Catalytic and enantioselective bromoetherification of olefinic 1,3-diols: Mechanistic insight

Article abstract of DOI:10.1016/j.tet.2015.09.016

How can high enantioselectivity be achieved when the racemic background reaction proceeds at a rate comparable to that of the catalytic asymmetric reaction? We attempted to rationalize this counterintuitive observation by studying the effect of (1) catalyst structure, (2) temperature and addition sequence of components, (3) catalyst loading, and (4) Br?nsted acid additives. In the course of our investigation, it was found that increasing the amount of catalyst used led to inhibition of the stoichiometric reaction. Olefinic 1,3-diol 1, 5 mol % of catalyst 3a, 1 equiv of MsOH, and NBS were added at low temperature in a specific sequence to provide the best performance for the enantioselective bromoetherification.

Full text of DOI:10.1016/j.tet.2015.09.016

Tetrahedron xxx (2015) 1e7
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic and enantioselective bromoetherification of olefinic
1,3-diols: mechanistic insight
,b,
*
Zhihai Ke a, Chong Kiat Tan b, Yi Liu b, Keefe Guang Zhi Lee b, Ying-Yeung Yeung a
a Department of Chemistry, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China
b Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2015
Received in revised form 28 August 2015
Accepted 2 September 2015
Available online xxx
How can high enantioselectivity be achieved when the racemic background reaction proceeds at a rate
comparable to that of the catalytic asymmetric reaction? We attempted to rationalize this counterin-
tuitive observation by studying the effect of (1) catalyst structure, (2) temperature and addition sequence
of components, (3) catalyst loading, and (4) Brønsted acid additives. In the course of our investigation, it
was found that increasing the amount of catalyst used led to inhibition of the stoichiometric reaction.
Olefinic 1,3-diol 1, 5 mol % of catalyst 3a, 1 equiv of MsOH, and NBS were added at low temperature in
a specific sequence to provide the best performance for the enantioselective bromoetherification.
Ó 2015 Published by Elsevier Ltd.
Keywords:
Asymmetric halogenation
Bromoetherification
Chiral sulfide catalyst
Lewis base
Brønsted acid
1. Introduction
Despite the successful deployment of the optimized conditions
for the catalytic and enantioselective bromoetherification of 1, it
Over the last couple of years, a range of new methods for
asymmetric halocyclizations have been described. However, most
of these methods are applicable only to halolactonizations or re-
lated amidations.1e3 On the other hand, suitable methods for
asymmetric haloetherifications are rare, and are of general in-
terest.4 Recently-published studies from our laboratory detailed the
optimization and development of a novel organocatalytic method
for catalytic enantioselective bromoetherification of olefinic 1,3-
diol 1 using a mono-functional C2-symmetric cyclic sulfide 3a as
the catalyst (Scheme 1).5
In the course of optimizing the bromoetherification of olefinic
1,3-diol 1, several interesting phenomena were identified: (1) the
protecting group of the catalyst is of great importance in controlling
the er; (2) the er and dr are affected by the sequence in which the
reagent, catalyst, and substrate are added; (3) an increase in cata-
lyst loading leads to a reduction in reaction yield while the er and dr
are maintained; (4) the MsOH additive (1 equiv) alone can catalyze
the racemic bromoetherification with reaction rate similar to that
of the MsOH/cyclic sulfide 3a catalyzed asymmetric reaction, while
the cyclic ether product 2 can be still achieved in the catalytic
asymmetric process with high er.
was nonetheless of significant interest to elucidate these in-
teresting and unusual observations. In this article, the interesting
phenomena and the mechanistic insights will be discussed.
2. Results
2.1. The effect of catalyst structure
Based on the optimized conditions in our previous report,
a combination of 10 mol % catalyst loading, reaction temperature at
ꢀ78 ꢁC, and reaction time at 48 h was defined as the most general
set of reaction parameters with which to examine a variety of
catalysts (Scheme 1).5 Olefinic 1,3-diol 1a and NBS were used as the
substrate and the halogen source, respectively. In addition, 1 equiv
of MsOH was used as an additive.
Catalyst 3ae3d, 3i, 3k, 3l, and 3m were synthesized using the
method developed by our group.3g,5 The seven-membered ring
cyclic sulfides 3ee3g could be prepared from the dimesylate6
which is derived from D-mannitol. The 1,2-diol protecting group
in 3j could be modified using the procedure shown in Scheme 2.
The key to this synthesis is the formation of the bis-epoxide7 which
can be ring-opened by phenol derivatives to form analogs of the
desired catalysts. The cyclization of the di-mesylate to form the
strained 5,5-trans bicyclic ring system proved to be rather difficult,
and required microwave conditions to perform this transformation.
* Corresponding author. Tel.: þ852 39436377; fax: þ852 26035057; e-mail ad-
dresses: yyyeung@cuhk.edu.hk, chmyyy@nus.edu.sg (Y.-Y. Yeung).
http://dx.doi.org/10.1016/j.tet.2015.09.016
0040-4020/Ó 2015 Published by Elsevier Ltd.
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2
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
instead of cyclic selenide 3m (29% yield, 65.5:34.5 er). We ob-
served that the sterically-bulkier 2,6-diisopropylphenol derived
analogue 3b gave the desired substituted THF in a lower er (94%
yield, 92:8 dr, 46.5:53.5 er). Catalysts with dimethyl and diiso-
propyl substituents directly linked to the bicyclic core (3c and 3d)
gave the desired products 2a and 2a0 with 50:50 er, while main-
taining moderate levels of conversion and yield. Cyclic sulfides in
seven-membered rings (3ee3h) also performed poorly in the re-
action. Unfortunately, a 2,5-diphenylpyrimidine derived group
(3g) stymied the reaction, leading to 27% yield of the desired
product.
