Simple method for the preparation of dimethyl acetals from ketones with montmorillonite K 10 and p-toluenesulfonic acid

Article abstract of DOI:10.1080/00397910600639315

A simple method for conversion of ketones to their corresponding dimethyl acetals using montmorillonite K 10 and p-toluenesulfonic acid as acidic cocatalysts under very mild reaction conditions is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600639315

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Simple Method for the Preparation of
Dimethyl Acetals from Ketones with
Montmorillonite K 10 and p‐Toluenesulfonic
Acid
a
b
Horacio Mansilla & David Regás
a
Instituto de Productos Naturales y Agrobiología del C.S.I.C. , La Laguna,
Tenerife, Spain
b
Instituto Universitario de Bioorgánica “Antonio González,” , Universidad
de la Laguna , La Laguna, Tenerife, Spain
Published online: 16 Feb 2007.
To cite this article: Horacio Mansilla & David Regás (2006) Simple Method for the Preparation of Dimethyl
Acetals from Ketones with Montmorillonite K 10 and p‐Toluenesulfonic Acid, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:15, 2195-2201, DOI:
10.1080/00397910600639315
To link to this article: http://dx.doi.org/10.1080/00397910600639315
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Synthetic Communications , 36: 2195–2201, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600639315
Simple Method for the Preparation
of Dimethyl Acetals from Ketones
with Montmorillonite K 10
and p-Toluenesulfonic Acid
Horacio Mansilla
Instituto de Productos Naturales y Agrobiolog ´ı a del C.S.I.C.,
La Laguna, Tenerife, Spain
David Reg a´ s
Instituto Universitario de Bioorg a´ nica “Antonio Gonz a´ lez,”
Universidad de la Laguna, La Laguna, Tenerife, Spain
Abstract: A simple method for conversion of ketones to their corresponding dimethyl
acetals using montmorillonite K 10 and p-toluenesulfonic acid as acidic cocatalysts
under very mild reaction conditions is described.
Keywords: Dimethyl acetals, ketones, montmorillonite K 10, p-toluenesulfonic acid
INTRODUCTION
[1]
Acetals are important carbonyl protecting groups in organic synthesis.
Acetalization is typically carried out by treatment of the carbonyl
compound with the alcohol and/or the corresponding orthoformate in the
presence of protic acids, Lewis acids, or acidic catalysts. Among the
different types of acetals used in organic synthesis, dimethylacetals are
useful protecting groups. They can also be employed in the preparation of
other types of acetals via transacetalization. They are synthesized using
Received in the UK October 24, 2005
Address correspondence to Horacio Mansilla, Instituto de Productos Naturales y
Agrobiolog ´ı a del C.S.I.C., Avda. Fco, Sanchez 3, 38206, La Laguna, Tenerife,
Spain. Fax: þ922 31 84 42; E-mail: hmansill@ull.es
2
195

2
196
H. Mansilla and D. Reg a´ s
[
2]
[3]
[9]
[4]
homogeneous acidic catalysts such as PTSA, triflic acid, HCl, DCC-
[
5]
[6]
[7]
[8]
[10]
SnCl4,
TMSOTf,
LaCl3,
Sc(OTf)3,
Bi(OTf)3,
Bi(NO ) ,
3 3
[
11]
[12]
RuCl3,
acidic montmorillonite clay K 10,
the presence of trimethylorthoformate and montmorillonite clay K 10,
and TiCl4.
On the other hand, some solid catalysts such as
[
13]
[14]
[15]
zeolites,
and sulfonic resins,
in
16]
[
[
17]
[18]
Ce-exchanged clay,
[
siliceous mesoporous silica,
with methanol have also been employed for the preparation
and amorphous
19]
SO H-SiO
3
2
of dimethylacetals. This diversity of methods is accounted for by the fact
that not all of them can be applied to the different types of ketones but
rather that they are complementary. Acetal formation is strongly influenced
by both electronic and steric effects, ketone reactivity generally following
the order acyclic ꢀ cyclohexanones . cyclopentanones . a,b-unsaturated
ketones ꢀ a,a-disubstituted ketones .. aromatic ketones. In these last
compounds, the acetalization rate is strongly influenced by both the
presence of two favorable aryl groups by way of the stabilization of the inter-
mediate cation and by steric crowding during the initial formation of a hemi-
acetal. Herein, we report an alternative method for the preparation of dimethyl
acetals from ketones using the combination acidic montmorillonite clay K 10/
PTSA under mild reaction conditions (Scheme 1).
RESULTS AND DISCUSSION
When benzophenone dimethyl acetal was prepared using trimethyl orthofor-
mate/K 10 in accordance with the method of Taylor,
[13]
the corresponding
acetal was obtained with a yield of 99% with respect to the converted
ketone (64%), even after prolonged periods of time, in contrast with that
described by the author (100% isolated yield). This procedure employs rela-
tively large amounts (2.7–3 g per gram of ketone) of K 10 montmorillonite
w
clay (Girdler ). On the other hand, the reaction of benzophenone with
trimethyl orthoformate and methanol in the presence of PTSA (2% mmol in
regard to the ketone) for 48 h led to the formation of the acetal with a 97%
yield over the converted ketone (61%).
In the light of these results we examined the combination K 10/PTSA in the
formation of dimethyl acetals from ketones. After several attempts we found that
the reaction of benzophenone with trimethyl orthoformate and methanol in the
presence of K 10 (Aldrich) containing 5% of PTSA (20% weight relative to
Scheme 1.

