Environment friendly organic synthesis using bismuth compounds. An efficient method for carbonyl-ene reactions catalyzed by bismuth triflate

Article abstract of DOI:10.1016/j.tetlet.2005.09.035

Bismuth triflate (0.1 mol %) is a highly efficient catalyst for the cyclization of citronellal 1, a reaction that yields a ratio of 80:20 of isopulegol 2 and neoisopulegol 3. This methodology has also been extended to the synthesis of substituted piperidines. The bismuth triflate catalyzed ene reaction of aldehyde 4 gives a 70:30 mixture of piperidines 5 and 6. The advantages of these methods include the use of a highly efficient catalyst that is relatively nontoxic, cheap and easy to handle.

Full text of DOI:10.1016/j.tetlet.2005.09.035

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7747–7750
Environment friendly organic synthesis using bismuth
compounds. An efficient method for carbonyl-ene
reactions catalyzed by bismuth triflate
Erin D. Anderson, Justin J. Ernat, Mai P. Nguyen, Ann C. Palma and Ram S. Mohan*
Laboratory for Environment Friendly Organic Synthesis, Department of Chemistry, Illinois Wesleyan University,
Bloomington, IL 61701, USA
Received 26 July 2005; revised 5 September 2005; accepted 7 September 2005
Available online 23 September 2005
Abstract—Bismuth triflate (0.1 mol %) is a highly efficient catalyst for the cyclization of citronellal 1, a reaction that yields a ratio of
80:20 of isopulegol 2 and neoisopulegol 3. This methodology has also been extended to the synthesis of substituted piperidines. The
bismuth triflate catalyzed ene reaction of aldehyde 4 gives a 70:30 mixture of piperidines 5 and 6. The advantages of these methods
include the use of a highly efficient catalyst that is relatively nontoxic, cheap and easy to handle.
Ó 2005 Elsevier Ltd. All rights reserved.
The intramolecular carbonyl-ene reaction is a useful
0.1 mol% Bi(OTf)3.xH2O
way to generate a C–C bond and has been well studied.1
OH
Of particular interest is the cyclization of citronellal to
yield isopulegol, an important intermediate in an indus-
trial synthesis of menthol. The selectivity of this cycliza-
tion depends on the Lewis acid, solvent, and reaction
temperature. Some of the catalysts that have been used
for this purpose include ZnBr2,2 Sc(OTf)3,3 Mo(II) com-
plexes such as BnEt3N+[Mo(CO)4ClBr2]À,4 SnCl4,2 hy-
drous zirconia,5 InCl3,6 NbCl5,6 TaCl5,6 and silica
supported heteropoly acids such as H3PW12O40.7 How-
ever, many of these catalysts suffer from some draw-
backs. They are either very expensive and moisture
sensitive [Sc(OTf)3], or are corrosive and toxic (InCl3
and SnCl4) while, others require elaborate preparation
in the laboratory. Our continued interest in bismuth
compounds, due largely to their remarkably low toxi-
city, low cost, ease of handling, and high catalytic effi-
ciency prompted us to investigate the bismuth triflate,
Bi(OTf)3ÆxH2O, catalyzed cyclization of citronellal
(Scheme 1).8–10 The cyclization of citronellal catalyzed
by BiCl3 (2–5 mol %) has been previously reported.11
We now report that Bi(OTf)3ÆxH2O (0.1 mol %) is a
highly efficient catalyst for the cyclization of citronellal
Solvent
OH
O
1
3
2
Scheme 1.
1, a reaction that yields isopulegol 2 and neoisopulegol
3 in a 80:20 ratio, respectively (Scheme 1).
An attempt to see if complexation of the carbonyl group
in citronellal to bismuth triflate induces a shift in the
NMR signal was unsuccessful due to fast reaction times.
The cyclization of citronellal in CDCl3 catalyzed by
0.1 mol % Bi(OTf)3ÆxH2O was complete in less than
5 min at rt. The best selectivity was obtained in CH2Cl2
(Table 1, entries 1 and 2) while the use of THF (Table 1,
entry 3) gave a ca. 50:50 ratio of 2:3. At À78 °C, the
reaction in CH2Cl2 proceeded smoothly in the presence
of 1.0 mol % Bi(OTf)3ÆxH2O (Table 1, entry 2). How-
ever, no change in the ratio of isopulegol to neoisopule-
gol was observed even at this low temperature. The
cyclization also worked in DME and toluene but no
reaction was observed in CH3CN. In contrast to the
high catalytic efficiency of Bi(OTf)3ÆxH2O, ytterbium tri-
flate (Table 1, entry 7) proved inefficient. A catalytic
loading of 10.0 mol % and a reaction time of 1 h were re-
quired. Other reported catalysts for this cyclization are
Keywords: Bismuth and compounds; Carbonyl-ene reaction; Cycliza-
tions; Lewis acids.
*
Corresponding author. Tel.: +1 309 556 3829; fax: +1 309 556
3864; e-mail: rmohan@iwu.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.035

