Bismuth compounds in organic synthesis. Bismuth nitrate catalyzed chemoselective synthesis of acylals from aromatic aldehydes

Article abstract of DOI:10.1016/j.tet.2004.02.046

Aromatic aldehydes are smoothly converted into the corresponding acylals in good yields in the presence of 3-10mol% Bi(NO₃) ₃·5H₂O. Ketones are not affected under the reaction conditions. The relatively non-toxic nature of the catalyst, its ease of handling, easy availability and low cost make this procedure especially attractive for large-scale synthesis.

Full text of DOI:10.1016/j.tet.2004.02.046

Tetrahedron 60 (2004) 3675–3679
Bismuth compounds in organic synthesis. Bismuth nitrate
catalyzed chemoselective synthesis of acylals
from aromatic aldehydes
*
David H. Aggen, Joshua N. Arnold, Patrick D. Hayes, Nathaniel J. Smoter and Ram S. Mohan
Laboratory for Environment Friendly Organic Synthesis, Department of Chemistry, Illinois Wesleyan University, 201 E. Beecher Street,
Bloomington, IL 61701, USA
Received 6 February 2004; revised 24 February 2004; accepted 24 February 2004
Abstract—Aromatic aldehydes are smoothly converted into the corresponding acylals in good yields in the presence of 3–10 mol%
Bi(NO3)3·5H2O. Ketones are not affected under the reaction conditions. The relatively non-toxic nature of the catalyst, its ease of handling,
easy availability and low cost make this procedure especially attractive for large-scale synthesis.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
catalysts for synthesis of acylals.19 Lewis acids such as
Cu(OTf)2 (2.5 mol%)20 and Sc(OTf)3 (2 mol%)21 are also
efficient for this conversion. Many of these reagents are
highly corrosive and difficult to handle while some Lewis
acid catalysts such as copper and scandium triflate are rather
expensive and moisture sensitive. Some procedures require
the use of a large excess (5–8 equiv.) of acetic anhydride to
effect acylal formation.7 Further, there are very few reports
in the literature on formation of acylals using other
anhydrides.11 Given the synthetic utility of acylals, newer
reagents that are inexpensive, non-toxic, chemoselective
and effective for acylal formation with a variety of
anhydrides would provide a valuable addition to the
literature.
Acylals (geminal diesters) are frequently used as protecting
groups for aldehydes because they are stable to neutral and
basic conditions.1 In addition, the acylal functionality can be
converted into other useful functional groups by reaction
with appropriate nucleophiles.2 For example, recently a
novel synthesis of chiral allylic esters has been developed
using palladium-catalyzed asymmetric allylic alkylation of
gem-diesters.3 The synthesis of homoallyl acetates by
allylation of 1,1-diacetates has also been reported.4 We
have reported the use of bismuth triflate, Bi(CF3SO3)3·4H2O
as a highly efficient and relatively non-toxic catalyst for the
synthesis of acylals.5 Although bismuth compounds are
attractive due to their remarkably low toxicity,6 low cost and
ease of handling, one drawback of bismuth triflate is that it
is not yet commercially available and must be synthesized in
the laboratory. Our continued work with bismuth com-
pounds has led to the discovery of bismuth nitrate
pentahydrate, Bi(NO3)3·5H2O, an inexpensive, easy-to-
handle, commercially available solid as a versatile catalyst
for the chemoselective formation of acylals from aromatic
aldehydes. The most commonly used reagent for acylal
formation is acetic anhydride which results in the formation
of 1,1-diacetates. Some examples of the reagents and
catalysts that have been developed for this purpose include
LiOTf,7 ceric ammonium nitrate,8 InCl3,9 H2NSO3H,10
LiBF4,11 H2SO4,12 PCl3,13 NBS,14 I2,15 TMSCl-NaI,16
anhydrous ferrous sulfate17 and FeCl3.18 Several inorganic
heterogeneous catalysts have also been developed as
2. Results and discussion
We now report that bismuth nitrate, Bi(NO3)3·5H2O is an
efficient catalyst for the chemoselective conversion of
aromatic aldehydes to a variety of acylals (Scheme 1 and
Table 1).
