Sulphide as a leaving group: Highly stereoselective bromination of alkyl phenyl sulphides

Article abstract of DOI:10.1039/c9sc03560e

A conceptionally novel nucleophilic substitution approach to synthetically important alkyl bromides is presented. Using molecular bromine (Br₂), readily available secondary benzyl and tertiary alkyl phenyl sulphides are converted into the corresponding bromides under exceptionally mild, acid- and base-free reaction conditions. This simple transformation allows the isolation of elimination sensitive benzylic β-bromo carbonyl and nitrile compounds in mostly high yields and purities. Remarkably, protic functionalities such as acids and alcohols are tolerated. Enantioenriched benzylic β-sulphido esters, readily prepared by asymmetric sulpha-Michael addition, produce the corresponding inverted bromides with high stereoselectivities, approaching complete enantiospecificity at -40 °C. Significantly, the reported benzylic β-bromo esters can be stored without racemisation for prolonged periods at -20 °C. Their synthetic potential was demonstrated by the one-pot preparation of γ-azido alcohol (S)-5 in 90% ee. NMR studies revealed an initial formation of a sulphide bromine adduct, which in turn is in equilibrium with a postulated dibromosulphurane intermediate that undergoes C-Br bond formation.

Full text of DOI:10.1039/c9sc03560e

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Sulphide as a leaving group: highly stereoselective
bromination of alkyl phenyl sulphides†
Cite this: DOI: 10.1039/c9sc03560e
Daniele Canestrari,a Caterina Cioffi,a Ilaria Biancofiore,ab Stefano Lancianesi,a
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
a
Lorenza Ghisu,a Manuel Ruether,c John O'Brien,c Mauro F. A. Adamo
*
a
*
and Hasim Ibrahim
A conceptionally novel nucleophilic substitution approach to synthetically important alkyl bromides is
presented. Using molecular bromine (Br2), readily available secondary benzyl and tertiary alkyl phenyl
sulphides are converted into the corresponding bromides under exceptionally mild, acid- and base-free
reaction conditions. This simple transformation allows the isolation of elimination sensitive benzylic b-
bromo carbonyl and nitrile compounds in mostly high yields and purities. Remarkably, protic
functionalities such as acids and alcohols are tolerated. Enantioenriched benzylic b-sulphido esters,
readily prepared by asymmetric sulpha-Michael addition, produce the corresponding inverted bromides
with high stereoselectivities, approaching complete enantiospecificity at ꢀ40 ꢁC. Significantly, the
reported benzylic b-bromo esters can be stored without racemisation for prolonged periods at ꢀ20 ꢁC.
Their synthetic potential was demonstrated by the one-pot preparation of g-azido alcohol (S)-5 in 90%
ee. NMR studies revealed an initial formation of a sulphide bromine adduct, which in turn is in
equilibrium with a postulated dibromosulphurane intermediate that undergoes C–Br bond formation.
Received 18th July 2019
Accepted 7th August 2019
DOI: 10.1039/c9sc03560e
rsc.li/chemical-science
intermediates by added exogenous bromide ions (Finkelstein
reaction).6b,9d
Introduction
The above methods showcase the recent progress made in
the deoxybromination of alkyl alcohols; however, challenges
remain such as alkene side product formation from elimi-
nation sensitive bromides, limited scope and functional
group tolerance, difficulties in removing by-products such as
phosphine oxides, requirement of multiple reagents and
bromide racemisation from optically active alkyl
alcohols.6a,10
We have recently reported a novel nucleophilic chlorination
approach to obtaining alkyl chlorides from readily available
alkyl phenyl sulphides.11 This mild and rapid (dichloroiodo)
benzene (PhICl2) promoted transformation proceeded formally
via a SN2 chloride ion attack on a proposed, oxidatively gener-
ated chlorosulphonium chloride intermediate.
Considering the above-mentioned limitations in the prepa-
ration of alkyl bromides from alcohols, we posed the question
whether sulphides could be used as precursors for alkyl
bromides. Sulphides can be accessed by a number of methods,
especially via thiol addition to widely available and inexpensive
Michael acceptors. However, it was unclear if this was a viable
approach, since Br2 and other Br+ equivalents are weaker oxi-
dising agents than PhICl2 (vide infra).
