Sulfoximine-directed single and double ortho-lithiation: Stereoselective rearrangements of o,oa'-Dilithiophenylsulfoximines to o,N- dilithiosulfinylanilines through anionic fries rearrangements of o,oa'-dilithiophenylsulfinamides

FULL PAPER

DOI: 10.1002/ejoc.201100066

Sulfoximine-Directed Single and Double ortho-Lithiation: Stereoselective

Rearrangements of o,oЈ-Dilithiophenylsulfoximines to

o,N-Dilithiosulfinylanilines through Anionic Fries Rearrangements of

o,oЈ-Dilithiophenylsulfinamides

Michael Wessels,^[a][‡]Vishal Mahajan,^[a][‡‡]Stephan Boßhammer,^{[a][‡‡‡]}Gerhard Raabe,^[a]

and Hans-Joachim Gais*^[a]

Keywords: Sulfoximines / Lithiation / Sulfur heterocycles / Rearrangement / Sulfinamides

Treatment of various phenylsulfoximines with nBuLi

(1 equiv.) at –78 °C in THF resulted in single ortho-lithiations

and gave the corresponding o-lithiosulfoximines. According

to NMR spectroscopy, the o-lithiosulfoximines are generally

stable at 0 °C. The o-lithiosulfoximines were efficiently

trapped through deuteration, alkylation, silylation, and phos-

phanylation. Treatment of cyclic phenylsulfoximines also

containing H atoms at their α-positions with nBuLi (1 equiv.)

at –78 °C furnished the o-lithiosulfoximines with high selec-

tivity, whereas similar treatment at –50 °C to room tempera-

oximines with nBuLi (2 equiv.) at low temperatures led to

double ortho-lithiation and furnished the corresponding o,oЈ-

dilithiosulfoximines. At elevated temperatures, cyclic o,oЈ-di-

lithiophenylsulfoximines underwent multi-step rearrange-

ments with formation of o,N-dilithiated benzothiazepine and

benzothiazocine S-oxide derivatives in high yields. The

acyclic o,oЈ-dilithiophenylsulfoximine underwent a similar

rearrangement and gave the corresponding o,N-dilithio-sulf-

inylaniline derivative. The rearrangements involve 1) elimi-

nation of the lithium sulfinamide from the o,oЈ-dilithiosulfox-

ture yielded the corresponding α-lithiosulfoximines. At ele- imine, 2) a Li–N addition of the lithium sulfinamide to the o-

vated temperatures, o-lithiosulfoximines also possessing α-H

atoms underwent quantitative o,α-transmetalation to afford

the corresponding α-lithiosulfoximines. Treatment of α,α-di-

substituted cyclic and α,α,α-trisubstituted acyclic phenylsulf-

lithiobenzyne, and 3) an anionic Fries rearrangement of the

o,oЈ-dilithiophenylsulfinamide. The rearrangements of the

o,oЈ-dilithiophenylsulfoximines proceeded with overall re-

tention of configuration at sulfur.

should allow direct access to ortho-substituted phenylsulf-

oximines, which are of interest as drug candidates^[7]and

chiral ligands in asymmetric metal catalysis.^[8]

Introduction

The directed ortho-lithiation of benzene derivatives is of

considerable synthetic importance and mechanistic inter-

est.^[1]One of the most powerful ortho-directing metalation

groups (oDMGs) is the sulfonyl group.^[1]Although the di-

rected ortho-lithiation of phenylsulfones (I) (Figure 1) had

received much attention, that of phenylsulfoximines (II),^[2]

chiral aza-analogues of I, has only little been studied.^[3,4]o-

Lithiophenylsulfoximines, however, could provide new po-

tential for asymmetric synthesis because of the chirality, nu-

cleophilicity, nucleofugacity, and Lewis basicity of the sulf-

oximine group,^[5]features not possessed in this combination

by other chiral oDMGs.^[6]Finally, o-lithiosulfoximines

Figure 1. Phenylsulfones and phenylsulfoximines.

A particularly interesting and unique aspect of the sulf-

onyl group is its ability to act as a double oDMG for benz-

ene systems. Stoyanovich et al. described the facile directed

double ortho-lithiation of tert-butylsulfonylbenzene with

nBuLi, which gave o,oЈ-dilithio-tert-butylsulfonylbenzene.^[9]

Interestingly, the o,oЈ-dilithiosulfone, but not the corre-

sponding o-lithiosulfone, eliminated lithium tert-butylsulf-

inate at elevated temperatures with formation of o-lithio-

benzyne. Attempts to find other double oDMGs of benzene

and derivatives, however, were unsuccessful.^[1,10,11]An ac-

cepted mechanistic concept in directed ortho-lithiation is

the complex-induced proximity effect,^[12]which features co-

ordination of the base by the oDMG before the proton

transfer occurs. The strong Lewis basicities of sulfoximines,

[a] Institute of Organic Chemistry, RWTH Aachen University,

Landoltweg 1, 52074 Aachen, Germany

Fax: +49-2418092665

E-mail: gais@rwth-aachen.de

[‡] Present address: Novartis Pharma AG, Forum 1,

Novartis Campus, 4056 Basel, Switzerland

[‡‡]Present address: SAI Advantium Pharma Ltd., Chrysalis

Enclave, International Biotech Park, Phase II

Hinjewadi, Pune 411057, India

[‡‡‡]Present address: Momentive Performance Materials GmbH,

Chempark Leverkusen

51368 Leverkusen, Germany

Eur. J. Org. Chem. 2011, 2431–2449

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FULL PAPER

which can be attenuated by the substituents on the N

Here we describe directed single and double ortho-

atoms,^[5]should make the sulfoximine group a powerful lithiation of phenylsulfoximines (II) with formation of the

oDMG for single and perhaps also double lithiation. Be- o-lithiosulfoximines III and IV and the o,oЈ-dilithiosulfox-

cause of our interest in the synthetic application of sulfox- imines V (Figure 3). It is shown that ortho-lithiation is in

imines^[13]and sulfoximine-substituted organometallics^[14]certain cases much faster than α-lithiation. It is also demon-

and the scarcity of information on the directed ortho- strated that the transmetalation of the o-lithiosulfoximines

lithiation of II,^[3]we decided to study the potential of the IV to the corresponding α-lithiosulfoximines (not shown)

sulfoximine group as a single and double oDMG of benz- and the double o,α-lithiation of sulfoximines with genera-

ene systems on a broader basis in order to seek answers to tion of the hitherto little explored o,α-dilithiosulfoximines

the following questions.

VI^[16]are both facile processes.

Firstly, what are the scope and limitations of directed

single ortho-lithiation of phenylsulfoximines?

Secondly, is there competition between ortho- and α-

lithiation in phenylsulfoximines that also possess H atoms

at their α-positions?

Thirdly, under what conditions does o,α-transmetalation

of o-lithiosulfoximines occur?

Fourthly, is directed double ortho-lithiation of phenyl-

sulfoximines feasible?

Fifthly, will o,oЈ-dilithiosulfoximines undergo elimination

of the sulfinamide to give o-lithiobenzyne and if so, do

these two species combine in a nucleophilic addition?

Some time ago we developed an efficient synthesis of the

α-substituted cyclic sulfoximines 1–6 (Figure 2), in which

the SN moieties are incorporated in rings,^[15]and so the

phenylsulfoximines 1–6 were selected as substrates for the

present study. Whereas the sulfoximines 1–3 have no H

atoms at their α-positions, the sulfoximines 4–6 each have

one H atom at the α-position. The sulfoximines 1–6 should

therefore be suitable substrates for study both of sulfox-

imine-directed single o- and α-lithiation and of double o,α-

and o,oЈ-lithiation. The acyclic sulfoximines 7^[3]and 8, with

no H atoms at their α-positions, were also included in the

investigation of the single and double ortho-lithiation in or-

der to obtain a more general picture. It was planned to

follow the course of the lithiation of the sulfoximines 1–8

through trapping experiments with electrophiles and NMR

spectroscopy. The sulfoximines 4–6 should thus be particu-

larly valuable probes because any persisting or transient

lithiation at their α-positions should manifest itself in inver-

sion of configuration at these stereogenic C atoms upon

treatment with an electrophile.^[15]

Figure 3. o-Lithio-, o,oЈ-dilithio-, and o,α-dilithiosulfoximines.

Furthermore, we also report on the observation of un-

precedented and stereoselective rearrangements of the o,oЈ-

dilithiophenylsulfoximines V to the o,N-dilithiosulfinylanil-

ines VIII, which involve 1) elimination-additions of the lith-

ium sulfinamides, and 2) anionic Fries rearrangements

(AFRs) of the intermediate o,oЈ-dilithiophenylsulfinamides

VII (Figure 4). The AFR, which generally consists of a 1,3-

X

_ArǞC_Armigration of a functional group of the o-met-

alated aryl derivative IX with formation of X (Figure 5), is

well documented for derivatives containing C- and P-based

migrating groups (Y = C, P).^[1,17]In contrast, ARFs of

compounds IX containing S-based groups (Y = S) have re-

ceived much less attention. Although AFRs of o-lithiosulf-

onamides IX (X = NRЈ, Y = S, Z = O, n = 2) to o-amino-

sulfones X (X = NRЈ, Y = S, Z = O, n = 2)^[1d]were discov-

ered several decades ago,^[18,19]those of o-lithiotriflates IX

(X = Z = O, n = 2) had only recently been described,^[20]

Figure 4. Rearrangements of o,oЈ-dilithiophenylsulfoximines and

AFRs of o,oЈ-dilithiophenylsulfinamides.

Figure 2. Cyclic and acyclic phenylsulfoximines.

Figure 5. AFR of ortho-metalated benzene derivatives.

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Sulfoximine-Directed o-Lithiation and Stereoselective Rearrangements

and AFRs of the chiral o-lithiosulfinamides IX (X = NRЈ, II. Directed Single ortho-Lithiation of Sulfoximines

Y = S, Z = O, n = 1), which are of considerable synthetic

α-Monosubstituted Sulfoximines

and mechanistic interest, had up until now not been investi-

gated.^[21]

Treatment of the monosubstituted sulfoximines 4–6, each

with only one H atom at its α-position and two H atoms at

its o- and oЈ-positions, with nBuLi (1.1 equiv.) at –78 °C for

10 min selectively afforded the corresponding o-lithiosulf-

oximines 17–19 (Scheme 2). Formation of the o-lithiosulf-

oximines was verified by trapping experiments: methylation

of 17 with MeI at –78 °C furnished the methyl-substituted

sulfoximine 20 in 69% yield, a similar methylation of 18

delivered the methyl-substituted sulfoximine 21 in 71%

yield, and the silylation of 18 with ClSiMe₃gave the silyl-

substituted sulfoximine 22 in 60% yield. Finally, the o-

lithiosulfoximine 19 was deuterated at –78 °C, which quan-

titatively yielded the sulfoximine o-d-6 with a D content of

Ն95%. No competing formation of the corresponding α,α-

disubstituted sulfoximines derived from 4–6 was observed

in the above transformations.

Results and Discussion

I. Synthesis of Sulfoximines

The enantiopure sulfoximines 3–5 were synthesized in

high yields from the starting S-configured sulfoximine 9,^[15]

through a highly diastereoselective alkylation of the α-

lithiosulfoximine 10^[22](Scheme 1).^[15]Similar alkylation of

10 with ClCH₂SiMe₃gave the sulfoximine 6 with Ն98% de

and in 97% yield. Treatment of the methyl-substituted

sulfoximines 11^[15]and 12^[15]with nBuLi at –50 °C gave the

corresponding α-lithiosulfoximines 13^[22]and 14,^[22]methyl-

ation of which with MeI afforded the corresponding di-

methyl-substituted sulfoximines 1 and 2 in 54% and 52%

yields, respectively. Similarly, the sulfoximine ent-2 was syn-

thesized by starting from ent-12. The acyclic sulfoximines

7

^[3]and 8 were prepared from the corresponding starting R-

configured S-methyl sulfoximines 15^[23,24]and 16,^[25]

through successive treatment with nBuLi (1 equiv.) and MeI

(1 equiv.), followed by two repetitions of this sequence with-

out isolation of intermediates. The sulfoximines 7 and 8

were obtained in 80% and 76% yields, respectively.

Scheme 2. Directed ortho-lithiation of α-monosubstituted cyclic

sulfoximines.

According to the complex-induced proximity effect,^[12]

the ortho-lithiation of sulfoximines 4–6 with nBuLi should

proceed through the formation of a complex of type XI

followed by an intramolecular H atom transfer. The H atom

transfer requires the phenyl ring in the complex XI to be

orientated approximately orthogonal to the S–O bond. In

the case of an o,α-disubstituted sulfoximine such as 22 the

Scheme 1. Synthesis of cyclic and acyclic phenylsulfoximines.

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FULL PAPER

attainment of the required S–Ph conformation should be

hampered because of steric interaction between the substit-

uents R¹and R², so lithiation of 22 in the α-position could

perhaps be preferred over an o-lithiation. The silyl-substi-

tuted sulfoximine 22 was therefore subjected to the standard

deprotonation/silylation sequence. However, treatment of

22 with nBuLi (1.1 equiv.) at –78 °C also resulted in ortho-

lithiation and gave the o-lithiosulfoximine 23 (cf. Scheme 2),

silylation of which afforded the bis(silyl)-substituted sulfox-

imine 24 in 60% yield. The selective ortho-lithiation of the

sulfoximines 4–6 is noteworthy. Despite the presence of a H

atom at the α-position, each sulfoximine undergoes selective

lithiation at its o-position at –78 °C with nBuLi. Generally,

treatment of a phenylsulfoximine containing a H atom at

its α-position with nBuLi affords the corresponding α-

lithiosulfoximine.^[5,14]It should be emphasized, however,

that the observation of the formation of an α-lithiosulfox-

imine does not preclude a prior lithiation at the o-position

followed by a transmetalation (see below), both of which

might have occurred unnoticed. The lower kinetic acidities

of the H atoms at the α-positions in sulfoximines 4–6 and

22 might be due to steric hindrance to the deprotonation

with nBuLi exerted by the S-phenyl group. According to

NMR spectroscopy the sulfoximines 4–6 and 22 preferen-

tially adopt a conformation as depicted in the complex XI,

in which the H_αatom occupies the hindered pseudoaxial

position.

Scheme 3. Silicon/lithium exchange in the o,oЈ-bissilylsulfoximine

24.

benzyllithium derivative 25 (Scheme 4), treatment of which

with MeI gave the ethyl-substituted sulfoximine 26 in 90%

yield.

Silicon-Lithium Exchange and Lateral Lithiation

Having the bis(silyl)-substituted sulfoximine 24 to hand,

we were interested to see whether deprotonation of this

sterically crowded sulfoximine at the α-position could be

achieved. Surprisingly, treatment of 24 with nBuLi

(1.1 equiv.) at –50 °C, a temperature optimal for achieve-

ment of α-lithiation (see below), gave not the corresponding

α-lithiosulfoximine but the o-lithiosulfoximine 23

(Scheme 3). Deuteration of this afforded the deuterated sulf-

oximine o-D-22 with a D content of Ն95% in 95% yield.

