sulfoximines: structures, properties and synthetic ... · thiazyl trifluoride (n ≡sf3).13 they...

REVIEW 1

Synthesis 2000, No. 1, 1–64 ISSN 0039-7881 © Thieme Stuttgart · New York

Sulfoximines: Structures, Properties and Synthetic ApplicationsMichael Reggelin,* Cornelia ZurFachbereich Chemie und Pharmazie der Johannes Gutenberg-Universität Mainz, Duesbergweg 10−14, 55099 Mainz, GermanyFax +49(6131)394778; E-mail: [email protected]; Homepage: http://cortex.chemie.uni-mainz.deReceived 8 July 1999Dedicated to C. R. Johnson, the pioneer of sulfoximine chemistry

Abstract: This review presents a comprehensive treatment of sulf-oximine chemistry particularly emphasising synthetic develop-ments and structural work after 1985. Following a brief introduc-tion, the structures and properties of sulfoximines and metallatedsulfoximines are discussed. The second section deals with the prep-aration of sulfoximines emphasising new methods. The main part ofthe review is concerned with reactions of sulfoximines. The materi-al in this section is organised based on the reactivity pattern dis-played by the various sulfoximines. Therefore they are groupedroughly into three classes of compounds. The first group of sulfox-imines comprises compounds acting as C-nucleophiles, the secondone contains electrophilic sulfoximines and the last group is madeup of sulfoximines being useful as (chiral) ligands particularly fortransition metals. Finally the ability of sulfoximines to act as “chiralchemical chameleons” and their rôle in biological and medicinalchemistry is briefly discussed.

Introduction and Classification1 Structure and Properties of Sulfoximines2 Preparation of Sulfoximines2.1 Classical Routes and Newer Developments2.1.1 From Sulfoxides and Sulfilimines2.1.2 From Sulfonimidoyl halogenides and Sulfonimidates2.1.3 From other Sulfoximines2.1.3.1 N-Substituted Sulfoximines2.1.3.2 Vinyl Sulfoximines2.1.3.3 Allylic Sulfoximines2.2 Heterocyclic Sulfoximines2.3 Remarks on the Synthesis of Chiral, Non-Racemic Sulf-

oximines3 Reactions of Sulfoximines3.1 Type I Sulfoximines: Nucleophilic Sulfoximines3.1.1 Type Ia3.1.1.1 Diastereoselective Alkylations and Additions of Lithiated

Sulfoximines to R'R''C=X3.1.1.2 Resolution of Chiral Ketones and Directed Additions3.1.1.3 Alkyliden Transfer Reactions Including Ylide Chemistry3.1.2 Type Ib: Enolates Bound to the Sulfoximine N-Atom3.1.3 Type Ic: 2-Alkenyl Sulfoximines in Asymmetric Synthe-

sis3.1.3.1 Allyl Sulfoximine-Allyl Sulfinamide Rearrangements3.1.3.2 Hydroxyalkylation of 2-Alkenyl Sulfoximines3.2 Type II Sulfoximines: Electrophilic Sulfoximines3.2.1 Type IIa: Conjugate Addition of Nucleophiles3.2.2 Type IIa: Pericyclic Reactions3.2.3 Type IIb: The Sulfonimidoyl Group as a Chiral Leaving

Group3.3 Type III Sulfoximines: Ligands4 Miscellaneous5 Conclusion and Outlook

Key words: sulfoximines

Introduction and Classification

In the years between 1946 and 1950 a series of papers waspublished all dealing with a toxic factor occurring in manyproteins treated with "Agene", which is essentially nitro-gen trichloride1−6 (Figure 1).

Figure 1 Identification of the toxic factor isolated from "agenized"zein or wheat and first presentation of the sulfonimidoyl moiety as anew functional group.

In a rather tedious procedure Bentley and Whitehead wereable to isolate this substance and identified it as a sulfur-containing compound with the empirical formulaC5H12N2O3S which yielded, after reduction with Raney-

2 M. Reggelin, C. Zur REVIEW


nickel, a-aminobutyric acid.4 From their experiments theyconcluded that "a molecule, C5H12N2O3S, can be regardedformally as being derived from methionine sulphoxide bythe addition of =NH, or from methionine sulphone by thereplacement of O by =NH".4 Furthermore, they recog-nised that "in such a molecule there is clearly the possibil-ity that the sulphur atom is asymmetric".4 Indeed theywere able to separate two diastereomeric forms of the newcompound with the new functional group by fractionatedcrystallisation of the corresponding picrates. The newclass of compounds was called sulphoximines following aproposal of Sir R. Robinson7 and the toxic factor was giv-en the name methionine sulphoximine. Although since1965 the official IUPAC name is sulfoximide8 this desig-nation is seldomly used. The term sulfoximine has wonrecognition instead and will be used throughout this arti-cle, too. Since these days of pioneering work, which wasinitiated by a biological effect, there was a rapidly increas-ing interest in the chemical properties of this new func-tional group (Figure 2).

Although the number of publications related to the phy-siological properties of mainly two sulfoximines - me-thionine sulfoximine MSO and buthionine sulfoximineBSO (Figure 3, see also Section 4) - always exceeded thenumber of papers related to structural and synthetic as-

Biographical Sketches

Cornelia Zur was born inBerlin in 1970 and graduat-ed from the University ofRostock in 1994. In 1998she obtained her PhD at thesame university, working inthe group of Prof. R. Mieth-chen on the topic of perfluo-roalkylated carbohydrates.Since March 1998 she is

postdoc in the group of Prof.M. Reggelin at the Universi-ties of Frankfurt/Main andMainz (Germany). At themoment she is concernedwith the combinatorial syn-thesis of polyketide precur-sors on soluble polymericsupports.

Michael Reggelin was bornin Elbingerode/Harz in1960. He received his un-dergraduate education at theuniversities of Giessen andGöttingen and graduatedfrom the University of Kiel,receiving his PhD with Prof.D. Hoppe in 1989. He start-ed his current position asProfessor of Chemistry atMainz University in 1998after postdoctoral work atthe Technical University ofMunich with Prof. H.

Kessler, and Habilitation in1997 at the University ofFrankfurt in Prof. Griesing-er's group. Professor Regge-lin is currently GoeringVisiting Professor of Organ-ic Chemistry at the Univer-sity of Wisconsin, Madison.

Professor Reggelin's re-search interests are: (a) De-velopment of newstereoasymmetric reactions(asymmetric allyl transfer,aldol reactions, asymmetriccatalysis with helical-chiral

ligands). (b) NMR spectros-copy on reacting systemsand reactive intermediates(allyllithium, allyltitaniumand allylpalladium com-pounds). (c) Synthesis ofpolyketide libraries basedon iterative asymmetric al-dol reactions on polymericsupports. (d) Asymmetricsynthesis of highly substi-tuted azaheterocyclic com-pounds as topologicalmimics of beta-turns.

1970 1980 1990 2000

0

100

200

300

400

500

Year

Num

ber

ofpublic

ations

Figure 2 Development of the number of publications related to sulf-oximines in the time between 1967 and 1999. Black bars: Publicati-ons including work on methionine and buthionine sulfoximine. Redbars: Publications excluding work on methionine and buthionine sulf-oximine.

REVIEW Sulfoximines: Structures, Properties and Synthetic Applications 3


pects, the hope for finding useful chemical applicationswas and still is unbroken.

Figure 3 The most important biologically active sulfoximines.

Indeed, sulfoximines promise to be an extremely versatileclass of compounds as is illustrated in Figure 4.

Figure 4 Features of sulfoximines accounting for their unusualchemical versatility.

The whole unit is electron-withdrawing, which, taken to-gether with the depicted reactivity pattern, justifies thefollowing classification of sulfoximines and their reac-tions:

Type I: Sulfoximines as C-Nucleophiles

This class can be subdivided into 3 subtypes differing inthe site where the reaction with the electrophile takesplace (Figure 5).

Type Ia: The reaction takes place at the Ca-carbon nextto the sulfoximine moiety.

Type Ib: The reaction takes place at a negatively po-larised carbon atom adjacent to the sulfoximine nitrogen.

Type Ic: The reaction takes place at the vinylogous po-sition at C-3.

The C-substituent denoted with Cu, which almost all sul-foximine based reagents have in common, is an unreactivecarbon substituent, typically an aromatic system.

Type II: The Sulfoximine Reacts as an Electrophile

Figure 6 General structure of Type II sulfoximines: The sulfoximi-ne acts as an electrophile. RS: Sulfur-bound substituent, Cu: unreacti-ve C-substituent (e.g. aryl, tBu), RN: Nitrogen-bound substituent.

In this class two subtypes have to be discussed:

Type IIa: The sulfonimidoyl moiety remains in the re-action product.

Two major reactivities are encountered here: Michael ad-ditions of nucleophiles to vinyl sulfoximines and pericy-clic reactions with the sulfonimidoyl substituted fragmentbeing the electron deficient reaction partner.

Type IIb: The sulfonimidoyl group acts as a (chiral)leaving group.

The reactions of this type of sulfoximine are characterisedby the uptake of a nucleophile followed by elimination ofthe sulfonimidoyl group. Contrasting the reactivity of theType I reagents here the sulfoximine plays the rôle of anelectrophile. This ambivalent behaviour has led Trost tospeak of them as "chemical chameleons" (see Section 4).9

Type III: The sulfoximine serves as a (chiral) ligand.

Figure 7 General structure of Type III sulfoximines: The sulfoximi-ne serves as a (chiral) ligand. RS: Sulfur-bound substituent eventuallybearing additional coordination sites, Cu: unreactive C-substituent(e.g. aryl, tBu), RN: Nitrogen-bound substituent, may also be hydro-gen.

Figure 5 General structure of Type I sulfoximines: The sulfoximi-ne acts as a C-nucleophile. Structural fragments in brackets may bepresent and stand for special cases for Ra and RN, respectively. Cu:unreactive C-substituent (e.g. aryl, tBu)

EWG

M

R S

R

R

M

RO

N

C

R

Ru

E

Z

αβ

2N

1N

Type I: Sulfoximines as C-Nucleophiles

Type Ia

Type Ib

Type Ic

Centre of Reactivity Optional Units

S

O

N

C

R

u

R2N

1N

RS

(+)

Type IIa: The sulfonimidoyl moiety remains in the product.

Type IIb: The sulfonimidoyl behaves as a chiral leaving group.

S

O

N

Cu

R RS N

M M



This class of sulfoximines is characterised by a residue(RS) providing additional coordination sites and a sulfox-imine N-atom bound to a metal or exposing coordinationsites via an attached substituent (RN). Compounds of thiskind have been synthesised for their own right as well aspotential ligands in metal catalysed asymmetric transfor-mations (see Section 2.1.3.1 and 3.3).

