Molten salt as a green reaction medium: Efficient and chemoselective dithioacetalization and oxathioacetalization of aldehydes mediated by molten tetrabutylammonium bromide

Article abstract of DOI:10.1071/CH03318

Tetrabutylammonium bromide in the molten state has been demonstrated to be a very efficient catalyst and reaction medium for the highly chemoselective dithioacetalization and oxathioacetalization of aldehydes. The tetrabutylammonium bromide is recycled fo

Full text of DOI:10.1071/CH03318

Short Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 605–608
Molten Salt as a Green Reaction Medium: Efficient and Chemoselective
Dithioacetalization and Oxathioacetalization of Aldehydes Mediated by
Molten Tetrabutylammonium Bromide
Brindaban C. RanuA,B and Arijit DasA
A
Department of Organic Chemistry, Indian Association for the Cultivation of Science,
Jadavpur, Calcutta 700 032, India.
Author to whom correspondence should be addressed (e-mail: ocbcr@iacs.res.in).
B
Tetrabutylammonium bromide in the molten state has been demonstrated to be a very efficient catalyst and
reaction medium for the highly chemoselective dithioacetalization and oxathioacetalization of aldehydes. The
tetrabutylammonium bromide is recycled for subsequent reactions.
Manuscript received: 15 December 2003.
Final version: 3 February 2004.
(
)n
The protection of a carbonyl group is often required in
a multi-step organic synthesis to avoid nucleophilic attack
at the carbonyl centre. Among various carbonyl protecting
groups, dithioacetals and oxathioacetals are preferred for
many substrates because of their inherent stability under
R
H
R
H
X
X
XH XH
Bu 4NBr
O
n
( )n
X, Xϭ S, S or S, O
nϭ 1, 2
[1]
both acidic and basic conditions. On the other hand, both
Scheme 1.
[2a,b]
[2c,d]
dithioacetals
and oxathioacetals have been used
successfully as acyl anion equivalents in C C bond forming
reactions. In addition, dithioacetals are also used as interme-
diates in the conversion of a carbonyl group into a hydro-
carbon derivative. Thus, synthesis of these compounds is
of much importance. In a classical procedure, dithioacetals
are prepared by the reaction of a carbonyl compound with a
commercially available, non-toxic inorganic salt, tetrabutyl-
ammonium bromide, can be used in the molten state as a
catalyst as well as reaction medium for the dithioacetalization
and oxathioacetalization of aldehydes (Scheme 1).
[3]
The experimental procedure is very simple. A mixture
of the aldehyde and ethane/propane dithiol (or 2-mercapto-
ethanol) was added to molten tetrabutylammonium bromide
[
4]
dithiol in the presence of a strong protic acid such as HCl
[5]
◦
or a Lewis acid like BF3 · OEt2. However, these procedures
using strong acids may not be safe for acid-sensitive groups.
Thus, several other, relatively mild, catalysts such as Nafion-
(mp 102–103 C), and the reaction mixture was stirred at 90–
◦
100 C until completion of the reaction (TLC). The product
dithioacetal or oxathioacetal was isolated by direct distilla-
tion under reduced pressure from the reaction mixture. The
products are of high purity and are identified by their IR, and
[
6]
[7]
[8]
[9]
H, AlCl3, TiCl4, LiBF4, magnesium and zinc tri-
[
10]
[11]
[12]
[13]
[18]
flates,
TaCl3–SiO2,
and TMSOTf
Sc(OTf)3,
Cu(OTf)2–SiO2,
ZrCl4–SiO2,
[
14]
[15]
[16]
[17]
1
13
InCl3,
Amberlyst,
I2,
NiCl2,
H and C NMR spectroscopic data. The tetrabutylammo-
[
19]
have been employed in a variety of organic
nium bromide remaining in the reaction flask was washed
with hexane (2 × 0.5 mL), dried under vacuum, and recycled
for subsequent uses without any loss of efficiency.
solvents and also under solvent-free conditions. On the
[
20]
[21]
ZnCl2–
other hand, several procedures using HCl,
HClO4,
[22]
[23]
[24]
[25]
p-TsOH,
BF3–OEt2,
Bu4NBr3,
and Amberlyst
ZrCl4,
as catalyst have
A wide range of structurally diverse aldehydes, includ-
ing aromatic, aliphatic, and heterocyclic ones, underwent
dithioacetalizationandoxathioacetalizationbythisprocedure
to provide the corresponding dithiolanes or oxathiolanes.
[
26]
[27]
[28]
Na2SO4,
TMSOTf,
been reported for oxathioacetalization. But most of these
metal halides and triflates are highly expensive, some are
toxic, and the solvents like chlorinated hydrocarbons used in
these processes are not ecologically friendly. Hence, a proce-
dure using an efficient, inexpensive, and non-toxic catalyst is
considered to be of much practical utility.
[
30−34]
The results are summarized in Table 1.
A variety of
substitutuents such as Cl, NO , OMe, OAc, and O-allyl
2
on the aromatic ring of the aldehydes are compatible with
this reagent. The conjugated aldehydes (entries 11, 12) are
converted into the corresponding dithioacetals without any
damage to the double bond. The clean thioacetalization of
As a part of our program to develop efficient and green
[29]
synthetic procedures,
we have discovered that a cheap,
©
CSIRO 2004
10.1071/CH03318
0004-9425/04/060605

