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Ecient 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
ecient approach toward the construction of medium-sized
lactone using a zwitterion as the catalyst (5 mol %) and Nbromosuccinimide (NBS) as the stoichiometric halogen source.
Zwitterion 1a was used in our study, and 1a can easily be
synthesized using Ishiharas approach by a one-step reaction
between 3,5-(bistriuoromethyl)phenyl isothiocyanate and
N,N-dimethylaminopyridine (DMAP). The structure of 1a
was unambiguously conrmed by an X-ray crystallographic
study.11 Surprisingly, this interesting class of catalyst has only
been applied in the trans-esterication 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 mechanism is that an electrophilic halogen is rst transferred from a
halogen source to an olen 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

ABSTRACT: Catalytic bromolactonization of long-chain

olenic acids resulting in the ecient synthesis of mediumsized lactones is reported using a zwitterionic catalyst and
stoichiometric N-bromosuccinimide halogen source. The
reaction was found to be more ecient at 0 C than at
room temperature, which could be attributed to the
temperature dependence of the zwitterionic catalyst.

edium ring size lactones, seven- to nine-membered

lactones, for example, are the fundamental units of many
natural products.1 However, the synthesis of these mediumsized 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 exibility,
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 dicult to achieve as
the rate of cyclization of -bromoalkanoic acids to form sevenmembered lactones were found to be more than 104 times
slower, and eight- and nine-membered lactones 106 times
slower, relative to the formation of ve-membered lactones.4
Several ring closure reactions of bifunctional aliphatic
molecules, including olen 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 thermodynamic barriers to the cyclization, high temperature or metalbased catalysts is sometimes used.8 Hence, a mild and ecient
method to synthesize such medium rings would be highly
desirable and is envisaged to have great utility in organic
synthesis.
Halolactonization of olenic substrates is a powerful method
in the formation of lactones. The resultant halogens on the
lactones can easily be manipulated, which provide exible
handles for further functionalization. Signicant eorts have
been devoted to research on various methods to synthesize
small halolactones, i.e., ve- and six-membered lactones.9 In a
sharp contrast, the application of halolactonization to mediumring 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) hexauorophosphate was
2012 American Chemical Society

Scheme 1. Strategy of Zwitterion Catalyzed

Bromolactonization

Received: July 23, 2012

Published: September 21, 2012
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dx.doi.org/10.1021/ja307210n | J. Am. Chem. Soc. 2012, 134, 1649216495

Journal of the American Chemical Society

Communication

Table 2. Bromolactonization of 2ca

sulfur in zwitterion 1a could react with NBS to give

intermediate A; this interaction could eect the dissociation
of NBS and could oer 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 olen 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.
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
Table 1. Bromolactonization of 2 Using Dierent Catalystsa

entry

catalyst

substrate, n

time
(h)

1
2
3
4
5
6
7
8

none
1a
DMAP
DABCO
DMF
DBU
HMPA
1a

2a, 1
2a, 1
2a, 1
2a, 1
2a, 1
2a, 1
2a, 1
2b, 2

54
0.75
5
3
18
7
3.5
6

isolated yield
(%)
99
92
69
92
49
94
92
89

a
Reactions were carried out with olenic acid 2 (0.25 mmol), catalyst
(0.025 mmol), NBS (0.5 mmol) in CH2Cl2 (5.0 mL). DABCO = 1,4diazabicyclo[2.2.2]octane, DBU = diazabicyclo[5.4.0]undec-7-ene,
HMPA = hexamethylphosphamide.

