Mild and efficient chemoselective protection of aldehydes as dithioacetals employing N-bromosuccinimide

Article abstract of DOI:10.1055/s-2002-20469

A mild and chemoselective dithioacetalization procedure for the protection of aromatic, aliphatic, and alkenyl aldehydes in presence of catalytic amount of N-bromosuccinimide under neutral conditions is described.

Full text of DOI:10.1055/s-2002-20469

474
LETTER
Mild and Efficient Chemoselective Protection of Aldehydes as Dithioacetals
Employing N-Bromosuccinimide
Chemoselective
P
r
h
otectionof
A
m
ldehydes as
D
ithioa
e
cetals d Kamal,* Gagan Chouhan
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)7173757; E-mail: ahmedkamal@iict.ap.nic.in
Received 6 December 2001
ious aldehydes selectively produced the corresponding
1,3-dithiolanes and 1,3-dithianes in high yields
(Scheme 1).
Abstract: A mild and chemoselective dithioacetalization procedure
for the protection of aromatic, aliphatic, and alkenyl aldehydes in
presence of catalytic amount of N-bromosuccinimide under neutral
conditions is described.
( )n
Key words: N-bromosuccinimide, aldehydes, dithioacetals, 1,3-
dithiolanes, 1,3-dithianes
S
S
O
dithiol, NBS (15 mol%)
CH2Cl2, 30-180min.
R
H
R
H
The protection of carbonyl compounds as acetals and
dithioacetals is important in the total synthesis of complex
natural products.1 Apart from their synthetic utility in the
prepration of natural products involving lithiation of 1,3-
dithianes, their stability under acidic and basic conditions
make them versatile carbonyl protecting groups.2,3 In the
literature, there are many methods reported for the prepar-
ation of thioacetals from carbonyl compounds employing
1
2
R=aryl, alkyl, alkenyl
n=2,3
Scheme 1
The reaction proceeds smoothly at ambient temperature in
essentially mild and almost neutral conditions. This has
been further substantiated by protecting an acid sensitive
substrate such as furfural as its 1,2-ethanedithiol deriva-
tive in almost quantitative yield without the formation of
any side products. This reaction under acidic condition is
usually problematic. It is observed that both activated and
weakly activated aromatic aldehydes form dithioacetals in
good to high yield, whereas in case of aliphatic aldehydes
the yields are slightly lower. The results have been sum-
marized in the Table, which exhibits the scope and the
generality of the reaction with respect to different, aro-
matic, aliphatic and alkenyl aldehydes. Moreover, this
procedure is highly chemoselective, providing selective
protection of an aldehyde in the presence of a ketone. In a
representative example, an equimolar mixture of p-chlor-
obenzaldehyde and p-bromoacetophenone when allowed
to react with 1,3-propanedithiol and catalytic amount of
NBS (15 mol%) in dichloromethane yielded 1,3-dithiane
derivative of p-chlorobenzaldehyde while the p-bromoac-
etophenone is completely recovered back, illustrating the
chemoselectivity of the present method (Scheme 2).
6
acid catalysts such as HCl gas,4 ZnCl2,5 Zn or Mg(OTf)2
and BF3 Et2O.7 Some other acid catalysts used for this
purpose include AlCl3,8 TiCl4,9 LaCl3,10 SiCl4,11
(CH3)3SiCl.12 Cu(OTf)2–SiO2,13 ZrCl4–SiO2,14 WCl6,15
5
M LiC1O4 (LPDE)/diethylether,16 TaCl5–SiO2,17 BiCl3
and Bi(SO4)3.18 Mixed reagent systems such as alkyl thi-
osilane/Lewis acid19 and silica gel supported thionyl
chloride20 including some reagents such as polyphos-
phoric acid trimethylsilyl ester21 and 2-chloro-1,3,2-
dithiaborolane22 have also been developed for the forma-
tion of thioacetals. A large number of these methods in-
volve harsh reaction conditions and offer poor selectivity,
when applied to mixtures of aldehydes and ketones. Al-
24
though, some recent methods employing LiBr23, InCl3
and LiBF425 have been reported to show chemoselectivity,