Scheme 4. Selective lateral lithiation of the sulfoximine 20.

α,α-Disubstituted Sulfoximines

The ortho-lithiation of the α,α-disubstituted sulfoximines

Almost quantitative desilylation of the phenylsilane 24 had 1–3 was next investigated (Scheme 5), for the following

therefore occurred with nBuLi, with formation of the o- reasons. Firstly, the synthesis of the o-lithiosulfoximines 27–

lithiosulfoximine 23. Although silylation of aryllithium de- 29 would allow NMR spectroscopic characterization and

rivatives is a frequently employed reaction in the synthesis determination of their stabilities, because ortho,α-transmet-

of arylsilanes, silicon/lithium exchange of an arylsilane alation is not possible. Secondly, investigation of double or-

upon treatment with a lithiumorganyl with formation of the tho-lithiation of the sulfoximines 1–3 would be aided by

corresponding aryllithium derivative has only rarely been characterization of the corresponding o-lithiosulfoximines.

observed.^[26]The alternative mode of formation of o-D-22 ortho-Lithiations of the sulfoximines 1 and 2 readily took

from 24, involving α-lithiation followed by a rearrangement place upon treatment with nBuLi (1.1 equiv.) at –78 °C and

of the corresponding α-lithiosulfoximine to the correspond- gave the corresponding o-lithiosulfoximines 27 and 28.

ing α-silylated o-lithiosulfoximine, the deuteration and desi- Deuteration of 27 and 28 afforded the corresponding deu-

lylation of which could yield o-D-22, can be excluded be- terated sulfoximines o-D-1 and o-D-2, both with D contents

cause of the lack of stereoscrambling at the stereogenic cen- of Ն95%, in 90% and 84% yields, respectively.

ter and the D incorporation at the α-position.^[15]

The o-lithiosulfoximine 27 was characterized by NMR

Finally, the reactivity of the methyl-substituted sulfox- spectroscopy. The ¹³C NMR spectrum of 27 in [D₈]THF at

imine 20 towards nBuLi was briefly investigated in order to –78 °C showed the signal of the C2 atom carrying the Li

determine whether ortho-, α-, or lateral lithiation would be atom at δ = 203 ppm (Table 1). Thus, on going from the

preferred.^[1c]Interestingly, treatment of the sulfoximine 20 sulfoximine 1 to the o-lithiosulfoximine 27 the signal of the

with nBuLi (1.1 equiv.) at –78 °C selectively afforded the C2 atom experiences a downfield shift of 72 ppm. A similar

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Sulfoximine-Directed o-Lithiation and Stereoselective Rearrangements

phosphanyl sulfoximines as chiral ligands,^[28]the synthesis

of the o-lithiosulfoximine 30 and its reaction behavior with

P-based electrophiles were investigated (Scheme 6). Treat-

ment of the sulfoximine 8 with nBuLi (1.1 equiv.) at –50 °C

furnished the o-lithiosulfoximine 30, treatment of which

with ClPPh₂and with ClP(O)Ph₂gave the corresponding P-

substituted sulfoximines 31 and 32 in 88% and 75% yields,

respectively. o-Phosphanylphenylsulfoximines of type 31

and 32 have not been described before. Desilylation of the

silyl sulfoximine 32 furnished the NH-sulfoximine 33, the

substrate for functionalization at the N atom.

Scheme 5. Directed ortho-lithiation of α,α-disubstituted cyclic sulf-

oximines.

shift was observed in the case of o-lithiosulfones.^[27]The o-

lithiosulfoximines 27 and 28 were stable in THF solution

up to 0 °C for a reasonable period of time but slowly de-

composed at room temperature (see below).

Scheme 6. Directed ortho-lithiation of acyclic sulfoximines.

III. ortho,α-Transmetalation

Table 1. NMR spectroscopic data (in part) for the sulfoximine 1 in

CDCl₃and the o-lithiosulfoximine 27 in [D₈]THF at 20 °C.

The experiments with the sulfoximines 4–6, 22, and 1–3

had shown that ortho-lithiation of α-mono- and α,α-disub-

stituted sulfoximines is a facile process even at low tempera-

tures. During the study of ortho-lithiation we came across

an interesting temperature effect. Whereas treatment of the

sulfoximine 4 with nBuLi (1.1 equiv.) at –78 °C afforded the

o-lithiosulfoximine 17 (Scheme 7), for example, similar

treatment at –50 °C to 20 °C yielded the α-lithiosulfoximine

34,^[15]which upon deuteration gave the sulfoximine α-D-

epi-4 with high diastereoselectivity. These observations gave

a strong indication of facile transmetalation of the o-lithio-

sulfoximine to afford the corresponding α-lithiosulfoximine.

Nuclei

Sulfoximine 1

o-Lithiosulfoximine 27

[a,b]

[a]

[b,c]

[c]

δ_H

δ_C

δ_H

δ_C

1

2

3

4

5

6

135.4

130.9

132.9

128.6

130.9

145.8

203.0

142.1

127.9

123.1

127.2

7.97

7.54

7.64

7.54

7.97

–

7.99

6.96

6.90

7.60

[a] Relative to TMS. [b] Center of the signal; see Exp. Section.

[c] Relative to THF.

As the last example of an α,α-disubstituted sulfoximine,

the ortho-lithiation of the sulfoximine 3 was studied (cf.

Scheme 5). The o-lithiosulfoximine 29 was obtained from 3

upon treatment with nBuLi (1.1 equiv.) at –78 °C. Deutera-

tion of 29 at –78 °C after stirring of its THF solution for

10 min at room temperature gave the deuterated sulfox-

imine o-D-3 (Ն95% D) in 90% yield.

ortho-Lithiation of the acyclic phenylsulfoximines 7 and

8 was only briefly studied because of the attention it had

received previously.^[3]Because of the envisioned investiga-

tion of double ortho-lithiations of acyclic and cyclic sulf-

oximines (see below) and our interest in the synthesis of Scheme 7. ortho,α-Transmetalation of the o-lithiosulfoximine 17.

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In order to obtain more detailed information about the 22, each with a H atom at its α-position, and the transmet-

transmetalation, the o-lithiosulfoximine 19 was also studied alation of the o-lithiosulfoximines 17 and 19 are the first

(Scheme 8).

examples of transformations of this type of sulfoximines.

Recently, a report describing the selective ortho-lithiation of

an α,α-disubstituted methylphenylsulfone and the facile o,α-

transmetalation of the corresponding o-lithiosulfone has

appeared.^[29]We and others had previously shown that α-

lithiosulfones, for example, are converted upon treatment

with nBuLi to the corresponding o,α-dilithiosulfones,^[30–32]

which undergo transmetalation at elevated temperatures

with formation of the corresponding α,α-dilithiosulf-

ones.^[27,30]

IV. Double ortho,α-Lithiation of Sulfoximines

Double ortho,α-lithiation of phenylsulfones with nBuLi

occurs readily,^[27,30–32]and the experiments with the o-

lithiosulfoximines 17 and 19 had revealed ortho,α-transmet-

alation to be a facile process even at low temperatures. We

thus expected that double ortho,α-lithiation of phenylsulf-

oximines should also be a straightforward process.^[16]

Treatment of the unsubstituted sulfoximine 9 with nBuLi

(2.2 equiv.) at –50 °C readily gave the o,α-dilithiosulfox-

imine 40, treatment of which with MeI afforded the o,α-

dimethyl-substituted sulfoximine 41 with Ն95% de and in

76% yield (Scheme 10). The formation of 41 was somewhat

surprising because methylations of an acyclic o,α-dilithio-

sulfoximine^[16]and of o,α-dilithiosulfones^[29]with MeI were

accompanied by o,α-transmetalation and gave the corre-

sponding α,α-dimethylated sulfones. The double ortho,α-

lithiation is not restricted to α-unsubstituted sulfoximines.

Double lithiation of the α-mono-substituted sulfoximine 6

with nBuLi (2.2 equiv.) at –50 °C afforded the o,α-dilithio-

sulfoximine 42.^[22]Deuteration of 42 furnished the bisdeut-

erated sulfoximine o,α-D₂-epi-6 (Ն95 o-D, Ն95% α-D) in

94% yield.

Scheme 8. ortho,α-Transmetalation of the o-lithiosulfoximine 19.

Warming of a solution of 19 from –78 °C to 20 °C led

within 1 h to complete transmetalation of the o-lithiosulfox-

imine to afford the isomeric α-lithiosulfoximine 35, the deu-

teration of which gave the α-deuterated sulfoximine α-D-

epi-6 with Ն95% de in 93% yield. Information about the

time required for the completion of the transmetalation was

gained as follows. A similar experiment was run with 19

except that the solution of the o-lithiosulfoximine was

stirred at 20 °C only for 10 min. In this case deuteration

gave a mixture of α-D-epi-6 (Ն95% D, Ն95% de) and o-D-

6 (Ն95% D) in a ratio of 66:44.

Lithiation/deuteration experiments were also performed

with the starting unsubstituted cyclic sulfoximines 36 and 9

(Scheme 9). Treatment of the sulfoximines 36 and 9 with

nBuLi (1.1 equiv.) at –50 °C gave the corresponding α-

lithiosulfoximines 39 and 10, deuteration of which afforded

the α-D-substituted sulfoximines α-D-36 (Ն95% D,

Ն95% de) and α-D-9 (Ն95% D, Ն95% de), respectively.

Because experiments with 36 and 9 were not run at –78 °C,

no differentiation between the two alternative pathways

leading to 39^[22]and 10^[22]– α-lithiation or o-lithiation to

37 and 38 followed by a transmetalation – can be made in

this case. The selective o-lithiation of sulfoximines 4–6 and

Scheme 9. Lithiation of unsubstituted cyclic sulfoximines.

Scheme 10. Double ortho,α-lithiations of cyclic sulfoximines.

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Sulfoximine-Directed o-Lithiation and Stereoselective Rearrangements

V. Directed Double ortho-Lithiations of Phenylsulfoximines

and Rearrangements of o,oЈ-Dilithiophenylsulfoximines

Cyclic Sulfoximines

Information about single ortho- and α-lithiations and

double ortho,α-lithiations of sulfoximines having been ob-

tained, investigation of directed double ortho-lithiation was

of particular interest. The dimethyl-substituted cyclic sulf-

oximine ent-2 was therefore treated with nBuLi (2.5 equiv.)

at –50 °C for 30 min, after which the reaction mixture was

quenched with D₂O (Scheme 11). This reaction sequence

gave a mixture of the bisdeuterated sulfoximine o,oЈ-D₂-ent-

2 and the monodeuterated sulfoximine o-D-ent-2 in a ratio

of approximately 1:1 according to NMR spectroscopy.

Treatment of ent-2 with nBuLi under these conditions had

thus given a mixture of the o-lithiosulfoximine 28 and the

o,oЈ-dilithiosulfoximine 43 in a ratio of approximately 1:1.

Scheme 12. Synthesis of the benzothiazocine S-oxide derivative o-

d-45 from the six-membered cyclic phenylsulfoximine ent-2.

configuration (see below), o-D-45 was assigned the S con-

1

figuration. The H NMR spectrum of 45 showed a charac-

teristic shift difference for the signals of the H atoms in the

3- and 6-positions (Table 2). Because of the anisotropic ef-

fect of the sulfinyl group, the signal of H-10 appears at

lower field than that of H-7. This effect allowed the deter-

mination of the position of the D atom in o-D-45.

Table 2. NMR spectroscopic data (in part) for the sulfinylanilines

58 and 45 in CDCl₃and for the lithium salts 61 and 47 in [D₈]-

THF at 20 °C.

Scheme 11. Directed double ortho-lithiation of the cyclic sulfox-

imine ent-2.

The incomplete lithiation of ent-2 with formation of 43

and 28 might have been due to a too short reaction time,

and so the metalation conditions were modified. The sulf-

oximine ent-2 was treated with nBuLi (2.2 equiv.) at –50 °C

and the reaction mixture was kept for 30 min at this tem-

perature. Subsequently, the mixture was allowed to warm

to 20 °C for 1 h, whereupon a yellow solid deposited, and

Nuclei Sulfinylaniline

Lithium sulfinylanilide

58

45

δ_H

61

47

δ_H

[a,b]

[a]

[a,b]

[a]

[b,c]

[c]

δ_H

δ_C

δ_H

δ_C

was then quenched with D₂O and finally subjected to an

aqueous workup. Surprisingly, this modified procedure led

to the isolation of the benzothiazocine S-oxide derivative o-

D-45 in 95% yield (Scheme 12). NMR spectroscopy showed

o-D-45 to contain a D atom (97% D) at the o-position to

the N atom. Omission of the quenching of the reaction mix-

ture with D₂O gave 45.

9a/10a

5a/6a

6/7

7/8

8/9

–

6.85

7.28

7.20

7.71

132.0^[d]

145.4

120.3

130.7

122.6

122.2

–

6.52

7.11

6.70

7.60

118.4

147.2

114.7 6.40

130.8 6.48

115.4 5.55

125.3 6.85

–

6.39

6.57

5.73

7.33

112.4

162.3

120.4

128.9

103.1

125.3

9/10

[a] Relative to TMS. [b] Center of signal; see Exp. Section. [c] Rela-

tive to THF. [d] Signal could not be unambiguously assigned.

The structure of o-D-45 was confirmed by NMR spec-

troscopy in comparison with its lower homologue (see be-

The isolation of o-D-45 shows that the o,oЈ-dilithiophen-

low). Analogously to its lower homologue, which was ob- ylsulfoximine 43 had undergone a rearrangement to the

tained from the S-configured sulfoximine 1 and had the R o,N-dilithiobenzothiazocine 44 (Figure 6). The reaction of

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the o,N-dilithiobenzothiazocine 44 with D₂O must initially

have afforded the bisdeuterated benzothiazocine o,N-D₂-45.

Because of the subsequent aqueous workup of the reaction

mixture, a D/H-exchange of o,N-D₂-45 at the N atom had

occurred,^[33]giving the monodeuterated benzothiazocine o-

D-45. Chromatography of o,N-D₂-45 on silica gel was also

accompanied by D/H-exchange and gave o-D-45. Confirm-

ation for the facile D/H-exchange at the N atom in o,N-D₂-

45 with H₂O was provided by deprotonation/deuteration

experiments with 45 and 58 (see below). The alternative for-

mation of the monolithiated benzothiazocine derivative 46

(Figure 6) instead of the dilithiated derivative 44 in the reac-

tion between ent-2 and nBuLi (cf. Scheme 12) can be ruled

out. The NH acidity of the phenylogous sulfinamide 45

should be significantly higher than its CH_orthoacidity.^[34,35]

The aryllithium derivative 46 would thus not be stable un-

der the reaction conditions but would undergo transmet-

alation to the lithium salt 47.