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E. D. Anderson et al. / Tetrahedron Letters 46 (2005) 7747–7750
Table 1. Cyclization of citronellal catalyzed by Bi(OTf)3ÆxH2O13,14
LA
O
OH
OH
1
3
2
Entry
Catalyst
Mol %
Solvent, T (°C)a
t (min)b
2:3c
1
2
3
4
5
6
7
Bi(OTf)3ÆxH2O
Bi(OTf)3ÆxH2O
Bi(OTf)3ÆxH2O
Bi(OTf)3ÆxH2O
Bi(OTf)3ÆxH2O
Bi(OTf)3ÆxH2O
Yb(OTf)3ÆxH2O
0.10
1.0
1.0
1.0
1.0
CH2Cl2
CH2Cl2 À78 °C
THF
5
60
10
50
300
10
78:22
79:21
52:48
61:39d
NRe
DME
CH3CN
Toluene
CH2Cl2
1.0
10.0
68:32
78:22
60
a All reactions were carried out at rt using racemic citronellal unless otherwise mentioned. Citronellal was purified by distillation or flash chro-
matography prior to use.
b Reaction progress was followed by GC and TLC.
c Ratios were obtained by GC analysis of the crude reaction mixture. Products were separated and isolated by flash chromatography. Products were
identified by comparison of their 1H and 13C NMR spectra with those reported in the literature. Typical isolated yields were 35–40% of 2 and 10–
12% of 3.
d Crude product contained 39% unreacted citronellal.
e Starting material was recovered unchanged.
also not nearly as efficient as bismuth triflate (equimolar
amounts of ZnBr2, 5.0 mol % Sc(OTf)3, 10.0 mol %
NbCl5). While ZnBr2 gave the best stereoselectivity
(94% isopulegol),2 NbCl5 only afforded a 50:50 ratio
of 2:3.6 Scandium triflate afforded a ratio of 2:3 that
was similar to that obtained with bismuth triflate at
room temperature.3 However, in contrast to Bi(OTf)3Æ
xH2O, at À78 °C Sc(OTf)3 gave a 94:6 mixture of 2:3.
The high catalytic efficiency of bismuth triflate coupled
with its low cost, ease of handling (anhydrous solvents
are not required), and low toxicity make this an attrac-
tive procedure for the large-scale synthesis of isopulegol
from citronellal.
formation of a complex mixture of fairly non-polar
products that contained several peaks in the olefinic
region. Similar low yields were reported in the Sc(OTf)3
catalyzed (5 mol %) cyclization of citronellal and were
attributed to the reaction of isopulegol with citronellal.3
We found the ratio of isopulegol to neoisopeulegol to be
quite reproducible and control experiments using
authentic samples showed that both isopulegol 2 and
neoisopulegol 3 were stable to the reaction conditions.
Significantly improved yields were not obtained even
when the reaction was carried out at À78 °C.
We have also extended this methodology to the intra-
molecular ene reaction of aldehyde 4 to synthesize substi-
tuted piperidines 5 and 6 (Table 2). These cyclizations
have been previously carried out with several catalysts
The typical isolated yields (of 2 and 3) were around
40–50%. The low isolated yields were attributed to the
Table 2. Synthesis of substituted piperidines catalyzed by Bi(OTf)3ÆxH2O
Ts
Ts
Ts
N
N
N
0.1 mol% Bi(OTf)3.xH2O
Solvent
OH
OH
O
4
5
6
Entry
Catalyst
Mol %
Solvent, T (°C)a
t (min)b
8:9c
1
2
3
4
5
6
Bi(OTf)3ÆxH2O
Bi(OTf)3ÆxH2O
Bi(OTf)3ÆxH2O
Bi(OTf)3ÆxH2O
Yb(OTf)3ÆxH2O
TMSOTf
0.1
5.0
1.0
1.0
20.0
1.0
CH2Cl2
10
120d
10
70:30
67:33
67:33
72:28
59:41
40:60
CH2Cl2 À70 °C
CH2Cl2
THF
CH2Cl2
[bmim][OTf] 230 °C
25
360e
5
a All reactions were carried out at rt unless otherwise mentioned.
b Reaction progress was followed by TLC.
c Ratios were obtained by NMR analysis of the crude reaction product as described in Ref. 12. Products were separated and isolated by flash
chromatography. Products were identified by comparison of their 1H and 13C NMR spectra with those reported in the literature.12
d Crude product contained 35% unreacted starting material.
e Crude product contained 43% unreacted starting material.