1 Structure and Properties of Sulfoximines

Sulfoximines are constitutionally and configurationallystable compounds which can be manipulated without spe-cial care. In 1998 a search in the Cambridge StructuralDatabase (CSD)10 yielded 131 answers from which thedata presented in Table 1 could be extracted.

As expected, the coordination sphere of the sulfur centreis a slightly distorted tetrahedron with S−N bond lengths(d = 153.7 pm) lying clearly between a typical S−N singlebond and the S−N triple bond (d = 144.1 pm) found in thefirst fully characterised thiazyne synthesised by Yoshimu-ra et al. in 1998.11, 12 Thiazynes are constitutional isomersof sulfoximines whose chemistry is largely unexplored asopposed to the rich inorganic chemistry emanating fromthiazyl trifluoride (N≡SF3).13 They are rather unstable andtheir exposure to acid, base or heat rapidly rearrangesthem to the corresponding sulfoximines.12 It is interestingto note that already in 1969 Schmidbaur had discussed thethiazyne structure 3 as a possible alternative to the sulfox-imine structure 2 of the corresponding trimethylsilylatedcompounds (Figure 8).14

Figure 8 Sulfoximine 2 and thiazyne 3 being constitutionalisomers.

But, together with the IR data compiled in Table 2 (e.g.compare 10 and 11), there is clear evidence for the doublebond character of the S−N and S−O bonds in sulfox-imines. Furthermore Table 2 provides spectral informa-tion (IR, 1H-, 13C-, 15N-, 33S NMR) on a selected subset ofsulfoximines including two bis-sulfoximines from the au-thors unpublished work.15, 16 Although the parent com-pound 4 (Table 2) has been synthesised as early as 1950by Bentley7 the first X-ray crystallographic determinationof its structure did not appear before 199717 (CSD: RE-GYEH). The IR spectra of sulfoximines are characterisedby two strong absorption bands for the O=S=N unit (typ-ical values are: nas ≈ 1200 cm−1 and ns ≈ 1100 cm−1) andone for the NH stretch vibration (for the "free sulfox-imines") somewhere between 3100 cm−1 and 3400 cm−1

(in solution). In the 1H NMR spectra of sulfoximines theC-bound aliphatic protons in the a-position of the sulfon-imidoyl moiety typically resonate in the range of d = 3.0-3.5 ppm depending on the nature of the N-bound substit-uent. In the carbon spectra the corresponding C-atoms ap-pear in the range of 40 and 50 ppm. Characteristic shiftvalues for a vinylic fragment bound to a sulfonimidoylunit (13)15 as well as for an allylic sulfoximine (14)16, 18

can also be taken from Table 2.

Due to the amphoteric character of the sulfoximine nitro-gen, the acidic protons in the a-position, and the potential-ly stereogenic sulfur atom (C1 ≠ C2), compounds bearingthis functional group are expected to be characterised bya rich and versatile chemistry (Figure 4). Of special inter-est for C−C bond forming processes is the acidity of the a-protons, which can be fine-tuned by the substituent on thesulfoximine nitrogen. A large body of work related to thequestion of how sulfur stabilises a carbanionic centre ad-jacent to it exists in the literature. Elegant experimentalwork on the related a-sulfonyl "carbanions",25−28theoretical29, 30 and spectroscopical studies31−34 have shedsome light into the dark of these reactive intermediates.From these studies a structural picture emerges that can bedescribed as follows (Figure 9):

From base induced H/D-exchange experiments it can bededuced that the observed retention of configuration at the

Table 1 Average Bond Lengths and Bond Angles for 131 Sulfoximines and One Thiazynea

a The data for thiazyne 1 was taken from ref. 11.

Sulfoximines Thiazyne 1

Sulfoximines: C-S S-O S-N C-S-C C-S-O C-S-N O-S-N

d [pm] 177.2 144.4 153.7 θ [°] 104.9 108.8 107.0 119.3

Thiazyne 1:d [pm] 179.8 161.6 144.1 θ [°] 104.0 97.5 116.15 122.03



Table 2 Spectroscopic Data and CSD-Refcodes10 of Selected Sulfoximines

a Data in the first column: S-bound methyl group.b Data in the second column: chemical shift of the S-bound ipso-C. c Cambridge Structural Data Base.10

Compound IR [cm–1] NMR CSDc Remarks

# nas(SON) ns(SON) n(NH) d(1H) [ppm]a d(13C)a,b [ppm]

Me2S(O)NH 4 1195 1043 3190/3331 3.05 2.43 (NH) 45.26 REGYEH Ref. 17, 19

Me2S(O)NH2Br 5 n.d. n.d. 3132/2989 n.d. – n.d. REGXUW Ref. 17

Me2S(O)NBr 6 1183 1025 – 3.19 – 41.02 – Ref. 20

Me2S(O)NSO2Me 7 1211 1089 – 3.44 – 44.41 – Ref. 21

Me2S(O)NSiMe3 2 1285/1304 1157/1160 – 2.97 0.13 (SiCH) n.d. – Ref 12, 22

MePhS(O)NH 8 1220 1090 3250 2.9 3.45 (NH) – Ref. 23

MePhS(O)NMe 9a 1240 1145 – 3.08 2.66 (NCH) 44.8 138.7 – d(13C): 29.4 (NMe)Ref. 24

Ph2S(O)NH 10 1225 1097 n.d. – n.d. – 143.5 – d(15N): 88.5212

Ph2(S≡N)OMe 11 1340 – – 3.7 (OCH) – – – d(15N): 126.43d(13C): 48.2 (OMe)

1315 1416, 18

NMR IR [cm–1] NMR IR [cm–1] NMR

δ(33S, sulfolan)= -84 ppm, δ(33S, CS2) = +287 ppm

1235/1135 δ(1H) [ppm] J [Hz] δ(13C) [ppm] 1240/1110 δ(1H) [ppm] J [Hz] δ(13C) [ppm]

3205/3155 HA: 6.37 AM: 0.5 C1: 140.91 HA/HB: 3.86HX: 5.77

AX/BX: 7.3MX: 10.2

C1: 60.85

HM: 5.94 AX: 16.4 C2: 125.76 HM: 5.01 NX: 17.1 C2: 126.12

HX: 6.72 MX: 9.5 HN: 5.20 MN: 1.2 C3: 122.89

1516 1615

R = Phth R = Val(OH) δ(HA)= δ(HA’) = 3.395 ppm, δ(HB)= δ(HB’) = 3.472 ppm

δ(1H) = 5.47 ppm δ(1H) = 4.85 ppm JAA’ = 1.8 Hz

δ(13C) = 74.35 ppm δ(13C) = 70.24 ppm JAB = JA’B’ = -13.4 Hz

JAB’ = JA’B = +12.3 Hz

νas(SON) = 1230 cm-1 νas(SON) = 1260 cm

-1 JBB’ = 1.8 Hz

νs(SON) = 1100 cm-1 νs(SON) = 1130 cm

-1 δ(13C) = 51.96 ppm; ν(NH) = 3320, 3280, 3260 cm-1



metallated carbon is a result of a restricted rotation aroundthe Ca−S bond. Alternative mechanisms involving a pyra-midal configurated Ca-atom were excluded.

In the preferred conformations 17 and 19 with respect tothis bond, the non-bonding electron pair of the metallatedcarbon is positioned gauche between the two heteroatomsbound to sulfur in a sulfone37, 38 or a sulfoximine.35,37,39−43

For the latter this conformational preference gives rise totwo planar-chiral conformers being epimers at the sametime. A view along the Ca-S bond of the lithiated allylsulfoximine 22, which has been characterised by X-raystructural analysis,40 nicely demonstrates this typical con-formation.

Both conformers (epimers) are stabilised by bonding in-teractions between two orbitals in antiplanar orientation:the nC-orbital at the metallated carbon and the emptys*S-C-orbital which is the antibonding orbital of the bondbetween sulfur and the non-metallated carbon. This kindof stabilisation is confirmed by ab initio calculations,29, 30

and experimental data. The doubly 13C-labelled lithiosulfoximine 20 has been studied by low-temperature13C NMR spectroscopy (Figure 10).35 From the analysisof the temperature dependence of the signals from thediastereotopic methyl groups a barrier of diastereotopo-merisation of 9.2 kcal/mol (203 K) was calculated. Inagreement with the mechanism of stabilisation discussedabove, in the lithiotriflone 21 (Figure 9) with its lowenergy s*-orbital this barrier increases to 17.2 kcal/mol(239 K) as shown by Gais et al. in 1989.36

NMR spectroscopic investigations of lithiosulfides,-sulfoxides, -sulfones, and -sulfoximines have been per-

formed by Chassaing and Marquet as early as in 1978.32

Gais et al. extended this work to the lithiated sulfoximines25 (CSD: FISZOW)10, 39 and 20 (Figure 10).35

In 1996 Reggelin et al. studied the lithio- and titanosulfox-imines 28 and 29 by 2D NMR and were able to derive asolution structure of 29 from distance geometry calcula-tions (ensemble DDD)45-47 using NOE-derived distancedata.44, 48

An important NMR parameter related to the degree of hy-bridisation and planarisation of the metallated carbon isthe 1JCH-coupling with its directly bound proton as hasbeen emphasised by the early work of Marquet, Chassaingand Waack.49, 50 Lithiated sulfoximines, as their sulfonecounterparts, show a marked solvent dependency on their1JCH-couplings. In the lithio sulfoximine 25 this couplingis found to be increased by 5 Hz with respect to the neutralstarting material in cyclohexane, but this difference in-creases to 15 Hz in THF indicating a nearly planar Ca inthis solvent.39 Not unexpectedly and in accordance withthe data derived from a lithiated allyl sulfone38 Reggelinet al. found a 1JCH of 166 Hz and 164 Hz for 28 and 29, re-spectively, which corresponds to an increase in this cou-pling in comparison to the neutral compounds by 24 Hz inboth cases (Table 3).48

Obviously, the additional conjugation by the allylic frag-ments leads to a further flattening of the metallated carbonwhich can be regarded from this data as being completelyplanar. The chemical shift data given in Table 3 illuminatestructural aspects of the lithiated sulfoximines 28 and 29as well as those of the titanated species 30 and 31, respec-tively. The pronounced high-field-shift of the g-carbon

O

X

R

φ = +90° φ = -90°

nC

σ*S-C

S

RH

XO

σ*S-CnC

S

HR

XO

σ*S-CnC

(negative hyperconjugation) Achiral, Cs - symmetric (if X = O) (negative hyperconjugation)

ZIXWAE

H3C

S

O

NMe

Ph

H3C

20

PhO

H3C

S

O

CF321

H3C

H3C

H

S

O

NSiMe3

Ph22 22

17 18 19

∆G = 9.2 kcal / MolTop35

∆G = 17.2 kcal / Mol23936

H

Figure 9 Metallated sulfoximines: Mode of stabilisation, preferred conformations and barriers of epimerisation. ZIXWAE: CSD-Code for22,10 a partial structure of which is drawn to demonstrate the typical conformation of lithiated sulfoximines.



