Direct conversion of acetals to esters with high regioselectivity via O,P-acetals

Article abstract of DOI:10.1039/c1ob05687e

A new direct conversion of O,O-acetals to esters via O,P-acetal intermediates was developed. The regioselective cleavage of unsymmetrical cyclic acetals occurred to give the more crowded esters as single isomers.

Full text of DOI:10.1039/c1ob05687e

View Article Online / Journal Homepage / Table of Contents for this issue
Organic &
Biomolecular
Chemistry
Dynamic Article Links
Cite this: Org. Biomol. Chem., 2011, 9, 5648
www.rsc.org/obc
COMMUNICATION
Direct conversion of acetals to esters with high regioselectivity via
O,P-acetals†
Tomohiro Maegawa, Kazuki Otake, Akihiro Goto and Hiromichi Fujioka*
Received 2nd May 2011, Accepted 9th June 2011
DOI: 10.1039/c1ob05687e
A new direct conversion of O,O-acetals to esters via O,P-
acetal intermediates was developed. The regioselective cleav-
age of unsymmetrical cyclic acetals occurred to give the more
crowded esters as single isomers.
When O,P-acetal from P(OEt)3 was treated with n-BuLi, the
yield of the desired ester 2a was low (entry 1).5 The O,P-acetal was
not converted to the ester at all in the case of NaH and t-BuOK
(entries 2 and 3). On the other hand, when LiHMDS, NaHMDS
and KHMDS were used, the reactions smoothly proceeded and
the desired ester 2a was obtained in good yields after a 2 h
reaction (entries 4–6). Since a slight amount of a side product
3 was obtained in these reactions due to the reaction of the O,P-
acetal anion and TESOTf, 3 eq. of Et3N was added in order to
quench TESOTf after the formation of the O,P-acetal (entry 7).
Consequently, the yield was improved to 83% and the side product
3 was not detected. O,P-acetals from PPh3 and P(o-tol)3 were not
effective for this phosphonate oxygenation.
O,O-Acetals are often used as a protecting group for carbonyl
functions.1 They can also be converted into other functional
groups. For example, there have been many reports of the direct
conversion of O,O-acetals to esters,2 but most of them required a
transition metal catalyst or peroxide. In this communication, we
describe the new and efficient one-pot conversion of O,O-acetals
to esters. The reaction is quite regioselective and unsymmetrical
cyclic acetals can afford single esters (Scheme 1).
With the optimal reaction conditions (Table 1, entry 7), various
O,O-acetals were converted to the corresponding esters via the
O,P-acetals. As shown in Table 2, not only aliphatic dimethyl and
diethyl acetals, but also diisopropyl acetal were converted to esters
in good yields (entries 1–3). Aromatic acetals 1d–1f also gave the
corresponding esters in good to excellent yields (entries 4–6). For
the cyclic acetals 1g and 1h, the silylated esters 2g and 2h were
obtained in good yields (entries 7 and 8).
Next, we planned the regioselective synthesis of esters from
unsymmetrical cyclic acetals obtained from unsymmetrical 1,2-
diols and aldehydes. We have reported the highly chemoselective
transformation of acetals in the presence of ketals in combination
with TESOTf and 2,4,6-collidine.3a–c,f ,h This excellent selectivity
is attributed to the discrimination of the steric environment
by TESOTf, which selectively coordinates to the less hindered
oxygen atom. We then expected the regioselective opening of
the unsymmetrical cyclic acetals in combination with P(OEt)3
