Intramolecular hydroalkoxylation in Bronsted acidic ionic liquids and its application to the synthesis of (±)-centrolobine

Article abstract of DOI:10.1039/c0ob00701c

The SO₃H-tethered imidazolium and triazolium salts, nonvolatile and recyclable Bronsted acidic ionic liquids, efficiently mediate intramolecular hydroalkoxylations of alkenyl alcohols. They have been successfully employed in the synthesis of (±)-centrolobine.

Full text of DOI:10.1039/c0ob00701c

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Intramolecular hydroalkoxylation in Brønsted acidic ionic liquids and its
application to the synthesis of ( )-centrolobine†
Yunkyung Jeong, Do-Young Kim, Yunsil Choi and Jae-Sang Ryu*
Received 10th September 2010, Accepted 25th October 2010
DOI: 10.1039/c0ob00701c
The SO3H-tethered imidazolium and triazolium salts, non-
volatile and recyclable Brønsted acidic ionic liquids, effi-
ciently mediate intramolecular hydroalkoxylations of alkenyl
alcohols. They have been successfully employed in the syn-
thesis of ( )-centrolobine.
In this study, both Brønsted acidic imidazolium ILs and
triazolium ILs have been used as non-volatile acidic media. The
Brønsted acidic imidazolium ILs 1–4 (Fig. 1) were synthesized
by literature procedures,20 and the SO3H-tethered triazolium IL
5 was prepared as shown in Scheme 1. First, n-butyl triazole (6)
was alkylated with 1,4-butane sultone, and subsequently generated
triazole sulfonate 7 was acidified with a stoichiometric amount of
TfOH. The novel SO3H-tethered triazolium salt 5 was free-flowing
liquid at room temperature.
Substituted tetrahydrofurans and tetrahydropyrans are frequently
found in many cyclic ether antibiotics and other biologically active
natural products.1 One of the most straightforward synthetic
approaches to these oxygen heterocycles is intramolecular hy-
droalkoxylation/cycloisomerization of unsaturated alcohols.2 In
particular, the intramolecular insertions of the O–H bonds across
the unactivated C C bond have drawn wide attention due to
their high atom economy and synthetic efficiency. Recently, it was
reported that intramolecular hydroalkoxylation of unactivated
olefins could be promoted by Brønsted acid,3,4 lanthanide,5
platinum,6 palladium,7 aluminium,8 gold,9 silver,10 copper,11 iron,12
ruthenium,13 and rhodium14 catalysts with varying degrees of
success.
Fig. 1 Brønsted acidic ILs.
Although the acid-catalyzed intramolecular hydroalkoxylation
of alkenyl alcohols has been reported for catalytic TfOH,3 it occurs
mainly with over-stoichiometric amounts of acid.4 Because of
environmental concerns associated with highly acidic reagents or
reaction media, the development of environmentally benign and
recyclable reagents has become a crucial and demanding area.
In recent years, ionic liquids15 (ILs) have attracted increasing
interest as recyclable solvents or catalysts. Particularly, Brønsted
acidic ILs are recognized as potential alternatives to conventional
acid catalysts due to their non-volatile and recyclable properties.
Therefore, their applications have been extended to esterification,16
nitration,17 Diels–Alder reaction,18 and hydroamination.19 Rel-
evant to the development of green reagents for the synthesis
of oxygen heterocycles, we describe herein intramolecular hy-
droalkoxylation of alkenyl alcohols in recyclable Brønsted acidic
ILs. This protocol also has been successfully applied to the
synthesis of ( )-centrolobine.
Scheme 1 Synthesis of SO3H-tethered triazolium IL.
