LiBF4 catalyzed chemoselective conversion of aldehydes to 1,3-oxathiolanes and 1, 3-dithianes

Article abstract of DOI:10.1055/s-2001-10780

Lithium tetrafluoroborate is found to be an efficient catalyst for the chemoselective protection of both aromatic and aliphatic aldehydes as 1,3-oxathiolanes and 1,3-dithianes under mild reaction conditions. Due to the neutral reaction conditions, this me

Full text of DOI:10.1055/s-2001-10780

238
LETTER
LiBF4 Catalyzed Chemoselective Conversion of Aldehydes to 1,3-Oxathiolanes
and 1, 3-Dithianes#
J. S. Yadav,* B. V. S. Reddy, Sushil Kumar Pandey
Organic Division-1, Indian Institute of Chemical Technology, Hyderabad- 500007, India
Fax +91 (91)40 7170512; E-mail: yadav@iict.ap.nic.in
Received 19 December 2000
alytic amount of lithium tetrafluoroborate in acetonitrile
Abstract: Lithium tetrafluoroborate is found to be an efficient cat-
under neutral reaction conditions.10 The reaction of benz-
alyst for the chemoselective protection of both aromatic and aliphat-
aldehyde with 2-mercaptoethanol in the presence of 10%
ic aldehydes as 1,3-oxathiolanes and 1,3-dithianes under mild
LiBF4 in acetonitrile gave 1,3-oxathiolane derivative in
90% yield. Similarly, various aldehydes were selectively
converted into the corresponding oxathioacetals in high
yields. The reactions proceeded smoothly at ambient tem-
perature in essentially mild and neutral conditions. The
procedure is highly chemoselective that provides selec-
tive protection of aldehydes in the presence of ketones in
multifunctional compounds. The results as summarized in
the Table show the scope and generality of the reaction
with respect to various aromatic, aliphatic and heterocyc-
lic aldehydes. The ketones like benzophenone, acetophen-
one, 3-pentanone and 2-heptanone did not yield any prod-
uct even after long reaction time. Furthermore, chemose-
lectivity of the present method was observed by the use of
ketoaldehydes (entry k). Acid sensitive substrates like fur-
fural is also protected as 1,3-oxathiolane in good yield
without the formation of any side products which are nor-
mally encountered in acidic conditions. The tolerance of
various functional groups under the present reaction con-
ditions have been examined by reacting the substrates
bearing OBn, OPh, OMe, methylenedioxy, nitro and ole-
finic groups and the reaction conditions are compatible
with these functional groups. Aldehydes containing elec-
tron withdrawing groups in the aromatic ring took longer
reaction times to afford comparable yields with those of
electron rich counterparts. However, cyclic ketones like
cyclohexanone, and tetralone required longer reaction
times to give moderate yields of products while the acyc-
lic ones remain unchanged under the present reaction con-
ditions. Probably, the lower reactivity of alkyl and aryl ke-
tones compared to cyclic ketones did not yield any
product under the present reaction conditions. This gives
an added selectivity to protect the cyclic keto group leav-
ing the acyclic one free for further manipulation. Further-
more, when 2-mercapto ethanol was replaced with 1,2-
ethanedithiol or 1,3-propanedithiol, it gave the corre-
sponding dithioacetals in good yields.
reaction conditions. Due to the neutral reaction conditions, this
method is compatible with acid sensitive substrates.
Key words: lithium tetrafluoroborate, aldehydes, 1,3-oxathiolanes,
1,3-dithianes
Acetals, dithioacetals and oxathioacetals are the most
commonly used protecting groups for aldehydes and ke-
tones in multi-step synthesis of many natural products1.
Among various acetals, oxathioacetals and dithioacetals
are versatile2, because of their ease of installation/removal
and also their stability under a variety of reaction condi-
tions. In addition to carbonyl protection, they behave as
masked acyl anions3 or masked methylene functions4 in
carbon-carbon bond forming reactions. Generally, oxa-
thioacetals are prepared by the condensation of carbonyl
compounds with 2-mercaptoethanol using strong protic5
or Lewis acids6,7 as catalysts, but these procedures are of-
ten accompanied by longer reaction times, unsatisfactory
yields and the use of stoichiometric amount of catalysts.
