Structural, Mechanistic, Spectroscopic, and Preparative Studies on the Lewis Base Catalyzed, Enantioselective Sulfenofunctionalization of Alkenes

Structural, Mechanistic, Spectroscopic, and Preparative Studies on the

Lewis Base Catalyzed, Enantioselective Sulfenofunctionalization of

Alkenes

Eduard Hartmann and Scott E. Denmark*

Department of Chemistry, University of Illinois, 600 S. Mathews Ave. Urbana, IL, 61801

e-mail: sdenmark@illinois.edu

Dedication ((optional))

The full details of mechanistic investigation on enantioselective sulfenofunctionalization of alkenes

under Lewis base catalysis are described. Solution spectroscopic identification of the catalytically

active sulfenylating agent has been accomplished along with the spectroscopic identification of

putative thiiranium ion intermediates generated in the enantiodetermining step. The structural

insights gleaned from these studies informed the design of new catalyst architectures to improve

enantioselectivity. In addition, structural modification of the sulfenylating agents had a significant

and salutary effect on the enantioselectivity of sulfenofunctionalization which was demonstrated to

be general for trans disubstituted alkenes. Whereas electronic modulation had little effect on the

rate and selectivity, steric bulk on arylsulfenylphthalimides was very beneficial.

Keywords: sulfenofunctionalization, thiiranium ions, Lewis base catalysis, selenophosphoramides,

sulfenylating agents

Introduction

The importance of organosulfur compounds^[i,ii]manifests itself in the myriad of constructive and

functional manipulations involving these as building blocks as well as in the abundance of sulfur-

containing natural products.^{[iii ]}Among a variety of methods for the introduction of sulfur groups, the

vicinal sulfenofunctionalization of alkenes represents a powerful approach. In this context, the role of

thiiranium ions as versatile reactive intermediates has been extensively studied since the 1960's^[iv]

and a practical method for their generation is the addition of electrophilic sulfur(II)^[v]reagents to

alkenes (Scheme 1). Subsequent invertive capture with nucleophiles affords 1,2-difunctionalized

products with defined relative configuration of the introduced functionalities. The applicability of this

reaction has been demonstrated with a variety of sulfenylating agents and nucleophiles. ^[ii]However,

despite the sound understanding of the mechanism, catalytic asymmetric sulfenofunctionalizations

have remained largely under-developed.

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10.1002/hlca.201700158

Only recently have catalytic, enantioselective sulfenylations of activated alkenes derived from

aldehydes,^[vi]ketones,^[vii]and amides^[viii]been reported. In addition, the catalytic, enantioselective

sulfenoetherification of unactivated alkenes under chiral Brønsted acid catalysis has been described,

albeit with moderate enantioselectivities.^[ix]The necessity for generating enantioenriched thiiranium

ions has been elegantly circumvented by asymmetric desymmetrization of meso-thiiranium ions,

wherein ring-opening by a nucleophile is the stereodetermining step.^[x,xi]Notwithstanding this

progress, there remains a dearth of methods that control the absolute stereochemical outcome of

1,2-sulfenofunctionalizations, and this pertains especially to isolated alkenes.

Scheme 1. Sulfenofunctionalization of unactivated alkenes.

The difficulties in developing catalytic enantioselective processes originate, inter alia, from the

inherent high reactivity of electrophilic sulfur reagents, which may account for a pronounced,

racemic background reaction. In addition, even if the background reaction can be suppressed and the

thiiranium ions can be generated enantioselectively in the first place, several mechanisms can erode

the configurational integrity of this intermediate before the attack of a nucleophile at the carbon

atom (Scheme 2). One plausible pathway for racemization leads through an open carbocation

intermediate resulting in configurational instability of the thiiranium ion (Scheme 2a).^{[ xii ]}

Furthermore, the Lewis acidic sulfur center itself can be attacked by the nucleophile, thus liberating

an achiral sulfenyl transfer reagent that decreases the enantiomeric purity of thiiranium ions upon

redelivering the sulfenyl cation to an alkene (Scheme 2b).^[xiii]Finally, racemization via "olefin-to-

olefin" transfer cannot be excluded at all, although detailed mechanistic studies revealed that for

thiiranium ions this transfer proceeds only at ambient temperature (Scheme 2c).^[xiv]

Scheme 2. Racemization mechanisms of thiiranium ions.

As

a consequence, for many years only two examples of direct enantioselective

sulfenofunctionalizations were known, both employing chiral reagents in stoichiometric amounts.

Rayner and coworkers synthesized a number of camphoric acid-derived, enantiomerically enriched

thiosulfonium salts.^[xv]Their application in the sulfenocyclization reactions, however, afforded the

corresponding products with poor enantioselectivity (Scheme 3a). The second, more successful

example, was reported by Pasquato and coworkers using

a binaphthyl-derived reagent

(Scheme 3b).^{[ xvi ]}Under optimized conditions the enantioselective sulfenylation followed by

nucleophilic capture of the thiiranium ion furnished the sulfenofunctionalized product with an

appreciable enantiomeric purity of 88% ee. If substoichiometric amounts of the chiral sulfenylating

reagent were used at elevated temperature (–20 °C) a significant erosion of the enantiomeric

composition was observed. Obviously, one of the above mentioned racemization mechanisms

becomes prevalent under these conditions preventing the elaboration of a catalytic protocol.

Scheme 3. Reagent controlled enantioselective sulfenofunctionalization.

Background

As part of the ongoing program to apply the concept of Lewis base activation of Lewis acids^[xvii,xviii]to

reactions of main group elements, we envisioned the possibility of generating reactive, ionic

sulfenylating species from weakly electrophilic sulfur(II) sources (Scheme 4). On the one hand, this

approach would allow for the utilization of sulfur reagents with attenuated reactivity and thus,

reduced tendency for an uncatalyzed background reaction. On the other hand, the transfer of the

sulfenium ion to the alkene double bond could be rendered enantioselective by the judicious choice

of a chiral Lewis base catalyst. If reaction conditions can be optimized such that the aforementioned

racemization pathways for the enantiomerically enriched thiiranium are suppressed, a catalytic,

enantioselective process is feasible.

Scheme 4. Lewis base catalyzed sulfenofunctionalization of unactivated alkenes.

At the outset, the general feasibility of a Lewis base catalyzed chalcogenofunctionalization of

unactivated alkenes was examined. Previous investigations systematically investigated the stability of

seleniranium^{[ xix , xx ]}and thiiranium ions^{[xiv, xxi ]}to establish boundary conditions for catalytic,

enantioselective chalcogenofunctionalizations. On the basis of these examinations the first

enantioselective sulfenoetherification was realized using a selenophosphoramide catalyst and a

phthalimide derivative as the sulfenylating reagent (upper, Scheme 5).^[xxii]Moreover, a Brønsted acid

is required as a co-activator for the otherwise unreactive sulfenylating agents, and its specific

function has been examined in a recent study from these laboratories.^[xxiii]Under the optimized

reaction conditions representative olefins are converted into the corresponding tetrahydropyrans

with good to excellent site selectivities and high enantioselectivities. By changing the substitution

pattern of the olefins, the constitutional isomers (i.e. tetrahydropyrans) are accessible albeit with

decreased enantioselectivities. Preliminary attempts of capturing the thiiranium ions

intermolecularly with an external nucleophile is also possible.

