Enantiospecific on-water bromination: A mild and efficient protocol for the preparation of alkyl bromides

Article abstract of DOI:10.1039/d0gc02855j

Herein we report the first example of an on-water enantiospecific synthesis of alkyl bromides. This procedure allowed the conversion of secondary activated alkyl sulphides to benzylic alkyl bromides, which were obtained in 80-99% yields. The reaction carried out on enantio-pure sulphides provided the corresponding bromides in high yields and enantioselectivity (up to 92% ee; 94% es) at room temperature. The on-water conditions reduced significantly the reaction times compared to similar procedures run in organic media. The condition identified made use of no solvent, required no temperature control and produced a smooth organic phase easily separated for further synthetic use on a multigram-scale without the need for any organic extraction. Therefore, the present constitutes the most operationally simple and environmentally benign approach to a class of much sought organic intermediates. This journal is

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ARTICLE
Enantiospecific on-water bromination: a mild and efficient
protocol for the preparation of alkyl bromides†
Francesco Allettoa and Mauro F. A. Adamo*a
Received 00th January 20xx,
Accepted 00th January 20xx
Herein we report the first example of an on-water enantiospecific synthesis of alkyl bromides. This procedure allowed the
conversion of secondary activated alkyl sulphides to benzylic alkyl bromides, which were obtained in 80-99% yields. The
reaction carried out on enantio-pure sulphides provided the corresponding bromides in high yields and enantioselectivity
(up to 92% ee; 94% es) at room temperature. The on-water condition reduced significantly the reaction times compared to
similar procedures run in organic medias. The condition identified made use of no solvent, required no temperature control
and produced a smooth organic phase easily separated for further synthetic use on a multigram-scale without the need for
any organic extraction. Therefore, the present constitutes the most operationally simple and environmentally benign
approach to a class of much sought organic intermediates.
DOI: 10.1039/x0xx00000x
procedure required strictly anhydrous conditions and to be operated
at -40 °C to ensure high enantiospecificity.
Introduction
In an attempt to study a range of electrophilic brominating
Compounds bearing the C–Br moiety are of great synthetic value
as they easily form carbon–carbon or carbon–heteroatom bonds and
they are ubiquitous in natural bioactive compounds.1–3 Given the
vast number of alkyl bromides used in the manufacture of active
pharmaceutical ingredients (API) and fine chemicals, the literature
presents many procedures to insert bromine into organic molecules,
with the Appel reaction being the most commonly applied
procedure.4 However, the Appel procedure often give rises to
unwanted side products especially when carried out on compounds
prone to elimination;5 in addition, the atom efficiency of the Appel is
heavily impaired by the stochiometric production of phosphine
oxides, difficult to separate from the desired products.6 Although
catalytic Appel has been developed to improve the atom efficiency,6–
reagents, we have noted that the reaction of (S)-1 (Table 1) was
significantly accelerated when run in the presence of water. The
bromination of compound (S)-1 using N-bromosuccinamide (NBS)
required 60 hours to achieve 80% conversion when run in
dichloromethane (0.2M). However, the same reaction run neat and
in the presence of water reached full conversion in just 2 hours. It
should be noted that reaction of organic products in the presence of
water could take place in two different modalities, namely in-water
or on-water.11 In the in-water processes, water is the actual solvent
and the reaction happens in the water bulk.11 On the other hand, the
term on-water is used to label the chemical transformations where
the transition state occurs at the organic side of the organic–water
interface. This term was first introduced by Sharpless, Fokin and co-
workers upon observation of the acceleration that water provided to
Lewis acid catalysed reactions.12 When compared to the respective
reaction in organic solution, the on-water effect is capable of
accelerate a reaction rate up to 200-fold.13 In addition, setting-up a
reaction as on-water presents other returns such as efficiency, safety
and cost-reduction. Despite the technical advantage and cost-
efficiency associated with the concept of reactions on-water, the
number of reports on enantioselective on-water syntheses is limited
to those reported by Mukherjee.14 Brominations in a water
environment (both in and on) includes bromination of alkenes via
Br2/H2O in which the water is also a reagent required to add the
hydroxy-group. Further examples includes transformations at an sp2
carbon, such as Katta’s catalyst-free bromination on
(hetero)aromatics15 and Li’s oxidative bromination of aryls.16 The
bromination at sp3 carbon is limited to the report of Iskra17 on the
reactivity of H2O2–HBr system versus NBS in electrophilic and radical
reactions. Hence, the development of on-water reactions that
provides enantio-enriched material is still in its infancy.
