Studies toward Lewis basic thiocarbamate and thiourea mediated bromolactonization: The effect of a trace amount of water on the reactivity and enantioselectivity

Article abstract of DOI:10.1016/j.tetlet.2011.07.049

The effects of trace amounts of water on thiocarbamate- and thiourea-catalyzed bromolactonization reactions are studied. It was found that the thiourea- and the N-Me thiocarbamate-catalyzed bromolactonization reactions were sensitive to trace amounts of m

Full text of DOI:10.1016/j.tetlet.2011.07.049

Tetrahedron Letters 52 (2011) 4892–4895
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Studies toward Lewis basic thiocarbamate and thiourea mediated
bromolactonization: the effect of a trace amount of water on the reactivity
and enantioselectivity
⇑
Chong Kiat Tan, Feng Chen, Ying-Yeung Yeung
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
The effects of trace amounts of water on thiocarbamate- and thiourea-catalyzed bromolactonization
reactions are studied. It was found that the thiourea- and the N–Me thiocarbamate-catalyzed bromolact-
onization reactions were sensitive to trace amounts of moisture. In contrast, the N–H thiocarbamate-
catalyzed bromolactonization proceeded equally smoothly in both anhydrous and non-anhydrous
solvents.
Received 16 June 2011
Revised 30 June 2011
Accepted 11 July 2011
Available online 21 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Bromolactonization
Catalysis
Water effect
Lewis base
Asymmetric reaction
Halolactonization is an important reaction in organic synthesis
as the corresponding halolactones are very useful building blocks
for many natural products and drug molecules.1 Recently, the
study of catalytic halolactonization has undergone a renaissance.
In particular, bromolactonization has been studied extensively
using N-bromosuccinimide (NBS) as the halogen source. Various
NBS activators, such as Lewis acids,2 Lewis bases,3 hydrogen-
bonding type catalysts,4 amides,5 and aryl iodides6 have been re-
ported. Highly reactive brominating sources (e.g., Et2SBrÁSbCl5Br)
were also studied as stoichiometric reagents, which are potentially
useful for bromolactonization.7 Despite these significant advances,
the catalytic and enantioselective versions of halolactonizations,
especially bromolactonization, are still lacking because a suitable
catalytic system remains elusive.8–10
effect, which led us to our eventual selection of the thiocarbamate
motif over that of other structurally similar compounds.
At the outset of this work, we were aware of the various
attempts to activate NBS as described above. Since a suitable cata-
lytic asymmetric system had yet to emerge from these studies, we
decided to begin our search by examining the feasibility of utilizing
an underexplored Lewis basic sulfur activated electrophilic bromi-
nating source for enantioselective bromolactonization.12 Indeed,
MeO
S
O
N
H
O(cinchonine)
O
Recently, we described an efficient amino-thiocarbamate
Br
OH
MeO
1
(10 mol%)
R
catalyzed enantioselective bromolactonization.11 A number of
NsNH2 (50 mol%)
NBS, CHCl3/toluene (1:2), -78 o
O
R
c-lactones 3 and d-lactones 6 were prepared with high ee values.
2
3
C
up to 99% yield
93% ee
Mechanistic studies show that both the S and the N–H of the thio-
carbamate are responsible for the high enantioselectivity (Scheme
1). The exquisite need for the thiocarbamate is intriguing as it is
not a common functional group in organocatalysis. Amino-thiocar-
bamates 1 and 4 were developed after an extensive study of the
readily available thiocarbamates and thioureas 7–10 (Table 1). In
this report, we describe the groundwork, in particular the water
MeO
S
O
O
R
N
H
O(quinidine)
4(10 mol%)
R
OH
MeO
NBS, CHCl3/toluene (1:2), -78 o
C
O
Br
5
6
up to 99% yield
95% ee
⇑
Corresponding author. Tel.: +65 65167760; fax: +65 67791691.
E-mail address: chmyyy@nus.edu.sg (Y.-Y. Yeung).
Scheme 1. Asymmetric bromolactonization of alkenoic acids 2 and 5.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.049