Scheme 5. Lewis base catalyzed enantioselective sulfenofunctionalization.

The generality of this catalytic system has been demonstrated using various nucleophiles. In

addition to the use of hydroxyl groups in sulfenoetherification reactions^[xxii], electron-rich arenes

have been deployed in carbosulfenylation of olefins affording trans-tetrahydronaphthalenes with

complete diastereospecificity and high enantiomeric ratios (middle, Scheme 5).^[xxiv]The protocol has

been applied to tosyl-protected amines that can be engaged in sulfenoamination reactions yielding

enantioenriched nitrogen heterocycles (lower, Scheme 5).^[xxv]More recently, the process has been

extended to include sulfenocyclization reactions involving both phenols^[xxvi]and anilines^[xxvii]with

great success. The catalytic, enantioselective sulfenylation of ketone-derived enoxysilanes has also

been demonstrated (not shown).^[xxviii]

A catalytic cycle has been proposed on the basis of spectroscopic observations and kinetic

studies (Scheme 6).^[xxi,xxix]The cycle commences with the sulfenylation of Lewis base mediated by

MsOH to generate the catalytically active species which is the resting state of the catalyst with a

diagnostic ³¹P NMR chemical shift at δ = 59.9 ppm. Subsequently, in the turnover-limiting and

stereodetermining step, the arylsulfenyl group is transferred to the alkene forming the

enantiomerically enriched thiiranium ion. Its stereospecific capture by an internal or external

nucleophile delivers the sulfenofunctionalized product and regenerates the catalyst.

Scheme 6. Proposed catalytic cycle.

Results from the kinetic study suggest that the catalytically active species is the sulfenylated

catalyst [(R₂N)₃P=Se–SPh]⁺X^–generated upon the MsOH mediated reaction of

N-phenylsulfenylphthalimide with the Lewis base.^[xxix]Its existence is supported by ³¹P NMR

spectroscopy, in which the diagnostic signal for selenophosphoramide (80–90 ppm, depending on

the catalyst structure) disappears and a new resonance at around 60 ppm is observed. This value is in

accord with previously reported and structurally related compounds of the type [(R₂N)₃P=Se–YAr]⁺X^–.

[xix,xxiv,xxx]

The proposed active species is assumed to transfer the sulfenium ion to an alkene thus

forming a thiiranium ion. Since this event most likely constitutes the enantiodetermining step,

detailed knowledge about the geometries of the active species structure could help understanding

the trajectory of the alkene approach and thus the origin of enantioselectivity. A preliminary

stereochemical model has been proposed by positing that the PhS-Se moiety of the catalytically

active species is oriented toward the binaphthyl backbone.^[xxivb]Thus, the approaching alkene faces

steric interaction with one of the naphthyl subunits resulting in the discrimination of the

enantiotopic faces of the alkene. This assumption is supported by DFT calculations,^[xxix]however, no

experimental evidence had been provided until this point. To obtain a quantitative insight into the 3-

dimensional structure of species [(R₂N)₃P=Se–SPh]⁺X^–, its isolation and crystallographic

characterization was planned.

Initially, the focus was on the identification of suitable conditions for generating the active

species [(R₂N)₃P=Se–SPh]⁺X^–without any byproducts that would disrupt the crystallization process.

The first approach relied on the reaction of a selenophosphoramide Lewis base with

[PhS(SMe₂)]SbCl₆^[xxxi]which had been used as a transfer agent of the S-phenyl group to alkenes. As it

turned out, this reagent was also competent in transferring the sulfenyl moiety to the catalyst

forming the active species along with SMe₂as the sole byproduct (equation 1). The formation of the

active species was confirmed by the appearance of a diagnostic signal at 60.4 ppm in the ³¹P NMR

spectrum.^[xxix]Unfortunately, during the crystallization attempts, a disproportionation reaction

occurred reducing the sulfenyl group to PhS–SPh while oxidizing the selenophosphoramide to the

dicationic dimer [(R₂N)₃P=Se–Se=P(NR₂)₃]²⁺2SbCl₆(equation 2). An X-ray crystal structure^[xxix]of this

–

species could be obtained providing a first glimpse into how the groups in the actual active agent

might be oriented. However, the key objective was to crystallize a species that resembles the actual

catalytically active sulfenylating agent as closely as possible. Therefore, further modification and

optimization was required.

Project Goals

Despite the positive developments, further improvement of the catalyst performance of the Lewis

base catalyzed sulfenofunctionalization is desirable for some of the substrates. For instance, efficient

discrimination between enantiotopic faces of terminal, 1,1-disubstituted and trisubstituted double

bonds still remains a challenge. Beyond an empirical attempt to solve this problem, the in-depth

understanding of processes occurring during the sulfenofunctionalization as well as detailed

knowledge about the structure of the active sulfenylating agent can contribute substantially to the

rational design of a more potent catalytic system. Given the thiiranium ion as the common

intermediate, a more enantioselective preparation thereof would be beneficial to all conceivable

substrate classes of this transformation. Therefore, the project goals encompassed:

•

crystallographic characterization of the catalytically active species of the Lewis base

catalyzed sulfenofunctionalization

•

rationalization of the stereochemical outcome of the reaction in order to advance and

further generalize the methodology, and to enable the rational design of a more selective

catalyst

•

synthesis of new Lewis base catalysts (in an empirical approach) and their evaluation in the

sulfenofunctionalization reaction

exploitation of the gained knowledge for the general improvement of the catalytic system

Results

1. Investigations Toward the Isolation of the Catalytically Active Species. The possibility to isolate the

catalytically active species through the reaction of a Lewis base and [PhS(SMe₂)]SbCl₆was initially

investigated. To avoid the disproportionation reaction caused by the lability of the Se–SPh bond

when using a selenophosphoramide^[xxix]the donor atom of the catalyst was replaced by a sulfur atom.

Thiophosphoramides are comparably efficient and selective catalysts in sulfenoetherification

reactions^[xxi]and it is expected that disproportionation of the S–SPh bond in the active species would

become thermodynamically less favorable in comparison to the selenophosphoramide analogue.

However, when a thiophosphoramide Lewis base was combined with [PhS(SMe₂)]SbCl₆, an

equilibrium between the reactants was established (Scheme 7). This equilibrium was evidenced by

the ³¹P NMR chemical shift which, depending on the stoichiometry of the reactants employed,

ranged between the ³¹P NMR chemical shift of the catalyst and the active species. When equimolar

amounts of catalyst (±)-1a and [PhS(SMe₂)]SbCl₆were used, a rather broad signal at 65.9 ppm in

³¹P NMR spectrum was observed. Employing an excess of the sulfenylating agent shifted the ³¹P NMR

–

signal to 69.5 ppm (sharp signal) indicating the saturation of (±)-1a as (±)-2aa⁺SbCl₆. In contrast,

when an excess of catalyst (±)-1a was used, the ³¹P NMR signal of the equilibrium (78.6 ppm) was

shifted toward the ³¹P NMR signal of (±)-1a.