Changing the tert-butyl substituent in 3a into tert-amyl did not
influence the selectivity (3i, 74% yield, 94:6 dr, 84:16 er). However,
a significant effect on enantioselectivity was observed when the
two methyl groups were removed from the 1,3-dioxolane (3j, 64%
yield, 88:12 dr, 51:49 er). In a direct comparison, the deprotected
diol derived catalyst (3k) delivered the product in 90% yield with
91:9 dr, 77.5:22.5 er. A further modification using 2,2-di-tert-butyl
[1,3,2] dioxasilole (3l) led to a drop in reactivity (47% yield, 88:12 dr,
68.5:31.5 er).
2.2. The effect of addition sequence and reaction temperature
During our reaction optimization study, it was observed that
the addition sequence of the reagent, substrate, and catalyst is of
critical importance to the reaction performance. The effect of the
addition sequence in the bromoetherification of 1a was in-
vestigated as indicated in Scheme 3: (1) 1a and catalyst 3a were
dissolved in CH2Cl2 at ꢀ78 ꢁC. A pre-cooled solution of MsOH in
CH2Cl2 (freshly prepared for each experiment) was added to the
reaction mixture. After the addition, solid NBS was added. The
product 2a was obtained in 80% yield and 71% ee (2) NBS was
added to a solution of 1a and catalyst 3a in CH2Cl2 at ꢀ78 ꢁC. After
5 min, a pre-cooled solution of MsOH in CH2Cl2 was added to the
mixture. 61% ee of 2a was obtained. (3) A pre-cooled solution of
MsOH in CH2Cl2 was added to a solution of NBS and catalyst in
CH2Cl2 at ꢀ78 ꢁC. Substrate 1a was added and 2a was furnished in
50% ee (4) NBS and MsOH were pre-mixed in CH2Cl2 at ꢀ78 ꢁC.
Following which, catalyst 3a and substrate 1a were added con-
secutively to yield 2a in 54% ee (5) Addition sequence was the
same as that in equation (1) but the reaction was performed at
25 ꢁC. The substrate was consumed quickly. However, a complex
mixture was obtained and the yield of the desired product 2a was
low.
Scheme 1. Effect of catalyst structure on the asymmetric bromoetherification and
desymmetrization of 1a.
Scheme 2. Preparation of cyclic sulfide catalyst 3j.
Scheme 3. Study of the addition sequence.
Among a range of catalysts surveyed, increased reactivity and
enantioselectivity were achieved when cyclic sulfide 3a was used
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Z. Ke et al. / Tetrahedron xxx (2015) 1e7
3
Table 2-1
We also studied reactions in the absence of the cyclic sulfide
catalyst 3 (Scheme 4). It was found that MsOH alone could mediate
the cyclization of 1a at room temperature to give 5 in 90% yield
(Scheme 4, eq 1). When MsOH, NBS and 1a were mixed at room
temperature, a mixture of 2a (90%) and 5 (8%) was obtained
(Scheme 4, eq 2). The formation of 5 was totally suppressed when
the reaction was conducted at ꢀ78 ꢁC (Scheme 4, eq 3).
Effect of catalyst loading on the asymmetric bromoetherification and desymmetri-
zation of 1aa
Entrya
3a (mol %)
Yield (%)b
drc
er
1
2
3
4
5
1
2
5
10
20
42
98
97
80
72
82:18
93:7
93:7
92:8
92:8
51:49
83:17
85.5:14.5
85.5:14.5
85.5:14.5
a
Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a,
methanesulfonic acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the
absence of light.
b
Isolated yield.
c
Determined by 1H NMR.
2.4. The effect of MsOH additive
Scheme 4. Study of reaction without catalyst 3.
The effect of MsOH loading on the asymmetric reaction was
studied (Table 3). 2a was obtained in 61% yield with moderate dr
and negligible er in the absence of MsOH additive (Table 3, entry 1).
The overall performance was improved when MsOH was added. It
is particularly intriguing that the enantioselectivity of the reaction
using 3a as the catalyst is strongly dependent on the presence of
MsOH (85.5:14.5 er with 1 equiv MsOH and 52:48 er without
MsOH), whereas the product yield is comparable in both cases
(Table 3, entries 1e3). However, when 1.5 equiv of MsOH was used,
the er showed a significant depreciation (Table 3, entry 4).
Since it is known that different counterions exert an influence
on the reactivity and selectivity of the halocyclization,8 we deemed
it important to verify whether other carboxylic/Brønsted acids
would perform comparably to MsOH. As such, we examined dif-
ferent achiral Brønsted acid sources, focusing on those providing
a range of steric and electronic variation (Table 4). Aliphatic alka-
nesulfonic acids generally increased the enantioselection with in-
creasing acidity (Table 4, entries 2e4). This effect did not extend to
aromatic sulfonic acids, as the p-toluenesulfonic acid performed
better than the more acidic triflic acid (Table 4, entries 7 and 8). We
also considered that the carboxylate ion may be a more competitive
counterion for the selective bromoetherification than succinimide
(Table 4, entries 9 and 10), but that turned out not to be the case.
Chiral organic acids, including both enantiomers of camphor
sulfonic acid and BINOL-derived phosphoric acid, were proven to
be inferior in inducing er as compared to MsOH (Table 4, entries
5e6, 11e12). In addition, the chirality of the counterion appears to
play an unimportant role on the reaction performance.
A survey on the effect of reaction temperature on the bromoe-
therification revealed that a low reaction temperature is important
for good yield, er, and dr of the desired product 2a (Table 1).
