Catalytic enantioselective bromolactonization of alkenoic acids in the presence of palladium complexes

Article abstract of DOI:10.1016/j.tetlet.2012.10.051

The catalytic enantioselective bromolactonization of alkenoic acids promoted by chiral palladium complexes has been developed, allowing facile synthesis of the corresponding γ-lactones with excellent enantioselectivity (up to 97% ee). The method reported

Full text of DOI:10.1016/j.tetlet.2012.10.051

Tetrahedron Letters 53 (2012) 6984–6986
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Tetrahedron Letters
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Catalytic enantioselective bromolactonization of alkenoic acids
in the presence of palladium complexes
⇑
Hyun Joo Lee, Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The catalytic enantioselective bromolactonization of alkenoic acids promoted by chiral palladium com-
Received 29 August 2012
Revised 8 October 2012
Accepted 12 October 2012
Available online 23 October 2012
plexes has been developed, allowing facile synthesis of the corresponding
enantioselectivity (up to 97% ee). The method reported represents a practical entry for the preparation
of chiral -lactone derivatives.
c-lactones with excellent
c
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric catalysis
Chiral palladium catalysts
Bromolactonization
c
-Lactones
Alkenoic acids
Halolactonization of unsaturated carboxylic acids is an impor-
tant and fundamental synthetic transformation in organic chemis-
try as the corresponding halolactones are very useful building
blocks, which can be employed as synthetic intermediates for
divergent transformations.1 Accordingly, the development of
methods for the catalytic enantioselective halolactonizations has
become of great interest, and some notable successes have been re-
corded.2 Despite these significant advances, the catalytic enantio-
selective bromolactonization is still lacking because a suitable
catalytic system remains elusive.3–5 There have been a few re-
ported examples of catalytic enantioselective bromolactonization
of 4-aryl 4-pentenoic acids.6 The Yeung group has reported the cat-
alytic enantioselective bromolactonization in the presence of ami-
no-thiocarbamate catalysts.6a,c The Borhan group has reported the
enantioselective bromolactonization using a peptide bromoiod-
inane approach.6c Very recently, the Martin group described organ-
ocatalytic enantioselective bromolactonization using binol-derived
bifunctional catalyst.6d Although, a few efficient methods have
been achieved by these systems, an effective method for the cata-
lytic asymmetric halolactonization of 4-aryl 4-pentenoic acids is
highly desirable. To the best of our knowledge, there is no report
for the enantioselective bromolactonization using chiral palladium
complexes which are air- and moisture-stable.7
chiral palladium complexes.9 Herein, we wish to describe the
enantioselective bromolactonization of alkenoic acids catalyzed
by palladium complexes.
To determine suitable reaction conditions for the catalytic enan-
tioselective bromolactonization of alkenoic acids, we initially inves-
tigated the reaction system with 4-phenyl 4-pentenoic acid (2a)
and bromine sources in the presence of 10 mol % of dicationic palla-
dium complexes 1 (Fig. 1) in CHCl3 at room temperature. The impact
of the structure of brominating reagents was initially examined. The
commonly used N-bromosuccinimide, N-bromophthalimide, N-
bromosaccharin, dibromobarbituric acid, and dibromoisocyanuric
acid gave bromolactoniation product as racemic mixture. Fortu-
nately, we found that bromolactonization using 2,4,4,6-tetrab-
romocyclohexadienone (TBCO) as brominating reagent and
catalyst 1a proceeded with high yield and moderate enantioselec-
tivity (Table 1, entry 1). To improve the enantioselectivity, we
examined the impact of the structure of ligands of palladium com-
plexes 1 on enantioselectivities (11–69% ee, Table 1, entries 1–12).
Under the standard reaction conditions, catalyst 1c gave better
enantioselectivity (69% ee, Table 1, entry 3). Next, we examined
the reaction in various solvents (Table 1, entries 13–19). The use
of halogenated solvents such as CH2Cl2, CHCl2CH2Cl, CH2Br2, and
CF3CH2OH gave the good results (Table 1, entries 13–15 and 19),
where bromolactonization in toluene, THF, and MeOH led to lower
enantioselectivities (Table 1, entries 16–18). Decreasing the catalyst
loading to 5 mol % and lowering the temperature to ꢀ40 °C led to a
slight decrease in the selectivities (Table 1, entries 20 and 21).
With optimal reaction condition in hand, we studied the
generality of the enantioselective bromolactonization of 4-aryl
As part of research program related to the development of syn-
thetic methods for the enantioselective construction of stereogenic
carbon centers,8 we recently reported asymmetric reactions using
⇑
Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.051

H. J. Lee, D. Y. Kim / Tetrahedron Letters 53 (2012) 6984–6986
6985
Table 2
1a
: Ar = Ph, X = BF4
2+
Catalytic enantioselective bromolactonization of alkenoic acids 2a
1b : Ar = Ph, X = OTf
1c
: Ar = Ph, X = SbF6
PAr2
Pd
PAr2
OH2
cat. 1c (10 mol%)
O
-
Br
1d : Ar = Ph, X = ClO4
1e : Ar = Ph, X = OTs
O
OH
2X
R
TBCO (1.1 eq.)