Dimethyl Acetals from Ketones
2197
the ketone) led to the formation of the corresponding acetal with total conversion
and almost quantitative yield entry 16). Using this method different kinds of
ketones were converted to their corresponding dimethyl acetals (Table 1).
Although the reaction times in general are long, the reaction works well and
under very mild conditions, without the formation of by-products, permitting
the facile separation and recycling of starting ketones when the conversions
are moderate, as occurred in the cases of 2-methylcyclohenanone (entry 4),
Table 1. Protection of ketones as dimethyl acetals in the presence of montmorillonite
a
K 10/PTSA
Time
(h)
Isolated
yield (%)
Yield based on
conversion (%)
b
Entry
Substrate
3-Octanone
Cyclopentanone
1
2
3
4
5
6
7
8
9
10
5
82
96 (85)
93 (41)
92 (100)
94 (32)
89 (82)
83 (100)
90 (100)
97 (100)
95 (100)
97 (96)
97 (100)
91 (100)
—
c
38
92
Cyclohexanone
1
c
2-Methylcyclohexanone
Cycloheptanone
Cyclooctanone
12
5
30
73
83
90
97
95
93
97
5
Cyclododecanone
Acetophenone
1-Acetonaphtone
12
2
5
10
11
12
13
14
15
16
Benzylideneacetophenone
b-Phenylpropiophenone
1,3-Diphenylacetone
Dicyclohexyl ketone
24
24
24
d
91
e
NR
—
50
0
2,4 -Dichloroacetophenone
9-Fluorenone
Benzophenone
72
96
48
96 (52)
99 (94)
93
99, (89 ), 100 (99), 97 (92 ),
f
f
g
90)
g
(
98 (91)
0
0
h
17
18
19
20
4,4 -Dimethoxybenzophenone
96
h,i
72
94
86
98
94
98 (96)
97 (89)
98 (100)
94 (100)
4,4 -Dichlorobenzophenone
Dimedone
Ethyl acetoacetate
j
k
24
24
a 1
The structures of the products were established from their spectral ( H NMR,
1
3
C NMR, and MS) data.
b
Conversion in parentheses.
c
1
13
By H NMR and C NMR analysis.
d
Small amounts of the corresponding vinyl ether (7%) were also isolated.
e
Only minuscule amounts of the corresponding vinyl ether were detected.
Reuse 1.
f
g
h
i
Reuse 2.
Double amount of MK 10/p-TsOH pergram of ketone was used.
In 1,2-dichloroethane at 608C.
No trimethyl orthoformate was added.
j
k
b-Keto enol ether exclusively.