2.3. The effect of catalyst loading
For the asymmetric bromoetherification of 1a using 3a as the
catalyst, 2a was obtained in low yield and er when 1 mol % of
catalyst was used (Table 2-1, entry 1). The yield and er were dra-
matically improved when the catalyst loading was increased to
2 mol % (Table 2-1, entry 2). The performance was not improved
significantly when 5 mol % of 3a was used (Table 2-1, entry 3).
While the er and dr maintained when the catalyst loading was
further increased (Table 2-1, entries 4 and 5), the yield un-
expectedly dropped.
We also examined the effect of catalyst loading on the
bromoetherification of 1b and a similar trend was observed
(Table 2-2). In a direct comparison, 10 mol % catalyst 3a delivered
the product 2b in 93% yield with 95.5:4.5 er (Table 2-2, entry 4). We
were able to decrease the catalyst loading to 2 mol % (Table 2-2,
entry 2) with minimal effect on the yield. Furthermore, lowering
the catalyst loading to 1 mol % (Table 2-2, entry 1) gave 2b in 83%
yield, 55.5:44.5 er. Again, an increase in catalyst loading led to
a reduction in product yield but same er and dr were obtained
(Table 2-2, entries 4 and 5).
Table 2-2
Table 1
Effect of catalyst loading on the asymmetric bromoetherification and desymmetri-
Effect of reaction temperature on bromoetherification and desymmetrization of 1aa
zation of 1ba
Entrya
T (ꢁC)
Yield (%)b
drc
er
Entrya
3a (mol %)
Yield (%)b
drc
ee %
1
2
3
4
5
ꢀ78
ꢀ60
ꢀ40
ꢀ20
0
80
78
68
65
62
92:8
85.5:14.5
78.5:21.5
77.5:22.5
73.5:26.5
71:29
1
2
3
4
5
1
2
5
10
20
83
92
98
93
77
88:12
93:7
>99:1
>99:1
>99:1
55.5:44.5
95.5:4.5
95.5:4.5
95.5:4.5
95.5:4.5
89:11
88:12
85:15
83:17
a
a
Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a
(10 mol %), methanesulfonic acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2
(1.5 mL) in the absence of light.
Reactions were conducted with alkenoic diol 1b (0.05 mmol), catalyst 3a,
methanesulfonic acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the
absence of light.
b
b
Isolated yield.
Isolated yield.
c
c
Determined by 1H NMR.
Determined by 1H NMR.
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4
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
Table 3
and structurally well-defined catalyst pocket. The locked confor-
mation of the bicyclic core (acetonide fused cyclic sulfide) would
affect the stereo control of the reaction. Acetonide, a common
protecting group for 1,2-diols, is critical in obtaining high er. Re-
moving the isopropylidene bridge (3k) led to a decrease of the
enantioselectivity of the bromoetherification of 1a. The two methyl
groups of the isopropylidene in 3a were also found to be re-
sponsible to the high enantioselectivity. The ee dropped signifi-
cantly when changing the isopropylidene protecting group into
a methylene (catalyst 3j) or a bis(tert-butyl) silyl ether (catalyst 3l).
In particular, almost no ee was observed when 3j was used, sug-
gesting that the isopropylidene in 3a might offer suitable steric
bulkiness in the enantio-determining step.
Effect of methanesulfonic acid loading on the asymmetric bromoetherification and
desymmetrization of 1aa
Entrya
MsOH (equiv)
Yield (%)b
drc
er
1
2
3
4
0
61
88
80
79
86:14
91:9
92:8
91:9
52:48
68:32
85.5:14.5
69.5:30.5
0.5
1.0
1.5
a
Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a
(0.005 mmol), methanesulfonic acid and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the
absence of light.
b
Isolated yield.
c
3.2. The reaction efficiency
Determined by 1H NMR.
The methaneseleninic acid was more effective in promoting the
It is surprising to see that a high catalyst loading led to a de-
crease in conversion, while the ee and dr are maintained. Based on
the previous mechanistic study,5 a 3a-Br intermediate which con-
tains a SeBr Lewis base-coordinated Br system might exist
(Scheme 5). The olefin moiety in substrate 1 could then attack the
activated electrophilic Br in 3a-Br to form the corresponding bro-
miranium intermediate A which could further undergo cyclization
to yield the cyclic ether product 2.
reaction but did so in a less selective manner (54:46 er; Table 4,
entry 13). Interestingly, adamantine-1-sulfonic acid, which is much
more sterically bulky than MsOH, caused a substantial decrease in
enantioselection to 54.5:45.5 er (Table 4, entry 14). Use of 1-
adamantanol led to similar results (52:48 er; Table 4, entry 15).
3. Discussion
3.1. The structureeactivity relationship
Section 2.1 showed the results of our investigation on the cat-
alyst structure and its influence on the enantioselectivity. It turned
out that small changes in the catalyst structure led to fluctuations in
the enantioselectivity. Five-membered cyclic sulfides without aro-
matic substituents (3c and 3d) and seven-membered cyclic sulfides
(3ee3g) were ineffective in achieving asymmetric bromoether-
ification. Changing the 4-tert-butyl group on the phenyl rings in 3a
into 2,6-diisopropyl (3b) led to a drop in the er, which might be due
to the excessively sterically hindered system. The role of the trans-
fused ring system in 3a and 3i was expected to lock the confor-
mation of the cyclic sulfide five-membered ring, resulting in a rigid
Scheme 5. Sulfide-Br complexes.