R
NCMe
CF3CH2OH, rt
1f
: Ar = Ph, X = NTf2
O
3
1g : Ar = 4-methylphenyl, X = SbF6
2
1h
: Ar = 3,5-dimethylphenyl, X = SbF6
Entry
2, R
Time (h)
Yieldb (%)
eec (%)
2+
F
O
2+
1
2
3
2a, Ph
2
2
1
2
8
2
2
2
12
3a, 98
3b, 97
3c, 99
3d, 99
3e, 77
3f, 97
3g, 83
3h, 90
3i, 72
75
85
97
91
95
89
63
59
32
O
2b, 4-MeC6H4
2c, 4-MeOC6H4
2d, 4,5-Me2C6H3
2e, 4,5-(MeO)2C6H3
2f, 4-ClC6H4
2g, 2-thienyl
2h, 9-anthracenyl
2i, Me
PPh2
Pd
PPh2
PAr
Pd
O
O
OH2
F
F
2 OH2
O
O
-
-
2X
2X
4
NCMe
NCMe
5d
6e
7
PAr2
O
F
O
8
9
1i : X = SbF6
1j
: Ar = 3,5-di-tert-butyl-4-
methoxyphenyl, X = SbF6
OMe
a
2+
Reaction conditions: 4-aryl 4-pentenoic acid (2, 0.2 mmol), TBCO (0.22 mmol),
catalyst 1c (0.02 mmol) in CF3CH2OH at room temperature.
N
N
2+
b
Isolated yield.
PPh2
Pd
PPh2
OH2
NCMe
PPh2
c
MeO
MeO
Enantiopurity was determined by HPLC analysis using chiralpak IC column.
This reaction was carried out at 0 °C in CHCl3.
-
d
2X
-
OH2
2X
e
20 mol % catalyst loading.
Pd
NCMe
P
Ph2
OMe
substitutions on the aryl ring of the 4-aryl 4-pentenoic acids 2b–
f provided reaction products in high yields and high to excellent
enantioselectivities. In particular, better results are obtained with
substrates having electron rich aromatics. It is interesting because
in the case of reported organocatalytic methods, such substrates
tend to decrease the selectivity.6 Heteroaryl- and naphthyl-substi-
tuted alkenoic acids 2g–h provided products with moderate to
high selectivity (59–63% ee, entries 7 and 8). However, diminished
yield and enantioselectivity were observed with 4-alkyl-substi-
tuted 4-pentenoic acid 2i (Table 2, entry 9). The absolute configu-
ration of 3 was established by comparison of the optical rotation
and chiral HPLC analysis with previously reported values.6
Furthermore, 5-phenyl 5-hexenoic acid 4 was also used as a
substrate in this bromolactonization reaction with TBCO as the
bromine source in the presence of 10 mol % of palladium complex
1c in CF3CH2OH. It was found that the corresponding bromolactone
product 5 was obtained in moderate yield and enantioselectivity
(Scheme 1). The absolute configuration of 5 was established by
comparison of the optical rotation and chiral HPLC analysis with
previously reported values.4a,6c
1k : X = SbF6
1l : X = SbF6
Figure 1. Structures of chiral palladium catalysts.
Table 1
Optimization of the reaction conditionsa
cat. 1 (10 mol%)
O
Br
O
OH
Ph
Ph
TBCO (1.1 eq.), rt
O
2a
3a
Entry
Cat. 1
Solvent
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20d
21e
1a
1b
1c
1d
1e
1f
1g
1h
1i
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
CHCl2CH2Cl
CH2Br2
PhMe
THF
MeOH
CF3CH2OH
CF3CH2OH
CF3CH2OH
9
2
2
2
2
2
2
2
2
2
2
2
8
8
8
8
3
7
2
5
5
92
97
99
95
93
97
91
90
92
92
98
93
97
95
98
97
95
98
98
98
90
17
11
69
65
13
61
17
22
65
57
15
47
67
39
53
10
3
1j
1k
1l
O
O
cat. 1c (10 mol%) Br
O
1c
1c
1c
1c
1c
1c
1c
1c
1c
TBCO (1.1 eq.)
CF3CH2OH, rt
Ph
OH
Ph
50% yield, 43% ee
4
5
5
Scheme 1. Catalytic enantioselective bromolactonization of 5-phenyl 5-hexenoic
acid 4.