Figure 10 Metallated sulfoximines structurally characterised by NMR and/or X-ray. The deprotonation sites are denoted by filled circles,stars at C-atoms indicate 13C-isotopes. Bold upper-case letters within brackets denote CSD-refcodes.10 Numbers in square brackets designatethe corresponding literature references.

Table 3 Selected NMR-Data of Metallated Allyl Sulfoximines

a For side-chains R(1) and R(2) see Figure. 10. R(3)*: (R)-CH(iPr)CH2OTBS.51 SM: starting material.

Compounda Ha [ppm] Hr [ppm]

Hs [ppm] Ha [ppm] Ca [ppm] Cr [ppm] Cs,a [ppm] JCa

H [Hz]

28

3.10 (10.8 Hz)

SM:

4.10/3.98

6.44

SM:

5.79

3.23 (5.6 Hz)

SM:

5.14 (10.6 Hz)

3.60 (16.5 Hz)

SM:

4.99 (17.0 Hz)

60.41 (+0.41)

SM:

60.00

139.3 (+11.3)

SM:

128.00

81.11 (–41.6)

SM:

122.70

166 (+24)

SM:

142

29

3.10 (10.7 Hz)

SM:

3.89/3.87

6.42

SM:

5.65

3.22 (12.8 Hz)

SM:

5.04 (10.3 Hz)

3.56 (16.4 Hz)

SM:

4.86 (17.1 Hz)

60.81 (+0.79)

SM:

60.02

136.8 (n.d.)

SM:

n.d.

80.86 (–42.1)

SM:

122.95

164 (+24)

SM:

140.0

30

3.77 (10.9 Hz)

SM:

4.08/3.94

6.04

SM:

5.78

4.64(11.0 Hz)

SM:

5.13 (10.0 Hz)

4.74 (16.9 Hz)

SM:

4.99 (17.2 Hz)

65.56 (+4.66)

SM:

60.90

132.7 (+4.43)

SM:

128.27

118.5 (–4.71)

SM:

123.21

144 (+3)

SM:

141

31

3.33 (10.5 Hz)

SM:

4.08/3.94

5.24

SM:

5.78

4.47 (10.4 Hz)

SM:

5.13 (10.0 Hz)

4.82 (16.6 Hz)

SM:

4.99 (17.2 Hz)

69.61 (+8.71)

SM:

60.90

132.5 (+4.23)

SM:

128.27

110.6 (–12.6)

SM:

123.21

136 (–4)

SM:

141



(Cs,a) of the first two compounds (-41.6 and -42.1 ppm,respectively) can be traced back to a considerable increasein electron density evoked by the metallation. The allylicmoiety of 28 and 29 can thus be described as a delocalisedp-electron system which is corroborated by the 1H-chem-ical shifts of Ha and the terminal Hs- and Ha-protons. Thechemical shift of the a-carbon Ca, which is apparently un-affected by the lithiation can be explained as the conse-quence of two counteracting effects. The high-field shiftevoked by the increase of the electron density is counter-balanced by a low-field shift caused by the increased s-character of that carbon after metallation. The latter effectis nicely reflected by the enormous increase of the 1JC

aH-

coupling (24 Hz, Table 3). The large coupling constantsbetween Ha and Hr (∼ 11 Hz for all compounds) give astrong hint to a transoid orientation around the Ca-Crbond. Similar observations were described by Gais for alithioallyl sulfone.38

Things are markedly different with the titanium com-pounds 30 and 31.44 Both were prepared from the corre-sponding lithium compounds by transmetallation usingClTi(OiPr)3 (see Section 3.1.3.2 for preparative applica-tions).18, 52 It is not clear yet whether they are slowly inter-converting Ca-epimers or interconverting aggregates ofhomochiral units. From their 13C-shifts at the allyl termi-nus and from their 1JCH-couplings it can be deduced thatthese species are best described as a-titanated allyl sulfox-imines. A 1H NMR study on an isopropyl substituted, ti-tanated sulfoximine led Gais et al. to similarconclusions.53 Contrasting the synthetic potential of these

titanosulfoximines (3.1.3.2), our knowledge about theirstructure and dynamics has to be described as dramatical-ly underdeveloped.

Up to now only five X-ray structures of a-metallated sulf-oximines were described in the literature (Figure 11).

The first lithiosulfoximine fully characterised by X-raystructural anlysis was [(S)-24]4 • 2 TMEDA published byGais in 1986.35 Unlike the structures of related lithiatedsulfones, 24 crystallises as a tetramer. Two pairs of lithi-um atoms and sulfonimidoyl methanid units are coordi-nated differently. Most interesting is the observation thateach of the Li-atoms in the second pair is coordinated bythree sulfoximine N-atoms and one anionic carbon. This(weak) Li-C bond (d = 249 pm) was not found in the cor-responding lithiosulfone. The C- and N-trimethylsilylatedlithiosulfoximine 25 crystallises without donor ligands asa tetrameric aggregate with a Li4O4-cube.

39 Every Li-atomis pentacoordinated by O- and C-atoms of a first, the N-and O-atom of a second and the O-atom of a third sulfon-imidoyl unit. The metallated carbon atom is positioned17 pm above the plane defined by its substituents, whichentails a marked pyramidalisation.

In 1995 and 1996 two X-ray structural analyses of lithiat-ed allyl sulfoximines appeared in the literature. The al-ready mentioned 3-methylbut-2-enyl substituted sulf-oximine 22 (Figure 10 and 11) crystallises in the presenceof 12-crown-4 as a pair of the complexed lithium cation[Li(12-crown-4)2]

+ and a sulfonimidoyl substituted allylicanion.40 A partial structure of the latter is shown in Figure11 together with its CSD-refcode (ZIXWAE).10 As ex-

Figure 11 Schakal-plots and CSD-refcodes of metallated sulfoximines characterised by X-ray.10

FECRAG

TISMIR

TUDHEF

24

FISZOW

25 27

26

ZIXWAE

22

26 (TISMIR) [ref. 41]

LiS

Ph

O

MeN

Ph

PhH

24 (FECRAG) [ref. 35]

S

Ph

O

MeN

H

H Li

M

( ) [ ]25 FISZOW ref. 39

S

Ph

O

e3SiN

SiMe3

H Li

T

22 (ZIXWAE) [ref. 40]

S

Ph

O

MSN

Me

MeH

Li

27 (TUDHEF) [ref. 42]

S

Ph

O

MeN

Ph

Ph

Li



pected, a conformation of the anion is favoured in whichthe p-orbital of the allylic p-system at C1 is orientedgauche to both the oxygen and the nitrogen atom (see alsoFigure 9). The structural changes evoked by the lithiationare compiled in Table 4 by comparison of 22 to a closelyrelated neutral precursor 33.

Noticeable is the almost planar coordination of the metal-lated C1 (q (C2, C1, S) = 124.1°) which is in agreementwith the already discussed NMR results on the allyliclithiosulfoximines 28 and 29 (Table 3). In 1996 Müller etal. published a crystal structure of the 3,3-diphenyl substi-tuted derivative 26 (CSD : TISMIR, Figure 10 and11).10, 41 It crystallises as a centrosymmetric dimer with aneight membered (Li-N-S-O)2-ring as the main structuralelement. This, together with the missing Li-C interac-tions, renders this structure very similar to the ones oflithiosulfones. The first crystal structure of a vinyliclithiosulfoximine 27 was published in 1997, again byMüller et al.42 Compound 27 also crystallises as a cen-trosymmetric, THF-solvated dimer (CSD : TUDHEF,Figure 10 and 11)10 but this time featuring an eight-mem-bered ring with the atomic sequence (Li-C-S-O)2. TheO-atom of one THF molecule, the sulfoximine O- and N-atoms and the metallated carbon are coordinated to thelithium cation in a distorted tetrahedral arrangement.

It should be mentioned that very recently Gais et al. suc-ceeded in the crystallisation of the first titanated allylicsulfoximine.54 Two sulfonimidoyl units are attached tothe central, hexacoordinated titanium atom. Surprisinglynot the sulfoximine oxygen but the nitrogen atoms are co-ordinated to titanium! The synthetic consequences of thistitanium mediated dimerisation of two sulfonimidoylmoieties are discussed in Section 3.1.3.2 of this review.

Finally it should be noted that a-zincated sulfoximines areknown as well.55 Their synthesis, structures and propertieswill be discussed in Section 3.3 (Scheme 125).

2 Preparation of Sulfoximines

Since the days of Bentley and Whitehead a number ofroutes furnishing sulfoximines have been developedwhich may be called "classic routes" from a present day’spoint of view. A large body of work in this context ema-nated from the laboratories of Johnson who was for manyyears the main actor in this field. Many reviews dealingwith sulfoximine chemistry have been published describ-ing its development up to the early 1990s.56-65 For thatreason the discussion of the "pre-1985"-access routes tosulfoximines will be rather brief here to gain space forsome newer developments.

2.1 Classical Routes and Newer Developments

Two main classes of non-sulfoximine starting materialsdiffering in the oxidation state of the central sulfur atomcan be distinguished: sulfoxides 34 and sulfilimines 35(sulfur(IV) compounds) on the one hand (Scheme 1) andsulfonimidoyl halogenides and sulfonimidates (sulfur(VI)compounds) on the other hand (Scheme 9). A third majorsource for sulfoximines of course is the derivatisation ofsome "key sulfoximines" which is of special importancein the field of optically active sulfoximines (see Section2.3).

2.1.1 From Sulfoxides and Sulfilimines

In a way, the oldest method for the oxidative imination ofsulfoxides using hydrazoic acid generated in situ by reac-tion of NaN3 with conc. sulfuric acid is still one of themost important (Scheme 1, Path D).73-76 Despite potentialhazards associated with the application of hydrazoic acid,this method is of major importance for the large scale syn-thesis of the "key sulfoximine" rac-8 (Scheme 2 and Sec-tion 2.3).