)

–

Scheme 7. Equilibrium between catalyst (±)-1a and active species (±)-2aa⁺SbCl₆

.

Besides the complication arising from reversibility, solubility was a serious problem limiting the

type of solvents that could be used for crystallization. At this point it was decided to change the

strategy and move away from the use of [PhS(SMe₂)]SbCl₆. In order to counteract the reversible

formation of the active species, thiophosphoramide (±)-1a was reacted with PhSCl and NaBArF₂₄

furnishing (±)-2aa⁺BArF₂₄as a pale yellow, air stable solid (Scheme 8). This approach not only

–

enabled the irreversible generation of the active species (±)-2aa⁺, but also allowed for the

–

introduction of the weakly coordinating BArF₂₄counteranion,^[xxxii]which greatly improved the

solubility properties of complex (±)-2aa⁺BArF₂₄^–. Also in this case, formation of (±)-2aa⁺was initially

confirmed by the ³¹P NMR chemical shift (65.8 ppm).

Ultimately, crystals suitable for X-ray analysis were obtained by slow evaporation of a saturated

solution of (±)-2aa⁺BArF₂₄^–in dichloromethane.^[xxix]The molecular structure was confirmed by the X-

ray crystal structure analysis of (±)-2aa⁺(Scheme 8, (S)-enantiomer shown).^[xxxiii]Several features of

this structure are noteworthy. First, the diisopropylamino group is rotated such that the C(32)-N(3)

bond occupies a nearly antiperiplanar orientation to the S(1)-P(1) bond while the C(29)-N(3) bond is

synperiplanar to this. Torsion angles of 169.1 ° for S(1)-P(1)-N(3)-C(32) and –15.0 ° for S(1)-P(1)-N(3)-

C(29), respectively, define this arrangement. The sum of the angles about the N(3) atom is >359.8 °

indicating near perfect planarity. This alignment is most likely a consequence of a generalized

stereoelectronic effect in which the N(3) nonbonding electron pair is delocalized into the P(1)-N(1)

and P(1)-N(2) σ* orbitals. Such stereoelectronic effects have been previously observed in similar

structures.^[xxxiv,xxxv]

To avoid destabilizing steric interactions with the diisopropylamino group, the S–SPh subunit is

oriented back toward the binaphthyl backbone as is evidenced by a 175.1° torsion angle of the N(3)-

P(1)-S(1)-S(2) subunit. With a torsion of 96.0° of the P(1)-S(1)-S(2)-C(1) moiety, the P(1)-S(1) vector is

almost perpendicular to the plane defined by the S(1)-S(2)-C(1) atoms. On the basis of the X-ray

crystal structures of neutral 10-S-3 compounds^{[xxxvi,xxxvii]}and by analogy to the well known 10-Se-3 T-

shaped charge transfer complexes^[xxx]the active sulfenylating agent was anticipated to be a bent ion

pair complex (8-S-2) which is now verified crystallographically by the S(1)-S(2)-C(1) angle of 104.1°.

The S(1)-S(2) bond (2.06 Å) is in the range of a sulfur–sulfur single bond length observed in

disulfides.^[xxxviii]The P(1)-S(1) bond (2.10 Å) of the active species is significantly lengthened compared

to the 1.95 Å found for the P=S double bond in (Me₂N)₃P=S^[xxxix]and is closer to a typical P–S single

bond.^[xl]

BArF₂₄

Me

SPh

PhSCl (1.0 equiv)

NaBArF₂₄(1.0 equiv)

N

S

P

Ni-Pr₂

CH₂Cl₂

rt

90%

Ni-Pr₂

N

Me

–

( )-1a

( )-2aa⁺BArF₂₄

³¹P NMR: 65.8 ppm

(X-ray crystal structure)

Scheme 8. Synthesis of the catalytically active species (±)-2aa⁺and its X-ray crystal structure. (Hydrogens and BArF₂₄^–counteranion omitted for clarity).

With a viable protocol for the irreversible generation of the catalytically active species from

catalyst (±)-1a and PhSCl, the next objective was to determine if a similar species could be generated

from the sterically demanding (2,6-diisopropylphenyl)sulfenyl chloride. As was the case previously

(Scheme 8), the reaction of (±)-1a and (2,6-diisopropylphenyl)sulfenyl chloride yielded the active

–

species (±)-2ab⁺BArF₂₄as a pale yellow solid (upper, Scheme 9). The formation of (±)-2ab⁺was

evident from the ³¹P NMR chemical shift of 67.9 ppm. In addition, the reaction of a

selenophosphoramide with the sterically demanding sulfenyl chloride was examined to furnish the

–

corresponding active species 2bb⁺BArF₂₄as a shiny yellow solid with a ³¹P NMR chemical shift of

61.3 ppm (upper, Scheme 9). Finally, an achiral version of the active species was accessed by reaction

of HMPA(S) (1c) and PhSCl (lower, Scheme 9). All of the active species were surprisingly stable to air

and moisture.

i-Pr

ClS

BArF₂₄

i-Pr

(1.0 equiv)

NaBArF₂₄(1.0 equiv)

i-Pr

Me

N

X

S

N

P

X

i-Pr

Ni-Pr₂

CH₂Cl₂

rt

P

N

Ni-Pr₂

N

Me

( )-1a (X = S)

87 % (X = S)

95% (X = Se)

( )-2ab⁺BArF₂₄^–(X = S): ³¹P NMR: 67.9 ppm

(R)-2bb⁺BArF₂₄^–(X = Se): ³¹P NMR: 61.3 ppm

(R)-1b (X = Se)

BArF₂₄

SPh

PhSCl (1.0 equiv)

NaBArF₂₄(1.0 equiv)

S

P

S

P

NMe₂

Me₂N

NMe₂

CH₂Cl₂

rt

Me₂N

90%

2ca⁺BArF₂₄

–

1c

³¹P NMR: 63.9 ppm

Scheme 9. Preparation of various catalytically actives species.

2. Reaction of the Catalytically Active Species with Alkenes. The kinetic competency of the

putative catalytically active species (±)-2aa⁺BArF₂₄to sulfenylate alkene double bonds was

–

demonstrated in a stoichiometric reaction with substrate 3a to afford thioetherification product (±)-

4aa (Scheme 10). The reaction did not proceed to full conversion, most likely because, over time, the

H⁺BArF₂₄generated effects a protonation of the nucleophilic OH group of the remaining substrate

–

thus inhibiting product formation. However, more importantly, this control experiment substantiates

the role of (±)-2aa⁺as the active sulfenylating species.

H

Ph

O

BArF₂₄

Me

SPh

N

Ph

O

S

3a

P

Ni-Pr₂

CDCl₃, rt

17 h

90% conv.

N

PhS

Me

( )-4aa

–

( )-2aa⁺BArF₂₄

Scheme 10. Reaction of catalytically actives species (±)-2aa⁺BArF₂₄^–with alkene 3a.

