A simple and efficient procedure for the synthesis of ketone di-sec-alkyl acetals

Article abstract of DOI:10.1055/s-0028-1087534

Ketone di-sec-alkyl acetals are obtained in good to excellent yields by treatment of ketones with tri-sec-alkyl orthoformate and the corresponding alcohol in the presence of a catalytic amount of cerium(III) trifluoromethanesulfonate. Georg Thieme Verlag

Full text of DOI:10.1055/s-0028-1087534

LETTER
487
A Simple and Efficient Procedure for the Synthesis of Ketone Di-sec-alkyl
Acetals
Synthesis of
K
u
etone
D
i-sec
m
-
alkyl
A
cetals iaki Ono, Hirotaka Takenaka, Yuko Eguchi, Masato Endo, Tsuneo Sato*
Department of Life Science, Kurashiki University of Science and the Arts, Kurashiki 712-8505, Japan
Fax +81(86)4401062; E-mail: sato@chem.kusa.ac.jp
Received 22 September 2008
In the first place, we undertook to examine the preparation
of diisopropyl acetals of ketones. To a mixture of cyclo-
pentanone in 2-propanol–toluene (1:1) in the presence of
1 mol% of cerium(III) trifluoromethanesulfonate was
Abstract: Ketone di-sec-alkyl acetals are obtained in good to excel-
lent yields by treatment of ketones with tri-sec-alkyl orthoformate
and the corresponding alcohol in the presence of a catalytic amount
of cerium(III) trifluoromethanesulfonate.
Key words: acetals, cerium(III) trifluoromethanesulfonate, ke-
tones, Lewis acids, tri-sec-alkyl orthoformates
Table 1 Diisopropyl Acetalization of Ketones Catalyzed by Ce(OTf)3a,11
R
O-i-Pr
R
Ce(OTf)3
(i-PrO)3CH
+
O
i-PrOH, toluene
R
O-i-Pr
R
Acetalization is among the most frequently used reactions
for the protection of ketones in organic synthesis.1 In ad-
dition, ketone acetals can be converted to a variety of oth-
er functional groups and hence serve as useful
intermediates in organic synthesis.2 Whereas the literature
provides many examples3 of the synthesis of ketone
di-prim-alkyl acetals, relatively few examples4–6 of the
preparation of ketone di-sec-alkyl acetals have been re-
ported. Howard et al.4 reported the preparation of ketone
di-sec-alkyl acetals by alcohol interchange reactions with
ketone dimethyl acetals and secondary alcohols promoted
by PTSA. The yields of the products are often low, and the
procedure is rather laborious. Although Roelofsen et al.5
reported the synthesis of ketone di-sec-alkyl acetals from
the parent ketones and secondary alcohols using molecu-
lar sieves in the presence of PTSA, this involves some an-
noying problems; only reactive ketones such as acetone
and cyclohexanone could be used, and significant
amounts of elimination byproducts (vinyl ethers) were of-
ten produced under the conditions. Therefore, we have
been interested in developing a simple, efficient, and
widely applicable di-sec-alkyl acetalization of ketones.
Herein we wish to report a simple, efficient, and versatile
procedure for the di-sec-alkyl acetalization of various ke-
tones with tri-sec-alkyl orthoformates in the presence of a
catalytic amount of cerium(III) trifluoromethane-
sulfonate7 (1 mol%, Scheme 1).8
Entry
1
R2C=O
Temp (°C) Time
Yield (%)b
O
0
6 h
90
94
O
O
2
3
r.t.
5 min
r.t.
0.5 h
95
O
4
5
6
r.t.
r.t.
0
2.5 h
4 h
79
80
78
n-C5H11
O
Bn
O
20 h
COOMe
O
7c
0
20 h
71
c-C6H11
O
8c
9
0
29 h
63d
99
Ph
S
CHO
r.t.
0.5 h
R2
10
11
r.t.
r.t.
4 h
94
98
CHO
CHO
R2
R3
R1
R1
R1
R1
n-Pr
O
R3
R2
Ce(OTf)3 (1 mol%)
R2R3CHOH, toluene
+
O CH
O
5 min
Ph
3
O
a Reaction conditions: R2C=O (1.0 mmol), (i-PrO)3CH (1.3 mmol),
Ce(OTf)3 (0.01 mmol), i-PrOH (1 mL), toluene (1 mL), unless other-
wise noted.
R3
Scheme 1
b Isolated yield of pure diisopropyl acetal. No vinyl ether was detected
in the crude product.
c (i-PrO)3CH (3.0 mmol) was used.
SYNLETT 2009, No. 3, pp 0487–0489
Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087534; Art ID: U10108ST
x
x.
x
x.
2
0
0
9
d A total of 6% of 1-methylethoxy-1-phenylethene was detected in the
crude product. The ketone (25%) remained intact.
© Georg Thieme Verlag Stuttgart · New York

