Synthesis and Configurational Assignment of Vinyl Sulfoximines and Sulfonimidamides

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Synthesis and Conﬁgurational Assignment of Vinyl Sulfoximines

and Sulfonimidamides

Gregory B. Craven,* Edward L. Briggs, Charlotte M. Zammit, Alexander McDermott, Stephanie Greed,

Dominic P. A ﬀ ron, Charlotte Leinfellner, Hannah R. Cudmore, Ruth R. Tweedy, Renzo Luisi,

James A. Bull,* and Alan Armstrong *

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ABSTRACT: Vinyl sulfones and sulfonamides are valued for their use as

electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI)

aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less

studied and have yet to be applied to the ﬁeld of protein bioconjugation.

Herein, we report a range of diﬀerent synthetic methodologies for

constructing vinyl sulfoximine and vinyl sulfonimidamide architectures

that allows access to new areas of electrophilic chemical space. We

demonstrate how late-stage functionalization can be applied to these motifs

to incorporate alkyne tags, generating fully functionalized probes for future

chemical biology applications. Finally, we establish a workﬂow for

determining the absolute conﬁguration of enantioenriched vinyl sulfox-

imines and sulfonimidamides by comparing experimentally and computa-

tionally determined electronic circular dichroism spectra, enabling access to

conﬁgurationally assigned enantiomeric pairs by separation.

been employed to target cysteine residues on a variety of

proteins including mitogen-activated protein kinase 1

(ERK2),⁹mutant KRas(G12C),¹⁰Bruton’s tyrosine kinase

(BTK),¹¹and ubiquitin-speciﬁc protease 7 (USP7)¹²(Figure

1b). Synthetic routes to these scaﬀolds are well established,

and probe speciﬁcity is engineered by installation of

pharmacophores that bind the target protein and orientate

the electrophile to react with a nearby nucleophilic amino

acid.¹³

We speculated that vinyl sulfoximines and sulfonimidamides

could similarly act as protein reactive warheads in covalent

probes.¹⁴The value of these aza-analogues compared to the

established vinyl S(VI) electrophiles would arise from their

ability to oﬀer alternative hydrogen-bonding architectures,

additional vectors for pharmacophore incorporation, and likely

diﬀerent reactivity proﬁles. Moreover, the new nitrogen center

oﬀers a convenient handle for the attachment of chemical

biology functionalities, such as alkynes and ﬂuorophores, to

generate fully functionalized probes.¹⁵As these derivatives are

chiral at sulfur, they present increased complexity and potential

INTRODUCTION

■

Sulfoximines and sulfonimidamides, the mono aza-analogues of

sulfones and sulfonamides, respectively, are gaining traction as

valuable pharmacophores in medicinal chemistry (Figure

1a).^1,2Architecturally, these motifs carry asymmetry at the

tetrahedral sulfur center, oﬀer hydrogen-bond acceptor and

donor functionalities for NH derivatives, and aﬀord new

vectors along which to generate structural complexity.

Bioactive sulfoximines date back to the discovery of

methionine sulfoximine, which was later discovered to be a

prodrug inhibitor of glutamine synthetase.³More recently, new

synthetic methodologies have facilitated the incorporation of

sulfoximine and sulfonimidamide motifs into drug discovery

programs, through which their high chemical and stereo-

chemical stability as well as favorable physicochemical

properties have been uncovered.⁴Indeed, three sulfoximine

compounds have entered clinical trials in recent years, with

their desirable drug metabolism and pharmacokinetics

(DMPK) proﬁles being cited as key triggers for candidate

selection.⁵

Vinyl sulfones and sulfonamides are well-characterized

electrophiles and have been extensively utilized as reactive

warheads in protein-targeted covalent probes.⁶For example,

substituted vinyl sulfones are found in cysteine-targeting

covalent cathepsin inhibitors,⁷terminal vinyl sulfones have

been used in lysine-targeting cyclin-dependent kinase 2

(Cdk2) inhibitors,⁸and terminal vinyl sulfonamides have

Received: February 15, 2021

Published: May 18, 2021

https://doi.org/10.1021/acs.joc.1c00373

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Figure 1. (a) S(VI) aza-isosteres. (b) Examples of established vinyl sulfone- and sulfonamide-based covalent inhibitors and proposed scaﬀolds for

future aza-analogues.

Scheme 1. Previous Routes to Vinyl Sulfoximines

complementarity as probes. A recent work from Cravatt has

demonstrated the value of using stereochemically paired fully

functionalized probes in the context of proteomic screening,

oﬀering an internal control for nonspeciﬁc protein binding.¹⁶

More broadly, electrophilic fragments are now routinely

screened to identify starting points for covalent probes, and

novel electrophilic functionalities are desirable to expand the

diversity of covalent fragment libraries.^17,18

Over the last 30 years, β-substituted (E)-vinyl sulfoximines

have been prepared by a variety of approaches utilizing

carbonyl addition and then β-hydroxy activation/elimination,¹⁹

Peterson oleﬁnation,²⁰and Horner−Wadsworth−Emmons

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Scheme 2. Synthetic Methods Described in this Work to Access Vinyl Sulfoximines and Sulfonimidamides

(HWE) oleﬁnation²¹(Scheme 1). More recently, Arvidsson

reported an improved HWE sequence that is both high

yielding and protecting group free.²²These methodologies

demonstrate the chemical stability and tractability of the vinyl

sulfoximine motif, and one such recent study has given rise to

the ﬁrst examples of bioactive vinyl sulfoximines that are

thought to activate the transcription factor nuclear factor

erythroid 2-related factor 2 (Nrf2), although a covalent

mechanism of action was not proposed.²³However, these

synthetic routes have clear limitations; they generally utilize

multiple-step sequences that are reliant on the use of hydrazoic

acid or O-(mesitylenesulfonyl)hydroxylamine (MSH) for

sulfoxide imidation, both of which are known for their thermal

instability.^24,25There are very few examples of terminal vinyl

sulfoximines or enantioenriched vinyl sulfoximines. Moreover,

the ﬁrst two examples of vinyl sulfonimidamides were only

reported very recently,²⁶despite the prevalence of the

analogous vinyl sulfonamides, which we attribute to the

historically limited synthetic methodology regarding sulfoni-

midamides.

presumably due to the instability of terminal vinyl sulﬁdes to

acid. Improved methods that expand the diversity of accessible

products, minimize the use of dangerous reagents and enable

the synthesis of fully functionalized probes for future chemical

biology investigations would be of considerable interest.

Here, we report the development of new and improved

synthetic routes for the preparation of vinyl sulfoximines,

exploiting recent developments in the synthesis of aza-S(VI)

derivatives. Three orthogonal routes to access terminal and

substituted vinyl NH-sulfoximines are investigated, including

highly enantioenriched examples (Scheme 2). Furthermore, we

report some of the ﬁrst examples of vinyl NH-sulfonimida-

mides. These studies considerably extend the scope of the

hypervalent iodine-mediated NH-transfer methods and

provide a comparison of available routes, highlighting strategies

for diﬀerent substitution patterns. A simple propargylation

reaction to convert these products into fully functionalized

probes is demonstrated. Finally, we generate stereochemically

paired vinyl sulfoximine and sulfonimidamide derivatives, by

late-stage chiral separation, and establish a method for their

conﬁgurational assignment by combining density-functional

theory (DFT) calculations and circular dichroism (CD). These

approaches allow access to a range of stereochemically deﬁned

structures of interest as probes.

It is notable that in recent years the methods for sulfoximine

and sulfonimidamide syntheses have developed consider-

ably.²⁷⁻²⁹In our groups, we have developed a safe and

eﬀective method for the NH transfer to sulfoxides to form

sulfoximines using ammonium carbamate and (diacetoxy)-

iodobenzene.³⁰Similarly, we and others have developed a one-

pot oxidation and imidation protocol for the direct conversion

RESULTS AND DISCUSSION

■

Substituted Vinyl (E)-Sulfoximines from Methyl

Sulﬁdes and Sulfoxides. Our initial investigations focused

on the established HWE approach to vinyl sulfoximine

synthesis but commencing from simple sulﬁdes and applying

recent methods for NH transfer, using (diacetoxy)iodobenzene

and ammonium carbamate, to improve the eﬃciency and

safety.^31aAccordingly, methyl sulﬁdes 1a and 1b were

converted into the corresponding NH-sulfoximines 2a and

2b in very good yields (Scheme 3a). After tert-butyldiphe-

nylsilyl (TBDPS) protection of the sulfoximine nitrogen to

of sulﬁdes to sulfoximines.^31,32Stockman and Lu

̈

cking

established a related process for the preparation of

sulfonimidamides from sulﬁnamides.³³We have developed

the synthesis of sulfonimidamides from sulfenamides by NH

and O transfer.³⁴It is notable that using this NH-transfer

methodology, the reaction of phenylvinylsulfoxide was eﬀective

in generating phenylvinyl sulfoximine, although in moderate

yield (54%).³⁰However, the corresponding method from the

sulﬁde was ineﬀective (14% yield for phenylvinyl sulﬁde),^31a

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Scheme 3. Synthesis of Substituted (E)-Vinyl Sulfoximines from (a) Methyl Sulﬁdes and (b) Enantioenriched Methyl

Sulfoxides

give intermediates 3a and 3b, a one-pot HWE procedure was

implemented using a range of aldehyde coupling partners to

furnish NTBDPS-protected vinyl sulfoximines 4a−g. Finally,

TBDPS deprotection with tetra-n-butylammonium ﬂuoride

(TBAF) aﬀorded vinyl NH-sulfoximines 5a−g. Both aromatic

and aliphatic aldehydes gave similarly high yields for the two

steps (5a and 5b). Incorporation of an alkyne functionality was

well tolerated (5c and 5e), which is encouraging for the

potential to generate future fully functionalized probes. The

method also performed well using the more electron-rich

anisole-derived sulfoximine (5e−g) and using heteroaromatic

aldehydes (5d, 5f, 5g).

Stereochemically enriched sulfoximines are ﬁnding increas-

ing utility in drug discovery and asymmetric synthesis but

represent synthetically challenging targets.^4,5,35Application of

an analogous synthetic sequence to enantioenriched sulfoxides

(S)-6 and (R)-6 using 4-ethynylbenzaldehyde furnished

products (S)-5h and (R)-5h, respectively, with retention of

the conﬁguration at sulfur and without loss of enantiomeric

excess (ee) (Scheme 3b).³⁰The stereospeciﬁcity of this route

and conﬁgurational stability of the intermediates and products

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Scheme 4. Synthesis of Substituted (E)-Vinyl Sulfoximines via Alkyne Hydrothiolation

a

b

Used 10 mol % RhCl(PPh₃)₃, 65 °C. 9f is exempliﬁed in ref 13 using similar conditions.

Table 1. Synthesis of Terminal Vinyl Sulfoximines via Alcohol Elimination

are encouraging for the design of future stereochemically

deﬁned vinyl sulfoximines. Indeed, powerful methods are well

established for the enantioselective oxidation of unsymmetrical

methyl sulﬁdes,³⁶which could be combined with this HWE

route to provide access to a broad range of enantioenriched

vinyl sulfoximines. By incorporating alkyne functionalities into

(S)-5h and (R)-5h, these structures represent the ﬁrst example

of stereochemically paired fully functionalized vinyl sulfox-

imine probes.

Substituted (E)-Vinyl Sulfoximines via Alkyne Hydro-

thiolation. Next, we sought to develop a more eﬃcient route

to vinyl sulfoximines to expand the product scope and notably

avoid the use of protecting groups and possible regiochemical

ambiguity in the deprotonation step of dialkyl sulfoximines.

We anticipated that direct oxidation/imidation of vinyl

thioethers would be the most direct path. A range of metal-

catalyzed alkyne hydrothiolation reactions have been devel-

oped that facilitate the synthesis of branched,^37,38linear (E)-

vinyl thioethers,³⁹or linear (Z)-vinyl thioethers⁴⁰in high

selectivity. For this study, we were interested in linear (E)-vinyl

sulfoximines and applied a Wilkinson’s catalyst-mediated

alkyne thiolalkyation methodology reported by Love, which

gives high levels of stereocontrol using 1,2-dichloroethane

(DCE) as the solvent.⁴¹The (E)-vinyl thioether products 9

were then converted to the corresponding (E)-vinyl sulfox-

imines 10 using our NH/O-transfer method (Scheme 4).^31a

This two-step sequence provided eﬃcient access to a diverse

range of vinyl sulfoximines in good to excellent yields,

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Scheme 5. Synthesis of Terminal Vinyl Sulfonimidamides via Alcohol Elimination

tolerating silyl (10a, 10b), aryl (10c−e), and alkyl (10f)

alkynes in combination with aryl (10a, 10c, 10d, and 10f) and

alkyl (10b and 10e) thiols. The success of this methodology

for alkyl thiols is particularly exciting since access to such

products by HWE chemistry is challenging. Indeed, the

incorporation of an aryl bromide containing alkyne (10e)

and thiol (10d) will enable elaboration of these scaﬀolds in

multiple vectors using transition-metal-catalyzed coupling

chemistry. Pleasingly, we were also able to remove the Boc

protection group from 10f to aﬀord amine 10g, oﬀering a

useful handle for functionalization at the amine.

Terminal Vinyl Sulfoximines via Alcohol Elimination.

An alternative synthetic approach was needed to access

terminal vinyl sulfoximines. We implemented a two-step

sequence based on the controlled activation and elimination

of β-hydroxyethyl sulfoximines (Table 1). β-Hydroxy thio-

ethers 11a−d were converted to the corresponding sulfox-

imines 12a−d in fair-to-excellent yields. Treating alcohols

12a−d with a slight excess of methanesulfonyl chloride and

base led to activation and elimination of the alcohol to give the

desired NH vinyl sulfoximines 13a−d. The methodology is

suitable for producing aromatic (13a and 13b), heteroaromatic

(13c), and alkyl (13d) vinyl sulfoximines. The mesylation step

generally proceeded with good O/N chemoselectivity;

however, we were additionally able to isolate the N-mesyl

vinyl sulfoximines in some cases (14a and 14d) as side

products. We anticipate that the N-mesyl vinyl sulfoximines

would be more electrophilic and reactive than the NH

analogues and may represent an interesting new class of

electrophile in their own right.

ammonium carbamate and iodosylbenzene to give the THP-

protected β-hydroxy sulfonimidamide 17a in 57% yield over

two steps. After THP deprotection, mesylation and in situ

elimination aﬀorded the desired vinyl sulfonimidamide 18a in

46% over two steps. Notably, the mesylation reaction

proceeded with excellent O/N chemoselectivity for the alcohol

over the sulfonimidamide. This novel class of electrophile was

stable toward silica gel chromatography and showed no

noticeable degradation when stored at −20 °C in dimethyl

sulfoxide (DMSO) over 6 months. To further exemplify the

methodology, we synthesized three additional vinyl sulfonimi-

damides 18b−d. Starting with racemic 1-methyl-3-phenyl-

piperazine 16b gave vinyl sulfonimidamide 18b (diastereomer

ratio (dr) 1:2). Encouragingly, the reaction sequence was

successful with nortriptyline 15c, demonstrating that bioactive

motifs can also be converted into vinyl sulfonimidamides. This

route has delivered some of the ﬁrst examples of a chemical

motif that has signiﬁcant potential for future probe design.

N-Propargylation of Vinyl Sulfoximines and Sulfoni-

midamides. The incorporation of alkyne tags onto small

molecules is a highly valuable transformation that enables

chemical biology experiments such as activity-based protein

proﬁling and ﬂuorescence microscopy.⁴²In the context of

covalent protein targeting probes, the addition of an alkyne tag

generates a fully functionalized probe that facilitates visual-

ization and quantiﬁcation of target engagement.¹⁵The

majority of the previously established covalent warheads do

not possess convenient chemical handles for attachment of

alkyne tags.^14bAs such, the design of fully functionalized

probes often requires preinstallation of the alkyne handle into

the pharmacophore, which can be synthetically challenging.⁴³

Therefore, a general method for late-stage propargylation of

small molecules would present signiﬁcant beneﬁts and

opportunities to chemical biologists.

Terminal Vinyl Sulfonimidamides via Alcohol Elimi-

nation. We envisioned that an analogous β-hydroxyethyl

activation/elimination strategy could be implemented to

generate vinyl sulfonimidamides by combining it with our

sulfenamide oxidation/imidation method.³³Accordingly,

phenyl piperidine (15a) was treated with tetrahydropyranyl

(THP)-protected β-hydroxyethyl disulﬁde (16) and silver

nitrate to generate the corresponding sulfenamide (Scheme 5).

The inclusion of Et₃N, in modiﬁed conditions, gave improved

results by reducing the acidity of the reaction. The sulfenamide

was then simultaneously imidated and oxidized using

Functionalization, including propargylation, of sulfoximine-

NH groups has been widely reported, though for sulfonimi-

damides much less so.⁴⁴⁻⁴⁶Vinyl sulfoximines and sulfonimi-

damides are electrophilic in nature, which raises potential

reaction compatibility concerns. Pleasingly, however, a diverse

range of vinyl sulfoximines and sulfonimidamides could be

eﬃciently propargylated using sodium hydride and propargyl

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Scheme 6. N-Propargylation of Vinyl Sulfoximines and Sulfonimidamides

bromide (Scheme 6). Terminal (19a), substituted (19b and

19c), and heteroaromatic (19d) vinyl sulfoximines as well as

tertiary amines-containing vinyl sulfonimidamides (19e, 19f)

and bioactive-pharmacophore containing vinyl sulfonimida-

mide (19g) were all well tolerated.

functional and the 6-31G* basis set. The low-energy

conformers (within 3 kcal/mol of the lowest) were further

optimized using cam-B3LYP/6-311++g(d,p) in a conductor-

like polarizable continuum model (CPCM) of acetonitrile. We

identiﬁed four minimum energy conformers of (R)-5h that are

signiﬁcantly populated at ambient temperature (Figure 2a). In

the two lowest energy conformers (3 and 1), the vinyl group

eclipses the SO bond, with the two structures varying in the

orientation of the NH group. Conformers 15 and 13, which are

slightly higher in energy, have the vinyl group eclipsing the S

N bond. The electronic transitions of each conformer of (R)-

5h were then calculated, and the UV−vis and ECD spectra

were simulated and summed according to their Boltzmann

weighting (Figure 2b). It should be noted that the calculated

ECD spectra of conformers 3 and 1 were similar to each other

in the experimental range (190−340 nm), while the calculated

spectra of conformers 13 and 15 were also similar to each

other, but with the signiﬁcant peaks being opposite in sign to

those of 3/1. The weighted ECD spectrum is therefore

sensitive to the relative conformer energies at the vinyl-SO

dihedral. We then measured the ECD and UV−vis spectra of

(R)-5h in acetonitrile experimentally and compared them to

the calculated spectra using SpecDis, a dedicated software

package for comparing ECD/UV spectral similarity.⁵⁵Aligning

the UV−vis spectra required a 11 nm positive shift correction

factor of the calculated spectrum, giving good spectral matches

that are characterized by a sharp peak at 197 nm and a broad

peak between 270 and 320 nm. Applying the same 11 nm

correction factor to the calculated ECD spectrum gave

excellent correlation with the experimental ECD, deﬁned by

a trough between 200 and 217 nm, a double peak between 217

and 256 nm, and a second trough between 256 and 316 nm.

To quantify the ECD spectral match, we applied similarity

factor analysis, which gave an 80.7% match for the

experimental (R)-5h ECD spectrum with the calculated (R)-

5h spectrum but only a 0.7% match with the calculated (S)-5h

spectrum. The resulting δ score of 80.0% represents a high

conﬁdence assignment and validates that this workﬂow is

reliable and should be suitable for assigning the conﬁguration

Conﬁgurational Assignment of Enantioenriched

Vinyl Sulfoximines and Sulfonimidamides. The binding

between proteins and chemical probes often exhibits

discriminatory aﬃnity for diﬀerent stereoisomers. Indeed, the

clinical candidate sulfoximine inhibitors roniciclib, atuveciclib,

and ceralasertib are all enantiopure.⁵Therefore, the develop-

ment of future probes relies on both access to enantioenriched

vinyl sulfoximines and sulfonimidamides and the ability to

assign their absolute conﬁguration. Through the HWE reaction

sequence, highly enantioenriched vinyl sulfoximines (S)-5h

and (R)-5h (Scheme 3b) were prepared with a synthetically

deﬁned conﬁguration. However, the other synthetic routes to

vinyl sulfoximines and sulfonimidamides described herein

generate racemic products with respect to the chiral sulfur

center. Chiral separation, typically conducted by high-perform-

ance liquid chromatography (HPLC) or supercritical ﬂuid

chromatography (SFC), oﬀers an alternative method for

accessing enantioenriched products and has been highly

successful with regard to the production of enantiopure

sulfoxide drugs.^47,48The value of such separation is dependent

on the reliable assignment of absolute conﬁguration, which is

typically accomplished by X-ray crystallography,⁴⁹NMR,⁵⁰or

computational and experimental circular dichroism.⁵¹Elec-

tronic circular dichroism (ECD) is among the most versatile of

these techniques and has previously been successfully applied

to the stereochemical assignment of sulfoxide drugs and

sulfonimidamides.⁵²⁻⁵⁴To establish whether ECD could be

reliably applied to the conﬁgurational assignment of vinyl

sulfoximines and sulfonimidamides, we ﬁrst investigated

whether quantum mechanical calculations could predict the

experimentally observed ECD spectrum for (R)-5h with high

conﬁdence.

A conformational search (see the Supporting Information)

was performed on the vinyl sulfoximine unit using the B3LYP

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Vinyl sulfonimidamide 19g was separated into its two

enantiomers 19g-A and 19g-B, which were isolated in very

high enantiomeric purity. The biaryl system is achiral and was

anticipated not to make a signiﬁcant contribution to the ECD

spectrum, while the ﬂexible nature of the alkyl linker would

make the conformational modeling challenging. Accordingly,

we modeled (R)-20 as the key substructure, which yielded

three low-energy conformers. In analogy with vinyl sulfoximine

5h and 10g, the two lower-energy conformers (diﬀering by

0.17 kcal mol⁻¹) have the vinyl group eclipsing the SO

bond, with the two structures varying in the orientation of the

N-propargyl group, while for the higher-energy conformer

(+0.75 kcal mol⁻¹), the vinyl group eclipses the SN bond

(Figure S4). Comparing the calculated and experimental UV−

vis and ECD spectra led to an unambiguous assignment of

19g-A = (R) and 19g-B = (S) conﬁgurations with a high

conﬁdence (δ score = 91.5%) (Figure S5).

Chiral separation of 19f gave four stereoisomers 19f-A−D

that were each isolated in high levels of stereo purity. By

comparing the NMR spectra of each isomer, 19f-A and 19f-D

were assigned as one enantiomeric pair and 19f-B and 19f-C as

the other, although no information about their relative

conﬁguration could be obtained. We then modeled both

(R,S)-19f and (S,S)-19f, which gave four and ﬁve low-energy

(≤1.5 kcal mol⁻¹) conformers, respectively, with the piperazine

ring adopting a chairlike conformation and the phenyl ring

pointing axially in each case (Figure S6). Conformers in which

the phenyl ring points equatorially were substantially higher in

energy (≥2.2 kcal mol⁻¹) for both (R,S)-19f and (S,S)-19f and

made little-to-no contribution to the calculated ECD. Of note,

while for (R,S)-19f the two lowest energy conformers have the

vinyl group eclipsing SO, for (S,S)-19f the lowest four

conformers are of very similar energy, two them having the

vinyl group eclipsing SN, and two having it eclipse SO.

Determining the conﬁguration of diastereoisomers by ECD is

typically challenging because they often have closely related

ECD spectral proﬁles. However, in this case, the calculated

Boltzmann-weighted ECD spectra of all four stereoisomers

gave strikingly diﬀerent shapes. Comparing the UV and ECD

spectra of each isomer with the modeled spectra, we found that

19f-A has a nearly exact match (98.9%) with (R,S)-19f and

19f-B gave an excellent match (97.4%) with (S,S)-19f,

allowing us to make a high conﬁdence assignment of all four

isomers (Figure S7).