Scheme 1.
The experimental procedure for the synthesis of the acylals
is simple and involves stirring the aldehyde and the
corresponding anhydride as a solution in acetonitrile. The
product is isolated by extraction with a relatively non-toxic
and industry-friendly solvent, ethyl acetate. A wide variety
of aromatic aldehydes (Table 1, entries 1–6) underwent
Keywords: Bismuth nitrate; Acylals; Environment-friendly; Anhydrides.
*
Corresponding author. Tel.: þ1-309-556-3829; fax: þ1-309-556-3864;
e-mail address: rmohan@iwu.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.046

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D. H. Aggen et al. / Tetrahedron 60 (2004) 3675–3679
Table 1. Formation of acylals using Bi(NO3)3·5H2O in CH3CN
Entrya
118
Substrate
Anhydride (RCO)2O Time
Product
Yieldb
87
13C NMR data (CDCl3)
PhCHO
R¼CH3
1.5 h PhCH(OCOR)2
(R¼CH3) d 20.5, 89.4, 126.4, 128,4, 129.5,
135.3, 168.5
R¼CH3
R¼n-Pr
6 h
16 h
80c
91
(R¼n-Pr) d 13.4, 18.1 35.8, 89.3, 126.5,
128.4, 129.5, 135.7, 171.3
R¼iPr
4 h
3 h
68
(R¼i-Pr) d 18.4, 18.6, 39.7, 89.3, 126.3,
128.4, 129.3, 135.7, 174.6
226
R¼CH3
76c
(R¼CH3) d 20.5, 89.0, 128.1, 128.7, 133.9,
135.6, 168.6
R¼n-Pr
R¼iPr
4 h
80
82
(R¼n-Pr) d 13.3, 18.1, 35.7, 88.7, 127.9,
128.7, 134.2, 135.4, 171.2
15 h
(R¼i-Pr) d 18.4, 18.6, 39.7, 85.7, 127.9,
128.6, 134.3, 135.3, 174.6
326
R¼CH3
4 h
86
d 20.7, 88.7, 124.9, 126.7, 129.8,
129.8, 134.4, 137.3, 168.5
426
R¼CH3
2.5 h
79
d 20.8, 21.2, 89.7, 126.5, 129.2,
132.5, 139.7, 168.7
R¼CH3
R¼CH3
14 h
77d
85e
526
2.5 h
d 20.6, 88.2, 121.7, 124.4, 129.7,
132.8, 137.4, 148.1, 168.5
67
R¼CH3
R¼CH3
15 h
57
d 20.5, 54.9, 89.2, 111.9, 115.0,
118.6, 129.5, 136.7, 159.5, 168.5
718
6 h
82c
R¼CH3
R¼CH3
18 h
16 h
94d
91
826
d 20.7, 20.9, 88.9, 121.7, 127.9,
132.9, 151.4, 168.5, 169.1
f
9
R¼CH3
R¼CH3
NR
107
14 h
19 h
59c
91
d 24.5, 18.1, 20.8, 25.5, 89.6,
120.0, 128.0, 128.2, 156.8, 168.7
115
R¼CH3
a
Superscript against the entry # refers to literature reference for the product.
Refers to yield of isolated product. Yields are not optimized. Unless otherwise mentioned, the purity was estimated to be .98% by 1H and 13C NMR
spectroscopy.
b
c
d
e
f
Reaction was carried out with 5.0 mol% Bi(NO3)3·5H2O.
Reaction was carried out with 3.0 mol% Bi(NO3)3·5H2O.
Reaction carried out under solvent-free conditions at reflux temperatures. Based on H NMR analysis, the crude product contained 4% aldehyde.
