Efficient medium ring size bromolactonization using a sulfur-based zwitterionic organocatalyst

Article abstract of DOI:10.1021/ja307210n

Catalytic bromolactonization of long-chain olefinic acids resulting in the efficient synthesis of medium-sized lactones is reported using a zwitterionic catalyst and stoichiometric N-bromosuccinimide halogen source. The reaction was found to be more efficient at 0 °C than at room temperature, which could be attributed to the temperature dependence of the zwitterionic catalyst.

Full text of DOI:10.1021/ja307210n

Communication
pubs.acs.org/JACS
Efficient Medium Ring Size Bromolactonization Using a Sulfur-Based
Zwitterionic Organocatalyst
Yi An Cheng, Tao Chen, Chong Kiat Tan, Jun Jie Heng, and Ying-Yeung Yeung*
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
S
* Supporting Information
used as the stoichiometric halogen source in the medium-sized
iodolactone formation.10 Herein we describe a facile and
ABSTRACT: Catalytic bromolactonization of long-chain
olefinic acids resulting in the efficient synthesis of medium-
sized lactones is reported using a zwitterionic catalyst and
stoichiometric N-bromosuccinimide halogen source. The
reaction was found to be more efficient at 0 °C than at
room temperature, which could be attributed to the
temperature dependence of the zwitterionic catalyst.
efficient approach toward the construction of medium-sized
lactone using a zwitterion as the catalyst (5 mol %) and N-
bromosuccinimide (NBS) as the stoichiometric halogen source.
Zwitterion 1a was used in our study, and 1a can easily be
synthesized using Ishihara’s approach by a one-step reaction
between 3,5-(bistrifluoromethyl)phenyl isothiocyanate and
N,N-dimethylaminopyridine (DMAP). The structure of 1a
was unambiguously confirmed by an X-ray crystallographic
study.11 Surprisingly, this interesting class of catalyst has only
been applied in the trans-esterification reactions.12 In fact,
zwitterionic catalysts are useful in organic synthesis. For
instance, Ooi et al. recently developed several elegant
zwitterionic protocols which were found to be useful in some
important reactions.13
In electrophilic halolactonization, a widely accepted mech-
anism is that an electrophilic halogen is first transferred from a
halogen source to an olefin to form a halonium ion, followed by
an intramolecular attack by a carboxylate group.9 Zwitterion 1a
contains an anionic sulfur and a cationic nitrogen centers
(Scheme 1 and Figure S1).12,14 We rationalize that the basic
edium ring size lactones, seven- to nine-membered
Mlactones, for example, are the fundamental units of many
natural products.1 However, the synthesis of these medium-
sized lactones remains a challenging task, in which both
enthalpic and entropic factors impede the cyclization of a linear
substrate to form a medium-sized ring.2 A substrate with a long
carbon backbone has a high degree of conformational flexibility,
and consequently negative entropic change results during the
ring closing reaction. The enthalpic factor arises from several
steric factors, of which transannular strain is the most highly
prevalent in medium-ring formation.3 Illuminati and co-workers
demonstrated that such cyclizations are difficult to achieve as
the rate of cyclization of ω-bromoalkanoic acids to form seven-
membered lactones were found to be more than 104 times
slower, and eight- and nine-membered lactones 106 times
slower, relative to the formation of five-membered lactones.4
Several ring closure reactions of bifunctional aliphatic
molecules, including olefin metathesis5 and lactonization
using hydroxyl carboxylic acid substrates,6 have been
documented.7 High-dilution and/or slow addition techniques
are usually employed to avoid undesired intermolecular
reaction between the substrates. To overcome the thermody-
namic barriers to the cyclization, high temperature or metal-
based catalysts is sometimes used.8 Hence, a mild and efficient
method to synthesize such medium rings would be highly
desirable and is envisaged to have great utility in organic
synthesis.
Scheme 1. Strategy of Zwitterion Catalyzed
Bromolactonization
Halolactonization of olefinic substrates is a powerful method
in the formation of lactones. The resultant halogens on the
lactones can easily be manipulated, which provide flexible
handles for further functionalization. Significant efforts have
been devoted to research on various methods to synthesize
small halolactones, i.e., five- and six-membered lactones.9 In a
sharp contrast, the application of halolactonization to medium-
ring lactone synthesis is very uncommon since a suitable
reaction protocol is elusive. A representative example was
reported by Rousseau and co-workers, in which a highly
reactive bis(sym-collidine)iodine(I) hexafluorophosphate was
Received: July 23, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja307210n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
sulfur in zwitterion 1a could react with NBS to give
intermediate A; this interaction could effect the dissociation
of NBS and could offer a highly electrophilic Br source
(Scheme 1).15 Ion exchange between the succinimide anion
and the carboxylic acid could next give the corresponding
ammonium carboxylate, and the sulfur activated bromide could
react with the olefin to yield intermediate B. The proximity of
the carboxylate anion and the bromonium ion ring could then
facilitate the cyclization to furnish the lactone, and zwitterion
1a could be regenerated.