In a study by Brown in 2000, it was found that the collidine in
the brominating reagent bis(sym-collidine)bromonium triflate
would dissociate to form a mono-collidine-coordinated Br species
before interacting with the olefin to form the bromiranium in-
termediate.9 In the case of 3a-catalyzed bromoetherification, we
speculate that another molecule of Lewis basic sulfide 3a could also
Table 4
interact with the 3a-Br species (instead of the p-electron of 1a) to
Effect of various acid additives on the asymmetric bromoetherification and de-
give a 3a-Br-3a complex that is similar to the bis(collidine)-Br
system in Brown’s case. A higher loading of catalyst 3a might
shift the equilibrium in favor of the formation of 3a-Br-3a, which
might result in lower conversions due to the trapping of the elec-
trophilic Br (Tables 2-1 and 2-2). Since the same bromiranium in-
termediate A is still involved, the er and dr should remain
unaffected even at high catalyst loading.
symmetrization of 1aa
Entrya
Acid
Yield (%)b
drc
er
1
2
3
4
5
6
7
8
Nil
MsOH
61
80
87
95
88
78
95
32
87
96
96
86:14
92:8
94:6
94:6
94:6
94:6
94:6
90:10
94:6
94:6
94:6
52:48
85.5:14.5
53.5:46.5
50.5:49.5
81:19
Ethanesulfonic acid
Propanesulfonic acid
(S)-Camphor sulfonic acid
(R)-Camphor sulfonic acid
TsOH
3.3. Effect of addition sequence and temperature
According to the results presented in Section 2.2, the perfor-
mance of the catalytic bromoetherification was affected by the
components’ addition sequence. The reaction was best performed
when NBS was added at last and at ꢀ78 ꢁC. Other addition se-
quences led to lower enantioselectivities and/or reaction yields.
When adding MsOH as the last component in the reaction
(Scheme 3, eq 2), 3a alone could catalyze the reaction with low
enantioselectivity as indicated in Table 3, entry 1. This might be the
reason for the reduced ee of the overall reaction. Alternatively,
when the substrate was added last, i.e., Scheme 3 equation (3) or
(4), the prior incubation of catalyst 3a, NBS and MsOH might have
led to catalyst decomposition. Indeed, a complex mixture was ob-
tained when catalyst 3 was incubated with NBS for a few hours.
When using such incubated catalyst 3 in the asymmetric bromoe-
therification of 1, 2 was obtained in dramatically diminished er.
81:19
78.5:21.5
67.5:32.5
82:18
81.5:18.5
76:24
TfOH
TFA
9
10
11
Chloroacetic acid
(S)-(þ)-1,10-Binaphthyl-2,20-diyl
hydrogenphosphate
(R)-(þ)-1,10-Binaphthyl-2,20-diyl
hydrogenphosphate
Methane seleninic acid
Adamantane-1-sulfonic acid
1-Adamantanol
12
93
94:6
72.5:27.5
13
14
15
96
90
85
94:6
93:7
92:8
54:46
54.5:45.5
52:48
a
Reactions were conducted with alkenoic diol 1a (0.05 mmol), catalyst 3a
(0.005 mmol), acid (0.05 mmol) and NBS (0.06 mmol) in CH2Cl2 (1.5 mL) in the
absence of light.
b
Isolated yield.
c
Determined by 1H NMR.
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Z. Ke et al. / Tetrahedron xxx (2015) 1e7
5
Lewis-basic sulfide catalysts are susceptible to decay by stoi-
chiometric quantities of oxidants. It has been reported that tetra-
hydrothiophene could decompose through a thiocarbenium ion
intermediate when it was treated with N-chlorosuccinimide.10 In
our catalyst system, we suspect that a similar decomposition path-
way might occur. Intermediate 3-Br, which was generated from 3
and NBS, could undergo de-hydrobromination to give the thio-
carbenium ion B. Subsequent nucleophilic addition to B by nucleo-
philes such as water (from moisture) or the substrate’s hydroxyl
group could give a mixture of thioacetals C and D. (Scheme 6).
for high enantioselectivity to be achieved. A possible reason for this
observation could be that a more configurationally-stable bro-
miranium ion A, containing a relatively stable and dissociative
mesylate counter-anion, was formed. It would lead to less race-
mization and higher enantioselectivity.
As shown in Table 3, the addition of less or more than 1 equiv of
MsOH resulted in much reduced enantioselectivity of the bro-
moether products (Table 3, entries 2 and 4). In the absence of MsOH
additive (Table 3, entry 1), bromiranium ion intermediate E would
be formed (Scheme 9). As it contains a relatively more associative
succinimide counter-anion, it might be less configurationally-
stable as compared to A. Therefore, the reaction pathway in-
volving intermediate E would lead to poorer enantioselectivity due
to the racemization of the bromiranium ion through an olefin-to-
olefin degeneration.12 When adding 0.5 equiv of MsOH in the re-
action (Table 3, entry 2), a mixture of A and E would be present in
the reaction, leading to a lower overall er as compared to the result
in Table 3, entry 3. When adding 1.5 equiv of MsOH in the reaction
(Table 3, entry 4), excess amount of MsOH could catalyze the ra-
cemic bromoetherification, which would then reduce the er of the
reaction.
Scheme 6. A possible decomposition pathway when incubating catalyst 3 with NBS
and MsOH.
When the reaction was conducted at relatively high tempera-
tures (e.g., room temperature) (Scheme 3, eq 5), we speculate that
catalyst 3 might also decompose through ring-opening of the cyclic
sulfide system10 in addition to the decomposition pathway shown
in Scheme 7. Since 3-Br is a Swern-type intermediate,10 another
possible explanation is that the substrate’s alcohol group might be
oxidized (Scheme 6). These possible decomposition pathways
could consume both the catalyst and substrate, leading to lower ers
and yields of the desired product 2.
Scheme 9. Counteranions of the bromiranium intermediate.