Alkyl bromides are versatile and extensively utilised synthetic
intermediates, constitute precursors for a wide range of C–C1
and C–heteroatom2 bond forming reactions, and are motifs
found in biologically active natural products.3 Given their
importance, numerous methods have been developed for their
preparation,4 with protocols relying on the nucleophilic
substitution of alkyl alcohols with bromide ions remaining
the most widely applied and studied.5,6 Among them, the use
of phosphorus(V) or phosphorus(III) reagents is particularly
widespread (Scheme 1a).7 Catalytic variants of the phosphor-
us(V) based Appel reaction have been developed recently,8
including a catalytic system for the direct deoxybromination of
alcohols.8b Other innovative modes for catalytic activation of
alkyl alcohols towards bromide ion substitution have recently
emerged;6b,9 however, these protocols proceed through in situ
substitution of catalytically formed alkyl chloride
aCentre for Synthesis and Chemical Biology (CSCB), Department of Chemistry, Royal
College of Surgeons in Ireland, 123 St. Stephen's Green, Dublin 2, Ireland. E-mail:
madamo@rcsi.ie; hasimibrahim@rcsi.ie
bIRBM Science Park S.p.A, Department of Medicinal Chemistry, Via Pontina, 30.600,
00071 Pomezia RM, Italy
Herein, we delineate how the concept of ‘sulphide as leaving
group’ was exploited for the bromination of alkyl phenyl
sulphides using Br2, an inexpensive laboratory commodity
(Scheme 1b). This study culminated in the development of an
cTrinity Biomedical Sciences Institute, School of Chemistry, The University of Dublin,
Trinity College, Dublin 2, Ireland
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic characterization for all new compounds, including details of
NMR experiments and racemisation study. See DOI: 10.1039/c9sc03560e
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intermediates could reductively collapse to form concurrently
alkyl bromides and organosulphenyl bromides has to the best
of our knowledge, not been reported. Herein, we show that, with
the right choice of the substituents on the sulphur, such
a transformation is indeed feasible, and in doing so uncover
that aryl sulphides can be considered a valuable, heretofore
unexplored leaving group for highly stereoselective, non-
neighbouring group assisted, nucleophilic bromination.
Results and discussion
As part of our studies on desulphurative chlorination with
PhICl2, we examined the ability of other electrophilic chlori-
nating reagents, and specically that of elemental chlorine, to
promote chlorination of b-sulphido esters. In a preliminary
experiment, we treated b-sulphido ester 1a with Cl2 gas and
observed a rapid consumption of the starting material within 3
minutes. 1H NMR analysis of the crude material showed the
formation of b-chloro ester 2a as the major product, accompa-
nied by dehydrochlorination-derived methyl cinnamate (3a) in
a ratio of 70 : 30 (Scheme 2). In spite of signicant alkene side-
product formation, this experiment clearly demonstrated that
molecular chlorine could promote desulphurative chlorination.
This reactivity formed the basis for our efforts to examine
elemental bromine in the desulphurative bromination of b-
sulphido esters.
Scheme 1 Nucleophilic bromination of alkyl phenyl sulphides in
context.
In an initial experiment, adding 1.0 equivalent of neat Br2 to
our test substrate b-sulphido ester 1a in dry dichloromethane
and monitoring the progress of the reaction by H NMR spec-
exceptionally mild, chemoselective and highly stereoselective
nucleophilic bromination reaction.
1
The reaction of diorganosulphides with Br2 has been known
for over 100 years to oxidise the sulphur(II) centre;12 however,
conicting reports on the nature of the formed species have
been disclosed. Depending on sulphide substitution, tempera-
ture, methods of generation, isolation and structural analysis
(i.e. in the solid state or in solution),13 it has been suggested that
the reaction could, via an equilibrium, generate tetrahedral
sulphur(II) molecular complexes A (MCs), trigonal pyramidal
sulphur(IV) bromosulphonium bromides B or trigonal bipyra-
midal (TB) sulphur(IV) dibromosulphurane adducts C (Scheme
1c).13,14 NMR spectroscopic studies in support of adducts A and/
or C in solution have been reported.15
In the case of dialkyl substitution, the treatment of bromine
adducts with Lewis acidic metal halides (MXn) was reported to
form bromosulphonium [BrMXn] salts B0 by irreversible
bromide ion complexation.13b,14c,16 These salts have found
widespread application in organic synthesis as, for example,
bromonium ion (Br+) equivalents and/or oxidants.16,17 Dibro-
mosulphuranes C have been proposed as intermediates in
several transformations. For instance, in his seminal work on
organosulphuranes, Martin employed dibromosulphuranes as
intermediates en route to alkoxysulphuranes,18 such as the
versatile Martin sulphurane reagent.19 These reactions proceed
via alkoxide displacement of the apical bromide ligands. In
a related transformation, sulphuranes C were converted into the
corresponding sulphoxides upon treatment with water and
a base (Scheme 1c).20 However, that dibromosulphurane
troscopy showed, within 15 minutes, complete conversion to b-
bromo ester 4a, accompanied by small amounts of
dehydrobromination-derived methyl cinnamate (3a) (Table 1,
entry 1). This experiment clearly indicated that Br2 could not
only promote bromination of sulphide 1a, but also, gratifyingly,
with very little alkene side-product formation. Moreover, this
surprising outcome was even more profound when considering
the large difference in oxidising power between Cl2 and Br2.