2
198
H. Mansilla and D. Reg a´ s
0
0
2
,4 -dichloroacetophenone (entry 14) or diaryl ketones such as 4,4 -dichloroben-
zophenone (entry 18). The case of 9-fluorenone is particulary interesting (entry
5), its dimethyl acetal having previously been prepared by reaction of fluore-
1
none with diphenyldiazomethane and DDQ in the presence of methanol, con-
[20]
[
3
9]
sidering that the use of methods such as those employing Bi(OTf) or triflic
[
3]
acid proved unsuccessful. The application of the present method afforded
the corresponding acetal with an excellent yield and almost total conversion.
In the case of dicyclohexyl ketone (entry 13), the formation of the acetal was
not observed, and only small amounts of enol ether were detected. This can be
attributed to the large steric impediment introduced by the two cyclohexyl
0
groups at the contiguous positions a,a to the carbonyl group. A similar consider-
ation can be applied to the case of 2-methylcyclohexanone (entry 4), whose yield
decreased considerably in relation to that of cyclohexanone (entry 2). When the
method was applied to a b-diketone such as the dimedone (entry 19), the
formation of the b-keto enol ether was observed exclusively without the
necessity of adding trimethyl orthoformate.
Likewise, we explored the possibility of extending this methodology to
the preparation of diethyl acetals of ketones,
[21]
under identical conditions,
using ethanol and triethyl orthoformate. A significant decrease of both conver-
sions and yields were observed in general, even after long reaction times, as
seen in the cases of some significant ketones (Table 2). It is noteworthy that
in the case of cyclohexanone (entry 1), the reaction afforded by-products
that dramatically decreased the yield. Also in this case, when a b-diketone
such as dimedone was employed, the corresponding b-keto enol ether was
obtained exclusively and without the necessity of adding the orthoester.
Table 2. Protection of ketones as diethyl acetals in the presence of montmorillonite
a
K 10/PTSA
Time
(h)
Isolated
yield (%)
Yield based on
conversion (%)
b
Entry
Substrate
Cyclohexanone
Benzophenone
1
2
3
4
5
6
48
96
31
52
44
10
69
48 (65)
91 (57)
96 (46)
83 (12)
95 (72)
97 (85)
0
c
4,4 -Dimethoxybenzophenone
4,4 -Dichlorobenzophenone
96
0
c,d
72
96
9-Fluorenone
Dimedone
e
f
24
83
a
1
The structures of the products were established from their spectral ( H NMR,
C NMR, and MS) data.
1
3
b
Conversion in parentheses.
c
Double amount of MK 10/p-TsOH per g of ketone was used.
d
In 1,2-dichloroethane at 608C.
No triethyl orhtoformate was added.
b-Keto enol ether exclusively.
e
f

Dimethyl Acetals from Ketones
2199
In conclusion, a very simple method has been developed for the
protection of ketones as dimethyl acetals using minimal amounts of acidic
montmorillonite K 10 and PTSA under mild reaction conditions. Moreover,
the method can be applied on a multigram scale (20 g), and montmorillonite
K 10 could be recovered and reused at least two times without an appreciable
loss of activity (entry 16).
EXPERIMENTAL
Montmorillonite K 10 was obtained from Aldrich Company in two different
batches, and no differences were observed in the results obtained. Methanol
and ethanol were dried by passage through Linde type 4A molecular sieves.
Hexane and other solvents were dried by conventional methods, and ortho-
1
esters were used as received. Melting points are uncorrected. H NMR and
3
1
C NMR spectra were recorded on Bruker Avance 300 spectrometer at 300
and 75 MHz respectively in C D as a solvent, and d values are expressed
6
6
in parts per million. The mass spectra were recorded on VG Autoscope
Fisons Instruments) spectrometer.
(
General Acetalization Procedure
To a well-stirred suspension of K 10 montmorillonite clay (190 mg) in dry
methanol (4 ml), trimethyl orthoformate (3 ml) and p-TsOH (10 mg) were
added successively, at room temperature. After 5 min, ketone (1 g) neat or
dissolved in the minimal amount of dry methanol or a dry inert solvent
such as hexane, dichloromethane, 1,2-dichloroethane, or nitromethane was
added. The mixture was stirred at room temperature for the specified time,
and the reaction was monitored by TLC or GC. Montmorillonite was
removed by filtration and washed with dichloromethane. The filtrate was suc-
cessively washed with saturated Na CO solution and water and dried over
2
3
anhydrous MgSO . The solvent was evaporated in vacuo. The pure products
4
were obtained from the crude by crystallization or chromatography over
silica gel or neutral alumina with mixtures of hexane–EtOAc as eluents.
Montmorillonite K 10 could be recovered and reused by washing with
distilled water and then with methanol and drying overnight at 1308C.
1
13
All the products were characterized by H NMR, C NMR, and mass
spectral analysis.
Selected Spectral Data
Cyclododecanone dimethyl acetal: A colorless oil; H NMR d: 3.08 (s, 6H),
1
1
.67 (m, 4H), 1.33 (m, 18H); C NMR d: 104.3, 47.5, 29.9, 26.6, 26.4, 22.8,
2.3, 19.8; MS m/z (%): 228 (M , 3), 197 (M 2OMe, 17), 101 (78), 55 (100).
3
1
2
þ
þ