1
No reaction occurred even under reflux conditions.

D. H. Aggen et al. / Tetrahedron 60 (2004) 3675–3679
3677
smooth reaction to give the corresponding acylal in good
yield. Phenolic ester groups which are fairly unstable at low
and high pH were stable to the reaction conditions (entry 8).
In contrast to aromatic aldehydes, the results with saturated
aliphatic aldehydes were less promising. Aliphatic alde-
hydes reacted sluggishly even under solvent-free conditions,
and even after 12 h, 50% of unreacted starting material
remained. Acylal formation employing acetic anhydride
was attempted with several aldehydes including heptanal,
hexanal and phenylpropionaldehyde. In all cases, the
product mixture consisted of the expected acylal, unreacted
starting material and several unidentifiable by-products.
NMR analysis of the crude product in each case indicated
that the side products were not consistent with the self-aldol
condensation of these aldehydes. The spectra were also not
consistent with the enol acetates that would form from the
elimination of the expected acylal. Although t-butyl-
dimethylsilyl (TBDMS) groups are relatively acid-sensitive,
under the reaction conditions a moderate yield of the acylal
from the TBDMS protected phenol (entry 10) was obtained.
Deprotection of the TBDMS occurred to the extent of 15%.
The pure acylal was obtained by column chromatography.
In contrast, THP ethers proved unstable to the reaction
conditions. When the THP ether of p-hydroxybenzaldehyde
was subjected to the reaction conditions, acylal formation
occurred but significant deprotection of the THP ether was
also observed. Ketones proved completely resistant to acylal
synthesis with acetic anhydride: no diacetate formed even
under reflux conditions. The chemoselectivity of this
method was demonstrated using acetylbenzaldehyde
(entry 11). Smooth conversion of the aldehyde to the
corresponding diacetate was observed while the ketone
functionality remained unaffected (Scheme 2).
in which a solution of p-anisaldehyde in CH3CN was stirred
with bismuth nitrate indicated that the starting aldehyde is
stable to bismuth nitrate.
This observation suggested that the complex mixture results
from reaction of the corresponding acylal product. It was not
possible to get a pure sample of the acylal by column
chromatography. In order to test whether the side-products
arose as a result of activation of the acylal product by the
electron-releasing p-methoxy group, the reaction was also
attempted with m-methoxybenzaldehyde (at the meta
position, the 2I effect of the OCH3 group would be
operative but not the þR effect). In this case, it was possible
to obtain the corresponding acylal in a 57% yield
(unoptimized) after column chromatographic purification.
When the pure acylal from m-methoxybenzaldehyde was
subjected to the reaction conditions with acetic anhydride,
nitration products were formed to the extent of 5–10%.
It has also been reported in the literature that toluene can be
nitrated by Bi(NO3)3·5H2O impregnated on K10 mont-
morillonite in the presence of acetic anhydride.22 However,
the authors found that the nitration was quite solvent
sensitive and no nitration occurred in acetonitrile. It is
speculated that acetyl nitrate is an intermediate. We
attempted the acylal formation reaction with p-tolualdehyde
using both 3 and 10 mol% Bi(NO3)3·5H2O as the catalyst. In
both cases, in addition to the expected acylal, side products
formed to the extent of 10–20%. NMR analysis of the crude
product indicated that the use of 10 mol% Bi(NO3)3·5H2O
gave rise to more impurities than when 3 mol% Bi(NO3)3·
5H2O was used. While the side-products were not isolated,
the spectral data of the crude material is consistent with
formation of nitration products. The pure acylal was isolated
by column chromatography. In contrast, it was not possible
to obtain the acylal from p-hydroxybenzaldehyde in good
yield. The product mixture was found to be very complex
indicating that the OH group activates the ring toward
substitution reactions. However, in the absence of bismuth
nitrate, reaction of p-hydroxybenzaldehyde with acetic
anhydride gave a good yield of p-acetoxybenzaldehyde
(entry 8). When p-acetoxybenzaldehyde was subjected to
the reaction conditions, smooth conversion to the acylal
occurred. These results are consistent with the hypothesis
that once the ring is no longer activated, ring substitution
reactions do not occur and the acylal can be obtained in
good yields (Scheme 4).