Table 4 Structural Changes Evoked by Lithiation of an Allylic Sulfoximine 40

33: C1-S S-O S-N C1-C2 C2-C3

d [pm] 179.6 145.6 151.5 150.7 133.4C1-S-C C1-S-O C-S-N O-S-N C2-C1-S

θ [°] 103.3 110.3 102.8 122.9 110.5

22: C1-S S-O S-N C1-C2 C2-C3

d [pm] 161.9 144.9 151.7 146.6 128.9C1-S-C C1-S-O C-S-N O-S-N C2-C1-S

θ [°] 109.7 110.2 114.0 114.0 124.1



The major disadvantages of this entry are C-S-bond fis-sion in the case of branched alkyl substituents and partialracemisation of non-racemic sulfoximines during the im-ination process. Much more reliable in this respect are re-actions involving nitrenes or at least reactiveintermediates behaving analogously. Famous examplesare iminations involving TsN3

77, 78 (Scheme 1, Path E) orvarious N-amino substituted compounds (Scheme 1, PathH).85-91 An interesting application of this chemistry, go-ing beyond its immediate importance as a source of (opti-cally active) sulfoximines is a thermal fragmentationreaction yielding sterically congested alkenes (Scheme3).87

Scheme 3

In general, the reaction between the nitrene source and thesulfoxide proceeds with retention of configuration at

sulfur68, 85, 92, 93 and thus offers the opportunity to prepareoptically pure sulfoximines from optically pure sulfox-ides. An interesting variant of the tosylimination reactionwas published very recently by Müller and Vogt (Scheme4).94

Scheme 4

With N-tosylimino phenyl iodinane as oxidant and cata-lytic amounts of copper(I) triflate (CuOTf) enantiomeri-cally pure sulfoximines were obtained in high yields withretention of sulfur configuration. Major disadvantages ofthese Path E methods are the difficulties accompaniedwith the removal of the N-bound substituent as exempli-fied by the N-tosylated and phthalimidoylated systems 40and 42 (Scheme 5).

Scheme 5

Scheme 1 Synthesis of sulfoximines from sulfoxides 34 and sulfilimines 35. A: TsN=S=NTs;66, 67 TsN=S=O;66 ArSO2NH2, P4O10, Et3N;68 B:tBuOCl, (-)-Menth-ONa, H2NR

3;69 C: KMnO4;7 MCPBA;70 NaIO4, RuO2;71 H2O2, NaOH;72 D: NaN3, H2SO4;73-76 E: hn or heat or Raney-Cu,heat;77, 78 F: Et3N;79, 80 G: 2 h, r.t., then 10 % NaOH;81-84 H: r.t.85-91

Scheme 2



The detosylation with concentrated sulfuric acid is oftencomplicated by a considerable loss of material and partialracemisation. The sodium anthracenide method intro-duced by Johnson in 1989 works better but only for di-alkyl substituted sulfoximines.95 For the NPht-derivatives42 no deprotection scheme deliberating the "free" sulfox-imines is described in the literature. In view of this situa-tion the new iron(II)-mediated imination procedureinvolving Boc-azide found by Bach et al. seems to bevery promising (Scheme 6).96

Scheme 6

As expected, the imination is completely stereoselective(retention) and the deprotection occurs under typical con-ditions employing trifluoroacetic acid. Complementingthis work some ten years before Reggelin found it advan-tageous to remove the Boc-group in sulfoximines using ei-ther titanium tetrachloride or even better aluminiumtrichloride/anisole (Scheme 7).15

Scheme 7

Complete deprotection occurred within minutes and with-out deterioration of the enantiomeric excess. In a very re-cent publication Bolm et al. demonstrated the usefulnessof these two new metal catalysed imination procedures inthe synthesis of chiral benchrotrenes and ferrocenes.97

The most flexible entry to enantiomerically pure "free"sulfoximines appears to be the MSH-method (Scheme 1,Path G, MSH: o-mesitylene sulfonyl hydroxylamine) 81-83

developed in 1974 by Johnson and co-workers.84 Thehighly reactive, but not unproblematic98 reagent allowsthe transformation of a broad range of (optically active)sulfoxides into the corresponding sulfoximines with com-plete retention of configuration (see Section 3.3).

The oxosulfonium salt from the reaction of DMSO with t-butyl hypochlorite can be substituted with aromaticamines yielding N-aryl sulfoximines (Scheme 1, Path F,R1 = R2 = Me). This method appears not to be as flexibleas the ones involving N-aryl sulfinamides (Scheme 9, PathG via B, R3 = aryl) or as a very recent variant based onpalladium complex catalysed cross coupling reactions99

employing aryl halogenides and free sulfoximines (seeSection 2.1.3.1).

To complete this brief discussion of sulfur(IV)-precursorsfor the synthesis of sulfoximines, the oxidation of sulfil-imines should be mentioned (Scheme 1, Path C).7, 70-72

Sulfilimines 35 are configurationally stable 100-102 aza-an-alogs of sulfoxides which can be synthesised by oxidativeimination of sulfides69 (Scheme 1, Path B) or imination ofsulfoxides (Path A). The latter process offers the opportu-nity to obtain optically active sulfilimines from chiral,non-racemic sulfoxides and iminating reagents such asbis(N-tosyl) sulfurdiimide66, 67, N-sulfinyl-p-toluene sul-fonamide66 or aryl sulfonamides in the presence of P2O5/Et3N.

68 Their oxidation to sulfoximines can be achievedwith a multitude of oxidation agents including KMnO4,

7

MCPBA,70 NaIO4/RuO2,71 and alkaline H2O2.

72 Again,most of these conversions proceed with retention of thesulfur configuration and allow the preparation of opticallyactive sulfoximines. In a recent publication Colonna andCurci employed highly reactive dioxiranes such as dime-thyl dioxirane to oxidise sulfilimines stereoselectivelyand in high yields (Scheme 8).103

Scheme 8

As a major advantage of the dioxiranes as electrophilic O-transfer reagents, the authors emphasised their low ten-dency to N-oxidation, thus reducing the amount ofbyproducts emerging from that side reaction.

2.1.2 From Sulfonimidoyl halogenides and Sulfonimi-dates

Sulfinamides 51, which are easily prepared from sulfinylchlorides 50 (X = Cl) (Scheme 9, Path A) and primaryamines, can be oxidised employing different sources ofelectrophilic chlorine104-106 (Path B). The most conve-nient reagent in this respect seems to be t-butyl hypochlo-rite introduced by Johnson in 1979.105 The resultingsulfonimidoyl chlorides 52 (X = Cl) react with O-nucleo-philes yielding sulfonimidates (X = OR),104, 105 or with N-nucleophiles furnishing sulfonimidamides (X = NR2).

105

Finally they can be used as electrophiles in Friedel-Craftsreactions (Path F) with activated benzene derivatives andin Lewis acid mediated C-C bond forming processes giv-ing rise to the formation of b-oxo sulfoximines (Path E).Unfortunately they are rather sensitive to reduction whichprevents them from being useful in sulfoximine prepara-tions with polar organometallics such as organolithium-or Grignard reagents.107

A special case, however, is the transfer of an ethyl groupfrom EtAlCl2 found by Harmata in 1989 (Scheme 10).

108



A special feature of this process is its tolerance of func-tional groups susceptible to reactions with organometal-lics (e.g. nitro groups). A major disadvantage of course isthe restriction to the synthesis of ethyl sulfoximines.

Scheme 10

Successful ways to circumvent the sulfonimidoyl chlo-ride’s sensitivity towards reduction either is to exchangechlorine for fluorine (yielding sulfonimidoyl fluorides,Scheme 9, 52, X = F)107 or to use sulfonimidates in reac-tions with polar organolithium or -magnesium com-pounds (Scheme 9, Path G). Although open chainsulfonimidates (52, X = OR) suffer from severe draw-backs - especially if chiral, non-racemic sulfoximines arethe targets (see Section 2.3 for details), the cyclic deriva-tives 53, for the first time synthesised in 1992 by Reggelinet al., have proven to be very efficient reaction partners fora variety of organometallic reagents (Scheme 9, PathD).109, 110 They are stable, crystalline compounds whichcan be prepared from different amino acids (R = CH3, iPr,

iBu, Ph) in enantiomerically pure form. Details of thispreparation, their application in the synthesis of opticallyactive sulfoximines and in sulfoximine-based asymmetricsyntheses will be discussed in the appropriate sections ofthis review (Sections 2.3 and 3.1.3.2).

2.1.3 From other Sulfoximines

There are a number of sulfoximines which are best syn-thesised by transformation of other sulfoximines, whichare readily available and easy to functionalise. It is inter-esting to note that there are indeed only "a handful" ofsuch "key sulfoximines" dominating this aspect of sulfox-imine synthesis (Scheme 11).

Scheme 11

Scheme 9 Synthesis of sulfoximines from sulfonimidoyl halogenides and sulfonimidates.



Furthermore, it will turn out that these compounds are the"main actors" in the synthetic applications of sulfox-imines as well (see Section 3).

For the moment, constitutional aspects are discussed inparticular. In a later section (Section 2.3) the relevancy ofthese "key sulfoximines" for the preparation of enantio-merically pure sulfoximines will be stressed.

2.1.3.1 N-Substituted Sulfoximines

The two main routes to N-substituted sulfoximines usingtetracoordinated sulfur as starting material are depicted inScheme 12.

Scheme 12 Main access routes to N-substituted sulfoximines. LG:leaving group, ERn: element E with n attached substituents (ligands).

Via these routes numerous derivatives have been preparedas can be taken from the compilation in Scheme 13.

Due to the rather pronounced acidity of the NH-proton offree sulfoximines (pKa = 24.3)

111 its substitution by elec-trophiles is straightforward. Silylations can be achievedusing the corresponding halides and imidazole112 as a baseor more conveniently just by heating the free sulfoximinewith Et2NSiMe3.

15, 113

For the carbamoylation (to yield compounds of Type III)it proved to be advantageous to deprotonate with potassi-um t-butanolate in THF before adding Boc2O or the chlo-roformate.15 The same is true for alkylations15 (Type IV)with the famous exception of N-methylation which worksbest under Eschweiler-Clark conditions (Scheme 14).114

Scheme 14 N-methylation of the key sulfoximine (S)-8 under Esch-weiler-Clark conditions.

The synthesis of N-transition metal (TS) substituted sulf-oximines (Type VII) is best accomplished by desilylatingamination of the corresponding transition metal halides(Scheme 15).

Scheme 13 Compilation of N-substituted sulfoximines. LnTM:Transition metal atom coordinated by n ligands.

Scheme 15 Transition metal complexes derived from N-trimethylsilyl-S,S-dimethyl sulfoximine 2. Cp* = ethyl tetramethyl cyclopentadienyl.