Scheme 13. Rearrangement of a six-membered cyclic o,oЈ-dilithio-

sulfoximine to an o,N-dilithiobenzothiazocine S-oxide derivative.

Support for the proposed elimination of 49 from the o,oЈ-

dilithiosulfoximine 43 with formation of o-lithiobenzyne

(48) and their recombination through Li–N addition was

provided by an investigation of the reactivity of the o,oЈ-

dilithiosulfone 53 (Scheme 14).^[9]It was found that the

lithiation of the sulfone 51 with nBuLi (2 equiv.) gave – via

the o-lithiosulfone 52 – the o,oЈ-dilithiophenylsulfone 53,

which underwent elimination of lithium tert-butylsulfinate

with formation of o-lithiobenzyne (48). Addition of nBuLi

to 48 delivered the o,oЈ-dilithiobenzene 54, which was

trapped with CO₂as the isophthalic acid derivative 55. The

intermediate formation of o-lithiobenzyne (48)^[9c]in the

conversion of 53 to 54 was verified by trapping experiments

with a set of competing nucleophiles.^[9g]However, in strong

contrast with the behavior of the lithium sulfinamide 49

towards 48, no nucleophilic addition of the lithium tert-

butylsulfinate to the o-lithiobenzyne was observed.

Figure 6. Lithiated benzothiazocine S-oxide derivatives.

The following mechanistic scheme based on these results

is advanced for the rearrangement of 43 to 44 (Scheme 13).

The ortho-lithiation of the R-configured sulfoximine ent-2

proceeded rapidly at low temperatures and afforded the o-

lithiosulfoximine 28 (cf. Scheme 11). The further lithiation

of the o-lithiosulfoximine with nBuLi at low temperatures

was slower and furnished the o,oЈ-dilithiophenylsulfoximine

43, as shown by the deuteration experiment. Although 43

was reasonably stable at low temperatures, at elevated tem-

peratures it underwent elimination of the lithium sulfin-

amide 49 with formation of o-lithiobenzyne (48), both of

which are most likely not free but form a complex, perhaps

of type XII. In the next step the putative complex composed

of 49 and 48 reacted through Li–N addition at C5 and C6

of 48 with formation of the o,oЈ-dilithiosulfinamide 50. The

selective addition of the N atom to C6 and the Li atom to

C5 of 48 is perhaps due to the polarization of the triple

bond and coordination of the O atom of 49 to the Li atom

of the o-lithiobenzyne. Li–N addition of 49 to 48 with the

N atom to C5 of the o-lithiobenzyne can be excluded be-

cause of the isolation of o-D-45 bearing the D atom at the

o-position to the N atom. Finally, the o,oЈ-dilithiophenyl-

Scheme 14. Elimination of lithium sulfinate from the o,oЈ-dilithio-

sulfone 53 with formation of o-lithiobenzyne (48).^[9]

The facile multi-step rearrangement of the six-membered

sulfinamide 50 underwent an AFR with formation of the cyclic o,oЈ-dilithiophenylsulfoximine 43 to the o,N-dilithio-

o,N-dilithio-2-sulfinylaniline 44. benzothiazocine 44 called for a study of the five-membered

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Sulfoximine-Directed o-Lithiation and Stereoselective Rearrangements

cyclic o,oЈ-dilithiophenylsulfoximine 56 (Scheme 15). The rearrangement to 57. The o,oЈ-dilithiosulfoximine 56 thus

sulfoximine 1 was thus treated with nBuLi (2.0 equiv.) at underwent elimination of the lithium sulfinamide 59 and

–50 °C and the reaction mixture was kept for 30 min at this gave lithiobenzyne (48) (Scheme 16). The putative complex

temperature. Subsequently, the mixture was allowed to composed of 48 and 59 reacted through a Li–N addition

warm to 20 °C for 1 h, whereupon a yellow solid deposited, to furnish the o,oЈ-dilithiosulfinamide 60, the stereoselective

and was then successively quenched with D₂O and H₂O. AFR of which furnished 57.

This sequence finally led to the isolation of the benzothi-

azepine S-oxide derivative o-D-58 in 84% yield. NMR spec-

troscopy showed o-D-58 to contain a D atom (94% D) in

1

the position o to the N atom. The H NMR spectrum of

58 also displayed the characteristic shift difference for the

signals of the H atoms in the 6- and 9-positions (cf.

Table 2).

Scheme 16. Rearrangement of the five-membered cyclic o,oЈ-di-

lithiosulfoximine 56 to the o,N-dilithiobenzothiazepine S-oxide 57.

Lithiation of the Benzothiazepine and Benzothiazocine S-

Oxide Derivatives

As mentioned above, the syntheses of the benzothiazep-

ine 58 and the benzothiazocine 45 from the corresponding

sulfoximines 1 and ent-2 involve double ortho-lithiation of

the phenylsulfoximines and the rearrangement of the o,oЈ-

dilithiophenylsulfoximines to the o,N-dilithioheterocycles,

reactions validated by the deuteration experiments.

Furthermore, it was found that the o,oЈ-dilithiosulfoximines

rearranged much more rapidly than the corresponding o-

lithiosulfoximines (see below). Although this evidence

strongly supports the mechanism proposed in Schemes 13

and 16, it was of importance definitely to rule out an alter-

native pathway, which would consist of 1) a single ortho-

lithiation of the sulfoximine, 2) rearrangement of the o-

lithiosulfoximine with formation of the corresponding N-

lithioheterocycle, and 3) subsequent lithiation of this with

nBuLi at the o-position to the N atom with formation of

the o,N-dilithioheterocycle. In order to rule out this path-

way, the heterocycles 58 and 45 were each treated in a first

experiment with nBuLi (1.1 equiv.) at 20 °C, followed by

quenching of the reaction mixture with D₂O and a subse-

quent aqueous workup (Scheme 17). This led to the recov-

ery of the corresponding non-deuterated heterocycles 58

and 45 in high yields. However, because of the relatively

high NH-acidities estimated for the phenylogous sulfin-

amides^[35]58 and 45,^[34]their reactions with nBuLi

(1.1 equiv.) should have given the corresponding lithium

salts 61 and 47 and their deuteration with D₂O the corre-

sponding heterocycles N-D-58 and N-D-45. The isolation

Scheme 15. Synthesis of the benzothiazepine S-oxide o-D-58 from

the five-membered cyclic phenylsulfoximine 1.

The structure of 58 was determined by NMR spec-

troscopy and X-ray crystal structure analysis^[36](Figure 7).

According to the X-ray analysis, the benzothiazepine S-ox-

ide 58 has the R configuration. The benzothiazepine S-ox-

ide 58 adopts a chair-like conformation, in which the O

atom is in the pseudoequatorial position and the N atom

has the S configuration.

Figure 7. Structure of the benzothiazepine S-oxide 58 in the crystal.

Bonding parameters (interatomic distances in Å and angles in °):

S–O 1.497(3), S–C_aryl1.793(4), S–C_alkyl1.840(4), N–C_aryl1.383(6),

N–C_alkyl1.477(5), C_aryl–S–C_alkyl–C_alkyl–72.0(3), C_alkyl–C_alkyl–N–

C_aryl93.1(5). Color code: sulfur: yellow; oxygen: red; nitrogen:

green; carbon: black; hydrogen: white.

The conversion of 1 to o-D-58 by the procedure depicted of the D-free phenylogous sulfinamides 58 and 45 after

in Scheme 15 gives indirect confirmation of the double aqueous workup was therefore due to D/H-exchange^[33]of

lithiation of sulfoximine 1 with formation of the o,oЈ-di- N-D-58 and N-D-45, respectively, with H₂O. Direct verifi-

lithiosulfoximine 56 via the o-lithiosulfoximine 27 and its cation of the formation of the lithium salts in the reactions

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FULL PAPER

between the heterocycles and nBuLi was provided by NMR

spectroscopy. Treatment of the benzothiazocine 45 with

nBuLi (1.1 equiv.) in [D₈]THF at 20 °C gave the lithium salt

47, the NMR spectra of which showed the characteristic

chemical shifts and shift differences in comparison with 45

(cf. Table 2).^[37]In a second experiment, the benzothiazep-

ine 58 was subjected to successive treatment with nBuLi

(2.2 equiv.), D₂O, and H₂O in order to determine whether

this would result in lithiation not only at the N atom but

also at the o-position to the N or the S atom. However, the

starting benzothiazepine containing no D atom was also

isolated in this case. The lithium salt 61 is therefore not

lithiated with nBuLi at the o-position either to the N atom

or to the S atom.

Scheme 18. Synthesis of the acyclic 2-sulfinylaniline 62 from the

tert-butylsulfoximine 7.

posed on the basis of these observations (Scheme 19).

Lithiation of the o-lithiosulfoximine 63 at the o-position af-

forded the o,oЈ-dilithiophenylsulfoximine 64, which was not

stable under the reaction conditions but underwent elimi-

nation of the lithium sulfinamide 65 and formation of li-

thiobenzyne (48). The reaction between 48 and the salt 65

led to the o,oЈ-dilithiosulfinamide 66, which underwent a

stereoselective AFR and gave the N,C-dilithiosulfinylaniline

67.

Scheme 17. Reaction of the sulfinylanilines 58 and 45 with nBuLi.

Acyclic Sulfoximines

The facile stereoselective syntheses of the benzothiazep-

ine S-oxide 58 and the benzothiazocine S-oxide 45 from the

cyclic sulfoximines 1 and ent-2, respectively, via the corre-

sponding o,oЈ-dilithiosulfoximines, prompted an investiga-

tion of the acyclic sulfoximine 7 (Scheme 18). It was of con-

siderable interest to see whether the rearrangement of the

o,oЈ-dilithiophenylsulfoximines to o,N-dilithiosulfinylanil-

ines is a general phenomenon or restricted to cyclic sulfox-

Scheme 19. Directed double ortho-lithiation of the acyclic sulfox-

imine 7 and rearrangement of the o,oЈ-dilithiophenylsulfoximine 64.

Stereochemical Course of the Rearrangement

The rearrangement of the o,oЈ-dilithiosulfoximine 56 to

imines. Treatment of the R-configured sulfoximine 7 with the o,N-dilithiosulfinylaniline 57 had occurred with overall

nBuLi (1.1 equiv.) at –78 °C to 0 °C gave the o-lithiosulfox- retention of configuration at the S atom, as revealed by the

imine 63 (Scheme 19, below). The o-lithiosulfoximine was X-ray crystal structure analysis of the sulfinylaniline 58. Be-

stable in solution under these conditions for several hours cause of this result, we assume that the rearrangements of

and upon aqueous workup afforded 7 in 95% yield. How- the o,oЈ-dilithiosulfoximines 43 and 64 also occurred with

ever, treatment of 7 with nBuLi (2.2 equiv.) at –78 °C to retention of configuration. The first steps of the rearrange-

0 °C was accompanied by deposition of a yellow solid. ments of the o,oЈ-dilithiosulfoximines 43, 56, and 64 – the

Aqueous workup after 2 h at this temperature afforded the elimination of the lithium sulfinamides 49, 59, and 65,

sulfinylaniline 62 in 85% yield. The S configuration was respectively – would be expected to take place with reten-

assignedto62^[38]onthebasisoftheRconfigurationofthesulf- tion of configuration at the S atoms.^[5,13,39]Therefore, the

inylaniline 58, which was derived from the S-configured AFRs of the o,oЈ-dilithiosulfinamides 50, 60, and 66 to the

sulfoximine 1. According to chiral HPLC, sulfoximine 7 of o,N-dilithiosulfinylanilines 44, 57, and 67, respectively, had

Ն98% ee gave the sulfinylaniline 62 of Ն98% ee.

also proceeded with retention of configuration. Interest-

A mechanistic explanation for the rearrangement of the ingly, the anionic AFRs of chiral o-lithiophenoxydiaza-

acyclic sulfoximine similar to that put forward in the case phospholidine oxides also takes place with retention of con-

of the cyclic sulfoximines (cf. Schemes 13 and 16) is pro- figuration at P.^[40]Retention of configuration in the AFRs

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Sulfoximine-Directed o-Lithiation and Stereoselective Rearrangements

of o,oЈ-dilithiosulfinamides can be explained by the apical- assigned. After the mixture had been kept for 48 h at 20 °C,

equatorial substitution mechanism,^[41]an example of which the ¹H NMR spectrum only displayed the signals of 61 and

is shown for the rearrangement of 60 in Scheme 20. The those of the unidentified compound. Aqueous workup of

R-configured o,oЈ-dilithiosulfinamide reacts by apical C–Li the mixture afforded the benzothiazepine 58 and acyclic

addition to the SO group to furnish the transient four-mem- sulfinamide 70 in minute amounts.

bered cyclic sulfurane 68, the equatorial breakdown of

which affords the R-configured o,N-dilithiosulfinylaniline

57. Alternatively, the AFR of 60 could proceed by a one-

step process via the transition state 69, featuring apical C–

S bond formation, equatorial S–N bond cleavage, and coor-

dination of the Li atom to both the O and the N atom.

Scheme 21. Formation of the N-lithiobenzothiazepine 61 from the

Scheme 20. Course of the AFR of the o,oЈ-dilithiosulfinamide 60

cyclic o-lithiosulfoximine 27.

(coordination of the Li atoms by THF and possible aggregation

are not considered).