Given the accessibility of the catalytically active species, investigations on the fate of the Lewis

base catalyst after transfer of the sulfenium ion to the alkene were carried out next. It has been

proposed that the Lewis base remains coordinated to the thiiranium ion because in intermolecular

sulfenofunctionalizations the site selectivity of the nucleophilic attack at the thiiranium intermediate

is dependent on the catalyst. In the past, the existence of episulfuranes, i.e. three membered rings

with a tetracoordinate sulfur atom, was a matter of debate.^[xli,xlii]In general, these reactive species

occur only as transient/labile intermediates so that their existence is difficult to prove

experimentally. It would be of interest to gain more insight into the nature of the interaction

between Lewis base and thiiranium ion to enable the design of more efficient and selective catalysts.

The challenge is to identify whether reactants, catalysts, and conditions can be adjusted such that

Lewis base/thiiranium ion adducts can be observed by NMR spectroscopy or can even be isolated.

Preliminary investigations into the role of the Lewis base in stabilizing the thiiranium ion

involved the combination of (±)-2aa⁺BArF₂₄^–and (E)-4-octene (3b) in the absence of a nucleophile at

room temperature. This experiment resulted in the formation of two new species that were initially

–

assigned as diastereomeric, Lewis base-coordinated thiiranium ions 5ab⁺BArF₂₄^–and epi-5ab⁺BArF₂₄

(right, Scheme 11). The ratio of these two species (85:15) reflects the enantiomeric ratio that would

be obtained with enantiomerically enriched thiiranium ions upon capture with MeOH. Indeed,

–

nucleophilic capture of 5ab⁺BArF₂₄and epi-5ab⁺BArF₂₄with MeOH resulted in the exclusive

formation of the anti-configured product (in racemic form), which further supports the existence of

the suggested intermediates.

However, an alternative interpretation, that the observed intermediates represent structures

–

6ab⁺BArF₂₄and epi-6ab⁺BArF₂₄(left, Scheme 11) cannot be rigorously excluded. This kind of

intermediate results from the nucleophilic opening of the thiiranium ions by the Lewis base

itself.^[xlid,e,g]Since nucleophilic capture with MeOH produces exclusively anti-configured (±)-4ba,

–

intermediates 6ab⁺BArF₂₄^–and epi-6ab⁺BArF₂₄would have to be unreactive and in equilibrium with

–

5a⁺BArF₂₄and epi-5ab⁺BArF₂₄^–. Otherwise, direct nucleophilic displacement at 6ab⁺BArF₂₄and epi-

6ab⁺BArF₂₄^–would yield syn-(±)-4ba, which is not observed.

Furthermore, the presence of multiple signals in the ³¹P NMR spectrum could be a result of the

stereogenicity at the sulfur atom. Taking the lone pair into account, the geometry at sulfur in these

intermediates would be either trigonal bipyramidal^[xlid,f]or square pyramidal^[xlid](lower, Scheme 11).

However, it is unlikely that these rapidly interconverting species would be distinguishable at room

temperature by ³¹P NMR spectroscopy.

BArF₂₄

Me

nPr

3b

SPh

N

S

(excess)

P

Ni-Pr₂

CDCl₃

rt

Me

( )-2aa⁺BArF₂₄

³¹P NMR: 65.8 ppm

–

+ enantiomers

BArF₂₄

(R)-LB

BArF₂₄

(R)-LB

BArF₂₄

SPh

(R)-LB

Ph

???

S

+

nPr

SPh

6ab⁺BArF₂₄

epi-6ab⁺BArF₂₄

–

5ab⁺BArF₂₄

epi-5ab⁺BArF₂₄

–

85

:

15

³¹P NMR: 65.9 ppm

³¹P NMR: 67.8 ppm

MeOH

MeOH (6.0 equiv)

rt, 12 h, 70%

OMe

observed

not observed

SPh

syn-( )-4ba

SPh

anti-( )-4ba

BArF₂₄

nPr

Ph

nPr

S

nPr

Ph

(R)-LB

Ph

S

nPr

Ph

(R)-LB

nPr

trigonal bipyramidal

square pyramidal

Scheme 11. Reaction of the catalytically active species (±)-2aa⁺BArF₂₄^–with (E)-4-octene (3b) in the absence of a nucleophile.

Thus, neglecting stereogenicity at sulfur, the two observed ³¹P NMR signals represent

diastereomeric intermediates arising from the use of a chiral Lewis base. Consequently, the same

experiments with an achiral Lewis base should result in the formation of enantiomeric Lewis base-

coordinated thiiranium ions and thus, only one ³¹P NMR signal should be observable. Accordingly, the

achiral, catalytically active species 2ca⁺BArF₂₄was employed in analogy to the previous reaction

–

with (E)-4-octene (3b) (upper, Scheme 12). As predicted, only one ³¹P NMR signal was observed in

this experiment at 66.1 ppm. Similarly, the reaction with cyclohexene resulted in the formation of

only one intermediate that was captured with various nucleophiles to yield sulfenofunctionalized

products with anti relative configuration (lower, Scheme 12). It is noteworthy that species 5cc⁺

–

BArF₂₄does not posses overall C_Ssymmetry as might be expected from a meso-thiiranium ion. The

¹H NMR spectrum clearly indicates the existence of an unsymmetrical intermediate. This observation

is consistent with a Lewis base complexed thiiranium ion as neither of the four coordinate sulfur

species possesses C_Ssymmetry. However, a species of the type 6cc⁺BArF₂₄^–cannot be unambiguously

excluded.

Scheme 12. Reaction of the achiral, catalytically active 2ca⁺BArF₂₄^–with (E)-4-octene (3b) and cyclohexene.

At this point, no direct experimental evidence to either confirm or rule out one of the

conceivable intermediates could be provided. The most unambiguous proof would be an X-ray crystal

structure. Interestingly, the observed intermediates are rather stable to air and moisture and even

the nucleophilic capture is slow. In preliminary studies to obtain a suitable crystal of a stable

intermediate, 1,4-dihydronaphthalene (3d) was investigated as the alkene (Scheme 13). Control

experiments demonstrated the exclusive formation of the anti β-methoxy sulfide product 3da after

nucleophilic capture of the putative episulfurane with MeOH. Unfortunately, crystallization attempts

were unsuccessful.

Scheme 13. Reaction of the achiral, catalytically active 2ca⁺BArF₂₄^–with 1,4-dihydronaphthalene (3d) and crystallization attempts.