To simplify the procedure and ensure accurate addition of
Br2, we repeated this reaction with a 1.0 M solution of Br2 in dry
DCM, which gave complete conversion to the brominated
product in 25 minutes, and signicantly, without the formation
of alkene 3a (entry 2). We were delighted to isolate b-bromo
ester 4a in an excellent yield of 95% aer SiO2 chromatography.
Performing the same reaction in non-puried DCM gave
complete conversion in a shorter reaction time of 15 min but
with small amounts of alkene 3a (entry 3). The reaction pro-
ceeded equally well in toluene or dichloroethane (DCE), albeit
with slightly longer reaction times (entries 4 and 5), whereas
THF as solvent gave a complex mixture (entry 6). A marked
increase in the reaction rate was observed in MeCN; however,
Scheme 2 Reaction of b-sulphido ester 1a with Cl2.
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Table 1 Optimisation of reaction conditions with sulphide 1aa,b
Table 2 Scope for the bromination of phenyl sulphides 1a,b
Entry
Solvent
Temp (ꢁC)
Timec (min)
Ratiod 4a : 3a
1e
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
DCE
rt
rt
rt
rt
rt
rt
rt
0
15
25
15
30
30
90
5
60
180
900
98 : 2
100 : 0 (95)f
98 : 2
g
100 : 0
98 : 2
CM
THF
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
99 : 1 (72)f
100 : 0
100 : 0
100 : 0
ꢀ20
10
ꢀ40
a
Conditions: 1a (0.5 mmol), Br2 (0.5 mmol) as 1.0 M solution in
reaction solvent, and dry solvent (3.0 mL, 0.17 M); all reactions
b
proceeded to complete conversion ($98%). Styrene (0.65 mmol, 1.3
c
equiv.) was added to quench the reaction. Reaction progress was
monitored by 1H NMR spectroscopy using a stock solution of styrene
d
in CDCl3 (0.03 M). Determined by 1H NMR spectroscopy of the
e
f
crude material. Neat Br2 (0.5 mmol) used. Isolated yield aer SiO2
chromatography. g Non-puried CH2Cl2. CM ¼ complex mixture.
workup and purication gave bromo ester 4a in a lower yield of
72% (entry 7).
Conducting the reaction in DCM at lower temperatures
resulted in longer reaction times but gave clean conversions to
bromide 4a, with the reaction at ꢀ40 ꢁC requiring 15 hours for
completion (entries 8–10). This is in stark contrast to desul-
phurative chlorination with PhICl2, which showed an increase
in alkene side-product formation upon lowering the reaction
temperature to 0 ꢁC.11 Moreover, in contrast with the limited
solubility of PhICl2 in chlorinated solvents at lower tempera-
tures,21 reactions with Br2 remained homogeneous throughout.
Crucially, in all of the above reactions only small amounts or no
dehydrobrominated alkene 3a was observed,22 which is a testa-
ment to the exceptionally mild, base- and acid-free reaction
conditions.
a
Unless otherwise stated, reactions were performed on a 0.5 mmol scale
at 0.17 M (3 mL) using 0.5 mmol of Br2 as 1.0 M solution in CH2Cl2;
reaction progress was monitored by 1H NMR using a stock solution of
Using conditions from entry 2 in Table 1 we proceeded to
examine the scope of our bromination with various b-sulphido
carbonyl compounds, which generally gave good to excellent
yields of the corresponding bromide products (Table 2, 4a–4p).