Even though, silicon reagents such as trimethylsilyl tri-
flate, and triisoproylsilyl triflate8 are found to be efficient
catalysts for this conversion, there are still some limita-
tions including expensive catalysts, strongly acidic condi-
tions and moderate yields of products. Furthermore, very
few methods are reported for the chemoselective protec-
tion of aldehydes in the presence of ketones. Thus, there
is a need to develop a new, chemoselective and high yield-
ing protocol for the conversion of aldehydes to 1,3-oxa-
thiolanes under mild and neutral reaction conditions. Re-
cently, lithium tetrafluoroborate in acetonitrile (LTAN)
has received much attention as a powerful reaction medi-
um for various transformations9 including hydrolysis of
acetals, deprotection of silylethers, Diels-Alder reactions
and glycosid-ation reactions. Lithium tetrafluoroborate is
–
a mild Lewis acid, the counterion BF4 is non-nucleo-
philic and non-oxidizing and hence it acts as an efficient
catalyst for carrying out various organic transformations.
These special properties inherent to LiBF4 prompted us to
explore this catalyst for the conversion of aldehydes to
1,3-oxathioacetals and 1,3-dithioacetals.
In conclusion, the present procedure for the conversion
of aldehydes into oxathioacetals and dithioacetals is an
attractive and alternative to the existing ones due to its
greater selectivity, operational simplicity, high yields in a
short reaction time, easy work-up, mild and neutral
reaction conditions.
In this communication, we wish to report a novel and
highly chemoselective procedure for the conversion of al-
dehydes into 1,3-oxathiolanes and 1,3-dithianes using cat-
Synlett 2001, No. 2, 238–239 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
LiBF4 Catalyzed Chemoselective Conversion of Aldehydes
239
S
X
Acknowledgement
LiBF4
XH
+
R CHO
R
HS
CH3CN, r. t.
R = aryl, alkyl, naphthyl and heterocyclic
BVS thanks CSIR, New Delhi and SKP thanks IICT for the award
of fellowships.
X = O or S
Scheme
References and Notes
#
IICT Communication No. 4661
(1) a) Green, T. W.; Wuts, P. G. M.; Protective groups in organic
synthesis; 2nd ed; Wiley: New York 1991, pp 188-191.
b) Kocienski, P. J; Protecting groups; Thieme: Stuttgart,
1994, pp 156-170.
(2) a) Lynch, J. E.; Eliel, E. L. J. Am. Chem. Soc. 1984, 106, 2943.
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Chem. Int. Ed. Engl. 1965, 4, 1075. d) Corey E. J.; Seebach,
D. J. Org. Chem. 1966, 31, 4097.
(3) a) Eliel, E. L.; Morris-Natschke, S. J. Am. Chem. Soc. 1984,
106, 2937. b) Seebach, D. Synthesis 1969, 17. c) Bulman page
P. C.; Van Niel, M. B.; Prodger J. Tetrahedron 1989, 45, 7643.
d) Grobel, B. T.; Seebach, D. Synthesis 1977, 357.
(4) Pettit, G. W.; van Tamelen, E. E. Org. React. 1962, 12, 356,
(5) a) Ralls, J. W.; Dodson, R. M.; Riegel, B. J. Am. Chem. Soc.
1949, 71, 3320. b) Djerassi, C.; Gorman, M. J. Am. Chem. Soc.
1953, 75, 3704.
(6) a) Yadav, V. K.; Fallis, A. G. Tetrahedron Lett. 1988, 29, 897.
b) Wilson, Jr. G. E.; Huang, M. G.; Schloman, Jr. W. W. J.
Org.Chem. 1968, 33, 2133. c) Burczyk, B.; Kortylewicz, Z.
Synthesis 1982, 831.
(7) a) Karimi, B.; Seridj H. Synlett 2000, 805. b) Caputo, R.;
Ferreri, C.; Palumbo, G. Synthesis 1987, 386.