Interestingly, during the investigation into the use of new sulfenylating agents (vide infra), it was

found that in the catalytic, intermolecular sulfenoetherification of a terminal alkene (1-octene (3e)),

two phosphorus-containing species were present throughout the reaction. The major species

observed at –20 °C has a chemical shift of 65.8 ppm, whereas the minor species has a chemical shift

of 61.8 ppm in ³¹P NMR spectrum. This interesting observation was investigated in greater detail

(Scheme 14). To this end, catalyst (R)-1b was combined with 1.0 equiv of sulfenylating agent 7b and

5.0 equiv of MsOH to form the active species (R)-2bb⁺MsO^–with a ³¹P NMR chemical shift of 61.8

ppm. Subsequently, 1-octene (3e) was added at –20 °C and the reaction was monitored by ³¹P NMR

spectroscopy over a period of 12 h. During that time period, (R)-2bb⁺MsO^–(61.8 ppm) disappeared

slowly and a new species at 65.8 ppm, potentially (R)-5be⁺MsO^–, grew in. Eventually, this species was

treated with an excess of MeOH at room temperature to afford a 4:1 mixture of 4eb and 4eb'. The

enantiomeric excess for compound 4eb was determined to be 99:1. The constitutional site selectivity

as well as the enantioselectivity perfectly matches the results obtained from the catalytic

sulfenoetherification process (vide infra, Table 2). These experiments provide additional support for

the involvement of a Lewis base bound thiiranium ion intermediate.

iPr

O

N

S

iPr

O

7b

(1.0 equiv)

i-Pr

Me

Se

N

MsOH (5.0 equiv)

S

i-Pr

N

Se

P

Ni-Pr₂

P

OMs

N

CDCl₃, – 20 °C

Ni-Pr₂

Me

(R)-1b

(R)-2bb⁺MsO^–

³¹P NMR: 61.8 ppm

nHex

3e

(0.95 equiv)

CDCl₃, – 20 °C

i-Pr

OMe

nHex

OMs

iPr

MeOH

Me

i-Pr

S

iPr

(excess)

N

Se

S

iPr

nHex

+

nHex

S

P

rt

Ni-Pr₂

71%

iPr

OMe

Me

:

4

1

(R)-5be⁺MsO^–

³¹P NMR: 65.8 ppm

tentative assignment

4eb

4eb'

e.r. = 99:1

Scheme 14. Stoichiometric generation of active species (R)-2bb⁺MsO^–and its reaction with 1-octene (3e)

Because putative intermediate (R)-5be⁺MsO^–was stable toward moisture and air, it was decided

to generate this intermediate from the isolated active species (R)-2bb⁺BArF₂₄^–(prepared as shown in

–

Scheme 9) to avoid the presence of MsOH and phthalimide. Thus, (R)-2bb⁺BArF₂₄was combined

with an excess of 3e to form (R)-5be⁺BArF₂₄^–as indicated by the ³¹P NMR chemical shift of 65.5 ppm

(Scheme 15). After removal of excess alkene and CH₂Cl₂, intermediate (R)-5be⁺BArF₂₄^–was obtained

as a yellow solid that was stable to air and moisture. From an analysis of the ¹H NMR spectrum of the

intermediate, the relevant signals that belong to the episulfurane intermediate can be identified at

2.71 ppm (methine proton), 2.19 ppm and 1.65 ppm (diastereotopic methylene protons). However,

from the coupling pattern and the coupling constants it is difficult to unambiguously assign whether

these signals correspond to the proposed structure (R)-5be⁺BArF₂₄^–or rather the Lewis base-opened

structure (R)-6be⁺BArF₂₄^–(lower, Scheme 15). Attempts to crystallize the species were unsuccessful.

BArF₂₄

nHex

i-Pr

Me

i-Pr

3e

Me

(3.0 equiv)

S

i-Pr

N

S

Se

N

Se

P

nHex

P

CH₂Cl₂, rt

Ni-Pr₂

(then removed excess

alkene under high vac)

96% (yellow solid)

Me

–

(R)-2bb⁺BArF₂₄

³¹P NMR: 61.3 ppm

(R)-5be⁺BArF₂₄

³¹P NMR: 65.5 ppm

tentative assignment

BArF₂₄

iPr

Me

iPr

S

Me

Se

N

H

P

H

¹H NMR: 2.71 ppm (pentet)

N

H

Ni-Pr₂

Me

¹H NMR: 2.19 ppm and 1.65 ppm (multiplet)

–

(R)-6be⁺BArF₂₄

tentative assignment

Scheme 15. Stoichiometric reaction of (R)-5be⁺BArF₂₄^–and 1-octene (3e).

3. Synthesis and Evaluation of New Lewis Base Catalysts. According to the proposed model for the stereochemical outcome of the

sulfenofunctionalization,^[xxivb]modification of the binaphthyl backbone was expected to have an impact on the stereochemical outcome.

This assumption was corroborated by the insights gained from the X-ray crystal structure of (±)-2aa⁺implicating a role for the biaryl

backbone in the interaction with the approaching alkene during the stereodetermining thiiranium ion ring formation. Consequently, a

Lewis base catalyst with substituents in the 6,6'-position of the binaphthyl backbone was synthesized first (Scheme 16). The synthesis

involved site selective bromination of the enantiomerically enriched dicarbamate (S)-8 followed by a Suzuki coupling to yield the 6,6'-

biphenyl-substituted dicarbamate (S)-9. After reduction of (S)-9 to the N,N-dimethylated diamine (S)-10 using LiAlH₄, catalyst (S)-1d was

obtained by deprotonation of (S)-10 with n-BuLi and reaction with (diisopropylamino)phosphorus dichloride followed by oxidation of the

P(III)-intermediate with elemental selenium.

In addition to 6,6'-substitution, the introduction of substituents in the 3,3'-position was also investigated to achieve higher

enantioselectivities. However, concomitant with the increase of steric demand a decrease in reaction rate has to be expected. Therefore,

we decided to conduct the synthesis of the 3,3'-diphenyl-substituted binaphthyl-derived Lewis base first in racemic fashion and evaluate its

general capability in catalyzing sulfenofunctionalizations.

Scheme 16. Synthesis of a 6,6'-diphenyl-substituted binaphthyl-derived Lewis base (S)-1d.

A Pd-catalyzed, directed C–H arylation^[xliii]was the key step for the introduction of phenyl groups

ortho to the acetamido moieties ((±)-11 → (±)-12, upper, Scheme 17). After formation of the

dicarbamate, its reduction using LAH yielded compound (±)-13. This reduction was slower than with

(S)-9 and a higher boiling solvent (1,4-dioxane) was required to drive the reaction to completion. By

analogy to the synthesis of (S)-1d Lewis base catalyst (±)-1e was obtained using the established

procedures.

Scheme 17. Synthesis of a 3,3'-diphenyl-substituted binaphthyl-derived Lewis base (±)-1e.

Further catalyst modification focused on increasing the π-surface area on the chiral backbone to

have a beneficial effect on the enantiotopic face selection at the alkene. Therefore, a bipyrene-

derived Lewis base catalyst was synthesized (Scheme 18). At the outset, reduction of pyrene (14)^[xliv]

was followed by a selective nitration^[xlv]to give compound 15. Rearomatization gave access to 2-

nitropyrene, which was reduced to 2-aminopyrene (16).^[xlii]Subsequently, an oxidative coupling

mediated by MnO₂yielded the desired bipyrenyl diamine.^[xlvi]Since the diamine was not particularly

stable, it was immediately converted to the dicarbamate (±)-17 which was then reduced to (±)-18.

Numerous attempts to resolve racemic (±)-18 by fractional crystallization with various chiral acids

were unsuccessful. Finally, preparative HPLC was exploited for this separation.^[xlvii]The synthesis of

the Lewis base (R)-1f was achieved by analogy to the aforementioned strategy, however, unreacted

starting material (R)-18 (ca. 15%) was always isolated along with catalyst (R)-1f. Attempts to separate

the starting material by column chromatography resulted in decomposition of the catalyst. Also,

recrystallization did not provide satisfactory results. The catalyst/starting material mixture was used

for the test reactions.