Figure 2. (a) Molecular modeling of the low-energy conformations of

(R)-5h. (b) Comparison of calculated and experimental UV−vis and

ECD spectra for (R)-5h.

of vinyl sulfoximines and sulfonimidamides with unknown

stereochemistry.

Next, we selected three compounds 10g, 19g, and 19f for

chiral separation, which was performed using the automated

HPLC/SFC condition screening system at Reach Separa-

tions,⁵⁶and de novo conﬁgurational assignment by ECD using

the same modeling workﬂow and parameters as described for

(R)-5h (Table 2). Chiral separation of 10g, where the carbon

stereocenter is synthetically deﬁned as (S), gave two

diastereoisomers 10g-A and 10g-B as neutral amines. ECD

calculation for 10g is challenging because of the presence of

the second stereocenter and the conformational ﬂexibility of

the acyclic allylic amine. We examined two approaches to

simplify this problem. In the ﬁrst, we used a single ﬁxed, low-

energy conformation of the vinyl amine portion appended to

the four conformers of the allylic sulfoximine unit found for 5h.

We modeled both (R,S)-10g and (S,S)-10g in this way (Figure

S1). The (R,S)-10g and (S,S)-10g models gave distinct

calculated ECD spectra, and comparison with the experimental

spectra gave the best match for 10g-A = (R,S)-10g and 10g-B

= (S,S)-10g, with a mean similarity score of 78.6% (Figure S2).

This assignment is made with high conﬁdence given that the

mean similarity score for the opposite assignment is only

37.1%. To simplify the modeling further for future applications,

we also modeled a phenylvinyl sulfoximine substructure of 10g

that lacks the chiral amine functionality. We found that

comparing the predicted ECD spectrum of substructure-10g

with the experimental racemic-subtracted ECD spectrum of

10g gave the same assignment as modeling the full structure

with a similar conﬁdence level (δ score = 80.6%) (Figure S3).

CONCLUSIONS

■

Vinyl sulfoximines and sulfonimidamides oﬀer signiﬁcant

potential as functionalizable electrophilic warheads but have

seen little exploration to date. We have developed several new

synthetic approaches to these motifs that expand the potential

of these motifs and access a much wider range of derivatives.

First, we showcased a modiﬁed HWE sequence, from methyl

sulﬁdes, providing NH vinyl sulfoximines exclusively as the E-

isomers. Application of this HWE sequence to enantioenriched

methyl sulfoxides gave an eﬃcient route to enantioenriched

vinyl sulfoximines. Next, we developed a two-step route to

vinyl sulfoximines that exploits alkyne hydrothiolation and a

highly chemoselective one-pot transfer of NH and O to vinyl

sulﬁdes. This route is substantially shorter than previous

approaches and works well for both alkyl and aryl vinyl

sulfoximines.

Terminal vinyl sulfoximine and sulfonimidamides represent

particularly challenging synthetic targets that could have

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Table 2. Chiral Separation and Conﬁgurational Assignment of Vinyl Sulfoximine and Sulfonimidamides Stereoisomers by

Molecular Modeling and ECD

dried glassware, using standard techniques. Anhydrous solvents were

obtained by ﬁltration through drying columns (tetrahydrofuran

(THF), CH₂Cl₂, toluene). Forward-phase ﬂash column chromatog-

raphy was performed on an Isolera Spektra ﬂash puriﬁcation system

using Biotage SNAP KP-Sil ﬂash puriﬁcation cartridges or SNAP

Ultra ﬂash puriﬁcation cartridges, with the indicated solvent gradient.

Reversed-phase ﬂash column chromatography was performed using

Biotage SNAP Ultra C18 cartridges. Analytical thin-layer chromatog-

raphy (TLC) was performed on precoated aluminum-backed silica gel

plates. Visualization of the developed chromatogram was performed

by UV absorbance (254 nm) and/or stained with aqueous potassium

permanganate solution, aqueous ceric ammonium molybdate, or a

ninhydrin solution in ethanol. Nuclear magnetic resonance spectra

widespread application as warheads in covalent probes. We

developed a simple two-step route to terminal vinyl

sulfoximines from β-hydroxyethyl thioethers involving sulfox-

imine formation and alcohol activation/elimination. This

approach is also extended to terminal vinyl sulfonimidamides,

about which very little is known. Both vinyl sulfoximines and

sulfonimidamides can be readily N-functionalized with an

alkyne tag. These products have the potential to be utilized as

fully functionalized probes in a range of chemical biology

applications.

Finally, we developed a computational workﬂow for

assigning the conﬁguration of vinyl sulfoximines and

sulfonimidamides using ECD. After validating the approach

against a vinyl sulfoxide with a synthetically deﬁned and known

conﬁguration, we apply the approach to the de novo

assignment of enantiomeric and diastereoisomeric vinyl

sulfoximines and vinyl sulfonimidamides. This methodology

enables the implementation of chiral separation techniques to

be applied to separate racemic vinyl sulfoximines and

sulfonimidamides and assign their conﬁguration, giving access

to a range of new enantioenriched products.

1

were recorded on a 400 MHz spectrometer. Chemical shifts for H

NMR spectra are recorded in parts per million (ppm) from

tetramethylsilane with the residual protic solvent resonance as the

internal standard (chloroform: δ 7.27 ppm, methanol: δ 3.31 ppm).

Data are reported as follows: chemical shift (multiplicity [s, singlet; d,

doublet; t, triplet; m, multiple; and br, broad], coupling constant (in

hertz), integration). ¹³C NMR spectra are recorded with complete

proton decoupling. Chemical shifts are reported in parts per million

from tetramethylsilane with the solvent resonance as the internal

standard (¹³CDCl₃: δ 77.0 ppm, ¹³CD₃OD: δ 49.0 ppm). ¹⁹F NMR

spectra were recorded with complete proton decoupling. Chemical

shifts are reported in parts per million, referenced to ﬂuorobenzene as

a standard at δ −113.5 ppm. Commercial reagents were used as

supplied or puriﬁed by standard techniques where necessary. Optical

rotations (α′) were recorded at the indicated temperature (T °C) and

were converted to the corresponding speciﬁc rotations [α]^T_D.

Taken together, the methods we have exempliﬁed in this

work provide the tools to access new areas of electrophilic

chemical space. Our investigations into the application of vinyl

sulfoximines and sulfonimidamides to chemical biology are

currently underway.

General Procedure A: Preparation of NH-Sulfoximines from

Sulﬁdes by One-Pot N- and O-Transfer. The procedure was adapted

from Tota et al.^31aSulﬁde (4.8 mmol, 1.0 equiv), (diacetoxyiodo)-

benzene (12.0 mmol, 2.5 equiv), and ammonium carbamate (9.6

EXPERIMENTAL SECTION

General Experimental Considerations. All nonaqueous reac-

tions were carried out under an inert atmosphere (argon) with ﬂame-

■

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mmol, 2.0 equiv) were added to a ﬂask containing a stirrer bar.

MeOH (0.5 M) was added, and the reaction was stirred at 25 °C for 3

h. The solvent was removed under reduced pressure. Puriﬁcation by

ﬂash chromatography aﬀorded the sulfoximine product.

corresponding vinyl NH sulfoximine and in some cases N-mesylated

vinyl sulfoximine products.

General Procedure H: Synthesis of Sulfonimidamides from

Amines via a Sulfenamide Intermediate. The procedure was

adapted from Briggs et al.³⁴Amine (3.33 mmol, 1.33 equiv),

triethylamine (2.0−3.5 equiv), and silver nitrate (5.0 mmol, 2.0

equiv) were added to a stirred solution of disulﬁde 16 (2.5 mmol, 1.0

equiv) in MeOH (0.1 M) at 25 °C, under air, for 1 h. The reaction

mixture was ﬁltered and washed with MeOH (2 × 50 mL). The

ﬁltrate solvent was removed under reduced pressure. H₂O (75 mL)

was added to the crude mixture, and the aqueous mixture was

extracted with Et₂O (3 × 75 mL). The combined organic layers were

dried (Na₂SO₄) and ﬁltered, and the solvent was removed under

reduced pressure. Puriﬁcation by ﬁltration through a basic alumina

(activity IV) plug (2 cm thick) aﬀorded the corresponding crude

sulfenamide intermediate. Iodosylbenzene (6.25 mmol, 2.5 equiv) and

ammonium carbamate (5.0 mmol, 2.0 equiv) were added to the crude

sulfenamide (2.5 mmol, 1.0 equiv) in a ﬂask containing a stirrer bar

under an argon atmosphere. A solution of acetic acid (0.2 M solution,

corresponding to 1.0 equiv of AcOH) in iPrOH (0.2 M) was added,

and the reaction was stirred for 1 h. The solvent was then removed

under reduced pressure, and to the crude, sat. aq. NaHCO₃was added

(20 mL). The aqueous mixture was then extracted with CH₂Cl₂(3 ×

20 mL), and the combined organic layers were dried (Na₂SO₄) and

ﬁltered and the solvent was removed under reduced pressure.

Puriﬁcation by ﬂash chromatography aﬀorded the corresponding

sulfonimidamide products.

General Procedure I: Vinyl Sulfonimidamides Synthesis by THP

Deprotection and Alcohol Elimination. HCl (37% in H₂O, 1 mL)

was added to a stirred solution of sulfonimidamide (0.65 mmol, 1

equiv) in MeOH/THF (1:1, 12 mL) at 25 °C. After 30 min, sat. aq.

NaHCO₃was added (25 mL). The aqueous mixture was then

extracted with EtOAc (3 × 50 mL), the combined organic layers were

dried (Na₂SO₄) and ﬁltered, and the solvent was removed in vacuo to

aﬀord the crude alcohol intermediate. A solution of MsCl (0.68

mmol, 1 M in CH₂Cl₂, 1.05 equiv) was added dropwise to a solution

of the crude alcohol (0.65 mmol, 1.0 equiv) and triethylamine (4.0

equiv) in CH₂Cl₂(0.1 M) at 0 °C and left to warm to room

temperature for 16 h. The solvent was removed in vacuo, and

puriﬁcation by ﬂash chromatography aﬀorded the corresponding vinyl

sulfonimidamide products.

General Procedure B: TBDPS Protection of Sulfoximine. A

solution of imidazole (5.2 mmol, 2.0 equiv) in anhydrous

dimethylformamide (DMF) was added to sulfoximine (2.6 mmol,

1.0 equiv). The reaction mixture was cooled to 0 °C, and tert-

butyldiphenylsilyl chloride (3.3 mmol, 1.25 equiv) was added

dropwise to the mixture. The solution was heated to 60 °C using a

heating block and stirred for 64 h under nitrogen, after which the

reaction was quenched with water (10 mL). The aqueous layer was

extracted with CH₂Cl₂(3 × 20 mL), and the organic extracts were

washed with water (10 mL) and brine (10 mL). The combined

organic extracts were then dried (MgSO₄), ﬁltered, and concentrated

in vacuo. Puriﬁcation by ﬂash chromatography aﬀorded the TBDPS

protected sulfoximine product.

General Procedure C: Preparation of Vinyl Sulfoximines by a

Horner−Wadsworth−Emmons Reaction. nBuLi (1.35 mmol, 1.3 M

in hexane, 2.7 equiv) was added to a solution of diisopropylamine

(0.75 mmol, 1.5 equiv) in anhydrous THF at −78 °C under nitrogen.

The resulting solution was warmed to room temperature over 30 min,

before being cooled to −78 °C again. The TBDPS protected

sulfoximine (0.50 mmol, 1.0 equiv) in anhydrous THF was added

dropwise to the reaction mixture and stirred at −78 °C for a further 1

h. Diethylchlorophosphate (0.65 mmol, 1.3 equiv) was added

dropwise. After 5 min, tBuOK (0.65 mmol, 1.0 M in THF, 1.3

equiv) was added and the mixture was stirred for 10 min after which a

solution of aldehyde (1.00 mmol, 2.0 equiv) in anhydrous THF was

added. The solution was then allowed to warm to 0 °C and stirred for

2 h. The reaction was quenched with 5% w/w aq. H₃PO₄(10 mL).

The aqueous layer was extracted with Et₂O (3 × 20 mL), and the

organic extracts were washed with 5% w/w aq. H₃PO₄(2 × 20 mL).

The combined organic extracts were then dried (MgSO₄), ﬁltered,

and concentrated in vacuo. Puriﬁcation by ﬂash chromatography

aﬀorded the TBDPS protected vinyl sulfoximine product.

General Procedure D: TBDPS Deprotection of Vinyl Sulfoximines.

TBAF (0.29 mmol, 1.0 M in THF, 1.1 equiv) was added dropwise to

a solution of TBDPS protected vinyl sulfoximine (0.26 mmol, 1.0

equiv) dissolved in anhydrous THF under nitrogen at room

temperature. The reaction mixture was monitored by TLC every

hour until the reaction was complete. The reaction mixture was

ﬂushed through a silica plug with Et₂O and concentrated in vacuo.

Puriﬁcation by ﬂash chromatography aﬀorded the NH vinyl

sulfoximine product.

General Procedure E: Preparation of NH-Sulfoximines from

Sulfoxides by One-Pot N-Transfer. The procedure was adapted from

Zenzola et al.³⁰Sulﬁde (1.62 mmol, 1.0 equiv), (diacetoxyiodo)-

benzene (4.86 mmol, 3.0 equiv), and ammonium carbamate (6.48

mmol, 4.0 equiv) were added to a ﬂask containing a stirrer bar.

MeOH (0.5 M) was added, and the reaction was stirred at 25 °C for 3

h. The solvent was removed under reduced pressure. Puriﬁcation by

ﬂash chromatography aﬀorded the sulfoximine product.

General Procedure J: N-Propargylation of Vinyl Sulfoximines

and Sulfonimidamides. NaH (0.19 mmol, 60% in mineral oil, 1.2

equiv) was added to a solution of the sulfonimidamide (0.16 mmol,

1.0 equiv) in DMF (0.1 M) at 0 °C, and the reaction was stirred for

30 min. Propargyl bromide (0.22 mmol, 80% in toluene 1.5 equiv)

was added, and the reaction was allowed to warm to room

temperature for 3 h. H₂O (10 mL) was added, and the aqueous

mixture was extracted with EtOAc (3 × 20 mL). The combined

organic layers were dried (Na₂SO₄) and ﬁltered, and the solvent was

removed in vacuo. Puriﬁcation ﬂash chromatography aﬀorded the

corresponding N-propargyl sulfoximine or sulfonimidamide products.

Substituted Vinyl Sulfoximines 5a−g. Imino(methyl)(phenyl)-λ⁶-

sulfanone (2a). The title compound was prepared according to

General Procedure A employing diacetoxyiodobenzene (3.90 g, 12.1

mmol), ammonium carbamate (753 mg, 9.66 mmol), and thioanisole

(600 mg, 4.83 mmol) in MeOH (9.6 mL). Puriﬁcation via ﬂash

chromatography (KP-Sil, 0% grading to 100% EtOAc/pentane,

product eluted at 100%) aﬀorded 2a as a yellow oil (644 mg,

General Procedure F: Alkyne Hydrothiolation. The procedure was

adapted from Shoai et al.⁴¹RhCl(PPh₃)₃(0.05 mmol, 5 mol %) and

any other solid reagents (thiol (1.1 mmol, 1.1 equiv)/alkyne (1.0

mmol, 1.0 equiv)) were added to a microwave vial and sealed. The

ﬂask was evacuated and ﬁlled with N₂three times before adding any

liquid reagents (thiol (1.1 mmol, 1.1 equiv)/alkyne (1.0 mmol, 1.0

equiv)) and 1,2-dichloroethane (0.1 M) at 25 °C. The ﬂask was left to

stir for 18 h before the solvent was removed under reduced pressure.

Puriﬁcation by ﬂash column chromatography aﬀorded the corre-

sponding vinyl sulﬁde product.

General Procedure G: Terminal Vinyl Sulfoximine Synthesis by

Alcohol Mesylation and In Situ Elimination. Mesyl chloride (0.80

mmol, 1 M in CH₂Cl₂, 1.05 equiv) was added dropwise to a stirred

solution of triethylamine (3.04 mmol, 4.0 equiv) and alcohol (0.76

mmol, 1.0 equiv) in CH₂Cl₂(0.1 M) at 0 °C and left to warm to

room temperature. After 1 h, the solvent was removed under reduced

pressure. Puriﬁcation by ﬂash column chromatography aﬀorded the

1

86%); R_f= 0.42 (100% EtOAc); H NMR (400 MHz, CDCl₃) δ

7.97−7.95 (m, 2H), 7.58−7.55 (m, 1H), 7.51−7.48 (m, 1H), 3.06 (s,

3H), 2.02 (s, 1H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 143.4, 133.1,

129.3 (2 × C), 127.7 (2 × C), 46.0; high-resolution mass

spectrometry (HRMS) (electrospray ionization-time-of-ﬂight (ESI-

TOF)) m/z: calcd C₇H₁₀NOS⁺[M + H]⁺, 156.0478; found,

156.0482. Analytical data are in agreement with those reported in

the literature.³³

Imino(4-methoxyphenyl)(methyl)-λ⁶-sulfanone (2b)

The title compound was prepared according to General Procedure

A employing diacetoxyiodobenzene (10.4 g, 32.4 mmol), ammonium

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carbamate (2.02 g, 25.9 mmol), and (4-methoxyphenyl)(methyl)-

sulfane (2.0 g, 13.0 mmol) in MeOH (32 mL). Puriﬁcation via ﬂash

chromatography (KP-Sil, 0% grading to 100% EtOAc/pentane,

product eluted at 100%) aﬀorded 2b (1.70 g, 71%) as an orange

at 7% EtOAc) aﬀorded 4b (142 mg, 57%) as a clear yellow oil; R_f=

0.66 (10% EtOAc/pentane); IR (ﬁlm)/cm⁻¹3067, 2929, 2855, 1319,

1159, 1107, 820, 745, 700; ¹H NMR (400 MHz, CDCl₃) δ 7.80−7.78

(m, 2H), 7.68−7.63 (m, 4H), 7.42−7.38 (m, 1H), 7.35−7.32 (m,

2H), 7.29−7.21 (m, 6H), 6.62−6.57 (dd, J = 6.2, 8.6 Hz), 5.98−5.94

(dd, J = 1.5, 13.4 Hz), 1.89−1.82 (m, 2H), 1.60−1.45 (m, 6H), 1.18−

1.05 (m, 2H), 1.02 (s, 9H), 0.89−0.76 (m, 2H); ¹³C{¹H} NMR (101

Hz, CDCl₃) δ 147.9, 144.6, 136.6, 136.5, 135.7 (2 × C), 135.6 (2 ×

C), 132.3 (2 × C), 131.7, 128.9 (2 × C), 128.7 (3 × C), 127.3 (2 ×

C), 127.2 (2 × C), 39.3, 31.3 (2 × C), 27.2 (3 × C), 25.8 (2 × C),

25.5, 19.5; HRMS (ESI-TOF) m/z: calcd for C₃₀H₃₈NOSSi⁺[M +

H]⁺, 488.2443; found, 488.2447.

1

oil; R_f= 0.21 (100% EtOAc); H NMR (400 MHz, CDCl₃) δ 7.93−

7.91 (d, J = 8.9 Hz, 2H), 7.00−6.98 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H),

3.08 (s, 3H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 163.3, 134.9, 129.88

(2 × C), 114.4 (2 × C), 55.7, 46.5; HRMS (ESI-TOF) m/z: calcd for

C₈H₁₂NO₂S⁺[M + H]⁺, 186.0583; found, 186.0581. Analytical data

are in agreement with those reported in the literature.⁵⁷

tert-Butyl (Methyl(oxo)(phenyl)-λ⁶-sulfaneylidene)carbamate (3a)

The title compound was prepared according to General Procedure

B employing sulfoximine 2a (400 mg, 2.58 mmol). Puriﬁcation via

ﬂash chromatography (KP-Sil, 0% grading to 10% EtOAc/pentane,

product eluted at 8%) aﬀorded sulfoximine 3a (578 mg, 57%) as a

(E)-((tert-Butyldiphenylsilyl)imino)(4-ethynylstyryl)(phenyl)-λ⁶-

sulfanone (4c)

The title compound was prepared according to General Procedure

C employing sulfoximine 3a (600 mg, 0.51 mmol) in THF (9.6 mL),

nBuLi (1.3 M in hexane, 3.10 mL, 4.14 mmol), diisopropylamine

(0.30 mL, 2.25 mmol) in THF (9.6 mL), diethylchlorophosphate

(0.30 mL, 1.98 mmol), tBuOK (1.0 M in THF, 1.98 mL, 1.98 mmol),

and 4-ethynylbenzaldehyde (392 mg, 3.04 mmol) in THF (20 mL).

Puriﬁcation via ﬂash chromatography (KP-Sil, 0% grading to 10%

EtOAc/pentane, eluted at 8% EtOAc) aﬀorded 4c (175 mg, 68%) as

an orange oil; IR (ﬁlm)/cm⁻¹3067, 2925, 2851, 1325, 1160, 1107,

821, 745; ¹H NMR (400 MHz, CDCl₃) δ 7.95−7.93 (m, 2H), 7.77−

7.72 (m, 4H), 7.54−7.48 (m, 1H), 7.46−7.44 (m, 2H), 7.41−7.38

(m, 2H), 7.34−7.27 (m, 6H), 7.13−7.11 (m, 2H), 6.57 (d, J = 15.1

Hz, 1H), 3.16 (s, 1H), 1.13 (s, 9H); ¹³C{¹H} NMR (101 Hz, CDCl₃)

δ 144.1, 137.6, 136.3, 136.2, 135.69 (2 × C), 135.66 (2 × C), 133.4,

132.8, 132.4 (2 × C), 132.2, 129.0 (2 × C), 128.9 (2 × C), 128.1 (2

× C), 127.5 (2 × C), 127.43 (2 × C), 127.39 (2 × C), 123.9, 83.0,

79.2, 27.2, 19.5; HRMS (ESI-TOF) m/z: calcd for C₃₂H₃₂NOSSi⁺[M

+ H]⁺, 506.1968; found, 506.1970.

1

clear oil; R_f= 0.20 (15% EtOAc/pentane); H NMR (400 MHz,

CDCl₃) δ 7.87−7.85 (m, 2H), 7.71−7.69 (m, 2H), 7.65−7.63 (m,

2H), 7.46−7.42 (m, 1H), 7.39−7.35 (m, 2H), 7.30−7.21 (m, 6H),

2.78 (s, 3H), 1.02 (s, 9H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 144.5,

136.23, 136.19, 135.64 (2 × C), 135.60 (2 × C), 132.2, 129.1, 128.9,

128.9 (2 × C), 127.44 (2 × C), 127.41 (2 × C), 127.0, (2 × C), 49.0,

27.2, 19.41 (3 × C). HRMS (ESI-TOF) m/z: calcd for C₂₃H₂₈

NOSiS⁺[M + H]⁺, 394.1655; found, 394.1657. Analytical data in

agreement with those reported in the literature.⁵⁸

((tert-Butyldiphenylsilyl)imino)(4-methoxyphenyl)(methyl)-λ⁶-

sulfanone (3b)

The title compound was prepared according to General Procedure

B employing sulfoximine 2b (1.70 g, 2.58 mmol). Puriﬁcation via ﬂash

chromatography (KP-Sil, 0% grading to 20% EtOAc/pentane, product

eluted at 15%) aﬀorded sulfoximine 3b (447 mg, 41%) as an oﬀ-white

solid; R_f= 0.20 (10% EtOAc/pentane); mp (chloroform) = 83−85

°C; IR (ﬁlm)/cm⁻¹3071, 2929, 2855, 1595, 1498, 1308, 1259, 1155,

1107, 1029, 958, 835, 772, 700, 674; ¹H NMR (400 MHz, CDCl₃) δ

7.85 (d, J = 9.1 Hz, 2H), 7.78−7.76 (m, 2H), 7.73−7.71 (m, 2H),

7.37−7.28 (m, 6H), 3.85 (s, 3H), 2.83 (s, 3H), 1.09 (s, 9H); ¹³C{¹H}

NMR (101 Hz, CDCl₃) δ 162.6, 136.6, 136.5, 136.4, 135.7 (2 × C),

135.6 (2 × C) 129.1 (1 × C), 129.0, 129.1, 127.42 (3 × C), 127.38 (3

× C), 113.9 (2 × C), 55.6, 49.4, 27.2, 19.4 (3 × C); HRMS (ESI-

TOF) m/z: calcd for C₂₄H₃₀NO2SSi⁺[M + H]⁺, 424.1767; found,

424.1771.