Reaction times varied with substitution on the aryl ring, with
aryl groups having deactivating substituents requiring longer
reaction times (4 hours for 1f). Bromination of slow-reacting
sulphides could be accelerated by running the reaction at
double the concentration in DCM (1e), or in DCE as solvent at
b
styrene in CDCl3 (0.03 M). Isolated yield aer SiO2 chromatography.
c
d
e
Run at 0.33 M (1.5 mL). 5.0 mmol scale. Reaction performed in
f
g
DCE at 50 ꢁC. Run with 1.0 mmol (2.0 equiv.) of Br2. Contains 8%
h
i
alkene. Isolated yield aer trituration or recrystallisation. Yield of
the corresponding triuoroethyl ether derivative. j 1H NMR yield using
k
CH2Br2 as the internal standard. Isolated yield contains 26% 3,4-
dibromide side-product.
deoxybrominating reagents. The chemoselectivity for sulphido
alcohols 1t and 1u is even more striking, when considering that
the productive intermediate is formally a bromosulphonium
ion analogous to the one generated in Swern oxidation. These
brominations proceeded to complete conversion, with bromo
alcohol 4t obtained in a high 85% yield. Bromo alcohol 4u was
isolated in a moderate yield aer purication; nevertheless, it
could be generated in situ and taken further in a follow-up
ꢁ
ꢁ
50 C (1g and 1i). Both heating at 50 C and excess of Br2 were
needed for the bromination of sulphides 1h and 1o.
Remarkably, desulphurative bromination also occurred with
substrates having protic functionalities such as b-sulphido
acids 1n and 1o and sulphido alcohols 1t and 1u, a trans-
formation that would be incompatible with the use of the
aforementioned phosphorus(V) or phosphorus(III) based
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reaction. For instance, a one-pot bromination/mesylation
sequence of sulphido alcohol 1u gave bromo mesylate 4v in
45% yield (97% yield from sulphide 1v).
Performing the bromination on easily accessible b-sulphido
nitriles 1q and 1r gave rise to the corresponding b-bromonitriles
in fair to good yields. Our method provides a direct and simple
route to these novel and potentially versatile compounds,23
especially when considering that the only direct literature-
known method relies on the mostly low-yielding halodehydra-
tion of the corresponding alcohol precursors.24
Scale-up of the above reactions proceeded without problems.
For instance, a ten-fold scale-up, at 5 mmol, of the bromination
of sulphide 1f gave bromide 4f in an excellent 95% yield, thus
underlining the practicality of the herein reported bromination
protocol.
Bromination of sulphides containing electron-rich hetero-
arenes such as sulphido thiophene 1w proceeded to complete
conversion; however, attempts to purify the corresponding
bromide 4w by chromatography resulted in decomposition.
Ultimately, 2,2,2-triuoroethanol solvolysis afforded the 2,2,2-
triuoroethoxy derivative 4wa in 50% yield (see the ESI†).
Likewise, bromide 4x was sensitive towards purication by
chromatography and was isolated as the 2,2,2-triuoroethoxy
derivative 4xa in 78% yield.
Initial experiments with adamantyl sulphide 1y indicated
that tertiary alkyl sulphides were suitable substrates. Bromina-
tion of sulphide 1y proceeded with clean complete conversion
as indicated by the 1H NMR spectrum of the crude material.
However, the moderate yield of 68% for bromide 4y (as well as
for 4s) was due to the chromatographic separation from (PhS)2,
which possessed similar polarity. Bromination of tertiary
dimethylalkyl-derived sulphides proceeded to complete
conversion, but was accompanied by elimination side-products.
Thus, sulphide 1za gave within 30 min the corresponding
bromide in 51% 1H NMR yield together with minor elimination
side-products, whereas bromo tosylate 4zb could be isolated in
30% yield as an inseparable 3 : 1 mixture together with its
corresponding Br2 alkene addition side-product (see the ESI†).
Scheme 3 Synthesis of enantiomerically enriched b-sulphido methyl
esters.
optically active benzylic b-bromo esters from enantiomerically
enriched benzylic b-sulphido esters. Sulphide substrates were
prepared according to Wang's asymmetric sulpha-Michael
addition of thiophenol to hexauoroisopropyl cinnamates.27
As the bromination of b-sulphido hexauoroisopropyl esters 1j
and 1ea gave, aer purication by chromatography, bromides
containing 8% and 25% alkene, respectively, we decided to
investigate the corresponding b-sulphido methyl esters. Thus,
acid-catalysed methanolysis was achieved without erosion of
the enantiomeric purity for sulphides (S)-1j, (S)-1da and (S)-1ea
(Scheme 3). However, methanolysis of sulphido ester (S)-1ba
having 99% ee gave, under the studied conditions, partially
racemised (S)-1b in 78% ee.