8
challenges remain such as: (i) requirement of multiple reagents, (ii)
adoption of strictly anhydrous conditions, (iii) limited functional
group tolerance.5,9
We have recently reported a new protocol that provides alkyl
bromides in high yield and enantiospecificity.10 This new reaction
that we named desulphurative bromination converted phenyl alkyl
sulphides to bromides using reagents as simple as molecular
bromine. Mechanistic studies showed that key to the observed
reactivity was the formation of a di-bromo sulphurane which via an
equilibrium with its corresponding sulphonium bromide provided
the final product through a bromide-lead SN2 reaction. This
a Centre 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
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic characterization for all new compounds, including details of NMR
and HPLC experiments. See DOI: 10.1039/x0xx00000x
We now like to report an improved set of conditions for the
desulphurative bromination that proceeded (i) at room temperature
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(ii) without solvent, i.e. on-water, and (iii) in significantly shorter to molecular bromine (Table 1, entries 8a, 8b and 8c) and superior to
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DOI: 10.1039/D0GC02855J
reaction times. This procedure avoids using large quantities of other N-brominating reagents in terms of reaction times and yields
chlorinated solvents; therefore, this protocol qualifies as the first and of 2. Reaction of 1 and DBI provided desired 2 in comparable yields
green enantioselective methodology to access title compounds.
even when the reaction times were prolonged up to 120 minutes
(Table 1, entries 1a, 1b and 1c). This can be explained with the low
basicity of the debrominated heterocycle arising from reaction of
DBI. Dibromantin (DBDMH) provided compound 2 (Table 1, entry 5a,
5b and 5c) in a slightly decreased, although comparable, yield and
selectivity vs 3 and 4 than DBI and Br2. The observed erosion of yield
might be associated with the longer reaction times required to
achieve full conversion, during which a small portion of 2 was
degraded to 3 and consecutively to 4. Other brominating reagents,
such as NBS, N-bromophthalimide (NBP), 2,4,4,6-tetrabromo-2,5-
cyclohexadienone (TBCO), PyrBr3 and trimethylphenylammonium
tribromide (TMPAB3) gave compound 2 in low yields and in long
reaction times. Therefore, this study identified in DBI the best
alternative reagent to molecular bromine, which may provide some
technical advantage in large scale reactions on the consideration of
being a non-volatile solid.
Results and discussion
With the aim of assessing the efficiency of reagents other than
Br2 in the desulphurative bromination, we have screened a number
of commercially available electrophilic brominating reagents, under
reaction conditions previously identified.10 Therefore, racemic 1 was
selected as the standard substrate and its conversion to bromide 2
recorded (Table 1). Aim of this study was the selection of the reagent
that ensured the highest yield of desired 2 in the shortest reaction
time. For this reason, a sample was collected at 15 min, 30 min and
120 min and the yield of compounds 2, alkene 3 and di-brominated
4 was obtained via 1H NMR analysis. Throughout this study we
identified a number of potential brominating reagents with (Table 1,
entry 1a) dibromoisocyanuric acid (DBI) being effectively comparable
The reaction of
1 and DBI was briefly studied by: (i)
increasing DBI equivalents, (ii) change of temperature and (iii)
variation of concentration (Table 2). This study showed that DBI
should be limited to 1.0 equivalent to prevent formation of
Table 1 Brominating agent selection via 1H NMR analysis a. NBP = N-Bromophthalimide,
TMPAB3 = Trimethylphenylammonium tribromide.