C. K. Tan et al. / Tetrahedron Letters 52 (2011) 4892–4895
4893
Table 1
Lewis basic sulfur promoted bromolactonization
cat. (10 mol%)
alkenoic acid
bromolactone
NBS (1.2 equiv)
-78 oC, CH2Cl2
Catalyst:
Me
S
Me
Me
S
N
N
N
Ph
Ph
Ph
N
H
O
iPr
7
8
S
S
N
O
N
Me
N
N
H
10
9
Entrya
Alkenoic acid
Bromolactone
Catalyst
Time (h)
Yieldb (%), ee (%)
1
2
3
4
5
7
8
9
1
16
5
4
4
4
96, 0
95, 0
68, 0
95, 50
90, 12
O
OH
Ph
O
Br
O
10
2a
Ph
3a
6
7
7
4
40
12
75, 0
91, 70
O
O
Ph
OH
O
5a
Ph
6a
Br
a
Reactions were carried out with alkenoic acid (0.20 mmol), NBS (0.22 mmol), and catalyst (0.01 mmol) in CH2Cl2 (2 mL) at À78 °C.
b
Isolated yield.
Table 2
Effect of the water content on the reaction rate
O
O
O
S
O
O
cat. (5 mol%)
NBS (1.2 equiv)
CH2Cl2
+
H
Ph
6b
Ph
OH
Ph
6a
Br
Br
5a
Catalyst:
S
Me
Me
12 R = H
13
11
Ph
N
N
N
R
O
R = Me
Me Me
Entrya
Catalyst
Water contentb (ppm)
Temp (°C)
Time (min)
Yieldc (6a + 6b, %)
1
2
3
4
5
6
7
8
9
11
11
11
11
12
12
13
13
230
5
230
5
230
5
230
5
0
0
5
5
95 + 4
40 + 2
95 + 2
29 + 1
91 + 4
91 + 4
93 + 4
81 + 7
<1
À15
À15
À15
À15
À15
À15
0
10
10
10
10
10
10
30
None
230
a
b
c
Reactions were carried out with alkenoic acid 5a (0.20 mmol), NBS (0.22 mmol), and catalyst (0.01 mmol) in CH2Cl2 (2 mL).
Water content was determined using a Metrohm 831 KF coulometer.
The conversion yields were the average of two experiments and determined based on 1H NMR spectroscopy.
such a sulfur–bromine interaction has already been elucidated
using an X-ray crystallographic study.13
Thus, a number of C@S containing molecules (7–10, Table 1)
were screened for their potential as bromolactonization catalysts.