488
F. Ono et al.
LETTER
ticular note, no vinyl ethers were again produced under
the reaction conditions.14
Table 2 Di-sec-butyl and Dicyclohexyl Acetalization of Ketones
Using Ce(OTf)3
a
R1
In conclusion, the synthesis of a range of di-sec-alkyl ac-
etals from ketones has been accomplished using tri-sec-
alkyl orthoformate and cerium(III) trifluoromethane-
sulfonate.
R1 OR2
R1 OR2
Ce(OTf)3
(R2O)3CH
O
+
R2OH, toluene
R1
a: R2 = s-Bu
b: R2 = c-C6H11
Entry R1 C=O
(R2O)3CH
Temp Time
(°C)
Yield
2
(%)b
References and Notes
O
(1) (a) Kocienski, P. J. Protecting Groups, 3rd ed.; Thieme:
New York, 2004, Chap. 2. (b) Wuts, P. G. M.; Greene,
T. W. Greene’s Protective Groups in Organic Synthesis, 4th
ed.; Wiley: New York, 2007, Chap. 4.
(2) (a) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043.
(b) Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry
1990, 1, 477.
1
a
r.t.
10 min
10 min
85
O
2
b
r.t.
100
(3) (a) Meskens, F. A. J. Synthesis 1981, 501. (b) Sandler,
S. R.; Karo, W. Organic Functional Group Preparations,
2nd ed., Vol. III; Academic: New York, 1989, Chap. 1.
(c) Macpherson, D. T.; Harshad, K. R. In Comprehensive
Organic Functional Group Transformations, Vol. 4; Kirby,
G. W., Ed.; Pergamon: Oxford, 1995, 159.
O
3
a
0
12 h
2 h
75
78
n-C6H13
O
4
b
r.t.
(4) Howard, W. L.; Lorette, N. B. J. Org. Chem. 1960, 25, 525.
(5) Roelofsen, D. P.; van Bekkum, H. Synthesis 1972, 419.
(6) a-Hydroxy ketone di-sec-alkyl acetals were obtained by
addition of secondary alcohols to sec-alkyl epoxy ethers:
Stevens, C. L.; McLean, R. L.; Weinheimer, A. J. J. Am.
Chem. Soc. 1958, 80, 2276.
n-C6H13
5
6
Ph(CH2)2CHO
Ph(CH2)2CHO
a
r.t.
r.t.
10 min
20 min
96
b
100
a Reaction conditions: R1 C=O (1.0 mmol), (R2O)3CH (1.3 mmol),
2
Ce(OTf)3 (0.01 mmol), R2OH (1 mL), toluene (1 mL).
b Isolated yield of pure acetal. No vinyl ether was detected in the crude
product.
(7) For the use of Ce(OTf)3 in other types of reactions, see:
(a) Dalpozzo, R.; De Nino, A.; Maiuolo, L.; Procopio, A.;
Tagarelli, A.; Sindona, G.; Bartoli, G. J. Org. Chem. 2002,
67, 9093. (b) Keh, C. C. K.; Namboodiri, V. V.; Varma,
R. S.; Li, C.-J. Tetrahedron Lett. 2002, 43, 4993.
(c) Dalpozzo, R.; De Nino, A.; Maiuolo, L.; Procopio, A.;
Nardi, M.; Bartoli, G.; Romeo, R. Tetrahedron Lett. 2003,
44, 5621. (d) Bartoli, G.; Dalpozzo, R.; De Nino, A.;
Maiuolo, L.; Nardi, M.; Procopio, A.; Tagarelli, A. Eur. J.
Org. Chem. 2004, 2176. (e) Bartoli, G.; Dalpozzo, R.;
De Nino, A.; Maiuolo, L.; Nardi, M.; Procopio, A.;
Tagarelli, A. Green Chem. 2004, 6, 191. (f) Bartoli, G.;
De Nino, A.; Dalpozzo, R.; Maiuolo, L.; Nardi, M.;
Procopio, A.; Tagarelli, A. Lett. Org. Chem. 2005, 2, 51.
(8) MacKenzie et al. reported the reaction of acetone, tri-sec-
butyl orthformate, S-BuOH, and PTSA did not occur and the