undesired dibromide
4 (Table 2, entry 2). On the other hand,
when only 0.5 equivalents of DBI were employed, the reaction
proceeded to 80% conversion in 10 minutes but then stopped
(Table 2, entry 3). Temperatures over rt promoted elimination
(Table, entry 5), meanwhile no significant effect was observed
upon carrying out the conversion of 1 to 2 at 0 °C (Table 2, entry
4). This is remarkable as desulphurative bromination conducted
with Br2 showed a notable dependence of the reaction time on
temperature within the same temperature ranges.10
Entry
1a
2a
3a
4a
5a
6a
7a
8a
1b
2b
3b
4b
5b
6b
7b
8b
1c
Oxidant
Time
Conversion b
100% (91%) c
0%
2 : 3 : 4 b
97 : 1 : 2
0 : 0 : 0
DBI (1.0 equiv)
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
30 min
30 min
30 min
30 min
30 min
30 min
30 min
30 min
120 min
120 min
120 min
120 min
120 min
120 min
120 min
120 min
In conclusion, this study confirmed that bromination of
NBS (2.0 equiv)
NBP (2.0 equiv)
TBCO (1.0 equiv)
DBDMH (1.0 equiv)
PyrBr3 (1.0 equiv)
TMPABr3 (1.0 equiv)
Br2 (1.0 equiv)
compound
1 to desired 2 is best achieved using 1.0 equivalent
0%
12%
0 : 0 : 0
of DBI in methylene chloride at rt (Table 2, entry 1).
10 : 2 : 0
28 : 5 : 0
4 : 0 : 0
A significant breakthrough was obtained when the reaction of 1
and DBI was studied in a variety of media (Table 3). The use of
solvents containing Lewis bases, such as acetone, MeCN and
THF (Table 3, entry 1-3), provided a complex mixture (CM) of
products, which could not be analysed. The reaction carried out
33%
4%
1%
1 : 0 : 0
100%
100%
0%
98 : 1 : 1
97 : 0 : 3
0 : 0 : 0
DBI (1.0 equiv)
NBS (2.0 equiv)
NBP (2.0 equiv)
TBCO (1.0 equiv)
DBDMH (1.0 equiv)
PyrBr3 (1.0 equiv)
TMPABr3 (1.0 equiv)
Br2 (1.0 equiv)
in DMF provided
accompanied by a significant proportion of elimination product
(Table 3, entry 4). The use of toluene (Table 3, entry 5)
a substantial amount of desired 2
0%
17%
0 : 0 : 0
15 : 2 : 0
75 : 3 : 2
19 : 1 : 0
3 : 0 : 0
98 : 0 : 2
97 : 0 : 3
4 : 1 : 0
3
80%
20%
provided
2
in only 10% yield after 10 min. The reaction carried
3%
100%
100%
5%
DBI (1.0 equiv)
a
Table 2 Initial optimization: changes of major conditions
.
2c
3c
NBS (2.0 equiv)
NBP (2.0 equiv)
TBCO (1.0 equiv)
DBDMH (1.0 equiv)
PyrBr3 (1.0 equiv)
TMPABr3 (1.0 equiv)
Br2 (1.0 equiv)
Entry Oxidant equiv
Conc
0.2M
0.2M
0.2M
0.2M
0.2M
0.1M
Temp
rt
Conversion c
100%
2 : 3 : 4 c
96 : 2 : 2
95 : 0 : 5
76 : 4 : 0
96 : 2 : 2
88 : 0 : 12
86 : 4 : 5
1%
1 : 0 : 0
1
2
3
4
5
6
1.0
2.0
0.5
1.0
1.0
1.0
4c
5c
20%
98%
18 : 2 : 0
95 : 0 : 5
41 : 1 : 0
4 : 0 : 0
rt
rt
100%
80%
6c
7c
42%
4%
0 °C
50 °C b
rt
100%
100%
95%
8c
100%
98 : 0 : 2
a Conditions: 1 (0.20 mmol), oxidant, CH2Cl2 (0.2 M), rt. b Conversion and relative ratios
of products 2, 3, 4 were obtained by evaporation of the reaction mixture, dilution with
CDCl3 and 1H NMR analysis. c isolated yield of 2 after column chromatography on silica
gel (PE : EtOAc = 98 : 2).
a
b
c
Conditions: 1 (0.20 mmol), DBI, CH2Cl2, 10 min. Reaction performed in DCE.
Conversion and relative ratios of products 2, 3, 4 were obtained by evaporation of the
reaction mixture, dilution with CDCl3 and 1H NMR analysis.