Scheme 18. Synthesis of a bipyrene-derived Lewis base catalyst (R)-1f.

With the new Lewis base catalysts now in hand, their performance in sulfeno-functionalization

reactions was tested (Scheme 19). For this purpose the well-investigated sulfenoetherification^[xxii]

was chosen as reference reaction. In addition, sulfenoaminations^[xxv]were examined. The

enantiomerically enriched 6,6'-diphenyl-substituted selenophosphoramide (S)-1d afforded good

results with regard to conversion and enantioselectivity in both reactions. Despite the fact that no

improvement was achieved with this particular catalyst, the high enantioselectivities give reason to

hope for an improvement employing other, more bulky substituents in the 6,6'-position.

Investigations toward 3,3'-substitution on the binaphthyl moiety revealed that reactions in the

presence of catalyst (±)-1e are too slow, even at room temperature, so that the background reaction

would erode any enantioselectivity using the enantiomerically enriched Lewis base. However, other

substituents in this position have yet to be tested. The bipyrene-derived selenophosphoramide (R)-1f

was successfully employed in sulfenofunctionalizations. Using the enantiomerically enriched catalyst

an e.r of 94:6 was obtained in the sulfeno-etherification reaction. Despite the high enantioselectivity

no improvement was achieved and, in the light of the synthetic effort required to access this catalyst,

it would be reasonable to pursue the synthesis of other scaffolds, e.g. phenanthrene-derived

selenophosphoramides.

Scheme 19. Evaluation of new Lewis base catalysts in sulfenofunctionalization reactions.

To reduce the steric bulk at the 3,3'-position, the synthesis of a biphenathrene-based catalyst

was investigated (Scheme 20). This substitution pattern should constitute a more rigid system that

might combine high enantioselectivity with sufficiently high reactivity. The initial approach for the

synthesis of the biphenanthrene backbone encompassed the oxidative coupling of 2-

aminophenathrene (19) using a MnO₂-mediated coupling^[xliv]which resulted in the formation of the

undesired carbazole 20 (first row, Scheme 20).^[xlviii]Next, Ullmann-type coupling reactions were

examined (second and third row, Scheme 20). Unfortunately, these attempts resulted in

debromination or no reaction at all. Finally, an attempted Suzuki-coupling was also unsuccessful

(fourth row, Scheme 20).

The failure to access the biphenanthrenyldiamine backbone from precursors already bearing the nitrogen substituent directed

efforts to the Bucherer reaction as a way to access the desired structure starting from 9-phenanthrol (26) and hydrazine.^[xlix]Although this

]

method is effective for the synthesis of BINAM, with 9-phenanthrol carbazole 20 was obtained (upper, Scheme 21).^[^xliiiSimilarly, starting

from the readily available biphenanthrol and MeNH₂, the N-methylated carbazole was obtained as the major product (lower, Scheme 21).

In view of the effort required for the synthesis of new Lewis base catalysts, at this point it was decided to pursue a different strategy to

increase the enantioselectivity, namely changing the sulfenylating agent.

Scheme 20. Attempted synthesis of a biphenanthrenyldiamine.

Scheme 21. Attempted synthesis of a biphenanthrenyldiamine starting from 9-phenanthrol (26) a biphenanthrol (27), respectively.

4. Synthesis and Evaluation of New Sulfenylating Agents. To date, the most selective catalyst for

the sulfenofunctionalization is the BINAM-derived selenophosphoramide 1b (vide infra, Table 1 and

Table 2). Prior optimization studies identified the importance of a methyl substituent on the internal

nitrogen atoms as well as the isopropyl groups on the external nitrogen.^[l]As described in the

previous section, attempts to further enhance the catalyst performance by modifying the biaryl

backbone have not been successful. An alternative approach to improve the enantioselectivity of the

process would be to change the sulfenylating agent (Scheme 22). Insights gained from the X-ray

–

crystal structure of (±)-2aa⁺BArF₂₄implicate a role for the arylsulfenyl group in interaction with the

approaching alkene during the stereodetermining thiiranium ion ring formation. Thus, it appeared

plausible that electronic and particularly steric properties of the arylsulfenyl group could impact the

stereochemical outcome of the reaction. To test this hypothesis, a variety of electronically and

sterically disparate N-arylsulfenylphthalimides were synthesized and tested.

HO

O

Ph

S

SAryl

S

P

Me

Ph

R

N

R

influence of the sulfenyl group

*

on enantiotopic face discrimination ??

Me

Scheme 22. Influence of the sulfenylating agent on enantioselectivity.

4.1 Synthesis of Thiophenols. At the outset, thiophenols 30b, h, and l were synthesized by adapting a procedure used by Rundel^[li]for

the synthesis of sterically demanding thiophenols. Formation of the Grignard reagent from the corresponding aryl bromide was followed

by capture with elemental sulfur and reduction with LiAlH₄(Scheme 23). Generally, moderate to good yields were obtained using this

protocol. The 2,6-diisopropoxythiophenol (30k) was accessed by ortho-lithiation^[lii]and subsequent capture with elemental sulfur, however,

the reaction did not proceed to full conversion and a mixture of 30k starting compound 31k was isolated. Attempts to separate the two

compounds using chromatography were unsuccessful so that the mixture was used for the synthesis of the corresponding N-

arylsulfenylphthtalimide. All other aryl thiophenols are commercially available.

Mg (1.10 equiv), THF, Δ

then S₈(1.05 equiv)

Br

1.

2.

SH

LAH,

Δ

R

29

30

SH

Et

i-Pr

30h

30b

30l

65%

79%

82%

SH

1.

2.

nBuLi (1.2 equiv)

hexane, Δ

PrO

Oi-Pr

i-

PrO

Oi-Pr

PrO

Oi-Pr

i-

+

S₈(1.0 equiv)

rt to Δ

31

30k

31

Scheme 23. Synthesis of thiophenols.

30%

60 %

4.2 Synthesis of New Sulfenylating Agents. The synthesis of sulfenylating agents was accomplished using a slightly modified

procedure from Reese in which the corresponding thiophenol was combined with bromine and phthalimide (Scheme 24).^[liii]Because

conditions were not optimized for the individual thiophenols, the yields for the respective sulfenylating agent ranged from low (e.g. 18%

for 7n) to high (e.g. 91% for 7c). Despite varying yields, this protocol provided access to the desired products. Only 4-nitrothiophenol was

not compatible with these conditions. Thus, to obtain the desired sulfenylating agent (7j), 4-nitrophenylsulfenyl chloride was combined

with phthalimide in the presence of Et₃N. All of the sulfenylating agents were crystalline solids allowing for their purification by

recrystallization.