Scheme 2.
The formation of acylals from aromatic aldehydes bearing
activating groups such as OCH3 and OH proved trouble-
some. When p-anisaldehyde (p-methoxybenzaldehyde) was
subjected to the reaction conditions with acetic anhydride,
the resulting product mixture was found to be complex
(Scheme 3). 1H NMR analysis of the product mixture
indicated that in addition to the expected acylal, at least
three other compounds were present (1H NMR indicated the
presence of methoxy groups, d 3–4). A control experiment
The reaction also worked with other acid anhydrides
including butyric anhydride and isobutyric anhydride
while most literature methods for acylal formation employ
only acetic anhydride. It was difficult to separate the
unreacted butyric and isobutyric anhydrides from the
corresponding acylal product. The hydrolysis of higher
Scheme 3.

3678
D. H. Aggen et al. / Tetrahedron 60 (2004) 3675–3679
Scheme 4.
anhydrides with aqueous Na2CO3 is also considerably
slower than the hydrolysis of acetic anhydride due to
solubility problems. A practical solution to this problem was
found by using methanol/aqueous Na2CO3 in the work-up.
Pivalic anhydride and benzoic anhydride proved too
unreactive at room temperature and significant reaction
was not observed at higher temperatures. When bismuth
nitrate is heated, it undergoes decomposition accompanied
by the formation of a brown gas (NO2). Therefore, all
reactions were carried out at room temperature with the
exception of entry 5.
From our studies it is also evident that it is difficult to
control the amount of nitric acid in the solution and hence
bismuth nitrate is a more convenient reagent than nitric acid
to catalyze this reaction. In the presence of water, bismuth
nitrate is converted to bismuth subnitrate, BiONO3. Bismuth
subnitrate is commercially available and hence the reaction
was also attempted with bismuth subnitrate. The reaction of
benzaldehyde with acetic anhydride catalyzed by bismuth
subnitrate was only 50% complete in 2 h.
3. Conclusions
While detailed mechanistic studies were not conducted, a
few other points merit comment and are summarized in
Scheme 5. No acylal formation was observed in the absence
of bismuth nitrate. The possibility that the reaction is
catalyzed by nitric acid released from bismuth nitrate
pentahydrate in CH3CN was considered. A suspension of
bismuth nitrate in water as well as CH3CN is acidic (pH¼2).
However, the reaction of benzaldehyde with acetic
anhydride using 0.6 equiv. of HNO3 did not afford the
desired acylal in good yield. When the amount of HNO3 was
increased to 1.2 equiv. the starting aldehyde was recovered
unchanged. The reaction of benzaldehyde with acetic
anhydride catalyzed by bismuth nitrate in the presence of
proton-spongew (N,N,N0,N0-tetramethyl-1,8-naphthalene-
diamine)23 was also carried out. Although the reaction
was slow, the desired product was formed in 61% yield after
chromatographic purification. The lower yield resulted
primarily from the small-scale of this experiment and the
difficulty in separating the proton-spongew from the acylal
product. Although this result does suggest that the reaction
is catalyzed by bismuth(III) acting as a Lewis acid, protic
acid catalysis cannot be completely ruled out. In contrast,
studies using bismuth bromide as a catalyst for deprotection
of oximes as well as for synthesis of cyclic ethers using
intramolecular etherification reactions of d-trialkylsilyloxy
aldehydes and ketones suggest that its main role is to
generate HBr, which is the active catalyst.24
In summary, a new catalytic method employing bismuth
nitrate catalysis has been developed for the conversion of
aromatic aldehydes to acylals with a variety of anhydrides.