E. D. Anderson et al. / Tetrahedron Letters 46 (2005) 7747–7750
7749
3. Aggarwal, V. K.; Vennall, G. P.; Davey, P. N.; NewMan,
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D. P. J. Braz. Soc. 2004, 15, 813.
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bismuth Chemistry; Suzuki, H., Matano, Y., Eds.; Elsevier:
Amsterdam, 2001.
9. For recent reviews on use of bismuth(III) compounds in
organic synthesis see: (a) Leonard, N. M.; Wieland, L. C.;
Mohan, R. S. Tetrahedron 2002, 58, 8373; (b) Gaspard-
Iloughmane, H.; Le Roux, C. Eur. J. Org. Chem. 2004,
2517; For some recent applications of Bi(OTf)3 as a
catalyst in organic synthesis, see: (c) Anzalone, P. A.;
Baru, A. R.; Danielson, E. M.; Hayes, P. D.; Nguyen, M.
P.; Panico, A. F.; Smith, R. C.; Mohan, R. S. J. Org.
Chem. 2005, 70, 2091; (d) Sreedhar, B.; Swapna, V.;
Sridhar, Ch.; Saileela, D.; Sunitha, A. Synth. Commun.
2005, 35, 1177; (e) Sreedhar, B.; Swapna, V.; Sridhar, Ch.
Catal. Commun. 2005, 6, 293; (f) Khodaei, M.; Khosorpur,
A. R.; Kookhazadeh, M. Can. J. Chem. 2005, 83, 209; (g)
Yadav, J. S.; Reddy, B. V. S.; Swamy, T.; Rao, R. K.
Tetrahedron Lett. 2004, 45, 6037; (h) Yadav, J. S.; Reddy,
B. V. S.; Premalatha, K. Synlett 2004, 963; (i) Matsushita,
Y.; Sugamoto, K.; Matsui, T. Tetrahedron Lett. 2004, 45,
4723; (j) Ollevier, T.; Lavie-Compin, G. Tetrahedron Lett.
2004, 45, 49; (k) Arnold, J. N.; Hayes, P. D.; Kohaus, R.
L.; Mohan, R. S. Tetrahedron Lett. 2003, 44, 9173.
10. Bismuth triflate was purchased from Lancaster Chemical
Company. It can also be synthesized in the laboratory
including MeAlCl2, HCl, AlCl3, Sc(OTf)3, SnCl4, and
CF3SO3H.12 In addition to being highly corrosive, most
of these reagents were not very catalytic (10–50 mol %
was required) while HCl was used in excess. We now
report an efficient synthesis of 3,4-disubstituted piperi-
dines catalyzed by as little as 0.1 mol % bismuth triflate.
The intramolecular ene reaction of 4 afforded a 67:33
mixture of substituted piperidines 5 and 6, respectively.
It has been reported that the use of 30 mol % MeAlCl2
at À78 °C afforded a 70:30 ratio of 5:6, respectively,
while the use of 50 mol % Sc(OTf)3 gave a 50:50 mixture
of 5:6.11 Thus bismuth triflate (0.1 mol %) has proven to
be remarkably efficient for this type of ene cyclization.
Interestingly, the major product of cyclization of 4 with
bismuth triflate is the cis isomer 5, unlike the cyclization
of citronellal, which afforded isopulegol, the trans isomer
as the major product. Both 5 and 6 were separable by
flash chromatography.
The cyclization of 4 at À70 °C proceeded only in the
presence of 5.0 mol % Bi(OTf)3ÆxH2O and even after
2 h, a considerable amount of starting material re-
mained. Once again, in contrast to the high catalytic effi-
ciency of Bi(OTf)3ÆxH2O, Yb(OTf)3ÆxH2O proved quite
inefficient for the cyclization of 7 (Table 2, entry 5). In
order to determine if a greater amount of the thermody-
namic product 6 was obtained at elevated temperatures,
the cyclization was carried out in the ionic liquid [bmi-
m][OTf], which allowed the reaction to be conveniently
heated to 230 °C. Analysis of the crude product mixture
showed that the cyclization at this temperature yielded a
40:60 mixture of 5 and 6. It has been reported that
the use of 30 mol % MeAlCl2 affords a stereoselective
reaction giving predominantly the trans isomer 6 at
elevated temperatures (8:92 ratio of 5 and 6 at 61 °C
in CHCl3).12
`
from triphenylbismuth and triflic acid, see: Labrouillere,
M.; Le Roux, C.; Gaspard, H.; Laporterie, A.; Dubac, J.;
Desmurs, J. R. Tetrahedron Lett. 1999, 40, 285; Recently,
a synthesis of bismuth triflate from bismuth oxide and
In summary, a highly catalytic method for the carbonyl-
ene reaction catalyzed by bismuth triflate has been
developed. The advantages of this method include the
use of as little as 0.1 mol % catalyst, which is relatively
non-toxic and easy to handle.
´
triflic acid in aqueous ethanol has been reported. Repichet,
S.; Zwick, A.; Vendier, L.; Le Roux, C.; Dubac, J.
Tetrahedron Lett. 2002, 43, 993; A more convenient
procedure for the synthesis of bismuth triflate uses
chlorobenzene as the solvent, see: Peyronneau, S. M.;
Arrondo, C.; Vendier, L.; Roques, N.; Le Roux, C.
J. Mol. Catal. A 2004, 211, 89.
Acknowledgments
11. Peidro, L.; Le Roux, C.; Laporterie, A.; Dubac, J.
J. Organomet. Chem. 1996, 521, 397. Although the authors
do not report the ratio of the diastereomeric products
obtained from cyclization of citronellal, isopulegol is
reported to be the major product (70%).
We are grateful to the National Science Foundation for
an RUI (Research at An Undergraduate Institution)
grant. We also wish to acknowledge Research Corpora-
tion for a Cottrell College Science Award. R.M. wishes
to thank The Camille and Henry Dreyfus Foundation
for a Henry Dreyfus Teacher Scholar Award.
12. Williams, J. T.; Bahia, P. S.; Snaith, J. S. Org. Lett. 2002,
4, 21.
13. Representative procedure for cyclization of citronellal
catalyzed by Bi(OTf)3ÆxH2O: A solution of citronellal 1
(2.00 g, 12.97 mmol) in CH2Cl2 (40 mL) was stirred at rt
as Bi(OTf)3ÆxH2O (8.5 mg, 0.013 mmol, 0.1 mol %) was
added. After 25 min, the reaction mixture was diluted with
CH2Cl2 (20 mL) and washed with saturated aqueous
NaHCO3 (15 mL). The aqueous layer was extracted with
CH2Cl2 (15 mL) and the combined organic layers were
washed with saturated NaCl (15 mL), dried (Na2SO4), and
concentrated on a rotary evaporator to yield 1.82 g of a
crude product. The product was purified by flash chro-
matography on silica gel (75 g) using ethyl acetate/hexane
(5:95, v/v) as the eluent to yield 0.69 g (35%) of isopulegol
References and notes
1. (a) Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed.
Engl. 1978, 17, 476; (b) Snider, B. B. Acc. Chem. Res.
1980, 13, 426; (c) Mikami, K.; Shimizu, M. Chem. Rev.
1992, 92, 1021; (d) Comprehensive Organic Synthesis;
Barry, M. Trost, Ed.; Pergamon Press, 1991; Vol. 2,
p 527.
2. Nakatani, Y.; Kawashima, K. Synthesis 1978, 147.

