Bismuth(III) triflate: A safe and easily handled precursor for triflic acid: Application to the esterification reaction

Article abstract of DOI:10.1080/00397910903046846

A series of carboxylic acids were converted into their corresponding methyl esters using bismuth(III) triflate as a catalyst in methanol. Good to excellent yields were obtained for different aliphatic or aromatic starting materials. In the reaction, bismuth triflate acts as a precursor that, upon hydrolysis, liberates sufficient triflic acid to catalyze the esterification.

Full text of DOI:10.1080/00397910903046846

This article was downloaded by: [Duke University Libraries]
On: 07 August 2012, At: 09:14
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Bismuth(III) Triflate: A Safe and Easily
Handled Precursor for Triflic Acid:
Application to the Esterification Reaction
Franciane Ho A Kwie a b , Cécile Baudoin-Dehoux a b , Casimir Blonski
a b & Christian Lherbet a b
a CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules
d'Intérêt Biologique, Toulouse, France
b Université de Toulouse, Laboratoire de Synthèse et Physico-Chimie
de Molécules d'Intérêt Biologique, Toulouse, France
Version of record first published: 04 Mar 2010
To cite this article: Franciane Ho A Kwie, Cécile Baudoin-Dehoux, Casimir Blonski & Christian Lherbet
(2010): Bismuth(III) Triflate: A Safe and Easily Handled Precursor for Triflic Acid: Application to the
Esterification Reaction, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 40:7, 1082-1087
To link to this article: http://dx.doi.org/10.1080/00397910903046846
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,

demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 40: 1082–1087, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903046846
BISMUTH(III) TRIFLATE: A SAFE AND EASILY
HANDLED PRECURSOR FOR TRIFLIC ACID:
APPLICATION TO THE ESTERIFICATION REACTION
1,2
Franciane Ho A Kwie,1,2 Cecile Baudoin-Dehoux,
´
Casimir Blonski,1,2 and Christian Lherbet1,2
1
`
CNRS, Laboratoire de Synthese et Physico-Chimie de Molecules d’Interet
´
´ ˆ
Biologique, Toulouse, France
2
´
`
Universite de Toulouse, Laboratoire de Synthese et Physico-Chimie de
Molecules d’Interet Biologique, Toulouse, France
´
´ ˆ
A series of carboxylic acids were converted into their corresponding methyl esters using
bismuth(III) triflate as a catalyst in methanol. Good to excellent yields were obtained
for different aliphatic or aromatic starting materials. In the reaction, bismuth triflate acts
as a precursor that, upon hydrolysis, liberates sufficient triflic acid to catalyze the
esterification.
Keywords: Bismuth triflate; carboxylic acid; esterification
INTRODUCTION
Protecting groups play a fundamental role in synthetic organic chemistry. The
most common reaction to protect carboxylic acid is esterification. Different proce-
dures are available to synthesize methyl ester; the most common is the use of
MeOH=H2SO4 or dimethoxypropane=HCl or diazomethane generated in situ from
N-methyl-N-nitrosourea.[1]
Over the past few years, bismuth compounds have been reported as nontoxic
and easy-to-handle catalysts, which have been proved useful for organic synthesis.[2]
Bismuth(III) salts have been found to catalyze a number of reactions. Among them,
we reported the synthesis of iso(thio)chromans via a thia- or oxa-Pictet–Spengler
reaction in the presence of aldehydes.[3]
Recently, Buzin et al. used bismuth triflate to prepare crystalline aliphatic
polyesters from aliphatic dicarboxylic acids (ADAs) with aliphatic diols.[4] Bismuth
triflate was also found to catalyze the condensation of various alcohols with different
acyl anhydrides to prepare the corresponding esters.[5] Surprisingly, methyl esterifi-
cation of carboxylic acids was not investigated using bismuth salts as a catalyst.
In this study, we disclose the usefulness of bismuth(III) triflate to provide methyl
Received February 10, 2009.
Address correspondence to Christian Lherbet, LSPCMIB–UMR=CNRS 5068, Universite Paul
´
Sabatier, 118 route de Narbonne, F-31062 Toulouse cedex 9, France. E-mail: lherbet@chimie.ups-tlse.fr
1082