(E)-((tert-Butyldiphenylsilyl)imino)(phenyl)(2-(pyridin-2-yl)-

vinyl)-λ⁶-sulfanone (4d)

The title compound was prepared according to General Procedure

C employing sulfoximine 3a (200 mg, 0.51 mmol) in anhydrous THF

(3.2 mL), nBuLi (1.3 M in hexane, 1.05 mL, 1.37 mmol),

diisopropylamine (0.10 mL, 0.77 mmol) in THF (3.2 mL),

diethylchlorophosphate (0.09 mL, 0.66 mmol), tBuOK (1.0 M in

THF, 0.66 mL, 0.66 mmol), and picolinaldehyde (0.12 mL, 1.02

mmol) in THF (8 mL). Puriﬁcation via ﬂash chromatography (KP-

Sil, 0% grading to 20% EtOAc/petroleum ether, eluted at 20%

EtOAc) aﬀorded 4d (148 mg, 60%) as a yellow oil; R_f= 0.19 (10%

EtOAc/petroleum ether); IR (ﬁlm)/cm⁻¹3067, 2929, 2855, 1580,

1468, 1427, 1327, 1170, 1107, 820, 704; ¹H NMR (400 MHz,

CDCl₃) δ 8.54−8.53 (d, J = 4.6 Hz, 1H), 7.97−7.94 (m, H), 7.80−

7.74 (m, 4H), 7.64−7.60 (m, 1H), 7.50−7.44 (m, 1H), 7.40−7.36

(m, 2H), 7.32 (d, J = 15.2 Hz), 7.32−7.27 (m, 5H), 7.25−7.18 (m,

2H), 7.13−7.11 (d, J = 7.8 Hz, 1H), 1.14 (s, 9H). ¹³C{¹H} NMR

(101 Hz, CDCl₃) δ 151.9, 150.0, 143.8, 137.1, 136.7, 136.3, 135.7 (2

× C), 135.7 (2 × C), 132.2, 128.9 (3 × C), 127.6 (2 × C), 127.4 (2 ×

C), 127.3 (2 × C), 124.8, 124.2, 27.3 (3 × C), 19.5. HRMS (ESI-

TOF) m/z: calcd for C₂₉H₃₁N₂OSSi⁺[M + H]⁺, 483.1926; found,

483.1931.

(E)-((tert-Butyldiphenylsilyl)imino)(phenyl)(styryl)-λ⁶-sulfanone

(4a)

The title compound was prepared according to General Procedure

C employing sulfoximine 3a (200 mg, 0.51 mmol) in anhydrous THF

(3.2 mL), nBuLi (1.3 M in hexane, 1.05 mL, 1.37 mmol),

diisopropylamine (0.11 mL, 0.72 mmol) in THF (3.2 mL),

diethylchlorophosphate (0.14 mL, 0.66 mmol), tBuOK (1.0 M in

THF, 0.66 mL, 0.66 mmol), and benzaldehyde (0.10 mL, 1.02 mmol)

in THF (8 mL). Puriﬁcation via ﬂash chromatography (KP-Sil, 0%

grading to 100% EtOAc/pentane, eluted at 9% EtOAc) aﬀorded vinyl

sulfoximine 4a (147 mg, 60%) as a clear oil; R_f= 0.49 (10% EtOAc/

pentane); IR (ﬁlm)/cm⁻¹3064, 2930, 2855, 1677, 1614, 1293, 1148,

1107, 969, 816, 745, 700; ¹H NMR (400 MHz, CDCl₃) δ 7.87−7.85

(m, 2H), 7.71−7.65 (m, 4H), 7.44−7.40 (m, 1H), 7.37−7.33 (m,

3H), 7.31 (d, J = 15.2 Hz, 1H), 7.26−7.20 (m, 8H), 7.14−7.12 (m,

2H), 6.53 (d, J = 15.2 Hz), 1.05 (s, 9H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 144.3, 138.9, 136.4, 136.3, 135.69 (2 × C), 135.66 (2 × C),

134.8, 133.0, 132.0, 131.9, 130.3 (2 × C), 128.9 (2 × C), 128.8 (3 ×

C), 128.3 (2 × C), 27.2, 19.5; HRMS (ESI-TOF) m/z: calcd for

C₃₀H₃₂NOSiS⁺[M + H]⁺, 482.1968; found, 482.1982.

(E)-((tert-Butyldiphenylsilyl)imino)(4-ethynylstyryl)(4-methoxy-

phenyl)-λ⁶-sulfanone (4e)

The title compound was prepared according to General Procedure

C employing sulfoximine 3b (200 mg, 0.47 mmol) in THF (3.2 mL),

nBuLi (1.3 M in hexane, 1.05 mL, 1.37 mmol), diisopropylamine

(0.10 mL, 0.77 mmol) in THF (3.2 mL), diethylchlorophosphate

(0.09 mL, 0.66 mmol), tBuOK (1.0 M in THF, 0.66 mL, 0.66 mmol),

and ethynylbenzaldehyde (123 mg, 0.94 mmol) in THF (8 mL).

Puriﬁcation via ﬂash chromatography (KP-Sil, 0% grading to 20%

EtOAc/petroleum ether, eluted at 12% EtOAc) aﬀorded 4e (128 mg,

51%) as a clear oil; R_f= 0.35 (20% EtOAc/pentane); IR (ﬁlm)/cm⁻¹

3291, 2929, 2855, 1595, 1495, 1312, 1259, 1148, 1107, 1028, 805,

704; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.9 Hz, 2H), 7.77−

7.71 (m, 4H), 7.37 (d, J = 8.4 Hz, 2H), 7.35−7.24 (m, 7H), 7.09 (d, J

= 8.4 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 6.56 (d, J = 15.2 Hz, 1H),

3.84 (s, 3H), 3.16 (s, 3H), 1.12 (s, 9H); ¹³C{¹H} NMR (101 Hz,

(E)-((tert-Butyldiphenylsilyl)imino)(2-cyclohexylvinyl)(phenyl)-

λ⁶-sulfanone (4b)

The title compound was prepared according to General Procedure

C employing sulfoximine 3a (200 mg, 0.51 mmol) in anhydrous THF

(3.2 mL), nBuLi (1.3 M in hexane, 1.05 mL, 1.37 mmol),

diisopropylamine (0.1 mL, 0.77 mmol) in anhydrous THF (3.2

mL), diethylchlorophosphate (0.09 mL, 0.66 mmol), tBuOK (1.0 M

in THF, 0.66 mL, 0.66 mmol), and cyclohexanecarboxaldehyde (0.12

mL, 1.02 mmol) in anhydrous THF (8.0 mL). Puriﬁcation via ﬂash

chromatography (KP-Sil, 0% grading to 10% EtOAc/pentane, eluted

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CDCl₃) δ 162.6 (2 × C), 136.7, 136.5, 136.3, 135.8, 135.7 (3 × C),

133.5, 133.4, 132.4 (2 × C), 129.6 (2 × C), 129.0 (2 × C), 128.0 (2

× C), 127.4 (4 × C), 123.7, 114.1 (2 × C), 83.1, 79.1, 55.6, 27.2 (3 ×

C), 19.5; HRMS (ESI-TOF) m/z: calcd for C₃₃H₃₄NO₂SSi⁺[M +

H]⁺, 536.2080; found, 536.2074.

CDCl₃) δ 7.96−7.93 (m, 2H), 7.59−7.55 (m, 1H), 7.52−7.48 (m,

2H), 6.86 (dd, J = 8.7 Hz, 6.5 Hz), 6.30 (dd, J = 14.1 Hz, 1.4 Hz,

1H), 2.44 (bs, 1H), 2.20−2.13 (m, 1H), 1.75−1.72 (m, 4H), 1.67−

1.64 (m, 1H), 1.31−1.06 (m, 5H); ¹³C{¹H} NMR (101 Hz, CDCl₃)

δ 150.7, 143.1, 132.6, 130.0, 129.10 (2 × C), 127.7 (2 × C), 39.8 (1 ×

C), 31.4, 31.3, 25.8 (2 × C), 25.6 (1 × C); HRMS (ESI) m/z: calcd

for C₁₄H₂₀NOS⁺[M + H]⁺, 250.1266; found, 250.1263.

(E)-((tert-Butyldiphenylsilyl)imino)(4-methoxyphenyl)(2-(thiazol-

2-yl)vinyl)-λ⁶-sulfanone (4f)

(E)-(4-Ethynylstyryl)(imino)(phenyl)-λ⁶-sulfanone (5c)

The title compound was prepared according to General Procedure

C employing sulfoximine 3b (300 mg, 0.71 mmol) in THF (4.8 mL),

nBuLi (1.3 M in hexane, 1.50 mL, 1.91 mmol), diisopropylamine

(0.15 mL, 1.07 mmol) in THF (4.8 mL), diethylchlorophosphate

(0.13 mL, 0.92 mmol), tBuOK (1.0 M in THF, 0.92 mL, 0.92 mmol),

and 1,3-thiazole-2-carbaldehyde (0.13 mL, 1.42 mmol) in THF (10

mL). Puriﬁcation via ﬂash chromatography (KP-Sil, 0% grading to

50% EtOAc/hexane, eluted at 30% EtOAc) aﬀorded 4f (311 mg,

84%) as a yellow oil; R_f= 0.38 (EtOAc/hexane); IR (ﬁlm)/cm⁻¹

3071, 2959, 2855, 1595, 1494, 1312, 1259, 1151, 1107, 1028, 820,

704; ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.7 Hz, 2H), 7.81 (d,

J = 3.2 Hz, 1H), 7.78−7.72 (m, 4H), 7.37 (d, J = 15.3 Hz), 7.35 (d, J

= 3.32 Hz, 1H), 7.32−7.28 (m, 6H), 6.96 (d, J = 15.3 Hz, 1H), 6.90

(d, J = 8.8 Hz, 2H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 162.9, 162.0,

144.5, 137.1, 136.1 (2 × C), 135.7 (4 × C), 135.0, 129.9 (2 × C),

129.0, 128.7, 127.4 (6 × C), 121.4, 114.2 (2 × C), 55.6, 27.3 (3 × C),

19.5; HRMS (ESI-TOF) m/z: calcd for C₂₈H₃₁N₂O₂S₂Si⁺[M + H]⁺,

519.1591; found, 519.1599.

The title compound was prepared according to General Procedure

D employing vinyl sulfoximine 4c (690 mg, 1.37 mmol) and TBAF

(1.0 M in THF, 50 mL, 1.51 mmol) in THF (25 mL). Puriﬁcation via

ﬂash chromatography (KP-Sil, 0% grading to 100% EtOAc/pentane,

eluted at 50% EtOAc) aﬀorded 5c (300 mg, 82%) as a white solid; R_f

= 0.43 (50% EtOAc/pentane); mp (CHCl₃) 133−135 °C; IR (ﬁlm)/

cm⁻¹3279, 3061, 2579, 2361, 1614, 1445, 1217, 1125, 974, 799, 753,

1

687; H NMR (400 MHz, CDCl₃) δ 8.04−8.02 (m, 2H), 7.62−7.57

(m, 2H), 7.56−7.52 (m, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.41 (d, J =

8.4 Hz, 2H), 6.92 (d, J = 15.3 Hz, 1H), 3.19 (s, 1H), 2.95 (bs, 1H);

¹³C{¹H} NMR (101 Hz, CDCl₃) δ 142.5, 140.4, 133.0, 132.7 (2 ×

C), 130.5, 129.3 (2 × C), 128.3 (2 × C), 128.0 (2 × C), 124.6, 82.9,

79.7; HRMS (ESI-TOF) m/z: calcd for C₁₆H₁₄NOS⁺[M + H]⁺,

268.0796; found, 268.0804.

(E)-Imino(phenyl)(2-(pyridin-2-yl)vinyl)-λ⁶-sulfanone (5d)

The title compound was prepared according to General Procedure

D employing vinyl sulfoximine 4d (70 mg, 0.15 mmol) and TBAF

(1.0 M in THF, 0.16 mL, 0.16 mmol) in THF (2.8 mL). Puriﬁcation

via ﬂash chromatography (KP-Sil, 0% grading to 100% EtOAc/

petroleum ether, eluted at 100% EtOAc) aﬀorded 5d (25 mg, 69%) as

a white solid; R_f= 0.39 (100% EtOAc); mp (CHCl₃) = 94−96 °C; IR

(ﬁlm)/cm⁻¹3258, 3056, 1580, 1469, 1431, 1215, 1111, 969, 797, 753,

(E)-((tert-Butyldiphenylsilyl)imino)(4-methoxyphenyl)(2-(quinox-

alin-2-yl)vinyl)-λ⁶-sulfanone (4g)

The title compound was prepared according to General Procedure

C employing sulfoximine 3b (300 mg, 0.71 mmol) in anhydrous THF

(4.8 mL), nBuLi (1.3 M in hexane, 1.50 mL, 1.91 mmol),

diisopropylamine (0.15 mL, 1.07 mmol) in THF (4.8 mL),

diethylchlorophosphate (0.13 mL, 0.92 mmol), tBuOK (1.0 M in

THF, 0.92 mL, 0.92 mmol), and quinoxaline-2-carbaldehyde (200

mg, 1.42 mmol) in THF (10 mL). Puriﬁcation by ﬂash

chromatography (KP-Sil, 0% grading to 50% EtOAc/hexane, eluted

at 26% EtOAc) aﬀorded 4g (271 mg, 68%) as an orange oil; R_f= 0.33

(40% EtOAc/hexane); IR (ﬁlm)/cm⁻¹3071, 2963, 2855, 1595, 1494,

1

708; H NMR (400 MHz, CDCl₃) δ 8.60−8.59 (d, J = 4.5 Hz, 1H),

8.06−8.04 (m, 2H), 7.69 (m, 1H), 7.60 (d, J = 15.2 Hz, 1H), 7.59−

7.54 (m, 1H), 7.54−7.51 (m, 2H), 7.46 (d, J = 15.3 Hz, 1H), 7.40−

7.38 (d, J = 7.8 Hz, 1H), 2.67 (bs, 1H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 151.4, 150.2, 142.0, 139.6, 137.0, 134.2, 133.0 (2 × C),

129.2 (2 × C), 128.2, 125.2, 124.7; HRMS (ESI-TOF) m/z: calcd for

C₁₃H₁₃N₂OS⁺[M + H]⁺, 245.0749; found, 245.0755. Analytical data

are in agreement with those reported in the literature.²²

1

1312, 1259, 1148, 1107, 1058, 820, 764, 704; H NMR (400 MHz,

CDCl₃) δ 8.55 (s, 1H), 8.07−8.05 (m, 1H), 8.00−7.97 (m, 1H), 7.93

(d, J = 8.9 Hz, 2H), 7.80−7.74 (m, 6H), 7.38 (d, J = 15.3 Hz, 1H),

7.28 (d, J = 15.3 Hz, 1H), 7.28−7.26 (m, 6H), 6.94 (d, J = 8.81 Hz,

2H), 3.85 (s, 3H), 1.15 (s, 9H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ

163.0, 147.2, 144.9, 142.3 (2 × C), 139.7, 136.1, 135.7 (4 × C),

134.9, 132.9, 130.7 (2 × C), 130.1 (2 × C), 129.6, 129.2, 129.1 (2 ×

C), 127.4 (6 × C), 114.3 (2 × C), 55.7, 27.3 (3 × C), 19.5; HRMS

(ESI-TOF) m/z: calcd for C₃₃H₃₄N₃O₂SSi⁺[M + H]⁺, 564.2141;

found, 564.2154.

(E)-(4-Ethynylstyryl)(imino)(4-methoxyphenyl)-λ⁶-sulfanone (5e)

The title compound was prepared according to General Procedure

D employing vinyl sulfoximine 4e (70 mg, 0.15 mmol) and TBAF

(1.0 M in THF, 0.16 mL, 0.16 mmol) in THF (2.8 mL). Puriﬁcation

via ﬂash chromatography (KP-Sil, 0% grading to 100% EtOAc/

petroleum ether, eluted at 48% EtOAc) aﬀorded 5e (32 mg, 72%) as

an orange oil; R_f= 0.24 (50% EtOAc/petroleum ether); IR (ﬁlm)/

cm⁻¹3283, 3049, 2940, 2840, 1595, 1494, 1461, 1312, 1259, 1215,

1177, 1110, 976, 805; ¹H NMR (400 MHz, CDCl₃) δ 7.95−7.93 (d, J

= 8.6 Hz, 2H), 7.52 (d, J = 15.4 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H),

7.39 (d, J = 8.0, 2H), 6.98 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 15.4 Hz,

1H), 3.85 (s, 3H), 3.18 (s, 1H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ

163.3, 139.4, 133.8, 133.1, 132.6 (2 × C), 131.1, 130.2 (2 × C), 128.2

(2 × C), 124.4, 114.5 (2 × C), 82.9, 79.5, 55.7; HRMS (ESI-TOF)

m/z: calcd for C₁₇H₁₆NO₂S⁺[M + H]⁺, 298.0902; found, 298.0895.

(E)-Imino(4-methoxyphenyl)(2-(thiazol-2-yl)vinyl)-λ⁶-sulfanone

(5f)

(E)-Imino(phenyl)(styryl)-λ⁶-sulfanone (5a)

The title compound was prepared according to General Procedure

D employing vinyl sulfoximine 4a (125 mg, 0.26 mmol) and TBAF

(1.0 M in THF, 0.29 mL, 0.29 mmol) in anhydrous THF (4.7 mL).

Puriﬁcation via ﬂash chromatography (KP-Sil, 0% grading to 100%

EtOAc/pentane, eluted at 58% EtOAc) gave vinyl sulfoximine 5a as a

1

yellow oil (47 mg, 74%); R_f= 0.58 (100% EtOAc); H NMR (400

MHz, CDCl₃) δ 8.05−8.02 (m, 2H), 7.62 (d, J = 15.2 Hz, 1H), 7.60−

7.56 (m, 1H), 7.55−7.51 (m, 2H), 7.49−7.46 (m, 2H), 7.40−7.37

(m, 3H), 6.93 (d, J = 15.3 Hz, 1H), 2.68 (bs, 1H); ¹³C{¹H} NMR

(101 Hz, CDCl₃) δ 142.8, 141.6, 132.8, 132.7, 130.9, 129.5, 129.2 (2

× C), 129.0 (2 × C), 128.5 (2 × C), 127.9 (2 × C); HRMS (ESI-

TOF) m/z: calcd for C₁₄H₁₄NOS⁺[M + H]⁺, 244.0807; found,

244.0796. Analytical data are in agreement with those reported in the

literature.²²

The title compound was prepared according to General Procedure

D employing vinyl sulfoximine 4f (250 mg, 0.48 mmol) and TBAF

(1.0 M in THF, 0.53 mL, 0.53 mmol) in THF (9 mL). Puriﬁcation by

ﬂash chromatography (KP-Sil, 0% grading to 100% EtOAc/hexane,

eluted at 80% EtOAc) aﬀorded 5f (114 mg, 85%) as a yellow oil; R_f=

0.40 (80% EtOAc/hexane); IR (ﬁlm)/cm⁻¹3259, 2926, 2840, 1593,

1494, 1312, 1258, 1231, 1126, 1108, 1090, 1021, 833; ¹H NMR (400

MHz, CDCl₃) δ 7.94 (d, J = 8.94 Hz, 2H), 7.88 (d, J = 3.2 Hz, 1H),

7.65 (d, J = 15.2 Hz, 1H), 7.44 (d, J = 3.2 Hz, 1H), 7.24 (d, J = 15.3

Hz, 1H), 6.98 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 2.93 (bs, 1H);

¹³C{¹H} NMR (101 Hz, CDCl₃) δ 163.6, 161.4, 144.9, 135.0, 132.8,

131.1, 130.5 (2 × C), 127.1, 122.1, 114.6 (2 × C), 55.7; HRMS (ESI-

(E)-(2-Cyclohexylvinyl)(imino)(phenyl)-λ⁶-sulfanone (5b)

The title compound was prepared according to General Procedure

D employing vinyl sulfoximine 4b (115 mg, 0.24 mmol) and TBAF

(1.0 M in THF, 0.26 mL, 0.26 mmol) in THF (4.5 mL). Puriﬁcation

via ﬂash chromatography (KP-Sil, 0% grading to 100% EtOAc/

pentane, eluted at 50% EtOAc) aﬀorded 5b (44 mg, 74%) as a yellow

oil; R_f= 0.42 (50% EtOAc/pentane); IR (ﬁlm)/cm⁻¹3270, 2924,

+

TOF) m/z: calcd for C₁₂H₁₃N₂O₂S₂[M + H]⁺, 281.0418; found,

1

2851, 1625, 1446, 1226, 1125, 969, 7511, 688; H NMR (400 MHz,

281.0410.

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(E)-Imino(4-methoxyphenyl)(2-(quinoxalin-2-yl)vinyl)-λ⁶-sulfa-

none (5g)

(S,E)-((tert-Butyldiphenylsilyl)imino)(4-ethynylstyryl)(p-tolyl)-λ⁶-

sulfanone ((S)-4h). The title compound was prepared according to

General Procedure C employing sulfoximine (S)-3h (100 mg, 0.25

mmol, er >99:1) in THF (1.6 mL), nBuLi (1.3 M in hexane, 0.52 mL,

0.68 mmol), diisopropylamine (0.05 mL, 0.37 mmol) in THF (1.6

mL), diethylchlorophosphate (0.05 mL, 0.32 mmol), tBuOK (1.0 M

in THF, 0.32 mL, 0.32 mmol), and 4-ethynylbenzaldehyde (85 mg,

0.47 mmol) in THF (4 mL). Puriﬁcation by ﬂash chromatography

(KP-Sil, 0% grading to 10% EtOAc/hexane, product eluted at 8%

EtOAc) aﬀorded (S)-4h (88 mg, 69%, er >99:1) as a yellow oil; R_f=

0.22 (10% EtOAc/hexane); IR (ﬁlm)/cm⁻¹3291, 3049, 2955, 2855,

The title compound was prepared according to General Procedure

D employing vinyl sulfoximine 4g (270 mg, 0.48 mmol) and TBAF

(1.0 M in THF, 0.53 mL, 0.53 mmol) in THF (9.0 mL). Puriﬁcation

by ﬂash chromatography (KP-Sil, 0% grading to 100% EtOAc/hexane,

eluted at 90% EtOAc) aﬀorded 5g (120 mg, 77%) as a brown oil; R_f=

0.51 (100% EtOAc/hexane); IR (ﬁlm)/cm⁻¹3250, 3060, 2840, 1591,

1491, 1413, 1364, 1256, 1230, 1178, 1126, 1013, 969, 827, 760, 670;

¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 8.10−8.07 (m, 1H),

8.04−8.00 (m, 3H), 7.81−7.77 (m, 3H), 7.67 (d, J = 15.2 Hz), 7.00−

7.03 (m, 2H), 3.87 (s, 3H), 3.04 (bs, 1H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 163.6, 146.7, 145.0, 142.6, 142.3, 137.8, 135.5, 132.8, 131.0,

130.9, 130.6 (2 × C), 129.7, 129.3, 127.1, 114.6 (2 × C), 55.7;

HRMS (ESI-TOF) m/z: calcd for C₁₇H₁₆N₃O₂S⁺[M + H]⁺,

326.0958; found, 326.0974.

