Ruthenium(III) chloride-catalyzed thioacetalization of carbonyl compounds: Scope, selectivity, and limitations

Article abstract of DOI:10.1002/adsc.200404323

A variety of carbonyl compounds can be easily and rapidly converted to the corresponding cyclic and acylic dithioacetals in the presence of a catalytic amount of ruthenium chloride in acetonitrile at room temperature. Some of the major advantages of this

Full text of DOI:10.1002/adsc.200404323

FULL PAPERS
Ruthenium(III) Chloride-Catalyzed Thioacetalization of
Carbonyl Compounds: Scope, Selectivity, and Limitations
Surya Kanta De
Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy, Purdue Cancer Center, Purdue
University, West Lafayette, IN 47907, USA
Fax: (þ1)-765-494-1414, e-mail: skd125@pharmacy.purdue.edu
Received: October 22, 2004; Accepted: January 24, 2005
Abstract: A variety of carbonyl compounds can be simplicity, very short reaction times, high yields, and
easily and rapidly converted to the corresponding cy- also compatibility with other protecting groups.
clic and acylic dithioacetals in the presence of a cata-
lytic amount of ruthenium chloride in acetonitrile at
room temperature. Some of the major advantages of Keywords: aldehydes, chemoselectivity, dithioacetals,
this protocol are high chemoselectivity, operational ketones, protecting groups; ruthenium chloride
Introduction
Results and Discussion
In view of the tremendous versatility of thioacetals in or- The reaction of 4-methoxybenzaldehyde with 1,2-eth-
ganic synthesis as carbonyl protecting groups,[1] a large anedithiol in the presence of 1 mol % of RuCl3 in aceto-
number of procedures has been reported for their prep- nitrile at room temperature afforded the desired 2-(4-
aration. The dithioacetals are also utilized as masked methoxyphenyl)-1,3-dithiolane in 94% yield. Similarly,
acyl anions[2] or masked methylene functions[3] in car- several activated and deactivated aromatic aldehydes
bon-carbon bond forming reactions. In the literature and aliphatic aldehydes underwent the protection reac-
there is quite a plethora of procedures reported for the tion rapidly to give the corresponding 1,3-dithiolanes,
protection of carbonyl compounds as dithioacetals em- 1,3-dithianes, and diethyl dithioacetals (Scheme 1).
ploying HCl,[4] BF3 ·OEt2,[5] PTSA,[6] Bu4NBr3,[7] The results shown in Table 2 clearly indicate the scope
TMSOTf,[8] SO2,[9] LiBr,[10] LiBF4,[11] AlCl3,[12] TiCl4,[13] and generality of the reaction with respect to different
ZrCl4,[14] 5 M LiClO4,[15] InCl3,[16] Sc(OTf)3,[17] and aromatic, aliphatic, heterocyclic, unsaturated alde-
I2[18]as catalysts or as stoichiometric reagents. However, hydes. In order to find a suitable solvent system for the
many of these methods have some drawbacks such as thioacetalization of aldehydes, several solvents were ex-
low yields of the products,[7] long reaction times,[14] harsh amined under the same reaction conditions. The results
reaction conditions,[4,5,6] difficulties in work-up,[12,13] use are summarized in Table 1. Acetonitrile was found to be
of stoichiometric[5,9] and/or relatively expensive re- the best solvent as it gave the best results (entry 1). Di-
agents,[7,8,14,15] and low yields when applied to ketones. chloromethane, tetrahydrofuran, 1,4-dioxane, toluene,
Interestingly, only a few of these methods have demon- benzene, ethyl acetate, and DMF can be used as alterna-
strated chemoselective protection of aldehydes in the tive solvents, although longer reaction times were need-
presence of ketones. Some of the methods mentioned ed to complete the thioacetalization reaction.
above are incompatible with other protecting groups
such as TBS ethers[5b,10b,11b,18b] and fail to protect deacti-
vated aromatic substrates.[17] Therefore, there is further
scope to explore mild and efficient methods for thioace-
talization of carbonyl compounds.
In this communication, I report a mild and efficient
procedure for the conversion of carbonyl compounds
into 1,3-dithiolanes, 1,3-dithianes, and diethyl dithioace-
tals using a catalytic amount of ruthenium chloride in
acetonitrile at room temperature.
Scheme 1.
Adv. Synth. Catal. 2005, 347, 673–676
DOI: 10.1002/adsc.200404323
ꢀ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
673