orthoester was recovered unchanged: MacKenzie, C. A.;
Stocker, J. H. J. Org. Chem. 1955, 20, 1695.
added 1.3 equivalents of triisopropyl orthoformate at 0 °C
and stirred at the same temperature for six hours. The usu-
al workup of the reaction mixture afforded cyclopenta-
none diisopropyl acetal in 90% yield (Table 1, entry 1).9
1
The H NMR (500 MHz) analysis of the crude product
showed no formation of 1-cyclopentenyl isopropyl ether.
A screening of cosolvents revealed that toluene as a co-
solvent gave the best result.10
The scope and generality of the present method was then
tested by converting various other ketones into the corre-
sponding diisopropyl acetals, and the results are summa-
rized in Table 1. A wide range of cyclic (entries 1–3) and
acyclic (entries 4–7) ketones underwent smooth diisopro-
pyl acetalization without any trace of byproducts arising
from elimination to furnish the desired products in good to
excellent yields.12 In the acetalization of acetophenone, a
typical aromatic ketone, a small amount of the vinyl ether
was produced together with acetophenone diisopropyl ac-
etal (63%, entry 8).13 In addition, when the present proto-
col was applied to the synthesis of diisopropyl acetals of
aldehydes, essentially quantitative yields were obtained
(entries 9–11). Next, to study the versatility of our proto-
col, the di-sec-alkyl acetalization of ketones with tri-sec-
alkyl orthoformates other than triisopropyl orthformate
using the same catalyst was investigated (Table 2). Tri-
sec-butyl and tricyclohexyl orthoformates reacted
smoothly to give the corresponding di-sec-butyl and di-
cyclohexyl acetals of ketones in reasonable yields. Of par-
(9) When this reaction was attempted in the absence of i-PrOH
or triisopropyl orthformate, diisopropyl acetalization did not
proceed at all.
(10) None (85%), CH2Cl2 (80%), Et2O (83%), THF (81%),
MeCN (76%).
(11) Typical Procedure (Table 1, Entry 1)
To a mixture of cyclopentanone (84 mg, 1.0 mmol),
Ce(OTf)3 (Alfa Aesar, 5.9 mg, 0.01 mmol), i-PrOH (1 mL),
and toluene (1 mL) triisopropyl orthoformate (247 mg, 1.3
mmol)was added at 0 °C. After the mixture was kept stirring
at the same temperature for 6 h, it was quenched by adding
Et3N (101 mg, 1.0 mmol). The resulting mixture was passed
through a short plug of neutral Al2O3 (activity III), which
was then washed with Et2O (30 mL), and the solvent was
removed under reduced pressure. The 1H NMR (500 MHz)
analysis of the crude product showed the absence of
1-cyclopentenyl isopropyl ether. The residue was chroma-
tographed on neutral Al2O3 (activity III, hexane) to afford
cyclopentanone diisopropyl acetal (168 mg, 90%). 1H NMR
(500 MHz, CDCl3): d = 1.17 (d, J = 6.1 Hz, 12 H), 1.65–1.70
Synlett 2009, No. 3, 487–489 © Thieme Stuttgart · New York