4894
C. K. Tan et al. / Tetrahedron Letters 52 (2011) 4892–4895
Table 3
The catalytic ability of the molecules was investigated with the
unsaturated carboxylic acids 2a and 5a and NBS as the stoichiom-
etric brominating agent. In general, the thioureas and thiocarba-
mates were found to be competent bromolactonization catalysts
and were able to furnish moderate ees in some cases (Table 1,
entries 4 and 7).
However, in the course of our research, the efficiency and the
enantioselectivity obtained with the N–Me thiocarbamate 10 and
thioureas 7 and 9 catalyzed bromolactonization reactions were
hard to be reproduced unless strict control of the moisture content
was applied. In stark contrast, the yields and ees of the N–H thio-
carbamate 1, 4, and 8 catalyzed reactions were stable despite
applying less rigor in our reaction set-up. The yields and enantiose-
lectivities of the amino-thiocarbamate 1 and 4 catalyzed bromol-
actonizations (Scheme 1) were reproducible even when
non-anhydrous NBS was used.11,14
Effect of the water content on the enantioselectivity
O
O
O
cat. (10 mol%), NBS (1.2 equiv)
CHCl3/toluene (1:2)
Ph
OH
Ph
6a
-78 oC, 44 h
Br
5a
Entrya
Catalyst
Water contentb (ppm)
Yieldc (%)
ee (%)
1
2
3
4
5
1
1
46
672
46
672
672
96
98
80
94
20
76
74
17
10
0
10
10
None
To obtain a better understanding of this phenomenon, a careful
study of the relationship between the water content and the bro-
molactonization reaction rate was performed using the simplified
thiourea 11, and thiocarbamates 12, and 13 as the catalysts (Table
2) with alkenoic acid 5a as the test substrate.15
a
Reactions were carried out with alkenoic acid 5a (0.15 mmol), NBS (0.18 mmol)
and catalyst (0.015 mmol) in CHCl3/toluene (4.5 mL, 1:2 v/v).
b
Water content was determined using a Metrohm 831 KF coulometer.
Isolated yield.
c
From this study it emerged that the rate of the thiourea 11 cat-
alyzed bromolactonization was highly dependent on the water
content. For an anhydrous system (water content was 5 ppm),
42% (0 °C, 5 min) and 30% yields (À15 °C, 10 min) of lactone 6 were
achieved (Table 2, entries 2 and 4). On the other hand, the same
reaction proceeded smoothly in the relatively high water content
(230 ppm) system and high conversions (99% at 0 °C and 5 min;
97% at À15 °C and 10 min) were observed (Table 2, entries 1 and
3). The effect of water on the bromolactonization using thiocarba-
mate catalyst 12 was less apparent. The results showed that thio-
carbamate 12 was able to catalyze the reaction equally smoothly
using both anhydrous and non-anhydrous systems (Table 2, entries
5 and 6). In contrast, the effect of the water content on the reaction
rate was quite significant when the N-methylated thiocarbamate
13 was used (Table 2, entries 7 and 8). In the absence of any cata-
lyst, the reaction was sluggish (Table 2, entry 9), thus proving that
water alone did not catalyze the bromolactonization.16
The effect of water on the enantioselectivity of the asymmetric
bromolactonization was also investigated. A set of parallel bromol-
actonization reactions under anhydrous (water content = 46 ppm)
and non-anhydrous (water content = 672 ppm) conditions were
performed using catalysts 1 and 10 (Table 3). As shown, the enanti-
oselectivity conferred by 10 suffered a drop under non-anhydrous
conditions (Table 3, entries 3 and 4). In comparison, catalyst 1 was
only affected slightly by moisture (Table 3, entries 1 and 2).
The effect of water on the bromolactionization was rather
intriguing as it had led to an increased reaction rate, but a de-
creased enantioselectivity when the N–Me thiocarbamate 10 was
used. Since water was proven not to catalyze the bromolactoniza-
tion (Table 2, entry 9), the promotion of reaction rate under high
moisture content appears to proceed via another pathway.
Since the complex formed between the Lewis basic sulfur and
NBS (e.g., 14) is believed to be the active intermediate, one possi-
bility is that water might collapse the complex to afford a new spe-
cies which is: (1) a better bromination mediator than the N–Me
thiocarbamate and the thiourea; (2) catalyzing the reaction
through a non-asymmetric pathway. Although the nature of the
possible alternative pathway due to the moisture remains un-
clear17 and requires further investigation, the small interference
of water on the N–H thiocarbamate catalyzed reaction was the
deciding factor for our eventual selection of the thiocarbamate mo-
tif for further development. The stability of the N–H thiocarbamate
may also suggest that the N–H thiocarbamate–NBS complex (e.g.,
15, a proposed intermediate in the previous study)11 could be more
resistant to moisture-promoted decomposition (Fig. 1).
O
Br
S
N
O
O
N
O
Br
H
S
N
N
X
O
Me
X = O, NMe
14
15
Figure 1. Catalyst–NBS complexes 14 and 15.
In summary, we have demonstrated the stability of N–H thioc-
arbamates over thiourea and N–Me thiocarbamate in bromolact-
onization reactions under high moisture content. The purpose of
our study was not to rule out the possibility of developing asym-
metric bromination or other halogenation reactions using tetra-
substituted thiourea or N–Me thiocarbamate as the catalyst. In-
stead, we wanted to show that the observation of high tolerance
to moisture led us to select the N–H thiocarbamate for further
development as a chiral catalyst for asymmetric bromolactoniza-
tion. The less moisture sensitive thiocarbamate is operationally
more convenient to use in which no rigorous moisture control is
necessary.
Acknowledgment
We thank the National University of Singapore for financial sup-
port (Grant No. 143-000-428-112).
References and notes
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16. Representative procedure for the anhydrous reaction: The alkenoic acid
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into a flame-dried two-necked round-bottomed-flask and evacuated under
vacuum for 4 h. The flask was shielded from light by wrapping in aluminum
foil. Thereafter, the contents were subjected to 3 cycles of vacuum evacuation
and nitrogen flushing.
A continuous flow of nitrogen was maintained
throughout the reaction. Anhydrous (5 ppm H2O content) CH2Cl2 (2 mL) was
then injected into the flask and the mixture was stirred at À15 °C (dry ice in an
ethylene glycol bath). N-Bromosuccinimide (42.7 mg, 0.24 mmol, 1.2 equiv)
was added and the reaction was monitored by TLC. The reaction mixture was
quenched with sat. Na2SO3 (2.0 mL) at À15 °C and then warmed to 25 °C. The
solution was acidified with aqueous HCl (10%) dropwise until pH 2.0. The crude
product and unreacted starting material were then extracted with CH2Cl2
(3 Â 5 mL). The combined extracts were concentrated in vacuo. The conversion
yield was determined via integration of the corresponding peaks in the 1H NMR
spectra. The physical data of the lactone products were in full accordance with
literature values.
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