The formation of the lithium salt 61 from the o-lithio-

sulfoximine 27 is interpreted as depicted in Scheme 22. The

o-lithiosulfoximine 27 was not stable at 20 °C for an ex-

VI. Rearrangement of a Cyclic o-Lithiophenylsulfoximine

tended period of time but slowly underwent elimination of

The o,oЈ-dilithiosulfoximine 56 (cf. Scheme 16) and its the lithium sulfinamide 59 and formation of benzyne

higher homologue 43 (cf. Scheme 13) were not stable but (71).^[43]The N–Li addition of the salt 59 to benzyne^[44]led

underwent elimination of the corresponding lithium sulfin- to the formation of the o-lithiosulfinamide 72, the AFR of

amides even at low temperatures, with formation of o- which afforded the lithium salt 61. Examples of additions

lithiobenzyne (48). This is in contrast with the reactivity of of sulfinamides to benzyne have recently been described.^[21]

the o-lithiosulfoximines 27 and 28 (Scheme 5), which ac- The above results show that not only o,oЈ-dilithiosulfox-

cording to the deuteration experiments and NMR spec- imines but also o-lithiosulfoximines undergo rearrangements

troscopy are significantly more stable towards elimination. to the corresponding 2-sulfinylaniline derivatives. NMR

Singly and doubly ortho-lithiated phenylsulfones exhibit spectroscopic investigation of 28 in THF at room tempera-

similar differences in stability.^[9,42]Whereas the ortho- ture also revealed a slow rearrangement of the six-mem-

lithiated tert-butylsulfonylbenzene 52 is stable at 0 °C, the bered o-lithiosulfoximine to the lithium salt 47 in this case.

o,oЈ-dilithiosulfone 53 is already prone to elimination below The relative low reactivities of o-lithiosulfoximines towards

0 °C (cf. Scheme 14). In order to obtain more detailed infor- lithium sulfinamide elimination is not too surprising in view

mation about the stability of o-lithiosulfoximines, the o- of the low nucleofugacity of the N-methyl-substituted sulf-

lithiosulfoximine 27 was studied by NMR spectroscopy.

oximine group.^[25,45]This contrasts with the higher reactivi-

The o-lithiosulfoximine 27 was prepared by treatment of ties of the o,oЈ-dilithiosulfoximines towards lithium sulfin-

the sulfoximine 1 with nBuLi (1.1 equiv.) in [D₈]THF at amide elimination. This can perhaps be explained at least

–70 °C. Then, the solution was sealed in an NMR tube and in part by a different degree of activation of the sulfoximine

subsequently allowed to warm to room temperature group by Li coordination. It is well established that electro-

(Scheme 21). Initially, the ¹H NMR spectrum only indi- philic activation of the N-methyl-substituted sulfoximine

1

cated the presence of 27. However, the H NMR spectrum group through, for example, alkylation^[5,46,47]or acyl-

of the solution of 27 at 20 °C showed the slow and gradual ation^[48]at the N atom greatly enhances its nucleofugacity.

formation of the lithium salt 61 at the expense of the o- The o,oЈ-dilithiosulfoximines and o-lithiosulfoximines per-

1

lithiosulfoximine. After 12 h at 20 °C, the H NMR spec- haps adopt monomeric structures of the types XIII and

trum showed a mixture of the o-lithiosulfoximine 27 and XIV, respectively, in which the sulfoximine group is either

the salt 61 in a ratio of approximately 1:1. At this point the coordinated through the O and the N atom to two Li atoms

¹H NMR spectrum also revealed the appearance of a fur- or through the N atom to only one Li atom, respec-

ther species, the structure of which, however, could not be tively.^[14a,16]The Li coordination would be expected to

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M. Wessels, V. Mahajan, S. Boßhammer, G. Raabe, H.-J. Gais

FULL PAPER

cause electrophilic activation of the sulfoximine group, rivatives provide a ready access to interesting chiral S-

which should thus be stronger in o,oЈ-dilithiosulfoximines benzoheterocycles.^[49]

than in o-lithiosulfoximines. The reactivity difference be-

tween singly and doubly ortho-lithiated tert-butylsulfonyl-

benzene could also be explained in part by similar argu-

ments.

Experimental Section

General: Reactions involving dioxygen- and water-sensitive com-

pounds were carried out in dry solvents under argon by use of

standard Schlenk, cannula, and syringe techniques in oven-dried

glassware. The sulfoximines 3,^[15]4,^[15]5,^[15]7,^[3]9,^[15]11,^[15]12,^[15]

and 15^[46]were prepared according to the literature. All reagents

employed were obtained from commercial suppliers. nBuLi was re-

ceived as a 1.6 m solution in n-hexane and standardized with the

aid either of diphenylacetic acid or of phenanthroline and benzyl

alcohol. THF was distilled from sodium-benzophenone ketyl.

Flash column chromatography was performed on silica gel 60

(0.040–0.063 mm). Thin-layer chromatography (TLC) was per-

formed on pre-coated alumina sheets (E. Merck, silica gel 60 F₂₅₄).

¹H, ¹³C, and ³¹P NMR spectra were recorded with Varian (Gem-

ini 300, Mercury 300, Inova 400) instruments. Chemical shifts are

given in ppm relative to Me₄Si (¹H: δ = 0.00 ppm, ¹³C: δ =

0.00 ppm) as internal reference, or to residual solvents signals

(THF: ¹H: δ = 1.73 and 3.58 ppm, ¹³C: δ = 25.4 and 67.6 ppm;

CHCl₃: ¹H: δ = 7.26 ppm, ¹³C: δ = 77.0 ppm) for ¹H and ¹³C spec-

tra, and to H₃PO₄as external reference for the ³¹P spectra. The

coupling constants are given in Hertz. The multiplicities and shapes

of the signals are denoted as follow: s = singlet, d = doublet, t =

triplet, br = broad, sym = symmetrical signal, and combinations

thereof. Assignment of the peaks in the ¹H NMR spectra was

achieved through GMQCOSY, GNOE, or GTOCSY experiments.

Assignment of the peaks in the ¹³C NMR spectra was achieved

through APT, DEPT, and HETCOR experiments. IR spectra were

recorded with a Perkin–Elmer PE 1760 FT spectrometer as KBr

pellets or in solution. Absorptions are given in cm^–1in a range

from 4000 to 850 cm^–1, and the following abbreviations are used to

describe their relative intensities: w = weak, m = medium, s =

strong. Mass spectra were recorded with a Varian Mat 212 S and

a Finnigan MAT 312 for ionization through EI (Electronic impact,

70 eV) and CI (chemical ionization, 100 eV). Only peaks of m/z

Ͼ 80 and intensities Ͼ10%, except decisive ones, are given. High-

resolution mass spectrometry (HRMS) was performed with a Fin-

nigan MAT 95 (EI) or a Micromass LCT (LC-TOF-HRMS, col-

umn Acquit UPLC BEH C₁₈) instrument. Elemental analyses were

Scheme 22. Rearrangement of the o-lithiosulfoximine 27.

Conclusions

The sulfoximine moiety is a powerful directed single and

double ortho-lithiation group. Lithiation of cyclic sulfox-

imines also bearing H atoms at their α-positions with nBuLi

can be highly ortho-selective and fast at low temperatures.

The o-lithiosulfoximines show high reactivity towards elec-

trophiles. The transmetalation of o-lithiosulfoximines to the

corresponding α-lithiosulfoximines is also fast and occurs

even at low temperatures. An interesting feature of the cy-

clic and acyclic sulfoximines is their facile double ortho- done with a Heraeus CHN-Rapid instrument. Optical rotations

were measured with a Perkin–Elmer Polarimeter PE 241 and given

in grad ϫ mL/dm ϫ g, and the concentration c in g/100 mL. The

measurements were run at approximately 22 °C. Melting points

were measured in open glass capillaries with a Büchi 510 SMP-20

melting point apparatus and are uncorrected.

lithiation. Whereas the o-lithiosulfoximines are stable at

0 °C, o,oЈ-dilithiosulfoximines undergo interesting multi-

step rearrangements to give N,C-dilithio-2-sulfinylaniline

derivatives even at lower temperatures. The rearrangements

of the o,oЈ-dilithio-phenylsulfoximines involve: 1) stereo-

selective elimination of the lithium sulfinamide with reten-

tion of configuration and the formation of o-lithiobenzyne,

2) reaction of the lithium sulfinamides with the o-lithiobenz-

yne through Li–N addition to give the o,oЈ-dilithiophenyl-

sulfonamides, and 3) AFRs of the o,oЈ-dilithiophenylsulfin-

amides with retention of configuration to afford the o,N-

dilithiosulfinylanilines. The retention of configuration in

the AFRs of the o,oЈ-dilithiosulfinamides can be explained

General Procedure for the α-Methylation of the Sulfoximines 11 and

12 (GP 1): nBuLi (1.1 equiv. of 1.60 m in n-hexane) was added

dropwise at –50 °C to a solution of the sulfoximine in THF

(10 mLmmol^–1). After the mixture had been stirred for 10 min at

room temperature, it was cooled to –78 °C and the electrophile was

added. The mixture was then stirred for 3 h at this temperature,

poured into saturated aqueous NH₄Cl, and extracted with EtOAc.

The combined organic phases were dried (MgSO₄) and concen-

trated in vacuo. Purification by chromatography gave the pure sub-

either through the two-step apical-equatorial substitution stituted sulfoximine.

mechanism via a four-membered cyclic sulfurane or by a

General Procedure for the ortho-Lithiation of Sulfoximines and Deu-

one-step process via a sulfurane-like transition state. The

stereoselective conversions of the cyclic phenylsulfoximines

teration of o-Lithiosulfoximines (GP 2): nBuLi (1.1 equiv. of 1.60 m

in n-hexane) was added dropwise at –78 °C to a solution of the

into the benzothiazepine and benzothiazocine S-oxide de- sulfoximine in THF (10 mLmmol^–1). After the mixture had been

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Sulfoximine-Directed o-Lithiation and Stereoselective Rearrangements

stirred for 10 min at this temperature, it was treated at –78 °C with

the deuterium-containing reagent. The mixture was then allowed to

warm slowly to room temperature, poured into saturated aqueous

NH₄Cl, and extracted with EtOAc. The combined organic phases

were dried (MgSO₄) and concentrated in vacuo. The crude sulfox-

imine was analyzed by NMR spectroscopy without further purifi-

cation.

12.3, 6.0, 2.7 Hz, 1 H, NCH₂CH₂), 2.35 (ddd, J = 12.9, 8.0, 7.8 Hz,

1 H, NCH₂CH₂), 3.70 (ddd, J = 10.7, 8.5, 6.1 Hz, 1 H, NCH₂),

3.94 (ddd, J = 10.7, 7.4, 2.5 Hz, 1 H, NCH₂), 7.51–7.57 (m, 2 H,

Ph), 7.61–7.67 (m, 1 H, Ph), 7.95–7.99 (m, 2 H, Ph) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 22.1 (d), 23.6 (d), 39.0 (u), 51.1 (u), 65.9

(u), 128.6 (d), 130.5 (d), 133.2 (d), 135.4 (u) ppm. IR (KBr): ν =

˜

3433 (w), 3062 (w), 2997 (w), 2970 (m), 2915 (m), 2862 (s), 1446

(s), 1385 (w), 1368 (w), 1326 (m), 1236 (s), 1196 (s), 1138 (s), 1100

(s), 1055 (s), 1025 (m), 994 (m), 966 (m), 930 (m), 892 (s), 856

(s) cm^–1. MS (EI, 70 eV): m/z (%) = 209 [M]⁺(7), 154 (18), 126

(12), 125 (100), 84 (11), 77 (12). C₁₁H₁₅NOS (209.31): calcd. C

63.12, H 7.22, N 6.69; found C 62.72, H 7.41, N 6.61.

(+)-(1S)-6,6-Dimethyl-1-phenyl-3,4,5,6-tetrahydro-1λ⁴-1,2-thiazine

1-Oxide (2): Treatment of the sulfoximine 12 (1.1 g, 5.26 mmol)

with MeI (1.12 g, 7.88 mmol) as described in GP 1 and chromatog-

raphy (EtOAc/MeOH 9:1) gave the sulfoximine 2 (601 mg, 52%) as

General Procedure for the ortho-Alkylation of the Cyclic Sulfox-

imines 4 and 5 (GP 3): nBuLi (1.1 equiv. of 1.60 m in n-hexane) was

added dropwise at –78 °C to a solution of the sulfoximine in dry

THF (10 mLmmol^–1). After the mixture had been stirred for

10 min at this temperature, it was treated at –78 °C with the electro-

phile. The mixture was then stirred for 3 h at –78 °C. The mixture

was poured into saturated aqueous NH₄Cl and extracted with

EtOAc. The combined organic phases were dried (MgSO₄) and

concentrated in vacuo. Purification by chromatography gave the

substituted sulfoximine.

a colorless solid; R_f= 0.44 (EtOAc/MeOH 9:1); m.p. 95 °C. [α]_D

=

+25.7 (c = 0.82 in CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 1.16

(s, 3 H, Me), 1.29 (s, 3 H, Me), 1.54–1.59 (symm, 1 H,

CH₂CH₂CH₂), 1.80 (ddd, J = 14.0, 5.2, 1.8 Hz, 1 H, CCH₂), 2.06–

2.16 (symm, 1 H, CH₂CH₂CH₂), 2.53 (td, J = 14.0, 3.4 Hz, 1 H,

CCH₂), 3.45 (ddt, J = 1.8, 3.1, 13.1 Hz, 1 H, NCH₂), 3.65 (td, J =

3.7, 13.1 Hz, 1 H, NCH₂), 7.51–7.55 (m, 2 H, Ph), 7.60–7.64 (m, 1

H, Ph), 7.99–8.03 (m, 2 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃):

δ = 21.1 (u), 23.7 (d), 25.9 (d), 35.9 (u), 43.2 (u), 56.1 (u), 128.5

General Procedure for the Lithiation of the Sulfoximines 36 and 9

(GP 4): nBuLi (1.1 equiv. of 1.60 m in n-hexane) was added drop-

wise at –50 °C to

a solution of the sulfoximine in THF

(10 mLmmol^–1). After the mixture had been stirred for 10 min at

room temperature, it was cooled to –78 °C and CF₃COOD was

added. The mixture was then allowed to warm to room temperature

and poured into saturated aqueous NaHCO₃. The mixture was ex-

tracted with EtOAc, and the combined organic phases were dried

(MgSO₄) and concentrated in vacuo. The residue was analyzed by

NMR spectroscopy.

(d), 130.2 (d), 133.0 (d), 134.5 (u) ppm. IR (KBr): ν = 3690 (w),

˜

3677 (w), 3651 (w), 3631 (w), 3433 (m), 3163 (w), 3094 (m), 3064

(m), 3051 (m), 2983 (m), 2942 (s), 2842 (s), 2676 (w), 2190 (w),

2020 (w), 1942 (w), 1815 (w), 1720 (w), 1629 (w), 1582 (m), 1471

(s), 1448 (s), 1386 (m), 1367 (m), 1349 (m), 1311 (w), 1277 (m),

1241 (s), 1204 (s), 1120 (s), 1090 (s), 1071 (s), 1036 (s), 995 (s), 953

(s), 891 (s), 860 (s), 826 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 223

[M]⁺(10), 208 (50), 126 (14), 125 (100), 77 (10), 69 (11), 55 (16).

C₁₂H₁₇NOS (223.34): calcd. C 64.54, H 7.67, N 6.27; found C

64.53, H 7.84, N 6.18.