Employing this strategy, Roesky et al. were able to pre-pare a number of dimethyl sulfoximinato complexeswhich often have been characterised by X-ray struc-tural analysis (the CSD-refcodes are given in theScheme).10, 115, 116 If sulfoximine 2 is treated with chlo-rodiphenyl-phosphane in diethyl ether the diphenylphos-phane 64 is obtained in 99% yield. Its further reactionwith Me3SiN3 furnished the sulfonimidoyl substituted N-trimethylsilyl phosphoranylidene amine 65 which itself isa good ligand in a number of transition metal complexes(Scheme 16).10, 115 It should be pointed out that themode of their preparation is compatible with the synthe-sis of optically active complexes which in turn may be in-teresting in the context of asymmetric catalysis (seeSection 3.3).

In a recent publication Bolm and Hildebrand described avery interesting palladium-complex catalysed N-arylationprocess yielding sulfoximines of Type IV (R = aryl)(Scheme 17).99

Typical reaction conditions are 5 mol% Pd(OAc)2/7.5 mol% rac-BINAP/Cs2CO3 in refluxing toluene. Theyields increased when the aromatic ring was substitutedby electron-withdrawing groups (EWG). Despite its nov-elty this discovery already had some impact on the synthe-sis of another class of very interesting sulfoximines as willbe discussed in Section 2.2.

Finally a high yield process to N-nitro substituted sulfox-imines (Type XII) is worth mentioning (Scheme 18).117

Starting with a number of free sulfoximines 66 Winternitzet al. were able to prepare the corresponding N-nitro sub-stituted derivatives 71. The method proved to be suited foroptically active sulfoximines as well and the derived nitrosulfoximines have been used as "chiral lynchpins" for theconstruction of chiral ring systems9 (see Section 4).

2.1.3.2 Vinyl Sulfoximines

Vinyl sulfoximines have been prepared for the followingreasons:

As precursors for allylic sulfoximines to which they canoften be isomerized (see Section 2.1.3.3)

As Michael acceptors in conjugate addition reactions (seeSection 3.2.1)

As reactants for pericyclic reactions (Diels-Alder reac-tions and 1,3-dipolar cycloadditions, see Section 3.2.2)

Until 1985 1-alkenyl sulfoximines received only limitedattention.118, 119 Attracted by the possibility to use thesechiral unsaturated compounds in cycloaddition reactionsor as electrophiles in conjugate additions Gais et al. devel-oped an "in situ Peterson reaction" for their synthesis(Scheme 19).119

Scheme 19

The enantiomerically pure sulfoximine (S)-9b, readilyavailable from the key sulfoximine (S)-8 (see Section 2.3),was metallated, silylated, and metallated again. The re-sulting lithiated trimethylsilylmethyl sulfoximine 73 wasallowed to react with aldehydes and ketones yielding, af-ter silanolate elimination, the desired vinyl sulfoximines(S)-74. The yields were good and in particular the E-selec-tivity was excellent (typically ≥ 98% ds). This stands in aremarkable contrast to Peterson-olefinations with compa-rable sulfones which usually produced mixtures of E- andZ-olefins.120

If the carbonyl compound was prone to enolisation theyields decreased as expected. To circumvent this problemGais et al. inverted the order of reagent addition, thus theyeliminated LiOSiMe3 by lithiation of silyl ethers as exem-

Scheme 16 Transition metal complexes derived from 65. CSD-refe-rence codes are given in upper-case letters.10 Cp: cyclopentadienylCp*: pentamethyl cyclopentadienyl.

Scheme 17 Palladium complex catalysed N-arylation of sulfoximi-nes. EWG: electron-withdrawing group. Insinuated phosphorus li-gand: typically BINAP.

Scheme 18



plified by the advanced intermediate 75 from the synthesisof carbaprostacyclines (Scheme 20).121

This really amazing reaction sequence starts with a highlyexo-selective addition of the lithiated sulfoximines (S)-9aLi or (R)-9aLi to the protected ketone 75 (93% yield,≥ 98% ds) yielding the corresponding b-hydroxy sulfox-imines. These diastereomeric compounds were silylatedand each of the resulting b-silyloxy sulfoximines 76 and77, respectively, eliminated LiOSiMe3 with high asym-metric induction, thus furnishing the axially chiral olefinsZ-78 and E-79, respectively.

Sense and extent of the asymmetric induction only de-pended on the absolute configuration at the sulfur atom(reagent control). As a reasonable explanation for this re-markable process Gais et al. discussed a dynamic kineticdiastereomer differentiation based on the configurationallability of lithiated sulfoximines (see Section 1) and on thestereoelectronic demands for the silanolate extrusion.

Some years later, Craig et al. synthesised vinylic sulfox-imines 80 in a way resembling the Peterson olefinationchemistry of the Gais group, although they used a Wittig-Horner reagent to achieve the elimination (Scheme 21).122

Starting from racemic and enantiomerically pure 9b, lithi-ation followed by addition of one equivalent of potassiumt-butylate gave some kind of a dimetallated species. Itselectrophilic substitution with diethyl chlorophosphatefollowed by treatment with an aldehyde yielded the corre-sponding metallated hydroxyphosphonate which col-lapsed to produce the desired vinyl sulfoximines 80 inhigh yields and excellent E/Z-selectivities (≥ 93% E).

Beside these Peterson and Wittig-Horner reaction basedentries a considerable number of protocols relying on thestraightforward hydroxyalkylation-elimination strategyusing metallated alkyl sulfoximines as starting materialexist. Several examples illustrating this route are com-piled in Scheme 22.

Scheme 22 Addition-elimination routes to vinyl sulfoximines.A: CDI: carbonyl diimidazole; B: Tf: trifluoromethane sulfonyl;C: Ts: toluene sulfonyl.

Scheme 20

Scheme 21



In 1987 Hwang et al. published a paper describing the firstpreparation of free vinyl sulfoximines (A). Carbonyl addi-tion to lithiated N-silyl sulfoximine 9cLi delivered the b-hydroxy sulfoximine 83 which could be further manipu-lated to yield free vinyl sulfoximines 85 or N-formyl or N-acetyl sulfoximines 84. Again in most cases where alde-hydes were employed the E-configuration at the doublebond was strongly favoured.

Some years later Craig et al. used the N-TMS protectedsulfoximine rac-9c in the hydroxyalkylation reaction witha large variety of aldehydes (B).123 After reaction withmethyl chloroformate the resulting carbonates 86 elimi-nated in a clean reaction using potassium t-butylate as abase furnishing geometrically pure E-vinyl sulfoximinesE-87. These latter compounds were successfully N-acylat-ed using Tf2O/pyridine to give the N-trifluoromethyl sul-fonyl vinyl sulfoximines E-88 characterised by aparticularly electron deficient double bond. This proce-dure appears to be the method of choice when a maximumof constitutional flexibility is needed.

On the other hand, if N-tosylated sulfoximines are accept-able the route via methane sulfonates developed by Jack-son et al. may be recommended (C).124 Theenantiomerically pure vinyl sulfoximines (R)-88 could bedeprotonated and the resulting vinyl lithium compoundwas reacted with various electrophiles (El = SiMe3, Me,Et) to the corresponding 1-substituted vinyl sulfoximines(R)-89.

To close this Section on the preparation of vinyl sulfox-imines an interesting and completely different approachshould be discussed (Scheme 23).125

Scheme 23 Vinyl sulfoximines via enol tosylate 91. LiTMP: lithi-um tetramethyl piperidide. M: Li, (MgHal).

The idea behind this chemistry is to place a leaving groupin the vinyl position of the sulfonimidoyl moiety followedby a 1,4-addition-elimination sequence. Tosylation of theenolate derived from methyl sulfoximine 9d via formyla-tion with DMF furnished the enol tosylate 91. This key in-termediate underwent a number of reactions with "higherorder" cuprates, vinyl or alkynyl alanes giving rise to a va-riety of unsaturated sulfoximines which would have beendifficult to prepare by other means.

2.1.3.3 Allylic Sulfoximines

Allylic sulfoximines play a very special rôle in the chem-istry of this functional group. This is true for at least tworeasons.

1) Allylic sulfoximines are not or are only in low yieldsaccessible from sulfur(IV) precursors (Pyne 1993).126

This is especially true for chiral, non-racemic allylic sul-foximines. Both, 2-alkenyl sulfoxides as well as 2-alkenylsulfilimines suffer from [2,3]-sigmatropic shifts accom-panied by racemisation (Scheme 24).

Scheme 24 2-Alkenyl sulfoxides (X=O) and 2-alkenyl sulfilimines(X=NR) racemise via [2,3]-sigmatropic rearrangements.

In the sulfur(VI)-series other difficulties arise (Scheme25). Both principally suited precursors, the sulfonimidoylfluorides 99 as well as sulfonimidates 97 are difficult toprepare in an enantiomerically pure state. Their commonprecursor, sulfonimidoyl chloride 98, is configurationallyrather unstable on the timescales of fluorination or esteri-fication.

Scheme 25 Synthesis of sulfonimidates 97 and sulfonimidoyl fluo-rides 99 from sulfonimidoyl chlorides 98. 18-cr-6: 18-crown-6.

In addition, the sulfonimidoyl fluorides themselves ap-pear to be configurationally unstable.

2) As will become clear from Sections 3.1.3 and 3.2.3, op-tically pure 2-alkenyl sulfoximines are by far the mostsuccessful sulfoximines in asymmetric synthesis.

Before we come back to the problem of preparing enantio-merically pure allylic sulfoximines, a brief summary oftheir historical development will be given (Scheme 26).The first synthesis of a (racemic) allylic sulfoximine canbe traced back (once again) to Johnson. In 1979 he pre-pared the N-methyl derivative rac-101 from the sulfon-imidate rac-100 using allyllithium as carbon nucleophile(the corresponding Grignard reagent failed to react).104

Ten years later Reggelin et al. synthesised the firstenantiomerically pure allylic sulfoximines 103 andepi-103 (Reaction B).15 As chiral sulfur(VI)-electrophileserved the epimeric mixture of the sulfonimidoyl fluo-rides 102/epi-102 with (S)-phenyl ethylamine as chiralauxiliary. Its reaction with allyl lithium proceeded with



52% yield to the readily separable allyl derivatives103/epi-103. Unfortunately these results were publishedonly as a Ph.D. thesis. Another two years later Gais et al.prepared the advanced allylic sulfoximine 104 from thebase promoted isomerisation of the vinylic precursor 79(Scheme 26, C; see also Section 2.1.3.2, Scheme 20), thusbringing enantiomerically pure allylic sulfoximines to theattention of the scientific community.121

In the same year (1991, received 20. 8. 1991) Harmata etal. published an article about the preparation of racemicallylic sulfoximines via AlCl3 mediated allyl transfer fromallyltrimethylsilan and allyltributylstannane (Scheme 26,reaction D).127 Furthermore, he also was successful insubstituting a sulfonimidoyl fluoride furnishing the allylsulfoximine rac-106 - albeit in a somewhat lower yield.

