34 Org. Synth. 2012, 89, 34-43 Published on the Web 8/24/2011

© 2012 Organic Syntheses, Inc.

DISCUSSION ADDENDUM for:

2-Trimethylsilylethanesulfonyl Chloride (SES-Cl)

Me3Si

NaHSO3PhCO3t-Bu

aq. MeOH50 °C

Me3SiSO3Na

SOCl2cat. DMF

0 °C to rtMe3Si

SO2Cl

Prepared by Joshua R. Sacher and Steven M. Weinreb.*1

Original article: Weinreb, S. M.; Chase, C. E; Wipf, P.; Venkatraman, S.

Org. Synth. 1997, 75, 161.

Sulfonamides are among the most stable amine protecting groups that

are able to tolerate a broad range of reaction conditions. This stability,

however, can sometimes be problematic for protecting group removal, often

requiring harsh conditions. The 2-(trimethylsilyl)ethanesulfonyl (SES) group

provides a sulfonamide that combines the compatibility with many synthetic

transformations with relatively benign removal conditions. The chemistry of

reactions involving the SES group has previously been reviewed;2

herein, we

report some of the more recent examples of its use in methodology and total

synthesis.

The SES group can be installed on a primary or secondary amine

using 2-(trimethylsilyl)ethanesulfonyl chloride (SES-Cl) and a base,

typically a tertiary amine or sodium hydride.3 An alternate procedure using

silver cyanide has been used to improve yields in difficult protections.4

Generally, cesium fluoride in DMF or tetrabutylammonium fluoride (TBAF)

in acetonitrile at elevated temperature is sufficient to remove the SES

group,3 producing TMS-F, ethylene, sulfur dioxide, and the free amine.

Additionally, the SES group can be cleaved by HF,5

tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF),6 or

refluxing 6 N HCl.7 In certain special cases, judicious selection of the

deprotection strategy can lead to different products, as demonstrated in the

formation of either pyrrole 2 or pyrroline 3 from the corresponding SES-

protected pyrroline 1 (Scheme 1).8

DOI:10.15227/orgsyn.089.0034

Org. Synth. 2012, 89, 34-43 35

NSES

F- or base

MeO2C

RHN

MeO2C

R HF, 0 °CH2N

MeO2C

R

F

12 3

Scheme 1

In addition to its use in introducing a protecting group, SES-Cl can

also effectively acidify an amine nitrogen and simultaneously provide a

leaving group, as demonstrated in a synthesis of L-azetidine-2-carboxylic

acid (9), a naturally occurring non-proteogenic amino acid.9 N-Sulfonylation

of amino alcohol 4 with SES-Cl, followed by treatment of the resulting bis-

SES compound 5 with base, gave the orthogonally-protected cyclic amino

acid 6 (Scheme 2). The SES and t-butyl ester protecting groups were

removed selectively with TBAF or TFA, to yield amine 7 and acid 8,

respectively, while global deprotection to form amino acid 9 was

accomplished with HF.

HO NH2

CO2tBu SES-Cl (2 eq)

Et3N, DMF, 0 °C66%

SESO NH

CO2tBu

SESCs2CO3, MeCN

rt, 12 h, 97%or

20 min, μW, 99%

N

CO2tBu

SES

TBAF

75%

TFA

99%

HF0 °C

97%

NH

CO2tBu

N

CO2H

SES

NH

CO2H

L-azetidine-2-carboxylic acid (9)

4 5 6

6

7 8

Scheme 2

Although the traditional manner of SES group installation involves

protection of an existing amine, it has become increasingly common to use

related derivatives to introduce a SES-protected nitrogen into a molecule.

One of the most common SES derivatives, 2-

(trimethylsilyl)ethanesulfonamide (SES-NH2), is easily prepared from the

chloride by reaction with anhydrous ammonia10

or ammonium hydroxide.11

36 Org. Synth. 2012, 89, 33-43

SES-NH2 has been shown to be effective in palladium-catalyzed

sulfonamidations involving electron deficient aryl and heteroaryl halides

(Scheme 3).12

Both aryl bromides 10 and chlorides 11 give good to excellent

yields of the corresponding aryl sulfonamides 12 and 13, and the reaction

tolerates a wide range of functionality.