Advantages of this method include: (1) the use of an
inexpensive, air-stable, commercially available and rela-
tively non-toxic catalyst and (2) the observed
chemoselectivity.
4. Experimental
4.1. General
NMR spectra were recorded on a JEOL Eclipse NMR
spectrometer at 270 MHz (1H) and 67.5 MHz (13C) in
CDCl3 as the solvent. Flash chromatography was performed
on Merck Silica gel (230–400 Mesh).25 Reaction progress
was monitored by TLC, GC analysis or by NMR
spectroscopy. Thin layer chromatography was performed
on aluminum backed silica gel plates. Spots were visualized
under UV light or by spraying the plate with phosphomo-
lybdic acid followed by heating. GC analysis was carried
out on a Varian CP 3800 Gas Chromatograph. Although all
the products have been previously reported in the literature,
the 13C spectral data for many of the acylals is not available.
Hence, 13C NMR data for selected acylals is reported in
Table 1. Reagent grade acetonitrile was used for all
reactions. The TBDMS ether from p-hydroxybenzaldehyde
(entry 10, Table 1) was prepared by treatment of p-hydroxy-
benzaldehyde with tert-butyldimethylsilyl chloride in the
presence of DMAP and triethylamine.
4.1.1. Representative procedure for formation of acylal
using acetic anhydride. A solution of p-tolualdehyde
(1.00 g, 8.32 mmol) in reagent grade CH3CN (5 mL) was
stirred as acetic anhydride (2.36 mL, 24.96 mmol, 3 equiv.)
and Bi(NO3)3·5H2O (0.404 g, 0.832 mmol, 10 mol%) were
Scheme 5.

D. H. Aggen et al. / Tetrahedron 60 (2004) 3675–3679
3679
5. Carrigan, M. C.; Eash, K. J.; Oswald, M. C.; Mohan, R. S.
Tetrahedron Lett. 2001, 42, 8133.
added. The resulting mixture was stirred under N2 at room
temperature for 2.5 h and then aqueous saturated Na2CO3
solution (20 mL) was added. The resulting mixture was
stirred for 20 min and then extracted with EtOAc
(3£25 mL). The combined organic layers were washed
with saturated NaCl solution (20 mL) and dried (Na2SO4).
The solvents were removed on a rotary evaporator to yield
1.71 g of the crude product. A portion of the product
(1.66 g) was purified by flash column chromatography on
70 g of silica gel (ethyl acetate/hexane, 1:9 as the eluent) to
yield 1.43 g (overall yield 79%) of the acylal which was
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1
characterized by H and 13C NMR spectroscopy.
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4.1.2. Representative procedure for formation of acylal
using higher anhydrides. A solution of p-chlorobenzalde-
hyde (1.00 g, 7.11 mmol) in reagent grade CH3CN (5 mL)
was stirred as isobutyric anhydride (3.54 mL, 21.3 mmol,
3 equiv.) and Bi(NO3)3·5H2O (0.345 g, 0.71 mmol,
10 mol%) were added. The resulting mixture was stirred
under N2 at room temperature for 15 h and then CH3OH/
aqueous Na2CO3/H2O (1:1:1, v/v/v) was added. The
mixture was then stirred for 30 min and then extracted
with EtOAc (3£25 mL). The combined organic layers were
washed with saturated NaCl solution (15 mL) and dried
(Na2SO4). The solvents were removed on a rotary
evaporator and the product was then placed under high
vacuum at 40 8C (oil bath) to yield 1.74 g (82%) of the
desired acylal which was characterized by 1H and 13C NMR
spectroscopy.
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Acknowledgements
The authors wish to acknowledge funding by the National
Science Foundation (RUI grant 0078881). R. M. would also
like to thank The Camille and Henry Dreyfus Foundation
for a Henry Dreyfus Teacher Scholar Award.
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