In the course of our experiments, we found that the addition of
MsOH to the reaction mixture provided the best selectivities, even
when compared to other Brønsted acids. The possible reasons for
this observation were discussed below.13
Based on the acid additive screening results shown in Table 4,
several observations can be summarized as follows: (1) the pKa of
the acid seems to be important to the overall performance of the
cyclization, and the acidity of MsOH might be an optimal case
which could promote the reaction with high er; (2) the stereo-
chemistry of the counter-anion partner might not play a crucial role
in the enantio-determining step (Table 4, entries 5e6, 11e12); (3)
the er is significantly affected by the size of the counter-anion, and
a higher er could be obtained with a smaller size sulfonate (Table 4,
entries 2e4, 14). A possible explanation is that a larger-sized
counter-anion (e.g., adamantane sulfonate) might hinder the nu-
cleophilic attack of the hydroxyl group on the bromiranium ion.
Thus, the background uncatalyzed cyclization process might pro-
ceed well to give racemic products in the presence of a large
counteranion.
MsOH is a competent Brønsted acid for promoting both the
catalyzed and the uncatalyzed cyclization reactions. However, it
was observed that the catalyzed and uncatalyzed cyclizations have
similar reaction rates (Scheme 3 eq 1 vs Scheme 4 eq 3). If the rate
of the uncatalyzed racemic background reaction is comparable to
that of the reaction catalyzed by the chiral Lewis base, highly
enantiomerically enriched 2a should not be obtainable. Counter-
intuitively, we obtained 2a in high enantioselectivity using the
above system.14 The striking behavior of this catalytic system is
reminiscent of Jacobsen’s analysis of the asymmetric catalytic
pathway in the Povarov reaction.15 In that study, a similar obser-
vation was made in that a Brønsted acid catalyzed racemic back-
ground reaction was suppressed, a phenomenon that they ascribed
to ‘negative catalysis’.16
Scheme 7. Possible decomposition pathways of the catalyst
temperature.
3 at relatively high
Based on the results in Scheme 4 and Table 1, one of the
side reactions is the proton-mediated cyclization of 1 (Scheme 8).
In addition, it appears that low temperature is beneficial to the re-
action due to several aspects: (1) suppression of the proton-
mediated cyclization; (2) alleviation of catalyst decomposition
through pathways shown in Schemes 6 and 7; (3) retardation of the
substrate’s hydroxyl group oxidation (Scheme 6). We suspect that
MsOH might react with NBS to give MsOBr in situ (together with the
formation of the weakly acidic succinimide byproduct) which could
be a highly active brominating agent.11 This proposal could explain
bromoetherification being preferred over proton-mediated hal-
ocyclization when mixing 1a and MsOH, followed by the addition of
NBS. Indeed, when mixing NBS and MsOH in CDCl3, NBS disappeared
and molecular succinimide was formed. In addition, a new methyl
signal at 2.78 ppm (vs MsOH’s methyl signal at 2.63 ppm) was ob-
served which could be attributed to the formation of MsOBr.
Scheme 8. Plausible mechanism of the MsOH-mediated cyclization of 1a.
3.4. The role of MsOH
Very recently, Denmark and co-workers reported an interesting
phenomenon on ‘negative catalysis’ in the asymmetric carbo-
sulfenylation reaction promoted by Lewis basic selenide and
Earlier experiments demonstrated that a stoichiometric amount
of MsOH with respect to the substrate is an essential requirement
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6
Z. Ke et al. / Tetrahedron xxx (2015) 1e7
ethanesulfonic acid.14 In their study, it was found that the rate of
the Lewis basic selenide-catalyzed reaction is similar to the unca-
talyzed reaction, which is highly similar to our observation in the
bromoetherification of 1. A possible explanation for the inhibition
of the racemic background reaction under catalytic conditions may
be found in the buffering effect of the sulfonate ‘triple ion’.
In devising the mechanistic proposal of the bromoetherification
of 1, we attempted to rationalize our observations in line with
critical insights from Denmark’s studies: The true background re-
action under ‘catalytic conditions’ was significantly slower than the
uncatalyzed background reaction, and is therefore not accurately
represented by simply removing the catalyst. Based on Denmark’s
proposal, we believe that both sulfonate and succinimide ions
(necessary consequences of the formation of the catalytically active
species) were effective inhibitors of the racemic background
reaction.
On the basis of the aforementioned details, a mechanistic pro-
posal is constructed as depicted in Scheme 10. NBS is activated by
chiral cyclic sulfide catalyst 3 to give active species 3-Br through
a Lewis base activated Lewis acid mechanism. 3-Br then delivers
the Br asymmetrically to the olefin to give A. We propose that
MsOH facilitates the formation of the cyclic sulfide-Br complex 3-Br
through the protonation of succinimide (also see Section 3.3) and
enhances the turnover as described in Denmark’s proposal.14 For
the uncatalyzed reaction through intermediate G, the pathway
could be suppressed by the buffering effect of succinimide and
sulfonate anions.
uncatalyzed processes being similar, and (b) that excessive catalyst
loading leads to
enantioselectivity.
a
decrease in yield without affecting
5. Experimental section
5.1. General
All reactions that required anhydrous conditions were carried by
standard procedures under nitrogen atmosphere. Commercially
available reagents were used as received. The solvents were dried
over a solvent purification system from Innovative Technology. In-
frared spectra were recorded on a BIO-RAD FTS 165 FTIR spectro-
photometer and reported in wave numbers (cmꢀ1). Melting points
1
€
were determined on a BUCHI B-540b melting point apparatus. H
NMR and 13C NMR spectra were recorded on a Bruker ACF300
(300 MHz), Bruker DPX300 (300 MHz) or AMX500 (500 MHz)
spectrometer. Chemical shifts (
d
) are reported inppm relative toTMS
(d
0.00) for the 1H NMR and to chloroform (
d
77.0) for the 13C NMR
measurements. Optical rotations were recorded on a Jasco DIP-1000
polarimeter. Analytical thin layer chromatography (TLC) was per-
formed with Merck pre-coated TLC plates, silica gel 60F-254, layer
thickness 0.25 mm. Flash chromatography separations were per-
formed on Merck 60 (0.040e0.063 mm) mesh silica gel.