XR

Br

H2N SESPd(OAc)2, Xantphos

Cs2CO3, dioxane100–120 °C

67–98%

XR

HN

SES

X

X

R

Cl

X

X

R

HN

SES

X = C, NR = H, COR, CO2R, CHO, CN, F, NO2, CF3

10

11

12

13

Scheme 3

SES-NH2 has also been N-alkylated in high yield with benzyl alcohol

(14) under ruthenium13

and copper14

catalysis to give benzyl sulfonamide 15

(Scheme 4). When benzylic acetate 16 was used in place of the alcohol, the

sulfonamide alkylation to form 17 has been shown to take place rapidly at

ambient temperature.15

OH

orCu(OAc)2, K2CO3air, 150 °C, 12 h

94%

NH

SES+

Ru/Fe3O4, K2CO3150 °C, 12 h

95%SES NH2

SES NH2 OAc

MeO

NH

MeO

SESCu(OTf)2, t-BuOOAc

DCE, 25 °C, 6 h78%

+

14 15

16 17

Scheme 4

SES-Sulfonamides bearing a terminal alkene moiety can undergo a

cyclization in the presence of a metal catalyst or oxidant (Scheme 5). For

example, utilizing a chiral copper catalyst, Chemler and coworkers

Org. Synth. 2012, 89, 34-43 37

performed an enantioselective carboamination of 18, which they proposed

occurs via a single-electron mechanism involving radical 19 to form

hexahydro-1H-benz[f]indole 20.16

In contrast to the 5-exo cyclization observed with metal catalysts,

Michael and coworkers demonstrated that oxidative cyclization of 21 with

hypervalent iodine gave solely the 6-endo product 24.17

A plausible

rationalization for this transformation involves opening of an oxidatively-

formed aziridinium intermediate 22 with trifluoroacetate resulting in the

observed endo selectivity. Hydrolysis of the trifluoroacetate 23 gave the

SES-protected hydroxypiperidine 24. In this system, the SES protecting

group gave slightly better yields than the corresponding tosyl, or 2- and 4-

nosylsulfonamides.

NH

SESPhI(OTFA)2, TFA

CH2Cl2, rt, 24 h94%

NSES

OR

NH

SES

PhPh

Cu(OTf)2, (R,R)-Ph-Box

K2CO3, MnO2PhCF3, 120 °C, 24 h

93%, dr >20:1, 83% ee

NSES

Ph

NSES

Ph

NSES

23 R = TFA24 R = H

18 19 20

21 22

Scheme 5

Iodosulfonamidation methodology using SES-NH2 and a cationic

iodine complex developed by Danishefsky18

was recently adopted by

Jurczak and Chaladaj in a formal synthesis of galantinic acid (25) (Scheme

6).19

Activation of the enol ether 26 with I(sym-coll)2PF6, followed by

opening of the iodonium intermediate by SES-NH2, gave the

iodosulfonamide 27 with good diastereoselectivity. Under basic aqueous

conditions, sulfonamidoalcohol 29 was produced by hydrolysis of the SES-

aziridine intermediate 28. Reductive opening of the pyran ring, protection of

the resulting diol as the acetonide, and hydrogenolysis of the PMB group

gave advanced intermediate 30 that could easily be converted to galantinic

acid (25).

38 Org. Synth. 2012, 89, 33-43

O

AcO OPMB I(sym-coll)2PF6CH2Cl2

71%, 93% ee

SES NH2

O

AcO OPMB

I

HNSES

Et3N

THF/H2Ort, 12 h

O

AcO OPMB

NSES

O

AcO OPMB

HN

SES

OH3 steps

O O

OHNH

SES

OH

60% from iodosulfonamide

OH OH

OHNH2

OH O

galantinic acid (25)

26 27

28 29

30

Scheme 6

SES-sulfonamide has also been used in aziridination reactions,

typically as the derived ([N-SES]imino)phenyliodinane (SESN=IPh)20

or in

a one-pot procedure using SES-NH2 and PhI=O.21

Recently, a catalytic

asymmetric modification of this aziridination was used by Trost and

colleagues in a total synthesis of (–)-oseltamivir (31) (Scheme 7).22

The

choice of sulfonamide and catalyst in the aziridine formation was a key in

this concise synthesis. Of the sulfonamides examined, only SES-NH2,

coupled with a bulky rhodium catalyst, were found to give satisfactory

results in the conversion of diene 32 to aziridine 33. Regioselective opening

of 33 with 3-pentanol then gave the corresponding ether 34, which was

acetylated and deprotected to give the free base of (–)-oseltamivir (31).

Org. Synth. 2012, 89, 34-43 39

NPhth CO2Et

H2N SESRh2(esp)2 (2 mol%)

PhI(O2CCMe3)2MgO, PhCl, 0 °C to rt

86%NPhth CO2Et

NSES

BF3•OEt2

3-pentanol75 °C65%

NPhth CO2Et

HN

O

SES

1) Ac2O DMAP, Py μW, 150 °C, 1h, 84%

2) TBAF, THF, rt, 95%

3) H2NNH2 EtOH, 68 °C, 100% H2N CO2Et

AcHNO

(–)-oseltamivir (31)

32 33

34

Scheme 7

Recently, Komatsu and coworkers developed a high yielding, metal-

free sulfonamide aziridination method using SES-NH2 and t-butyl

hypoiodite to convert styrene (35) into SES-aziridine 36 (Scheme 8).23

In a

screening of sulfonamides, SES-NH2 was found to be superior to 2-

nitrophenyl-, n-butyl-, and p-toluenesulfonamides. The authors note that the

SES group is particularly useful in aziridine chemistry because it can be

removed without intervention of undesirable side reactions.