Surya Kanta De
FULL PAPERS
Table 1. Solvent effects in the thioacetalization of benzalde-
hyde with 1,2-ethanedithiol in the presence of a catalytic
amount of RuCl3.
procedure is very simple and convenient. Ketones also
furnished excellent yields of the corresponding 1,3-di-
thiolanes in the presence of 20 mol % ruthenium chlor-
ide and 1,2-ethanedithiols, although after relatively lon-
ger reaction times (Table 2, entries 20–22). In contrast,
many of the previously reported Lewis acid-catalyzed
methods did not work well with ketones and only a
few methods are available for the preparation of thio-
acetal derivatives which utilized stoichiometric amount
of catalysts.[5,9] Cyclohexenone and alkynyl ketones re-
acted with 1,2-ethanedithol in the presence of RuCl3 to
give the corresponding 1,3-dithiolanes in moderate
yields (entries 29 and 32,Table 2). The p-aminobenzal-
dehyde or N,N-dimethylaminobenzaldehyde due to
strong deactivation of the carbonyl group did not give
any satisfactory yields under these conditions, mostly
starting materials were recovered. Alternatively, the
Entry Solvent
Reaction time Yield [%][a, b]
1
2
3
4
5
6
7
8
Acetonitrile
Dichloromethane 1 h
10 min
92
81
71
61
58
61
62
40
Tetrahydrofuran
Benzene
1,4-Dioxane
Ethyl acetate
Toluene
2 h
2 h
4 h
6 h
6 h
6 h
DMF
[a]
[b]
NMR yield.
1 mmol benzaldehyde, 1.2 mmol 1,2-ethanedithiol, and
1 mol % RuCl3 were used.
It is noteworthy that the conversion can be achieved in amino group can coordinate to the ruthenium catalyst
the presence of other protecting groups such as acetyl, to deactivate the catalytic activity. In order to test this
benzyl, allyl, esters, and TBS ethers. The experimental hypothesis, the thioacetalization reaction of an aldehyde
Table 2. Ruthenium(III) chloride-catalyzed protection of aldehydes as dithiolanes, dithianes or diethyl dithioacetals at room
temperature.
Entry
Substrate
Reagent
Time
Yield [%][a]
1
2
3
4
5
6
7
8
9
Benzaldehyde
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2CH2SH
HSCH2CH2CH2SH
HSCH2CH3
10 min
10 min
10 min
28 min
10 min
12 min
10 min
35 min
15 min
25 min
45 min
20 min
15 min
35 min
10 min
25 min
20 min
25 min
20 min
25 h
92
94
88
79
85
89
82
76
90
81
72
85
91
79
93
79
4-Methoxybenzaldehyde
4-Chlorobenzaldehyde
4-Nitrobenzaldehyde
Furfural
4-Benzyloxybenzaldehyde
Cinnamaldehyde
3,4-Dimethoxybenzaldehyde
Thiophene-2-carboxaldehyde
4-Hydroxybenzaldehyde
2-Nitrobenzaldehyde
4-Carbomethoxybenzaldehyde
4-Allyloxybenzaldehyde
Hexaldehyde
4-TBSO-benzaldehyde
1-Octanal
Butyraldehyde
Decylaldehyde
4-Acetyloxybenzaldehyde
Acetophenone
4-Methoxyacetophenone
4-Chloroacetophenone
4-Benzoyloxybenzaldehyde
4-Bromobenzaldehyde
Benzaldehyde
4-Methoxybenzaldehyde
4-Chlorobenzaldehyde
Benzaldehyde
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
84
76
91
75[b]
78[b]
70b
90
16
22 h
30 min
15 min
15 min
12 min
45 min
50 min
22 h
24 h
24 h
24 h
92
88
92
79
HSCH2CH3
82
2-Cyclohexenone
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
HSCH2CH2SH
68[b]
10[b]
12[b]
61[b]
4-N,N-Dimethylaminobenzaldehyde
4-Aminobenzaldehyde
4-Phenyl-3-butyn-2-one
[a]
Yields refer to pure isolated products.
20 mol % catalyst used.
[b]
674
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Adv. Synth. Catal. 2005, 347, 673–676