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 eect of some common Lewis base catalysts
is listed in Table 1, showing the superiority of the catalytic
activity of zwitterion 1a.
Having demonstrated the catalytic ability of 1a, we further
examined the lactonization of larger ring systems. Bromolactonization of 5-hexenoic acid (2b) proceeded smoothly,
producing lactone 3b in 89% (Table 1, entry 8). The formation
of seven-membered lactone was less eective, 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(triuoromethyl)phenyl]thiourea (catalyst 1b),
Lewis acidic (Table 2, entry 10) and basic (Table 2, entries
1115) catalysts displayed little or no reactivity. Catalysts with
dierent N-Ar substituents (i.e., catalyst 1cf) and amino
group (i.e., catalyst 1g) returned with lower conversions (Table
2, entries 1620). 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 dierent

entry

catalyst

temp
(C)

yield
(%)

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25b
26c

1a
1a
DMAP
DMAP
1a
1a
1a
1a
1b
SnCl4
DBU
DABCO
Ph3P
Ph3PS
(Me2N)2CS
1c
1d
1e
1f
1g
1h
1i
1j
1k
1a
1a

25
0
25
0
8
15
52
78
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0

25
54
23
19
36
9
trace
trace
trace
trace
15
10
trace
trace
trace
10
33
33
46
30
12
17
trace
9
trace
27

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. bN-chlorosuccinimide was used as the
halogen source. cN-iodosuccinimide was used as the halogen source.

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 ninemembered 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) hexauorophosphate 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
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Communication

Table 3. Bromolactonization of 2a

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(triuoromethyl)isothiocyanate) in solution phase at low
temperature.
Low-temperature 1H 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 olenic acid 2 (0.25 mmol), catalyst
1a (0.0125 mmol), NBS (0.5 mmol) in CH2Cl2 (5.0 mL) at 0 C. The
yields were isolated yields. bThe parentheses indicates the yield of the
corresponding iodolactone when using bis(sym-collidine)iodine(I)
hexauorophosphate as the stoichiometric halogen source. For detail,
see ref 10b. cThe parentheses indicate the yield when using DMAP (5
mol %) as the catalyst.

Figure 2. Relationship between the 1a:DMAP ratio and the

temperature.

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 SBr and NBr 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 eect 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. 1aNBS Complexes.

A). Although zwitterion 1a and DMAP exist in equilibrium in

the solution phase and could be active catalysts, as indicated in
Table 1, NBS1a complexes appear to be the dominant active
species, since the NBSDMAP complex was not observed in
the NBS1a 1H NMR study (Figure S4).11
In summary, we have developed the rst 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
ecient 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.
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Communication