2 | J. Name., 2012, 00, 1-3
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Table 3 Secondary optimization: solvent effect a
.
considering that a colour change from an initial orange to final
colourless could be observed upon consumption of the brominating
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DOI: 10.1039/D0GC02855J
Entry
Oxidant
Solvent
Temp
RT
Conversion b
100%
2 : 3 : 4 b
complex mixture
complex mixture
complex mixture
48 : 41 : 0
reagent. The organic phase was then extracted with 0.4 mL of CDCl3
and the crude analysed via 1H NMR. In order to demonstrate that the
reaction occurred before extraction, we repeated the on-water
reaction of (S)-1 and DBI using d8-toluene as the extracting solvent,
which we showed before being an un-ideal solvent for this
transformation (Table 3, entry 5). This experiment provided identical
results showing therefore that the transformation of (S)-1 to (R)-2
occurred prior to work-up. It was also verified that extraction could
be avoided and crude (S)-1 obtained by evaporation of water. (S)-1
was obtained pure enough to be reacted in a following step when
obtained from a larger scale experiment, however for small scale
characterisation chromatography was used. All the reaction of (S)-1
and the oxidants employed occurred in an on-water modality. With
the exception of TBCO and NBP (Table 4, entries 3 and 4) all the
others experiment provided a full conversion of (S)-1, with DBI,
DBDMH and Br2 providing the shortest reaction times (Table 4,
entries 1, 5 and 6). Reaction of (S)-1 and DBI, NBS, DBDMH and Br2
gave desired (R)-2 in enantiopurity comprised between 63% and 67%
ee. In all of these experiments it was observed that addition of the
oxidant to a suspension of solid (S)-1 in water generated an orange
oil. Hence, the formation of two different non-miscible phases was
evident, which is in line with the description of on-water processes
as reported by Butler and Coyne.18 The reaction of NBS or DBI and
(S)-1 performed in the absence of water, i.e. neat, did not form a
biphasic system, but a semisolid aggregate that could not be stirred.
1
2
3
4
5
6
DBI (1.0 equiv) Acetone
DBI (1.0 equiv)
DBI (1.0 equiv)
DBI (1.0 equiv)
MeCN
THF
DMF
RT
RT
RT
100%
100%
89%
DBI (1.0 equiv) Toluene
DBI (1.0 equiv) H2O
RT
RT
10%
100%
10 : 2 : 0
100 : 0 : 0
a
b
Conditions: 1 (0.20 mmol), DBI (0.20 mmol), solvent (0.2 M), 10 min, rt. Conversion
and relative ratios of products 2, 3, 4 were obtained by evaporation of the reaction
mixture, dilution with CDCl3 and 1H NMR analysis.
out in water provided full conversion of
desired
1, quantitative yield of
2
uncontaminated by side products (Table 3, entry 6) as
evidenced in the crude 1H NMR. Noteworthy, the reaction rates
were comparable to the ones obtained in methylene chloride
(Table 2, entry 1). It was noted that neither substrate
were soluble in water: addition of substrate
produced a two-phase system in which solid
suspension. Treatment of biphasic water- with DBI gave rise to
an orange oil with concomitant disappearance of solid . This
observation, in conjunction with the acceleration previously
noted, led to the assignment of the observed transformation as
an on-water process. Water is the cheapest and greenest
solvent to be used in organic transformations and, with this in
mind, we underwent a subsequent round of screening of
brominating reagents (Table 4).
1
nor DBI
to water
was in
1
1
1
1
18
In analogy with other reported on-water reactions, it is plausible
As illustrated above, the number of enantioselective and
enantiospecific transformations that occur on-water is still limited.14
Therefore, we found intriguing that a transformation involving water
sensitive intermediates and reacting via an SN2 mechanism, hence
potentially enantiospecific, could equally take place in the presence
of large quantities of H2O nucleophile as it happens under on-water
conditions. With this in mind, we have reacted enantiopure (S)-1 with
a selection of brominating reagents. Delightfully, these experiments
demonstrated that compound (R)-2 could be obtained with
significant enantioenrichment (Table 4), showing an SN2 mechanism
operative under the on-water conditions. The experiments were
conducted as follows: 1.0 equiv of (S)-1 (98% ee) were premixed with
2 mL of water in a vial; an oxidant, as specified (Table 4), was then
loaded and the resulting biphasic system was stirred vigorously. The
progression of the reaction could be followed by visual observation,
that in this example water plays the role as the polar media favouring
the formation of a biphasic system and also alters the equilibrium
between sulphurane 5a and sulphonium 5b (Scheme 1), therefore
acting as a Lewis acid. Hence, the acceleration observed for the
desulphurative bromination could be explained considering that a
larger proportion of sulphonium 5b is formed in the presence of
water. We noted that the stirring rate had an effect on the reaction
time, which can be explained considering the larger surface contact
achieved between the organics and the water at vigorous stirring (i.e.