(+)-(1S,6S)-6-(Trimethylsilyl)methyl-1-phenyl-3,4,5,6-tetrahydro-

1λ⁴-1,2-thiazine 1-Oxide (6): nBuLi (1.84 mL of 1.60 m in n-hexane,

2.95 mmol) was added dropwise at –50 °C to a solution of the sulf-

oximine 9 (523 mg, 2.68 mmol) in dry THF (25 mL). After the mix-

ture had been stirred for 10 min at room temperature, ClCH₂SiMe₃

(492 mg, 4.02 mmol) was added at –78 °C. After the mixture had

been stirred at this temperature for 3 h, it was allowed to warm to

room temperature over 15 h. Saturated aqueous NH₄Cl was then

added and the mixture was extracted with EtOAc. The combined

organic phases were dried (MgSO₄) and concentrated in vacuo. Pu-

rification by chromatography (EtOAc/MeOH 9:1) gave the sulfox-

imine 6 (731 mg, 97%) with Ն98% de (¹H NMR, CH₂SiMe₃) as a

(–)-(R)-N-[(1,1-Dimethylethyl)diphenylsilyl]-S-(1,1-dimethylethyl)-

S-phenyl-sulfoximine (8): nBuLi (15.9 mL of 1.60 m in n-hexane,

25.4 mmol) was added dropwise at –78 °C to a solution of the sulf-

oximine 16 (10.00 g, 25.4 mmol) in THF (50 mL). After the mixture

had been stirred at this temperature for 30 min, MeI (1.59 mL,

25.4 mmol) was added. The mixture was then stirred for 30 min at

–78 °C, after which nBuLi (15.9 mL of 1.60 m in n-hexane,

25.4 mmol) was added dropwise at –78 °C. After the mixture had

been stirred at this temperature for 30 min, MeI (1.59 mL,

25.4 mmol) was added. The mixture was then stirred for 30 min at

–78 °C, after which nBuLi (15.9 mL of 1.60 m in n-hexane,

25.4 mmol) was added dropwise at –78 °C. After the mixture had

been stirred at this temperature for 30 min, MeI (1.59 mL,

25.4 mmol) was added. The mixture was then stirred for 30 min at

–78 °C. Subsequently, the mixture was treated with saturated

aqueous NH₄Cl and extracted with EtOAc. The combined organic

phases were dried (MgSO₄) and concentrated in vacuo. Purification

by chromatography (cyclohexane/EtOAc 5:1) gave the sulfoximine

8 as a colorless oil, which solidified upon standing; R_f= 0.60 (cy-

1

colorless solid; m.p. 75 °C. [α]_D= +27.8 (c = 1.05 in CDCl₃). H

NMR (300 MHz, CDCl₃): δ = –0.10 (s, 9 H, SiMe₃), 0.71 (dd, J =

2.7, 14.8 Hz, 1 H, CH₂Si), 0.92 (dd, J = 11.5, 14.7 Hz, 1 H, CH₂Si),

1.85–1.96 (m,

1

H, CH₂CH₂CH₂), 1.87–2.05 (m,

1 H,

CH₂CH₂CH₂), 2.12–2.21 (m, 2 H, CHCH₂), 2.93 (ddd, J = 14.4,

9.7, 2.3 Hz, 1 H, CHS), 3.39–3.49 (m, 1 H, CH₂N), 3.56–3.67 (m,

1 H, CH₂N), 7.50–7.58 (m, 2 H, Ph), 7.59–7.66 (m, 1 H, Ph), 7.79–

8.03 (m, 2 H, Ph) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = –1.1 (d),

18.2 (u), 26.5 (u), 29.8 (u), 43.3 (u), 59.4 (d), 128.9 (d), 128.2 (d),

133.1 (d), 136.8 (u) ppm. IR (capillary): ν = 3796 (s), 3378 (s), 3062

˜

(m), 2846 (w), 2674 (s), 2329 (s), 2243 (s), 1938 (s), 1819 (s), 1584

(s), 1349 (m), 1285 (m), 1160 (m), 1092 (w), 1069 (m), 1045 (m),

1030 (m), 987 (m), 892 (m) cm^–1. MS (EI, 70 eV): m/z (%) = 281

[M]⁺(1), 198 (11), 194 (65), 125 (72), 75 (11). C₁₄H₂₃NOSSi

(281.49): calcd. C 59.74, H 8.24, N 4.98; found C 59.49, H 8.28, N

5.29.

1

clohexane/EtOAc 1:1). [α]_D= –78.8 (c = 1.0 in CH₂Cl₂). H NMR

(300 MHz, C₆D₆): δ = 1.14 (s, 9 H, tBu), 1.32 (s, 9 H, tBu), 6.80–

(+)-(1S)-5,5-Dimethyl-1-phenyl-4,5-dihydro-3H-1λ⁴-isothiazole 1- 6.92 (m, 3 H, Ph), 7.12–7.25 (m, 6 H, Ph), 7.71–7.76 (symm, 2 H,

Oxide (1): Treatment of the sulfoximine 11 (624 mg, 3.56 mmol)

with MeI (550 mg, 3.84 mmol) as described in GP 1 and

Ph), 7.90–8.00 (m, 4 H, Ph) ppm. ¹³C NMR (100 MHz, C₆D₆): δ

= 20.1 (u), 23.9 (d), 27.7 (d), 61.6 (u), 129.02 (d), 129.11 (d), 130.6

(d), 131.8 (d), 136.2 (d), 136.9 (u), 137.4 (u), 139.4 (u) ppm. IR

chromatography (EtOAc/MeOH 9:1) gave the sulfoximine

1

(289 mg, 54%) as colorless solid; R_f= 0.25 (EtOAc/MeOH 9:1);

(KBr): ν = 3063 (m), 3023 (m), 2930 (s), 2855 (s), 1472 (s), 1429

˜

m.p. 78 °C. [α]_D= +45.0 (c = 1.05 in CHCl₃). ¹H NMR (400 MHz,

(m), 1388 (m), 1313 (s), 1183 (m), 1139 (s), 1106 (s), 820 (m) cm^–1.

CDCl₃): δ = 0.93 (s, 3 H, Me), 1.54 (s, 3 H, Me), 2.04 (ddd, J = MS (EI, 70 eV): m/z (%) = 378 [M – tBu]⁺(100), 322 (85), 304 (30),

Eur. J. Org. Chem. 2011, 2431–2449

www.eurjoc.org

2443

M. Wessels, V. Mahajan, S. Boßhammer, G. Raabe, H.-J. Gais

FULL PAPER

259 (15), 244 (10), 212 (18), 199 (10). C₂₆H₃₃NOSSi (435.69): calcd.

C 71.67, H 7.63, N 3.21; found C 72.05, H 7.28, N 3.21.

Me), 1.90–2.00 (m, 1 H, CCH₂), 2.20 (s, 3 H, Me), 2.21–2.34 (m,

1 H, CCH₂), 2.58 (dd, J = 14.0, 2.8 Hz, 1 H, CH₂Ar), 2.85 (dd, J

= 14.0, 11.8 Hz, 1 H, CH₂Ar), 3.06–3.15 (m, 1 H, CHS), 3.39–3.45

(m, 1 H, NCH₂), 3.61–3.68 (m, 1 H, NCH₂), 6.75 (s, 2 H, Ph),

7.55–7.61 (m, 2 H, Ph), 7.83–7.87 (m, 1 H, Ph), 8.13–8.18 (m, 1 H,

Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 2.8 (d), 20.3 (d), 21.1

(d), 26.2 (u), 26.8 (u), 30.1 (u), 43.9 (u), 60.8 (d), 129.4 (d), 129.4

(d), 130.4 (u), 130.8 (d), 132.5 (d), 136.2 (u), 137.0 (u), 137.0 (d),

(+)-(1S,6S)-6-Benzyl-1-(2-methylphenyl)-3,4,5,6-tetrahydro-1λ⁴-1,2-

thiazine 1-Oxide (20): Treatment of the sulfoximine 4 (646 mg,

2.26 mmol) with MeI (420 mg, 2.94 mmol) as described in GP 2

and chromatography (EtOAc/MeOH 9:1) gave the sulfoximine 20

(466 mg, 69%) with Ն98% de (¹H NMR, o,oЈ-Ph) as a colorless

oil; R_f= 0.62 (EtOAc/MeOH 9:1). [α]_D= +35.7 (c = 1.00 in

CH₂Cl₂). ¹H NMR (500 MHz, CDCl₃): δ = 1.73–1.91 (m, 2 H,

CH₂CH₂CH₂), 2.07–2.14 (m, 1 H, CCH₂), 2.16–2.26 (m, 1 H,

CCH₂), 2.67 (dd, J = 14.0, 9.8 Hz, 1 H, CH₂Ph), 2.84 (s, 3 H, Me),

2.84 (dd, J = 14.0, 4.6 Hz, 1 H, CH₂Ph), 3.35 (dddd, J = 12.5, 9.2,

4.6, 4.2 Hz, 1 H, CHS), 3.41–3.47 (m, 1 H, NCH₂), 3.59–3.66 (m,

1 H, NCH₂), 6.91–6.94 (m, 2 H, Ph), 7.10–7.19 (m, 3 H, Ph), 7.27–

7.34 (m, 2 H, Ph), 7.42–7.46 (m, 1 H, Ph), 8.07–8.11 (m, 1 H,

Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 20.8 (d), 25.6 (u), 27.3

(u), 37.4 (u), 43.7 (u), 59.2 (d), 126.3 (d), 126.6 (d), 128.4 (d), 129.0

142.0 (u), 142.6 (u) ppm. IR (KBr): ν = 3448 (w), 3054 (w), 2943

˜

(s), 2851 (s), 1613 (w), 1579 (w), 1560 (w), 1481 (m), 1455 (m), 1420

(m), 1381 (w), 1349 (w), 1285 (m), 1248 (s), 1206 (s), 1176 (m),

1156 (m), 1117 (s), 1065 (m), 1044 (m), 1000 (m), 896 (m), 847 (s),

806 (s) cm^–1. MS (EI, 70 eV): m/z (%) = 399 [M]⁺(3), 385 (13), 384

(41), 327 (16), 326 (70), 202 (51), 191 (28), 182 (43), 167 (27), 159

(15), 134 (11), 133 (100), 131 (10), 119 (13), 117 (12), 105 (13), 91

(15), 70 (41). C₂₃H₃₃NOSSi (399.68): calcd. C 69.12, H 8.32, N

3.50; found C 68.83, H 8.66, N 3.38.

(d), 131.2 (d), 133.0 (d), 133.1 (d), 134.5 (u), 136.5 (u), 138.1 (+)-(1S,6S)-1-[2,6-Bis(trimethylsilylphenyl)]-6-(2,4,6-trimethylbenz-

(u) ppm. IR (capillary): ν = 3060 (m), 3026 (m), 3002 (w), 2927 (s),

yl)-3,4,5,6-tetrahydro-1λ⁴-1,2-thiazine 1-Oxide (24): Treatment of

˜

2847 (m), 1496 (m), 1471 (m), 1454 (s), 1349 (w), 1272 (m), 1247 the sulfoximine 22 (272 mg, 0.68 mmol) and ClSiMe₃(80 mg,

(s), 1232 (s), 1208 (s), 1193 (s), 1159 (m), 1138 (s), 1113 (s), 1076 0.75 mmol) as described in GP 2 and chromatography (EtOAc/n-

(m), 1059 (m), 1036 (w), 1003 (m), 930 (w), 898 (m), 874 (w), 842 hexane 1:1) gave the sulfoximine 24 (193 mg, 60%) with Ն98% de

(m), 824 (m), 808 (m) cm^–1. MS (EI, 70 eV): m/z(%) = 299 [M]⁺

(¹H NMR, C₆H₂Me) as a colorless solid; R_f= 0.80 (EtOAc/n-hex-

1

(6), 161 (12), 160 (100), 139 (26), 117 (13), 111 (17), 91 (49), 77 (19), ane 1:1); m.p. 56 °C. [α]_D= +2.4 (c = 0.98 in CH₂Cl₂). H NMR

65 (10). HRMS for C₁₈H₂₁NOS [M]⁺: calcd. 299.134387; found

299.134297. C₁₈H₂₁NOS (299.13): calcd. C 72.20, H 7.07, N 4.68;

found C 71.82, H 7.25, N 5.12.

(400 MHz, CDCl₃): δ = 0.46 (s, 9 H, SiMe₃), 0.46 (s, 9 H, SiMe₃),

1.58–1.88 (m, 1 H, CH₂CH₂CH₂), 1.80 (s, 6 H, Me), 1.84–2.04 (m,

2 H, CCH₂, CH₂CH₂CH₂), 2.14 (dd, J = 13.7, 1.9 Hz, 1 H,

CH₂Ar), 2.18 (s, 3 H, Me), 2.28–2.40 (m, 1 H, CCH₂), 2.68 (dd, J

= 13.7, 11.8 Hz, 1 H, CH₂Ar), 2.78–2.87 (m, 1 H, CHS), 3.42–3.48

(m, 1 H, NCH₂), 3.74–3.83 (m, 1 H, NCH₂), 6.72 (s, 2 H, Ph),

7.53–7.57 (t, J = 7.4 Hz, 1 H, Ph), 7.93 (dd, J = 7.4, 1.3 Hz, 1 H,

Ph), 7.97 (dd, J = 7.4, 1.3 Hz, 1 H, Ph) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 4.3 (d), 4.39 (d), 20.1 (d), 21.1 (d), 24.5 (u), 26.4 (u),

30.1 (u), 43.0 (u), 60.3 (d), 129.4 (d), 130.6 (u), 130.8 (d), 136.0 (u),

136.9 (u), 137.9 (d), 142.2 (u), 144.2 (u), 145.8 (u) ppm. IR (KBr):

(+)-(1S,6S)-1-(2-Methylphenyl)-6-(2,4,6-trimethylbenzyl)-3,4,5,6-

tetrahydro-1λ⁴-1,2-thiazine 1-Oxide (21): Treatment of the sulfox-

imine 5 (440 mg, 1.30 mmol) with MeI (210 mg, 1.48 mmol) as de-

scribed in GP 2 and chromatography (EtOAc/MeOH 9:1) gave the

sulfoximine 21 (315 mg, 71%) with Ն98% de (¹H NMR, o,oЈ-Ph)

as a colorless solid; R_f= 0.57 (EtOAc/MeOH 9:1); m.p. 124 °C.

1

[α]_D= +33.4 (c = 1.2 in CH₂Cl₂). H NMR (500 MHz, CDCl₃): δ

= 1.71–1.85 (m, 2 H, CH₂CH₂CH₂), 1.95 (s, 6 H, Me), 1.99–2.06

(m, 1 H, CCH₂), 2.19 (s, 3 H, Me), 2.25–2.35 (m, 1 H, CCH₂), 2.63

(dd, J = 14.3, 3.0 Hz, 1 H, CH₂Ar), 2.86 (dd, J = 14.1, 11.0 Hz, 1

H, CH₂Ar), 2.86 (s, 3 H, Me), 3.19 (dddd, J = 12.6, 4.1, 11.1,

3.1 Hz, 1 H, CHS), 3.45 (ddt, J = 12.8, 4.3, 2.2 Hz, 1 H, NCH₂),

3.64 (dt, J = 13.1, 4.0 Hz, 1 H, NCH₂), 6.74 (s, 2 H, Ph), 7.32–7.35

(m, 1 H, Ph), 7.37–7.42 (m, 1 H, Ph), 7.48–7.53 (m, 1 H, Ph), 8.19–

8.23 (m, 1 H, Ph) ppm. ¹³C NMR (125 MHz, CDCl₃): δ = 20.1 (d),

21.0 (d), 21.3 (d), 26.3 (u), 27.3 (u), 30.2 (u), 44.1 (u), 58.4 (d),

126.6 (d), 129.4 (d), 130.5 (u), 131.9 (d), 133.4 (d), 133.6 (d), 134.1

ν = 3447 (w), 2946 (s), 2856 (m), 1614 (w), 1464 (m), 1383 (w),

˜

1340 (w), 1244 (s), 1204 (s), 1177 (w), 1145 (m), 1115 (s), 1083 (w),

1066 (w), 1043 (w), 998 (w), 892 (m), 847 (s), 805 (m) cm^–1. MS

(EI, 70 eV): m/z (%) = 471 [M]⁺(3), 458 (20), 457 (40), 456 (100),

399 (14), 398 (47), 269 (11), 254 (15), 239 (13), 202 (39), 133 (51),

73 (28), 45 (22). C₂₆H₄₁NOSSi₂(471.86): calcd. C 66.18, H 8.76, N

2.97; found C 65.81, H 8.69, N 2.67.