75
59
62
a
Reaction conditions: 4-phenyl 4-pentenoic acid (2a, 0.2 mmol), TBCO
(0.22 mmol), catalyst (0.02 mmol) at room temperature.
b
Isolated yield.
c
Enantiopurity was determined by HPLC analysis using chiralpak IC column.
5 mol % catalyst loading.
This reaction was carried out at ꢀ40 °C.
d
P
P
e
Pd
O
O
Br
Br
O
4-pentenoic acids 2 with TBCO in the presence of 10 mol % of cat-
alyst 1c.10 As it can be seen by the results summarized in Table 2,
the corresponding bromolactone products 3a–h were obtained in
high yields with moderate to excellent enantioselectivities (59–
97% ee). A range of electron-donating and electron-withdrawing
Br
Figure 2. Plausible transition state model.
Br
Ar

6986
H. J. Lee, D. Y. Kim / Tetrahedron Letters 53 (2012) 6984–6986
Chem., Int. Ed. 2010, 49, 7332; (c) Dobish, M. C.; Johnston, J. N. J. Am. Chem. Soc.
Although, the reason for the observed enantioselectivity is still
2012, 134, 6068.
unclear, we believe that 4-pentenoic acids 2 and TBCO are acti-
vated by the palladium catalyst 1. Alkene of 4-pentenoic acids at-
tacks electrophilic brominating reagent as shown in Figure 2. Then,
carboxylate attacks the cyclic bromonium ion to afford the bromol-
actonization product (Fig. 2). Investigations to obtain the clear
mechanistic feature are still in progress.
In summary, we have accomplished the efficient catalytic enan-
tioselective bromolactonization of 4-aryl 4-pentenoic acids with
TBCO in the presence of dicationic palladium complex as a chiral
catalyst. The air- and moisture-stable palladium catalyst 1c is
highly effective to give high yields and moderate to excellent
enantioselectivities (up to 97% ee) under mild reaction conditions.
Further study of palladium-catalyzed enantioselective bromolact-
onization of various alkenoic acid derivatives is in progress.
6. (a) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.; Yeung, Y. J. Am. Chem. Soc. 2010, 132,
15474; (b) Whitehead, D. C.; Fhaner, M.; Borhan, B. Tetrahedron Lett. 2011, 52,
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7. For recent selected reviews for the enantioselective reactions catalyzed by
chiral palladium complexes, see: (a) Smith, A. M. R.; Hii, K. K. Chem. Rev. 2011,
111, 1637; (b) Lectard, S.; Hamashima, Y.; Sodeoka, M. Adv. Synth. Catal. 2010,
352, 2708; (c) Sodeoka, M.; Hamashima, Y. Chem. Commun. 2009, 5787.
8. (a) Kim, D. Y.; Huh, S. C. Tetrahedron Lett. 2001, 57, 8933; (b) Kim, D. Y.; Huh, S.
C.; Kim, M. H. Tetrahedron Lett. 2001, 42, 6299; (c) Kim, D. Y.; Park, E. J. Org. Lett.
2002, 4, 545; (d) Park, E. J.; Kim, M. H.; Kim, D. Y. J. Org. Chem. 2004, 69, 6897;
(e) Kim, S. M.; Lee, J. H.; Kim, D. Y. Synlett 2008, 2659; (f) Jung, S. H.; Kim, D. Y.
Tetrahedron Lett. 2008, 49, 5527; (g) Kang, Y. K.; Kim, D. Y. J. Org. Chem. 2009, 74,
5734; (h) Kwon, B. K.; Kim, S. M.; Kim, D. Y. J. Fluorine Chem. 2009, 130, 759; Oh,
Y. Y.; Kim, S. M.; Kim, D. Y. Tetrahedron Lett. 2009, 50, 4674; (j) Lee, J. H.; Kim, D.
Y. Adv. Synth. Catal. 2009, 351, 1779; (k) Moon, H. W.; Cho, M. J.; Kim, D. Y.
Tetrahedron Lett. 2009, 50, 4896; (l) Mang, J. Y.; Kwon, D. G.; Kim, D. Y. J.
Fluorine Chem. 2009, 130, 259; (m) Kang, Y. K.; Kim, D. Y. Curr. Org. Chem. 2010,
14, 917; (n) Lee, J. H.; Kim, D. Y. Synthesis 2010, 1860–1864; (o) Kang, Y. K.; Kim,
S. M.; Kim, D. Y. J. Am. Chem. Soc. 2010, 132, 11847; (p) Moon, H. W.; Kim, D. Y.
Tetrahedron Lett. 2010, 51, 2906; (q) Kang, S. H.; Kim, D. Y. Adv. Synth. Catal.