1500 rpm: maximum rotation of the magnetic stirrer). This latter
observation supports the role of water as the Lewis acid and the
a
Table 4 Brominating agent selection in water environment
.
Entry
Oxidant
DBI
Ox equiv
1.0
Time
Conv b
100%
100%
80%
ee of 2 c
63
er of 2
82 : 18
84 : 16
73 : 27
NA
1
2
3
4
5
6
10 min
120 min
360 min
240 min
15 min
15 min
NBS
NBP
TBCO
DBDMH
Br2
2.0
2.0
1.0
67
46
NA
2%
1.0
1.0
100%
100%
64
67
82 : 18
84 : 16
a Conditions: (S)-
1
(0.20 mmol), oxidant, 2 mL water, rt. b Conversion was obtained
by evaporation of the reaction mixture, dilution with CDCl3 and 1H NMR analysis.
c
Desired
2 was isolated by column chromatography on silica gel (PE : EtOAc = 98 : 2)
Scheme
1
proposed role of water in the acceleration of desulfurative
and ees were determined by HPLC analysis on chiral stationary phase
.
bromination.
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Table 6 On-water reaction optimization a
.
acceleration observed on-water (Scheme 1). The absence of side-
products arising from elimination is a secondary yet important effect
provided by the aqueous environment, that diluted the bases
originating from the de-bromination of reagents. It also should be
mentioned that no alcohol arising from substitution at C–S or C–Br
bonds could be detected, proving unambiguously that the reaction
took place at the interface between the two phases, i.e. on-water.
This new procedure performed at lower levels of
enantiospecificity when compared with the one previously reported
by us run in 0.2 M methylene chloride solution.10 In order to address
the origin of the drop of enantiospecificity, i.e. SN2 vs SN1, we ran the
reaction of (S)-1 and Br2 at different concentrations (Table 5). This
study showed a significant effect of the concentration on the
enantiomeric excess of (R)-2. When the desulphurative bromination
was performed neat without any water environment compound 2
was obtained in 54% ee (Table 5, entry 1). It should be highlighted
that the addition of Br2 to pure (S)-1 generated a dense oily orange
phase that could be stirred. Dilution of the organic phase with
increasing amounts of methylene chloride restored the high ees to
the same levels as seen in previous studies (Table 5, entries 2, 3 and
4). The results of the neat experiment and the one carried out at 10M
gave comparable yields, ees and reaction times. However, Br2 the
reaction of (S)-1 and Br2 at 1 M, gave (R)-2 in 84% ee. This set of
experiments pointed out at the concentration as the most important
variable to achieve high ees. Hence, we demonstrated that the
erosion of ees was entirely depending upon the concentration of
reactants, rather than the effect a polar aqueous ambient may have
on the SN2 vs SN1 competitive mechanisms.
The organic phase dispersed in the water layer appeared non-
homogeneous and dense, consequently the stirring of the reaction
was unideal. In order to ease the formation of a smooth oily phase
and increase the area of interface we therefore tried to add an
organic thinner. We have selected NBS, Br2 and DBI as the oxidants
and studied the reaction in the presence of 1.0 equiv of methylene
chloride, chlorobenzene, dibutyl ether or ethyl acetate (Table 6,
entry 4-11). The reaction carried out using Br2 and PhCl provided the
best results in terms of reaction rates, which we have linked to the
formation of larger quantities of smaller droplets of organics in the
reaction, leading to a visibly improved area of interface (Figure 1).