Table 2. Bromolactonization of 2c
To test this hypothesis, we examined the bromolactonization
of 4-pentenoic acid (2a) and NBS in CH2Cl2 at 25 °C (Table
1). In the absence of catalyst, the reaction was sluggish and
a
Table 1. Bromolactonization of 2 Using Different Catalysts
temp
(°C)
yield
(%)
entry
catalyst
time
(h)
isolated yield
(%)
entry
catalyst
substrate, n
1
2
1a
1a
25
0
25
54
1
2
3
4
5
6
7
8
none
1a
2a, 1
2a, 1
2a, 1
2a, 1
2a, 1
2a, 1
2a, 1
2b, 2
54
0.75
5
99
92
69
92
49
94
92
89
3
DMAP
DMAP
1a
25
0
23
DMAP
DABCO
DMF
DBU
HMPA
1a
4
19
3
5
−8
−15
−52
−78
0
36
18
7
6
1a
9
7
1a
trace
trace
trace
trace
15
3.5
6
8
1a
9
1b
a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
SnCl4
DBU
DABCO
Ph3P
Ph3PS
(Me2N)2CS
1c
0
Reactions were carried out with olefinic acid 2 (0.25 mmol), catalyst
(0.025 mmol), NBS (0.5 mmol) in CH2Cl2 (5.0 mL). DABCO = 1,4-
diazabicyclo[2.2.2]octane, DBU = diazabicyclo[5.4.0]undec-7-ene,
HMPA = hexamethylphosphamide.
0
0
10
0
trace
trace
trace
10
0
0
completed in 54 h (Table 1, entry 1). In the presence of 10 mol
% of 1a, the reaction rate was increased dramatically, and the
lactonization was complete in 45 min (Table 1, entry 2). A
comparison of the effect of some common Lewis base catalysts
is listed in Table 1, showing the superiority of the catalytic
activity of zwitterion 1a.
0
1d
0
33
1e
0
33
1f
0
46
1g
0
30
1h
0
12
Having demonstrated the catalytic ability of 1a, we further
examined the lactonization of larger ring systems. Bromolacto-
nization of 5-hexenoic acid (2b) proceeded smoothly,
producing lactone 3b in 89% (Table 1, entry 8). The formation
of seven-membered lactone was less effective, in which 25%
yield of 3c was obtained after 6 h (Table 2, entry 1). Attempts
to vary the reaction temperature, interestingly, led us to identify
that the reaction proceeded smoother at lower temperature; at
0 °C, 54% of lactone 3c was isolated in 6 h, with the use of 5
mol % of 1a (Table 2, entry 2). In comparison, a lower yield
was obtained at 0 °C than at 25 °C when using DMAP as the
catalyst (Table 2, entries 3 and 4). Other catalysts including
N,N-[3,5-bis(trifluoromethyl)phenyl]thiourea (catalyst 1b),
Lewis acidic (Table 2, entry 10) and basic (Table 2, entries
11−15) catalysts displayed little or no reactivity. Catalysts with
different N-Ar substituents (i.e., catalyst 1c−f) and amino
group (i.e., catalyst 1g) returned with lower conversions (Table
2, entries 16−20). When the sulfur atom was replaced with
oxygen (i.e., catalysts 1h and 1i), the product yield was greatly
diminished and demonstrated the importance of the sulfur as
the catalytic center (Table 2, entries 21 and 22). Interestingly,
catalysts 1j and 1k gave a lower yield than 1a, suggesting that
the space between the cation and the anion may be critical
(Table 2, entries 23 and 24). In the investigation of different
1i
0
17
1j
0
trace
9
1k
0
b
25
1a
0
trace
27
c
26
1a
0
a
Reactions were carried out with 6-heptenoic acid (2c) (0.25 mmol),
catalyst 1 (0.0125 mmol), NBS (0.5 mmol) in CH2Cl2 (5.0 mL). The
yields were isolated yields. N-chlorosuccinimide was used as the
halogen source. N-iodosuccinimide was used as the halogen source.
b
c
halogen sources, it was found that both N-chlorosuccinimide
and N-iodosuccinimide did not perform better than NBS
(Table 2, entries 25 and 26).