1

1595, 1468, 1427, 1312, 1148, 1107, 1017, 969, 797, 741, 700; H

NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 8.3 Hz, 2H), 7.79−7.73 (m,

5H), 7.39 (d, J = 8.1 Hz, 2H), 7.37−7.24 (m, 8H), 7.10 (d, J = 8.3

Hz, 2H), 6.57 (d, J = 15.3 Hz, 1H), 3.17 (s, 1H), 2.40 (s, 3H), 1.14

(s, 9H); ¹³C{¹H} NMR (101 MHz, CDCl₃) δ 142.9, 141.2, 137.2,

136.5, 136.3, 135.7 (2 × C), 134.8, 133.5, 133.2, 132.4, 129.6 (2 ×

C), 129.0, 128.1, 127.7, 127.6, 127.4 (2 × C), 123.8, 83.1, 79.2, 27.2

(9 × C), 21.5, 19.5; HRMS (ESI-TOF) m/z: calcd for C₃₃H₃₄NOSSi⁺

[M + H]⁺, 520.2131; found, 520.2120.

Enantioenriched Vinyl Sulfoximines (S)-5h and (R)-5h. (S)-

Imino(methyl)(p-tolyl)-λ⁶-sulfanone ((S)-2h). The title compound

was prepared according to General Procedure E employing (S)-1-

methyl-4-(methylsulﬁnyl)benzene (S)-6 (500 mg, 3.13 mmol, er

>99:1). Puriﬁcation by ﬂash chromatography (KP-Sil, 0% grading to

100% EtOAc/pentane, product eluted at 100%) aﬀorded (S)-2h (473

(R,E)-((tert-Butyldiphenylsilyl)imino)(4-ethynylstyryl)(p-tolyl)-λ⁶-

sulfanone ((R)-4h). The title compound was prepared according to

General Procedure C employing sulfoximine (R)-3h (100 mg, 0.25

mmol, er >99:1) in THF (1.6 mL), nBuLi (1.3 M in hexane, 0.52 mL,

0.68 mmol), diisopropylamine (0.05 mL, 0.37 mmol) in THF (1.6

mL), diethylchlorophosphate (0.05 mL, 0.32 mmol), tBuOK (1.0 M

in THF, 0.32 mL, 0.32 mmol), and 4-ethynylbenzaldehyde (85 mg,

0.47 mmol) in THF (4 mL). Puriﬁcation by ﬂash column

chromatography (KP-Sil, 0% grading to 10% EtOAc/hexane, product

eluted at 8% EtOAc) aﬀorded (R)-4h (81 mg, 62%, er >99:1) as a

yellow oil; R_f= 0.17 (10% EtOAc/hexane); IR (ﬁlm)/cm⁻¹3291,

3049, 2955, 2855, 1681, 1554, 1472, 1427, 1312, 1151, 1107, 1017,

1

mg, 86%) as a clear oil; R_f= 0.20 (100% EtOAc); H NMR (400

MHz, CDCl₃) δ 7.90−7.88 (m, 2H), 7.34 (d, J = 8.0 Hz, 2H), 3.09 (s,

3H), 2.45 (s, 3H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 144.0, 140.5,

129.9 (2 × C), 127.7 (2 × C), 46.3, 21.5; HRMS (ESI-TOF) m/z:

calcd for C₈H₁₁NOS⁺[M + H]⁺, 170.0640; found, 170.0642.

Analytical data are in agreement with those reported in the

literature.³¹

(R)-Imino(methyl)(p-tolyl)-λ⁶-sulfanone ((R)-2h). The title com-

pound was prepared according to General Procedure E employing

(R)-1-methyl-4-(methylsulﬁnyl)benzene (250 mg, 1.62 mmol, er

>99:1). Puriﬁcation by ﬂash column chromatography (KP-Sil, 0%

grading to 100% EtOAc/pentane, product eluted at 100%) aﬀorded

1

972, 801, 741, 704; H NMR (400 MHz, CDCl₃) δ 7.82 (d, J = 8.3

Hz, 2H), 7.78−7.72 (m, 5H), 7.38 (d, J = 8.4 Hz, 2H), 7.33−7.23 (m,

8H), 7.10 (d, J = 8.3 Hz, 2H), 6.57 (d, J = 15.3 Hz, 1H), 3.16 (s, 1H),

2.40 (s, 3H), 1.13 (s, 9H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 142.9,

141.2, 137.2, 136.5, 136.3, 135.7 (2 × C), 134.8, 133.5, 133.2, 132.4,

129.6 (2 × C), 129.0, 128.1, 127.7, 127.6, 127.4 (2 × C), 123.7, 83.1,

79.2, 27.2 (9 × C), 21.5, 19.5; HRMS (ESI-TOF) m/z: calcd for

C₃₃H₃₄NOSSi⁺[M + H]⁺, 520.2131; found, 520.2130.

1

(R)-2h (255 mg, 94%) as a clear oil. R_f= 0.20 (100% EtOAc); H

NMR (400 MHz, CDCl₃) δ 7.90−7.88 (m, 2H), 7.33 (d, J = 8.0 Hz,

2H), 3.11 (s, 3H), 2.43 (s, 3H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ

143.9, 140.5, 129.9 (2 × C), 127.7 (2 × C), 46.4, 21.6; HRMS (ESI-

TOF) m/z: calcd for C₈H₁₁NOS⁺[M + H]⁺, 170.0640; found,

170.0641. Analytical data are in agreement with those reported in the

literature.⁵⁹

(S,E)-(4-Ethynylstyryl)(imino)(p-tolyl)-λ⁶-sulfanone ((S)-5h). The

title compound was prepared according to General Procedure D

employing sulfoximine (S)-4h (80 mg, 0.15 mmol, er >99:1).

Puriﬁcation by ﬂash column chromatography (KP-Sil, 0% grading to

100% EtOAc/hexane, product eluted at 48% EtOAc) aﬀorded (S)-5h

(39 mg, 92%, er >99:1) as an oﬀ-white solid; R_f= 0.34 (50% EtOAc/

hexane); mp (CHCl₃) = 147−149 °C; IR (ﬁlm)/cm⁻¹3280, 3045,

(S)-((tert-Butyldiphenylsilyl)imino)(methyl)(p-tolyl)-λ⁶-sulfanone

((S)-3h). The title compound was prepared according to General

Procedure B employing (S)-2h (531 mg, 3.14 mmol). Puriﬁcation by

ﬂash chromatography (KP-Sil, 0% grading to 10% EtOAc/pentane,

product eluted at 10%) aﬀorded (S)-3h (830 mg, 65%, >99:1 er) as a

clear oil; R_f= 0.43 (10% EtOAc/pentane); IR (ﬁlm)/cm⁻¹3049,

2955, 2855, 1599, 1427, 1427, 1326, 1293, 1162, 1107, 964, 820, 767,

741, 700; ¹H NMR (400 MHz, CDCl₃) δ 7.82−7.80 (m, 2H), 7.78−

7.76 (m, 2H), 7.73−7.70 (m, 2H), 7.41−7.28 (m, 6H), 7.23 (d, J=

8.1 Hz, 2H), 2.83 (s, 3H), 2.40 (s, 3H), 1.09 (s, 9H); ¹³C{¹H} NMR

(101 Hz, CDCl₃) δ 138.2, 136.5, 135.64 (2 × C), 135.58 (2 × C),

134.8, 129.7, 129.5 (2 × C), 129.0 (3 × C), 127.4, 127.0 (2 × C)

49.1, 27.2 (9 × C), 21.46, 19.40; HRMS (ESI-TOF) m/z: calcd for

C₂₄H₃₀NOSSi⁺[M + H]⁺, 408.1817; found, 408.1834.

1

1599, 1408, 1215, 1114, 1080, 976, 861, 797, 756; H NMR (400

MHz, CDCl₃) δ 7.90 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 15.3 Hz, 1H),

7.47 (d, J = 8.7 Hz, 2H), 7.41 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.4 Hz,

2H), 6.93 (d, J = 15.2 Hz, 1H), 3.19 (s, 1H), 2.43 (s, 3H), 2.38 (bs,

1H, NH); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 143.9, 139.9, 139.5,

133.0, 132.7 (2 × C), 130.7, 130.0 (2 × C), 128.3 (2 × C), 128.0 (2

× C), 124.4, 82.9, 79.6, 21.56; HRMS (ESI-TOF) m/z: calcd for

C₁₇H₁₆NOS⁺[M + H]⁺, 282.0953; found, 282.0952.

(R,E)-(4-Ethynylstyryl)(imino)(p-tolyl)-λ⁶-sulfanone ((R)-5h). The

title compound was prepared according to General Procedure D

employing sulfoximine (R)-4h (40 mg, 0.08 mmol, er >99:1).

Puriﬁcation by ﬂash column chromatography (KP-Sil, 0% grading to

100% EtOAc/hexane, product eluted at 48% EtOAc) aﬀorded (R)-5h

(17 mg, 79%, er >99:1) as an oﬀ-white solid; R_f= 0.34 (50% EtOAc/

hexane); mp (CHCl₃) = 147−149 °C; ¹H NMR (400 MHz, CDCl₃)

δ 7.89 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 15.3 Hz, 1H), 7.47 (d, J = 8.3

Hz, 2H), 7.40 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 6.92 (d, J

= 15.2 Hz, 1H), 3.18 (s, 1H), 2.43 (s, 3H), 2.40 (bs, 1H, NH);

¹³C{¹H} NMR (101 Hz, CDCl₃) δ 144.0, 140.0, 133.0 (2 × C), 132.7

(2 × C), 130.7, 130.0 (2 × C), 128.3 (2 × C), 128.1 (2 × C), 124.5,

82.9, 79.6, 21.6; HRMS (ESI-TOF) m/z: calcd for C₁₇H₁₆NOS⁺[M +

H]⁺, 282.0953; found, 282.0952.

(R)-((tert-Butyldiphenylsilyl)imino)(methyl)(p-tolyl)-λ⁶-sulfanone

((R)-3h). The title compound was prepared according to General

Procedure B employing (R)-2h (236 mg, 1.39 mmol). Puriﬁcation by

ﬂash column chromatography (KP-Sil, 0% grading to 10% EtOAc/

pentane, product eluted at 10%) aﬀorded (R)-3h (346 mg, 61%, er

>99:1) as a clear oil; R_f= 0.43 (10% EtOAc/pentane) IR (ﬁlm)/cm⁻¹

3067, 2955, 2855, 1590, 1472, 1427, 1323, 1293, 1162, 1107, 954,

1

820, 768, 741, 700; H NMR (400 MHz, CDCl₃) δ 7.82−7.80 (m,

2H), 7.78−7.76 (m, 2H), 7.73−7.70 (m, 2H), 7.37−7.29 (m, 6H),

7.23 (d, J = 9.0 Hz, 2H), 2.83 (s, 3H), 2.40 (s, 3H), 1.09 (s, 9H);

¹³C{¹H} NMR (101 Hz, CDCl₃) δ 138.2, 136.5, 135.6 (4 × C),

134.8, 129.7, 129.5 (2 × C), 129.0 (3 × C), 127.4, 127.0 (2 × C)

49.1, 27.2 (9 × C), 21.5, 19.4; HRMS (ESI-TOF) m/z: calcd for

C₂₄H₃₀NOSSi⁺[M + H]⁺, 408.1817; found, 408.1828.

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(E)-Trimethyl(2-(phenylthio)vinyl)silane (9a). The title compound

was prepared according to General Procedure F employing RhCl-

(PPh₃)₃(46 mg, 0.05 mmol), ethynyltrimethylsilane (0.14 mL, 1.0

mmol), and thiophenol (102 μL, 1.0 mmol). Puriﬁcation by ﬂash

column chromatography (KP-Sil, hexane) aﬀorded vinyl sulﬁde 9a

(179 mg, 86%) as a colorless oil; R_f= 0.80 (hexane); IR (ﬁlm)/cm⁻¹

3061, 2956, 2895, 1546, 1484, 1439, 1234, 1026, 841, 742; ¹H NMR

(400 MHz, CDCl₃) δ 7.59−7.01 (m, 5H), 6.59 (d, J = 18.0 Hz, 1H),

5.82 (d, J = 18.0 Hz, 1H), 0.00 (s, 9H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 145.0, 135.2, 129.4 (2 × C), 129.1 (2 × C), 125.6, 122.8,

−0.8 (9 × C); HRMS (atmospheric pressure chemical ionization

(APCI)⁺) m/z: calcd for C₁₁H₁₇SSi⁺[M + H]⁺, 209.0815; found,

209.0817. Analytical data are in agreement with those reported in the

literature.⁶⁰

120.7, 64.8, 34.6, 30.6, 27.6, 19.1, 13.7; HRMS (APCI⁺) m/z: calcd

for C₁₅H₂₀O₂SBr⁺[M + H]⁺, 343.0362; found, 343.0371.

tert-Butyl (S,E)-(tert-Butoxycarbonyl)(5-phenyl-1-(phenylthio)-

pent-1-en-3-yl)carbamate (9f). The title compound was prepared

according to an adaptation of General Procedure F, increasing the

reaction time to 72 h and employing RhCl(PPh₃)₃(73 mg, 0.08

mmol), tert-butyl (S)-(tert-butoxycarbonyl)(5-phenylpent-1-yn-3-yl)-

carbamate^13e(950 mg, 2.65 mmol), and thiophenol (301 μL, 2.94

mmol). Puriﬁcation by ﬂash column chromatography (SiO₂, 5%

EtOAc/hexane) aﬀorded vinyl sulﬁde 9f (1.22 g, 98%) as a colorless

oil; R_f= 0.75 (10% EtOAc/hexane); IR (ﬁlm)/cm⁻¹2978, 1737,

1

1799, 1342, 1244, 1140, 1114; H NMR (400 MHz, CDCl₃) δ δ

7.35−7.27 (m, 5H), 7.26−7.13 (m, 5H), 6.36 (dd, J = 15.2, 0.9 Hz,

1H), 6.06 (dd, J = 15.2, 7.6 Hz, 1H), 4.76 (q, J = 7.4 Hz, 1H), 2.62 (t,

J = 8.1 Hz, 2H), 2.29−2.14 (m, 1H), 2.14−1.95 (m, 1H), 1.49 (s,

18H). Analytical data are in agreement with those reported in the

literature.⁵⁹

(E)-(2-(Benzylthio)vinyl)trimethylsilane (9b). The title compound

was prepared according to General Procedure F employing RhCl-

(PPh₃)₃(92 mg, 0.10 mmol), ethynyltrimethylsilane (0.28 mL, 2.0

mmol), and benzyl mercaptan (0.23 mL, 2.0 mmol). Puriﬁcation by

ﬂash column chromatography (SiO₂, hexane) aﬀorded vinyl sulﬁde 9b

(356 mg, 80%) as a colorless oil; R_f= 0.60 (hexane); IR (ﬁlm)/cm⁻¹

3060, 3027, 2960, 2922, 2859, 1603, 1548, 1495, 1454, 1416, 1374,

(E)-Imino(phenyl)(2-(trimethylsilyl)vinyl)-λ⁶-sulfanone (10a).

The title compound was prepared according to General Procedure

A employing vinyl sulﬁde 9a (179 mg, 0.86 mmol). Puriﬁcation by

ﬂash column chromatography (KP-Sil, 0% grading to 100% EtOAc/

hexane, product eluted at 38% EtOAc) aﬀorded sulfoximine 10a (107

mg, 52%) as a colorless oil; R_f= 0.40 (50% EtOAc/hexane); IR

1

1334, 1200, 1103, 1070, 917, 850, 768, 701; H NMR (400 MHz,

CDCl₃) δ 7.38−7.27 (m, 5H), 6.55 (d, J = 18.1 Hz, 1H), 5.79 (d, J =

18.1 Hz, 1H), 3.95 (s, 2H), 0.06 (s, 9H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 138.3, 137.3, 129.0 (2 × C), 128.7 (2 × C), 127.4, 125.9,

36.1, −1.0 (9 × C); HRMS (APCI⁺) m/z: calcd for C₁₂H₁₈SSi⁺[M +

H]⁺, 222.0893; found, 222.0900.

1

(ﬁlm)/cm⁻¹2957, 2905, 1504, 1450, 1266, 1213, 978, 841, 789; H

NMR (400 MHz, CDCl₃) δ 8.02−7.89 (m, 2H), 7.64−7.43 (m, 3H),

7.15 (d, J = 17.6 Hz, 1H), 6.69 (d, J = 17.6 Hz, 1H), 0.11 (s, 9H);

¹³C{¹H} NMR (101 Hz, CDCl₃) δ 143.9, 143.4, 142.2, 132.9, 129.3

(E)-(4-Methoxystyryl)(naphthalen-2-yl)sulfane (9c). The title

compound was prepared according to General Procedure F

employing RhCl(PPh₃)₃(46 mg, 0.05 mmol), naphthalene-2-thiol

(176 mg, 1.1 mmol), and 1-ethynyl-4-methoxybenzene (129 μL, 1.0

mmol). Puriﬁcation by ﬂash column chromatography (SiO₂, 5%

Et₂O/hexane) aﬀorded vinyl sulﬁde 9c (227 mg, 78%) as a white

solid; R_f= 0.40 (5% Et₂O/hexane); mp = 103−105 °C; IR (ﬁlm)/

(2 × C), 128.3 (2 × C), −1.8 (9 × C); HRMS (ESI-TOF) m/z: calcd

for C₁₁H₁₈NOSSi⁺[M + H]⁺, 240.0873; found, 240.0871.

(E)-Benzyl(imino)(2-(trimethylsilyl)vinyl)-λ⁶-sulfanone (10b). The

title compound was prepared according to General Procedure A

employing vinyl sulﬁde 9b (205 mg, 0.92 mmol). Puriﬁcation by ﬂash

column chromatography (SiO₂, 50% EtOAc/hexane) aﬀorded

sulfoximine 10b (178 mg, 76%) as a colorless oil; R_f= 0.34 (50%

EtOAc/hexane); IR (ﬁlm)/cm⁻¹2955, 1494, 1453, 1248, 1215, 976,

842; ¹H NMR (400 MHz, CDCl₃) δ 7.42−7.32 (m, 5H), 7.05 (d, J =

17.8 Hz, 1H), 6.62 (d, J = 17.8 Hz, 1H), 4.30 (d, J = 13.2 Hz, 1H),

4.20 (d, J = 13.2 Hz, 1H), 2.63 (s, 1H), 0.14 (s, 9H); ¹³C{¹H} NMR

(101 Hz, CDCl₃) δ 148.0, 140.7, 130.9, 128.6, 128.5 (2 × C), 128.3,

62.7, −2.1 (9 × C); HRMS (ESI-TOF) m/z: calcd for C₁₂H₂₀NOSSi⁺

[M + H]⁺, 254.1035; found, 254.1027.

1

cm⁻¹3056, 3004, 1602, 1509, 1252, 1032, 950, 846, 801; H NMR

(400 MHz, CDCl₃) δ 7.87−7.75 (m, 4H), 7.53−7.44 (m, 3H), 7.38−

7.32 (m, 2H), 6.92−6.85 (m, 2H), 6.83 (s, 2H), 3.83 (s, 3H);

¹³C{¹H} NMR (101 Hz, CDCl₃) δ 159.5, 133.8, 133.4, 133.1, 132.1,

129.4, 128.6, 127.8, 127.5 (2 × C), 127.4, 127.2 (2 × C), 126.6,

125.9, 119.8, 114.2 (2 × C), 55.3; HRMS (APCI⁺) m/z: calcd for

C₁₉H₁₇OS⁺[M + H]⁺, 293.0995; found, 293.1003. Analytical data are

in agreement with those reported in the literature.⁶¹

(E)-Imino(4-methoxystyryl)(naphthalen-2-yl)-λ⁶-sulfanone (10c).

The title compound was prepared according to General Procedure A

employing vinyl sulﬁde 9c (197 mg, 0.67 mmol). Puriﬁcation by ﬂash

column chromatography (SiO₂, 50% EtOAc/hexane) aﬀorded

sulfoximine 10c (145 mg, 67%) as a colorless oil; R_f= 0.24 (50%

EtOAc/hexane); IR (ﬁlm)/cm⁻¹3268, 3056, 2840, 1602, 1509, 1256,

1215, 1174, 1066, 976, 864, 813, 757; ¹H NMR (400 MHz, CDCl₃) δ

8.64−8.60 (m, 1H), 8.02−7.94 (m, 3H), 7.92−7.89 (m, 1H), 7.67−

7.59 (m, 3H), 7.46−7.41 (m, 2H), 6.91−6.83 (m, 3H), 3.83 (s, 3H),

3.01 (s, 1H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 161.8, 141.5, 140.1,

134.8, 132.4, 130.2 (2 × C), 129.4, 129.3, 128.9, 128.8, 127.8, 127.4,

126.5, 125.3, 123.1, 114.4 (2 × C), 55.4; HRMS (APCI⁺) m/z: calcd

for C₁₉H₁₈NO₂S⁺[M + H]⁺, 324.1053; found, 324.1046.

(E)-(4-Bromophenyl)(styryl)sulfane (9d). The title compound was

prepared according to General Procedure F employing RhCl(PPh₃)₃

(92 mg, 0.1 mmol), 4-bromobenzenethiol (378 mg, 2.0 mmol), and

ethynylbenzene (0.22 mL, 2.0 mmol). Puriﬁcation by ﬂash column

chromatography (SiO₂, pentane) aﬀorded vinyl sulﬁde 9b (576 mg,

99%) as an oﬀ-white solid; R_f= 0.45 (pentane); mp = 77−78 °C; IR

(ﬁlm)/cm⁻¹3079, 3056, 3019, 2933, 1897, 1774, 1737, 1664, 1599,

1

1472, 1387, 1230, 1088, 1032, 989, 954, 813, 742, 693; H NMR

(400 MHz, CDCl₃) δ 7.50−7.42 (m, 2H), 7.39−7.19 (m, 7H), 6.87−

6.72 (m, 2H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 136.3, 134.7, 133.1,

132.3 (2 × C), 131.1 (2 × C), 128.8 (2 × C), 128.0, 126.2 (2 × C),

122.3, 120.9; HRMS (APCI⁺) m/z: calcd for C₁₄H₁₂SBr⁺[M + H]⁺,

290.9838; found, 290.9830.

(E)-(4-Bromophenyl)(imino)(styryl)-λ⁶-sulfanone (10d). The title

compound was prepared according to General Procedure A

employing vinyl sulﬁde 9d (291 mg, 1.0 mmol). Puriﬁcation by

ﬂash column chromatography (SiO₂, 30% EtOAc/hexane) aﬀorded

sulfoximine 10d (263 mg, 82%) as a yellow oil; R_f= 0.38 (30%

EtOAc/hexane); IR (ﬁlm)/cm⁻¹3257, 3056, 1729, 1613, 1572, 1464,

1386, 1237, 965, 790; ¹H NMR (400 MHz, CDCl₃) δ 7.94−7.85 (m,

2H), 7.70−7.60 (m, 3H), 7.51−7.45 (m, 2H), 7.44−7.34 (m, 3H),

6.91 (dd, J = 15.2, 1.0 Hz, 1H), 2.98 (s, 1H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 142.1, 142.0, 132.4 (3 × C), 131.0, 129.5 (2 × C), 129.0 (2

× C), 129.0, 128.5 (2 × C), 128.0; HRMS (APCI⁺) m/z: calcd for

C₁₄H₁₃NOSBr⁺[M + H]⁺, 321.9901; found, 321.9895.