H2N SES

t-BuOCl, NaI

MeCN, rt, 3 h97%

NSES

35 36

Scheme 8

Due to the electron-withdrawing nature of the sulfonamide moiety,

SES aziridines are useful substrates for ring opening reactions. For example,

in a synthesis of (+)-preussin (37), SES-aziridine 39 was opened by the

lithium anion of allyl sulfone 38 to give SES-sulfonamide 40.24

Isomerization of the alkene to intermediate 41 by treatment with TBAF at

elevated temperature promoted a stereoselective 5-endo-trig cyclization that

took place with concomitant SES removal. The resulting pyrrolidine 42 was

then converted to the natural product 37 in 3 steps.

40 Org. Synth. 2012, 89, 33-43

n-C9H19

NSES

Ph

PhO2S n-BuLiTHF/TMEDA, -78 °C

95%

n-C9H19

HNSES

PhO2S

Ph

TBAF

n-C9H19

HNSES

PhO2S

PhNH

n-C9H19

PhO2S

Ph

THF, 65 °C78%

N

Ph

HO

(+)-preussin (37)Me

3 steps

38 39 40

41 42

Scheme 9

2-(Trimethylsilyl)ethanesulfonyl azide (SES-N3), which is easily

prepared by reaction of SES-Cl with NaN3 in acetone,25a

has also been used

in metal-catalyzed aziridination reactions. For instance, Katsuki and

coworkers used SES-N3 to effect an asymmetric transformation of alkenes

43 to aziridines 44 using a chiral ruthenium-salen catalyst (Scheme 10).25

Interestingly, SES-N3 showed higher enantioselectivity than the

corresponding 2- or 4-nosylazides, while maintaining a similar yield.

RRu(salen)CO (1-5%)

R = Ph, 4-BrPh, C6H13, CO2Bn, CON(OMe)Bn, PhC C

28-100%, 77-99% ee RN

SESN3 SES

43 44

Scheme 10

SES-N3 has also been shown to participate in alkyne-azide 1,3-dipolar

cycloaddition reactions (Scheme 11). Thus, in the presence of a catalytic

amount of CuI and 2,6-lutidine, the reaction of the azide with

phenylacetylene (45) proceeds smoothly to give the 4-phenyl 1,2,3-triazole

46.26

By changing the base to triethylamine and adding an alcohol to the

reaction mixture, the corresponding N-protected imidate 48 can be isolated.27

If water is used, the acylated sulfonamide 49 is obtained in high yield.28

The

Org. Synth. 2012, 89, 34-43 41

reactions involving alcohol and water most likely proceed through addition

to a transient ketenimine intermediate 47.

SES N3

CuI (10 mol %)CHCl3

2,6-lutidine NN

N

Ph

SES

Ph25 °C, 12 h

84%

PhOBn

NSES

H2O, Et3NPh

HN

OSES

BnOH, Et3N

0 °C, 12 h84%

25 °C, 12 h97%

45

46

48

49

NSESX

Ph

47X = H or Cu

Scheme 11

N-Acyl-SES-sulfonimides can also be obtained from carboxylic acids

and SES-N3 via a one-pot, three-step sequence (Scheme 12).29

For example,

activation of acids 50 with t-butyl chloroformate, followed by treatment with

lithio trimethylsilyl thiolate, and methanolysis of the resulting silylated

compound gives the thioacid, which is immediately combined with SES-N3

to give the N-acylated sulfonimides 51. These sulfonimides can be N-

alkylated and the SES group can be selectively removed under mild

conditions.

BocHN

OR

OH

O1) t-butyl chloroformate, 2,6-lutidine, THF, 0 °C, 30 min

2) TMS-SLi, THF, 0 °C3) SES N3

BocHN

OR

NH

OSES

51a: R = H, 94%51b: R = Bn, 96%

50a: R = H50b: R = Bn

Scheme 12

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Steven M. Weinreb was born in Brooklyn, and grew up in Rochester, NY. He did his undergraduate work at Cornell University, and received a doctorate from the University of Rochester with Marshall Gates in 1967. He then held NIH Postdoctoral Fellowships at Columbia University during 1966-67 with Gilbert Stork and at MIT during 1967-70 with George Büchi. He began his independent scientific career at Fordham University in New York City as an Assistant Professor of Chemistry in 1970. In 1978, he joined the faculty at Penn State and was named Russell and Mildred Marker Professor of Natural Products Chemistry in 1987. Throughout his career he has been involved in research on the total synthesis of natural products, heterocyclic chemistry and the development of new synthetic methods

Joshua Sacher was born in Wilmington, Delaware in 1984. He obtained his B.S. degree in biochemistry from the University of Delaware in 2005. While at Delaware, he did undergraduate research with Douglass Taber and had an internship at Cephalon, Inc. He then joined the Weinreb group at Penn State University, where he is currently pursuing his Ph.D degree.