The use of PhCl over DCM produced a marginal yet measurable
increase in the ee of compound 2 (Table 6, entries 4 and 6). The use
of less hazardous thinners, such as dibutyl ether (Table 6, entry 7)
and ethyl acetate (Table 6, entry 8), is a feasible greener alternative
View Article Online
DOI: 10.1039/D0GC02855J
Ox equiv
2.0
1.0
Entry
1
2
Ox
NBS
Br2
DBI
Br2
DBI
Br2
Br2
Br2
NBS
Br2
Br2
Thinner
Neat
Neat
Temp
Time
ee of 2 d
67
er of 2
84 : 16
84 : 16
82 : 19
84 : 16
83 : 17
86 : 14
82 : 18
81 : 19
86 : 14
87 : 13
87 : 13
rt
rt
2 hrs
10 min
10 min
15 min
15 min
15 min
15 min
15 min
2 hrs
67
3
4
1.0
1.0
Neat
rt
rt
63
67
DCM b
PhCl b
PhCl b
Bu2O b
EtOAc b
PhCl b
PhCl b
PhCl b
5
6
1.0
1.0
rt
rt
65
72
7
8
1.0
1.0
rt
rt
64
62
9
2.0
rt
71
10
11
1.0
1.0
0 °C
-20 °C c
6 hrs
18 hrs
73
73
a Conditions: (S)-
to (S)-
c Reaction performed in 2 mL satd. aqueous NaBr instead of water
was isolated by column chromatography on silica gel (PE : EtOAc = 98 : 2) and ees
were determined by HPLC analysis on chiral stationary phase
1
(0.20 mmol), oxidant, 2 mL water. b 1.0 equiv of thinner added
1.
.
d Desired
2
.
enantiomeric excess which went from 72% ee (er 86:14) to 64% ee
(er 82:18). Reduction of the temperature from rt to 0 °C (Table 6,
entry 10) and then to -20 °C (Table 6, entry 11) had no effect on the
reaction ees, but increased the reaction times required to achieve
full conversion.
We have noted that although effective the use of 2.0 equiv of
NBS formed a gummy phase instead of a smooth oil, even with the
aid of a thinner. This may be un-ideal in an industrial scale-up and
may impose the aid of an organic extraction. On the other hand,
combination of DBI or Br2 and a thinner produced a smooth organic
phase easily separated for further purification on a gram-scale setup
to chlorobenzene, granting similar yields but
a slight lower
Table 5 Effect of concentration on reaction times and ees of desulfurative
bromination a.
Entry
Solvent
Neat
Conc
NA
Time
Conv b
100%
100%
100%
100%
ee of 2 c
54
er of 2
77 : 23
80 : 20
92 : 8
1
2
3
4
10 min
10 min
25 min
25 min
DCM
DCM
DCM
10 M
1 M
60
84
0.2 M
82
91 : 9
Figure 1 Picture of the on-water reaction of (S)-1 and Br2 in the presence of a thinner
(Table 6, entry 6). At 0 rpm denser drops of organic phase deposited at the bottom of
the vial. At maximum rotation of the magnetic stirrer (1500 rpm) the drops were finely
dispersed in the aqueous phase, greatly increasing the surface of interaction. After 15
minutes the organic phase appeared colourless marking the complete consumption of
Br2.
a Conditions: (S)-
was obtained by evaporation of the reaction mixture, dilution with CDCl3 and 1H NMR
analysis. c Desired
was isolated by column chromatography on silica gel (PE : EtOAc
1
(0.20 mmol), Br2 (0.2 mmol), rt, inert atmosphere. b Conversion
2
= 98 : 2) and ees were determined by HPLC analysis on chiral stationary phase
.
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without the need for any organic extraction. However, Br2 was
deemed as superior to DBI based upon the density of the organic
droplet formed. In addition, Br2 produced compound 2 in a slight
Table 7 Scope of the on-water desulfurative bromination.
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Scheme 2 Proposed mechanistic pathways: SN1 against SN2 and the rationale that
favours one or the other.
increased ees and with a considerably purer crude of reaction (see
ESI). In conclusion, this study identified in Br2 and 1.0 equiv of PhCl
as the best set of conditions to run the desulphurative bromination
on-water (Table 6, entry 6; Figure 1).