Subjecting sulphide (S)-1a to the optimised bromination at
room temperature (Table 1, entry 2) gave inverted bromide (R)-
4a in 83% ee and 86% es (Table 3, entry 1), which was subse-
quently conrmed to have an R absolute conguration (vide
infra). We were delighted to nd that lowering the reaction
temperature had a signicant effect on the enantioselectivity of
the reaction (Table 3, entries 2–4), with the bromination ran at
ꢀ40 ꢁC affording, aer 15 hours, bromide (R)-4a in an excellent
93% ee and 96% es. Similarly, bromination of sulphide (S)-1d at
ꢀ40 C gave bromide (R)-4d in 93% ee and 94% es (entry 5).28
ꢁ
The slow reacting sulphide (S)-1e gave at room temperature
bromide (R)-4e in high 86% ee and 88% es (entry 6). Lowering
the reaction temperature to 0 ꢁC gave bromide (R)-4e with
a slightly improved enantiomeric excess of 87%, but at the
expense of a signicant drop in the reaction rate (entry 7).
ꢁ
Finally, running sulphide (S)-1b having 78% ee at ꢀ40 C gave
bromide (R)-4b in 66% ee, which still corresponded to 85% es,
showing that the reaction tolerated sterically encumbered ortho-
substituted aryl groups (entry 8).
Optically active bromides
There are relatively few methods to access optically active,
racemisation-sensitive benzylic bromides. By far the most
widely applied methods rely on nucleophilic SN2 bromination
of optically active benzylic alcohols; however, these reactions
require accurate monitoring of reaction conditions and usually
yield partially racemised bromide products. Potentially very
useful, but rare, asymmetric protocols for obtaining benzylic
bromides are emerging. These include the recently reported Rh-
catalysed asymmetric Kharasch addition to styrenes,25 and the
Cu-catalysed formal asymmetric hydrobromination of
styrenes.26 However, these methods require the use of precious
metal-chiral phosphine catalysis and display limited substrate
scope.
Optically active benzylic bromides have been reported to be
prone to racemisation.1c,e,10 For instance, a sample of (R)-1-
(bromoethyl)benzene having 88% ee kept at 0 ꢁC was shown to
fully racemise within 8 hours.1c We therefore monitored the
congurational stability of a sample of b-bromo ester (R)-4a
ꢁ
having 93% ee over a three-month period at ꢀ20 C and room
temperature, and uncovered that when stored at ꢀ20 ꢁC, no
racemisation was detectable. In contrast, the sample stored at
room temperature showed partial racemisation with a drop in
enantiomeric excess to 78% aer the same period (see the ESI†
for further information). This is a very signicant nding as it
shows that optically active benzylic b-bromo esters can be
conveniently prepared using our method and stored for pro-
longed periods at ꢀ20 ꢁC (for at least three months) without
measurable racemisation.
Given the exceptionally mild reaction conditions to access
elimination-sensitive bromides, we proceeded to examine the
suitability of our method for the synthesis of highly versatile
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Table
3 Bromination of enantiomerically enriched b-sulphido
62% yield and 90% ee. Comparing the sign of the specic
optical rotation with that of the literature-known azido alcohol
(R)-530 conrmed that bromide 4a was formed with an R abso-
lute conguration and SN2 inversion from sulphide (S)-1a. Azido
alcohol (S)-5 can be considered an advanced intermediate en
route to (S)-dapoxetine,31 thus showcasing that the herein
described optically active b-bromo esters can serve as valuable
intermediates in the transition metal free synthesis of a host of
APIs having a benzylic chiral centre.
estersa,b
Ent. (S)-1
Temp. (ꢁC) Timec
(R)-4 yieldd (%) eee (%) es (%)
1
2
3
4
5
6
7
8
(S)-1a rt
(S)-1a
(S)-1a ꢀ20
(S)-1a ꢀ40
(S)-1d ꢀ40
(S)-1e rt
25 min 82
83
87
92
93
93
86
87
66
86
90
95
96
94
88
89
85
0
1 h
94
87
89
97
95
36
99
NMR study and mechanism
3 h
15 h
24 h
48 h
48 h
15 h
As outlined in the Introduction, there is uncertainty
surrounding the nature of the interaction of Br2 with sulphides,
with very few studies reported in solution. In order to gain
insight into the mechanism operating in the presented desul-
phurative bromination, we conducted a series of NMR experi-
ments. They were undertaken in light of the fact that the
(S)-1e
0
(S)-1b ꢀ40
a
Conditions: (S)-1 (0.25 mmol), Br2 (0.25 mmol) as 1.0 M solution in
b
CH2Cl2, and dry CH2Cl2 (1.5 mL, 0.17 M). Styrene (0.3 mmol, 1.3
c
32
15b,33
equiv.) was added to quench the reaction. Reaction progress was
reaction of both PhICl2 and Cl2
with sulphides leads to
monitored by 1H NMR spectroscopy using a stock solution of styrene
the oxidation of the sulphur(II) centre to sulphur(IV) forming
dichlorosulphuranes.
d
e
in CDCl3 (0.03 M). Isolated yield aer SiO2 chromatography. ee
values were determined by HPLC analysis on the chiral stationary phase.
