A remarkable bismuth nitrate-catalyzed protection of carbonyl compounds

Article abstract of DOI:10.1016/S0040-4039(02)02821-6

Bismuth nitrate has been found to be an outstanding catalyst for the protection of carbonyl compounds as acetal, ketal, mixed ketal and thioketal with an excellent yield.

Full text of DOI:10.1016/S0040-4039(02)02821-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1191–1193
A remarkable bismuth nitrate-catalyzed protection of
carbonyl compounds
Neeta Srivastava,† Swapan K. Dasgupta† and Bimal K. Banik*
The University of Texas, M. D. Anderson Cancer Center, Department of Molecular Pathology, 1515 Holcombe Blvd., Houston,
TX 77030, USA
Received 20 November 2002; revised 11 December 2002; accepted 12 December 2002
Abstract—Bismuth nitrate has been found to be an outstanding catalyst for the protection of carbonyl compounds as acetal, ketal,
mixed ketal and thioketal with an excellent yield. © 2003 Elsevier Science Ltd. All rights reserved.
The protection of carbonyl groups plays an important
role in organic, medicinal, carbohydrate, and drug
design chemistry. Tremendous effort has been made to
search for a suitable protective group for carbonyl
compounds.1 In spite of these efforts, acetal, 1-3-diox-
alane, mixed ketal, and thioketal protection remains the
most practical choice.2 In general, this method requires
protic or Lewis acids as catalysts.2 Lanthanides and
other metal-catalysts are found to be excellent in the
acetalization of carbonyl compounds.3,4 The most
important shortcomings of the acid-induced methods
are the long reaction time, high temperature conditions
(removing the water as an azeotrope with benzene), and
stoichiometric amounts of reagents.1,2 On the other
hand, lanthanides and Lewis-catalysts are substrate
selective, but a general method can not be achieved by
using these catalysts.3,4 Development of a catalytic ver-
sion of these methods with low-toxic, readily available,
economic reagents should greatly contribute to the
realization of environmentally benign processes.
that bismuth nitrate would be an efficient catalyst for
protection of the carbonyl groups. In this paper, we
describe our study of the protection of carbonyl com-
pounds as acetals, dioxalones, mixed ketals and thioke-
tals using a general bismuth nitrate method at room
temperature. Using this method, a facile diastereoselec-
tive synthesis of dioxolanones and oxathiolanones has
also been achieved. Notably, bismuth nitrate has been
found to be highly effective in the protection of alde-
hydes and ketones, even with 0.1 mol% of the reagent
(Scheme 1).
At the beginning of the study, several carbonyl com-
pounds were protected as acetals using catalytic
amounts of bismuth nitrate and methanol. A higher
proportion of bismuth nitrate (5 mol%) can accelerate
the reaction. However, this can cause serious setbacks
as well. Proper maintenance of the reaction time and
conditions is absolutely necessary for the success of the
reaction. Otherwise, a considerable amount of product
We have been engaged in bismuth-based organic trans-
formations.5 During this course of study, we have
discovered that aromatic nitration,5a,b the oxidation of
alcohols5c and the deprotection of oximes5d can all be
mediated by commercially available bismuth nitrate. In
principle, these reactions require the presence of acids.
Moreover, this reagent has been used for the deprotec-
tion of acetal-types of groups.6 As a result of these
studies and recognizing that acetalization–deacetaliza-
tion reactions are reversible reactions, we hypothesized
Keywords: bismuth nitrate; catalyst; protection; diastereoselectivity.
* Corresponding author. E-mail: bbanik@mail.mdanderson.org
† Contributed equally.
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02821-6