Analysis of the mechanistic pathways arising from sulphurane 5a
Considering our previously published data10 and the additional
information collected into this work (Table 7), a mechanistic analysis
can be proposed that explains the variation of the enantioselectivity
with the electronic properties of the substrates (Scheme 2). Initial
reaction between sulphide (S)-1 and the oxidating agent (i.e. Br2, DBI,
NBS or NBP) generated a sulphurane of structure 5a. It is established
that sulphuranes and sulphoniums are in equilibrium,19 therefore
species 5a can evolve to sulphonium 5b which further reaction is
irreversible. Species 5b can undergo two possible reactive pathways,
namely SN1 or SN2. The factors directing the evolution of 5b towards
(R)-2 (SN2 pathway) or racemic-2 (SN1 pathway) could be influenced
by the relative bond polarities of X–S (3) and S–Csp3 (2) bonds. The
driving force behind evolution of 5b towards their product lays in the
inclination of sulphur to gain back its neutrality. Therefore, when X–
S is considerably more polarized towards X compared to the
a
b
2.0 equiv of Br2 used. Product isolated as an inseparable mixture with 5-14%
alkene. Ee’s were determined by HPLC analysis on chiral stationary phase.
The scope of reaction was planned on secondary benzylic phenyl
sulphides bearing both electron-donating and electron-withdrawing
groups on the aromatic portion. The rationale of selecting this motif
laid in the availability of compounds 1 in enantiopure form from the
addition of thiophenol to cinnamates.20 In addition, the effect of
various functional groups such as esters, amides and mesylates on
the reaction enantiospecificity was also explored. The optimized
conditions involved reacting a suitable sulphide (S)-1a-l and Br2 in
water with 1.0 equiv of PhCl at rt. This reaction provided
corresponding (R)-2a-i in high yields and in up to 94% es. The
introduction of electron-donating group, such as o-CH3 on the phenyl
had no detrimental effect: compound (R)-2b was obtained in a
similar 77% es in spite of the presence of a sterically encumbering
group on the ortho position. As might be expected, the presence of
polarization of S–Csp3 (δ3
> δ2) intermediate 5b will break
preferentially giving rise to an SN1 pathway. On the contrary, when
S–Csp3 is considerably more polarized towards Csp3 compared to the
polarization of X–S (δ3 < δ2) then intermediate 5b would be
sufficiently stable to undertake an SN2 pathway. Based upon the
reasoning outlined above, it would be expected that when the
polarity of the S–Csp3 bond is shifted toward Csp3 via introduction of
electron-withdrawing moieties, the enantioselectivity of the
bromination would be enhanced, as an SN2 mechanism of reaction is
favoured.
Scope of reaction
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p-F on the aromatic ring in (R)-2c resulted in a similar ee as when no point of PhCl provided the additional advantage of simplifying the
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substituents are present, in line with the observation proposed by isolation of (R)-2a. Indeed, upon completiDoOnI:o1f0.1th03e9/rDe0aGctCio0n28t5h5eJ
Schuster.21 The introduction of electron-withdrawing groups on the water layer was selectively eliminated by vacuum-evaporation,
aromatic ring produced
a sharp increase in the observed leaving behind an organic phase that was thinned by the high boiling
enantiospecificity. Hence, compound (R)-2d bearing a p-CF3 was (132 °C) PhCl residue. The lower viscosity of crude (R)-2a allowed an
obtained in 94% es, meanwhile less strong EW substituents such as easier collection and purification without the need of liquid-liquid
Br or Cl yielded (R)-2e and (R)-2f in 80% es and 85% es respectively. extraction. This is very relevant bearing in mind scaling-up this
It was noted that to obtain (R)-2d the reaction required additional reaction further. In summary, this method, employed 1 equiv of
amounts of oxidant due to an operative electrophilic bromination of thinner rather than the 100-150 mL of solvent typically required for
the thiophenyl group as previously observed by us.10 We reported an extraction, that is standard to purify 10 mmol of organics.