In an initial experiment ran at an identical concentration to
the actual reaction, we treated a 0.17 M solution of sulphide 1a
ꢁ
in CD2Cl2 pre-cooled to ꢀ20 C with 1.0 equivalent of a 1.0 M
In order to demonstrate the versatility of our enantiomeri-
cally enriched b-bromo esters and to corroborate that the
desulphurative bromination occurred with the proposed inver-
sion of conguration, we converted bromo ester (R)-4a in
a reduction/azidation sequence into azido alcohol (S)-5 (Scheme
4). Aer examining several reducing reagents, we discovered
that DIBAL readily reduced the ester functionality in the pres-
ence of a benzylic bromide to afford bromo alcohol (R)-4t in an
excellent 93% yield, but with a partially eroded optical purity of
83% ee (Scheme 4). We believe that this is due to the propensity
of optically active bromo alcohol (R)-4t towards racemisation.29
Subsequent treatment of the crude product with sodium azide
in DMF gave azido alcohol (S)-5 in 86% yield and 83% ee.
Given that bromo alcohol (R)-4t is racemisation sensitive, we
devised an alternative one-pot protocol by submitting the in situ
generated bromo aluminium alcoholate (R)-6 to sodium azide
substitution and were delighted to obtain azido alcohol (S)-5 in
solution of Br2 in CD2Cl2 and monitoredꢁ the progress of the
1
reaction by H NMR spectroscopy at ꢀ20 C (Fig. 1). Aer one
minute of Br2 addition, and focusing on the benzylic proton, the
recorded spectrum showed the total absence of the benzylic
signal of sulphide 1a at 4.67 ppm with two new species
appearing as double doublets at 5.43 ppm and 4.84 ppm in
a ratio of 84 : 16. The major species was identied as bromo
ester 4a, with the minor unknown species converting to
bromide 4a upon further monitoring (Fig. 1). It was apparent
that the new unknown species – postulated as being a sulphide
bromine adduct intermediate 1a$Br2 (vide infra) – converted
ꢁ
rapidly to bromo ester 4a, even at ꢀ20 C.
Scheme 4 Preparation of enantiomerically enriched azido alcohol (S)- Fig. 1 1H NMR spectra (400 MHz) of the reaction of Br2 (1.0 M) with
5.
sulphide 1a (0.17 M) in CD2Cl2 at ꢀ20 ꢁC over a period of 90 min.
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Fig. 2 1H NMR spectra (800 MHz) of the Br2 (1.0 M) addition to
sulphide 1e (0.17 M) in CD2Cl2 at ꢀ20 ꢁC: (a) sulphide 1e at ꢀ20 ꢁC
before Br2 addition, (b) 2 minutes after Br2 addition and formation of
the 1e$Br2 adduct and (c) 1 hour after Br2 addition showing the
appearance of bromide 4e.
Fig. 4 1H NMR spectra (800 MHz) of the Br2 (1.0 M) addition to
sulphide 1e (0.17 M) in CD2Cl2 after raising the temperature to 20 ꢁC,
showing the progressive conversion of the 1e$Br2 adduct into bromide
4e and the presence of side product sulphide 1eb.
spectroscopy. The 13C NMR spectrum showed signicant shis
of signals compared to 1e (Fig. 3). These included large shis
for carbons anking the sulphur atom corresponding to an
upeld shi of the resonance of the Ci of 1e to 129.0 ppm (Dd ¼
ꢀ3.7 ppm) and a downeld shi of the benzylic carbon Ca to
0
52.9 ppm (Dd ¼ +4.6 ppm), as well as an upeld shi for Ci to
141.2 ppm (Dd ¼ ꢀ3.7 ppm) (Fig. 3b). In addition, notable shis
were observed for Cp of 1e to 130.6 ppm (Dd ¼ +2.3 ppm) and Cb
to 38.4 ppm (Dd ¼ ꢀ1.6 ppm).