6
06
B. C. Ranu and A. Das
Table 1. Dithioacetalization and oxathioacetylization of aldehydes catalyzed by molten tetrabutylammonium bromide
Entry
R
Dithiol/mercaptol Time [h] Product
Yield [%]A Ref.
S
PhCH
PhCH
1
PhCHO
HS(CH2)2SH
HS(CH2)3SH
HS(CH2)3SH
HS(CH2)2OH
HS(CH2)2SH
HS(CH2)2OH
HS(CH2)3SH
HS(CH2)2OH
7
84
88
83
81
90
76
78
74
[18]
[18]
[31]
[32]
[18]
[32]
[18]
[33]
S
S
S
2
3
4
5
6
7
8
PhCHO
7.5
7.2
7.3
7.5
8
S
S
p-ClC H CH
p-ClC6H4CHO
p-NO2C6H4CHO
p-NO2C6H4CHO
p-OMeC6H4CHO
p-OMeC6H4CHO
p-OAcC6H4CHO
6 4
O
S
p-NO2C6H4CH
p-NO2C6H4CH
p-OMeC H CH
S
S
O
6
4
S
S
S
p-OMeC6H4CH
p-OAcC H CH
7.8
8
O
6
4
S
S
S
CH
9
p-CH2=CHCH2OC6H4CHO HS(CH2)2SH
8
80
78
[30]
[30]
O
S
S
CHO
CH
1
0
HS(CH2)2SH
8.2
O
O
O
O
O
S
CHO
CH
1
1
1
2
HS(CH2)2OH
6.5
6.8
90
91
[32]
[34]
Ph
Ph
S
S
CH
CHO
CHO
HS(CH2)2SH
HS(CH2)2SH
S
CH
1
3
8
78
[34]
O
O
S
S
S
S
CH
1
1
1
1
4
5
6
7
CHO
HS(CH2)2SH
HS(CH2)2SH
HS(CH2)2SH
HS(CH2)2SH
8.2
3.7
12
75
91
81
79
S
S
CH (CH ) CH
CH3(CH2)8CHO
3
2 8
[18]
[18]
[18]
S
S
S
PhCH
PhCHO + PhCOCH3
decanol + cyclohexanone
S
S
CH (CH ) CH
14
3
2 8
S
S
CH
1
8
p-MeCOC6H4CHO
HS(CH2)2SH
8
76
[15]
COCH3
A
Yields refer to pure isolated products characterized by spectroscopic data (IR and H and 13C NMR).
1