Bi(OTf)3-CATALYZED ESTERIFICATION
1083
esters from their corresponding carboxylic acids. This work also provides insights
into the catalytic role of Bi(OTf)3 in the reaction.
RESULTS AND DISCUSSION
As a preliminary study, we tried different reaction conditions in a model
reaction to synthesize 4-methoxyphenylacetic acid methyl ester. As can be seen in
Table 1, in the presence of 0.1 equiv of bismuth(III) triflate, a refluxing solution
of 4-methoxyphenylacetic acid in methanol gave the corresponding methyl ester in
good yield (entry 2). The same reaction was performed in the absence of bismuth salt
to obtain the starting material (entry 1, Table 1). To further explore the role of the
catalyst in the reaction, we also tried bismuth chloride without success: only traces of
1
the ester were detected by H NMR (entry 3, Table 1). Bismuth halides or bismuth
triflate are known to be hydrolyzed to afford the corresponding Brønsted acid. In
our system, triflic acid released at the onset of the reaction appears to be the catalyst
of the esterification as reported elsewhere.[6] Bizier et al. observed a similar behavior
with indium(III) triflate.[7] Triflic acid has been proposed to be the active catalyst in
many catalytic processes.[7,8] In support of this hypothesis, we observed that triflic
acid is an efficient catalyst for esterification reaction (entry 4, Table 1). Moreover,
the addition of hindered 2,6-di-tert-butyl-4-methylpyridine (DTBMP) to the mix,
which should neutralize triflic acid, inhibits the reaction (entry 5, Table 1). This
observation indicates that a Brønsted acid is involved in the mechanism. To dis-
tinguish between methanolysis and hydrolysis of bismuth(III) triflate to get triflic
˚
acid, the reaction was run in the presence of 4-A molecular sieves in anhydrous meth-
anol to obtain the product in only 7% yield (entry 6, Table 1). This experiment
proves that triflic acid is generated upon hydrolysis of Bi(OTf)3.
We proceeded to examine the substrate scope of the reaction. The protecting
group 9-fluorenylmethoxycarbonyl (Fmoc) is stable to the reaction conditions
Table 1. Screening of the reaction conditions in the presence of Bi(III)
Entry
Catalyst
Time (h)
Yieldsa (%)
1
2
3
4
5
6
—
Bi(OTf)3 0.1 eq
24
3
7b
86
BiCl3 0.1 eq
TfOH 0.1 eq
6
Traces
87
2
Bi(OTf)3 0.1 eq þDTBMP 0.3 eq
3
5
Bi(OTf)3 0.1 eq
Anhydrous MeOH, 4 A MS
3
7
c
˚
aYields for isolated compounds.
bPercentage conversion estimated by 1H NMR.
cMolecular sieves (MS) were activated at 150 ꢀC under strong vacuum.

1084
F. H. A. KWIE ET AL.
Table 2. Scope of the esterification reaction
Entry
Substrate
R1OH
Time (h)
Yieldsa (%)
1
2
MeOH
EtOH
3
6
86
95
3
4
MeOH
MeOH
4
7
98
88
5
6
MeOH
MeOH
6
69
10
0
7
8
MeOH
EtOH
5.5
73
62
8
9
MeOH
10
85
10
11
MeOH
MeOH
6.5
Not isolated
31b
16
18
12
MeOH
89
aYields for isolated compounds.
bPercentage conversion estimated by 1H NMR.