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E. D. Anderson et al. / Tetrahedron Letters 46 (2005) 7747–7750
2 and 0.21 g (11%) of neoisopulegol 3. Both products were
washed with 10% aqueous Na2CO3 (15 mL) and saturated
NaCl (15 mL). The organic layer was dried (Na2SO4) and
concentrated on a rotary evaporator to give 1.55 g of an
oil with a pale yellow tint. The crude product was purified
by flash chromatography on silica gel (100 g) using ethyl
acetate/hexane (30:70, v/v) as the eluent to yield 0.719 g
(48%) of the cis diastereomer 5 as a colorless oil and
0.300 g of the trans diastereomer 6 as a white solid (20%).
Mp of 6: 154–156 °C (Lit.:12 149–151 °C). Both isomers
have been previously reported.12
1
analyzed by H and 13C NMR spectroscopy and GC as
well as by comparison of their spectra with those of
authentic samples.
14. Representative procedure for the synthesis of substituted
piperidines catalyzed by Bi(OTf)3ÆxH2O: A solution of
aldehyde 4 (1.51 g, 5.11 mmol) in anhydrous CH2Cl2
(20 mL) was stirred at rt as Bi(OTf)3ÆxH2O (3.3 mg,
0.00511 mmol, 0.1 mol %) was added. After 15 min, the
reaction mixture was diluted with CH2Cl2 (20 mL) and