Synthesis of the o-Lithiosulfoximine 23 from the Bissilane 24 and Its

Deuteration: Treatment of the bissilane 24 (44 mg, 0.09 mmol) with

nBuLi (0.06 mL of 1.60 m in n-hexane, 0.10 mmol) as described in

GP 2, 10 min stirring at room temperature, and addition of

(u), 136.2 (u), 136.9 (u), 138.9 (u) ppm. IR (KBr): ν = 3056 (w),

˜

3011 (w), 2929 (s), 2851 (s), 2732 (w), 2683 (w), 2246 (w), 1610 (w),

1593 (w), 1570 (w), 1447 (s), 1379 (m), 1352 (w), 1247 (s), 1209 (s), CH₃CO₂D (0.01 mL of 17 m in THF, 0.23 mmol) at –78 °C gave

1192 (s), 1177 (s), 1156 (s), 1116 (s), 1058 (s), 1033 (m), 1001 (m),

896 (s), 878 (m), 855 (s), 834 (s), 807 (s) cm^–1. MS (EI, 70 eV): m/z

(%) = 341 [M]⁺(15), 221 (13), 202 (54), 173 (13), 159 (13), 157 (10),

139 (70), 134 (11), 133 (100), 131 (11), 129 (12), 119 (13), 118 (17),

117 (17), 111 (16), 105 (12), 91 (16), 77 (14), 70 (80). C₂₁H₂₇NOS

(341.52): calcd. C 73.86, H 7.97, N 4.10; found C 73.48, H 7.67, N

3.99.

the sulfoximine o-D-22 (36 mg, 95%) with a D content of Ն95%

(¹H NMR, o,oЈ-Ph) as a colorless oil.

(+)-(1S,6S)-6-Benzyl-1-(2-ethylphenyl)-3,4,5,6-tetrahydro-1λ⁴-1,2-

thiazine 1-Oxide (26): nBuLi (0.29 mL of 1.6 m in n-hexane,

0.47 mmol) was added dropwise at –50 °C to a solution of the sul-

foximine 20 (127 mg, 0.42 mmol) in THF (10 mL). After the mix-

ture had been stirred for 10 min at room temperature, whereupon

it attained a red color, it was treated at –78 °C with MeI (90 mg,

0.64 mmol) and stirred for 3 h at this temperature. The mixture was

then poured into saturated aqueous NH₄Cl (20 mL) and extracted

with EtOAc (3ϫ 20 mL). The combined organic phases were dried

(+)-(1S,6S)-6-(2,4,6-Trimethylbenzyl)-1-(2-trimethylsilylphenyl)-

3,4,5,6-tetrahydro-1λ⁴-1,2-thiazine 1-Oxide (22): Treatment of the

sulfoximine 5 (380 mg, 1.16 mmol) with ClSiMe₃(190 mg,

1.30 mmol) as described in GP 2 and chromatography (EtOAc)

gave the sulfoximine 22 (276 mg, 60%) with Ն98% de (¹H NMR, (MgSO₄) and concentrated in vacuo. Purification by chromatog-

o,oЈ-Ph) as a colorless solid; R_f= 0.64 (EtOAc); m.p. 62 °C. [α]_D

=

raphy (EtOAc/MeOH 9:1) gave the sulfoximine 26 (118 mg, 90%)

+40.6 (c = 0.52 in CH₂Cl₂). ¹H NMR (400 MHz, CDCl₃): δ = 0.47 with Ն98% de (¹H NMR, o,oЈ-Ph) as a colorless oil; R_f= 0.57

1

(s, 9 H, SiMe₃), 1.68–1.88 (m, 2 H, CH₂CH₂CH₂), 1.93 (s, 6 H,

2444

(EtOAc/MeOH 9:1). [α]_D= +16.4 (c = 2.25 in CH₂Cl₂). H NMR

www.eurjoc.org

Eur. J. Org. Chem. 2011, 2431–2449

Sulfoximine-Directed o-Lithiation and Stereoselective Rearrangements

(400 MHz, CDCl₃): δ = 1.34 (t, J = 7.7 Hz, 3 H, Me), 1.70–1.91

as a white foam, which solidified upon standing; R_f= 0.62 (cyclo-

(m, 2 H, CH₂CH₂CH₂), 2.04–2.13 (m, 1 H, CCH₂), 2.14–2.26 (m, hexane/EtOAc 1:1). [α]_D= +19.9 (c = 1.0 in CH₂Cl₂). ¹H NMR

1 H, CCH₂), 2.68 (dd, J = 14.0, 10.2 Hz, 1 H, CH₂Ph), 2.84 (dd,

J = 14.0, 4.4 Hz, 1 H, CH₂Ph), 3.22–3.39 (m, 3 H, 1 H, CH₂Me),

(400 MHz, C₆D₆): δ = 1.10 (s, 9 H, tBu), 1.39 (s, 9 H, tBu), 6.67

(dt, J = 6, 1 Hz, 1 H, Ph), 6.74 (dt, J = 6, 1 Hz, 1 H, Ph), 7.00–

3.43 (ddt, J = 12.9, 4.4, 1.9 Hz, 1 H, NCH₂), 3.62 (td, J = 12.6, 7.20 (m, 11 H, Ph), 7.28–7.31 (m, 2 H, Ph), 7.42–7.49 (m, 2 H, Ph),

3.3 Hz, 1 H, NCH₂), 6.91–6.94 (m, 2 H, Ph), 7.10–7.20 (m, 3 H, 7.75–7.77 (m, 2 H, Ph), 7.85–7.90 (m, 5 H, Ph) ppm. ¹³C NMR

Ph), 7.28–7.34 (m, 1 H, Ph), 7.36–7.40 (m, 1 H, Ph), 7.47–7.53 (m,

(100 MHz, CDCl₃): δ = 20.0 (u), 24.3 (d) (d, J_P,C= 5.3 Hz), 27.6

(u), 63.3 (u), 131.6 (d), 133.6 (d), 134.0 (d) (d, J_P,C= 9.1 Hz), 134.2

1 H, Ph), 8.08–8.12 (m, 1 H, Ph) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 16.4 (d), 25.9 (u), 25.95 (u), 27.6 (u), 37.6 (u), 44.1 (d) (d, J_P,C= 9.9 Hz), 136.0 (d) (d, J_P,C= 5.3 Hz), 136.1 (d), 136.7

(u), 60.7 (d), 126.3 (d), 126.9 (d), 128.3 (d), 128.7 (d), 131.3 (d),

131.5 (d), 133.5 (d), 134.2 (u), 136.7 (u), 144.9 (u) ppm. IR (capil-

(u), 137.2 (u), 138.3 (u), 140.4 (u), 140.6 (u), 141.2 (u) ppm. ³¹P

NMR (162 MHz, C₆D₆): δ = –3.3 ppm. MS (EI, 70 eV): m/z (%) =

563 [M – tBu]⁺(6), 506 (100), 472 (3), 428 (3), 396 (2), 308 (7), 259

(2), 230 (1). MS (CI, CH₄): m/z (%) = 620 [M]⁺(8), 563 (65), 542

lary): ν = 3060 (m), 3026 (m), 2930 (s), 2848 (m), 2848 (w), 1602

˜

(w), 1496 (m), 1473 (m), 1454 (m), 1442 (m), 1349 (w), 1247 (s),

1207 (s), 1189 (s), 1159 (m), 1139 (m), 1113 (s), 1076 (m), 1057 (m), (45), 506 (100), 309 (86). C₃₈H₄₂NOPSSi (619,87): calcd. C 73.63,

1038 (w), 1003 (w), 897 (m), 874 (w), 842 (m), 824 (m), 804

(m) cm^–1. MS (EI, 70 eV): m/z (%) = 313 [M]⁺(5), 161 (13), 160

(100), 135 (40), 117 (12), 91 (38). HRMS for C₁₉H₂₃NOS [M]⁺:

calcd. 313.150037; found 313.150036.

H 6.83, N 2.26; found C 74.41, H 7.02, N 2.00.

(+)-(R)-({2-[N-(1,1-Dimethylethyl)diphenylsilyl]-S-(1,1-dimethyleth-

yl)-sulfonimidoyl}phenyl)diphenylphosphane Oxide (32): nBuLi

(3.9 mL of 1.60 m in n-hexane, 6.33 mmol) was added dropwise at

–78 °C to a solution of the sulfoximine 8 (2.12 g, 4.87 mmol) in

THF (15 mL). After the mixture had been stirred for 30 min at this

temperature, ClP(O)Ph₂(1.14 mL, 6.33 mmol) was added and the

mixture was stirred for 2 h at –78 °C. Saturated aqueous NH₄Cl

(30 mL) was then added and the mixture was extracted with

CH₂Cl₂. The combined organic phases were dried (MgSO₄) and

concentrated in vacuo. Purification by chromatography (cyclohex-

ane/EtOAc 5:1) gave the phosphane oxide 32 (2.33 g, 75%) as a

white foam; R_f= 0.15 (cyclohexane/EtOAc 1:1). [α]_D= –39.8 (c =

1.10 in CH₂Cl₂). ¹H NMR (300 MHz, C₆D₆): δ = 1.16 (s, 9 H,

tBu), 1.35 (s, 9 H, tBu), 6.70–6.75 (m, 1 H, Ph), 6.80–6.85 (m, 1

H, Ph), 6.90–7.10 (m, 6 H, Ph), 7.20 (br. s, 6 H, Ph), 7.40–7.48 (m,

Synthesis and Deuteration of the o-Lithiosulfoximine 27: Treatment

of the sulfoximine 1 (42 mg, 0.20 mmol) with nBuLi (0.143 mL of

1.60 m in n-hexane, 0.22 mmol) as described in GP 2, 10 min stir-

ring at –78 °C, and addition of CH₃CO₂D (40 μL of 17 m in THF,

0.68 mmol) gave the sulfoximine o-D-1 (38 mg, 90%) with a D con-

tent of Ն95% (¹H NMR, o,oЈ-Ph) as a colorless oil.

Synthesis and Deuteration of the o-Lithiosulfoximine 28: Treatment

of the sulfoximine 2 (37 mg, 0.17 mmol) with nBuLi (0.12 mL of

1.60 m in n-hexane, 0.18 mmol) as described in GP 2, 10 min stir-

ring at –78 °C, and addition of CH₃CO₂D (40 μL of 17 m in THF,

0.68 mmol) gave the sulfoximine o-D-2 (32 mg, 84%) with a D con-

tent of Ն95% (¹H NMR, o,oЈ-Ph) as a colorless oil.

1 H, Ph), 7.60–7.80 (m, 8 H, Ph), 7.95–8.04 (m, 1 H, Ph) ppm. ¹³

C

Synthesis and Deuteration of the o-Lithiosulfoximine 29: Treatment

of the sulfoximine 3 (131 mg, 0.44 mmol) with nBuLi (0.30 mL of

1.60 m in n-hexane, 0.48 mmol) as described in GP 2, 10 min stir-

ring at room temperature, and addition of CH₃CO₂D (0.10 mL of

17 m in THF, 1.76 mmol) gave o-d-3 (122 mg, 92%) with a D con-

tent of Ն95% (¹H NMR, o,oЈ-Ph) as a colorless oil.

NMR (100 MHz, C₆D₆): δ = 20.0 (u), 24.7 (d), 27.7 (d), 64.5 (u),

127.41 (d), 127.46 (d), 128.97 (d), 129.05 (d), 130.52 (d), 130.86 (d),

130.97 (d), 131.09 (d), 133.10 (d), 133.21 (d), 134.72 (d), 134.82 (d),

136.28 (d), 136.42 (d), 136.51 (u), 136.76 (u), 137.74 (u) ppm (the

splitting of signals due to J_P,Ccould not be determined unambigu-

ously). ³¹P NMR (162 MHz, C D ): δ = 28.4 ppm. IR (KBr): ν =

˜

6

(1S)-5,5-Dimethyl-1-(2-lithiophenyl)-4,5-dihydro-3H-1λ⁴-isothiazole

1-Oxide (27): nBuLi (0.3 mL of 1.63 m in [D₈]THF, 0.49 mmol) was

added dropwise at –78 °C to a solution of the sulfoximine 1 (93 mg,

0.45 mmol) in [D₈]THF (0.3 mL), whereupon the mixture turned

red. The mixture was then transferred by cannula to a Schlenk

NMR tube, which was cooled to –78 °C and afterwards sealed un-

3056 (m), 2933 (s), 2854 (s), 1632 (s), 1473 (m), 1433 (s), 1313 (s),

1199 (s), 1152 (s), 1111 (s) cm^–1. MS (CI, CH₄): m/z (%) = 636

[M]⁺(5), 580 (5), 578 (2), 522 (2), 502 (2), 330 (15), 307 (16), 279

(81), 224 (100), 199 (10), 179 (19), 161 (4), 146 (17).

C₃₈H₄₂NO₂PSSi (635.86): calcd. C 71.78, H 6.66, N 2.20; found C

71.97, H 6.81, N 2.03.

1

der argon. H NMR (500 MHz, [D₈]THF, room temperature): δ =

(+)-(R)-{2-[S-(1,1-Dimethylethyl)-sulfonimidoyl]phenyl}diphenyl-

phosphane Oxide (33): NBu₄F (12.1 mL of 1.0 m in THF, 12.1

mmol) was added at room temperature to a solution of sulfoximine

32 (1.94 g, 3.1 mmol) in THF (10 mL). After the mixture had been

stirred at room temperature for 12 h, it was concentrated in vacuo.