Butyl (E)-3-((4-Bromostyryl)thio)propanoate (9e). The title

compound was prepared according to an adaptation of General

Procedure F, including heating to 65 °C using a heating block and

increasing the catalyst loading to 10 mol %, employing RhCl(PPh₃)₃

(92 mg, 0.1 mmol), 1-bromo-4-ethynylbenzene (181 mg, 1.0 mmol),

and butyl 3-mercaptopropanoate (178 μL, 1.1 mmol). Puriﬁcation by

ﬂash column chromatography (SiO₂, 5% Et₂O/hexane) aﬀorded vinyl

sulﬁde 9e (185 mg, 53%) as a white solid; R_f= 0.14 (5% Et₂O/

hexane); mp = 55−57 °C; IR (ﬁlm)/cm⁻¹2959, 2870, 1722, 1595,

1

1487, 1401, 1364, 1241, 1178, 1107, 939, 827; H NMR (400 MHz,

CDCl₃) δ 7.45−7.37 (m, 2H), 7.19−7.11 (m, 2H), 6.71 (d, J = 15.5

Hz, 1H), 6.43 (d, J = 15.6 Hz, 1H), 4.11 (t, J = 6.7 Hz, 2H), 3.07 (t, J

= 7.3 Hz, 2H), 2.71 (t, J = 7.3 Hz, 2H), 1.66−1.58 (m, 2H), 1.46−

1.31 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 171.6, 135.7, 131.7 (2 × C), 127.0 (2 × C), 126.6, 125.1,

Butyl (E)-3-(2-(4-Bromophenyl)vinylsulfonimidoyl)propanoate

(10e). The title compound was prepared according to General

Procedure A employing vinyl sulﬁde 9e (96 mg, 0.28 mmol).

Puriﬁcation by ﬂash column chromatography (SiO₂, 50% EtOAc/

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hexane) aﬀorded sulfoximine 10e (84 mg, 80%) as a white solid; R_f=

0.23 (50% EtOAc/hexane); mp = 57−59 °C; IR (ﬁlm)/cm⁻¹3280,

2959, 2870, 1729, 1617, 1487, 1244, 1211, 1185, 1069, 1006, 857,

801; ¹H NMR (400 MHz, CDCl₃) δ 7.59−7.52 (m, 2H), 7.47 (d, J =

15.3 Hz, 1H), 7.41−7.33 (m, 2H), 6.89 (d, J = 15.3 Hz, 1H), 4.04 (t,

J = 6.7 Hz, 2H), 3.46 (td, J = 7.4, 1.7 Hz, 2H), 2.84 (td, J = 7.2, 2.2

Hz, 2H), 2.73 (s, 1H), 1.61−1.48 (m, 2H), 1.39−1.24 (m, 2H), 0.89

(t, J = 7.4 Hz, 3H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 170.5, 142.6,

132.4 (2 × C), 131.3, 129.8 (2 × C), 128.1, 125.6, 65.2, 51.6, 30.4,

28.4, 19.0, 13.6; HRMS (APCI⁺) m/z: calcd for C₁₅H₂₁NO₃SBr⁺[M

+ H]⁺, 374.0420; found, 374.0437.

tert-Butyl (tert-Butoxycarbonyl)((3S,E)-5-phenyl-1-

(phenylsulfonimidoyl)pent-1-en-3-yl)carbamate (10f). The title

compound was prepared according to General Procedure A

employing vinyl sulﬁde 9f (87 mg, 0.18 mmol). Puriﬁcation by

ﬂash column chromatography (KP-Sil, 0% grading to 10% MeOH/

CHCl₃, eluted at 8% MeOH) aﬀorded sulfoximine 10f (55 mg, 91%)

as a colorless oil in a 1:1 mixture of diastereoisomers; R_f= 0.60 (5%

MeOH/CHCl₃); IR (ﬁlm)/cm⁻¹2978, 1740, 1703, 1368, 1233,

1140; ¹H NMR (400 MHz, CDCl₃) δ 8.02−7.93 (m, 2H), 7.63−7.48

(m, 3H), 7.25−7.11 (m, 5H), 7.05 (dd, J = 15.1, 5.1 Hz, 1H), 6.45

(dd, J = 15.1, 2.9 Hz, 1H), 5.02−4.89 (m, 1H), 2.88 (s, 1H), 2.70−

2.55 (m, 2H), 2.37−2.20 (m, 1H), 2.16−2.00 (m, 1H), 1.45 (s, 9H),

1.45 (s, 9H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 152.3 (2 × C),

144.6, 144.6, 142.5, 140.8, 132.9 (2 × C), 129.3 (2 × C), 128.6 (2 ×

C), 128.4 (2 × C), 128.0 (2 × C), 126.3, 83.2 (2 × C), 55.8, 34.0,

33.8, 32.4, 28.0 (6 × C); HRMS (ESI-TOF) m/z: calcd for

C₂₇H₃₇N₂O₅S⁺[M + H]⁺, 501.2423; found, 501.2434.

6.2 Hz, 2H), 3.41 (t, J = 6.2 Hz, 2H); ¹³C{¹H} NMR (101 Hz,

DMSO-d₆) δ 149.9, 148.6, 129.9 (2 × C), 124.1 (2 × C), 58.8, 55.7;

HRMS (APCI⁺) m/z: calcd for C₈H₁₁N₂O₄S⁺[M + H]⁺, 231.0434;

found, 231.0433.

Benzo[d]thiazol-2-yl(2-hydroxyethyl)(imino)-λ⁶-sulfanone (12c).

The title compound was prepared according to General Procedure A

employing sulﬁde 11c (211 mg, 1.0 mmol). Puriﬁcation by ﬂash

column chromatography (SiO₂, 40% acetone/pentane) aﬀorded

sulfoximine 12c (131 mg, 54%) as a white solid; R_f= 0.24 (40%

acetone/pentane); mp = 125−127 °C; IR (ﬁlm)/cm⁻¹3283, 1468,

1

1315, 1241, 1212, 1051, 980, 764; H NMR (400 MHz, CDCl₃) δ

8.27−8.18 (m, 1H), 8.07−7.98 (m, 1H), 7.69−7.56 (m, 2H), 4.23−

4.09 (m, 3H), 3.79−3.68 (m, 1H), 3.66−3.60 (m, 2H); ¹³C{¹H}

NMR (101 Hz, CDCl₃) δ 169.2, 152.7, 137.5, 127.9, 127.7, 125.4,

+

122.3, 57.8, 56.6; HRMS (APCI⁺) m/z: calcd for C₉H₁₁N₂O₂S₂[M

+ H]⁺, 243.0256; found, 243.0260.

Benzyl(2-hydroxyethyl)(imino)-λ⁶-sulfanone (12d). The title

compound was prepared according to General Procedure A

employing sulﬁde 11d (0.15 mL, 1.0 mmol). Puriﬁcation by ﬂash

column chromatography (SiO₂, 1−5% MeOH/CH₂Cl₂) aﬀorded

sulfoximine 12d (180 mg, 91%) as a white solid; R_f= 0.10 (4%

MeOH/CH₂Cl₂); mp = 94−96 °C; IR (ﬁlm)/cm⁻¹3258, 3202

(broad), 2989, 2904, 2855, 1495. 1387, 1342, 1275, 1234, 1208, 1167,

1

1118, 1081, 1029, 998, 876, 835, 723, 693; H NMR (400 MHz,

DMSO-d₆) δ 6.97−6.82 (m, 5H), 4.61 (t, J = 5.2 Hz, 1H), 3.88 (s,

2H), 3.16 (s, 1H), 2.85 (s, 2H), 2.01 (q, J = 1.8 Hz, 2H); ¹³C NMR

(101 MHz, DMSO-d₆) δ 131.1 (2 × C), 130.4, 128.3 (2 × C), 128.0,

61.6, 55.6, 54.3; HRMS (APCI⁺) m/z: calcd for C₉H₁₄NO₂S⁺[M +

H]⁺, 200.0740; found, 200.0738.

((S,E)-3-Amino-5-phenylpent-1-en-1-yl)(imino)(phenyl)-λ6-sulfa-

none (10g). Triﬂuoroacetic acid (1.1 mL) was added dropwise to a

solution of sulfoximine 10f (194 mg, 0.39 mmol) in CH₂Cl₂(3.8 mL)

at 0 °C, and the reaction was stirred for 3 h. The solvent was then

removed under reduced pressure. The crude was dissolved in 20 mL

of CH₂Cl₂and washed with sat. aq. NaHCO₃(3 × 20 mL). The

solvent was removed under reduced pressure, and puriﬁcation by ﬂash

column chromatography (KP-Sil, 0% grading to 10% MeOH/CHCl₃,

eluted at 5% MeOH) aﬀorded sulfoximine 10g (89 mg, 76%) as a

yellow oil in a 1:1 mixture of diastereoisomers; R_f= 0.50 (10%

MeOH/CH₂Cl₂); IR (ﬁlm)/cm⁻¹3273, 3027, 2922, 1602, 1446,

1222, 1088, 969, 749, 685; ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J

= 7.2 Hz, 2H), 7.60−7.47 (m, 3H), 7.29−7.22 (m, 2H), 7.20−7.08

(m, 3H), 6.90 (dd, J = 14.8, 5.8 Hz, 1H), 6.53 (d, J = 14.9 Hz, 1H),

3.55−3.44 (m, 1H), 2.70−2.61 (m, 2H), 2.44 (s, 1H), 1.90−1.70 (m,

2H), 1.39 (s, 2H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 148.9, 148.8,

142.9, 141.1, 141.1, 132.9, 131.7, 129.3 (2 × C), 128.6 (2 × C), 128.4

(2 × C), 128.0 (2 × C), 126.2, 51.6, 38.4, 38.3, 32.1; HRMS (APCI⁺)

m/z: calcd for C₁₇H₂₁N₂OS⁺[M + H]⁺, 301.1369; found, 301.1377.

(2-Hydroxyethyl)(imino)(phenyl)-λ⁶-sulfanone (12a). The title

compound was prepared according to General Procedure A

employing sulﬁde 11a (135 μL, 1.0 mmol) in MeOH (2.0 mL) at

25 °C. After 3 h, the solvent was removed under reduced pressure.

Puriﬁcation by ﬂash column chromatography (SiO₂, 50% acetone/

pentane) aﬀorded sulfoximine 12a (136 mg, 73%) as a colorless oil; R_f

= 0.29 (50% acetone/pentane); IR (ﬁlm)/cm⁻¹3261, 1446, 1215,

Imino(phenyl)(vinyl)-λ⁶-sulfanone (13a) and N-(Oxo(phenyl)-

(vinyl)-λ⁶-sulfaneylidene)methanesulfonamide (14a). The title

compounds were prepared according to General Procedure G

employing sulfoximine 12a (141 mg, 0.76 mmol). Puriﬁcation by

ﬂash column chromatography (SiO₂, 50% EtOAc/pentane) aﬀorded

vinyl sulfoximine 13a (63 mg, 50%) and mesylated vinyl sulfoximine

14a (11 mg, 6%), both as colorless oils. Analytical data for vinyl

sulfoximine 13a: R_f= 0.23 (50% EtOAc/pentane); IR (ﬁlm)/cm⁻¹

1

3269, 3064, 1446, 1223, 1129, 977, 731, 693; H NMR (400 MHz,

CDCl₃) δ 8.04−7.94 (m, 2H), 7.67−7.58 (m, 1H), 7.57−7.51 (m,

2H), 6.75 (dd, J = 16.4, 9.5 Hz, 1H), 6.43 (dd, J = 16.4, 0.6 Hz, 1H),

5.99 (dd, J = 9.5, 0.5 Hz, 1H), 2.88 (s, 1H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 141.7, 140.5, 133.0, 129.2 (2 × C), 128.1 (2 × C), 126.6.

Analytical data are in agreement with those reported in the

literature.³⁰Analytical data for mesylated vinyl sulfoximine 14a: R_f

= 0.29 (50% EtOAc/pentane); IR (ﬁlm)/cm⁻¹3269, 3060, 1308,

1230, 1140, 1099, 1066, 969, 801, 745; ¹H NMR (400 MHz, CDCl₃)

δ 8.07−7.96 (m, 2H), 7.76−7.67 (m, 1H), 7.67−7.57 (m, 2H), 6.83

(dd, J = 16.3, 9.6 Hz, 1H), 6.52 (dd, J = 16.3, 1.3 Hz, 1H), 6.23 (dd, J

= 9.6, 1.4 Hz, 1H), 3.18 (s, 3H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ

137.5, 137.0, 134.5, 129.7 (2 × C), 129.4, 128.0 (2 × C), 45.4.

Analytical data are in agreement with those reported in the

literature.⁶²

Imino(4-nitrophenyl)(vinyl)-λ⁶-sulfanone (13b). The title com-

pound was prepared according to General Procedure G employing

sulfoximine 12b (57.5 mg, 0.25 mmol). Puriﬁcation by ﬂash column

chromatography (SiO₂, 0−10% Et₂O/CH₂Cl₂) aﬀorded vinyl

sulfoximine 13b (26.5 mg, 52%) as an oﬀ-white solid; R_f= 0.35

(10% Et₂O/CH₂Cl₂); mp = 95−97 °C; IR (ﬁlm)/cm⁻¹3280, 3105,

3064, 1607, 1528, 1349, 1312, 1230, 1174, 1141, 977, 857, 738, 705;

¹H NMR (400 MHz, CDCl₃) δ 8.51−8.21 (m, 2H), 8.25−8.09 (m,

2H), 6.75 (dd, J = 16.3, 9.5 Hz, 1H), 6.53 (dd, J = 16.3, 0.7 Hz, 1H),

6.12 (dd, J = 9.4, 0.7 Hz, 1H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ

150.6, 148.1, 139.7, 129.6 (2 × C), 129.0, 124.5 (2 × C); HRMS

(ESI-TOF) m/z: calcd for C₈H₉N₂O₃S [M + H]⁺, 213.0334; found,

213.0339.

1

1095, 1059, 987, 760, 723, 699; H NMR (400 MHz, CDCl₃) δ

8.04−7.98 (m, 2H), 7.71−7.64 (m, 1H), 7.64−7.57 (m, 2H), 4.70 (t,

J = 6.1 Hz, 1H), 4.08 (ddd, J = 12.6, 6.5, 3.8 Hz, 1H), 3.90−3.78 (m,

1H), 3.32 (dt, J = 6.1, 2.9 Hz, 2H), 2.88 (s, 1H); ¹³C{¹H} NMR (101

Hz, CDCl₃) δ 141.8, 133.6, 129.4 (2 × C), 128.3 (2 × C), 58.2, 56.4.

Analytical data are in agreement with those reported in the

literature.^31b

2-Hydroxyethyl(imino)(4-nitrophenyl)-λ⁶-sulfanone (12b). The

title compound was prepared according to General Procedure A

employing sulﬁde 11b (199 mg, 1.0 mmol). Puriﬁcation by ﬂash

column chromatography (SiO₂, 1−5% MeOH/CH₂Cl₂) aﬀorded

sulfoximine 12b (201 mg, 87%) as a white solid; R_f= 0.15 (4%

MeOH/CH₂Cl₂); mp = 131−133 °C; IR (ﬁlm)/cm⁻¹3571, 3381,

3153, 3104, 2960, 1633, 1607, 1521, 1469, 1431, 1349, 1308, 1215,

Benzo[d]thiazol-2-yl(imino)(vinyl)-λ⁶-sulfanone (13c). The title

compound was prepared according to General Procedure G

employing sulfoximine 12c (133 mg, 0.55 mmol). Puriﬁcation by

ﬂash column chromatography (SiO₂, 30% acetone/pentane) aﬀorded

vinyl sulfoximine 13c (48 mg, 39%) as a white solid; R_f= 0.39 (30%

1

1141, 1088, 1029, 992, 947, 857, 731; H NMR (400 MHz, DMSO-

d₆) δ 8.39 (d, J = 8.9 Hz, 2H), 8.15 (d, J = 8.9 Hz, 2H), 3.68 (t, J =

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acetone/pentane); mp = 99−101 °C; IR (ﬁlm)/cm⁻¹3261, 1468,

1315, 1259, 1237, 1111, 977, 760, 723; ¹H NMR (400 MHz, CDCl₃)

δ 8.24−8.17 (m, 1H), 8.02−7.95 (m, 1H), 7.66−7.53 (m, 2H), 7.02

(dd, J = 16.4, 9.5 Hz, 1H), 6.71 (dd, J = 16.4, 1.0 Hz, 1H), 6.28 (dt, J

= 9.5, 0.9 Hz, 1H), 3.56 (s, 1H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ

169.5, 153.0, 137.7, 137.5, 131.0, 127.7, 127.4, 125.3, 122.2; HRMS

4-Methyl-2-phenyl-1-(2-((tetrahydro-2H-pyran-2-yl)oxy)-

ethylsulfonimidoyl)piperazine (17b). The title compound was

prepared according to General Procedure H employing 1-methyl-3-

phenylpiperazine (587 mg, 3.3 mmol), triethylamine (693 μL, 5.0

mmol), silver nitrate (849 mg, 5.0 mmol), and disulﬁde 16 (806 mg,

2.5 mmol) in MeOH (25 mL) followed by ammonium carbamate

(390 mg, 5.0 mmol), iodosylbenzene (1.37 g, 6.25 mmol), and acetic

acid (143 μL, 2.5 mmol) in iPrOH (13 mL). Puriﬁcation by ﬂash

column chromatography (SiO₂, 70% EtOAc in pentane) aﬀorded

sulfonimidamide 17b (292 mg, 32% over two steps) as a complex

mixture of diastereomers as a brown oil; R_f= 0.11 (70% EtOAc in

pentane); IR (ﬁlm)/cm⁻¹3272, 2937, 2870, 2791, 1453, 1244, 1148,

1118, 1029, 976, 917; ¹H NMR (400 MHz, CDCl₃) δ 7.71−7.64 (m,

4H), 7.38−7.32 (m, 4H), 7.31−7.27 (m, 2H), 5.14 (d, J = 3.4 Hz,

1H), 5.10 (d, J = 4.3 Hz, 1H), 4.60−4.53 (m, 2H), 4.13−4.01 (m,

2H), 3.89−3.74 (m, 6H), 3.54−3.45 (m, 2H), 3.41−3.05 (m, 6H),

2.98−2.78 (m, 4H), 2.52−2.47 (m, 2H), 2.31−2.28 (m, 6H), 2.30 (s,

2H), 2.22−2.11 (m, 2H), 1.84−1.64 (m, 4H), 1.64−1.45 (m, 8H);

¹³C{¹H} NMR (101 Hz, CDCl₃) δ 139.7, 128.5, 128.4, 128.3, 128.13,

+

(APCI⁺) m/z: calcd for C₉H₉N₂OS₂[M + H]⁺, 225.0151; found,

225.0153.

Benzyl(imino)(vinyl)-λ⁶-sulfanone (13d) and N-(Benzyl(oxo)-

(vinyl)-λ⁶-sulfaneylidene)methanesulfonamide (14d). The title

compounds were prepared according to General Procedure G

employing sulfoximine 12d (70 mg, 0.35 mmol). Puriﬁcation by

ﬂash column chromatography (KP-Sil, 0% grading to 50% acetone in

pentane) aﬀorded vinyl sulfoximine 13d (22 mg, 35%) as a colorless

oil and mesylated vinyl sulfoximine 14d (26 mg, 29%) as a white

solid. Analytical data for vinyl sulfoximine 13d: R_f= 0.30 (50%

1

EtOAc/pentane); IR (ﬁlm)/cm⁻¹3273, 1215, 967, 701; H NMR

(400 MHz, DMSO-d₆) δ 7.42−7.25 (m, 5H), 6.76 (dd, J = 16.4, 9.6

Hz, 1H), 6.07−5.92 (m, 2H), 4.34 (s, 2H), 3.93 (br s, 1H); ¹³C{¹H}

NMR (101 MHz, DMSO-d₆) δ 138.9, 131.0 (2 × C), 130.0, 128.1,

128.0, 127.7, 61.4; HRMS (ESI-TOF) m/z: calcd for C₉H₁₂NOS⁺[M

+ H]⁺, 182.0640; found, 182.0640. Analytical data for mesylated vinyl

sulfoximine 14d: R_f= 0.40 (10% Et₂O/CH₂Cl₂); mp = 139−140 °C;

IR (ﬁlm)/cm⁻¹3109, 3070, 2982, 2933, 1744, 1532, 1495, 1457,

128.10, 127.5, 127.4, 99.1, 99.0, 62.3, 62.2, 61.93, 61.89, 59.1, 58.5,

56.2, 55.9, 55.4, 55.2, 53.64, 53.63, 46.30, 46.27, 42.1, 41.9, 30.4, 30.3,

25.2, 19.32, 19.29; HRMS (ESI-TOF) m/z: calcd for C₁₈H₃₀N₃O₃S

[M + H]⁺, 368.2008; found, 368.2006.

N-(3-(10,11-Dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene)-

propyl)-N-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-sul-

fonimidamide (17c). The title compound was prepared according to

General Procedure H employing nortriptyline hydrochloride (1.00 g,

3.33 mmol), triethylamine (1.20 mL, 8.75 mmol), silver nitrate (849

mg, 5.0 mmol), and disulﬁde 16 (806 mg, 2.5 mmol) in MeOH (25

mL) followed by ammonium carbamate (390 mg, 5.0 mmol),

iodosylbenzene (1.37 g, 6.25 mmol), and acetic acid (143 μL, 2.5

mmol) in iPrOH (13 mL). Puriﬁcation by ﬂash column

chromatography (SiO₂, 20% acetone in pentane) aﬀorded sulfonimi-

damide 17c (375 mg, 33% over two steps, dr 1:1) containing a small

amount of an unidentiﬁed and inseparable impurity as a brown oil; R_f

= 0.18 (20% acetone in pentane); IR (ﬁlm)/cm⁻¹3309, 3015, 2937,

1

1409, 1383, 1305, 1230, 1137, 1066, 969, 897, 783, 746, 701; H

NMR (400 MHz, CDCl₃) δ 7.41−7.38 (m, 5H), 6.53 (dd, J = 16.3,

9.7 Hz), 6.36−6.24 (m, 2H), 4.73 (s, 2H), 3.14 (s, 3H); ¹³C{¹H}

NMR (101 MHz, CDCl₃) δ 133.4, 133.2, 131.7 (2 × C), 129.9, 129.2

(2 × C), 126.3, 62.3, 45.4; HRMS (APCI⁺) m/z: calcd for

+

C₁₀H₁₄NO₃S₂[M + H]⁺, 260.0415; found, 260.0408.

Terminal Vinyl Sulfonimidamides 18a−d. 1,2-Bis(2-((tetrahydro-

2H-pyran-2-yl)oxy)ethyl)disulfane (16). Pyridinium p-toluenesulfo-

nate (2.00 g, 7.90 mmol) was added to a solution of 2-hydroxyethyl

disulﬁde (10.0 mL, 81.7 mmol) and 3,4-dihydropyran (30.0 mL, 328

mmol) in CH₂Cl₂(100 mL) at 0 °C. The solution was allowed to

warm to room temperature and was stirred for 18 h. The solvent was

removed in vacuo and the crude residue was puriﬁed by ﬂash column

chromatography (KP-Sil, 0% grading to 50% Et₂O in pentane, eluted

at 10%), which aﬀorded disulﬁde 16 (22.7 g, 86%) as a colorless oil;

R_f= 0.44 (25% Et₂O in pentane); IR (ﬁlm)/cm⁻¹3008, 2941, 2870,

1438,1349, 1200, 1118, 1077, 1025, 753; ¹H NMR (400 MHz,

CDCl₃) δ 4.64 (dd, J = 4.2, 2.9 Hz, 2H), 4.04−3.92 (m, 2H), 3.88

(ddd, J = 11.2, 8.0, 3.5 Hz, 2H), 3.69 (dt, J = 10.4, 6.7 Hz, 2H), 3.58−

3.47 (m, 2H), 3.01−2.85 (m, 4H), 1.89−1.66 (m, 4H), 1.65−1.46

(m, 8H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 99.1 (2 × C), 66.1 (2 ×

C), 62.4 (2 × C), 39.2 (2 × C), 30.7 (2 × C), 25.6 (2 × C), 19.5 (2 ×

1

1643, 1483, 1442, 1244, 1121, 1077, 1028, 969, 766; H NMR (400

MHz, CDCl₃) δ 7.29−7.25 (m, 1H), 7.23−7.13 (m, 6H), 7.06−7.03

(m, 1H), 5.85 (td, J = 7.4, 1.4 Hz, 1H), 4.60 (dd, J = 4.5, 3.0 Hz, 1H),

4.10 (ddt, J = 10.9, 9.3, 6.1 Hz, 1H), 3.90−3.80 (m, 2H), 3.65−3.13

(m, 9H), 2.97 (s, 1H), 2.76 (s, 3H), 2.44−2.34 (m, 2H), 1.83−1.70

(m, 2H), 1.61−1.49 (m, 4H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ

145.1, 140.8, 139.7, 139.4, 137.0, 130.1, 128.5, 128.1, 128.0, 127.6,

127.3, 127.2, 126.1, 125.7, 99.2, 62.6, 61.8, 61.6, 50.5, 50.3, 33.7, 32.0,

30.5, 28.6, 25.2, 19.5; HRMS (ESI-TOF) m/z: calcd for

C₂₆H₃₅N₂O₃S [M + H]⁺, 455.2368; found, 455.2354.