there is further scope to explore mild and efficient meth-
ods for thioacetalization.
In this communication, we wish to report a mild and high-
ly chemoselective procedure for the conversion of alde-
hydes into 1,3-dithiolanes and 1,3-dithianes using
catalytic amount of N-bromosuccinimide (NBS) in
dichloromethane under almost neutral reaction condi-
tions.26
S
1,3-propanedithiol,
CHO
Cl
Cl
Br
78%
0%
NBS (15 mol%)
S
S
O
The reaction of benzaldehyde with 1,2-ethanedithiol in
the presence of 15 mol% NBS in dichloromethane gave
1,3-dithiolane derivative in 80% yield. Similarly 1,2-
ethanedithiol and 1,3-propanedithiol on reaction with var-
CH2Cl2,r.t.,30 min
CH3
S
Scheme 2
The role of NBS is not clear but a plausible explanation is
that NBS reacts first with the dithiol to generate HBr,
which may activate the carbonyl group for further reaction
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1437-2096,E;2002,0,03,0474,0476,ftx,en;D19801ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Chemoselective Protection of Aldehydes as Dithioacetals
475
with dithiol to produce hemithioacetal-type intermediate
(3), which loses water molecule to afford dithiol protected
aldehyde (Scheme 3). However, the possibility of NBS
generating Br2 cannot be ruled out.
Table Preparation of 1,3-Dithiolanes and 1,3-Dithianes using NBS
Entry (1) Producta (2)
Time (min) Yield (%)b
S
S
a
40
30
80
90
( )n
H
O
H Br
O
S
S
R
H
H Br
HBr
O
b
c
F
HS SH
HS
R
H
R
H
S
3
( )n
S
S
( )n
H
30
75
73
H3CO
H
S
SH
R
H
S
Br
Br
( )n
R
H
- H2O
S
S
-HBr
3
( )n
O
O
S
R
S
d
120
S
Scheme 3
S
e
f
30
80
61
Cl
In conclusion, both aromatic and aliphatic aldehydes have
been converted to their corresponding dithioacetals em-
ploying NBS as a catalyst in extremely mild conditions.
Moreover, the high chemoselectivity, good to high yields,
short reaction times and non-aqueous work up makes the
present method a practical protocol for dithioacetalization
process.
S
S
180
S
N
Bz
S
S
g
h
i
90
90
40
70
68
75
S
S
Acknowledgement
One of the authors GC is thankful to IICT, Hyderabad for the award
of research fellowship.
NO2
S
References
S
(1) Greene, T. W. Protective Groups in Organic Synthesis; John
Wiley: New York, 1981, 129.
S
O
O
j
120
72
(2) (a) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097.
(b) Seebach, D. Synthesis 1969, 17. (c) Groebel, B.-T.;
Seebach, D. Synthesis 1977, 357. (d) Seebach, D. Angew.
Chem., Int. Ed. Engl. 1979, 18, 239. (e) Bulman Page, P. C.;
van Niel, M. B.; Prodger, J. C. Tetrahedron 1989, 45, 7643.
(3) For example of natural products syntheses using the
umpolung reaction see: (a) Mori, Y.; Kohchi, Y.; Suzuki, M.
J. Org. Chem. 1991, 56, 631. (b) Rychnovsky, S. D. Chem.
Rev. 1995, 95, 2021. (c) Smith, A. B. III.; Condon, S. M.;
McCauley, J. A. Acc. Chem. Res. 1998, 31, 35.
(4) (a) Autenrieth, W. Chem. Ber. 1899, 32, 1383. (b) Bulman
Page, P. C.; Prodger, J. C.; Westwood, D. Tetrahedron 1993,
49, 10355.
(5) Evans, D. A.; Truesdale, L. K.; Grimm, K. G.; Nesbitt, S. L.
J. Am. Chem. Soc. 1977, 99, 5009.
(6) Corey, E. J.; Shimoji, K. Tetrahedron Lett. 1983, 24, 169.
(7) Fieser, L. F. J. Am. Chem. Soc. 1954, 76, 1945.
(8) Ong, B. S. Tetrahedron Lett. 1980, 21, 4225.
(9) Kumar, V.; Dev, S. Tetrahedron Lett. 1983, 24, 1289.
(10) Garlaschelli, L.; Vidari, G. Tetrahedron Lett. 1990, 31,
5815.
(11) Ku, B.; Oh, D. Y. Synth. Commun. 1989, 19, 433.
(12) Ong, B. S.; Chan, T. H. Synth. Commun. 1977, 7, 283.
(13) Anand, R. V.; Sarvanan, P.; Singh, V. K. Synlett 1999, 413.
S
S
k
l
90
60
63
S
HO
180
S
H3CO
S
S
S
m
n
30
30
30
78
70
90
Cl
S
H3CO
S
S
o
S
O
a All products were characterized by 1H NMR, IR and Mass spectra.
b Isolated yields after column chromatography on silica gel.
Synlett 2002, No. 3, 474–476 ISSN 0936-5214 © Thieme Stuttgart · New York