Due to the configurational lability of the sulfur(VI) ha-lides neither their direct substitution with allyl metal com-pounds nor the preparation of sulfonimidates asalternative precursors were suitable routes to 2-alkenylsulfoximines.

This situation changed with the introduction of 4,5-dihy-drooxathiazole 2-oxides such as 53a as enantiomericallypure sulfur(VI)-electrophiles.109, 110 As cyclic sulfonimi-dates they are highly reactive towards a wide variety of or-ganolithium and organomagnesium compounds withoutbeing sensitive to reduction (see also Scheme 43 in Sec-tion 2.3). In particular allyl and crotyl sulfoximines 108(R = H) and 108 (R = Me) can be prepared in 97% and89% yield.109 The latter compound is formed with uniformE-geometry at the double bond which is remarkable tak-

Scheme 26



ing into account the many equilibrating species constitut-ing the crotyl Grignard reagent. Of course the addition-elimination-isomerisation (AEI)-chemistry of Gais de-picted in Scheme 27 (see also Sections 2.1.3.2. and 3.2.3)can be implemented into a general scheme of access tochiral, non-racemic sulfoximines offered by the cyclicsulfonimidates.

Enantiomerically pure methylsulfoximine 115, either pre-pared via resolution of the corresponding free sulfoximine(typically 9a, see Section 2.3) or nucleophilic ring open-ing of imidate 53a, is hydroxyalkylated using a cy-clic52, 128, 129 or open chain130 ketone. The resulting b-hy-droxy sulfoximine 116 is transformed into a vinyl sulfox-imine (not shown) which is isomerised to the target allylicsulfoximine 117 under basic conditions. For the case ofcyclic ketones (4-7-membered rings) the resulting sulf-oximines are necessarily E-configurated and, with the ex-ception of the 4-membered ring, the equilibrium is far onthe side of the allylic system.128 Following this route Gaisand Reggelin synthesised a number of enantiomericallypure cycloalkenylmethyl sulfoximines, examples ofwhich are depicted in Scheme 28.51

The myrtenyl sulfoximine 120 and a series of allylic sulf-oximines 121 with the sulfonimidoyl moiety directly at-tached to the ring have been synthesised via direct nucleo-philic substitution of ent-53a and 4-epi-53a using adeseleninating lithiation as source for the allyllithiumcompound.52, 129

Somewhat more sophisticated was the preparation of thedimethylated cyclohexenylmethyl sulfoximine 122.129

Here the route via enone 123 secured the position of thedouble bond during the elimination step.

If the carbonyl compound 114 (Scheme 27) is open chain,things get more complicated, and for R2 ≠ H only mixturesof E and Z allylic sulfoximines could be obtained.130 In1998 Gais et al. found that uniformly configurated vinylcuprates 110 add stereoselectively to chloromethyl sulf-oximines (Scheme 26, Reaction F), which solved theproblem to find an entry to pure Z-configurated 2-alkenylsulfoximines.131 Although the yields were not too high themethod is extremely useful and allowed the synthesis ofboth the Z-2-alkenyl sulfoximines 111 (R1 = H, R2 = Me,Scheme 26), and 111 (R1 = H, R2 = Ph), which are diffi-cult to prepare by other means.

Summarising the access modes to enantiomerically pureallylic sulfoximines it can be stated that there are onlythree routes with acceptable constitutional and configura-tional scope:

A) The addition-elimination-isomerisation (AEI)-se-quence developed by Gais et al.128, 132

B) Addition of vinyl cuprates to chloromethyl sulfox-imines also developed by Gais.131

C) Nucleophilic ring opening of cyclic sulfonimidates53 (Schemes 9 and 27, see also Section 2.3).109, 110 Thismethod is especially broad in constitutional scope andcovers both direct access via 2-alkenyl metal compoundsor AEI-chemistry via methyl sulfoximines such as 115(Scheme 27).

Scheme 27 Addition-elimination-isomerisation (AEI) sequenceyielding allylic sulfoximines. Depending on the source of the methylsulfoximine 115 R3 is either Me, Bn, CH2CH2OMe128 or a valine de-rived side chain.18, 51, 52, 129

Scheme 28 Cyclic allylic sulfoximines prepared via the addition-elimination-isomerisation (AEI) sequence, deseleninating lithiationand other more specialized routes. See ref. 51 for a decoding of theN-bound side chain.



2.2 Heterocyclic Sulfoximines

In principle, three different types of heterocyclic systemscan be constructed from the general formula of a sulfox-imine (Scheme 29).

Bicyclic sulfoximines of Type III are rather exotic deriva-tives and therefore only a few examples are mentioned forthe sake of completeness (Scheme 30).

Scheme 30

The heterocyclic 126 was obtained by reaction of tetra-methylene sulfoximine 125 (which is a Type I cyclic sul-foximine) with a malonester derived enol ether 124.83

In 1987 Ried et al. found the cyclisation of N-cyaniminosulfoximines 129 to yield thienothiadiazines 130 (Scheme31).133

Scheme 31

The possibility of employing N-cyanimino sulfoximines129 (R1 = SMe) as precursors for the synthesis of N-thia-zole sulfoximines 131 may be regarded as a late adden-dum to Section 2.1.3.1 (Scheme 32).133

Type I cyclic sulfoximines (Scheme 29) can be preparedin a straightforward manner from the corresponding sulf-oxides via one of the above mentioned imination routes

(Section 2.1.1, Scheme 1). Therefore it is not unexpectedthat this type has a rather long history. As early as in 1965D. J. Cram134 synthesised optically active sulfoximine 133via sulfoxide 132 and (+)-camphor-10-sulfonyl chlorideas a resolving agent (Scheme 33).

Scheme 33

Some years later purely aliphatic Type I sulfoximineshave been synthesised using the same route.23, 135, 136

When both C-atoms in a Type I sulfoximine (Scheme 29)were members of aromatic ring systems the hydrazoicacid imination procedure failed and alternative routes hadto be used. This was exemplified in 1974 by Stoss andSatzinger, both of them industrial chemists at the GödeckeAG (Scheme 34).137

Scheme 34

Tricyclic compounds of type 137 had been of interest asneuroleptica, thymoleptica and spasmolytica. Here eitheroxidative imination with TsN3 followed by sulfuric acidmediated hydrolysis or direct synthesis with MSH wassuccessful.

There are three main entries to Type II cyclic sulfoximines(Scheme 35).138, 139

Routes A und B are closely related since they both exploitthe nucleophilicity of the sulfoximine nitrogen to achievethe ring closure. They are differentiated here on the one

Scheme 29 The three possible types of cyclic sulfoximines.

Scheme 32



hand to emphasise the different reaction conditions em-ployed and on the other hand to account for the fact thatmost of the sulfoximines synthesised via route B are ben-zoanellated systems as shown.

The third route (C) is completely different: It starts with anucleophilic addition of a N-aryl substituted sulfonimi-doyl chloride 142 to a substituted alkene or alkyne underthe influence of a Lewis acid such as AlCl3. The interme-diate carbocation undergoes a Friedel-Crafts-like electro-philic substitution reaction finally furnishing thebenzothiazines 143. The first racemic Type II sulfoximinehas been synthesised by Johnson in 1971 (R1 = Ph, R2 = H,n = 1).140 27 years later Gais et al. synthesised a number ofenantiomerically pure sulfoximines of this type via nu-cleophilic displacement reactions of a suitably substitutedN-sidechain. (Scheme 36).141

Scheme 36

The conformationally restricted sulfoximines 147 areshown to react highly stereoselectively in electrophilicsubstitutions at the Ca-atom which contrasts the usuallylow selectivities in such reactions using open chain sulf-oximines (see Section 3.1.1.1). Furthermore, after depro-

tonation at Ca sulfoximines 147 can be used as chiral non-transferable ligands in asymmetric cuprate addition reac-tions (see 3.3).

The Stoß and Satzinger-benzothiazines 141 (Scheme 35,B) are available from suitably substituted aromatic sulfox-ides 140 by imination with HN3.142-144 This method seemsto be quite general and a large number of derivatives havebeen prepared this way. Due to the fact that these com-pounds have been prepared in an industrial environmentfor screening purposes, potential applications as reagentsor building blocks for organic synthesis have never beeninvestigated.

This appears to be quite different for the Harmata-typebenzothiazines 143 (Scheme 35 C) which are character-ised by an N-aryl-bond. In 1987, during an attempt to syn-thesise alkynyl sulfoximines, Harmata et al. discovered anovel route to this class of compounds.145, 146 Since thattime they developed this discovery147 not only into a quitegeneral entry to benzothiazines but also demonstrated itsusefulness for the preparation of o-allylanilines 150(Scheme 37).148

Scheme 37

The low diastereoselectivity in the electrophilic substitu-tion step, although not relevant here, is typical for lithiatednon-allylic sulfoximines (see 3.1.1.1, but 3.1.3) and is ob-served for a closely related vinylic "carbanion", too (Sec-tion 3.1.1.1, Scheme 47).146

As can be derived from the above discussion, until 1998only racemic derivatives had been described, thus imped-ing their application as chiral templates in asymmetricsynthesis. Fortunately in 1998 Bolm and Hildebrandfound a possibility to couple free sulfoximines with arylhalides (see 2.1.3.1, Scheme 17) which enabled Harmatato switch the starting material from the configurationallyproblematic sulfonimidoyl chlorides149 to configuration-ally stable sulfoximines (Scheme 38).150

This way he not only succeeded in the synthesis of enan-tiomerically pure benzothiazines 156 and the related ke-tones 157; with the corresponding 1,3-dibromides 155(R2 = Br) and 1,4-dibromides 155 (R1 = Br) the bis-ben-zothiazines 159 and 160, respectively, were obtained.

Scheme 35 Entries to Type II cyclic sulfoximines: LG: leavinggroup; For B: n = 1, 2; X: CH2Cl, CO2R, CONH2; Y: O, NH, H2; R1:Me, Bu, Et; R2: H, Me, Cl.



These chiral, conformationally rigid heterocycles are ob-viously very attractive candidates as chiral ligands inasymmetric catalysis. Especially the (not yet synthe-sised!) system 161 potentially derived from the o-dibro-mide promises to be extremely interesting in this respect.

2.3 Remarks on the Synthesis of Chiral, Non-Ra-cemic Sulfoximines

The overwhelming majority of contemporary chemistryinvolving chiral, non-racemic sulfoximines emanatesfrom a very small number of "key intermediates" (Scheme39).