and TESOTf. The resulting O,P-acetals would be converted to
esters as a single regioisomer connecting to the more hindered
hydroxyl group (Scheme 2). Although there are now a number
of methods for the conversion of unsymmetrical cyclic acetals
to esters, satisfactory results have not yet been obtained.2 For
example, the reaction of an unsymmetrical cyclic acetal 4a using
Scheme 1 Oxidation of O,O-acetals to esters via O,P-acetals.
Recently, we demonstrated the formation of pyridinium in-
termediates (N,O-acetals) from O,O-acetals and pyridines, and
investigated their reactivity.3 As an extension of this study, we
also studied the reactivity of phosphonium intermediates (O,P-
acetals) using phosphines instead of pyridines and developed
the efficient nucleophilic substitution of O,P-acetals from P(o-
tol)3.4 During the course of our study, we found the novel
conversion of O,O-acetals to esters in one-pot via O,P-acetal
intermediates.
2h
oxidating reagents, t-BuOOH-VO(OAc)2 and DMDO,2m gave
isomeric mixtures in 70 : 30 and 89 : 11, respectively. To our
delight, the ring-opening reaction of 4a proceeded regioselectively
and gave the corresponding ester 5a as a single isomer under our
reaction conditions though the yield was 18% (Table 3, entry
1).6 While an increase in NaHMDS did not have a significant
influence on the yield of 5a (entry 2), the addition of 15-
crown-5 substantially improved the yield (entry 3).7 The reaction
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6
Yamada-oka, Osaka, 565-0871, Japan. E-mail: fujioka@phs.osaka-u.ac.jp;
Fax: +8168798229; Tel: +8168798225
† Electronic supplementary information (ESI) available: Experimental de-
tails and the charts of 1H, 13C and 31P NMR. See DOI: 10.1039/c1ob05687e
5648 | Org. Biomol. Chem., 2011, 9, 5648–5651
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Table 1 Oxygenation of O,P-acetalsa
Entry
PR3
Base
Time (h)
Yield (%)
8
1
2
3
4
5
6
7c
P(OEt)3
n-BuLi
NaH
t-BuOK
LiHMDS
NaHMDS
KHMDS
NaHMDS
3
5
5
2
2
2
2
b
—
—
b
75
79
78
83
a The reaction conditions: To a solution of 1a (1.0 eq.) and PR3 (3.0 eq.) in THF (0.2 M) was added TESOTf (2.0 eq.) at 0 ◦C, and the solution was stirred
for 0.5 h under a N2 atmosphere. Then the reaction mixture was cooled to -78 ◦C and base (3.0 eq.) was added. After being stirred for 0.5 h, N2 was
replaced with O2. b O,P-acetal was not converted to ester at all. c 3.0 eq. of Et3N was added before the addition of NaHMDS.
Table 2 Oxidation of acetals to esters via O,P-acetals
Entry
Substrate
Time (h)
Product
Yield (%)
1
2
3
R2 = Me (1a)
R2 = Et (1b)
R2 = i-Pr (1c)
2
3
2
R2 = Me (2a)
R2 = Et (2b)
R2 = i-Pr (2c)
83
79
83
4
5
6
R3 = p-Me (1d)
R3 = p-Br (1e)
R3 = o-MeO (1f)
2
1
4
R3 = p-Me (2d)
R3 = p-Br (2e)
R3 = o-MeO (2f)
75
90
70
7
2
86
8
2
84
Scheme 2 Oxygenation of unsymmetrical cyclic acetal to ester via regioselective formation of O,P-acetal.
of other unsymmetrical acetals also afforded the corresponding
esters in good yields (entries 4–6). However, the reaction of
5eresulted in a low yield because the elimination reaction
occurred concomitantly (entry 7).
In summary, we have developed a method for the direct
conversion of O,O-acetals to esters via O,P-acetal intermediates.
The feature of our reaction is the highly regioselective formation
of more crowded esters from unsymmetrical cyclic acetals.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5648–5651 | 5649
©