Scheme 24. Synthesis of New Sulfenylating Agents

4.3 Evaluation of New Sulfenylating Agents. To test the hypothesis that steric and electronic properties of the arylsulfenyl group

could impact the stereochemical outcome of the reaction, N-arylsulfenylphthalimides 7a–7n were evaluated in the sulfenoetherification of

hydroxyl substituted alkene 3a using selenophosphoramide (R)-1b as the catalyst (Table 1). The enantiomeric composition of the resulting

tetrahydropyrans 4ab–4an were compared against the those obtained for the phenylsulfenyl substituted product 4aa (95.3:4.7 e.r.,

entry 1). Interestingly, almost no electronic effect on enantioselectivity was observed regardless of changes in the electron density of the

phenyl ring (entries 2–4). More striking still was the lack of a significant electronic effect on reaction rate varying by only a factor of 2–3

between 7c (4-methoxy) and 7j (4-nitro).

To evaluate the influence of steric effects, different ortho-substituents were installed into the arylsulfenyl moiety. The presence of

an ortho-methyl group increased the enantioselectivity of the reaction to 97.2:2.8 e.r. for tetrahydropyran 4ae (entry 5). Essentially the

same ratio of enantiomers was obtained for product 4af containing two ortho-methyl substituents (entry 6). Surprisingly, no decrease in

reactivity was encountered with these sulfenylating agents. On the contrary, the rate of formation of product 4af was faster as compared

to that for 4aa and 4ae. Although a number of different, subtle factors could be contributing, this small increase could arise owing the

electron donating effect of the methyl groups. Further increasing the steric bulk around the sulfur atom by incorporating ethyl substituents

again led to a slight enhancement in enantioselectivity (entries 7, 8) Logically, the impact of ortho-isopropyl groups was next investigated

(7i, 7b). Whereas monoisopropyl substituted product 4ai was obtained with somewhat diminished enantiomeric purity (96.3:3.7 e.r.,

entry 9), the sulfenoetherification with 7b bearing two isopropyl groups produced tetrahydropyran 4ab with a remarkably high

enantiomeric ratio of >99:1 at –20 °C (entry 10). In this scenario, the reactivity gain from electron donation is obviously outweighed by the

steric encumbrance leading to a slow conversion at –20 °C. Gratifyingly, at 0 °C the reaction proceeded at a reasonable rate (80% conv.

after 24 h) accompanied by only a marginal erosion of the enantiomeric ratio (entry 11). Even at room temperature a high level of

enantiocontrol was achieved (entry 12). For the sake of completeness, other N-arylsulfenylphthalimides 7k–7n were inspected (entries 13–

]

16), all being inferior to sulfenylating agent 7b.^[^xxix

Table 1. Evaluation of new sulfenylating agents in the sulfenoetherification of 3a.

Entry ^a

e.r. ^b

Sulfenylating agent 7

Product 4

Time [h]

Conversion [%]

1

7a

7c

4aa

4ac

24

93

95.3:4.7

2

3

4

24

51

100

>95

88

95.1:4.9

95.6:4.4

95.7:4.3

7d

4ad

7j

4aj

5

6

7

8

9

7e

7f

4ae

4af

4ag

4ah

4ai

21

42

24

48

>95

100

>95

67

97.2:2.8

97.1:2.9

97.5:2.5

98.0:2.0

96.3:3.7

7g

7h

7i

10

11

12

13

14

15

7b

7k

7l

4ab

4ak

4al

65

24 ^c

12 ^d

24

70

80

99.1:0.9

99.0:1.0

98.0:2.0

94.0:6.0

92.6:7.4

100

80

48

80

7m

4am

21

95

16

7n

4an

48

90

91.8:8.2

^aGeneral reaction conditions: 5 mm NMR tube, 4a (70.0 μmol), 7 (74.0 μmol), MsOH (70.0 μmol), (R)-1b (10 mol%), CDCl₃(0.11 M), –20 °C. Conversion was

determined by assuming that, besides small quantities of the respective tetrahydrofuran (<5%), 3a was converted only to 4a, as no other significant product

was detected by ¹H NMR spectroscopy. ^bDetermined by CSP-SFC analysis. ^cReaction conducted at 0 °C. ^dReaction conducted at room temperature

Apart from the improvement of the enantioselectivity, another intriguing observation was

made, namely the marginal difference in reaction rate when using electronically disparate

sulfenylating agents. Even more surprising is the fact that electron-donating sulfenylating agents

seem to accelerate the reaction. This is counterintuitive because it was hypothesized that electron-

withdrawing groups on the aryl ring increase the electrophilicity of the sulfur atom rendering it even

more reactive toward the nucleophilic attack by the olefin during the rate-determining thiiranium ion

formation. Since this was not the case, it was interesting to obtain more quantitative results so as to

confirm the initial observations. To that end, a kinetic study using NMR spectroscopic analysis with

the new sulfenylating agents was conducted whereby product formation and starting material

consumption was measured against an internal standard.

In the series of para-substituted phenylsulfenyl-derived reagents, the electron rich 4-

methoxyphenyl (7c) was the fastest (t_1/2≈ 4 h), whereas the parent reagent 7a and 4-

trifluoromethylphenyl substituted 7d reacted at comparable rates (t_1/2≈ 9 h, Scheme 25). 4-

Nitrophenyl derivative 7j was not part of the study due to solubility problems of the sulfenylating

agent.

100

80

60

40

20

0

100

80

60

40

20

0

6

12

18

24

30

36

42

48

0

6

12

18

24

30

36

42 48

time (h)

parent

para-MeO

para-CF3

parent

para-MeO

para-CF3

Scheme 25. Comparison of reaction rates of para-substituted phenylsulfenylphthalimides.

Comparing ortho alkyl-substituted arylsulfenyl reagents, the methyl-substituted 7e is slightly faster (t_1/2≈ 6 h) than the parent

sulfenylating agent (Scheme 26). The ethyl-substituted 7g, on the other hand, is slower (t_1/2≈ 12 h), which might be explained by the

increased steric bulk of the substituent. As expected, the isopropyl-substituted reagent 7i led to a significantly decreased reaction rate (t_1/2

≈ 30 h).

100

80

60

40

20

0

100

80

60

40

20

0

6

12 18 24 30 36 42 48

time (h)

0

6

12

18

24

30

36

42

48

time (h)

parent

monoethyl

monomethyl

monoisopropyl

parent

monoethyl

monomethyl

monoisopropyl

Scheme 26. Comparison of reaction rates of ortho-monosubstituted phenylsulfenylphthalimides.

Introduction of a second methyl substituent in the 2-position of the phenyl group (7f) results yet

again in an increase of the reaction rate (t_1/2≈ 3 h, Scheme 27). Also, with a second ethyl group (7h,

t

_1/2≈ 6 h), the reaction rate is enhanced as compared to the parent reagent (7a, t_1/2≈ 9 h) as well as

to the mono ethyl-substituted reagent (t_1/2≈ 12 h, Scheme 27). As expected from previous results,

incorporation of a second isopropyl group leads to a very slow reaction. The apparent non-

dependency of reaction rate on the alkene concentration (indicated by a straight line for 7b,

Scheme 27) suggests a change in the mechanism. Under these conditions, opening of the thiiranium

ion might become rate-determining, which would display 0^thorder kinetics. However, more accurate

measurements are needed to confirm this proposition.