The S-methyl-S-phenyl sulfoximines 8 and ent-8 havebeen resolved for the first time in 1965151 using (+)-10-camphorsulfonic acid (CSA) as resolving agent. Sincethat time a number of improvements to the protocol haveappeared.114, 152, 153 In 1997 Gais et al. published a proce-dure based on the method of half quantities(Scheme 40).154

The method relies on the separation of the diastereomericsalt (+)-8/(+)-CSA from sulfoximine (-)-8 rather than onthe separation of the two diastereomeric salts (+)-8/(+)-CSA from (-)-8/(+)-CSA present in equal amounts if oneequivalent of (+)-CSA is used. This mode of resolution ishighly efficient and large quantities (up to 0.75 mol) ofenantiomerically pure material can be obtained this way.

Scheme 40

Scheme 38

Scheme 39



Before we leave the topic of resolution, interesting workrelated to kinetic resolutions of some special sulfoximinesusing chiral hosts should be mentioned. In 1988 Toda etal. described the resolution of m-tolyl-S-methyl sulfox-imine 163 via enantiomer differentiating complexationwith (R)-binaphthol (Scheme 41).155

Scheme 41

Not unexpectedly the method is highly sensitive to thetype of substituents at both variable positions of the sulfuratom. With the acetylenic host 164 also purely aliphaticsulfoximines such as 165 and 166 are amenable to thiskind of kinetic resolution (Scheme 42).

Scheme 42

The synthesis of the N-modified derivatives 9a-e (andtheir enantiomers, Scheme 39) is achieved as described inSection 2.1.3.1. The cyclic sulfonimidates 53a and epi-53a as well as a number of derivatives differing in the 4-position of the heterocyclic ring are accessible from dif-ferent amino acids. These preparations are briefly depict-ed in Scheme 43, together with some aspects of theirapplications in organic synthesis.18, 52, 109, 110, 129

The synthesis of 53a and epi-53a includes the preparationof the two diastereomeric sulfinamides 169 and epi-169from O-silylated (S)-valinol 170 and the commerciallyavailable sodium salt of p-toluenesulfinic acid 171. Thesesulfinamides have the fortunate property that only onediastereoisomer (epi-169) readily crystallises from t-butylmethyl ether, so that its synthesis (and isolation) is quiteeasy.

As already mentioned (in Section 2.1.2) sulfinamides canbe oxidised with t-butyl hypochlorite to yield sulfonimi-doyl chlorides such as 173 with retention of sulfur config-uration at low temperatures (Scheme 44).

But usually the latter are not configurationally stable atthe elevated temperatures necessary for a subsequent re-action with nucleophiles.104, 156 Here, in contrast, the in-tramolecular attack of the alcohol in the presence of abulky base such as DBU is rapid enough even at low tem-peratures, so that the isomeric purity of the starting mate-rial can be conserved in the product. The reaction has beencarried out successfully with up to 400 mmol of 172(R = iPr) and with various other sulfinamides (as pure dia-stereomers or as mixtures), which were synthesised fromthe corresponding amino alcohols following standard pro-cedures.109, 110 It is worth mentioning here that no concur-rent oxidation of the primary alcohol by t-butylhypochlorite occurred.

The resulting dihydrooxathiazole 2-oxides 53a and epi-53a are characterised by two electrophilic positions (Aand B, Scheme 43). A is attacked by C-nucleophiles (Li/Mg) giving rise to a multitude of enantiomerically puresulfoximines 167 including the already mentioned allylicsulfoximines 108 and epi-108. If Bu3SnLi is used as a nu-cleophile then B-site attack occurs giving rise to the β-aminostannanes 168 (97% yield).16

Finally it should be noted that in cases where opticallypure sulfoxides appear to be the superior starting materialsthe most reliable entry to enantiomerically pure sulfox-imines is the MSH-method (Section 2.1.1, Scheme 1, PathG). This may be challenged by the BocN3-method devel-oped by Bach et al.96 The TsN3-route and in particular theentries using N-amino derivatives are recommended onlyif the N-substituent is either of minor importance or nec-essary for subsequent reactions (Section 2.1.1, Scheme 1).

3 Reactions of Sulfoximines

As already pointed out in the introduction, sulfoximinesdisplay a multitude of reactivities. In the course of writingthis article it appeared to be advantageous to organise thematerial by the introduction of three types of sulfoximines(see introduction). These types are not structural sub-classes but they reflect a certain reactivity. Sulfoximinesreacting as nucleophiles are included in Type I (Figure 5),those reacting as nucleophiles are designated as Type II(Figure 6) and finally those being useful as (chiral)ligands reside in the Type III (Figure 7) group. Of coursethere is an overlap between these types and in some casesthe capability of sulfoximines to act both as a nucleophileand as an electrophile is the major aspect of a given syn-thetic transformation. Those reactions illuminating themultifaceted rôle certain types of sulfoximines can play inorganic synthesis are separately discussed in Section 4 ofthis article.

3.1 Type I Sulfoximines: Nucleophilic Sulfox-imines

Reactions with the sulfoximine acting mainly as the nu-cleophilic reaction partner are discussed here. Sulfox-



imines displaying this reactivity can be divided into threesubclasses reflecting the site at which the reaction takesplace (Section 1, Figure 5).

3.1.1 Type Ia

a-Metallated non-allylic sulfoximines reacting with elec-trophiles such as alkyl halogenides, carbonyl compoundsand aza-analogs of the latter are the subjects of this Sec-tion.

3.1.1.1 Diastereoselective Alkylations and Additions of Lithiated Sulfoximines to R¢R¢¢C=X

Due to the acidic character of the a-protons insulfoximines157 (see Section 1) deprotonation is easilyachieved by strong bases such as butyllithium yielding thecorresponding a-metallated compounds 179 (Scheme 45,M = Li).

Scheme 45 Typical reactions of Type Ia sulfoximines. Cu: un-reactive C-substituent (e.g. aryl, tBu), El: electrophile, X: O, N.

RM RM

pTolS

ONa

O

H2NOSiMe3

53a

(oily)169

171

170

Bu3SnLiBu3SnLi

pTolS

N

O

OH

HpTol

SN

O

OH

H

A

epi - 108

pTolS

R

O

NOH

167

pTolS

O

NOH

RpTolS

R

O

NOH

epi - 167

inversion inversion

(high bias to crystallise)

BO

SN

O

pTol

A

B

A

OS

N

O

pTol

(low bias to crystallise)

epi - 53a168

pTolS

N

O

O

SnBu3

H

168

pTolS

N

O

O

SnBu3

H

epi - 169 (crystalline)

171

pTolS

ONa

O

170

H2NOSiMe3

108

pTolS

O

NOH

R

Scheme 43

Scheme 44



These chiral carbon nucleophiles can be alkylated (PathA) or reacted with carbonyl compounds or imines (Path C,B). The constitutional outcome of the hydroxyalkylationreactions (B or C, X = O) strongly depends on the elec-tron-withdrawing capability of the nitrogen bound substit-uent (RN). If RN is strongly electron-withdrawing (e.g.RN = Ts) then the intermediate O-metallated b-hydroxy-sulfoximine 176 collapses to the epoxide 178. If RN isalkyl or substituted silyl, then 176 or 175 are stable andcan be isolated. The Raney-Ni-mediated desulfuration ofthe latter finally yields the alcohols 177 (X = O). This se-quence has been used to prepare optically pure tertiary al-cohols from various ketones employing the N,S-dimethylsulfoximine 9a as a source of chirality (Scheme46).158

Scheme 46

If aldehydes (R1 = H) are used instead of ketones the cor-responding diastereomeric hydroxy sulfoximines (180/epi-180, R1 = H) were extremely difficult to separate andthe desulfurization of the mixture yielded secondary alco-hols (181/ent-181, R1 = H) of only 25 - 46% ee,158 thusdemonstrating the low diastereoselectivity of the electro-phile uptake. This lack of diastereoselectivity was ofcourse not unexpected for such a simple system.

The same is true for the N-trimethylsilylated sulfoximine(S)-9c prepared113 (see Section 2.1.3.1) and studied byHwang in 1987 (Table 5).159

With increasing steric demand of the silyl group, Hwanget al. observed an increase in the diastereoselectivity (upto 89:11) in the reaction of (S)-9 with pivaldehyde. Threeyears later, Pyne et al. slightly improved this diastereose-

lectivity to 94:6 by replacement of the SiMePh2 group in(S)-9f for an Sit-BuPh2 group [(S)-9e].64, 160 Furthermoreit was shown that for (S)-9e this diastereoselectivity waslargely independent of the aldehyde chosen.

One of the rare examples for the hydroxyalkylation of avinylsulfoximine is represented by the reaction depicted inScheme 47.146

Scheme 47

The benzothiazine rac-183 is readily deprotonated by n-butyllithium to give the corresponding vinyllithium deriv-ative which reacts with aldehydes to the epimeric alcohols184/epi - 184 with low diastereoselectivity.

Additions of lithiated sulfoximines to imines

In 1990 Pyne et al. elaborated the chemistry ema-nating from their N-silylated building block 9e (Scheme48).64, 160

Scheme 48

Treatment of lithiated rac-9e with various imines fur-nished epimeric mixtures of b-amino sulfoximines rac-185 and rac-186. Depending on the nature of the substit-uent R the major diastereomers rac-186 were producedwith modest to high diastereoselectivities (79-95% ds).Interestingly the relative topicity of attack of the lithio-sulfoximine onto the imine is inverted with respect to theone found with aldehydes.

When the lithiated benzyl substituted sulfoximine rac-187Li is employed in the reaction with imines (its appli-cation as a nucleophile in the reaction with aldehydes isnot recommended because all four possible diastereomersare formed)64 two out of four possible diastereomers wereobtained (Scheme 49).161, 162

Again the relative topicity of attack is inverted and there-fore the major diastereomer rac-188 has the relative con-figuration (1S*, 2S*, SS) as was revealed by crystalstructure analysis.

Table 5 Diastereoselective Hydroxyalkylation of (S)-9

Sulfoximine X 182 : epi-182 Reference

(S)-9c SiMe3 71 : 29 159(S)-9d SiMe2t-Bu 89 : 11 159(S)-9f SiMePh2 89 : 11 159(S)-9e Si(t-Bu)Ph2 94 : 6 160



The reaction of rac-187Li with the BF3-complex of theisoquinoline derivative 190 gave 1-benzyl tetrahydro iso-quinoline rac-189 with 92% ds.162

Alkylations

As expected, alkylations of simple sulfoximines are notvery stereoselective as is exemplified in Scheme 50 forthe N-nitro sulfoximines 1919 (see also Section 2.1.3.1,Scheme 18 and Section 4, Scheme 143).