5.2. (3aS,4S,6S,6aS)-2,2,4,6-Tetramethyltetrahydrothieno[3,4-
d][1,3]dioxole 3c
A solution of the known dimesylate (916 mg, 2.64 mmol) and
sodium sulfide nonahydrate (freshly recrystallized in EtOH, 2.54 g,
10.58 mmol) were both charged into a biotage microwave vessel
(20 mL) and dissolved in DMF (15 mL). The reaction mixture was
then microwaved at 135 ꢁC for 5 min. The reactionwas monitored by
thin layer chromatography (TLC). Water (35 mL) was then added to
the mixture at room temperature and the aqueous layer was
extracted with diethyl ether (2ꢂ35 mL). The combined organic
layers were washed with water (2ꢂ35 mL) and dried over MgSO4.
After filtration, the solution was concentrated in vacuo (the evapo-
ration was realized carefully at room temperature). Purification by
flash column chromatography (hexane/ethyl acetate 25:1) afforded
3c (355 mg, 71%) as a colorless oil. ½a D25
ꢀ245 (c 1.0, CHCl3); IR (KBr):
ꢃ
2975, 2893,1453,1241,1184,1077 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
4.44 (dd, J¼4.3, 2.1 Hz, 2H), 3.27 (m, 2H), 1.47 (s, 6H), 1.32 (d,
J¼6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d 119.7, 81.5, 34.7, 27.1,18.0;
HRMS (EI) calcd for C9H16O2S [M]þ: 188.0871; found: 188.0870.
5.3. (3aR,4S,8S,8aR)-2,2-Dimethylhexahydrothiepino[4,5-d]
[1,3]dioxole-4,8-diol 3e
3e was prepared using a literature procedure.6 White solid, mp
93e94 ꢁC; ½a 2D5
ꢃ
ꢀ122 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3):
d
4.27 (m, 4H), 3.05 (br s, 2H), 2.95 (dd, J¼15.0, 4.8 Hz, 2H), 2.54 (dd,
J¼15.0, 5.8 Hz, 2H), 1.38 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 108.5,
Scheme 10. Plausible mechanism of the bromoetherification of 1.
75.7, 66.0, 37.3, 26.8; HRMS (EI) calcd for C9H16O4S [M]þ: 220.0769;
found: 220.0770.
4. Conclusion
5.4. (3aS,4S,8S,8aS)-4,8-Bis(benzyloxy)-2,2-
dimethylhexahydrothiepino[4,5-d][1,3]dioxole 3f
Research into the enantioselective Lewis base catalyzed,
Brønsted acid promoted bromoetherification reaction has offered
insights which account for previously observed interesting phe-
nomena. The effect of (1) catalyst structure, (2) temperature and
addition sequence of components, (3) catalyst loading, and (4)
MsOH additive were discussed. The possible reasons of some un-
usual observations are (a) the inclusion of MsOH affords high
enantioselectivity, despite the rate of the catalyzed reaction and
To 125 mg (3.12 mmol) of 60% NaH was added under nitrogen
7 mL of THF and 568 mg (2.58 mmol) of the thiepane derivative 3e.
The reaction mixture was stirred for 30 min and treated with
a solution of 0.3 mL of benzyl bromide and 2 mg (0.012 mmol) of KI
in 1.8 mL of THF. After 7 h, 125 mg (3.12 mmol) of 60% NaH and
0.3 mL (2.71 mmol) of benzyl bromide were added. Stirring was
continued for 12 h, then H2O was added and the mixture extracted
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Z. Ke et al. / Tetrahedron xxx (2015) 1e7
7
with Et2O (3ꢂ30 mL). The organic layer was dried and evaporated
to give 0.99 g (2.39 mmol, 96%) of 3f as a yellow solid which was
purified by flash chromatography (SiO2; CH2Cl2/hexane 3:1), giving
J¼3.2 Hz, 2H), 4.33 (dd, J¼9.5, 8.2 Hz, 2H), 4.17 (dd, J¼9.5, 5.7 Hz,
2H), 4.08 (m, 2H), 1.29 (s, 18H); 13C NMR (125 MHz, CDCl3):
156.0,
144.1, 126.3, 114.1, 78.3, 66.8, 48.0, 34.1, 31.5; HRMS (EI) calcd for
C
26H36O4S [M]þ: 444.2334; found: 444.2330.
d
a solid with mp 56e57 ꢁC. ½a D25
ꢃ
ꢀ40.1 (c 1.0, CHCl3); IR (KBr): 2945,
1246, 1184, 1078 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
7.40 (m, 10H),
4.93 (d, J¼12.0 Hz, 2H), 4.72 (d, J¼12.0 Hz, 2H), 4.70 (m, 2H), 4.20
Acknowledgements
(m, 2H), 2.93 (dd, J¼15.1, 5.1 Hz, 2H), 2.63 (dd, J¼15.1, 6.1 Hz, 2H),
1.56 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 138.7, 128.3, 127.6, 127.5,
We thank the financial support from National University of
Singapore (grant no. 143-000-605-112), A*STAR-Public Sector
Funding (grant no. 143-000-536-305), and GSK-EDB (grant no. 143-
000-564-592).
