Lithium bromide-catalyzed highly chemoselective and efficient dithioacetalization of α,β-unsaturated and aromatic aldehydes under solvent-free conditions

Article abstract of DOI:10.1055/s-1999-3679

Chemoselective dithioacetalization of aromatic- and α,β- unsaturated aldehydes in the presence of other structurally different aldehydes and ketones was achieved efficiently in the presence of catalytic amounts of LiBr under solvent-free conditions. Due to the neutral reaction conditions, this method is compatible with acid sensitive substrates.

Full text of DOI:10.1055/s-1999-3679

58
SHORT PAPER
Lithium Bromide-Catalyzed Highly Chemoselective and Efficient
Dithioacetalization of α,â-Unsaturated and Aromatic Aldehydes under
Solvent-Free Conditions
Habib Firouzabadi,* Nasser Iranpoor,* Babak Karimi
Chemistry Department, College of Sciences, Shiraz University, Shiraz 71454, Iran
Fax: +98(71)20027
Received 30 January 1998; revised 27 May 1998
Abstract: Chemoselective dithioacetalization of aromatic- and
a,b- unsaturated aldehydes in the presence of other structurally dif-
ferent aldehydes and ketones was achieved efficiently in the pres-
ence of catalytic amounts of LiBr under solvent-free conditions.
Due to the neutral reaction conditions, this method is compatible
with acid sensitive substrates.
Key words: dithioacetalization, thioacetals, lithium bromide, sol-
vent-free conditions, 1,3-dithianes, 1,3-dithiolanes
Scheme
and 1,3-propanedithiol, 1.1 equiv) and monothiols (ben-
The protection of carbonyl groups as dithioacetals1 (1,3-
dithianes, 1,3-dithiolanes, or acyclic dithioacetals) is a fre-
quently used synthetic technique for the preparation of many
organic compounds including multifunctional complex mol-
ecules. This popularity of dithioacetals is due in part to their
stability under usual acidic or basic conditions and also be-
cause of their behavior as masked acyl anions2Ð4 or masked
methylene functions.5 In this regard, there have been con-
tinued improvements in the methods of preparation of
dithioacetals. In general, these compounds are prepared
by protic or Lewis acid-catalyzed condensation of carbo-
nyl compounds with thiols.1 Several types of Lewis acid
catalysts were introduced previously for this purpose such
as, ZnCl2,6 LnCl3,7 anhydrous FeCl3/SiO2,8 AlCl3,9 ZrCl41/
zyl mercaptane, thiophenol, and cyclohexanethiol, 2.0Ð
2.1 equiv) was achieved efficiently by heating their sol-
vent-free mixture with the substrate and 0.25Ð0.4 equiva-
lents of LiBr at 75Ð80¡C19 (Table 1, 2aÐe). The efficiency
of the method can be clearly visualized by the condensa-
tion of benzaldehyde with cyclohexanethiol in almost
quantitative yield (Table 1, 2e). Several types of substitut-
ed benzaldehydes with electron-donating and electron-
withdrawing groups and 1-naphthaldehyde can be also
protected in a similar manner (Table 1, 2fÐk). The present
thioacetalization procedure is also applicable for cinnam-
aldehyde and citral (Table 1, 2lÐp). It was observed that
under similar reaction conditions, saturated aldehydes
(Table 1, entries 18, 19), aromatic and aliphatic ketones
(Table 1, entries 20, 21), as well as acetals (Table 1, entry
2) remained intact even after several hours. It should be
mentioned that this method is not suitable for dithioacetal-
ization in solvents such as THF, CH2Cl2 and the substrates
were re-isolated.
10
11
12
13
14
¥
¥
SiO2, TeCl4, SnCl2 2H2O, SiCl4, MgI2 Et2O, etc.
Many of these methods require harsh reaction conditions,
expensive reagents, or give poor selectivity when applied
to a mixture of aldehydes or aldehydes and ketones. An-
other approach to this problem, i.e. dithioacetalization of
aldehydes and ketones under neutral conditions has been
reported very recently by means of 5 M ethereal solution
of LiClO4.15 However, this method works much better
with acetals than with the corresponding aldehydes and
LiClO4 is rather expensive. In this report we wish to intro-
duce lithium bromide as an efficient catalyst for highly
chemoselective dithioacetalizations of aromatic and α,â-
unsaturated aldehydes in the presence of other, structural-
ly different aldehydes and ketones under solvent-free con-
ditions (Scheme).
The selectivity of the present method is demonstrated by
competition experiments using structurally differing car-
bonyl compounds. The results are shown in Table 2. Benz-
aldehyde and cinnamaldehyde both were cleanly
thioacetalized quantitatively in the presence of acetophe-
none, butyraldehyde and cyclohexanone. As proposed for
the ethereal LiClO4 method,15 we also believe that Li+ un-
der solvent-free conditions activates the carbonyl group
for the initial addition of a thiol molecule. This is followed
by the dehydration of the intermediate hemithioacetal,
which is attacked by a second thiol moiety. Due to the
neutrality of the reaction medium, this method is very use-
ful for substrates with a high degree of acid sensitivity.
The use of LiBr as chemical reagent has been reported
previously for acylation of ferrocene,16 transesterification
of peptide esters and cleavage of resin-bound peptides,17
and the Knoevenagel condensation of aldehydes with ma-
lononitrile in the solid state.18 In this report, dithioacetal-
ization of benzaldehyde with dithiols (1,2-ethanedithiol
In conclusion, the striking selectivity and easy workup of
the presented procedure can be utilized in the selective
conversion of aromatic and α,â-unsaturated aldehydes to
Synthesis 1999, No. 1, 58Ð60 ISSN 0039-7881 © Thieme Stuttgart · New York