N-Benzyl-N-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)ethane-1-

sulfonimidamide (17d). The title compound was prepared according

to General Procedure H employing silver nitrate (603 mg, 4.0 mmol),

triethylamine (554 μL, 4.0 mmol), N-methylbenzylamine (346 μL,

2.66 mmol), and disulﬁde 16 (645.0 mg, 2.0 mmol) in MeOH (20

mL) followed by ammonium carbamate (390 mg, 5.0 mmol),

iodosylbenzene (1.37 g, 6.25 mmol), and acetic acid (143 μL, 2.5

mmol) in iPrOH (13 mL). Puriﬁcation by ﬂash column

chromatography (KP-Sil 0% grading to 100% MeOH in CH₂Cl₂,

product eluted at 7%) aﬀorded sulfonimidamide 17d (324 mg, 52%

over two steps, dr 1:1) as a yellow oil; R_f= 0.28 (100% EtOAc); IR

(ﬁlm)/cm⁻¹3280, 2937, 2870, 1454, 1349, 1245, 1122, 1077, 1028,

+

C); HRMS (APCI⁺) m/z: calcd for C₁₄H₂₆O₄S₂[M]⁺, 322.1267;

found, 322.1276.

4 - P h e n y l - 1 - ( 2 - ( ( t e t r a h y d r o - 2 H - p y r a n - 2 - y l ) o x y ) -

ethylsulfonimidoyl)piperidine (17a). The title compound was

prepared according to General Procedure H employing silver nitrate

(603 mg, 4.0 mmol), triethylamine (554 μL, 4.0 mmol), disulﬁde 16

(644 mg, 2.0 mmol), and 4-phenyl piperidine (427 mg, 2.66 mmol) in

MeOH (26 mL) followed by ammonium carbamate (223 mg, 2.86

mmol), iodosylbenzene (788 mg, 3.58 mmol), and acetic acid (80 μL,

1.4 mmol) in iPrOH (7 mL). Puriﬁcation by ﬂash column

chromatography (KP-Sil, 50% grading to 100% EtOAc in pentane,

product eluted at 100%) aﬀorded sulfonimidamide 17a (400 mg, 57%

over two steps, dr 1:1) as a colorless oil; R_f= 0.40 (100% EtOAc); IR

(ﬁlm)/cm⁻¹3280, 2937, 2847, 1244, 1118, 1028, 931; ¹H NMR (400

MHz, CDCl₃) δ 7.36−7.27 (m, 2H), 7.25−7.14 (m, 3H), 4.71−4.57

(m, 1H), 4.24−4.09 (m, 1H), 4.09−3.96 (m, 2H), 3.96−3.81 (m,

2H), 3.60−3.48 (m, 1H), 3.40−3.16 (m, 2H), 2.93−2.75 (m, 2H),

2.57 (td, J = 12.1, 3.0 Hz, 1H), 2.28 (d, J = 7.8 Hz, 1H), 2.03−1.88

(m, 2H), 1.88−1.64 (m, 5H), 1.64−1.43 (m, 4H); ¹³C{¹H} NMR

(101 Hz, CDCl₃) δ 145.3, 128.8, 126.9, 126.7, 99.6, 99.5, 62.8, 62.0,

61.8, 50.1, 50.0, 47.5, 47.5, 47.2, 47.1, 42.5, 33.8, 33.6, 33.5, 30.8,

30.7, 25.4, 19.8; HRMS (ESI-TOF) m/z: calcd for C₁₈H₂₉N₂O₃S⁺[M

+ H]⁺, 353.1899; found, 353.1901.

1

976, 731; H NMR (400 MHz, CDCl₃) δ 7.30−7.27 (m, 5H), 4.65

(m, 1H), 4.52−4.32 (m, 2H), 4.24−4.10 (m, 1H), 3.97−3.84 (m,

2H), 3.58−3.50 (m, 1H), 3.47−3.25 (m, 2H), 2.81 (d, J = 3.2 Hz,

3H), 2.34 (d, J = 8.3 Hz, 1H), 1.92−1.71 (m, 2H), 1.66−1.47 (m,

4H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 137.0, 128.8, 128.1, 127.8,

99.5, 62.8, 62.0, 61.8, 54.9, 50.9, 35.4, 30.8, 25.4, 19.8; HRMS (ESI-

TOF) m/z: calcd for C₁₅H₂₅N₂O₃S⁺[M + H]⁺, 313.1580; found,

313.1578.

4-Phenyl-1-(vinylsulfonimidoyl)piperidine (18a). The title com-

pound was prepared according to General Procedure I employing

sulfonimidamide 17a (32 mg, 0.09 mmol). Puriﬁcation by ﬂash

column chromatography (KP-Sil, 50% grading to 100% EtOAc in

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pentane, product eluted at 100%) aﬀorded sulfonimidamide 18a (17

mg, 70% over two steps) as a colorless oil; R_f= 0.50 (100% EtOAc);

× C), 129.0 (2 × C), 128.2, 83.0, 70.6, 32.6; HRMS (ESI-TOF) m/z:

calcd for C₁₁H₁₂NOS⁺[M + H]⁺, 206.0640; found, 206.0647.

(E)-Phenyl(prop-2-yn-1-ylimino)(styryl)-λ⁶-sulfanone (19b). The

title compound was prepared according to General Procedure J

employing sulfoximine 5a (36 mg, 0.15 mmol). Puriﬁcation by ﬂash

chromatography (KP-Sil, 0% grading to 100% EtOAc/hexane, eluted

at 35% EtOAc) aﬀorded 19b (23 mg, 55%) as a dark-orange oil; R_f=

0.64 (50% EtOAc/pentane); IR (ﬁlm)/cm⁻¹3295, 3060, 1610, 1446,

1

IR (ﬁlm)/cm⁻¹3287, 2937, 1244, 1051, 924, 734; H NMR (400

MHz, CDCl₃) δ 7.37−7.27 (m, 2H), 7.25−7.13 (m, 3H), 6.52 (dd, J

= 16.6, 9.9 Hz, 1H), 6.26 (d, J = 16.6 Hz, 1H), 6.03 (d, J = 9.9 Hz,

1H), 4.02 (ddt, J = 11.9, 4.4, 2.5 Hz, 1H), 3.92 (ddt, J = 11.9, 4.6, 2.4

Hz, 1H), 2.72−2.44 (m, 3H), 2.37 (s, 1H), 2.01−1.87 (m, 2H),

1.87−1.72 (m, 2H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 145.2, 133.4,

128.7 (2 × C), 127.7, 126.9 (2 × C), 126.7, 47.8, 47.4, 42.3, 33.4,

33.1; HRMS (ESI^‑TOF) m/z: calcd for C₁₃H₁₉N₂OS⁺[M + H]⁺,

251.1218; found, 251.1207.

1

1267, 1215, 1133, 1081, 745, 686; H NMR (400 MHz, CDCl₃) δ

8.01−7.98 (m, 2H), 7.62−7.52 (m, 4H), 7.48−7.46 (m, 2H), 7.41−

7.36 (m, 3H), 6.89 (d, J = 15.3 Hz, 1H), 3.91 (dd, J = 14.8, 2.5 Hz,

1H), 3.81 (dd, J = 14.8, 2.6 Hz, 1H), 2.23 (t, J = 2.53 Hz, 1H);

¹³C{¹H} NMR (101 Hz, CDCl₃) δ 142.9, 139.3, 133.0, 132.7, 131.0,

4-Methyl-2-phenyl-1-(vinylsulfonimidoyl)piperazine (18b). The

title compound was prepared according to General Procedure I

employing sulfonimidamide 17b (238 mg, 0.65 mmol). Puriﬁcation

by ﬂash column chromatography (SiO₂, 20% acetone in pentane)

aﬀorded sulfonimidamide 18b (70 mg, 42% over two steps, dr 1:2) as

a brown oil; R_f= 0.27 (20% acetone in pentane); IR (ﬁlm)/cm⁻¹

129.4 (2 × C), 129.0 (2 × C), 128.6 (2 × C), 128.5 (2 × C), 127.2,

83.2, 70.5, 32.7; HRMS (ESI-TOF) m/z: calcd for C₁₇H₁₆NOS⁺[M +

H]⁺, 282.0953; found, 282.0960.

(E)-(2-Cyclohexylvinyl)(phenyl)(prop-2-yn-1-ylimino)-λ⁶-sulfa-

none (19c). The title compound was prepared according to General

Procedure J employing sulfoximine 5b (40 mg, 0.16 mmol).

Puriﬁcation via ﬂash column chromatography (KP-Sil, 0% grading

to 100% EtOAc/petroleum ether, eluted at 35% EtOAc) aﬀorded 19c

(35 mg, 77%) as a clear oil; R_f= 0.61 (50% EtOAc/pentane); IR

(ﬁlm)/cm⁻¹3295, 2926, 2851, 1446, 1267, 1218, 1133, 969, 752,

1

3272, 2937, 2795, 1453, 1267, 1244, 1148, 973, 924; H NMR (400

MHz, CDCl₃) δ 7.69 (dd, J = 7.3, 1.9 Hz, 2H), 7.63 (dd, J = 7.4, 1.8

Hz, 2H), 7.36−7.32 (m, 4H), 7.31−7.25 (m, 2H), 6.27−6.09 (m,

4H), 5.76−5.71 (m, 2H), 5.05−5.02 (m, 2H), 3.72−3.67 (m, 2H),

3.35−3.13 (m, 4H), 2.84−2.77 (m, 2H), 2.51−2.47 (m, 2H), 2.33 (s,

2H), 2.30−2.17 (m, 6H), 2.24−2.13 (m, 2H); ¹³C{¹H} NMR (101

Hz, CDCl₃) δ 139.6, 137.1, 136.4, 128.6, 128.4, 128.3, 128.2, 127.5,

125.3, 125.0, 58.8, 57.9, 56.3, 56.2, 54.9, 54.8, 46.3, 42.1, 41.9; HRMS

(ESI-TOF) m/z: calcd for C₁₃H₂₀N₃OS [M + H]⁺, 266.1327; found,

266.1334.

1

689; H NMR (400 MHz, CDCl₃) δ 7.91−7.89 (m, 2H), 7.60−7.56

(m, 1H), 7.54−7.50 (m, 2H), 6.83 (dd, J = 8.7, 6.3 Hz, 1H), 6.28 (d,

J = 15.2 Hz, 1H), 3.81 (dd, J = 14.7, 2.6 Hz, 1H), 3.71 (dd, J = 14.9,

2.5 Hz, 1H), 2.20 (t, J = 2.5 Hz, 1H), 2.18−2.12 (m, 1H), 1.74 (m,

4H), 1.67−1.63 (m, 1H), 1.30−1.09 (m, 5H); ¹³C{¹H} NMR (101

Hz, CDCl₃) δ 152.1, 139.3, 132.8, 129.3 (2 × C), 128.6 (2 × C),

127.8, 83.2, 70.3, 40.0, 32.6, 31.4, 31.2, 25.7, 25.6 (2 × C); HRMS

(ESI-TOF) m/z: calcd for C₁₇H₂₂NOS⁺[M + H]⁺, 288.1422; found,

288.1418.

N-(3-(10,11-Dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene)-

propyl)-N-methylethenesulfonimidamide (18c). The title com-

pound was prepared according to General Procedure I employing

sulfonimidamide 17c (516 mg, 1.13 mmol). Puriﬁcation by ﬂash

column chromatography (SiO₂, 50% EtOAc in pentane) aﬀorded

sulfonimidamide 18c (188 mg, 47%) as a brown oil; R_f= 0.33 (50%

EtOAc in pentane); IR (ﬁlm)/cm⁻¹3309, 3060, 3015, 2914, 1483,

(E)-Phenyl(prop-2-yn-1-ylimino)(2-(pyridin-2-yl)vinyl)-λ⁶-sulfa-

none (19d). The title compound was prepared according to General

Procedure J employing sulfoximine 5d (40 mg, 0.16 mmol).

Puriﬁcation by ﬂash column chromatography (KP-Sil, 0% grading

to 100% EtOAc/pentane, eluted at 56% EtOAc) aﬀorded 19d (31

mg, 77%) as a brown oil; R_f= 0.30 (50% EtOAc/pentane); IR (ﬁlm)/

cm⁻¹3298, 3056, 2926, 1580, 1267, 1215, 1129, 1080, 969, 752, 685;

¹H NMR (400 MHz, CDCl₃) δ 8.60−8.59 (d, J = 5.5 Hz, 1H), 8.02−

8.00 (m, 2H), 7.73−7.69 (m, 1H), 7.59 (d, J = 15.1 Hz, 1H), 7.61−

7.57 (m, 1H), 7.56−7.51 (m, 2H), 7.40 (d, J = 15.0 Hz, 1H), 7.38 (d,

J = 7.4 Hz, 1H), 7.28−7.25 (m, 1H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 151.4, 150.2, 141.3, 138.9, 137.0, 133.1, 131.8, 129.4 (2 ×

C), 128.8 (2 × C), 125.1, 124.8, 83.1, 70.5, 32.7; HRMS (ESI-TOF)

m/z: calcd for C₁₆H₁₅N₂OS⁺[M + H]⁺, 283.0905; found, 283.0920.

4-Phenyl-1-(N-(prop-2-yn-1-yl)vinylsulfonimidoyl)piperidine

(19e). The title compound was prepared according to General

Procedure J employing sulfonimidamide 18a (16 mg, 0.07 mmol).

Puriﬁcation by ﬂash column chromatography (KP-Sil, 35% grading to

100% EtOAc in pentane, eluted at 60%) aﬀorded sulfonimidamide

19e (10 mg, 52%) as a colorless oil; R_f= 0.70 (100% EtOAc); IR

(ﬁlm)/cm⁻¹3284, 2918, 2844, 1278, 1230, 1140, 924, 756; ¹H NMR

(400 MHz, CDCl₃) δ 7.36−7.28 (m, 2H), 7.25−7.16 (m, 3H), 6.52

(dd, J = 16.7, 9.9 Hz, 1H), 6.24 (d, J = 16.8 Hz, 1H), 6.01 (d, J = 10.0

Hz, 1H), 4.12−3.75 (m, 4H), 2.72−2.47 (m, 3H), 2.22 (t, J = 2.6 Hz,

1H), 2.02−1.69 (m, 4H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 145.2,

132.9, 128.7 (2 × C), 127.4, 126.9 (2 × C), 126.7, 83.0, 70.1, 47.6,

47.5, 42.2, 33.1, 33.0, 30.7; HRMS (ESI-TOF) m/z: calcd for

C₁₆H₂₁N₂OS⁺[M + H]⁺, 289.1369; found, 289.1371.

1

1453, 1267, 1107, 965, 742; H NMR (400 MHz, CDCl₃) δ 7.29−

7.27 (m, 1H), 7.26−7.09 (m, 6H), 7.08−7.02 (m, 1H), 6.42 (dd, J =

16.6, 9.8 Hz, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.90 (d, J = 9.9 Hz, 1H),

5.85 (t, J = 7.5 Hz, 1H), 3.46−3.23 (m, 3H), 3.17−3.05 (m, 1H),

3.02−2.92 (m, 1H), 2.85−2.75 (m, 1H), 2.71−2.60 (m, 3H), 2.44−

2.32 (m, 2H), 2.09 (s, 1H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 145.2,

140.7, 139.7, 139.4, 137.0, 133.4, 130.1, 128.5, 128.1, 128.0, 127.6,

127.23, 127.20, 126.6, 126.1, 125.8, 50.5 (2 × C), 33.7, 31.9, 28.3;

HRMS (ESI-TOF) m/z: calcd for C₂₁H₂₅N₂OS [M + H]⁺, 353.1688;

found, 353.1682.

N-Benzyl-N-methylethenesulfonimidamide (18d). The title com-

pound was prepared according to General Procedure I employing

sulfonimidamide 17d (144 mg, 0.46 mmol). Puriﬁcation by ﬂash

column chromatography (KP-Sil, 30% grading to 100% EtOAc/

pentane, eluted at 50%) gave sulfonimidamide 18d (22 mg, 23% over

two steps) as a pale-yellow oil; R_f= 0.25 (100% EtOAc); IR (ﬁlm)/

1

cm⁻¹3280, 3030, 1358, 1243, 1102, 969, 733; H NMR (400 MHz,

CDCl₃) δ 7.43−7.27 (m, 5H), 6.56 (dd, J = 16.6, 9.9 Hz, 1H), 6.31

(d, J = 16.6 Hz, 1H), 6.03 (d, J = 9.9 Hz, 1H), 4.30 (m, 2H), 2.73 (s,

3H), 2.47 (s, 1H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 136.6, 133.5,

128.8 (2 × C), 128.3 (2 × C), 127.9, 127.2, 55.0, 35.3; HRMS (ESI-

TOF) m/z: calcd for C₁₀H₁₅N₂OS [M + H]⁺, 211.0900; found,

211.0896.

N-Propargyl Vinyl Sulfoximines and Sulfonimidamides 19a−g.

Phenyl(prop-2-yn-1-ylimino)(vinyl)-λ⁶-sulfanone (19a). The title

compound was prepared according to General Procedure J employing

sulfoximine 11a (36 mg, 0.21 mmol). Puriﬁcation by ﬂash column

chromatography (KP-Sil, 0% grading to 50% EtOAc/pentane, product

eluted at 25%) aﬀorded sulfoximine 19a (25 mg, 57%) as a colorless

oil; R_f= 0.45 (50% EtOAc in pentane); IR (ﬁlm)/cm⁻¹3295, 2321,

4-Methyl-2-phenyl-1-(N-(prop-2-yn-1-yl)vinylsulfonimidoyl)-

piperazine (19f). The title compound was prepared according to

General Procedure J employing sulfonimidamide 18b (53 mg, 0.20

mmol, dr 1:2). Puriﬁcation by ﬂash column chromatography (SiO₂,

10% acetone in pentane) aﬀorded sulfonimidamide 19f (29 mg, 48%,

dr 1:2) as a brown oil; R_f= 0.26 (10% acetone in pentane); IR (ﬁlm)/

cm⁻¹3287, 2937, 2844, 2795, 1457, 1278, 1230, 1148, 972, 917, 767;

¹H NMR (400 MHz, CDCl₃) δ 7.77−7.72 (m, 2H), 7.70 (dd, J = 7.4,

1

1446, 1267, 1216, 1131, 971, 742; H NMR (400 MHz, CDCl₃) δ

7.95−7.90 (m, 2H), 7.62−7.51 (m, 3H), 6.68 (dd, J = 16.5, 9.6 Hz,

1H), 6.38 (d, J = 16.5 Hz, 1H), 6.03 (d, J = 9.9 Hz, 1H), 3.87 (dd, J =

17.2, 2.5 Hz, 1H), 3.79 (dd, J = 17.3, 2.5 Hz, 1H), 2.19 (t, J = 2.5 Hz,

1H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 138.5, 138.4, 133.3, 129.5 (2

1.8 Hz, 2H), 7.37−7.24 (m, 6H), 6.29 (dd, J = 16.5, 9.5 Hz, 1H), 6.16

(d, J = 16.5 Hz, 1H), 6.00 (dd, J = 16.5, 9.6 Hz, 1H), 5.89 (d, J = 16.5

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Hz, 1H), 5.77 (d, J = 9.6 Hz, 1H), 5.56 (d, J = 9.6 Hz, 1H), 4.98 (d, J

= 4.2 Hz, 1H), 4.94−4.90 (m, 1H), 3.89−3.85 (m, 4H), 3.66−3.57

(m, 2H), 3.29−3.22 (m, 2H), 3.15 (dt, J = 11.9, 1.8 Hz, 1H), 3.10

(dt, J = 11.6, 1.8 Hz, 1H), 2.91−2.87 (m, 1H), 2.81−2.77 (m, 1H),

2.56 (dd, J = 11.6, 4.5 Hz, 1H), 2.53−2.44 (m, 1H), 2.31−2.27 (m,

8H), 2.21 (t, J = 2.5 Hz, 1H), 2.19 (t, J = 2.5 Hz, 1H); ¹³C{¹H} NMR

(101 Hz, CDCl₃) δ 139.3, 136.8, 134.3, 129.3, 128.5, 128.2, 128.0,

127.7, 126.1, 124.8, 82.9, 82.6, 70.2, 69.9, 59.2, 57.2, 56.2, 55.9, 54.8,

54.7, 46.2, 41.9, 41.5, 30.8, 30.7; HRMS (ESI-TOF) m/z: calcd for

C₁₆H₂₂N₃OS⁺[M + H]⁺, 304.1484; found, 304.1497.

3.31−3.04 (m, 2H), 2.85−2.71 (m, 1H), 2.45 (dd, J = 11.9, 4.4 Hz,

1H), 2.28 (s, 3H), 2.22−2.12 (m, 2H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 140.5, 137.1, 128.7, 128.4, 127.6, 124.9, 82.5, 70.4, 57.4,

56.1, 54.9, 46.5, 42.1, 31.0.

Chiral Separation of 19g. Vinyl sulfonimidamide 19g (51.6 mg)

was dissolved to 16 mg/mL in 2:1 isopropyl alcohol (IPA)/CH₂Cl₂

and was then puriﬁed by HPLC using a Chiralpak IG (20 mm × 250

mm, 5 μm) column. Combined fractions of each enantiomer were

evaporated to dryness to aﬀord 19g-A (10.6 mg, 99% ee, [α]²_D¹−33 (c

0.01, CHCl₃)) and 19g-B (13.3 mg, 98% ee, [α]²_D¹+33 (c 0.01,

CHCl₃)) as brown glassy solids.

N-(3-(10,11-Dihydro-5H-dibenzo[a,d][7]annulen-5-ylidene)-

propyl)-N-methyl-N′-(prop-2-yn-1-yl)ethenesulfonimidamide

(19g). The title compound was prepared according to General

Procedure J employing sulfonimidamide 18c (70 mg, 0.20 mmol).

Puriﬁcation by ﬂash column chromatography (SiO₂, 30% EtOAc in

pentane) aﬀorded sulfonimidamide 19g (63 mg, 81%) as a brown oil;

R_f= 0.53 (50% EtOAc in pentane); IR (ﬁlm)/cm⁻¹3287, 3060, 3019,

Computational Methods. All calculations were performed using

Gaussian 16.⁶³Stationary points were conﬁrmed using frequency

calculations (default divergence criteria). Conformational searches

were carried out as described in the Supporting Information.

Electronic circular dichroism spectra were calculated for individual

conformers using time-dependent density-functional theory

(TDDFT) calculations at cam-B3LYP/6-311++g(d,p) in a continuum

solvent (CPCM) acetonitrile for up to 200 states. Copies of Gaussian

log ﬁles for optimizations and frequency calculations, TDDFT

calculations, and tables of ECD data are available from a data

depository via the data-set collection DOIs 10.14469/hpc/7859

(sulfoximines) and 10.14469/hpc/7577 (sulfonimidamides) and data

sets cited therein.

Electronic Circular Dichroism. The circular dichroism and UV−

vis spectra were recorded on a Chirascan spectrometer (Applied

Photophysics). A 0.1 cm path-length cuvette was loaded with 200 μL

of each compound (50 μM in acetonitrile) or acetonitrile blank. The

elipticity was measured from 340 to 195 nm in 1.0 nm intervals

(bandwidth = 2.0 nm) for 1.0 s per measurement. Measurements were

taken in duplicate and normalized against the acetonitrile control.