Molten Salt as a Green Reaction Medium
607
acid-sensitive molecules [furfural (entry 13) and thiophene-
then distilled from the reaction mixture under reduced pressure as a
1
colourless liquid (460 mg, 84%) whose spectroscopic data (IR and H
2
-carboxaldehyde (entry 14)] shows the advantage of this
13
[18]
and C NMR) are in good agreement with those reported.
semi-neutral reaction medium. It has been found that ketones
remained completely inert under the reaction conditions,
making this procedure chemoselective for aldehydes. Thus,
when an equimolar mixture of benzaldehyde and acetophe-
none was subjected to thioacetalization under this procedure,
the benzaldehyde was converted into the corresponding 1,3-
ditholane derivative, leaving acetophenone intact (entry 16).
This selective reaction of aldehydes over ketones was also
observed for a mixture of decanal and cyclohexanone (entry
This procedure was followed for the dithioacetalization and
oxathioacetalization of the aldehydes and ketones listed in Table 1. All
the products except one (entry 14) are known compounds, and are easily
identified by comparison of their spectroscopic data with those reported
(
these data are provided as Accessory Material). The characterization
data for the new dithioacetal (entry 14) are provided below.
2
-Thiophenyl-1,3-dithiolane (Entry 14)
This dithioacetal was obtained as a pale yellow liquid (Found: C 44.5, H
−
1
4
.2. C7H8S3 requires C 44.6, H 4.3%). νmax/cm 2920, 1412, 1269. δH
1
7) and 4-acetylbenzaldehyde (entry 18).
(
CDCl3) 3.01–3.52 (m, 4H), 5.94 (s, 1H), 6.94–6.96 (m, 1H), 7.07–7.11
The reactions in molten tetrabutylammonium bromide
TBAB) are, in general, very clean and high yielding. When
(m, 1H), 7.22–7.28 (m, 1H). δC (CDCl ) 39.9 (2C), 50.7, 125.5, 125.6,
126.5, 146.9.
3
(
a mixture of aldehyde and ethane dithiol (or 2-mercapto-
ethanol) was refluxed in THF in the absence of TBAB, no
reaction was observed; in addition, no conversion occurred
when solid TBAB in refluxing THF was used. Presumably,
molten tetrabutylammonium bromide acts as a ready source
of the bromide ion, which is hydrogen-bonding to –SH and
increasing the nucleophilicity of the S atom. This makes the
thiolate anion a better nucleophile and leads to more efficient
thioacetalization.
In conclusion, the present procedure using molten tetra-
butylammonium bromide as a reaction medium provides
an efficient method for the dithioacetalization and oxathio-
acetalization of aldehydes. The significant improvements
offered by this methodology are as follows: (a) simple
operation, (b) almost neutral (pH 6–7) reaction medium,
Acknowledgments
This work has enjoyed financial support from CSIR [grant
no. 01(1739)/02], New Delhi. A.D. also thanks CSIR for his
fellowship.
Accessory Material
IR and H and 13C NMR data for entries 1–15 and 18 (listed
in Table 1) are available from the author or, until June 2009,
the Australian Journal of Chemistry.
1
References
[1] T. W. Greene, P. G. M. Wuts, Protective Groups in Organic
Synthesis 3rd edn, 1999, pp. 329–347 (John Wiley: New
York, NY).
(
c) requirement of no additional catalyst and conventional
[
2] (a) E. J. Corey, D. Seebach, J. Org. Chem. 1966, 31, 4097.
b) P. C. Bulman Page, M. B. van Niel, J. C. Prodger, Tetrahedron
organic solvent, (d) excellent chemoselectivity of aldehyde
over ketone, (e) recyclability of TBAB and cost efficiency
(
1989, 45, 7643. doi:10.1016/S0040-4020(01)85784-7
(
no consumption of catalyst or organic solvent during the
(c) K. Fuji, M. Ueda, E. Fujita, J. Chem. Soc., Chem. Commun.
1
977, 814.
reaction, isolation of the product by direct distillation which
avoids the need for chromatography, and no generation of
waste), and (f ) environmentally friendly reaction condition,
which avoids toxic catalysts and hazardous organic solvents.
Moreover, this work demonstrates the potential of molten
tetrabutylammonium bromide as a catalyst as well as a reac-
tion medium, and broadens the scope for further useful
applications in green synthesis.
(
d) K. Fuji, M. Ueda, K. Sumi, K. Kajiwara, E. Fujita,T. Iwashita,
I. Miura, J. Org. Chem. 1985, 50, 657.
[
3] G. R. Pettit, E. E. van Tamelen, Org. React. 1962, 12, 356.
[4] (a) H. Zinner, Chem. Ber. 1950, 83, 275.
(b) P. C. Bullman Page, J. C. Prodger, D. Westwood, Tetrahedron
1
993, 49, 10355. doi:10.1016/S0040-4020(01)80562-7
[
[
5] L. F. Fieser, J. Am. Chem. Soc. 1954, 76, 1945.
6] G. A. Olah, S. C. Narang, D. Meidar, G. F. Salem, Synthesis
1
981, 282. doi:10.1055/S-1981-29415
7] B. S. Ong, Tetrahedron Lett. 1980, 21, 4225. doi:10.1016/S0040-
039(00)92868-5
[
[
[
4
Experimental
8] V. Kumar, S. Dev, Tetrahedron Lett. 1983, 24, 1289. doi:10.1016/
S0040-4039(00)81637-8
9] J. S. Yadav, B. V. S. Reddy, S. K. Pandey, Synlett 2001, 238.
General
NMR spectra were recorded on a Bruker DPX 300 instrument at
3
an FT 8300 Shimadzu spectrometer. Melting points were determined on
a glass disk with an electrical bath (Reichert, Austria), and are uncor-
rected. Elemental analyses were done on a Perkin–Elmer autoAnalyzer
1
13
[10] E. J. Corey, K. Shimoji, Tetrahedron Lett. 1983, 24, 169.
00 MHz for H and at 75 MHz for C. IR spectra were measured on
doi:10.1016/S0040-4039(00)81357-X
11] A. Kamal, G. Chouhan, Tetrahedron Lett. 2002, 43, 1347.
doi:10.1016/S0040-4039(01)02378-4
12] R. V. Anand, P. Sarvanan, V. K. Singh, Synlett 1999, 413.
13] H. K. Patney, S. Margan, Tetrahedron Lett. 1996, 37, 4621.
doi:10.1016/0040-4039(96)00892-1
14] S. Chandrasekhar, M. Takhi, Y. R. Reddy, S. Mohapatra,
C. R. Rao, K. V. Reddy, Tetrahedron 1997, 53, 14997. doi:
[
[
[
2
400 II. Tetrabutylammonium bromide (Lancaster, UK) was used as
provided. All aldehydes, dithiols, and 2-mercaptoethanol were distilled
before reaction.
[
Representative Procedure for Dithioacetalization of
Benzaldehyde (Entry 1)
1
0.1016/S0040-4020(97)01051-X
[
15] S. Muthusamy, S. A. Babu, C. Gunanathan, Tetrahedron Lett.
2001, 42, 359. doi:10.1016/S0040-4039(00)01966-3
[16] R. B. Perni, Synth. Commun 1989, 19, 2383.
A mixture of benzaldehyde (318 mg, 3.0 mmol) and ethane-1,2-dithiol
◦
(
376 mg, 4.0 mmol) was added to molten (mp 102–103 C) tetrabutyl-
ammonium bromide (290 mg, 30 mol %), and the homogenous mixture
was stirred at 90–100 C for 7 h (monitored by TLC). The product was
[17] S. Samajdar, M. K. Basu, F. T. Becker, B. K. Banik, Tetrahedron
Lett. 2001, 42, 4425. doi:10.1016/S0040-4039(01)00752-3
◦