2
200
H. Mansilla and D. Reg a´ s
Benzylideneacetophenone dimethyl acetal: White crystals (CH Cl –
2
2
1
hexane); mp 42–438C; H NMR d: 7.84 (d, J ¼ 7.8 Hz, 2H), 7.34–7.08
1
3
(
m, 10H), 6.26 (d, J ¼ 15.8 Hz, 1H), 3.23 (s, 6H); C NMR d: 141.5,
1
36.7, 131.5, 131.1, 128.6, 128.4, 128.2, 127.7, 127.3, 127.0, 101.8, 49.0;
þ
þ
MS m/z (%): 254 (M , 69), 223 (M 2 OMe, 100).
1
,3-Diphenylacetone dimethyl acetal: A colorless oil; H NMR d: 7.18–7.05
1
(
1
m, 10H), 3.07 (s, 6H), 2.83 (s, 4H); C NMR d: 136.8, 130.2, 127.6, 125.9,
3
þ
1
03.1, 47.3, 38.9; MS m/z (%): 225 (M 2 OMe, 20), 165 (100), 91 (95).
0
1
,4 -Dichloroacetophenone dimethyl acetal: A colorless oil; H NMR d:
2
2
2
1
.91 (s, 6H), 3.48 (s, 2H), 7.15 (d, J ¼ 8.4 Hz, 2H), 7.30 (d, J ¼ 8.4 Hz,
1
H); C NMR d: 46.2, 48.6, 101.6, 128.1, 128.2, 129.0, 129.1, 134.4,
3
þ
þ
37.2; MS m/z (%): 207 (M 2 OMe, 3), 205 (M 2 OMe, 20), 203
þ
(
M 2 OMe, 28), 187 (33), 185 (100).
1
Benzophenone diethyl acetal: White crystals (hexane); mp 50–518C; H NMR
d: 7.67 (d, J ¼ 7.2 Hz, 4H), 7.13–6.96 (m, 6H), 3.29 (ddd, J ¼ 7.0, 7.0, 7.0 Hz,
1
3
4
H), 1.07 dd, J ¼ 7.0, 7.0 Hz 6H); C NMR MHz, d: 143.4, 127.8, 127.2,
þ þ
1
26.9, 102.1, 56.8, 14.8); MS m/z (%): 256 (M , 3), 211 (M 2 OMe, 100).
0
1
,4 -Dimethoxybenzophenone diethyl acetal: A colorless oil; H NMR d:
4
7
7
1
5
.62 (d, J ¼ 6.9 Hz, 4H), 6.76 (d, J ¼ 7.0 Hz, 4H), 3.37 (ddd, J ¼ 7.0, 7.0,
1
3
.0 Hz, 4H), 3.24 (s, 6H), 1.13 (dd, J ¼ 7.0, 7.0 Hz, 6H); C NMR d:
þ
58.8, 135.9, 128.1, 113.0, 102.0, 55.6, 54.1, 14.8; MS m/z (%): 316 (M ,
), 271 (M 2 OMe, 100).
þ
1
9
-Fluorenone diethyl acetal: White crystals (hexane); mp 79–808C; H
NMR d: 7.55 (d, J ¼ 6.9 Hz, 2H), 7.34 (d, J ¼ 7.0 Hz, 2H), 7.15–7.03
(
m, 4H), 3.56 (ddd, J ¼ 7.0, 7.0, 7.0 Hz, 4H), 1.08 (dd, J ¼ 7.0, 7.0 Hz,
1
3
H); C NMR d: 143.3, 139.8, 129.3, 127.3, 124.6, 119.7, 107.0, 58.9,
6
þ
þ
1
5.2; MS m/z (%): 254 (M , 10), 209 (M 2 OMe, 92), 181 (100).
ACKNOWLEDGMENTS
This research was made possible by grant BQU2001-3184 from the Spanish
Ministry of Science and Technology. D. R. thanks CajaCanarias for a
SEGAI fellowship.
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Dimethyl Acetals from Ketones
2201
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