All of the above 1H and 13C NMR Dds are less pronounced at
20 ꢁC.15a Hence, taking into account the NMR spectroscopic
criteria proposed by Nakanishi to distinguish between MCs and
TBs of R1R2S$X2 adducts in solution,15b the observed shis –
most notably the upeld shi of Ci of the SPh group – are
generally consistent in terms of magnitude, direction and
temperature behaviour with the presence of a MC structure for
the 1e$Br2 adduct.15a These ndings provide, to the best of our
knowledge, strong evidence for the rst observation of
a benzylic sulphide Br2 adduct in solution.
Fig. 3 13C NMR spectra (201 MHz) of the Br2 (1.0 M) addition to
sulphide 1e (0.17 M) in CD2Cl2 at ꢀ20 ꢁC: (a) sulphide 1e at ꢀ20 ꢁC
before Br2 addition and (b) after Br2 addition, displaying significant
shifts of the formed 1e$Br2 adduct.
Aer 1 hour, signals assigned to bromide 4e were visible,
with further conversion to 4e being very slow at ꢀ20 C.34 We
ꢁ
thus raised the temperature of the experiment to 20 ꢁC and
continued monitoring the progress of the reaction for a further
14.5 hours, and observed that 1e$Br2 progressively converted to
bromide 4e (Fig. 4). Repeating this experiment at 20 ꢁC for 60 h
showed conversion of 1e$Br2 to 4e slowing markedly down to
87% aer approximately 48 hours (see the ESI† for spectra). It is
important to note that the actual bromination of 1e was carried
out at double the concentration (0.33 M) requiring 48 h for
complete conversion to 4e.
Given the high rate of bromination for 1a, we turned our
attention to the slow-reacting sulphide 1e (Fig. 2). Thus, adding
a 1.0 M solution of Br2 in CD2Cl2 to a pre-cooled 0.17 M solu-
tion of sulphide 1e and recording a 1H NMR spectrum at
ꢀ20 ꢁC showed, aer 2 min, the complete disappearance of 1e
and its conversion to a single new species, identied by the
complete disappearance of the benzylic proton signal at
4.69 ppm and the appearance of a new double doublet at
4.82 ppm (Fig. 2b). Other signicant shis included downeld
shis of the diastereotopic Hb hydrogen atoms at 2.94 and
2.99 ppm to 3.05 and 3.14 ppm, respectively, and a downeld
shi of the signal of hydrogens ortho to the sulphur by
0.14 ppm (not shown).
The reaction of 1e also showed the formation of a side
product observed with experiments at ꢀ20 ꢁC and 20 ꢁC, which
started to form aer the appearance of bromide 4e. This side
product was proposed as being sulphide 1eb derived from the
para bromination of the SPh group in 1e (Fig. 4), which was
conrmed aer comparison with an authentic sample. In an
Gratifyingly, the new species was sufficiently stable at ꢀ20 ꢁC
to allow its full characterisation by 1D and 2D NMR
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Conclusions
We have disclosed a novel nucleophilic bromination reaction
that employs easily accessible alkyl aryl sulphides as starting
materials and basic elemental Br2 as an oxidative brominating
agent. Reaction conditions are exceptionally mild, allowing the
isolation of otherwise difficult to access and highly versatile
benzylic b-bromo esters and nitriles in generally good to excel-
lent yields. The reaction tolerates various functionalities and,
remarkably, proceeds in the presence of protic functionalities
such as alkyl acids and alcohols; a transformation incompatible
with the vast majority of deoxybromination procedures. Opti-
cally active benzylic b-sulphido esters could be converted into
the corresponding inverted b-bromo esters with high stereo-
selectivities. These bromides are congurationally stable at
ꢀ20 ꢁC, which should pave the way for their exploitation as
highly useful chiral synthons in organic and medicinal chem-
istry. Their utility was demonstrated by the preparation of g-
azido alcohol (S)-5, an advanced intermediate en route to
dapoxetine, in 90% ee. The developed one-pot sequence from
bromo ester (R)-4a, consisting of a DIBAL ester reduction in the
presence of a benzylic bromide and subsequent invertive
nucleophilic azidation, proceeded with high stereochemical
delity. Signicantly, the required stereochemistry was intro-
duced into sulphide precursor (S)-1a via an asymmetric sulpha-
Michael reaction, thus bypassing the dependency on optically
active benzylic alcohols.