Bi(OTf)3-CATALYZED ESTERIFICATION
1085
Scheme 1. Methyl esterification of 2-formylbenzoic acid.
(entries 3, 4, and 5, Table 2). However, when the tert-butoxycarbonyl protecting
group (Boc) was used, no trace of product was observed (entry 6, Table 2). This
could be explained by the partial deprotection of the N-Boc-amine to afford the cor-
responding amine, which neutralizes any traces of triflic acid generated during the
reaction. Indeed, deprotection of the N-Boc group by bismuth(III) trichloride has
already been reported.[9] Furthermore, Bizier et al. showed no acetylation occurred
when glucosamine containing a free amino group is used as a substrate in the pres-
ence of indium chloride.[7] This experiment also confirmed that triflic acid is the
actual catalyst of the reaction.
A substrate bearing an a,b-unsaturated carboxylic acid (entry 7, Table 2) was
converted to its corresponding methyl ester in very good yield. The reaction with
(þ)-biotin was slow because of its poor solubility in MeOH. Finally, (þ)-biotin
methyl ester was obtained in 85% yield after 10 h (entry 9, Table 2).
Interestingly, the use of bismuth(III) triflate for the esterification of aromatic
carboxylic acid ended with the recovery of the starting material after 6.5 h (entry
10, Table 2). Successful esterification was performed with longer heating times
(entries 11 and 12, Table 2). This suggests that chemoselectivity between aromatic
and aliphatic carboxylic acids depends on the heating time.
We also showed that it is possible to carry out ethyl esterification in ethanol in
good yields (entries 2 and 8, Table 2).
When the reaction of 2-formylbenzoic acid was carried out under the same
reaction conditions, the corresponding methyl ester product was obtained in a
1=1.3 mixture with 3-methoxy-3H-isobenzofuran-l-one lactone (Scheme 1). With
the use of thionyl chloride instead of Bi(OTf)3, a 1.3=1 mixture of methyl ester
and lactone was obtained.[10]
CONCLUSION
This work demonstrates that bismuth(III) triflate promotes esterification of
carboxylic acids to their corresponding ethyl or methyl esters. It acts as a precursor,
which, upon hydrolysis, releases enough triflic acid to catalyze the esterification. The
easy handling of bismuth triflate and its chemoselectivity to aliphatic versus aromatic
carboxylic acids make this method notably advantageous. Moreover, the Bi(OTf)3=
residual H2O system could overcome the difficulties involved using triflic acid, and
its use could be extended to other acid-catalyzed reactions.
EXPERIMENTAL
All chemicals were obtained from Aldrich or Acros Organics and used without
further purification. Nuclear magnetic resonance spectra were recorded on a Bruker

1086
F. H. A. KWIE ET AL.
AC 300 spectrometer (1H and 13C NMR), and mass spectra were measured on a
Nermag R10–10C mass spectrometer. Optical rotations were measured on a Perkin-
Elmer model 141 polarimeter and are given in units of 10ꢁ1 deg ꢂ cm2 ꢂ gꢁ1
.
Typical Procedure
Bi(OTf)3 (0.1 eq) at room temperature, was added to a solution of carboxylic
acid (1 eq, 0.37 mmol) in MeOH or EtOH (2 mL). The reaction mixture was warmed
slowly to reflux and stirred for the desired time. The mixture was cooled and concen-
trated under reduced pressure. Then ethyl acetate (20 mL) was added, and the
organic layer was washed with NaHCO3 (20 mL) and water (2 ꢃ 20 mL), dried over
MgSO4, and concentrated under reduced pressure to give the desired compound. In
some cases, the products had to be purified by flash chromatography.
All compounds reported in Table 1 could be compared with commercially
available standards (entries 1, 2, 6–10, 12) or corresponded to previously reported
spectroscopic data (entry 3,[11] 2-formylbenzoic acid methyl ester,[10] 3-methoxy-3H-
isobenzofuran-l-one lactone[10]).
Data
Fmoc-bAla-OMe (Entry 4, Table 2). White powder. 1H NMR (CDCl3,
300 MHz) d 2.57 (t, J ¼ 5.9 Hz, 2H), 3.48 (m, 2H), 3.71 (s, 3H), 4.21 (t, J ¼ 6.9 Hz,
1H), 4.39 (d, J ¼ 7.0 Hz, 2H), 5.33 (br s, 1H), 7.31 (td, J ¼ 7.4 Hz, J ¼ 1.1 Hz, 2H),
7.4 (t, J ¼ 7.4 Hz, 2H), 7.59 (d, J ¼ 7.6 Hz, 2H), 7.76 (d, J ¼ 7.5 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) d 34.2, 36.5, 47.2, 51.8, 66.7, 119.9, 125.0, 127.0, 127.6,
141.3, 143.9, 156.3, 172.8; LRMS (DCI=NH3, m=z): calc. for C19H19NO4: 325.1.
Found: 343.1 (MþNHþ4 ).
1
Fmoc-Leu-OMe (Entry 5, Table 2). White solid upon standing. H NMR
(CDCl3, 300 MHz) d 0.95 (s, 3H), 0.97 (s, 3H), 1.65 (m, 2Hþ1H), 3.75 (s, 3H),
4.24 (t, J ¼ 6.9 Hz, 1H), 4.41 (d, J ¼ 7.3 Hz, 2H), 4.42 (m, 1H), 5.19 (d, J ¼ 8.6 Hz,
1H), 7.32 (t, J ¼ 7.4 Hz, 2H), 7.41 (t, J ¼ 7.4 Hz, 2H), 7.61 (m, 2H), 7.77 (d,
J ¼ 7.5 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 21.8, 22.8, 24.7, 41.7, 47.2, 52.3,
52.4, 66.9, 119.9, 125.0, 127.0, 127.7, 141.3, 143.7, 143.9, 155.9, 173.6; LRMS
21
(DCI=NH3, m=z): calc. for C22H25NO4: 367.2; found: 385.2 (MþNHþ4 ). ½aꢄD þ 4.6
(c 2, CHCl3).
21
(þ)-Biotin methyl ester (Entry 9, Table 2). White solid. ½aꢄD þ 54 (c 0.62,
23
CHCl3) [Ref. 12: ½aꢄD þ 52 (c 0.21, CHCl3)].
ACKNOWLEDGMENT
`
The authors are grateful to the Ministere de l’Enseignement et de la Recherche
Scientifique for financial support (F. H. A. K).