A. Angew. Chem., Int. Ed. 2010, 49, 8316. (f) Lumbroso, A.; Abermil,
N.; Breit, B. Chem. Sci. 2012, 3, 789.
(8) Furstner, A.; Muller, T. Synlett 1997, 1010.
(9) (a) Ranganathan, S.; Muraleedharan, K. M.; Vaish, N. K.;
Jayaraman, N. Tetrahedron 2004, 60, 5273. (b) Ranganathan, S.;
Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N. Tetrahedron 2007,
63, 8046.
(10) (a) Simonot, B.; Rousseau, G. J. Org. Chem. 1993, 58, 4.
(b) Simonot, B.; Rousseau, G. J. Org. Chem. 1994, 59, 5912.
(c) Rousseau, G.; Homsi, F. Chem. Soc. Rev. 1997, 26, 453. (d) Homsi,
F.; Rousseau, G. J. Org. Chem. 1998, 63, 5255. (e) Roux, M. C.;
Paugam, R.; Rousseau, G. J. Org. Chem. 2001, 66, 4304. (f) Rousseau,
G.; Strzalko, T.; Roux, M. C. Tetrahedron Lett. 2004, 45, 4503.
(11) Details in SI.
(12) Ishihara, K.; Niwa, M.; Kosugi, Y. Org. Lett. 2008, 10, 2187.
(13) (a) Uraguchi, D.; Koshimoto, K.; Ooi, T. J. Am. Chem. Soc.
2012, 134, 6972. (b) Ohmatsu, K.; Ito, M.; Kunieda, T.; Ooi, T. Nat.
Chem. 2012, 4, 473. (c) Uraguchi, D.; Koshimoto, K.; Miyake, S.; Ooi,
T. Angew. Chem., Int. Ed. 2010, 49, 5567. (d) Uraguchi, D.;
Koshimoto, K.; Ooi, T. J. Am. Chem. Soc. 2008, 130, 10878.
(14) The bond orders were determined by analyzing the bond
lengths indicated in the X-ray structure of 1a. For details, see Koleva,
B. B.; Kolev, T.; Seidel, R. W.; Tsanev, T.; Maye-Figga, H.; Spiteller,
M.; Sheldrick, W. S. Spectrochim. Acta, Part A 2008, 71, 695.
(15) Basic sulfur-containing molecules were found to be suitable in
the activation of brominating agents. For related references, see:
(a) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560. (b) Denmark, S. E.; Collins, W. R. Org. Lett. 2007, 9, 3801.
(c) Denmark, S. E.; Burk, M. T. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20655. (d) Denmark, S. E.; Kalyani, D.; Collins, W. R. J. Am. Chem.
Soc. 2010, 132, 15752. (e) Denmark, S. E.; Kornfilt, D. J. P.; Vogler, T.
J. Am. Chem. Soc. 2011, 133, 15308. (f) Snyder, S. A.; Treitler, D. S.;
Brucks, A. P. J. Am. Chem. Soc. 2010, 132, 14303. (g) Snyder, S. A.;
Treitler, D. S.; Brucks, A. P.; Sattler, W. J. Am. Chem. Soc. 2011, 133,
15898. (h) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y.-Y. J.
Am. Chem. Soc. 2010, 132, 15474. (i) Tan, C. K.; Zhou, L.; Yeung, Y.Y. Org. Lett. 2011, 13, 2738. (j) Tan, C. K.; Chen, F.; Yeung, Y.-Y.
Tetrahedron Lett. 2011, 52, 4892. (k) Zhou, L.; Chen, J.; Tan, C. K.;
Yeung, Y.-Y. J. Am. Chem. Soc. 2011, 133, 9164. (l) Chen, J.; Zhou, L.;
Tan, C. K.; Yeung, Y.-Y. J. Org. Chem. 2012, 77, 999. (m) Chen, J.;
Zhou, L.; Yeung, Y.-Y. Org. Biomol. Chem. 2012, 10, 3808. (n) Tan, C.
K.; Le, C.; Yeung, Y.-Y. Chem. Commun. 2012, 48, 5793. (o) Jiang, X.;
Tan, C. K.; Zhou, L.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2012, 51,
7779.
(16) We have also examined the formation of larger ring-sized
lactones. Good yields were obtained, but the exo/endo selectivity
dropped (see Scheme S1).
(17) Analysis on the crude product from Table 2, entry 2 using TLC,
1
H NMR, and LCMS showed that there was no signicant signal
corresponding to oligomeric product. However, starting material was
consumed, and appreciable amounts of side products (by TLC and 1H
NMR, an inseparable mixture) were detected when using other
catalysts (e.g., DMAP and DABCO); LCMS analysis on the side
products showed several mass signals corresponding to oligomeric
products.
(18) Bharatam, P. V.; Moudgil, R.; Kaur, D. J. Phys. Chem. A 2003,
107, 1627.

ASSOCIATED CONTENT

S Supporting Information
*

Experimental detail, CIF le 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.

AUTHOR INFORMATION

Corresponding Author

[email protected]
Notes

The authors declare no competing nancial interest.

ACKNOWLEDGMENTS
We thank the National University of Singapore (grant no. 143000-509-112) for nancial support. We acknowledge the
receipt of a NGS Scholarship (Y.A.C.), a NUS Research
Scholarship (T.C.), and Presidents Graduate Fellowship
(C.K.T.). Special thanks to Prof. K. Ishihara (Nagoya
University) for the valuable discussion.