Conﬁgurational Assignment by Comparison of the Calcu-

lated and Experimental ECD. Comparative analysis was performed

using SpecDis.⁵²For each structure/substructure, the computed ECD

and UV−vis spectra were summed according to their Boltzmann

weighting at 298 K. The relevant experimental ECD and UV−vis

spectra were then input and similarity analysis was performed by ﬁrst

aligning the UV spectra (shift range = −30 to +30 nm; bandwidth =

0.1−0.3; energy range = 200−340 nm) and then performing a local

reﬁnement to optimize the alignment of the ECD. Assignments were

made on the basis of both manual inspection of the ECD alignments

and the quantiﬁcation of the similarity scores.

1

2914, 2855, 1483, 1442, 1282, 1230, 1148, 969, 756; H NMR (400

MHz, CDCl₃) δ 7.32−7.25 (m, 1H), 7.26−7.09 (m, 6H), 7.08−7.02

(m, 1H), 6.49−6.38 (m, 1H), 6.15 (d, J = 16.7 Hz, 1H), 5.92−5.81

(m, 2H), 3.82 (d, J = 2.9 Hz, 2H), 3.51−3.11 (m, 5H), 3.03−2.93 (m,

1H), 2.87−2.74 (m, 1H), 2.69 (s, 3H), 2.41 (qd, J = 7.3, 1.4 Hz, 2H);

¹³C{¹H} NMR (101 Hz, CDCl₃) δ 145.0, 140.8, 139.7, 139.3, 137.0,

133.1, 130.0, 128.5, 128.1, 128.0, 127.6, 127.2 (2 × C), 126.4, 126.1,

125.8, 82.7, 70.0, 50.4 (2 × C), 33.7, 32.0, 30.6, 28.1; HRMS (ESI-

TOF) m/z: calcd for C₂₄H₂₇N₂OS⁺[M + H]⁺, 391.1844; found,

391.1854.

Chiral Separation of 10g. Vinyl sulfoximine 10g (68 mg) was

dissolved to 12 mg/mL in MeOH and was then puriﬁed by HPLC

using a Chiralpak IG (20 mm × 250 mm, 5 μm) column. Combined

fractions of each isomer were evaporated to dryness to aﬀord 10g-A

(12.9 mg, >99% diastereomeric excess (de)) and 10g-B (10.2 mg,

97% de) as yellow oils.

10g-A: IR (ﬁlm)/cm⁻¹3295, 3060, 2926, 1495, 1446, 1222, 753;

¹H NMR (400 MHz, CDCl₃) δ 8.00−7.96 (m, 2H), 7.61−7.52 (m,

3H), 7.28−7.09 (m, 5H), 6.93 (dd, J = 14.9, 5.8 Hz, 1H), 6.56 (dd, J

= 14.9, 1.4 Hz, 1H), 3.60−3.51 (m, 1H), 2.73−2.63 (m, 2H), 2.58 (s,

1H), 1.88−1.77 (m, 2H), 1.66 (s, 2H); ¹³C{¹H} NMR (101 Hz,

CDCl₃) δ 148.7, 142.9, 141.2, 133.0, 131.8, 129.3 (2 × C), 128.7 (2 ×

C), 128.5 (2 × C), 128.1 (2 × C), 126.3, 51.7, 38.4, 32.2.

10g-B: IR (ﬁlm)/cm⁻¹3306, 3063, 2922, 1495, 1446, 1222, 987,

1

752; H NMR (400 MHz, CDCl₃) δ 8.01−7.96 (m, 2H), 7.62−7.52

(m, 3H), 7.28−7.10 (m, 5H), 6.93 (dd, J = 14.9, 5.8 Hz, 1H), 6.55

(dd, J = 14.9, 1.4 Hz, 1H), 3.60−3.47 (m, 1H), 2.74−2.63 (m, 2H),

2.55 (s, 1H), 1.91−1.78 (m, 2H), 1.66 (s, 2H); ¹³C{¹H} NMR (101

Hz, CDCl₃) δ 148.9, 143.0, 141.1, 133.0, 131.8, 129.4 (2 × C), 128.7

(2 × C), 128.5 (2 × C), 128.1 (2 × C), 126.3, 51.7, 38.5, 32.12.

Chiral Separation of 19f. Vinyl sulfonimidamide 19f (21.8 mg)

was dissolved to 10 mg/mL in heptane/EtOH 6:4 and was then

puriﬁed by HPLC using an Amy-C (20 mm × 250 mm, 5 μm)

column. Combined fractions of each isomer were evaporated to

dryness to aﬀord 19f-A (2.5 mg, >99% ee, >99% de, [α]²_D¹= +28 (c

0.003, CHCl₃)), 19f-B (4.4 mg, >99% ee, >99% de, [α]²_D¹−37 (c

0.002, CHCl₃)), 19f-C (1.9 mg, 96% ee, >99% de, [α]²_D¹+31 (c 0.001,

CHCl₃)), and 19f-D (3.6 mg, >99% ee, 97% de, [α]²_D¹−28 (c 0.003,

CHCl₃)) as clear glassy solids.

ASSOCIATED CONTENT

■

sı

* Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00373.

Details of the relative energies and structures of

conformers of 10g, 19f, and 19g and full comparisons

of the computational and experimental UV and ECD

spectra (Figures S1−S7); H and ¹³C NMR spectra for

1

novel compounds; HPLC traces of enantioenriched

compounds; and computational data including Tables

S1−S7 (PDF)

Enantiomeric pair 19f-A and 19f-D; IR (ﬁlm)/cm⁻¹3287, 2937,

1

2795, 1457, 1282, 1140, 972, 917; H NMR (400 MHz, CDCl₃) δ

7.75 (dd, J = 8.0, 1.7 Hz, 2H), 7.40−7.27 (m, 3H), 6.00 (dd, J = 16.5,

9.6 Hz, 1H), 5.89 (d, J = 16.5 Hz, 1H), 5.55 (d, J = 9.5 Hz, 1H), 4.91

(d, J = 4.3 Hz, 1H), 3.86 (d, J = 2.5 Hz, 2H), 3.57 (s, 1H), 3.24 (d, J =

3.3 Hz, 1H), 3.09 (d, J = 11.6 Hz, 1H), 2.94−2.82 (m, 1H), 2.55 (dd,

J = 11.7, 4.5 Hz, 1H), 2.28 (s, 3H), 2.27 (m, 1H), 2.19 (t, J = 2.5 Hz,

1H); ¹³C{¹H} NMR (101 Hz, CDCl₃) δ 139.6, 134.6, 129.5, 128.2,

127.8, 126.2, 83.1, 70.1, 59.5, 56.5, 55.0, 46.5, 41.7, 30.9.

AUTHOR INFORMATION

■

Corresponding Authors

Gregory B. Craven − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.; The Astbury Centre for Structural

Molecular Biology, School of Molecular and Cellular Biology,

University of Leeds, Leeds LS2 9JT, U.K.; orcid.org/

0000-0003-3414-8348; Email: g.craven13@gmail.com

James A. Bull − Molecular Sciences Research Hub, Department

of Chemistry, Imperial College London, London W12 0BZ,

Enantiomeric pair 19f-B and 19f-C; IR (ﬁlm)/cm⁻¹3287, 2939,

2795, 1454, 1278, 1230, 1151, 976, 928; ¹H NMR (400 MHz,

CDCl₃) δ 7.75−7.62 (m, 2H), 7.38−7.27 (m, 3H), 6.28 (dd, J = 16.6,

9.5 Hz, 1H), 6.16 (d, J = 16.6 Hz, 1H), 5.76 (d, J = 9.5 Hz, 1H), 4.98

(d, J = 4.3 Hz, 1H), 3.86 (d, J = 2.5 Hz, 2H), 3.71−3.52 (m, 1H),

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U.K.; orcid.org/0000-0003-3993-5818; Email: j.bull@

imperial.ac.uk

for invaluable advice and discussions on CD spectra

calculations.

Alan Armstrong − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.; orcid.org/0000-0002-3692-3099;

Email: a.armstrong@imperial.ac.uk

REFERENCES

■

(1) (a) Lu

̈

cking, U. Sulfoximines: A Neglected Opportunity in

Medicinal Chemistry. Angew. Chem., Int. Ed. 2013, 52, 9399−9408.

(b) Lucking, U. Neglected Sulfur(vi) Pharmacophores in Drug

̈

Authors

Discovery: Exploration of Novel Chemical Space by the Interplay of

Drug Design and Method Development. Org. Chem. Front. 2019, 6,

1319−1324.

Edward L. Briggs − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.

Charlotte M. Zammit − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.

Alexander McDermott − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.

(2) Chinthakindi, P. K.; Naicker, T.; Thota, N.; Govender, T.;

Kruger, H. G.; Arvidsson, P. I. Sulfonimidamides in Medicinal and

Agricultural Chemistry. Angew. Chem., Int. Ed. 2017, 56, 4100−4109.

(3) Rowe, W. B.; Meister, A. Identification of L-Methionine-S -

Sulfoximine as the Convulsant Isomer of Methionine Sulfoximine.

Proc. Natl. Acad. Sci. U.S.A. 1970, 66, 500−506.

(4) (a) Sirvent, J. A.; Lucking, U. Novel Pieces for the Emerging

̈

Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation

of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical

Candidates. ChemMedChem 2017, 12, 487−501. (b) Frings, M.;

Bolm, C.; Blum, A.; Gnamm, C. Sulfoximines from a Medicinal

Chemist ’s Perspective: Physicochemical and in Vitro Parameters

Relevant for Drug Discovery. Eur. J. Med. Chem. 2017, 126, 225−245.

(c) Wiezorek, S.; Lamers, P.; Bolm, C. Conversion and Degradation

Pathways of Sulfoximines. Chem. Soc. Rev. 2019, 48, 5408−5423.

(d) Mäder, P.; Kattner, L. Sulfoximines as Rising Stars in Modern

Drug Discovery? Current Status and Perspective on an Emerging

Functional Group in Medicinal Chemistry. J. Med. Chem. 2020, 63,

14243−14275.

Stephanie Greed − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.

Dominic P. Aﬀron − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.

Charlotte Leinfellner − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.

Hannah R. Cudmore − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.

Ruth R. Tweedy − Molecular Sciences Research Hub,

Department of Chemistry, Imperial College London, London

W12 0BZ, U.K.

Renzo Luisi − Department of PharmacyDrug Sciences,

University of Bari, Bari 70125, Italy; orcid.org/0000-

0002-9882-7908

(5) (a) Lucking, U.; Jautelat, R.; Kruger, M.; Brumby, T.; Lienau, P.;

̈ ̈

Schäfer, M.; Briem, H.; Schulze, J.; Hillisch, A.; Reichel, A.; et al. The

Lab Oddity Prevails: Discovery of Pan-CDK Inhibitor (R)-S-

Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-Hydroxy-1-Methylpropyl]Oxy}-5-

(Trifluoromethyl)Pyrimidin-2-Yl]Amino}phenyl)Sulfoximide (BAY

1000394) for the Treatment of Cancer. ChemMedChem 2013, 8,

1067−1085. (b) Foote, K. M.; Nissink, J. W. M.; McGuire, T.;

Turner, P.; Guichard, S.; Yates, J. W. T.; Lau, A.; Blades, K.;

Heathcote, D.; Odedra, R.; et al. Discovery and Characterization of

AZD6738, a Potent Inhibitor of Ataxia Telangiectasia Mutated and

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00373

J. Med. Chem. 2018, 61, 9889−9907. (c) Lucking, U.; Scholz, A.;

̈

Author Contributions

All authors have given approval to the ﬁnal version of the

manuscript.

Lienau, P.; Siemeister, G.; Kosemund, D.; Bohlmann, R.; Briem, H.;

Terebesi, I.; Meyer, K.; Prelle, K.; Denner, K.; Bömer, U.; Schäfer, M.;

Eis, K.; Valencia, R.; Ince, S.; von Nussbaum, F.; Mumberg, D.;

Ziegelbauer, K.; Klebl, B.; Choidas, A.; Nussbaumer, P.; Baumann,

Funding

M.; Schultz-Fademrecht, C.; Ruhter, G.; Eickhoff, J.; Brands, M.

̈

We gratefully acknowledge EPSRC for funding (studentships

to E.L.B. and S.G. and doctoral prize fellowship to G.B.C.) and

The Royal Society [University Research Fellowship

(UF140161, to J.A.B.) and Research Grants (RG150444 and

RGF\EA\180031)]. This work was additionally supported by

grants from the Institute of Chemical Biology (Imperial

College London) and EPSRC (Studentship award EP/

F500416/1). The circular dichroism facility at the University

of Leeds was funded by the Wellcome Trust (094232).

Identification of Atuveciclib (BAY 1143572), the First Highly

Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of

Cancer. ChemMedChem 2017, 12, 1776−1793.

(6) (a) Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Bromme, D. Vinyl

Sulfones as Mechanism-Based Cysteine Protease Inhibitors. J. Med.

Chem. 1995, 38, 3193−3196. (b) Roush, W. R.; Gwaltney, S. L.;

Cheng, J.; Scheidt, K. A.; McKerrow, J. H.; Hansell, E. Vinyl Sulfonate

Esters and Vinyl Sulfonamides: Potent, Irreversible Inhibitors of

Cysteine Proteases. J. Am. Chem. Soc. 1998, 120, 10994−10995.

(c) Kerr, I. D.; Lee, J. H.; Farady, C. J.; Marion, R.; Rickert, M.; Sajid,

M.; Pandey, K. C.; Caffrey, C. R.; Legac, J.; Hansell, E.; McKerrow, J.

H.; Craik, C. S.; Rosenthal, P. J.; Brinen, L. S. Vinyl Sulfones as

Antiparasitic Agents and a Structural Basis for Drug Design. J. Biol.

Chem. 2009, 284, 25697−25703. (d) Pakavathkumar, P.; Noël, A.;

Lecrux, C.; Tubeleviciute-Aydin, A.; Hamel, E.; Ahlfors, J.-E.;

LeBlanc, A. C. Caspase Vinyl Sulfone Small Molecule Inhibitors

Prevent Axonal Degeneration in Human Neurons and Reverse

Cognitive Impairment in Caspase-6-Overexpressing Mice. Mol.

Neurodegener. 2017, 12, No. 22.

Notes

The authors declare no competing ﬁnancial interest.

A version of this manuscript was deposited on the preprint

repository ChemRxiv.⁶⁴

ACKNOWLEDGMENTS

■

The authors thank Reach Separations (BioCity NG1 1GF,

U.K.) for supporting this work by conducting preparatory and

analytical chiral HPLC of compounds 10g, 19f, and 19g. The

authors are grateful to Prof. Henry Rzepa (Imperial College)

(7) Jacobsen, W.; Christians, U.; Benet, L. Z. In Vitro Evaluation of

the Disposition of a Novel Cysteine Protease Inhibitor. Drug Metab.

Dispos. 2000, 28, 1343−1351.

7421

https://doi.org/10.1021/acs.joc.1c00373

J. Org. Chem. 2021, 86, 7403−7424

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

(8) Anscombe, E.; Meschini, E.; Mora-Vidal, R.; Martin, M. P.;

Staunton, D.; Geitmann, M.; Danielson, U. H.; Stanley, W. A.; Wang,

L. Z.; Reuillon, T.; Golding, B. T.; Cano, C.; Newell, D. R.; Noble, M.

E. M.; Wedge, S. R.; Endicott, J. A.; Griffin, R. J. Identification and

Characterization of an Irreversible Inhibitor of CDK2. Chem. Biol.

2015, 22, 1159−1164.

(9) Ward, R. A.; Colclough, N.; Challinor, M.; Debreczeni, J. E.;

Eckersley, K.; Fairley, G.; Feron, L.; Flemington, V.; Graham, M. A.;

Greenwood, R.; Hopcroft, P.; Howard, T. D.; James, M.; Jones, C. D.;

Jones, C. R.; Renshaw, J.; Roberts, K.; Snow, L.; Tonge, M.; Yeung, K.

Structure-Guided Design of Highly Selective and Potent Covalent

Inhibitors of ERK1/2. J. Med. Chem. 2015, 58, 4790−4801.

(10) Ostrem, J. M.; Peters, U.; Sos, M. L.; Wells, J. A.; Shokat, K. M.

K-Ras(G12C) Inhibitors Allosterically Control GTP Affinity and

Effector Interactions. Nature 2013, 503, 548−551.

(11) Li, X.; Zuo, Y.; Tang, G.; Wang, Y.; Zhou, Y.; Wang, X.; Guo,

T.; Xia, M.; Ding, N.; Pan, Z. Discovery of a Series of 2,5-

Diaminopyrimidine Covalent Irreversible Inhibitors of Bruton ’s

Tyrosine Kinase with in Vivo Antitumor Activity. J. Med. Chem.

2014, 57, 5112−5128.

(12) Turnbull, A. P.; Ioannidis, S.; Krajewski, W. W.; Pinto-

Fernandez, A.; Heride, C.; Martin, A. C. L.; Tonkin, L. M.;

Townsend, E. C.; Buker, S. M.; Lancia, D. R.; Caravella, J. A.;

Toms, A. V.; Charlton, T. M.; Lahdenranta, J.; Wilker, E.; Follows, B.

C.; Evans, N. J.; Stead, L.; Alli, C.; Zarayskiy, V. V.; Talbot, A. C.;

Buckmelter, A. J.; Wang, M.; McKinnon, C. L.; Saab, F.; McGouran, J.

F.; Century, H.; Gersch, M.; Pittman, M. S.; Marshall, C. G.;

Raynham, T. M.; Simcox, M.; Stewart, L. M. D.; McLoughlin, S. B.;

Escobedo, J. A.; Bair, K. W.; Dinsmore, C. J.; Hammonds, T. R.; Kim,

S.; Urbé, S.; Clague, M. J.; Kessler, B. M.; Komander, D. Molecular

Basis of USP7 Inhibition by Selective Small-Molecule Inhibitors.

Nature 2017, 550, 481−486.

(13) (a) Fang, Y.; Luo, Z.; Xu, X. Recent Advances in the Synthesis

of Vinyl Sulfones. RSC Adv. 2016, 6, 59661−59676. (b) Reuter, D.

C.; McIntosh, J. E.; Guinn, A. C.; Madera, A. M. Synthesis of Vinyl

Sulfonamides Using the Horner Reaction. Synthesis 2003, 2321−

2324. (c) Roush, W. R.; Cheng, J.; Knapp-Reed, B.; Alvarez-

Hernandez, A.; McKerrow, J. H.; Hansell, E.; Engel, J. C. Potent

Second Generation Vinyl Sulfonamide Inhibitors of the Trypanoso-

mal Cysteine Protease Cruzain. Bioorg. Med. Chem. Lett. 2001, 11,

2759−2762. (d) Craven, G. B.; Affron, D. P.; Raymond, P. N.; Mann,

D. J.; Armstrong, A. Vinyl Sulfonamide Synthesis for Irreversible

Tethering via a Novel α -Selenoether Protection Strategy. MedChem-

Comm 2019, 10, 158−163. (e) Kiemele, E. R.; Wathier, M.; Bichler,

P.; Love, J. A. Total Synthesis of K777: Successful Application of

Transition-Metal-Catalyzed Alkyne Hydrothiolation toward the

Modular Synthesis of a Potent Cysteine Protease Inhibitor. Org.

Lett. 2016, 18, 492−495.

(14) (a) Jones, L. H. Reactive Chemical Probes: Beyond the Kinase

Cysteinome. Angew. Chem., Int. Ed. 2018, 57, 9220−9223.

(b) Gehringer, M.; Laufer, S. A. Emerging and Re-Emerging

Warheads for Targeted Covalent Inhibitors: Applications in Medicinal

Chemistry and Chemical Biology. J. Med. Chem. 2019, 62, 5673−

5724. (c) Sutanto, F.; Konstantinidou, M.; Dömling, A. Covalent

Inhibitors: A Rational Approach to Drug Discovery. RSC Med. Chem.

2020, 11, 876−884.

G. B.; Affron, D. P.; Allen, C. E.; Matthies, S.; Greener, J. G.; Morgan,

R. M. L.; Tate, E. W.; Armstrong, A.; Mann, D. J. High-Throughput

Kinetic Analysis for Target-Directed Covalent Ligand Discovery.

Angew. Chem., Int. Ed. 2018, 57, 5257−5261. (d) Resnick, E.; Bradley,

A.; Gan, J.; Douangamath, A.; Krojer, T.; Sethi, R.; Geurink, P. P.;

Aimon, A.; Amitai, G.; Bellini, D.; Bennett, J.; Fairhead, M.; Fedorov,

O.; Gabizon, R.; Gan, J.; Guo, J.; Plotnikov, A.; Reznik, N.; Ruda, G.

F.; Díaz-Sáez, L.; Straub, V. M.; Szommer, T.; Velupillai, S.; Zaidman,

D.; Zhang, Y.; Coker, A. R.; Dowson, C. G.; Barr, H. M.; Wang, C.;

Huber, K. V. M.; Brennan, P. E.; Ovaa, H.; von Delft, F.; London, N.

Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening.

J. Am. Chem. Soc. 2019, 141, 8951−8968. (e) Douangamath, A.;

Fearon, D.; Gehrtz, P.; Krojer, T.; Lukacik, P.; Owen, C. D.; Resnick,

́

E.; Strain-Damerell, C.; Aimon, A.; Abrányi-Balogh, P.; Brandao-

Neto, J.; Carbery, A.; Davison, G.; Dias, A.; Downes, T. D.; Dunnett,

̃

L.; Fairhead, M.; Firth, J. D.; Jones, S. P.; Keeley, A.; Keseru, G. M.;

̈

Klein, H. F.; Martin, M. P.; Noble, M. E. M.; O’Brien, P.; Powell, A.;

Reddi, R. N.; Skyner, R.; Snee, M.; Waring, M. J.; Wild, C.; London,

N.; von Delft, F.; Walsh, M. A. Crystallographic and Electrophilic

Fragment Screening of the SARS-CoV-2 Main Protease. Nat.

Commun. 2020, 11, No. 5047. (f) Craven, G. B.; Affron, D. P.;

Kösel, T.; Wong, T. L. M.; Jukes, Z. H.; Liu, C.-T.; Morgan, R. M. L.;

Armstrong, A.; Mann, D. J. Multiparameter Kinetic Analysis for

Covalent Fragment Optimization Using Quantitative Irreversible

Tethering (QIT). ChemBioChem 2020, 21, 3417−3422.

́

̋

(18) Keeley, A.; Petri, L.; Abrányi-Balogh, P.; Keseru, G. M.

Covalent Fragment Libraries in Drug Discovery. Drug Discovery Today

2020, 25, 983−996.

(19) (a) Hwang, K.-J.; Logusch, E. W. A Convenient Synthesis of

Vinyl Sulfoximines from β -Hydroxyalkyl Sulfoximines. Tetrahedron

Lett. 1987, 28, 4149−4152. (b) Craig, D.; Geach, N. J. Synthesis of E -

N -Unfunctionalized α ,β -Unsaturated Sulfoximines and N -Trifluor-

omethanesulfonyl Derivatives. Synlett 1993, 1993, 481−482.

(20) Erdelmeier, I.; Gais, H.-J. Stereoselective Synthesis of

Enantiomerically Pure 1-(E )-Alkenylsulfoximines. Tetrahedron Lett.

1985, 26, 4359−4362.

(21) (a) Hwang, K. J. A Convenient Synthesis of Free Vinyl

Sulfoximines from Methyl Sulfoximines. Bull. Korean Chem. Soc. 2000,

21, 125−127. (b) McGrath, M. J.; Bolm, C. The Use of Chiral

Lithium Amides in the Desymmetrisation of N -Trialkylsilyl Dimethyl

Sulfoximines. Beilstein J. Org. Chem. 2007, 3, No. 33. (c) Kahraman,

M.; Sinishtaj, S.; Dolan, P. M.; Kensler, T. W.; Peleg, S.; Saha, U.;

Chuang, S. S.; Bernstein, G.; Korczak, B.; Posner, G. H. Potent,

Selective and Low-Calcemic Inhibitors of CYP24 Hydroxylase: 24-

Sulfoximine Analogues of the Hormone 1 α ,25-Dihydroxyvitamin D 3.