SHORT PAPER
Dithioacetalization of α,â-Unsaturated and Aromatic Aldehydes
59
Table 1 Dithioacetalization of Aldehydes with LiBr Under Non-Solvent Conditions
Entry
Product
R1
R2
R3
Subst./Thiol/
LiBr
Time
(min)
Yield mp (°C) or bp (°C)/Torr
(%)
Ratio
found
reported
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
2a
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
–(CH2)3–
–(CH2)3–
–(CH2)2–
Ph
1:1.1:0.25
1:1.1:0.3
1:1.1:0.3
1:2.1:0.3
1:2.0:0.3
1:2.1:0.4
1:1.1:0.25
1:1.1:0.25
1:1.1:0.25
1:1.1:0.25
1:1.1:0.25
1:1.1:0.4
1:2.1:0.3
1:2.1:0.3
1:1.1:0.3
1:1.1:0.4
1:1.1:0.4
1:1.1:0.4
1:1.1:0.4
1:1.1:0.4
1:1.1:0.4
15
120
15
20
20
20
15
30
20
20
15
35
20
20
15
20
50
99
30a
93
90
92
99
94
94
90
97
87
80
89
95
99
95
98
20c
71–72
–
7223
166/20
51–52
59–60
202/1
91–92
65–66
62–63
85–86
145/120
51–5215
PhCH2
60–6120
c-C6H11
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
Ph
200/120
4-MeC6H4
3-MeC6H4
3-ClC6H4
4-ClC6H4
4-MeOC6H4
1-naphthyl
PhCH=CH
PhCH=CH
PhCH=CH
PhCH=CH
91.5–92.521
66.5–67.021
62.5–63.523
85.5–86.523
2j
2k
2l
115–116 115–11622
144–145 145–14623
63–63.5 6415
b
15
2m
2n
2o
2p
2q
2r
2s
2t
PhCH2
–
–
–(CH2)2–
–(CH2)3–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)3–
–(CH2)3–
57–58
62–63
58–5915
63–6411
–
b
(E/Z)-Me2C=CHCH2CH2C(Me)=CH H
Me2C=CHCH2CH2CH(Me)CH2
Pr
Ph
–
H
H
Me
Me
180
180
180
180
–
–
–
–
d
–
–
–
–
–
d
d
PhCH2CH2
–
a
Benzaldehyde dimethyl acetals were used.
b
Oil, Structural assignment is based on spectroscopic data. 2p: MS (20 eV): m/z (relative intensity) = 228 (M, 0.6), 200 (21.20), 167 (8.1), 123
(12.0), 99 (53.4), 69 (100). 1H NMR (CDCl3/TMS): δ = 5.21–5.25 (m, 2H), 4.95 (m, 1H), 3.07–3.20 (m, 4H), 1.87–1.98 (m, 4H), 1.48–1.87
1
(m, 9H). 2m: MS (20 eV): m/z (relative intensity) = 362 (0.1), 239 (41.9), 147 (29.9), 115 (100), 91 (84.6), 103 (1.0), 77 (2.5). H NMR
(CDCl3/TMS): δ = 7.2 (m, 15 H), 6.2 (d, 1 H, J = 14 Hz), 5.9 (dd, 1 H, J = 14 Hz, 6.5 Hz), 4.6 (d, 1 H, 6.5 Hz), 3.6 (m, 4 H)
c
GC yield.
d
No reaction.
Table 2 Selective Dithioacetalization of Aromatic- and a,b-Unsatu-
rated Aldehydes vs. Other Carbonyl Compounds with LiBr as Cata-
lyst
SIL G/UV254 plates. Mass spectra were run on a Shimadzu GC
MS-QP 1000EX at 20 eV. IR spectra were recorded on a Perkin-
Elmer 781 spectrophotometer. The NMR spectra were recorded on
a Hitachi R-2413 60 MHz or Bruker Avance DPX 250 MHz spec-
trometer.
Substrates
Subst. 1/Subst. 2/ Time
Prod-
uct
Yielda
(%)
Thiol/LiBr Ratio
(min)
Dithioacetalization of Aldehydes; General Procedure