Scheme 50

On the other hand, higher selectivities should result whenthe conformational space available to the sulfoximine isrestricted by cyclisation. This is indeed the case, as hasbeen shown by Gais et al. in the course of their work onchiral, non-transferable ligands for cuprate addition reac-tions (Scheme 51, see also Section 3.3).141

Scheme 51

The cyclic sulfoximines 147a and 147b (see Section 2.2for details of their synthesis) can be deprotonated with bu-tyllithium and the resulting lithiated species reacted withremarkable stereocontrol (90% ≤ de ≤ 98%). The struc-tural analysis of the products (X-ray structural analysis of193b, R = Bn) revealed that the attack of the electrophileat the anionic carbon of the lithiosulfoximines preferen-

tially occurs from the side of the sulfoximine oxygen at-om, irrespective of the a-substituent. This stereochemicaloutcome of the reaction is easily understood in terms ofthe known conformational preferences of a-sulfonimidoylcarbanions (see Section 1, Figure 9) and of minimizationof the steric interactions of the substituents.141

Accordingly, it was possible to invert the absolute config-uration at the newly formed stereogenic centre at the a-carbon just by a protonation-reprotonation-sequence as isdepicted in Scheme 52

.

The deprotonation of 193b (R = Bn) restores the possibil-ity for electrophilic attack syn to the sulfoximine oxygen.If the electrophile is merely a proton, then overall epimer-isation is effected. Following this sequence, epi-193b(R = Bn) was obtained with 89% de. From the mechanis-tic rationale, briefly mentioned above and discussed in de-tail in the cited paper, it was anticipated that a change ofthe electrophile from a small proton to sterically more de-manding alkylating agents will entail increased diastereo-selectivities. Again in accordance with this expectationthe dialkylated sulfoximines 195 and epi-195 were ob-tained in modest to excellent yields and complete stereo-control (Scheme 53).

Scheme 53

The deprotonated sulfoximines 147a and 147b (Scheme51) were employed as chiral, non-racemic, non-transfer-able carbanionic ligands in copper mediated enantioselec-tive conjugate addition reactions (see Section 3.3).

The last example to be discussed here is of interest be-cause it demonstrates the effect of two interacting sourcesof chirality on the asymmetric induction in the case of analkylation reaction (Scheme 54).163

Scheme 49

Scheme 52



Scheme 54

By treatment of the (S,S)-configurated p-tolylsulfinyl-methyl sulfoximine 197 with alkylating agents underphase-transfer conditions (PTC) the alkylated product 199is formed with complete diastereocontrol. Reversal of theabsolute configuration at the sulfinyl sulfur atom reducesthis selectivity to about 80% ds. Obviously, in the lk-dia-stereomer the two stereogenic centres reinforce each otherto achieve a maximum asymmetric induction on the newlycreated stereogenic centre (matched asymmetric induc-tion), whereas in the ul-diastereomer epi-197 the interac-tion of the sulfur centres is counterproductive(mismatched asymmetric induction). A similar situationinvolving a pair of matched or mismatched stereogeniccentres within an auxiliary has been found by Reggelin etal. and will be discussed in Section 3.1.3.2.

Finally it is noteworthy that the replacement of the sulfi-nyl moiety by the non-stereogenic sulfonyl group as in198 leads to a complete loss of the diastereomeric selec-tivity! From that it must be concluded that the stereoselec-tion exerted by epi - 197 and particularly by 197 ismainly attributable to the sulfur(IV) centre or, even moreprobable, to a concerted action of both sources of chirali-ty.

3.1.1.2 Resolution of Chiral Ketones and Directed Addi-tions

By far the most frequent application of sulfoximines in or-ganic synthesis was and still is the resolution of chiral ke-tones via diastereomeric b-hydroxy sulfoximines(Scheme 55).114, 164-166

Deprotonation of the "key sulfoximine" (R)-9a and addi-tion of the resulting lithiosulfoximine (R)-9aLi to a chiral,racemic ketone 201 will result in a maximum number offour diastereomeric b-hydroxy sulfoximines 200. Fortu-nately it turned out that with cyclic ketones the diastereo-facial selectivity in the addition step is excellent in mostcases (for a discussion of the influence of substituents on

this p-facial diastereoselection see ref. 167) and thereforeonly two out of these four diastereomers are obtained.

These isomers can be separated chromatographically andfurther manipulated in the following two ways. Heating to80-120 °C will revert them to the resolved ketone and thesulfur ylide 202 which self quenches to the enantiopurestarting sulfoximine (R)-9a (black arrows, Path A). Theacid catalysed desulfuration with aluminium amalgam(red arrows, Path B) leads to optically pure alkenes 203,thus combining ketone methylenation with optical resolu-tion.168

There are hundreds of successful ketone resolutions de-scribed in the literature, some of them are compiled inChart 1, others will be discussed more detailed in the fol-lowing paragraph.10

The ketones in the first row in Chart 1 are examples fromthe seminal paper of Johnson and Zeller published in1984.164

Ketone 208 was a key intermediate in the total synthesisof (+)-epoxydictymene.169 The corresponding b-hydroxysulfoximines were derived from (S)-(+)-9a (dr = 1:1, theinduction on the carbinol centre was complete), easilyseparated by column chromatography and the thermalcracking of one of them yielded the desired (+)-enantio-mer of 208 with 97% yield. In a similar unproblematicway bicyclic enone 210 was resolved (two diastereomers,74% yield, dr ≈ 1:1). Both enantiomers were obtainedwith ≥ 95% ee.171 Exclusive exo-attack of the lithiosulfox-imine (S)-9aLi onto ketone 211 (two diastereomers, 92%yield, dr ≈ 1:1, separation followed by thermal cleavageof the corresponding hydroxysulfoximines (92% and 95%yield) delivered (+)- and (-)-211 in enantiomerically purestate. These ketones were valuable intermediates in the to-tal synthesis of sesquiterpene lactones.172

R

S

O

Ph

NMe

LiS

O

Ph CH3NMe

(R) - 9a(H2O)O

R

80 -120 °C

nBuLi

202

S

O

Ph

MeN

H

201

203

200

2eR

MeN

H

O

SPh

O

H

Al (Hg)

THF, HOAc

- H2O

(R) - 9aLi

A

B

Scheme 55



Resolution of 212,173 214,175 and 215176 was unproblemat-ic as in the already described cases. The diastereofacial se-lectivity on the C=O double bond was almost complete(only two diastereomers were formed) and no difficultiessuch as ketone enolisation or regiochemical problemswere encountered. Nevertheless there are more arduousexamples, one of which is the ketone 209. The reaction of209 with (S)-9aLi was slow and only incomplete conver-sion to the corresponding adducts was observed. Only af-ter transmetallation with cerium trichloride did a reactionoccur but the p-facial selectivity was low. All four possi-ble diastereomers were formed although one of them wasproduced only in trace amounts. Nevertheless, Paquette etal. succeeded in separating the mixture and both enant-iomers of ketone 209 could be isolated at last in goodyields.

It is noteworthy that the intermediate b-hydroxy sulfox-imines not only served as separable diastereomers duringthe resolution process, but also as an important source forstructural information. In many cases these compoundswere crystalline and amenable to X-ray structural analy-sis, which in turn allowed the determination of the abso-lute configuration of the ketone obtained after

thermolysis. The CSD-refcodes of b-hydroxy sulfox-imines used for that purpose are given in Chart 1 and thestructures can be viewed at the author’s homepage.10, 177

In 1998 an application of this resolution procedure waspublished illustrating the compatibility of the method witha large variety of functional groups (Scheme 56).178

Scheme 56

H3CO

H

CH3

CH3H3C

H

CH3O

OMe

O

H3C

O

H

OSEM

O O

Ph

O

O

CH3

O

H3C

O

O O

CH3

CH3H

H

O

O CH3

Paquette 1996 [170]

Refcode: TASMIJ

Paquette 1997 [169] Ruveda 1993 [171] Paquette 1996 [172]

Refcode: TENMEE

Johnson 1984 [164]

205

Johnson 1984 [164]

204

Johnson 1984 [164]

206

Johnson 1984 [164]

207

Paquette 1993 [174]

Refcode: EACROP

Paquette 1998 [173]

Refcode: not in CSD

Fitjer 1991 [175]

Refcode: VOVTUV

Spreitzer 1999 [176]

208

212 213 214

215

209 210 211

Chart 1 Examples of chiral ketones successfully resolved by the Johnson method. 3D-models of the compounds included in the CSD-database can be viewed on the author’s homepage.177



In the course of their efforts to synthesise C-linked iminodisaccharides Vogel et al. found it necessary to resolve thehighly functionalised ketone rac-216.

Despite many alternative electrophilic sites, attack of thelithiosulfoximine (R)-9aLi exclusively occurs at the car-bonyl carbon yielding the expected diastereomers 217 and218 with perfect diastereofacial control in 92% yield.Thermolysis of 218 finally delivered the desired ketoneenantiomer 216 in 52% yield.

It has been pointed out several times that thermolytic ylideextrusion from b-hydroxy sulfoximines occurs via a pre-ferred conformation of the latter (Scheme 55, 200). Thisconformation is characterised by a hydrogen bond involv-ing the OH- and N-methyl group of the hydroxy sulfox-imine. This, of course, entails a preferred orientation ofthe bulky phenyl group which in turn should influence thechemical shifts of nearby NMR-active nuclei and shouldaffect the rate of thermolysis of the individual b-hydroxysulfoximine diastereomers. Indeed, following these linesthe marked shift-differences observed in various diaste-reomeric pairs of hydroxy sulfoximines have been utilized

to derive a rule for the determination of the absolute con-figuration of the preceding ketones.179

The conformational dependence of the thermolysis ratewas impressively demonstrated by Kuehne et al. in a 1996publication describing the synthesis of mossambine(Scheme 57).180

Treatment of racemic ketone 219 with (S)-9aLi [(R)-9aLi] yielded the diastereomeric hydroxysulfoximines220 and 221 [ent-220 and ent-221]. It turned out that only221 and ent-221 underwent retroaddition to the corre-sponding ketones (+)-219 and (-)-219, respectively. TheH-bonded conformation (emphasised by red colour), ob-viously needed to achieve the ylide extrusion, is difficultto attain in the non-fragmenting enantiomers 220 and ent-220 due to unfavourable steric interactions of the sulfurbound phenyl group with the remainder of the molecule.This entails the lucky situation that the selective genera-tion of either enantiomer of 219 can be achieved withoutseparation of intermediate diastereomers just by heatingthe corresponding mixture of diastereomers 220 and 221.

N

H

N

H3CO2CO

N

N

COOCH3H

O

N

H

N

CO2CH3O

rac - 219

(-) - 219

(+) - 219

ent - 221220

221

Li S

NMe

Ph O

(R)(S)

Li S

NMe

Ph O

(R)

N

H

sulfoximines: structures, properties and synthetic ... · thiazyl trifluoride (n ≡sf3).13 they...

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