109.3, 77.6, 74.1, 73.5, 36.8, 26.9; HRMS (EI) calcd for C23H28O4S
[M]þ: 400.1708; found: 400.1710.
5.5. 6,60-((3aS,4S,8S,8aS)-2,2-Dimethylhexahydrothiepino[4,5-
d][1,3]dioxole-4,8-diyl)bis(oxy)bis(4-chloro-2,5-
diphenylpyrimidine) 3g
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.09.016.
3g was prepared in analogy to above procedure for 3f. White
solid, mp 142e143 ꢁC; ½a D25
ꢃ
ꢀ52.3 (c 1.0, CHCl3); IR (KBr): 2949,
1246, 1183, 1078 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
8.42 (m, 4H),
References and notes
7.45 (m, 16H), 5.98 (t, J¼5.1 Hz, 2H), 4.44 (m, 2H), 3.31 (dd, J¼15.6,
5.1 Hz, 2H), 3.01 (dd, J¼15.6, 5.7 Hz, 2H), 0.76 (s, 6H); 13C NMR
1. For recent reviews, see: (a) Chen, G. F.; Ma, S. M. Angew. Chem., Int. Ed. 2010, 49,
8306; (b) Castellanos, A.; Fletcher, S. P. Chem.dEur. J. 2011, 17, 5766; (c) Tan, C.
K.; Zhou, L.; Yeung, Y.-Y. Synlett 2011, 1335; (d) Snyder, S. A.; Treitler, D. S.;
Brucks, A. P. Aldrichimica Acta 2011, 44, 27; (e) Hennecke, U. Chem.dAsian. J.
2012, 7, 456; (f) Denmark, S. E.; Kuester, W. E.; Burk, M. T. Angew. Chem., Int. Ed.
2012, 51, 10938; (g) Murai, K.; Fujioka, H. Heterocycles 2013, 87, 763; (h) Tan, C.
K.; Yeung, Y.-Y. Chem. Commun. 2013, 7985.
(75 MHz, CDCl3):
d 166.5, 162.3, 159.7, 135.9, 131.5, 131.4, 130.2,
128.5, 128.3, 128.1, 118.5, 109.5, 75.3, 71.5, 35.6, 25.8; HRMS (EI)
calcd for C41H34Cl2N4O4S [M]þ: 748.1678; found: 748.1678.
5.6. (S)-3,5-Dihydrodinaphtho[2,1-c:10,20-e]thiepine 3h
2. For selected recent examples, see: (a) Huang, D.; Liu, X.; Li, L.; Cai, Y.; Liu, W.;
Shi, Y. J. Am. Chem. Soc. 2013, 135, 8101; (b) Zeng, X.; Miao, C.; Wang, S.; Xia, C.;
Sun, W. Chem. Commun. 2013, 2418; (c) Jaganathan, A.; Staples, R. J.; Borhan, B. J.
Am. Chem. Soc. 2013, 135, 14806; (d) Wolstenhulme, J. R.; Rosenqvist, J.; Lozano,
O.; Ilupeju, J.; Wurz, N.; Engle, K. M.; Pidgeon, G. W.; Moore, P. R.; Sandford, G.;
Gouverneur, V. Angew. Chem., Int. Ed. 2013, 52, 9796; (e) Romanov-Michailidis,
3h was prepared using a literature procedure.17 Brown solid, mp
177e178 ꢁC; ½a 2D5
ꢃ
þ280 (c 0.2, CHCl3); IR (KBr): 2915, 2833,
3.43 (s, 4H), 7.20e8.02 (m,
133.4, 133.2, 132.5, 131.2, 128.9,
677 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
12H); 13C NMR (125 MHz, CDCl3):
d
ꢀ
ꢀ
F.; Guenee, L.; Alexakis, A. Angew. Chem., Int. Ed. 2013, 52, 9266; (f) Tripathi, C.
B.; Mukherjee, S. Angew. Chem., Int. Ed. 2013, 52, 8450; (g) Brindle, C. S.; Yeung,
C. S.; Jacobsen, E. N. Chem. Sci. 2013, 4, 2100; (h) Zhang, W.; Liu, N.; Schiene-
beck, C. M.; Zhou, X.; Izhar, I. I.; Guzei, I. A.; Tang, W. Chem. Sci. 2013, 4, 2652; (i)
Hu, D. X.; Shibuya, G. M.; Burns, N. Z. J. Am. Chem. Soc. 2013, 135, 12960; (j)
Zhang, Y.; Xing, H.; Xie, W.; Wan, X.; Lai, Y.; Ma, D. Adv. Synth. Catal. 2013, 355,
68; (k) Yin, Q.; You, S.-L. Org. Lett. 2013, 15, 4266; (l) Mori, K.; Ichikawa, Y.;
Kobayashi, M.; Shibata, Y.; Yamanaka, M.; Akiyama, T. J. Am. Chem. Soc. 2013,
135, 3964.
127.8, 126.4, 126.1, 125.7, 125.1, 31.9; HRMS (EI) calcd for C22H16
S
[M]þ: 312.0973; found: 312.0971.