The scope and utility of this reaction are indicated by the 12
examples listed in Table 3. Excellent regioselectivities were
observed for the formation of seven-, eight-, and nine-
membered lactones which the exocyclized products were
obtained exclusively.16 In comparison, lower yields for the
corresponding iodolactones of 3j, 3k, and 3o were reported
using bis(sym-collidine)iodine(I) hexafluorophosphate as the
stoichiometric halogenating reagent.10b Notably, in the case of
formation of 3i and 3m, parallel experiments were performed
using DMAP (5 mol %) as the catalyst under the same
B
dx.doi.org/10.1021/ja307210n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
of the pure crystalline zwitterion 1a. This color change was
reversible. We speculated that the color change could be
attributed to the equilibrium in favor of zwitterion 1a over the
individual starting materials (i.e., DMAP and 3,5-bis-
(trifluoromethyl)isothiocyanate) in solution phase at low
temperature.
Table 3. Bromolactonization of 2
1
Low-temperature H NMR experiments were performed to
get further insight of this phenomenon. The methyl signals of
1a (3.25 ppm) and DMAP (3.00 ppm) were taken as reference
points in the comparison of the zwitterion 1a:DMAP ratio
(Figure S2).11 At 298 K, the 1a:DMAP ratio was found to be
1:17. As the temperature decreased, the 1a/DMAP ratio
increased, and the ratio (11:1) became steady at below 233 K
(Figure 2). This could provide an explanation that a better
conversion was achieved at 0 °C than at 25 °C.
a
Reactions were carried out with olefinic acid 2 (0.25 mmol), catalyst
1a (0.0125 mmol), NBS (0.5 mmol) in CH2Cl2 (5.0 mL) at 0 °C. The
b
yields were isolated yields. The parentheses indicates the yield of the
corresponding iodolactone when using bis(sym-collidine)iodine(I)
hexafluorophosphate as the stoichiometric halogen source. For detail,
see ref 10b. The parentheses indicate the yield when using DMAP (5
Figure 2. Relationship between the 1a:DMAP ratio and the
temperature.
c
mol %) as the catalyst.
Next, we examined the complex between NBS and zwitterion
1a. A 1:1 mixture of NBS and 1a gave a bright-yellow solution
at room temperature. The 1H NMR of such a mixture indicated
that there were two species (ca. 2.5:1). A small amount of free
catalyst 1a was observed, but no free DMAP was detected
(Figure S3).11 Since the negative charge in 1a can delocalize
between S and N atoms,18 we suspect that the two species
might be the S−Br and N−Br complexes (i.e., Figure 3, A and
conditions, and no reaction was observed. In all cases, slow
addition and high dilution were unnecessary to avoid the
dimerization/oligomerization process.10a,17
During our investigation, several interesting phenomena were
observed which allow us to get a better understanding on this
reaction. In the study on the temperature effect of the
zwitterion 1a catalyzed lactonization, we noticed that the
catalyst solution was colorless at 25 °C (Figure 1). However,
the solution turned light yellow at 0 °C and changed to bright
yellow at even lower temperatures, which resembled the color
Figure 3. 1a−NBS Complexes.
A′). Although zwitterion 1a and DMAP exist in equilibrium in
the solution phase and could be active catalysts, as indicated in
Table 1, NBS−1a complexes appear to be the dominant active
species, since the NBS−DMAP complex was not observed in
11
1
the NBS−1a H NMR study (Figure S4).
In summary, we have developed the first organocatalytic
halolactonization of unsaturated carboxylic acids using
zwitterion 1a, resulting in the formation of medium-sized
lactones. The catalyst can easily be synthesized by a one-step
coupling between DMAP and isothiocyanate. NBS was used as
the stoichiometric halogen source, which is inexpensive and
readily available. The lactonization was found to be more
efficient at lower temperature, potentially due to the more
favorable catalyst formation. Further investigations on other
applications and the mechanistic picture are underway.
Figure 1. Zwitterion 1a color: (a) Pure CH2Cl2 at 25 °C, and 1a in
CH2Cl2 (0.05 M) at (b) 25 °C and (c) −40 °C. (d) Pure crystalline
1a.
C
dx.doi.org/10.1021/ja307210n | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
■
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* Supporting Information
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Experimental detail, CIF file of the X-ray structure, and
spectroscopic and analytical data for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
chmyyy@nus.edu.sg
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the National University of Singapore (grant no. 143-
000-509-112) for financial support. We acknowledge the
receipt of a NGS Scholarship (Y.A.C.), a NUS Research
Scholarship (T.C.), and President’s Graduate Fellowship
(C.K.T.). Special thanks to Prof. K. Ishihara (Nagoya
University) for the valuable discussion.
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