100

80

60

40

20

0

100

80

60

40

20

0

6

12

18

24

30

36

0

6

12

18

24

30

36

time (h)

dimethyl

diethlyl

parent

dimethyl

diethyl

parent

diisopropyl

Scheme 27. Comparison of reaction rates of ortho-disubstituted phenylsulfenylphthalimides.

Because the reaction catalyzed by 7b was so slow at –20 °C, the reaction rates at 0 °C and at 23 ºC (room temperature) were

recorded (Scheme 28. A significant increase in reaction rate was observed at 0 °C (t_1/2≈ 12 h). Changing from 0 °C to 23 ºC, the reaction

rate increased again by a factor of 4 (t_1/2≈ 3 h). As mentioned above, increasing the temperature led to only a marginal erosion of

enantiomeric purity (c.f. Table 1, entries 10–12).

100

80

60

40

20

0

6

12 18 24 30 36 42 48

time (h)

rt

0 °C

–20 °C

Scheme 28. Comparison of reaction rates of 7b at different temperatures.

For the sake of completeness, N-alkylsulfenylphthalimides have also been examined in the course of this study (Scheme 29).

However, these sulfenylating agents afforded generally slower conversion or no reaction at all (as compared to N-

arylsulfenylphthalimides). For instance, methyl-substituted 7o did not proceed to full conversion within 48 h at –20 °C. Isobutyl-substituted

7p and benzyl-substituted 7q did not react at –20 °C at all, and even at room temperature the reaction was relatively slow. Isopropyl

reagent 7r did not react at all, not even at room temperature.

Since the presence of the catalytically active species was confirmed by ³¹P NMR spectroscopy for all of the sulfenylating agents

shown in Scheme 30, it can be ruled out that the formation is problematic. Consequently, the differences in reaction rates probably arise

from a decreased rate of the thiiranium ion formation. Although the lack of reactivity for 7r could be rationalized by bulkiness of the

isopropyl group, the slower reaction of 7o in comparison to 7a (Table 1, entry 1) is difficult to explain by steric effects. Thus, a profound

difference with regard to the electronic distribution/delocalization (on the sulfur) can be expected between arylsulfenyl-derived active

species on the one hand, and alkylsulfenyl-derived active species on the other.

Scheme 29. Reaction of 4a with N-alkylsulfenylphthalimides.

To obtain additional insights into the electronic perturbation in the proximity of the reactive

sulfur center, the ⁷⁷Se NMR chemical shift of the active species was considered as a potential

experimental indicator. Generation of the active species in stoichiometric quantities was achieved

using the conditions shown in Scheme 30 and the ⁷⁷Se NMR chemical shifts were recorded at room

temperature. The 4-MeO-substituted species (±)-2bc⁺displayed the most downfield shifted signal at

591 ppm. On the other hand, the alkyl-derived (±)-2bo⁺and (±)-2bq⁺display the highest upfield shifts

at 437 ppm and 396 ppm, respectively. If the ortho-substituted arylsulfenyl derived active species (±)-

2be ⁺and (±)-2bf ⁺are ignored in this series, a trend can be established, namely that an increased

down field shift of the selenium atom accounts for higher reactivity. However, when (±)-2be ⁺and

(±)-2bf ⁺are considered, there is no obvious correlation between the chemical shift of the active

species and its reactivity. The increased reactivity of (±)-2be ⁺and (±)-2bf ⁺compared to (±)-2ba⁺

might be a result of electron donation (by analogy to (±)-2bc⁺), but it could also arise from a better

accessibility of the sulfur atom in the active species. Assuming that additional substituents in the

ortho-position of the aryl group can push the reactive Se=S–Aryl moiety away from the binaphthyl

backbone and render the reactive sulfur center more accessible, an increase in reaction rate is

conceivable. At this point, it is not possible to rationalize the reaction rate differences by either steric

or electronic effects, most likely it is combination of both.

Me

O

MsO

SR

Se

N

MsOH (10 equiv)

N

P

+

N

SR

Ni-Pr₂

N

CDCl₃

rt

Me

O

( )-2b⁺MsO^–

⁷⁷Se NMR

( )-1b

7

(5.0 equiv)

(1.0 equiv)

Me

OMe

H

CF₃

Me

R =

Me

437 ppm

δ =

591 ppm

620 Hz

472 ppm

606 Hz

455 ppm

588 Hz

440 ppm

608 Hz

437 ppm

594 Hz

396 ppm

J_Se,P

=

619 Hz

596 Hz

( )-2bc⁺MsO^–

( )-2ba⁺MsO^–

( )-2be⁺MsO^–

( )-2bf⁺MsO^–

( )-2bo⁺MsO^–

( )-2bq⁺MsO^–

( )-2bd⁺MsO^–

Scheme 30. Comparison of the ⁷⁷Se NMR chemical shifts of different active species.

4.4 Substrate Scope. The general applicability of sterically demanding N-arylsulfenylimides as

efficient reagents for the highly enantioselective sulfenoetherification of other substrate classes was

next evaluated (Table 2). At first, reaction of 3a was conducted on a preparative scale with 7a, 7b, 7f,

and 7h to confirm the results from the initial survey (entries 1–4). Subsequently, representative

alkenes were subjected to the sulfenoetherification using sulfenylating agent 7b. Because a different

selenophosphoramide had been used in the originally reported conditions,^[21]reactions with the

parent sulfenylating agent 7a and catalyst (R)-1b were run in parallel to provide a valid comparison

with 7b. A significant improvement of enantioselectivity was seen in the reaction of terminal alkene

3g and 7b as compared to 7a (entry 5 vs. 6). Despite the already high enantiopurity of product 4ba

obtained from an intermolecular sulfenoetherification of 4-octene (3b), 7a and MeOH, the

enantiopurity of the corresponding product 4bb was further increased by using 7b (entry 7 vs. 8). The

suitability of a terminal double bond was also showcased in an intermolecular functionalization with

1-octene (3e) and MeOH as the nucleophile (entry 9 vs. 10). Product 4eb was accessed with excellent

enantioselectivity (98.6:1.4), whereas 4ea gave only a moderate selectivity which is in line with

stereochemical outcome previously observed with terminal alkene 4bb. Apart from the

sulfenoetherification, we were able to demonstrate the benefit of 7b in a sulfenoamination

reaction^[xxiii]using alkenyl sulfonamide 3h. Again an enhanced enantioselectivity was noted with 7b

forming product 4hb in 94.3:5.7 e.r. (entry 11 vs. 12).^[xxix]

Table 2. Substrate scope with new sulfenylating agents.

Entr

y

Yield [%]^e

e.r.ⁱ

Alkene 3

Sulfenylating agent 7

Product 4

Temp [°C]

Time [h]

1

3a

7a

7f

4aa ^b

–20

36

78

95.6:4.4^k

2

4af^a

–20

36

84

97.6:2.4^k

3

4

3a

7h

7b

4ah^a

–20

36

48

87^f

98.4:1.6^j,k

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Article Doi

Structural, Mechanistic, Spectroscopic, and Preparative Studies on the Lewis Base Catalyzed, Enantioselective Sulfenofunctionalization of Alkenes

DOI: 10.1002/hlca.201700158

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Article abstract of DOI:10.1002/hlca.201700158

Full text of DOI:10.1002/hlca.201700158

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