476
A. Kamal, G. Chouhan
LETTER
(14) Patney, H. K.; Margan, S. Tetrahedron Lett. 1996, 37, 4621.
(15) Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synlett 1998, 739.
(16) Saraswathy, V. G.; Geetha, V.; Sankararaman, S. J. Org.
Chem. 1994, 52, 4665.
(17) Chandrasekhar, S.; Takhi, M.; Reddy, Y. R.; Mohapatra, S.;
Rao, C. R.; Reddy, K. V. Tetrahedron 1997, 53, 14997.
(18) Komatsu, N.; Uda, M.; Suzuki, H. Synlett 1995, 984.
(19) Evans, D. A.; Grimm, K. G.; Truesdale, L. K. J. Am. Chem.
Soc. 1975, 97, 3229.
(26) Typical Experimental Procedure: To a stirred solution of
NBS (15 mol%) and the appropriate aldehyde (1 mmol) in
dichloromethane (10 mL) at r.t. was added 1,2-ethanedithiol
or 1,3-propanedithiol (1.2 mmol) under nitrogen atmo-
sphere. The mixture was stirred at r.t. for an appropriate time
(Table). After completion of the reaction as indicated by
TLC, the organic solvent was concentrated in vacuum and
the crude product was purified by silica gel column
chromatography to furnish the dithioalanes in good yields.
Spectroscopic data for compound b: 1H NMR (200 MHz;
CDCl3): = 3.2–3.6 (m, 4 H), 5.6 (s, 1 H), 6.9–7.1 (m, 2 H),
7.4–7.6 (m, 2 H). Compound h: = 0.9 (t, 3 H, J = 5.88 Hz),
1.3–1.5 (m, 2 H), 1.9–2.1 (m, 2 H), 3.1–3.3 (m, 4 H), 5.0 (d,
1 H, J = 8.2 Hz), 5.3–5.6 (m, 2 H). Compound m: = 1.85–
2.0 (m, 1 H), 2.1–2.2 (m, 1 H), 2.8–2.9 (m, 2 H), 2.95–3.1
(m, 2 H), 5.1 (s, 1 H), 7.2 (d, 2 H, J = 8.3 Hz), 7.4 (d, 2 H,
J = 8.3 Hz). Compound n: = 1.85–2.0 (m, 1 H), 2.1–2.2 (m,
1 H), 2.8–3.1 (m, 4 H), 3.7 (s, 3 H), 5.1 (s, 1 H), 6.8 (d, 2 H,
J = 7.3 Hz), 7.3 (d, 2 H, J = 7.3 Hz).
(20) Kamitori, Y.; Hojo, M.; Masuda, R.; Kimura, T.; Yoshida, T.
J. Org. Chem. 1986, 51, 1427.
(21) Kakimoto, M.; Seri, T.; Imai, Y. Synthesis 1987, 164.
(22) Morton, D. R.; Hobbs, S. J. J. Org. Chem. 1979, 44, 656.
(23) Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synthesis 1999, 58.
(24) Muthusamy, S.; Arulananda Babu, S.; Gunanathan, C.
Tetrahedron Lett. 2001, 42, 359.
(25) Yadav, J. S.; Reddy, B. V. S.; Pandey, S. K. Synlett 2001,
238.
Synlett 2002, No. 3, 474–476 ISSN 0936-5214 © Thieme Stuttgart · New York