REFERENCES

(1) (a) Norcross, R. D.; Paterson, I. Chem. Rev. 1995, 95, 2041.
(b) Furstner, A.; Kindler, N. Tetrahedron Lett. 1996, 37, 7005.
(c) Blunt, J. B.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26.
(2) (a) Sicher, J. Prog. Stereochem. 1962, 3, 202. (b) Illuminati, G.;
Mandolini, L. Acc. Chem. Res. 1981, 14, 95102. (c) Yet, L. Chem. Rev.
2000, 100, 29633007.
(3) Rousseau, G. Tetrahedron 1995, 51, 27772849.
(4) Galli, C.; Illuminati, G.; Mandolini, L.; Tamborra, P. J .Am. Chem.
Soc. 1977, 99, 25912597.
(5) For selected examples, see: (a) de Napoli, L.; Messere, A.;
Palomba, D.; Piccialli, V.; Evidente, A.; Piccialli, G. J. Org. Chem. 2000,
65, 3432. (b) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R.
H. J. Am. Chem. Soc. 2000, 122, 3783. (c) Takemoto, Y.; Noguchi, I.;
Iwata, C.; Tanaka, T.; Ibuka, T. Tetrahedron Lett. 2000, 41, 3653.
(d) Baba, Y.; Saha, G.; Nakao, S.; Iwata, C.; Tanaka, T.; Ibuka, T.;
Ohishi, H.; Takemoto, Y. J. Org. Chem. 2001, 66, 81. (e) Murga, J.;
Falomir, E.; Garcia-Fortanet, J.; Carda, M.; Marco, J. A. Org. Lett.
2002, 4, 3447. (f) Furstner, A.; Radkowski, K.; Wirtz, C.; Goddard, R.;
Lehmann, C. W.; Mynott, R. J. Am. Chem. Soc. 2002, 124, 7061.
(g) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199. (h) Furstner,
A. Eur. J. Org. Chem. 2004, 943. (i) Davoli, P.; Spaggiari, A.;
Castagnetti, L.; Prati, F. Org. Biomol. Chem. 2004, 2, 38. (j) Gradillas,
A.; Perez-Castells, J. Angew. Chem., Int. Ed. 2006, 45, 6086.
(k) Lejkowski, M.; Gais, H. J.; Banerjee, P.; Vermeeren, C. J. Am.
Chem. Soc. 2006, 128, 15378. (l) Aird, J. I.; Hulme, A. N.; White, J. W.
Org. Lett. 2007, 9, 631. (m) Furstner, A.; Bindl, M.; Jean, L. Angew.
Chem., Int. Ed. 2007, 46, 92759278. (n) Szostak, M.; Aube, J. Org.
Lett. 2009, 11, 3878. (o) Furstner, A. Chem. Commun. 2011, 47, 6505.
(6) For selected examples, see: (a) Tabuchi, T.; Kawamura, K.;
Inanaga, J.; Yamaguchi, M. Tetrahedron Lett. 1986, 27, 3889.
(b) White, J. D.; Johnson, A. T. J. Org. Chem. 1994, 59, 3347.
(c) Marcantoni, E.; Massaccesi, M.; Petrini, M. J. Org. Chem. 2000, 65,
4553. (d) Parenty, A.; Moreau, X.; Campagne, J.-M. Chem. Rev. 2006,
106, 911. (e) Pietruszka, J.; Rieche, A. C. M. Adv. Synth. Catal. 2008,
350, 1407.
(7) For some other examples, see: (a) OSullivan, P. T.; Buhr, W.;
Fuhry, M. A.; Harrison, J. R.; Davies, J. E.; Feeder, N.; Marshall, D. R.;
Burton, J. W.; Holmes, A. B. J. Am. Chem. Soc. 2004, 126, 2194.
(b) Kinoshita, H.; Shinokubo, H.; Oshima, K. Angew. Chem., Int. Ed.
2005, 44, 2397. (c) Shiina, I.; Hashizume, M.; Yumai, Y.; Oshiumi, H.;
Shimazaki, T.; Takasuna, Y.; Ibuka, R. Chem.Eur. J. 2005, 11, 6601.
(d) Shiina, I. Chem. Rev. 2007, 107, 239. (e) Crane, E. A.; Scheidt, K.
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