dimethyl
sulfoxide. a preparative, steric and mechanistic study. Tetrahedron, 34(11),
1651–1660.
• Williams, D. R., Heidebrecht, R. W., Jr. Total Synthesis of (+)-4,5-
Deoxyneodolabelline. J. Am. Chem. Soc. 2003, 125, 1843-1850.
• Eom, K. D., Raman, J. V., Kim, H., Cha, J. K. Total Synthesis of (+)-Asteltoxin. J.
Am. Chem. Soc. 2003, 125, 5415-5421.
• Thompson, S. K.; Heathcock, C. H. (1992). "Total synthesis of some
marasmane and lactarane sesquiterpenes". J. Org. Chem. 57 (22): 5979–
5989. doi:10.1021/jo00048a036.
• Martin, S. F., Humphrey, J. M., Ali, A., Hillier, M. C. Enantioselective Total 21
THANK YOU
!

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