View Article Online
Table 3 Oxidation of unsymmetrical acetals to esters via O,P-acetals
Entry
Substratea
Additive
Time (h)
Product
Yield (%)
1
None
None
15-crown-5
2
2
2
18
23
75
2b
3
4
5
6
15-crown-5
15-crown-5
15-crown-5
6
6
2
70
70
78
7
15-crown-5
6
34
a A mixture of isomers (4a; cis : trans = 5 : 4 4b; cis : trans = 1 : 1 4c; cis : trans = 2 : 1 4d; cis : trans = 4 : 1 4e; cis : trans = 5 : 4) was used. b 5.0 eq. of NaHMDS
was used.
(l) M. Curini, F. Epifano, M. C. Marcotullio and O. Rosati, Synlett, 1999,
Acknowledgements
777; (m) J. H. Espenson, Z. Zhu and T. H. Zauche, J. Org. Chem., 1999,
64, 1191; (n) R. Gopinath, A. R. Paital and B. K. Patel, Tetrahedron
This work was supported by a Grant-in-Aid for Scientific Research
(B) and for Scientific Research for Exploratory Research from
the Japan Society for the Promotion of Science. The financial
supports from the Hoansha Foundation and the Uehara Memorial
Foundation are also acknowledged.
Lett., 2002, 43, 5123; (o) B. Karimi and J. Rajabi,, Synthesis, 2003,
2373; (p) D. K. Mycock, A. E. Sherlock, P. A. Glossop and C. J. Hayes,
Tetrahedron Lett., 2008, 49, 6390; (q) C. Kuhakarn, W. Panchan, S.
Chiampanichayakul, N. Samakkanad, M. Pohmakotr, V. Reutrakul and
T. Jaipetch, Synthesis, 2009, 929.
3 (a) H. Fujioka, Y. Sawama, N. Murata, T. Okitsu, O. Kubo, S. Matuda
and Y. Kita, J. Am. Chem. Soc., 2004, 126, 11800; (b) H. Fujioka, T.
Okitsu, Y. Sawama, N. Murata, R. Li and Y. Kita, J. Am. Chem. Soc.,
2006, 128, 5930; (c) H. Fujioka, T. Okitsu, Y. Sawama, T. Ohnaka and
Y. K i t a , Synlett, 2006, 3077; (d) H. Fujioka, T. Ohnaka, T. Okitsu, O.
Kubo, K. Okamoto, Y. Sawama and Y. Kita, Heterocycles, 2007, 72, 529;
(e) H. Fujioka, T. Okitsu, T. Ohnaka, Y. Sawama, O. Kubo, K. Okamoto
and Y. Kita, Adv. Synth. Catal., 2007, 349, 636; (f) H. Fujioka, T. Okitsu,
T. Ohnaka, R. Li, O. Kubo, K. Okamoto, Y. Sawama and Y. Kita, J. Org.
Chem., 2007, 72, 7898; (g) H. Fujioka, O. Kubo, K. Okamoto, K. Senami,
T. Okitsu, T. Ohnaka, Y. Sawama and Y. Kita, Heterocycles, 2009, 77,
1089; (h) H. Fujioka, O. Kubo, K. Senami, K. Okamoto, T. Okitsu
and Y. Kita, Heterocycles, 2009, 79, 1113; (i) H. Fujioka, O. Kubo, K.
Senami, Y. Minamitsuji and T. Maegawa, Chem. Commun., 2009, 4429;
(j) H. Fujioka, K. Senami, O. Kubo, K. Yahata, Y. Minamitsuji and T.
Maegawa, Chem. Pharm. Bull., 2010, 58, 426.
Notes and references
1 (a) T. W. Greene and P. G. Wuts Protective Groups in Organic Synthesis,
3rd ed.; John Wiley and Sons: New York, 1999; (b) J. R. Hanson,
Protective Groups in Organic Synthesis, 1st ed.; Blackwell Science, Inc.,
Malden, MA, 1999.
2 For the representative oxidation reaction of acetals to esters, see: (a) E.
N. Marvell and M. J. Joncich, J. Am. Chem. Soc., 1951, 73, 973; (b) J.
B. Wright, J. Am. Chem. Soc., 1955, 77, 4883; (c) D. L. Heywood and
B. Phillips, J. Org. Chem., 1960, 25, 1699; (d) J. D. Prugh and W. C.
McCarthy, Tetrahedron Lett., 1966, 7, 1351; (e) P. Deslongchamps and
P. Atlani, Can. J. Chem., 1974, 52, 3651; (f) T. Hosokawa, Y. Imada and S.
Murahashi, J. Chem. Soc., Chem. Commun., 1983, 1245; (g) M. Masui, T.
Kawaguchi, S. Yoshida and S. Ozaki, Chem. Pharm. Bull., 1986, 34, 1837;
(h) N. Chidambaram, S. Bhat and S. Chandrasekaran, J. Org. Chem.,
1992, 57, 5013; (i) S. Bhat, A. R. Ramesha and S. Chandrasekaran,
Synlett, 1995, 329; (j) B. M. Choudary and P. N. Reddy, Synlett, 1995,
959; (k) T. Takeda, H. Watanabe and T. Kitahara, Synlett, 1997, 1149;
4 H. Fujioka, A. Goto, K. Otake, O. Kubo, K. Yahata, