Dithioacetalization of carbonyl compounds under catalyst-free condition

Article abstract of DOI:10.1080/17415993.2011.622394

Protection of carbonyl compounds with 1,3-propanedithiol under a catalyst-free condition in nitromethane as a solvent has been described.

Full text of DOI:10.1080/17415993.2011.622394

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Dithioacetalization of carbonyl
compounds under catalyst-free
condition
a
a
Batool Akhlaghinia & Ata Makarem
a
Department of Chemistry, Faculty of Sciences , Ferdowsi
University of Mashhad , Iran
Published online: 20 Oct 2011.
To cite this article: Batool Akhlaghinia & Ata Makarem (2011) Dithioacetalization of carbonyl
compounds under catalyst-free condition, Journal of Sulfur Chemistry, 32:6, 575-581, DOI:
10.1080/17415993.2011.622394
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Journal of Sulfur Chemistry
Vol. 32, No. 6, December 2011, 575–581
Dithioacetalization of carbonyl compounds under
catalyst-free condition
Batool Akhlaghinia and Ata Makarem*
Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Iran
(Received 5 August 2011; final version received 6 September 2011)
Protection of carbonyl compounds with 1,3-propanedithiol under a catalyst-free condition in nitromethane
as a solvent has been described.
Keywords: aldehydes; ketones; carbonyl protection; 1,3-dithiane; 1,3-propanedithiol
1
.
Introduction
The protection of functional groups constitutes an important and essential process in the synthesis
of polyfunctional molecules and complex natural products. Thioacetals play very important roles
in organic syntheses since they are widely used as protecting groups for carbonyl compounds and
applied as umpolung reagents in a diverse array of organic transformations (1–4). Thioacetals are
relatively stable toward a wide variety of reagents and are also useful in organic synthesis as acyl
carbanion equivalents in C−C bond-forming reactions (5, 6). Due to the resistance of thioacetals
toward hydrolytic cleavage under ordinary acidic and basic conditions, the protection of carbonyl
groups as their cyclic dithioacetals has long attracted considerable attention (7). To date, there
are many approaches developed for the synthesis of thioacetals by the condensation of carbonyl
compounds with thiols or dithiols using strong protic acids such as HCl (8) or Lewis acids such as
BF3·OEt2 (9) or ZnCl2 (10) as catalysts. Other Lewis acids include AlCl3 (11), WCl6 (5), InCl3
(
12), P2O5/SiO2 (13), and [bmim]HSO4 (14).
*
Corresponding author. Email: ata_makarem@yahoo.com
ISSN 1741-5993 print/ISSN 1741-6000 online
2011 Taylor & Francis
©
http://dx.doi.org/10.1080/17415993.2011.622394
http://www.tandfonline.com

5
76 B. Akhlaghinia and A. Makarem
A number of milder procedures employing lithium salts (15), NiCl2 (16), trichloroisocyanuric
acid(17), NBS(18), I2 (19)microwave(20), HBF4-SiO2 (21),Y(OTf)3 (22),VO(OTf)2 (23), ScCl3
24), and silica-functionalized sulfonic acid (25) have also been reported. Some of the methods
(
mentioned above suffer from destroying the catalyst in the work-up procedure in which the Lewis
acids may not be recovered and reused. Also, many of these procedures have some drawbacks
including longer reaction times, low yields, involvement of expensive catalysts, difficult handling
(
26) and the requirement of the volatile organic solvent, dichloromethane. In an endeavor to
change the current working practices to greener alternatives and to meet environmental demands
for protecting carbonyl group, recently a catalyst-free dithioacetalization in glycerol (27) has been
reported, but this method suffers from long reaction times. Herein, we report a novel and simple
catalyst-free method for dithioacetalization of carbonyl compounds with 1,3-propanedithiol under
mild conditions (Scheme 1).
S
O
R
HS
CH
SH
R
R'
3
NO
2
, reflux
R'
S
R : Ph , cinnamyl , alkyl
R' : H ,Ph , alkyl
Scheme 1. Protection of carbonyl compounds with 1,3-propanedithiol.
The use of several solvents without the intervention of catalysts has been reported for various
organic transformations. Watahiki et al. (28) reported the use of DMSO for cyanobenzoylation
of aldehydes with benzyl cyanide. The combination of DMSO with hexane was employed for
the cyanosilylation of aldehyde (29) as well as for the synthesis of silyl ethers from alcohols
and tert-butyldimethylsilyl chloride (30). Similarly, Watahiki et al. (31) describe the synthesis
of cyanohydrin carbonates in DMSO in the presence of molecular sieves. Kumamoto et al. (32)
◦
demonstrated the cyanation of acetal with trimethylsilyl cyanide in CH3NO2 at 60 C and high
pressure. Recently Kadam and Kim (33) reported the synthesis of trimethylsilyl ethers from
alcohols and HMDS in CH3NO2 without using a catalyst. In the course of our research program
to develop better and newer synthetic methodologies (34) and considering the activity of HMDS
in polar solvents, conversion of aldehydes and ketones into 1,3-dithianes under catalyst-free and
almost neutral reaction conditions was investigated.
2
. Results and discussion
The protection reaction of benzaldehyde in CH3NO2 was performed at room temperature with
.5 ml of CH3NO2 to obtain 2-phenyl-1,3-dithiane in high yield (Entry 1, Table 1). Surprisingly,
0
The reaction in refluxing CH3NO2, for different molar ratios of benzaldehyde/1,3-propanedithiol
gives the desired product with excellent yields in short reaction times (Entries 2 and 3, Table 1).
Refluxing enhanced the rate of the reaction and decreased the reaction time. For example, 0.5 ml
of CH3NO2 and 2 mmol of 1,3-propanedithiol are sufficient for the completion of the protection
reaction with 1 mmol of benzaldehyde at reflux in 10 min (Entry 3, Table 1).

Journal of Sulfur Chemistry 577
The polar protic solvent CH3OH at reflux produces a 10% yield of 2-phenyl-1,3-dithiane (Entry
◦
5
, Table 1). The polar aprotic solvents DMF and DMSO at 100 C give no product (Entries 8 and 9).
Also, CH3CN, THF, CHCl3, 1,4-dioxane and n-hexane at reflux give no product (Entries 4, 6, 7,
1
0 and 11, Table 1).
Protection of aldehydes and ketones under catalyst-free conditions in nitromethane with 1,3-
propandithiol exhibited high efficiency.
Various structurally diverse aldehydes and ketones 1–15 were converted to their corresponding
dithioacetals in excellent yields within short reaction times with 100% conversion (Table 2).
Aromatic aldehydes with electron-withdrawing groups require shorter reaction time compared
with aromatic aldehydes with electron-donating groups. This result may indicate that the electron-
donating ability of the substituent reduces the activity of carbonyl groups toward a nucleophile
which decreases the reaction rate. It is very interesting to note that cinnamaldehyde 7 and croton-
aldehyde 8 were protected within very short reaction times and gave high yields. Also because of
lower reactivity of the carbonyl group connected to the α position of the naphthyl ring, protection
of 10 required a longer reaction time (3.5 h). The protection reaction was also extended to aromatic
ketones 14 and 15. Acetophenone, in contrast to aliphatic ketones, could not be dithioacetalized
completely. It gave the corresponding dithioacetal in a very low yield even after 72 h of reaction
time. This may be due to the steric effect of the (Me) group in comparison to (H) in benzaldehyde.
The aromatic sterically hindered ketone 15 fails to undergo protection with 1,3-propanedithiol
even after 72 h of reaction time. This indicates that the steric effect is serious enough to prevent
the reaction from taking place.
Table 1. Reaction of benzaldehyde with 1,3-propanedithiol under a catalyst-free condition.
Entry
Solvent
Temperature
Time (h)
Yield (%)a
b
1
2
3
4
5
6
7
8
Nitromethane
Nitromethane
Nitromethane
Acetonitrile
Methanol
1,4-Dioxane
THF
DMF
DMSO
Chloroform
n-Hexane
Room temperature
Reflux
Reflux
Reflux
Reflux
50
3.5
10 (min)
90
90
91
0
10
0
0
0
0
0
c
b
d
2
2
2
2
2
2
2
2
d
d
Reflux
d
Reflux
d
o
100 C
d
o
9
0
1
100 C
d
1
1
Reflux
Reflux
d
0
Notes: aIsolated yield.
b
Benzaldehyde/1,3-propanedithiol/nitromethaneml: 1/2/0.5.
Benzaldehyde/1,3-propanedithiol/nitromethaneml: 1/1/0.5.
In other solvents: benzaldehyde/1,3-propanedithiol/solventml: 1/2/0.5.
c
d
The basis of the dramatic effect of nitromethane in this protection is unclear at present. How-
ever, it is conceivable that the oxygen atom of heteroatom oxide can activate the protecting
reagent (32, 33), through the hydrogen bonding with SH. Carbonyl groups react with the activated
HS(CH2)3SH-CH3NO2 complex I to produce the C−S bond (II). An intermolecular nucleophilic
attack in II with concomitant loss of a water molecule produces dithioacetals III. Regeneration of
CH3NO2 initiates the second cycle. Nevertheless, at this time, there is no experimental evidence

5
78 B. Akhlaghinia and A. Makarem
for the existence of I, and the actual role of CH3NO2 and its clarification will require further study
Scheme 2).
(
HS
SH
O–
O
–
H
3
C
N+
d
H
H
S
S
O
H
3
C
N
(CH )
2 3
S
S
R
–
O
d
R'
I
H O
2
O
R
R'
III
–
O
d
H
S
S
(
CH2)
3
H
3
C
N
–
d
O
R
R'
OH
II
Scheme 2. Mechanism of the protection reaction.
Table 2. Dithioacetalization of various structurally diverse aldehydes and ketones in CH3NO2 under catalyst-free
conditions.
Entrya
Substrate
Productb
Time (min)
m.p. ( C)
o
Yield (%)c
O
S
1
10
68–69, Lit (35):69–70
91
H
S
O
S
2
3
40
50
88–89, Lit (36):87
89
90
91
H
S
O
S
H
S
115, Lit (19):115–117
MeO
MeO
O
S
H
S
4
5
5
140–141, Lit (11):141–142
81, Lit (37):81–82
O N
2
O N
2
O
S
45
89
H
S
Cl
Cl
(
Continued)

Journal of Sulfur Chemistry 579
Table 2. Continued
Entrya
Substrate
Cl O
Productb
Cl
S
Time (min)
30
m.p. ( C)
o
Yield (%)c
88
6
89, Lit (38):90–92
H
O
S
S
7
8
10
5
57–58, Lit (39):57–58
92
91
H
S
O
S
−
H
S
O
S
9
10
−
89
90
H
S
5
5
H
O
S
S
1
0d
3.5 (h)
145–147, Lit (40):145–146
O
S
1
1
1
2
S
S
25
15
−
90
91
S
O
38–39, Lit (41): 39–40
S
O
S
1
1
1
3d
4d
5d
60
106, Lit (42):107
90
17
0
O
S
S
72 (h)
72 (h)
−
−
O
S
S
Notes: aSubstrate/1,3-propanedithiol/nitromethaneml: 1/2/0.5.
b
The products was identified by the comparison of its physical constants, IR and NMR spectral data with those of an authentic sample.
Isolated yield.
Substrate/1,3-propanedithiol/nitromethaneml: 1/3/2.
c
d