Purification by chromatography (EtOAc) gave the phosphine oxide

33 (1.01 g, 83%) as a colorless oil, which solidified upon standing;

R_f= 0.05 (cyclohexane/EtOAc 1:1). [α]_D= +142.5 (c = 1.10 in

CH₂Cl₂). ¹H NMR (300 MHz, C₆D₆): δ = 1.16 (s, 9 H, tBu), 6.85–

7.20 (m, 8 H, Ph), 7.92–94 (m, 2 H, Ph), 8.15–8.20 (m, 2 H, Ph),

8.25–8.33 (m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, C₆D₆): δ = 23.3

(u), 62.9 (u) (d, J_P,C= 5.8 Hz), 128.3 (d), 128.4 (d), 130.80 (d) (d,

J_P,C= 3.2 Hz), 130.83 (d) (d, J_P,C= 3.2 Hz), 131.7 (d), 131.8 (d) (d,

J_P,C= 7.9 Hz), 131.9 (d) (d, J_P,C= 7.1 Hz), 133.9 (d), 136.4 (u) (d,

0.96 (s, 3 H, Me), 1.44 (s, 3 H, Me), 1.95 (ddd, J = 12.2, 9.2, 4.6 Hz,

1 H, CCH₂), 2.19–2.28 (m, 1 H, CCH₂), 3.50–3.56 (m, 2 H, NCH₂),

6.90 (t, J = 7.0 Hz, 1 H, Ph), 6.96 (t, J = 6.7 Hz, 1 H, Ph), 7.60 (d,

J = 7.9 Hz, 1 H, Ph), 7.99 (d, J = 6.4 Hz, 1 H, Ph), 0.89 (m), 1.28

(m) (n-hexane), 1.71 (m), 3.58 (m) (THF) ppm. ¹³C NMR

(125 MHz, [D₈]THF): δ = 22.4 (d), 24.0 (d), 39.2 (u), 49.9 (u), 64.8

(u), 123.1 (d), 127.2 (d), 127.9 (d), 142.1 (d), 145.8 (u), 203.0 (d),

13.9 (n-hexane), 25.1 (m), 67.2 (m) (THF) ppm.

(–)-(R)-({2-[N-(1,1-Dimethylethyl)diphenylsilyl]-S-(1,1-dimethyleth-

yl)-sulfonimidoyl}phenyl)diphenylphosphane (31): nBuLi (15.7 mL of

1.60 m in n-hexane, 25.1 mmol) was added dropwise at –78 °C to a

degassed solution of the sulfoximine 8 (8.43 g, 19.3 mmol) in THF

(30 mL). After the mixture had been stirred for 30 min at this tem-

perature, ClPPh₂(5.51 mL, 25.1 mmol) was added and the mixture

was stirred for 2 h at –78 °C. Saturated aqueous NH₄Cl (30 mL)

was then added and the mixture was extracted with CH₂Cl₂. The

combined organic phases were dried (MgSO₄) and concentrated in

vacuo. Purification by chromatography (degassed silica gel, de-

gassed cyclohexane/EtOAc 5:1) gave the phosphane 31 (9.5 g, 88%)

J_P,C≈ 3 Hz), 137.5 (u) (d, J_P,C≈ 11 Hz), 139.3 (u) (d, J_{P, C}

≈

15 Hz) ppm. ³¹P NMR (162 MHz, C₆D₆): δ = 12.5 ppm. IR (KBr):

ν = 3069 (s), 2985 (s), 2933 (m), 2872 (m), 1901 (m), 1819 (m),

˜

1773 (m), 1682 (m), 1587 (s), 1475 (s), 1441 (s), 1395 (m), 1364 (m),

1244 (s), 1205 (s), 1129 (s), 1072 (m), 1018 (s), 996 (s). MS (EI,

70 eV): m/z (%) = 398 [M]⁺(2), 341 (60), 293 (13), 264 (100), 201

Eur. J. Org. Chem. 2011, 2431–2449

www.eurjoc.org

2445

M. Wessels, V. Mahajan, S. Boßhammer, G. Raabe, H.-J. Gais

FULL PAPER

(32). C₂₂H₂₄NO₂PS (394,47): calcd. C 66.48, H 6.09, N 3.52; found

C 66.60, H 6.34, N 3.45.

14.4 Hz, 1 H, CH₂Si), 1.20 (dd, J = 12.8, 14.4 Hz. 1 H, CH₂Si),

1.48–1.58 (m, 1 H, CCH₂), 1.90–2.15 (m, 2 H, CH₂CH₂CH₂), 2.72–

2.58 (m, 1 H, CCH₂), 3.18–3.32 (m, 1 H, CHS), 3.50–3.60 (m, 1

H, NCH₂), 3.70–3.82 (m, 1 H, NCH₂), 7.55–7.63 (m, 2 H, Ph),

7.65–7.75 (m, 1 H, Ph), 7.95–8.10 (m, 2 H, Ph) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = –1.0 (d), 16.5 (u), 17.2 (u), 26.0 (u), 43.0

(u), 55.8 (d), 128.4 (d), 129.2 (d), 132.8 (d) ppm.

ortho,α-Transmetalation of the o-Lithiosulfoximine 17. (–)-(1S,6R)-

6-Benzyl-1-phenyl-3,4,5,6-tetrahydro-1λ⁴-1,2-thiazine 1-Oxide (epi-

4): nBuLi (0.54 mL of 1.60 m in n-hexane, 0.87 mmol) was added

dropwise at –78 °C to a solution of the sulfoximine 4 (225 mg,

0.79 mmol) in THF (8 mL). After the mixture had been stirred for

10 min at room temperature, it was cooled to –78 °C and treated

with CF₃CO₂H (450 mg, 3.94 mmol). The mixture was then poured

into saturated aqueous NH₄Cl and extracted with EtOAc. The

combined organic phases were dried (MgSO₄) and concentrated in

vacuo. Purification by chromatography (EtOAc) gave the sulfox-

imine epi-4 (180 mg, 80%) with 89% de (¹H NMR, o,oЈ-Ph) as a

colorless solid; m.p. 63–64 °C. Quenching of the mixture with D₂O

instead of CF₃CO₂H gave the sulfoximine α-D-epi-4 with a D con-

tent of Ն95%; [α]_D= –35.4 (c = 1.18 in CHCl₃). ¹H NMR

(300 MHz, CDCl₃): δ = 1.44–1.48 (m, 1 H, CH₂CH₂CH₂), 1.86–

2.03 (m, 2 H, CH₂CH₂CH₂, CCH₂), 2.50 (dd, J = 13.7, 4.3 Hz, 1

H, CH₂Ph), 2.53–2.61 (m, 1 H, CCH₂), 2.83 (dd, J = 13.7, 11.3 Hz,

1 H, CH₂Ph), 3.32 (dddd, J = 11.3, 4.3, 4.3, 4.0 Hz, 1 H, CHS),

3.54–3.58 (m, 1 H, NCH₂), 3.71–3.77 (m, 1 H, NCH₂), 6.94–6.96

(m, 2 H, Ph), 7.15–7.24 (m, 3 H, Ph), 7.54–7.57 (m, 2 H, Ph), 7.61–

7.64 (m, 1 H, Ph), 8.07–8.10 (m, 2 H, Ph) ppm. ¹³C NMR

(75 MHz, CDCl₃): δ = 17.6 (u), 23.6 (u), 35.0 (u), 43.3 (u), 58.4

(d), 126.7 (d), 128.7 (d), 129.0 (d), 129.4 (d), 133.3 (d), 136.5 (u),

ortho,α-Transmetalation of the o-Lithiosulfoximine 19 after 6 min at

20 °C: Treatment of the sulfoximine 6 (70 mg, 0.24 mmol) with

nBuLi (0.15 mL of 1.60 m in n-hexane, 0.27 mmol) as described in

GP 2, 10 min stirring at 20 °C, and addition of CH₃CO₂D (80 μL

of 17 m in THF, 1.36 mmol) gave a mixture of the sulfoximines o-

D-6 with a D content of Ն95% (¹H NMR, o,oЈ-Ph) and α-D-epi-

6 in a ratio of 66:34 (53 mg, 76%) as a colorless oil.

ortho,α-Transmetalation of the o-Lithiosulfoximine 19 within 1 h at

20 °C: Treatment of the sulfoximine 6 (70 mg, 0.24 mmol) with

nBuLi (0.15 mL of 1.60 m in n-hexane, 0.27 mmol) as described in

GP 2, 1 h stirring at 20 °C, and addition of CH₃CO₂D (80 μL of

17 m in THF, 1.36 mmol) gave the sulfoximine α-D-epi-6 (64 mg,

91%) with a D content of Ն95% (¹H NMR, o,oЈ-Ph) and Ն98%

de as a colorless oil.

Lithiation of the Sulfoximine 36. (1S,6R)-5-Deutero-1-phenyl-4,5-di-

hydro-3H-1λ⁴-isothiazole 1-Oxide (α-D-36): Treatment of the sulf-

oximine 36 (28 mg, 0.15 mmol), nBuLi (0.11 mL, 0.17 mmol), and

CF₃COOD (0.39 mL of 2.0 m in THF, 0.77 mmol) as described in

GP 4 gave α-D-36 (27 mg, 96%) with 74% de and a D content of

Ն95% (¹H NMR, α-H) as a colorless oil.

136.8 (u) ppm. IR (KBr): ν = 3026 (w), 2962 (m), 2943 (s), 2915

˜

(m), 2857 (w), 2840 (s), 1600 (w), 1583 (w), 1494 (m), 1476 (m),

1458 (m), 1446 (s), 1385 (w), 1350 (w), 1305 (w), 1271 (w), 1222

(vs), 1148 (vs), 1118 (vs), 1101 (vs), 1089 (s), 1068 (s), 1026 (m),

1008 (s), 966 (m), 922 (w), 881 (s), 867 (m), 835 (vs), 797 (s) cm^–1.

MS (EI, 70 eV): m/z (%) = 285 [M]⁺(10), 194 (15), 160 (57), 131

(16), 126 (10), 125 (100), 117 (11), 104 (10), 97 (13), 91 (57), 78

(10), 77 (17). C₁₇H₁₉NOS (285.41): calcd. C 71.54, H 6.71, N 4.91;

found C 71.21, H 6.78, N 4.87.

Lithiation of the Sulfoximine 9. (1S,6R)-6-Deutero-1-phenyl-3,4,5,6-

tetrahydro-1λ⁴-1,2-thiazine 1-Oxide (α-D-9): Treatment of the sulf-

oximine 9 (93 mg, 0.48 mmol), nBuLi (0.33 mL, 0.52 mmol), and

CF₃COOD (1.19 mL of 2.0 m in THF, 2.38 mmol) as described in

GP 4 gave α-D-9 (89 mg, 95%) as a colorless oil with 81% de and

a D content of Ն95% (¹H NMR, α-H).

Synthesis and Deuteration of the o-Lithiosulfoximine 19: Treatment

of the sulfoximine 6 (70 mg, 0.24 mmol) with nBuLi (0.15 mL of

1.60 m in n-hexane, 0.27 mmol) as described in GP 2, 10 min stir-

ring at –78 °C, and addition of CH₃CO₂D (80 μL of 17 m in THF,

1.36 mmol) gave the sulfoximine o-D-6 (60 mg, 85%) with a D con-

tent of Ն95% (¹H NMR, o,oЈ-Ph) as a colorless oil.

(+)-(1S,6R)-6-Methyl-1-(2-methylphenyl)-3,4,5,6-tetrahydro-1λ⁴-

1,2-thiazine 1-Oxide (41): nBuLi (5.73 mL of 1.60 m in n-hexane,

9.17 mmol) was added dropwise at –50 °C to a solution of the sulf-

oximine 9 (814 mg, 4.17 mmol) in THF (40 mL). After the mixture

had been stirred for 10 min at room temperature, it was treated at

–78 °C with MeI (1.77 g, 12.5 mmol). The mixture was then stirred

for 3 h at –78 °C. The mixture was poured into saturated aqueous

ortho,α-Transmetalation of the o-Lithiosulfoximine 19 and Double

ortho,α-Lithiation of the Sulfoximine 6. (1S,6R)-6-(Trimethylsilyl)- NH₄Cl and extracted with EtOAc. The combined organic phases

methyl-1-phenyl-3,4,5,6-tetrahydro-1λ⁴-1,2-thiazine 1-Oxide (epi-6): were dried (MgSO₄) and concentrated in vacuo. Purification by

nBuLi (1.10 mL of 1.60 m in n-hexane, 1.72 mmol) was added drop- chromatography (EtOAc/MeOH 9:1) gave the sulfoximine 41

wise at –78 °C to a solution of the sulfoximine 6 (306 mg,

1.57 mmol) in THF (15 mL). After the mixture had been stirred

for 1 h at room temperature, it was cooled to –78 °C and treated

(707 mg, 76%) with Ն98% de (¹H NMR, Me) as a colorless solid;

R_f= 0.33 (EtOAc/MeOH 9:1); m.p. 48 °C. [α]_D= +45.9 (c = 1.17

in CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 1.08 (d, J = 6.6 Hz,

1

with CH₃CO₂H (450 mg, 3.94 mmol). The mixture was then 3 H, Me), 1.75–1.83 (m, 1 H, CH₂CH₂CH₂), 1.89–2.03 (m, 1 H,

poured into saturated aqueous NH₄Cl and extracted with EtOAc.

The combined organic phases were dried (MgSO₄) and concen-

trated in vacuo. Purification by chromatography (EtOAc/MeOH

9:1) gave the sulfoximine epi-6 (272 mg, 89%) with 89% de (¹H

NMR, o,oЈ-Ph). Quenching of the mixture with CH₃CO₂D after

1 h at room temperature gave the sulfoximine α-D-epi-6 with a D

content of Ն95%. Quenching of the mixture after 10 min at room

temperature with CH₃CO₂D gave a mixture of the sulfoximine α-

D-epi-6 with a D content of Ն95% and o-D-6 with a D content of

Ն95% in a ratio of 34:66. A similar experiment with nBuLi

(2 equiv.), a reaction time of 10 min at room temperature, and

quenching with D₂O gave o,α-D₂-epi-6 with Ն95% de and a D con-

tent of Ն95% for each of the o- and the α-positions. ¹H NMR

CH₂CH₂CH₂), 2.08–2.18 (m, 1 H, CCH₂), 2.18–2.28 (m, 1 H,

CCH₂), 2.99–3.26 (m, 1 H, CHS), 3.45 (ddt, J = 12.9, 4.1, 1.9 Hz,

1 H, NCH₂), 3.58 (dt, J = 12.9, 3.0 Hz, 1 H, NCH₂), 7.29–7.38 (m,

2 H, Ph), 7.44–7.50 (m, 1 H, Ph), 8.08–8.13 (m, 1 H, Ph) ppm. ¹³

C

NMR (100 MHz, CDCl₃): δ = 16.6 (d), 20.8 (d), 25.8 (u), 23.0 (u),

43.6 (u), 53.8 (d), 126.0 (d), 130.9 (d), 132.9 (d), 134.1 (u), 138.3

(u) ppm. IR (KBr): ν = 3435 (m), 3063 (w), 3019 (w), 2956 (s),

˜

2928 (s), 2850 (s), 2832 (s), 2672 (w), 1637 (w), 1596 (w), 1568 (w),

1473 (s), 1447 (s), 1380 (m), 1348 (m), 1335 (w), 1276 (m), 1255 (s),

1228 (s), 1206 (s), 1191 (s), 1166 (s), 1096 (s), 1111 (s), 1088 (s),

1059 (s), 1035 (s), 977 (s), 955 (s), 895 (s), 865 (m), 849 (s), 811

(s) cm^–1. MS (EI, 70 eV): m/z (%) = 223 [M]⁺(59), 168 (17), 140

(25), 139 (90), 137 (20), 132 (11), 125 (13), 111 (45), 92 (19), 91

(300 MHz, CDCl₃): δ = –0.08 (s, 9 H, SiMe₃), 0.42 (dd, J = 2.7, (14), 84 (100), 78 (16), 77 (50), 70 (10), 69 (27), 67 (14), 65 (18), 61

2446

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Eur. J. Org. Chem. 2011, 2431–2449

Sulfoximine-Directed o-Lithiation and Stereoselective Rearrangements

(16), 56 (13), 55 (15). C₁₂H₁₇NOS (223.34): calcd. C 64.54, H 7.67,

N 6.27; found C 64.16, H 7.91, N 6.24.

temperature, it was treated dropwise at room temperature with

CH₃CO₂D (28 μL of 17 m in THF, 0.48 mmol). The mixture was

then poured into saturated aqueous NaHCO₃and extracted with

EtOAc (3ϫ20 mL). The combined organic phases were dried

(MgSO₄) and concentrated in vacuo. The sulfinylaniline o-D-58

(42 mg, 84%) with a D content of 94% (¹H NMR, o,oЈ-Ph) was

obtained as a brown solid.