Having prepared both Brønsted acidic imidazolium and tria-
zolim ILs, we tested the intramolecular hydroalkoxylation of ( )-
6-methyl-5-hepten-2-ol (8a) in the presence of various Brønsted
acidic ILs (Table 1). The reaction was conducted in an NMR tube
in the presence of 1–10 mol% of Brønsted acidic IL at various
Center for Cell Signaling & Drug Discovery Research, College of Pharmacy
and Division of Life & Pharmaceutical Sciences, Ewha Womans Univer-
sity, 11-1 Daehyun-Dong, Seodaemun-Gu, Seoul 120-750, Korea. E-mail:
ryuj@ewha.ac.kr; Fax: +82 2 3277 2851; Tel: +82 2 3277 3008
† Electronic supplementary information (ESI) available: General experi-
mental procedures, spectral data, and copies of 1H and 13C NMR spectra
for the new compounds. See DOI: 10.1039/c0ob00701c
1
temperatures. The ensuing progress was monitored by H-NMR
based on a mesitylene internal standard. Most of the acidic ILs
were quite effective, except for imidazolium-TfOH salt 1 (Table
1, entry 1). The SO3H-tethered imidazolium salts and triazolium
374 | Org. Biomol. Chem., 2011, 9, 374–378
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Table 1 Intramolecular hydroalkoxylation of ( )-6-methyl-5-hepten-2-ol
(8a) in various Brønsted acidic ionic liquidsa
were similarly effective in the initial NMR screening studies,
IL 4 and 5 were more effective than IL 2 and 3 in large-scale
reactions. Thus, we selected 4 and 5 for further studies. All
cyclizations were monitored by NMR-scale reactions and followed
by preparative-scale reactions. Primary, secondary, aliphatic, and
aromatic alkenyl alcohols smoothly affordedfive- or six-membered
oxygen heterocycles under standard conditions. The reactions
were regioselective and preferentially generated Markovnikov
products.
Presumably, the cyclization occurred at the more substituted
carbocation intermediate. For 1,2-disubstituted alkenyl alcohol
8n, five-membered ring formation was favored more than six-
membered ring formation (Table 2, entries 25 and 26), and less
than 10% of the corresponding tetrahydropyran isomer 9n¢ was
isolated. However, 6-exo cyclic ether 9e was the sole product for
1,2-disubstituted alkenyl alcohol 8e, and no 7-endo cyclic ether
was observed (Table 2, entries 7 and 8). For low-MW alkenyl
alcohols, the conversions were clean, and no side products were
observed by thin-layer chromatography or NMR spectroscopy.
However, the isolation of these volatile products by chromatog-
raphy resulted in decreased isolated yields (Table 2, entries 1–
12). Conversely, non-volatile gem-diphenyl substituted alkenyl
alcohols reliably afforded higher isolated yields (Table 2, entries
19–26).
Entry Ionic liquid Mol (%) T/◦C Time/h Conversionb (%)
1
2
3
4
5
6
7
8
1
2
3
4
4
4
4
4
4
5
5
5
5
5
5
10
10
10
10
10
10
5
2
1
10
10
10
5
80
80
80
40
60
80
80
80
80
40
60
80
80
80
80
25
1
1
129
15
1
2
4
20
142
18
1
0
>95
>95
>95
>95
>95
>95
>95
>95
93
>95
>95
>95
>95
>95
9
10
11
12
13
14
15
2
4
20
2
1
a Reaction conditions: ( )-6-methyl-5-hepten-2-ol (8a) (7.3 mg, 55.9 mmol)
mesitylene (6.9 mg, 55.9 mmol), ionic liquid (1–10 mol%), benzene-d6
0.75 mL. b Conversion was determined by 1H NMR using an internal
standard (mesitylene).
In general, ILs are amenable to multiple recycling cycles,
which considerably decreases the production of environmentally
harmful waste and the cost of a process. Therefore, the reusability
of Brønsted acidic ILs also was investigated. For each cycling
reaction, alkenyl alcohol 8k and triazolium IL 5 were dissolved
salt were equally active and produced the tetrahydropyran 9a in
excellent yield.
Next, we further explored the substrate scope of intramolecular
hydroalkoxylation of a variety of alkenyl alcohols in SO3H-
tethered IL 4 and 5 (Table 2). Although all of 2, 3, 4 and 5
◦
in benzene and heated at 80 C for 44 h. After the reaction, the
Scheme 2 Synthesis of ( )-centrolobine.
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Table 2 Intramolecular hydroalkoxylation of alkenyl alcohols in Brønsted acidic ionic liquidsa
Entry
Substrate
Product
Ionic liquid
Time/h
Yieldb (%)
1
2
4 (50 mol%)
5 (50 mol%)
51
60
76 (56)
86 (53)
3
4
4 (10 mol%)
5 (10 mol%)
40
40
84 (48)c
92 (79)d
5
6
4 (50 mol%)
5 (50 mol%)
71
71
59 (62)
63 (34)
7
8
4 (50 mol%)
5 (50 mol%)
93
93
63 (39)
71 (32)
9
10
4 (50 mol%)
5 (50 mol%)
40
40
>95 (25)
>95 (19)
11
12
4 (100 mol%)
5 (100 mol%)
46
44
83 (52)
82 (52)
13
14
4 (100 mol%)
5 (100 mol%)
66
44
88 (77)
>95 (91)
15
16
4 (100 mol%)
5 (100 mol%)
55
55
89 (61)
91 (76)
17
18
4 (100 mol%)
5 (100 mol%)
76
76
>95 (62)
>95 (78)
19
20
4 (100 mol%)
5 (100 mol%)
71
24
>95 (96)
>95 (93)
21
22
4 (100 mol%)
5 (100 mol%)
2
3
>95 (86)
>95 (83)
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Table 2 (Contd.)