5
80 B. Akhlaghinia and A. Makarem
3
.
Conclusion
A novel and efficient uncatalyzed method for the dithioacetalization of aldehydes and ketones has
been developed. Aldehydes and ketones were protected in nitromethane as the solvent without the
aid of a catalyst. The reaction proceeds very cleanly and the work-up procedure is very simple.
The absence of a catalyst and mild reaction conditions are the advantages of the present study
compared with other reported catalytic methods. Hence, it can be claimed that this method is the
most economically convenient method for the protection of aldehydes and ketones.
4
4
.
Experimental section
.1. General remarks
The completion of reactions were monitored byTLC on silicagel polygram STL G/UV 254 plates.
Melting points were determined with an Electrothermal Type 9100 melting point apparatus. FT-IR
spectra were recorded on an Avatar 370 FT-IR Therma Nicolet spectrometer. NMR spectra were
recorded on a Brucker Avance instrument in CDCl3.
Caution: Using of nitromethane may incur notable safety precautions. It is highly recommended
to seek the Material Safety Datasheet.
4
.2. Experimental procedure for the dithioacetalization of benzaldehyde
To a solution of benzaldehyde (1 mmol) in nitromethane (0.5 ml), 1,3-propanedithiol (2 mmol)
was added and the mixture was refluxed. As monitored by TLC, benzaldehyde was consumed
within 10 min. The reaction mixture was allowed to cool to room temperature and concentrated
3
under reduced pressure. The concentrated residue was dissolved in CH2Cl2 (5 cm ) and washed
with 10% NaOH (2 × 2 ml) and distilled water (5 ml). The combined organic extract was dried
over anhydrous Na2SO4 and filtered. Removal of the solvent gave almost pure product, and further
purification was performed by column chromatography on silica-gel using n-hexane/ethylacetate
(
10/1 v/v) as eluent (Entry 1, Table 2).
1
2
-Phenyl-[1,3]dithiane(1): H NMR (400 MHz, CDCl3): δ = 1.95–2.02 (m, 1H), 2.18–2.23
(
2
m, 1H), 2.92–2.97 (m, 2H), 3.07–3.14 (m, 2H), 5.21 (s, 1H), 7.29–7.40 (m, 3H), 7.49–7.52 (m,
−
1
H). IR (KBr): 2949, 2890, 1450, 1275, 1179, 726, 696 cm .
1
2
-(4-Methoxy-phenyl)-[1,3] dithiane(3): H NMR (400 MHz, CDCl3): δ = 1.95–2.00 (m, 1H),
2
.16–2.23 (m, 1H), 2.90–2.95 (m, 2H), 3.05–3.12 (m, 2H), 3.82 (s, 3H), 5.17 (s, 1H), 6.88–6.91
(
7
d, 2H, J = 14.8 Hz), 7.41–7.44 (d, 2H, J = 14.4 Hz). IR (KBr): 2937, 2900, 1607, 1249, 1030,
−
1
75 cm .
1
2
-(Naphthalen-5-yl)-1,3-dithiane(10): H NMR (400 MHz, CDCl3): δ = 1.30–2.11 (m, 1H),
2
7
5
.20–2.32 (m, 1H), 3.01–3.05 (m, 2H), 3.11–3.28 (m, 2H), 5.97 (s, 1H), 7.29–7.62 (m, 3H),
.83–7.91 (m, 3H), 8.35 (d, 1H, J = 8.4). IR (KBr): 3045, 2930, 1596, 1506, 1419, 1273, 782,
−
1
46 cm
9
.
1
-Phenyl-1,5-dithia-spiro[5.5]undecane(13): H NMR (400 MHz, CDCl3): δ = 1.78–1.79 (m,
2
H), 1.86–1.90 (m, 2H), 2.01–2.06 (m, 4H), 2.49–2.49 (m, 2H), 2.52–2.53 (m, 1H), 2.80–2.83
(
7
m, 2H), 2.94–2.96 (m, 2H), 7.21–7.35 (m, 5H). IR (KBr): 3017, 2921, 1597, 1490, 1274, 760,
00, 535 cm .
−
1
Acknowledgement
We gratefully acknowledge the partial support of this study by Ferdowsi University of Mashhad Research Council.

Journal of Sulfur Chemistry 581
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