Low temperature NMR spectroscopic studies pointed to an
initial MC adduct formation between the starting sulphide and
Br2 en route to the bromide product. This was observed for
adducts 1a$Br2 and 1e$Br2, with the latter, derived from slow-
reacting sulphide 1e, being sufficiently stable at ꢀ20 ꢁC to
allow its full characterisation. Subsequent stereoinvertive C–Br
bond formation is postulated to occur from the highly reactive
isomeric dibromosulphurane TB adduct, proposed to be
present in equilibrium with the MC adduct.
Given the very recent progress made in the synthesis of
enantiomerically enriched benzylic aryl sulphides,39 we antici-
pate that the nucleophilic desulphurative bromination reported
herein will nd wide utility in the synthesis of optically active
benzylic bromides relevant to drug discovery, agrochemicals,
and materials.
Scheme 5 Proposed mechanism taking into account stereochemical
and NMR evidence, as well as side-product formation.
NMR experiment conducted at 20 ꢁC, sulphide 1eb converted
cleanly to bromide 4e upon addition of 1.0 equivalent of Br2 (see
the ESI† for spectra). However, the bromination was slower than
that with sulphide 1e, stopping at 82% conversion aer 60 h,
with complete conversion reached only aer a further addition
of 0.2 equivalents of Br2.
A preliminary mechanistic picture is emerging from the
above NMR experiments (Scheme 5). We propose that the
addition of Br2 to sulphide (S)-1 results in the formation of
sulphur(II) adduct 1$Br2-MC. Based on the facts that (i) PhSBr
is formed as a by-product and (ii) 1 equivalent of bromide ions
must be generated from Br2 for SN2 C–Br bond formation to
occur, we propose that 1$Br2-MC must be in equilibrium with
trigonal bipyramidal sulphur(IV) dibromosulphurane inter-
mediate 1$Br2-TB.15 However, due to its high reactivity, it is
very likely that 1$Br2-TB is present in very low concentrations.
Invertive bromide ion attack on 1$Br2-TB produces bromide
(R)-4 with concomitant release of PhSBr and one equivalent of
bromide ions. Therefore, only catalytic amounts of bromide
ions are required to initiate the reaction. Bromide ions could
be derived from the ionisation of 1$Br2-TB to form, in equi-
librium, trigonal pyramidal bromosulphonium bromide
[1$Br]Br. The fact that the reaction is signicantly faster in
coordinating MeCN (Table 1, entry 7) supports such
a hypothesis.35
As seen with sulphide 1e, slow-reacting sulphides can form
the para-brominated side product (S)-pBr-1, presumably via
reaction with generated 1$Br2-TB or possibly PhSBr3 formed in
situ (in equilibrium) from the generated PhSBr and Br2 from
1$Br2-MC.36 The exclusive para bromination of activated
aromatics with bromodimethylsulphonium bromide has been
reported.17b Under optimised reaction conditions, the reductive
coupling of two PhSBr molecules generates one molecule of Br2
that could oxidatively brominate (S)-pBr-1 in an analogous
manner to (S)-1 (Scheme 5).37
Conceptually, the in situ oxidative activation of sulphides
towards SN2 nucleophilic substitution should provide a plat-
form for the development of other C–X and C–C bond forming
reactions, and could prove to be a general, practical and viable
alternative to oxygen based leaving groups.
Conflicts of interest
There are no conicts to declare.
Finally, a pathway involving n / s* type activation of the
C–S bond in 1$Br2-MC towards bromide ion attack cannot be
ruled out at present,38 and will be the subject of a detailed
mechanistic analysis in the future.
Acknowledgements
This work was supported by IRC (grants GOIPG/2015/3942 and
EPSPG/2016/185 to D. C. and C. F.), the H2020 Programme
(MSCA-RISE Halo 734361) and the Enterprise-Ireland CF Fund
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(CF20144034). We thank Dr Gary Hessman (TCD) for HRMS
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synthesis of the corresponding optically active bromo ethyl 34 An NMR experiment ran at ꢀ20 ꢁC showed 8% conversion to
ester
(S)-4da
from
the
alcohol
precursor
by
4e aer 10 hours. See the ESI† for further information.
deoxybromination with PBr3. In our hands, the crude 35 HBr generated from the para bromination of the SPh group
material from this procedure (racemic alcohol) gave
a mixture containing ca. 42% 4da (see the ESI†).
29 Enantiomerically enriched bromo alcohol 4t (21% ee)
in slow-reacting substrates is unlikely the source of bromide
ions, because with sulphide 1e, side-product sulphide 1eb
appears aer initial formation of 4e. Furthermore,
sulphide 1eb undergoes clean bromination to 4e.
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a few days: A. Isleyen,
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Chem. Sci.