LETTER
(m, 4 H), 1.75–1.81 (m, 4 H), 4.01–4.09 (m, 2 H). 13C NMR
Synthesis of Ketone Di-sec-alkyl Acetals
489
(t, J = 7.7 Hz, 3 H), 1.14 (d, J = 6.4 Hz, 3 H), 1.16 (d, J = 6.1
Hz, 3 H), 1.26–1.35 (m, 2 H), 1.43–1.74 (m, 12 H), 3.82–
3.93 (m, 2 H). 13C NMR (125 MHz, C6D6): d = 9.5, 9.6, 21.3,
21.5, 23.8, 26.1, 31.3, 36.1, 36.2, 36.5, 66.8, 67.0, 101.3.
Cyclohexanone Dicyclohexyl Acetal
(125 MHz, CDCl3): d = 21.7, 24.4, 35.6, 63.8, 111.6.
2-Octanone Diisopropyl Acetal
1H NMR (500 MHz, CDCl3): d = 0.88 (t, J = 7.1 Hz, 3 H),
1.14 (d, J = 6.4 Hz, 12 H), 1.24–1.37 (m, 8 H), 1.27 (s, 3 H),
1.54–1.59 (m, 2 H), 3.99–4.08 (m 2 H). 13C NMR (125 MHz,
CDCl3): d = 14.1, 22.6, 23.7, 24.5, 24.6, 24.8, 29.7, 31.9,
39.8, 62.1, 102.6.
1H NMR (500 MHz, C6D6): d = 1.10–1.87 (m, 30 H), 3.82–
3.89 (m, 2 H). 13C NMR (125 MHz, C6D6): d = 23.8, 24.8,
26.2, 35.2, 36.7, 67.9, 101.5.
1-Cyclohexyl-1-ethanone Diisopropyl Acetal
1H NMR (500 MHz, C6D6): d = 0.92–2.10 (m, 11 H), 1.10
(d, J = 6.0 Hz, 6 H), 1.13 (d, J = 6.0 Hz, 6 H), 1.15 (s, 3 H),
3.97–4.05 (m, 2 H). 13C NMR (125 MHz, C6D6): d = 19.7,
24.6, 25.0, 27.1, 27.2, 29.0, 45.9, 62.0, 104.5.
(12) Other Brønsted and Lewis acids are less effective than
Ce(OTf)3 in our reaction system. The reaction of 2-octanone
under identical conditions are as follows: TfOH (23%),
BF3·OEt2 (0%), AlCl3 (15%), Mg(OTf)2 (0%), TMSOTf
(58%), Sc(OTf)3 (62%), Cu(OTf)2 (63%), Zn(OTf)2 (35%),
La(OTf)3 (36%), Gd(OTf)3 (63%), Bi(OTf)3·4H2O (51%).
(13) Reaction of benzophenone (r.t., 24 h) followed by the
standard workup gave benzophenone diisopropyl acetal
(5%) and the starting ketone (90%).
Acetophenone Diisopropyl Acetal
1H NMR (500 MHz, C6D6): d = 0.98 (d, J = 6.5 Hz, 6 H),
1.12 (d, J = 6.0 Hz, 6 H), 1.61 (s, 3 H), 3.96–4.04 (m, 2 H),
7.08–7.76 (m, 5 H). 13C NMR (125 MHz, C6D6): d = 24.2,
24.9, 28.3, 63.7, 101.3, 127.3, 127.6, 145.0.
(14) Di-sec-butyl acetalization of cyclohexanone by the
Roelofsen method5 afforded cyclohexanone di-sec-butyl
acetal (80%) and sec-butyl 1-cyclohexenyl ether (15%).
Cyclohexanone Di-sec-butyl Acetal
1H NMR (500 MHz, C6D6): d = 0.87 (t, J = 7.7 Hz, 3 H), 0.88
Synlett 2009, No. 3, 487–489 © Thieme Stuttgart · New York

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