1192
N. Sri6asta6a et al. / Tetrahedron Letters 44 (2003) 1191–1193
can revert to the starting carbonyl compound. After a
great deal of experimentation, we found that 0.1 mol%
bismuth nitrate was sufficient to obtain the desired
compounds in excellent yield and within a few hours
(Scheme 1, Table 1, entries 1–21). Nearly all types of
carbonyl compounds can be used with success. We
prepared other ketals, the results of which are promis-
ing. For example, dioxalones, mixed ketals, and thioke-
tals prepared under these conditions posed no
problems. In general, these reactions required a rela-
tively longer time to reach completion.
reagent stability, bismuth nitrate is a solid and a much
more stable reagent compared with bismuth triflate.
However, the catalytic activity of the two reagents is
almost identical. The fourth advantage is that the bis-
muth nitrate catalyzed reaction proceeds exceedingly
well at room temperature.
Realizing the versatility of our bismuth nitrate-cata-
lyzed protection of carbonyl compounds, we envision
that this method can provide easy access to diox-
olanones. Compounds of this type are frequently used
as starting materials for the synthesis of many natural
and non-natural compounds.10 The reaction of racemic
or optically active lactic acid, thiolactic acid and man-
delic acid with aldehydes, in principle, can produce two
isomeric compounds under these conditions. In confor-
mity of hypothesis, our bismuth nitrate-catalyzed reac-
tion produced a diastereoselective mixture of cis and
trans (85:15) dioxolanones and oxathiolanones with an
excellent yield (Scheme 2, Table 2). The isomeric ratios
were calculated by comparison of the NMR spectra of
authentic samples and those produced by our method.10
Bronsted acid-catalyzed acetalization with azeotropic
removal of water and Lewis acid-mediated reaction also
produced a similar mixture of isomers.
In light of Ram Mohan’ s report,6 our results deserve
special comments. It was reported that bismuth triflate
(0.1–1 mol%) catalyzes the protection of carbonyl com-
pounds in the presence of methanol/ethanol and tri-
alkylorthoformate. In this report, the actual protective
group was delivered from the trialkylorthoformate:
methanol or ethanol served as the catalyst. There is no
doubt that this method is excellent when compared
with the other methods in this field.1–4 However, our
bismuth nitrate-catalyzed method is more practical, and
is more convenient than the bismuth triflate-catalyzed
process. The first advantage of bismuth nitrate is its
commercial availability. Bismuth triflate is not commer-
cially available and must be prepared by one of the
following ways: the reaction of triflic acid on bismuth
tris-trifluoroacetate,7 the addition of triflic anhydride
on bismuth oxide,8 the reaction of a mixture of triflic
acid and its anhydride on bismuth oxide,8 or reaction of
triflic acid on triphenylbismuth.9 Therefore, effectively
in all cases an excess of expensive triflic reagent has to
be used. In most of the cases, the bismuth triflate
obtained from these procedures was obtained in its
hydrated form. The second advantage of our method is
that an alcohol is the actual reagent and, in contrast
with the bismuth triflate-catalyzed process, trialkyl-
orthoformate is not required. The third advantage is in
For a successful bismuth nitrate-catalyzed reaction of
this type, one would expect generation of nitric acid in
the reaction medium. A reaction in the presence of a
catalytic amount of nitric acid results in low yield of the
Scheme 2.
Table 1. Protection of carbonyl compounds by catalytic amounts (0.1 mol%) of bismuth nitrate
Entries
Carbonyl compounds
Alcohols/thiols
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Benzaldehyde
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
6
5
5
5
5
5
4
4
4
5
5
5
5
6
6
6
5
5
5
5
5
75
90
70
60
92
76
72
76
70
75
70
75
70
70
72
60
65
75
78
75
75
2-Bromobenzaldehyde
trans-Cinnamaldehyde
p-Anisaldehyde
Decyl aldehyde
3-Bromobenzaldehyde
Cyclohexanone
4-Methylcyclohexanone
4-tert-Butylcyclohexanone
Benzaldehyde
2-Bromobenzaldehyde
trans-Cinnamaldehyde
p-Anisaldehyde
Cyclohexanone
4-Methylcyclohexanone
Benzaldehyde
9
MeOH
10
11
12
13
14
15
16
17
18
19
20
21
Mercaptoethanol
Mercaptoethanol
Mercaptoethanol
Mercaptoethanol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethylene glycol
Ethanedithiol
Ethanedithiol
Ethanrdithiol
trans-Cinnamaldehyde
p-Anisaldehyde
Benzaldehyde
trans-Cinnamaldehyde
p-Anisaldehyde