(8) a) Ravindranathan, T.; Chavan, S. P.; Dantale, S. W.
Tetrahedron Lett. 1995, 36, 2285. b) Steinz, L.; Koutek B.;
Saman, D. Collect. Czeck. Chem. Commun. 1997, 62, 665.
(9) Sobhana babu B.; Balasubramanium, K. K. Acros Organics
Acta. 2000, 7, 1 and references cited therein.
(10) General procedure : A mixture of an aldehyde (5 mmol), 2-
mercaptoethanol or 1,2-ethanedithiol (6 mmol) and lithium
tetrafluoroborate (0.5 mmol) in acetonitrile (5 mL) was stirred
at room temperature for an appropriate time (Table). After
completion of the reaction, as indicated by TLC, the reaction
mixture was diluted with water and extracted twice with
dichloromethane (2 15 mL). The combined organic layers
were dried over anhydrous Na2SO4, concentrated in vacuo and
purified by column chromatography on silica gel (Merck, 100-
200 mesh, ethyl acetate:hexane 1:9) to give pure oxathioacetal
or dithioacetal. Spectroscopic data for compound d: 1H NMR
(200 MHz;CDCl3): 3.20 (m, 2H), 3.85 (m, 1H), 4.45 (m,
1H), 5.95 (s, 2H), 6.0 (s, 1H), 6.70 (d, 1H, J = 8.0 Hz), 6.90
(dd, 1H, J = 8.0 Hz and 2.7 Hz), 6.95 (d, 1H, J = 2.7 Hz).
Compound i: 1H NMR (200 MHz; CDCl3): 3.15 (m, 2H),
3.85 (m, 1H), 4.35 (m, 1H), 5.65 (d, 1H J = 8.2Hz), 6.25 (dd,
1H J = 16.4 Hz and 8.2 Hz), 6.60 (d,1H J = 16.4 Hz), 7.25-
7.35 (m, 5H). Compound n: 1H NMR (200 MHz; CDCl3):
1.95 (m, 2H), 2.20 (m, 2H), 2.80 (t, 2H, J = 6.8 Hz), 3.20 (m,
1H), 3.35 (m, 1H), 4.2 (m, 1H), 4.50 (m, 1H), 7.0 (d, 1H,
J = 8.0 Hz), 7.10 (t, 1H, J = 8.0 Hz), 7.15 (t, 1H, J = 8.0 Hz),
7.60 (d, 1H, J = 8.0 Hz).
Table LiBF4 catalyzed formation of 1,3-oxathiolanes and 1,3-di-
thianes.a
Yieldb
Reaction Time
Entry
Substrate
CHO
Thiol
(h)
(%)
SH
SH
a)
HS
HO
90
88
90
1.0
2.5
1.5
CHO
b)
c)
Cl
Cl
CHO
CHO
SH
HS
O
SH
SH
SH
0.5
92
95
89
HO
HO
HO
d)
O
CHO
MeO
1.5
2.0
e)
f)
MeO
CHO
OPh
CHO
SH
g)
h)
HO
87
94
5.0
0.5
1.0
NO2
H3C
CHO
SH
SH
HS
HO
HO
CHO
CH3
90
i)
j)
SH
CHO
CHO
2.0
3.5
0.5
85
O
80c
SH
SH
HO
HO
HO
k)
l)
92
CHO
O
O
CHO
O
SH
SH
m)
n)
1.0
4.0
90
84
HO
HS
SH
SH
3.5
82
o)
p)
1.5
8.0
Hexanal
90
0
HO
SH
SH
2-Heptanone
q)
HO
HO
0
6.0
8.0
r)
Benzophenone
Acetophenone
3-Pentanone
SH
SH
s)
0
0
HO
HO
t)
8.0
a All products were characterized by 1H NMR, IR and Mass spectra
and also by comparison with authentic samples.
b Isolated yields after purification.
c Mono protection of aldehyde was observed.
Article Identifier:
1437-2096,E;2001,0,02,0238,0239,ftx,en;S07600ST.pdf
Synlett 2001, No. 2, 238–239 ISSN 0936-5214 © Thieme Stuttgart · New York