5.7. (3aS,4S,6S,6aS)-2,2-Dimethyl-4,6-bis((4-tert-pentylphe-
noxy)methyl) tetrahydrothieno[3,4-d][1,3]dioxole 3i
3i was prepared in analogy to above procedure for 3c. White
3. (a) Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Org. Lett. 2011, 13, 2738; (b) Zhou, L.; Chen, J.;
Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2011, 133, 9164; (c) Tan, C. K.; Le, C.;
Yeung, Y.-Y. Chem. Commun. 2012, 5793; (d) Jiang, X.; Tan, C. K.; Zhou, L.; Yeung,
Y.-Y. Angew. Chem., Int. Ed. 2012, 51, 7771; (e) Cheng, Y. A.; Chen, T.; Tan, C. K.;
Heng, J. J.; Yeung, Y.-Y. J. Am. Chem. Soc. 2012, 134, 16492; (f) Zhou, L.; Tay, D. W.;
Chen, J.; Leung, G. Y. C.; Yeung, Y.-Y. Chem. Commun. 2013, 4412; (g) Chen, F.;
Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc. 2013, 135, 1232.
solid, mp 130e131 ꢁC; ½a D25
ꢀ33.4 (c 1.0, CHCl3); IR (KBr): 2964,
ꢃ
2363,1608,1512,1245, 1183, 1079 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
7.29 (d, J¼8.8 Hz, 4H), 6.93 (d, J¼8.8 Hz, 4H), 4.70 (dd, J¼4.5,1.9 Hz,
2H), 4.46 (dd, J¼10.0, 5.7 Hz, 2H), 4.13 (dd, J¼10.0, 7.0 Hz, 2H), 3.66
(m, 2H), 1.67 (q, J¼7.5, 4H), 1.57 (s, 6H), 1.32 (s, 12H), 0.74 (t,
4. For other haloetherifications, see: (a) Kang, S. H.; Lee, S. B.; Park, C. M. J. Am.
J¼7.2 Hz, 6H); 13C NMR (125 MHz, CDCl3):
d 156.2, 142.1, 126.8,
120.4, 114.4, 81.6, 68.7, 38.8, 37.2, 36.9, 28.5, 27.1, 9.1; HRMS (EI)
Chem. Soc. 2003, 125, 15748; (b) Kwon, H. Y.; Park, C. M.; Lee, S. B.; Youn, J. H.;
€
Kang, S. H. Chem.dEur. J. 2008, 14, 1023; (c) Hennecke, U.; Muller, C. H.;
€
calcd for C31H44O4S [M]þ: 512.2960; found: 512.2962.
Frohlich, R. Org. Lett. 2011, 13, 860; (d) Huang, D.; Wang, H.; Xue, F.; Guan, H.; Li,
L.; Peng, X.; Shi, Y. Org. Lett. 2011, 13, 6350; (e) Denmark, S. E.; Burk, M. T. Org.
Lett. 2012, 14, 256.
5. Ke, Z.; Tan, C. K.; Chen, F.; Yeung, Y.-Y. J. Am. Chem. Soc. 2014, 136, 5627.
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Merrer, Y.; Fuzier, M.; Dosbaa, I.; Foglietti, M.-J.; Depezay, J.-C. Tetrahedron 1997,
53, 16731.
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selectivity in analogous iodocyclization reactions was reported. See Dobish, M.
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5.8. (3aS,4S,6S,6aS)-4,6-Bis((4-tert-pentylphenoxy)methyl)
tetrahydrothieno[3,4-d][1,3]dioxole 3j
ꢀ
3j was prepared in analogy to above procedure for 3c. White
solid, mp 101e102 ꢁC; ½a D25
ꢃ
ꢀ98.5 (c 1.0, CHCl3); IR (KBr): 2965,
2393,1508,1241,1184,1027 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
7.30
(d, J¼8.8 Hz, 4H), 6.93 (d, J¼8.8 Hz, 4H), 5.65 (s, 2H), 4.62 (dd, J¼4.4,
1.9 Hz, 2H), 4.47 (dd, J¼9.8, 5.7 Hz, 2H), 4.15 (dd, J¼9.8, 7.2 Hz, 2H),
3.69 (m, 2H), 1.68 (q, J¼7.5 Hz, 4H), 1.33 (s, 12H), 0.75 (t, J¼7.2 Hz,
2840.
6H); 13C NMR (125 MHz, CDCl3):
d 156.0, 142.1, 126.8, 114.1, 104.8,
11. It has been proposed that AcOH could react with NBS to give AcOBr. For ref-
erences, see: (a) Chen, K.; Baran, P. S. Nature 2009, 459, 824; (b) Chen, K.;
Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 7247; (c) Levine, S. G.; Wall,
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Int. Ed. 1993, 32, 272.
82.6, 68.4, 38.1, 37.2, 36.8, 28.5, 9.0; HRMS (EI) calcd for C29H40O4S
[M]þ: 484.2647; found: 484.2641.
12. Brown, R. S. Acc. Chem. Res. 1997, 30, 131.
13. For sulfetherification, see Wang, H.; Huang, D.; Cheng, D.; Li, L.; Shi, Y. Org. Lett.
5.9. (2S,3S,4S,5S)-2,5-Bis((4-tert-butylphenoxy)methyl)tetra-
hydrothiophene-3,4-diol 3k
2011, 13, 1650.
14. Denmark, S. E.; Chi, H. M. J. Am. Chem. Soc. 2014, 136, 3655.
15. (a) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science 2010, 327, 986;
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3k was prepared by conventional hydrolysis of the ketal. White
solid, mp 134e135 ꢁC; ½a D25
ꢀ136 (c 1.0, CHCl3); IR (KBr): 3360,
ꢃ
2965, 2363,1608,1241,1184,1027 cmꢀ1; 1H NMR (500 MHz, CDCl3):
d
7.30 (d, J¼8.8 Hz, 4H), 6.86 (d, J¼8.8 Hz, 4H), 5.63 (s, 2H), 4.50 (d,
17. Foubelo, F.; Moreno, B.; Soler, T.; Yus, M. Tetrahedron 2005, 61, 9082.
Please cite this article in press as: Ke, Z.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.09.016