RuCl3-Catalyzed Thioacetalization of Carbonyl Compounds
FULL PAPERS
Table 3. Comparison of the effect of catalysts in thioacetali-
zation of benzaldehyde with 1,2-ethanedithiol.
Catalyst
Catalyst load
[mol%]
Time
Yield [%]
Sc(OTf)3
Pr(OTf)3
Y(OTf)3
Nd(OTf)3
Lu(OTf)3
In(OTf)3
CoCl2
4
5
5
10
20
15
5
10
1
10 min
30 min
90 min
2 h
3 h
8 min
1 h
85[17]
89[21]
93[19]
82
75
89[22]
91[20]
78[23]
92
Bi(NO3)3
RuCl3
5 h
10 min
tions was conducted between aldehydes and ketones,
the results of which are shown in Scheme 2. The alde-
hyde functionality of a keto-aldehyde was protected
chemoselectively under identical condition (Scheme 3).
However, other Lewis acids such as AlCl3 and BF3 ·
OEt2 do not show any selectivity between an aldehyde
and a ketone. The reaction of a keto-aldehyde with eth-
anedithiol in the presence of AlCl3 yielded the bis-di-
thioacetal (Scheme 4). These results indicate that the
present protocol is highly applicable for the chemoselec-
tive protection of aldehydes to the corresponding di-
thioacetals in the presence of ketone functions in mul-
ti-functional compounds.
Scheme 2.
Most recently, I have reported Y(OTf)3,[19] CoCl2,[20]
and Pr(OTf)3[21] as catalysts for the thioacetalization of
aldehydes. In comparison with other catalysts such as
CoCl2, Y(OTf)3, Pr(OTf)3, In(OTf)3, Sc(OTf)3, InCl3,
Bi(NO3)3, which are recently reported in the thioacetal-
ization of benzaldehyde, RuCl3 employed here shows a
more effective catalytic activity than the others in terms
of the amount of catalyst, yields, and reaction times (Ta-
ble 3). The efficacy of other Lewis acids such as
Nd(OTf)3, Lu(OTf)3, and Yb(OTf)3 was studied for
this reaction. Among these catalysts, RuCl3 was found
to be superior in terms of conversion and reaction times
(Table 3).
Scheme 3.
Conclusion
In conclusion, I have demonstrated a very simple and
convenient protocol for the protection of carbonyl com-
pounds in the presence of a wide range of other protect-
Scheme 4.
was performed in the presence of dimethylaniline, which ing groups by using a catalytic amount of RuCl3. More-
resulted in a dramatic effect with the thioacetalization over, highly deactivated aromatic aldehydes can be con-
reaction being almost completely suppressed. This re- verted to the corresponding dithioacetals without any
sult indicates the effect of coordination of the amino difficulty. A high degree of chemoselectivity, considera-
group to the ruthenium catalyst.
bly lower catalyst loading, very short reaction times,
This method is highly chemoselective, providing selec- good to high yields, and operational simplicity make
tive protection of an aldehyde in the presence of a ke- the present method a practical protocol for dithioacetal-
tone. Therefore, a set of competitive protection reac- ization processes.
Adv. Synth. Catal. 2005, 347, 673–676
asc.wiley-vch.de
ꢀ 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
675

Surya Kanta De
FULL PAPERS
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00066 mass spectrometer or a Finnigan 4000 mass spectrome-
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Compounds
To a stirred solution of an aldehyde (5 mmol) and 1,2-ethane-
dithiol (6 mmol) in acetonitrile (10 mL) was added RuCl3
(1 mol %) at room temperature. The reaction mixture was stir-
red at room temperature for an appropriate time (Table 1). Af-
ter completion of reaction as indicated by TLC, the mixture
was concentrated under vacuum and the crude residue was pu-
rified by silica gel column chromatography (eluted with hex-
ane-ethyl acetate, 9/1) to afford the dithiolane in good yields.
Most of the products are known and were determined using
comparison of their physical and spectral data with those re-
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676
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Adv. Synth. Catal. 2005, 347, 673–676