6
08
B. C. Ranu and A. Das
[
18] A. T. Khan, E. Mondal, P. R. Sahu, S. Islam, Tetrahedron Lett.
003, 44, 919. doi:10.1016/S0040-4039(02)02771-5
[29] (a) B. C. Ranu, A. Hajra, S. S. Dey, Org. Proc. Res. Dev. 2002,
6, 817. doi:10.1021/OP0255478
2
[
19] A. Martel, S. Chewchanwuttiwang, G. Dujardin, E. Brown,
(b) B. C. Ranu, A. Hajra, S. S. Dey, U. Jana, Tetrahedron 2003,
59, 813. doi:10.1016/S0040-4020(02)01587-9
(c) B. C. Ranu, S. S. Dey, A. Hajra, Green Chem. 2003, 5, 44.
doi:10.1039/B211238H
(d) B. C. Ranu, S. S. Dey, A. Hajra, Tetrahedron 2003, 59,
2417. doi:10.1016/S0040-4020(03)00289-8
Tetrahedron Lett. 2003, 44, 1491. doi:10.1016/S0040-4039(02)
0
2855-1
20] J. W. Ralls, R. M. Dodson, B. Riegel, J. Am. Chem. Soc. 1949,
1, 3320.
21] E. Mondal, P. R. Sahu, A. T. Khan, Synlett 2002, 463. doi:
0.1055/S-2002-20466
[
[
7
1
(e) B. C. Ranu, S. S. Dey, Tetrahedron Lett. 2003, 44, 2865.
doi:10.1016/S0040-4039(03)00439-8
[
[
22] C. Djerassi, M. Gorman, J. Am. Chem. Soc. 1953, 75, 3704.
23] G. E. Wilson, Jr, M. G. Huang, W. W. Schloman, Jr, J. Org.
Chem. 1968, 33, 2133.
[30] B. C. Ranu, A. Das, S. Samanta, Synlett 2002, 727. doi:10.1055/
S-2002-25347
[
24] E. Mondal, P. R. Sahu, G. Bose, A. T. Khan, Tetrahedron Lett.
[31] H. Firouzabadi, N. Iranpoor, H. Hazarkhani, Synlett 2001, 1641.
doi:10.1055/S-2001-17451
2
002, 43, 2843. doi:10.1016/S0040-4039(02)00345-3
[
[
25] B. Karimi, H. Seradj, Synlett 2000, 805.
26] J. Romo, G. Rosenkranz, C. Djerassi, J. Am. Chem. Soc. 1951,
[32] S. P. Chavan, P. Soni, S. K. Kamat, Synlett 2001, 1251. doi:
10.1055/S-2001-16045
7
3, 4961.
27] T. Ravindranathan, S. P. Chavan, W. Dantale, Tetrahedron Lett.
995, 36, 2285. doi:10.1016/0040-4039(95)00191-E
[33] J. S. Yadav, B. V. S. Reddy, S. Raghavendra, M. Satyanarayana,
Tetrahedron Lett. 2002, 43, 4679. doi:10.1016/S0040-4039(02)
00854-7
[
[
1
28] R. Ballini, G. Bosica, R. Maggi, A. Mazzacani, R. Righi,
[34] P. Kumar, R. S. Reddy, A. P. Singh, B. Pandey, Tetrahedron
Lett. 1992, 33, 825. doi:10.1016/S0040-4039(00)77725-2
G. Sartori, Synthesis 2001, 1826. doi:10.1055/S-2001-17532