N. Sri6asta6a et al. / Tetrahedron Letters 44 (2003) 1191–1193
1193
Table 2. Protection of aldehydes with a-hydroxy acids and thiolactic acid using 0.1 mol% of bismuth nitrate
Carbonyl compounds
Acids
Time (h)
Yields (%)
cis/trans
Pivaldehyde
Pivaldehyde
Pivaldehyde
Dihydrocinnamaldehyde
L(+)-Lactic acid
Mandellic acid
Thiolactic acid
Thiolactic acid
6
8
6
95
90
90
70
78/22
85/15
76/24
65/35
10
products (Table 1, entries 1, 7, 14 and 21). Precise
control of the acidity in a small-scale reaction with
corrosive nitric acid or any other strong acid is
extremely difficult. Considering the reversible nature of
these processes, this low yield is expected.
30, 6151; (b) Gorla, F.; Venanzi, L. M. Helv. Chim. Acta
1990, 73, 690.
5. (a) Samajdar, S.; Becker, F. F.; Banik, B. K. Tetrahedron
Lett. 2000, 41, 8017; (b) Samajdar, S.; Becker, F. F.;
Banik, B. K. Arkivoc 2001, TG-223; (c) Samajdar, S.;
Becker, F. F.; Banik, B. K. Synth. Commun. 2001, 31,
2691; (d) Samajdar, S.; Basu, M. K.; Becker, F. F.;
Banik, B. K. Synth. Commun. 2002, 32, 1917. For other
applications using bismuth salt from our laboratory, see:
(a) Banik, B. K; Venkatraman, M. S.; Mukhopadhyaya,
C.; Becker, F. F. Tetrahedron Lett. 1998, 39, 7247; (b)
Banik, B. K; Ghatak, A.; Venkatraman, M. S.; Becker,
F. F. Synth. Commun. 2000, 30, 2701; (c) Banik, B. K;
Ghatak, A.; Mukhopadhyaya, C.; Becker, F. F. J. Chem.
Res. 2000, 108.
In summary, the present bismuth nitrate-catalyzed
method of protection of carbonyl compounds is very
general, mild, cost-effective and convenient. We believe
that none of the other methods previously described in
the literature demonstrate this kind of simplicity and
effectiveness.11
Acknowledgements
6. Leonard, N. M.; Oswald, M. C.; Freiberg, D. A.; Nattier,
B. A.; Smith, R. C.; Mohan, R. S. J. Org. Chem. 2002,
67, 5202.
7. Singh, S.; Verma, A. R. D. Ind. J. Chem. 1983, 22A, 814.
8. Niyogi, D. G.; Singh, S.; Gill, S.; Verma, R. D. J.
Fluorine Chem. 1990, 48, 421.
We gratefully acknowledge the funding support
received for this research project from the University of
Texas M. D. Anderson Cancer Center for the partial
support of this research. We are thankful to NIH
Cancer Center Support Grant 5-P30-CA16672-25, in
particular, the shared resources of the Pharmacology
and Analytical Center Facility.
9. Frank, W.; Reiss, G. J.; Schneider, J. Angew Chem., Int.
Ed. 1995, 34, 2416. Also see: (a) Labrouillere, M.; Roux,
C. L.; Gaspard, H.; Dubac, L. J. Tetrahedron Lett. 1999,
40, 285; (b) Repichet, S.; Zwick, A.; Vendier, L.; Roux,
C. L.; Dubac, J. Tetrahedron Lett. 2002, 43, 993.
10. For examples, see: (a) Seebach, D.; Naef, R.; Calderari,
G. Tetrahedron 1984, 40, 1313; (b) Mashraqui, S. H.;
Kellogg, R. M. J. Org. Chem. 1984, 49, 2513; (c) Hoye,
T. R.; Peterson, B. H.; Miller, J. D. J. Org. Chem. 1987,
52, 1351; (d) Pearson, W. H.; Cheng, M.-C. J. Org.
Chem. 1987, 52, 1353; (e) Chapel, N.; Greiner, A.;
Ortholand, J.-Y. Tetrahedron Lett. 1991, 32, 1441; (f)
Ortholand, J.-Y.; Vicart, N.; Greiner, A. J. Org. Chem.
1995, 60, 1880; (g) Ishihara, K.; Karumi, Y.; Kubota, M.;
Yamamoto, H. Synlett 1996, 839.
11. General acetalization procedure: The carbonyl compound
(1 mmol) was dissolved in methanol (4 mL), and bismuth
nitrate (0.1 mmol) was added while stirring. After the
starting material was consumed as indicated by TLC, the
methanol was evaporated. The crude product was
extracted with dichloromethane, washed with saturated
NaHCO3, and dried over Na2SO4, and the solvent was
evaporated. Finally the pure products were obtained by
purification through basic alumina using ethyl acetate-
hexane (10:90) as the solvent. A similar procedure was
adopted with ethylene glycol, ethanedithiol, mercap-
toethanol, a-hydroxy acids and thiolactic acid in THF.
All the compounds were characterized by comparison
with an authentic sample (1H NMR).
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