Entry
Substrate
Product
Ionic liquid
Time/h
Yieldb (%)
23
24
4 (100 mol%)
5 (100 mol%)
1
1
>95 (93)
>95 (96)
25
26
4 (100 mol%)
5 (100 mol%)
41
117
>95 (87)e
>95 (81)f
a Yield was determined by 1H NMR using an internal standard (mesitylene). b Yields in parentheses refer to isolated yields of the preparative scale reaction:
alkenyl alcohol (1 mmol), ionic liquid (10–100 mol%), benzene (5 mL), 80 ◦C. c Inseparable trans/cis isomers (1.7 : 1) were observed. d Inseparable trans/cis
isomers (1.8 : 1) were observed. e 9n:9n¢ (78 : 9). f 9n:9n¢; (74 : 7).
Table 3 Reuse of the ionic liquid 5a
fluxing n-butyl vinyl ether. Allyl vinyl ether 12 generated in situ was
rapidly rearranged to g,d-unsaturated aldehyde 13 in 83% yield for
two steps. Subsequent addition of phenethyl magnesium bromide,
which was generated from 14 and magnesium in THF, provided
alkenyl alcohol 15, the precursor of hydroalkoxylation. Then,
we investigated Brønsted acidic IL-mediated hydroalkoxylation.
Gratifyingly, we found that both imidazolium IL 4 and triazolium
Cycle
Yieldb
IL 5 were effective for producing cyclized tetrohydropyran 16 in
77% and 82% yields, respectively, at room temperature. Notably,
only cis-disubstituted tetrahydropyran was isolated. The relative
stereochemistry was unambiguously determined by 1D NOE
experiments (see ESI†). Removal of the benzyl group was finally
achieved by catalytic hydrogenation in 98% yield. The physical and
spectroscopic data obtained for 17 were in full agreement with the
literature.22
1
2
3
95
87
88
a Reaction conditions: 2,2-diphenyl-4-penten-1-ol (8k) (238 mg,
1.00 mmol), ionic liquid 5 (412 mg, 1.00 mmol), benzene (5 mL), 80 ◦C,
44 h. b Isolated yield.
In conclusion, we developed an intramolecular hydroalkoxy-
lation approach to tetrahydropyrans and tetrahydrfuran in recy-
clable Brønsted acidic ILs. Both SO3H-tethered imidazolium and
triazolium ILs were effective for mediating cycloisomerization
of alkenyl alcohols and could be recycled without significant
loss of yields. In addition, the utility of this methodology was
demonstrated by the concise synthesis of ( )-centrolobine.
product 9k could be extracted with Et2O and decanted out from
IL 5. After drying IL 5 under reduced pressure, a second batch of
8k was added. IL 5 could be recycled up to three times without
significant loss in yield (Table 3).
To ensure the feasibility of intramolecular hydroalkoxylation
in Brønsted acidic ILs, we used this protocol for concise synthe-
sis of ( )-centrolobine (17) (Scheme 2). (-)-Centrolobine is an
antiprotozoal natural product isolated from the heartwood of
Centrolobium robustum and from the stem of Brosinium potabile
in the Amazon forest.21 Although several total syntheses have
been reported previously,22 there is no instance reported that
used intramolecular hydroalkoxylation as a key step in the
construction of the tetrahydropyran skeleton. In our strategy, it
was envisioned that the tetrahydropyran skeleton could be atom-
economically constructed from the alkenyl alcohol 15 via Brønsted
acidic IL-mediated intramolecular hydroalkoxylation. Therefore,
the synthesis iniatiated with allylic alcohol 11, obtained from
anisaldehyde (10) by vinyl magnesium bromide addition. Next,
11 was subjected to one-pot vinylation-Claisen rearrangement
conditions.23 This one-pot transformation involving vinylation
and Claisen rearrangement was quite effectively performed in re-
Acknowledgements
This research was supported by a Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(No. 2009-0066777). Y. Choi was supported by the Brain Korea
21 project.
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