Bi(OTf)3-CATALYZED ESTERIFICATION
1087
REFERENCES
1. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; John Wiley
& Sons: New york, 1999, and references cited therein.
2. (a) Leonard, N. M.; Wieland, L. C.; Mohan, R. S. Applications of bismuth(III)
compounds in organic synthesis. Tetrahedron 2002, 58, 8373–8397; (b) Gaspard-
Iloughmane, H.; Le Roux, C. Bismuth(III) triflate in organic synthesis. Eur. J. Org. Chem.
2004, 2517–2532.
´
3. Lherbet, C.; Soupaya, D.; Baudoin-Dehoux, C.; Andre, C.; Blonski, C.; Hoffmann, P.
Bismuth triflate- catalyzed oxa- and thia-Pictet–Spengler reactions: Access to iso- and
isothio-chroman compounds. Tetrahedron Lett. 2008, 49(38), 5449–5451.
4. Buzin, P.; Lahcini, M.; Schwarz, G.; Kricheldorf, H. R. Aliphatic polyesters by bismuth
triflate–catalyzed polycondensations of dicarboxylic acids and aliphatic diols. Macromole-
cules 2008, 41, 8491–8495.
5. (a) Orita, A.; Tanahashi, C.; Kakuda, A.; Otera, J. High efficient and versatile acylation of
alcohols with Bi(OTf)3 as catalyst. Angew. Chem. Int. Ed. 2000, 39, 2877–2879; (b)
Carrigan, M. D.; Freiberg, D. A.; Smith, R. C.; Zerth, H. M.; Rohan, R. S. A simple
and practical method for large-scale acetylation of alcohols and diols using bismuth tri-
flate. Synthesis 2001, 2091–2094; (c) Nagano, Y.; Orita, A.; Otera, J. Combined Lewis acid
catalysts in shotgun process: A convenient synthesis of the female sex pheromone of the
red-bollworm mouth. Tetrahedron 2002, 58, 8211–8217.
´
6. Dumeunier, R.; Marko, I. E. On the role of triflic acid in the metal triflate-catalysed
acylation of alcohols. Tetrahedron Lett. 2004, 45, 825–829.
7. Bizier, N. P.; Atkins, S. R.; Helland, L. C.; Colvin, S. F.; Twitchell, J. R.; Cloninger, M. J.
Indium triflate–catalyzed peracetylation of carbohydrates. Carbohydr. Res. 2008, 343,
1814–1818.
8. Ollevier, T.; Nadeau, E. An efficient and mild bismuth triflate–catalysed three-component
Mannich-type reaction. Org. Biomol. Chem. 2007, 5, 3126–3134.
9. Navath, R. S.; Pabbisetty, K. B.; Longqin, H. Chemoselective deprotection of N-Boc
group in amino acids and peptides by bismuth(III) trichloride. Tetrahedron Lett. 2006,
47, 389–393.
10. Morgan, D. O.; Ollis, W. D.; Stanforth, S. P. Preparation and cycloaddition reactions of
novel heterocyclic mesomeric betaines. Tetrahedron 2000, 56, 5523–5534.
11. Mineno, T.; Kansui, H. High-yielding methyl esterification catalyzed by indium(III)
chloride. Chem. Pharm. Bull. 2006, 54, 918–919.
12. Dixon, R. W.; Radmer, R. J.; Kuhn, B.; Kollman, P. A. Theoretical and experimental
studies of biotin analogues that bind almost as tightly to streptavidin as biotin. J. Org.
Chem. 2002, 67, 1827–1837.