(–)-(1S)-2,2-Dimethyl-3,4,5,6-tetrahydro-2H-benzo[b][1,4]thiazocine

1-Oxide (45): nBuLi (0.877 mL of 1.46 m in n-hexane, 1.223 mmol)

was added dropwise at –50 °C (dry ice, MeCN) to a solution of

the sulfoximine ent-2 (120 mg, 0.553 mmol) in THF (3 mL). Within

15 min the mixture became first yellow, then orange, and finally

brick red. After the mixture had been stirred for a further 15 min

at low temperature, whereupon a yellow solid deposited, it was al-

lowed to warm to room temperature and stirred for 1 h at this

temperature. TLC indicated the complete consumption of the start-

ing sulfoximine. The mixture was quenched by the addition of

aqueous NH₄Cl and extracted with EtOAc (3ϫ5 mL). The com-

bined organic layers were washed with brine and dried with

MgSO₄. Removal of the solvent in vacuo gave the benzothiazocine

45 (120 mg, 99%) as a pale yellow solid; R_f= 0.5 (EtOAc); m.p.

(+)-(1R)-2,2-Dimethyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine 1-

Oxide (58): nBuLi (0.40 mL of 1.60 m in n-hexane, 0.64 mmol) was

added dropwise at –50 °C to a solution of the sulfoximine 1 (68 mg,

0.32 mmol) in THF (5 mL), whereupon the mixture turned red.

After the mixture had been stirred for 12 h at room temperature, it

was poured into H₂O (10 mL) and extracted with EtOAc

(3ϫ20 mL). The combined organic phases were dried (MgSO₄)

and concentrated in vacuo. Purification by chromatography

(EtOAc/MeOH 9:1) gave the benzothiazepine 58 (57 mg, 84%) as

a brown solid; R_f= 0.33 (EtOAc/MeOH 9:1); m.p. 175 °C.

Recrystallization from CH₂Cl₂gave 58 as colorless single crystals

suitable for X-ray crystal structure analysis; [α]_D= +183.9 (c = 0.53

1

162–165 °C. [α]_D= –37.9 (c = 1.0 in CHCl₃). H NMR (500 MHz,

CDCl₃): δ = 0.91 (s, 3 H, Me), 1.50 (s, 3 H, Me), 1.62–1.82 (m, 3

H, CH₂CH₂CH₂, CCH₂), 1.85–1.95 (m, 1 H, CCH₂), 3.23–3.30 (m,

1 H, NCH₂), 3.77–3.89 (m, 1 H, NCH₂), 4.68–4.74 (br. s, 1 H,

NH), 6.48–6.54 (m, 1 H, 7-H), 6.67–6.73 (m, 1 H, 9-H), 7.08–7.14

(m, 1 H, 8-H), 7.59–7.63 (m, 1 H, 10-H) ppm. ¹³C NMR

(125 MHz, CDCl₃): δ = 18.3 (d), 22.9 (d), 28.3 (u), 34.1 (u), 44.0

(u), 63.4 (u), 114.7 (d), 115.4 (d), 118.4 (u), 125.3 (d), 130.8 (d),

1

in CH₂Cl₂). H NMR (400 MHz, CDCl₃): δ = 1.05 (s, 3 H, Me),

1.50 (s, 3 H, Me), 1.90 (ddd, J = 15.1, 5.2, 1.9 Hz, 1 H, CCH₂),

2.26 (ddd, J = 15.1, 11.6, 3.3 Hz, 1 H, CCH₂), 2.94 (ddd, J = 13.5,

11.5, 1.9 Hz, 1 H, NCH₂), 3.26 (ddd, J = 14.0, 5.2, 3.3 Hz, 1 H,

NCH₂), 6.84 (dd, J = 7.7, 1.1 Hz, 1 H, 6-H), 7.19 (td, J = 7.7,

1.4 Hz, 1 H, 8-H), 7.29 (td, J = 7.7, 1.6 Hz, 1 H, 7-H), 7.71 (dd, J

= 7.9, 1.7 Hz, 1 H, 9-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

17.2 (d), 26.0 (d), 40.6 (u), 43.2 (u), 54.5 (u), 120.4 (d), 122.6 (d),

147.2 (u) ppm. IR (KBr): ν = 3318 (s), 3147 (m), 3091 (w), 3064

˜

(w), 3044 (w), 2940 (m), 2916 (m), 2849 (w), 1590 (s), 1525 (s), 1487

(s), 1473 (s), 1446 (s), 1434 (m), 1419 (m), 1382 (w), 1363 (m), 1333

(m), 1294 (w), 1254 (m), 1209 (w), 1193 (w), 1159 (w), 1120 (w),

1103 (m), 1079 (w), 1052 (s), 1032 (s), 1016 (s), 981 (m), 919

(w) cm^–1. MS (EI, 70 eV): m/z (%) = 223 [M]⁺(24), 209 (11), 207

(14), 182 (13), 155 (46), 154 (32), 153 (11), 151 (11), 150 (10), 149

(17), 139 (12), 138 (16), 137 (100), 136 (58), 127 (23), 126 (22), 125

(44), 124 (27), 123 (14), 110 (27), 109 (23), 105 (12), 97 (13), 95

(11), 94 (15), 93 (10), 83 (28), 81 (12), 77 (10). C₁₂H₁₇NOS (223.34):

calcd. C 64.53, H 7.67, N 6.27; found C 64.34, H 7.78, N 6.10.

Quenching of the reaction mixture with D₂O, extraction with

EtOAc (3ϫ5 mL), washing of the combined organic layers with

brine, and drying (MgSO₄) gave the benzothiazocine o-D-45

(120 mg, 99%) containing a D atom (95%) at the o-position to the

N atom (¹H NMR spectroscopy).

127.2 (d), 130.8 (d), 132.1 (u), 145.4 (u) ppm. IR (KBr): ν = 3434

˜

(w), 3306 (s), 3092 (w), 3049 (m), 2982 (m), 2956 (s), 2929 (s), 2905

(m), 2858 (m), 2253 (w), 1675 (w), 1587 (s), 1508 (m), 1474 (s),

1417 (m), 1382 (m), 1365 (s), 1314 (m), 1280 (m), 1263 (s), 1159

(m), 1128 (m), 1097 (m), 1058 (s), 1020 (s), 974 (m), 948 (m), 868

(m), 856 (m) cm^–1. MS (EI, 70 eV): m/z (%) = 209 [M]⁺(16), 192

(19), 153 (56), 137 (10), 136 (100), 125 (20), 109 (15). HRMS for

C₁₁H₁₅NOS [M]⁺: calcd. 209.087437; found 209.087455.

C₁₁H₁₅NOS (209.31): calcd. C 63.12, H 7.22, N 6.69; found C

63.10, H 7.32, N 6.64.

Rearrangement of (1S)-5,5-Dimethyl-1-(2-lithiophenyl)-4,5-dihydro-

3H-1λ⁴-isothiazole 1-Oxide (27): nBuLi (0.3 mL of [D₈]THF,

0.49 mmol) was added dropwise at –78 °C to a solution of the sul-

foximine 1 (93 mg, 0.45 mmol) in [D₈]THF (0.3 mL), whereupon

the mixture turned red. The mixture was then transferred by can-

nula to a Schlenk NMR tube, which was cooled to –78 °C and

afterwards sealed under argon. The solution was allowed to warm

to room temperature. ¹H NMR spectroscopy (500 MHz, [D₈]THF,

room temperature) showed the formation of 27. The solution of 27

was then kept for 12 h at room temperature, after which a ¹H NMR

spectrum showed the presence of the salt 61 together with 27 in a

N-Lithiated (+)-2,2-Dimethyl-3,4,5,6-tetrahydro-2H-benzo-

[b][1,4]thiazocine 1-Oxide (47): nBuLi (0.16 mL of 1.60 m in n-hex-

ane, 0.25 mmol) was added at room temperature to a solution of

the sulfoximine 45 (51 mg, 0.23 mmol) in THF (0.5 mL), where-

upon the mixture turned red. The mixture was then concentrated

under high vacuum and the yellow solid was dissolved in dry [D₈]-

THF (0.7 mL). The solution of 47 was transferred by cannula to

a Schlenk NMR tube, which was sealed under argon. ¹H NMR

(500 MHz, [D₈]THF, room temperature): δ = 0.97 (s, 3 H, Me),

1.51 (s, 3 H, Me), 1.50–1.60 (m, 2 H, CH₂CH₂CH₂), 1.93–2.16 (m,

2 H, CCH₂), 3.37–3.47 (m, 1 H, NCH₂), 3.98–4.08 (m, 1 H, NCH₂),

5.73 (t, J = 6.8 Hz, 1 H, 9-H), 6.39 (d, J = 8.5 Hz, 1 H, 7-H), 6.54

(dt, J = 1.7, 6.3 Hz, 1 H, 8-H), 7.34 (dd, J = 1.7, 8.0 Hz, 1 H, 10-H),

1.86 (m), 3.70 (m) (THF) ppm. ¹³C NMR (125 MHz, [D₈]THF): δ

= 18.7 (d), 23.3 (d), 30.9 (u), 35.5 (u), 49.6 (u), 64.8 (u), 103.1 (d),

112.4 (u), 120.4 (d), 125.3 (d), 128.9 (d), 162.3 (u), 24.6 (m), 66.9

(m) (THF) ppm.

1

ratio of 1:1. After 48 h a H NMR spectrum showed the presence

of the salt 61 and several unassigned signals. Quenching of the

reaction mixture with D₂O, extraction with EtOAc (3ϫ 5 mL),

washing of the combined organic layers with brine, and drying

(MgSO₄) gave the benzothiazepine 58 together with a minor

amount of N-(3-methylbut-2-enyl)benzene-sulfinamide (70).

Compound 61: ¹H NMR (300 MHz, [D₈]THF): δ = 5.55 (td, J =

6.3, 1.3 Hz, 8-H), 6.40 (d, J = 8.7 Hz, 6-H), 6.48 (ddd, J = 7.7, 6.3,

1.6 Hz, 7-H), 6.85 (dd, J = 5.8, 2.0 Hz, 9-H) ppm.

(1R)-9-Deutero-2,2-dimethyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazep-

ine 1-Oxide (o-D-58): nBuLi (0.28 mL of 1.69 m in n-hexane,

0.47 mmol) was added dropwise at –50 °C to a solution of the sulf-

oximine 1 (51 mg, 0.24 mmol) in THF (5 mL), whereupon the mix-

ture turned red. After the mixture had been stirred for 3 h at room

Compound 70: ¹H NMR (400 MHz, CDCl₃): δ = 1.59 (s, 3 H, Me),

1.69 (s, 3 H, Me), 3.34 (dt, J = 13.2, 6.9 Hz, 1 H, NCH₂), 3.71

(ddd, J = 13.2, 6.9, 5.5 Hz, 1 H, NCH₂), 3.93 (m, 1 H, NH), 5.21

(tq, J = 7.2, 1.4 Hz, 1 H, CH=), 7.46–7.54 (m, 3 H, Ph), 7.70–7.75

(m, 2 H, Ph) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 18.1 (d),

Eur. J. Org. Chem. 2011, 2431–2449

www.eurjoc.org

2447

M. Wessels, V. Mahajan, S. Boßhammer, G. Raabe, H.-J. Gais

FULL PAPER

[6]

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26.04 (d), 38.8 (u), 120.6 (d), 126.2 (d), 129.0 (d), 131.0 (d), 137.3

(u), 142.0 (u) ppm. MS (EI, 70 eV): m/z (%) = 210 [M + 1]⁺(11),

125 (12), 93 (11), 84 (100), 69 (14), 51 (14).

(–)-(S)-2-(tert-Butylsulfinyl)-N-methylaniline (62): nBuLi (1.54 mL

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had been stirred for a further 15 min at low temperature, where-

upon a yellow solid deposited, it was allowed to warm to room

temperature and stirred for 1 h at this temperature. TLC indicated

the complete consumption of the starting sulfoximine. The mixture

was quenched by the addition of aqueous NH₄Cl or D₂O and ex-

tracted with EtOAc (3ϫ 5 mL). The combined organic layers were

washed with brine and dried with MgSO₄. Removal of the solvent

in vacuo and purification by chromatography (EtOAc) gave the

sulfinylaniline 62 (200 mg, 95%) as a pale yellow solid; m.p. 65–

68 °C. [α]_D= –60.6 (c = 1.05 in CHCl₃); HPLC (Chiralcel-OD-H,

n-heptane/iPrOH, 98:2, 0.75 mLmin^–1): R_f= 8.01 min. ¹H NMR

(400 MHz, CDCl₃): δ = 1.27 (s, 9 H, tBu), 2.79 (d, J = 5.2 Hz, 3

H, NMe), 6.57–6.64 (m, 2 H, Ph), 6.82 (br. s, 1 H, NH), 6.97–7.04

(m, 1 H, Ph), 7.25–7.32 (m, 1 H, Ph) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 23.6 (d), 29.6 (d), 58.5 (u), 110.9 (u), 114.2 (d), 128.9

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˜

1594 (s), 1461 (s), 1142 (s), 1119 (s) cm^–1. MS (EI, 70 eV): m/z (%)

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[12]

[13]

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft

(DFG) (SFB 380 and GK 440). We thank B. Sommer, Dipl.-chem.

S. Schüller, M. Gerencer, and C. Vermeeren for experimental assist-

ance, and Dr. J. Runsink and Dr. M. Schleusner for NMR spectro-

scopic investigations.

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Received: January 17, 2011

Published Online: March 18, 2011

Eur. J. Org. Chem. 2011, 2431–2449

www.eurjoc.org

2449

Article Doi

Sulfoximine-directed single and double ortho-lithiation: Stereoselective rearrangements of o,oa'-Dilithiophenylsulfoximines to o,N- dilithiosulfinylanilines through anionic fries rearrangements of o,oa'-dilithiophenylsulfinamides

DOI: 10.1002/ejoc.201100066

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