J. Med. Chem. 2004, 47, 6854−6863. (d) Gao, X.; Gaddam, V.;

Altenhofer, E.; Tata, R. R.; Cai, Z.; Yongpruksa, N.;

Garimallaprabhakaran, A. K.; Harmata, M. C-H Activation in S -

Alkenyl Sulfoximines: An Endo 1,5-Hydrogen Migration. Angew.

Chem., Int. Ed. 2012, 51, 7016−7019.

(22) Chinthakindi, P. K.; Nandi, G. C.; Govender, T.; Kruger, H. G.;

Naicker, T.; Arvidsson, P. I. An Efficient Protecting-Group-Free

Synthesis of Vinylic Sulfoximines via Horner-Wadsworth-Emmons

Reaction. Synlett 2016, 27, 1423−1427.

(23) Carlström, K. E.; Chinthakindi, P. K.; Espinosa, B.; Al Nimer,

F.; Arnér, E. S. J.; Arvidsson, P. I.; Piehl, F.; Johansson, K.

Characterization of More Selective Central Nervous System Nrf2-

Activating Novel Vinyl Sulfoximine Compounds Compared to

Dimethyl Fumarate. Neurotherapeutics 2020, 17, 1142−1152.

(24) Bräse, S.; Mende, M.; Jobelius, H. H.; Scharf, H.-D. Hydrazoic

Acid and Azides. Ullmann’s Encyclopedia of Industrial Chemistry;

Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2015;

pp 1−11.

(15) Cisar, J. S.; Cravatt, B. F. Fully Functionalized Small-Molecule

Probes for Integrated Phenotypic Screening and Target Identification.

J. Am. Chem. Soc. 2012, 134, 10385−10388.

(16) Wang, Y.; Dix, M. M.; Bianco, G.; Remsberg, J. R.; Lee, H.-Y.;

Kalocsay, M.; Gygi, S. P.; Forli, S.; Vite, G.; Lawrence, R. M.; Parker,

C. G.; Cravatt, B. F. Expedited Mapping of the Ligandable Proteome

Using Fully Functionalized Enantiomeric Probe Pairs. Nat. Chem.

2019, 11, 1113−1123.

(17) (a) Nonoo, R. H.; Armstrong, A.; Mann, D. J. Kinetic

Template-Guided Tethering of Fragments. ChemMedChem 2012, 7,

2082−2086. (b) Kathman, S. G.; Xu, Z.; Statsyuk, A. V. A Fragment-

Based Method to Discover Irreversible Covalent Inhibitors of

Cysteine Proteases. J. Med. Chem. 2014, 57, 4969−4974. (c) Craven,

(25) Mendiola, J.; Rincón, J. A.; Mateos, C.; Soriano, J. F.; de Frutos,

O.; Niemeier, J. K.; Davis, E. M. Preparation, Use, and Safety of O -

Mesitylenesulfonylhydroxylamine. Org. Process Res. Dev. 2009, 13,

263−267.

(26) Davies, T. Q.; Tilby, M. J.; Ren, J.; Parker, N. A.; Skolc, D.;

Hall, A.; Duarte, F.; Willis, M. C. Harnessing Sulfinyl Nitrenes: A

7422

https://doi.org/10.1021/acs.joc.1c00373

J. Org. Chem. 2021, 86, 7403−7424

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Unified One-Pot Synthesis of Sulfoximines and Sulfonimidamides. J.

Am. Chem. Soc. 2020, 142, 15445−15453.

(32) Also see: (a) Lohier, J.-F.; Glachet, T.; Marzag, H.; Gaumont,

A.-C.; Reboul, V. Mechanistic Investigation of the NH-Sulfoximina-

tion of Sulfide. Evidence for λ 6-Sulfanenitrile Intermediates. Chem.

Commun. 2017, 53, 2064−2067. (b) Chaabouni, S.; Lohier, J.-F.;

Barthelemy, A.-L.; Glachet, T.; Anselmi, E.; Dagousset, G.; Diter, P.;

Pégot, B.; Magnier, E.; Reboul, V. One-Pot Synthesis of Aryl- and

Alkyl S -Perfluoroalkylated NH -Sulfoximines from Sulfides. Chem. -

Eur. J. 2018, 24, 17006−17010. (c) Xie, Y.; Zhou, B.; Zhou, S.; Zhou,

S.; Wei, W.; Liu, J.; Zhan, Y.; Cheng, D.; Chen, M.; Li, Y.; et al.

Sulfimine-Promoted Fast O Transfer: One-Step Synthesis of

Sulfoximine from Sulfide. ChemistrySelect 2017, 2, 1620−1624.

(27) For reviews, see: (a) Bizet, V.; Hendriks, C. M. M.; Bolm, C.

Sulfur Imidations: Access to Sulfimides and Sulfoximines. Chem. Soc.

Rev. 2015, 44, 3378−3390. (b) Bull, J. A.; Degennaro, L.; Luisi, R.

Straightforward Strategies for the Preparation of NH-Sulfoximines: A

Serendipitous Story. Synlett 2017, 28, 2525−2538. (c) Nandi, G. C.;

Arvidsson, P. I. Sulfonimidamides: Synthesis and Applications in

Preparative Organic Chemistry. Adv. Synth. Catal. 2018, 360, 2976−

́

3001. (d) Wojaczynska, E.; Wojaczynski, J. Modern Stereoselective

Synthesis of Chiral Sulfinyl Compounds. Chem. Rev. 2020, 120,

4578−4611.

(33) Izzo, F.; Schäfer, M.; Stockman, R.; Lucking, U. A New,

̈

Practical One-Pot Synthesis of Unprotected Sulfonimidamides by

Transfer of Electrophilic NH to Sulfinamides. Chem. - Eur. J. 2017, 23,

15189−15193.

(34) Briggs, E. L.; Tota, A.; Colella, M.; Degennaro, L.; Luisi, R.;

Bull, J. A. Synthesis of Sulfonimidamides from Sulfenamides via an

Alkoxy-Amino-λ 6-Sulfanenitrile Intermediate. Angew. Chem., Int. Ed.

2019, 58, 14303−14310.

(35) Worch, C.; Mayer, A. C.; Bolm, C. Synthesis and Use of Chiral

Sulfoximines. Organosulfur Chemistry in Asymmetric Synthesis; Wiley-

VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2008; pp

209−232.

(36) Han, J.; Soloshonok, V. A.; Klika, K. D.; Drabowicz, J.; Wzorek,

A. Chiral Sulfoxides: Advances in Asymmetric Synthesis and Problems

with the Accurate Determination of the Stereochemical Outcome.

Chem. Soc. Rev. 2018, 47, 1307−1350.

(37) Kuniyasu, H.; Ogawa, A.; Sato, K.; Ryu, I.; Kambe, N.; Sonoda,

N. The First Example of Transition-Metal-Catalyzed Addition of

Aromatic Thiols to Acetylenes. J. Am. Chem. Soc. 1992, 114, 5902−

5903.

(38) Cao, C.; Fraser, L. R.; Love, J. A. Rhodium-Catalyzed Alkyne

Hydrothiolation with Aromatic and Aliphatic Thiols. J. Am. Chem. Soc.

2005, 127, 17614−17615.

(39) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. Highly Regio- and

Stereocontrolled Synthesis of Vinyl Sulfides via Transition-Metal-

Catalyzed Hydrothiolation of Alkynes with Thiols. J. Am. Chem. Soc.

1999, 121, 5108−5114.

(28) For selected leading methods for sulfoximine synthesis, see:

(a) Okamura, H.; Bolm, C. Rhodium-Catalyzed Imination of

Sulfoxides and Sulfides: Efficient Preparation of N-Unsubstituted

Sulfoximines and Sulfilimines. Org. Lett. 2004, 6, 1305−1307. (b) Lai,

C.; Mathieu, G.; Gabrielli Tabarez, L. P.; Lebel, H. Batch and

Continuous-Flow Iron(II)-Catalyzed Synthesis of Sulfilimines and

Sulfoximines Using N-Mesyloxycarbamates. Chem. - Eur. J. 2019, 25,

9423−9426. (c) Zenzola, M.; Doran, R.; Luisi, R.; Bull, J. A. Synthesis

of Sulfoximine Carbamates by Rhodium-Catalyzed Nitrene Transfer

of Carbamates to Sulfoxides. J. Org. Chem. 2015, 80, 6391−6399.

(d) Mendonca̧ Matos, P.; Lewis, W.; Argent, S. P.; Moore, J. C.;

Stockman, R. A. General Method for the Asymmetric Synthesis of N −

H Sulfoximines via C −S Bond Formation. Org. Lett. 2020, 22, 2776−

2780. (e) Aota, Y.; Kano, T.; Maruoka, K. Asymmetric Synthesis of

Chiral Sulfoximines via the S-Arylation of Sulfinamides. J. Am. Chem.

Soc. 2019, 141, 19263−19268. Also see refs 30 and 31.

(29) For selected leading methods for sulfonimidamide synthesis,

see: (a) Yu, H.; Li, Z.; Bolm, C. Copper-Catalyzed Trans-

sulfinamidation of Sulfinamides as a Key Step in the Preparation of

Sulfonamides and Sulfonimidamides. Angew. Chem., Int. Ed. 2018, 57,

15602−15605. (b) Gao, B.; Li, S.; Wu, P.; Moses, J. E.; Sharpless, K.

B. SuFEx Chemistry of Thionyl Tetrafluoride (SOF4) with

Organolithium Nucleophiles: Synthesis of Sulfonimidoyl Fluorides,

Sulfoximines, Sulfonimidamides, and Sulfonimidates. Angew. Chem.,

Int. Ed. 2018, 57, 1939−1943. (c) Zasukha, S. V.; Timoshenko, V. M.;

Tolmachev, A. A.; Pivnytska, V. O.; Gavrylenko, O.; Zhersh, S.;

Shermolovich, Y.; Grygorenko, O. O. Sulfonimidamides and

Imidosulfuric Diamides: Compounds from an Underexplored Part

of Biologically Relevant Chemical Space. Chem. - Eur. J. 2019, 25,

6928−6940. (d) Bremerich, M.; Conrads, C. M.; Langletz, T.; Bolm,

C. Additions to N-Sulfinylamines as an Approach for the Metal-Free

Synthesis of Sulfonimidamides: O-Benzotriazolyl Sulfonimidates as

Activated Intermediates. Angew. Chem., Int. Ed. 2019, 58, 19014−

19020. (e) Davies, T. Q.; Hall, A.; Willis, M. C. One-Pot, Three-

Component Sulfonimidamide Synthesis Exploiting the Sulfinylamine

Reagent N -Sulfinyltritylamine, TrNSO. Angew. Chem., Int. Ed. 2017,

56, 14937−14941. (f) Greed, S.; Briggs, E. L.; Idiris, F. I. M.; White,

(40) Gerber, R.; Frech, C. M. Alkyne Hydrothiolation Catalyzed by

a Dichlorobis(Aminophosphine) Complex of Palladium: Selective

Formation of Cis-Configured Vinyl Thioethers. Chem. - Eur. J. 2012,

18, 8901−8905.

(41) Shoai, S.; Bichler, P.; Kang, B.; Buckley, H.; Love, J. A. Catalytic

Alkyne Hydrothiolation with Alkanethiols Using Wilkinson ’s Catalyst.

Organometallics 2007, 26, 5778−5781.

(42) (a) Kolb, H. C.; Sharpless, K. B. The Growing Impact of Click

Chemistry on Drug Discovery. Drug Discovery Today 2003, 8, 1128−

1137. (b) Thirumurugan, P.; Matosiuk, D.; Jozwiak, K. Click

Chemistry for Drug Development and Diverse Chemical −Biology

Applications. Chem. Rev. 2013, 113, 4905−4979. (c) Horisawa, K.

Specific and Quantitative Labeling of Biomolecules Using Click

Chemistry. Front. Physiol. 2014, 5, No. 457.

(43) (a) Wright, M. H.; Sieber, S. A. Chemical Proteomics

Approaches for Identifying the Cellular Targets of Natural Products.

Nat. Prod. Rep. 2016, 33, 681−708. (b) Van Kersavond, T.; Nguyen,

M. T. N.; Verhelst, S. H. L. Synthesis and Application of Activity-

Based Probes for Proteases. Methods in Molecular Biology; Humana

Press Inc., 2017; Vol 1574, pp 255−266. (c) Pickens, C. J.; Johnson,

S. N.; Pressnall, M. M.; Leon, M. A.; Berkland, C. J. Practical

Considerations, Challenges, and Limitations of Bioconjugation via

Azide −Alkyne Cycloaddition. Bioconjugate Chem. 2018, 29, 686−701.

(44) (a) Teng, F.; Sun, S.; Jiang, Y.; Yu, J.-T.; Cheng, J. Copper-

Catalyzed Oxidative C(Sp3)−H/N −H Coupling of Sulfoximines and

Amides with Simple Alkanes via a Radical Process. Chem. Commun.

2015, 51, 5902−5905. (b) Zhu, H.; Teng, F.; Pan, C.; Cheng, J.; Yu,

J.-T. Radical N-Arylation/Alkylation of Sulfoximines. Tetrahedron

Lett. 2016, 57, 2372−2374. (c) Bohnen, C.; Bolm, C. N -

Trifluoromethylthiolated Sulfoximines. Org. Lett. 2015, 17, 3011−

3013. (d) Teng, F.; Cheng, J.; Yu, J.-T. Copper-Catalyzed N-

A. J. P.; Lucking, U.; Bull, J. A. Synthesis of Highly Enantioenriched

̈

Sulfonimidoyl Fluorides and Sulfonimidamides by Stereospecific

Sulfur −Fluorine Exchange (SuFEx) Reaction. Chem. - Eur. J. 2020,

26, 12533−12538. Also See refs 32 and 33.

(30) Zenzola, M.; Doran, R.; Degennaro, L.; Luisi, R.; Bull, J. A.

Transfer of Electrophilic NH Using Convenient Sources of Ammonia:

Direct Synthesis of NH Sulfoximines from Sulfoxides. Angew. Chem.,

Int. Ed. 2016, 55, 7203−7207.

(31) (a) Tota, A.; Zenzola, M.; Chawner, S. J.; John-Campbell, S. S.;

Carlucci, C.; Romanazzi, G.; Degennaro, L.; Bull, J. A.; Luisi, R.

Synthesis of NH-Sulfoximines from Sulfides by Chemoselective One-

Pot N- and O-Transfers. Chem. Commun. 2017, 53, 348−351.

(b) Degennaro, L.; Tota, A.; De Angelis, S.; Andresini, M.;

Cardellicchio, C.; Capozzi, M. A.; Romanazzi, G.; Luisi, R. Eur. J.

Org. Chem. 2017, 2017, 6486−6490. (c) Tota, A.; Carlucci, C.;

Pisano, L.; Cutolo, G.; Clarkson, G. J.; Romanazzi, G.; Degennaro, L.;

Bull, J. A.; Rollin, P.; Luisi, R. Synthesis of Glycosyl Sulfoximines by a

Highly Chemo- and Stereoselective NH- and O-Transfer to

Thioglycosides. Org. Biomol. Chem. 2020, 18, 3893−3897.

7423

https://doi.org/10.1021/acs.joc.1c00373

J. Org. Chem. 2021, 86, 7403−7424

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

Methylation/Ethylation of Sulfoximines. Org. Biomol. Chem. 2015, 13,

9934−9937. (e) Kim, J.; Ok, J.; Kim, S.; Choi, W.; Lee, P. H. Mild

Copper −TBAF-Catalyzed N -Arylation of Sulfoximines with Aryl

Siloxanes. Org. Lett. 2014, 16, 4602−4605. (f) Aithagani, S. K.; Dara,

S.; Munagala, G.; Aruri, H.; Yadav, M.; Sharma, S.; Vishwakarma, R.

A.; Singh, P. P. Metal-Free Approach for the Synthesis of N -Aryl

Sulfoximines via Aryne Intermediate. Org. Lett. 2015, 17, 5547−5549.

(g) Zou, Y.; Xiao, J.; Peng, Z.; Dong, W.; An, D. Transition Metal-

Free Aroylation of NH-Sulfoximines with Methyl Arenes. Chem.

Commun. 2015, 51, 14889−14892. (h) Zhao, Z.; Wang, T.; Yuan, L.;

Jia, X.; Zhao, J. Oxidative Acylation of Sulfoximines with

Methylarenes as an Acyl Donor. RSC Adv. 2015, 5, 75386−75389.

(i) Bala, B. D.; Sharma, N.; Sekar, G. Sulfoximinocarbonylation of

Aryl Halides Using Heterogeneous Pd/C Catalyst. RSC Adv. 2016, 6,

97152−97159.

(56) Reach Separations specialise in chromatography for the analysis

and puriﬁcation of small molecules with extensive equipment and

expertise: https://reachseparations.com/.

(57) Wimmer, A.; König, B. N-Arylation of NH -Sulfoximines via

Dual Nickel Photocatalysis. Org. Lett. 2019, 21, 2740−2744.

(58) Bach, T.; Körber, C. The Preparation of N-Tert-Butylox-

ycarbonyl-(Boc-)Protected Sulfoximines and Sulfimines by an Iron-

(II)-Mediated Nitrene Transfer from BocN3 to Sulfoxides and

Sulfides. Eur. J. Org. Chem. 1999, 1999, 1033−1039.

(59) Dong, S.; Frings, M.; Cheng, H.; Wen, J.; Zhang, D.; Raabe, G.;

Bolm, C. Organocatalytic Kinetic Resolution of Sulfoximines. J. Am.

Chem. Soc. 2016, 138, 2166−2169.

(60) Kuniyasu, H.; Ogawa, A.; Sato, K.; Ryu, I.; Kambe, N.; Sonoda,

N. The First Example of Transition-Metal-Catalyzed Addition of

Aromatic Thiols to Acetylenes. J. Am. Chem. Soc. 1992, 114, 5902−

5903.

(45) Izzo, F.; Schäfer, M.; Lienau, P.; Ganzer, U.; Stockman, R.;

(61) Zheng, Y.; Du, X.; Bao, W. L-Proline Promoted Cross-Coupling

of Vinyl Bromide with Thiols Catalyzed by CuBr in Ionic Liquid.

Tetrahedron Lett. 2006, 47, 1217−1220.

Lucking, U. Exploration of Novel Chemical Space: Synthesis and in

̈

Vitro Evaluation of N-Functionalized Tertiary Sulfonimidamides.

Chem. - Eur. J. 2018, 24, 9295−9304.

(46) Mabasa, T. F.; Awe, B.; Laming, D.; Kinfe, H. H. Design,

Synthesis and Antiplasmodial Evaluation of Sulfoximine-Triazole

Hybrids as Potential Antimalarial Prototypes. Med. Chem. 2019, 15,

685−692.

(47) (a) Gegenava, M.; Chankvetadze, L.; Farkas, T.; Chankvetadze,

B. Enantioseparation of Selected Chiral Sulfoxides in High-Perform-

ance Liquid Chromatography with Polysaccharide-Based Chiral

Selectors in Polar Organic Mobile Phases with Emphasis on

Enantiomer Elution Order. J. Sep. Sci. 2014, 37, 1083−1088.

(b) Sardella, R.; Ianni, F.; Di Michele, A.; Di Capua, A.; Carotti,

A.; Anzini, M.; Natalini, B. Enantioresolution and Stereochemical

Characterization of Two Chiral Sulfoxides Endowed with COX-2

Inhibitory Activity. Chirality 2017, 29, 536−540. (c) Ferretti, R.;

Carradori, S.; Guglielmi, P.; Pierini, M.; Casulli, A.; Cirilli, R.

Enantiomers of Triclabendazole Sulfoxide: Analytical and Semi-

preparative HPLC Separation, Absolute Configuration Assignment,

and Transformation into Sodium Salt. J. Pharm. Biomed. Anal. 2017,

140, 38−44.

̂

(62) Leca, D.; Song, K.; Amatore, M.; Fensterbank, L.; Lacote, E.;

Malacria, M. Iodine(III)-Mediated Preparations of Nitrogen-Con-

taining Sulfur Derivatives: Dramatic Influence of the Sulfur Oxidation

State. Chem. - Eur. J. 2004, 10, 906−916.

(63) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;

Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,

G. A.; Nakatsuji, H.; Li, X.; Caricato, M.; Marenich, A. V.; Bloino, J.;

Janesko, B. G.; Gomperts, R.; Mennucci, B.; Hratchian, H. P.; Ortiz, J.

V.; Izmaylov, A. F.; Sonnenberg, J. L.; Williams-Young, D.; Ding, F.;

Lipparini, F.; Egidi, F.; Goings, J.; Peng, B.; Petrone, A.; Henderson,

T.; Ranasinghe, D.; Zakrzewski, V. G.; Gao, J.; Rega, N.; Zheng, G.;

Liang, W.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;

Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;

Throssell, K.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.;

Bearpark, M. J.; Heyd, J. J.; Brothers, E. N.; Kudin, K. N.; Staroverov,

V. N.; Keith, T. A.; Kobayashi, R.; Normand, J.; Raghavachari, K.;

Rendell, A. P.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.;

Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.;

Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J.

Gaussian 16, revision C.01, Gaussian, Inc.: Wallingford, CT, 2019.

(64) Craven, G. B.; Briggs, E. L.; Zammit, C. M.; McDermott, A.;

Greed, S.; Affron, D. P.; Leinfellner, C.; Cudmore, H. R.; Tweedy, R.

R.; Luisi, R.; Bull, J. A.; Armstrong, A. Synthesis and Configurational

Assignment of Vinyl Sulfoximines and Sulfonimidamides. ChemRxiv

2021, DOI: 10.26434/CHEMRXIV.13947413.V1.

(48) (a) del Nozal, M. J.; Toribio, L.; Bernal, J. L.; Alonso, C.;

Jiménez, J. J. Chiral Separation of Omeprazole and Several Related

Benzimidazoles Using Supercritical Fluid Chromatography. J. Sep. Sci.

2004, 27, 1023−1029. (b) West, C.; Konjaria, M.-L.; Shashviashvili,

N.; Lemasson, E.; Bonnet, P.; Kakava, R.; Volonterio, A.;

Chankvetadze, B. Enantioseparation of Novel Chiral Sulfoxides on

Chlorinated Polysaccharide Stationary Phases in Supercritical Fluid

Chromatography. J. Chromatogr. A 2017, 1499, 174−182.

(49) Parsons, S. Determination of Absolute Configuration Using X-

Ray Diffraction. Tetrahedron: Asymmetry 2017, 28, 1304−1313.

(50) Seco, J. M.; Quinoá, E.; Riguera, R. The Assignment of

̃

Absolute Configuration by NMR. Chem. Rev. 2004, 104, 17−118.

(51) Polavarapu, P. Determination of the Absolute Configurations of

Chiral Drugs Using Chiroptical Spectroscopy. Molecules 2016, 21,

No. 1056.

(52) Berova, N.; Di Bari, L.; Pescitelli, G. Application of Electronic

Circular Dichroism in Configurational and Conformational Analysis

of Organic Compounds. Chem. Soc. Rev. 2007, 36, 914.

(53) Xiong, F.; Yang, B.-B.; Zhang, J.; Li, L. Enantioseparation,

Stereochemical Assignment and Chiral Recognition Mechanism of

Sulfoxide-Containing Drugs. Molecules 2018, 23, No. 2680.

(54) Worch, C.; Atodiresei, I.; Raabe, G.; Bolm, C. Synthesis of

Enantiopure Sulfonimidamides and Elucidation of Their Absolute

Configuration by Comparison of Measured and Calculated CD

Spectra and X-ray Crystal Structure Determination. Chem. - Eur. J.

2010, 16, 677−683.

(55) Bruhn, T.; Schaumlöffel, A.; Hemberger, Y.; Bringmann, G.

SpecDis: Quantifying the Comparison of Calculated and Exper-

imental Electronic Circular Dichroism Spectra. Chirality 2013, 25,

243−249.

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Synthesis and Configurational Assignment of Vinyl Sulfoximines and Sulfonimidamides

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