PhCHO
+
PhCOCH3
PhCH=CHCHO
2b
100
To a stirred mixture of the carbonyl compound 1 (10 mmol) and
dithiol (11 mmol) or monothiol (20Ð21 mmol) was added anhyd
LiBr (2.5Ð4.0 mmol). The mixture was heated to 75Ð80¡C and the
progress of the reaction was followed by TLC. After completion of
the reaction (15Ð50 min.), CH2Cl2 (100 mL) was added and the mix-
ture was washed successively with 10% NaOH solution (2 ×
25 mL), brine (15 mL), and H2O (15 mL). The organic layer was
separated and dried (Na2SO4). Evaporation of the solvent under re-
duced pressure gave almost pure product. Further purification was
achieved by column chromatography on silica gel or recrystalliza-
tion from appropriate solvent to give the desired product(s) in good
to excellent yield(s) (Table 1).
1:1:1.1:0.25
1:1:1.1:0.25
1:1:1.1:0.25
1:1:1.1:0.25
1:1:1.1:0.25
15
15
15
15
15
2s
2n
0
100
+
PhCOCH3
PhCHO
+
PrCHO
PhCHO
+
PhCH=CHCHO
PhCHO
+
2s
2b
0
100
2r
2b
0
29
2n
2b
71
100
cyclohexanone
–
0
Selective Dithioacetalization of Benzaldehyde vs. Acetophenone
with 1,2-Ethanedithiol; Typical Procedure
a The yields were determined by GC and 1H NMR spectroscopy.
To a stirred mixture of benzaldehyde (530 mg, 5 mmol), acetophe-
none (601 mg, 5 mmol) and 1,2-ethanedithiol (518 mg, 5.5 mmol)
was added anhyd LiBr (130 mg, 1.5 mmol). The mixture was heated
to 75Ð80¡C in 15 min, CH2Cl2 (70 mL) was added and the mixture
was washed successively with 10% NaOH solution (2 × 15 mL),
brine (10 mL), and water (10 mL). The organic layer was separated
and dried (Na2SO4) and concentrated under reduced pressure. The
NMR spectrum of the mixture was similar to the NMR spectrum
of a 1:1 authentic mixture of 2-phenyl-1,3-dithiolane and ace-
tophenone.
their corresponding dithioacetals in the presence of other
carbonyl moieties under very mild conditions.
All yields refer to isolated products unless otherwise stated. The
products were purified by column chromatography and the purity
determination of the products were accomplished by GC on a Shi-
madzu model GC-8A instrument or by TLC on Silica gel polygram
Synthesis 1999, No. 1, 58Ð60 ISSN 0039-7881 © Thieme Stuttgart · New York

60
H. Firouzabadi et al.
SHORT PAPER
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Acknowledgement
We are thankful to the Shiraz University Research Council for par-
tial support of this work.
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Synthesis 1999, No. 1, 58Ð60 ISSN 0039-7881 © Thieme Stuttgart · New York