2010, 352, 2783; (r) Lee, H. J.; Kang, S. H.; Kim, D. Y. Synlett 2011, 1559; (s)
Kang, Y. K.; Yoon, S. J.; Kim, D. Y. Bull. Korean Chem. Soc. 2011, 32, 1195; (t)
Yoon, S. J.; Kang, Y. K.; Kim, D. Y. Synlett 2011, 420; (u) Lee, H. J.; Woo, S. B.; Kim,
D. Y. Tetrahedron Lett. 2012, 53, 3373; (v) Lee, H. J.; Woo, S. B.; Kim, D. Y.
Molecules 2012, 17, 7523; (w) Woo, S. B.; Kim, D. Y. Beilstein J. Org. Chem. 2012,
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Acknowledgment
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2012-0008310).
References and notes
9. For recent selected examples of the enantioselective reactions catalyzed by
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Kim, D. Y. Org. Lett. 2005, 7, 2309; (b) Kim, H. R.; Kim, D. Y. Tetrahedron Lett.
2005, 46, 3115; (c) Kang, Y. K.; Kim, D. Y. Tetrahedron Lett. 2006, 47, 4565; (d)
Kang, Y. K.; Cho, M. J.; Kim, S. M.; Kim, D. Y. Synlett 2007, 1135; (e) Kang, Y. K.;
Kim, D. Y. Bull. Korean Chem. Soc. 2008, 29, 2093; (f) Lee, J. H.; Bang, H. T.; Kim,
D. Y. Synlett 2008, 1821; Kang, S. H.; Kang, Y. K.; Kim, D. Y. Tetrahedron Lett.
2009, 65, 5676; (h) Kang, S. H.; Kwon, B. K.; Kim, D. Y. Tetrahedron Lett. 2011, 52,
3247; (i) Kang, Y. K.; Suh, K. H.; Kim, D. Y. Synlett 2011, 1125; (j) Kang, Y. K.;
Kim, D. Y. Tetrahedron Lett. 2011, 52, 2356; (k) Kwon, B. K.; Mang, J. Y.; Kim, D.
Y. Bull. Korean Chem. Soc. 2012, 33, 2481; Kang, Y. K.; Kim, H. H.; Koh, K. O.; Kim,
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1. (a) Jayaraman, N. Tetrahedron Lett. 2004, 60, 5273; (b) Lava, M. S.; Banerjee, A.
K.; Cabrera, E. V. Curr. Org. Chem. 2009, 13, 720; (c) Rodriguez, F.; Fananas, F. J.
In Handbook of Cyclization Reactions; Ma, S., Ed.; Wiley-VCH: New York, 2010;
Vol. 4, pp 951–990.
2. For reviews of enantioselective halocyclizations, see: (a) Chen, G.; Ma, S. Angew.
Chem., Int. Ed. 2010, 49, 8306; (b) Tan, C. K.; Zhou, L.; Yeung, Y. Synlett 2011,
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(d) Castellanos, A.; Fletcher, S. P. Chem. Eur. J. 2011, 17, 5766.
3. For recent examples of enantioselective chlorolactonizations, see: (a)
Whitehead, D. C.; Yousefi, R.; Jaganathan, A.; Borhan, B. J. Am. Chem. Soc.
2010, 132, 3298; (b) Yousefi, R.; Whitehead, D. C.; Mueller, J. M.; Staples, R. J.;
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10. Typical procedure for the bromolactonization of 4-phenyl 4-pentenoic acid (2a)
with TBCO: To a stirred solution of TBCO (90.1 mg, 0.22 mmol) and catalyst 1c
(25.2 mg, 0.02 mmol) in trifluoroethanol (2 mL) was added 4-phenyl 4-
pentenoic acid (2a, 35.2 mg, 0.2 mmol) at room temperature. The reaction
mixture was stirred for 2 h at room temperature. After completion of the
reaction, the resulting solution was concentrated in vacuo and the obtained
residue was purified by flash chromatography (EtOAc/hexane, 1:3) to afford
the 50 mg (98%) of the bromolactonization product 3a. (R)-5-(bromomethyl)-
dihydro-5-phenylfuran-2(3H)-one (3a): ½a D23
ꢁ
= +27.9 (c = 1.00, CHCl3); 1H NMR
d 7.41–7.34 (m, 5H), 3.74 (d, J = 11.4 Hz, 1H), 3.69 (d,
(400 MHz, CDCl3)
J = 11.4 Hz, 1H), 2.84–2.76 (m, 2H), 2.60–2.49 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 175.4, 140.6, 128.7, 128.5, 124.8, 86.3, 40.9, 32.3, 28.9); HPLC (85:15,
n-hexane:i-PrOH, 214 nm, 0.6 mL/min) Chiralpack IC column, tR = 25.4 min
(major), tR = 30.2 min (minor), 75% ee.
5. For recent examples of enantioselective iodolactonizations, see: (a) Ning, Z.; Jin,
R.; Ding, J.; Gao, L. Synlett 2009, 2291; (b) Veitch, G. E.; Jacobsen, E. N. Angew.