that the reaction between (S)-1d and Br2 in dichloromethane
1
provided an intermediate that was visible in the H NMR and that
was assigned to be a sulphide Br2 adduct, precursor to sulphurane
5a.10 Conversely, when the reaction between (S)-1d and Br2 was
Conclusions
Herein we have described a highly enantiospecific green on-
water methodology for the preparation of highly enantioenriched
carried out as on-water mode, no intermediate could be detected via
1H NMR analysis of the reaction mixture. The fast decay of adduct,
(up to 92% ee) alkyl bromides. The reaction is mechanistically
sulphurane and sulphonium species under the on-water condition
remarkable and synthetically useful many folds. Firstly, its unobvious
could be explained again by the Lewis acid catalysis provided by
that SN2 reactions of highly reactive intermediates, such as
sulphoniums, may still be preferred over SN1 pathways at rt and in
the presence of large excess of water. Secondly, no other reaction of
sulphoniums with nucleophiles different from bromides was
observed which is surprising considering the amount of water being
present and the strength of nucleophiles being generated when DBI,
NBS and similar N-based brominating reagents are used. Thirdly, it
was established a strict relationship between the presence of
substituents capable of strong -I effects and the extent of a stereo
conservative mechanism of reaction. Fourthly, water has been
identified as a good enough Lewis acid to perturb the equilibrium
existing between sulphuranes and sulphoniums providing a steep
water, which favour 5b over 5a (Schemes 1 and 2). The introduction
of electron-withdrawing groups on the ester produced a sharp
increase in the enantiospecificity. For example, compound (R)-2a,
bearing a methyl ester, was obtained in 74% es, meanwhile (R)-2g,
bearing a bis-trifluoromethyl ester, was formed in significantly higher
87% es. This trend was proven to be general and compounds (R)-2h
and (R)-2i were similarly obtained in 92% es and 93% es respectively.
Less electron-withdrawing substrates provided lower level of
enantiospecificity such as (R)-2j, (R)-2k and (R)-2l which were
obtained in ca 70% es. It was therefore proven that pivotal to the
obtainment of high enantiospecificity is the introduction of a distal
electron-withdrawing group which was a success. However, it should
acceleration to desulphurative bromination. In addition, this
be considered that meanwhile compound (R)-2g-i were stable both
protocol provides a synthetically useful method of preparation of
alkyl bromides that does not require low temperatures, controlled
atmosphere and solvents. The E-factor for the procedure carried out
in a DCM solution10 was 34.6; meanwhile, the E-factor for this new
on-water protocol is 1.5, hence this latter is significantly greener.
Hence, this method is effectively green, expands the range of
brominating reagents that could be employed, is simple to execute
in solution and as isolates, their chromatographic purification was
accompanied by limited amounts of products of decomposition, i.e.
the alkene. One last consideration involves a discussion on the
stability of mesylates present in products (R)-2k and (R)-2l under the
on-water conditions which did not provide compounds of
substitution.
and constitutes one of the very few reports of enantioselective
synthesis that is carried out on-water. We believe this report to be of
Recycling of residual waters and large scale reaction
To further define the green impact of our on-water bromination,
we run a test to verify if the residual water, contaminated by HBr,
could be used in following bromination cycles. Hence, 1a was reacted
with 1.0 equiv of Br2, crude 2a extracted with Et2O, and analysed via
1H NMR to determine conversion of 1a and yield of 2a. The residual
water was used for a subsequent cycle by adding fresh 1a and Br2.
However feasible, we noted that the recycling of water containing
incremental amounts of HBr negatively impacted on the reaction
rate, effectively requiring greater amounts of Br2 to achieve full
conversion (see ESI). The decrease of the reaction rate is most
probably caused by the extraction of Br2 from the organic phase into
interest to whoever is concerned with the preparation of
enantiopure alkyl bromides and their use for the preparation of fine
chemicals and APIs at scale.23
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was supported by IRC and LifeScientific under Grant
Number [EPSPG/2017/287]
-
the aqueous phase due to the formation of Br3 , which could be
avoided by electrolytic removal of bromide from water layer and
regeneration of 0.5 equivalents of Br2 reagent.22
We have also demonstrated that the conversion of (S)-1a to (R)-
2a could be run at 3-gram scale (10 mmol) with small detriment of
yields and no loss of enantiospecificity. In this regard, the boiling
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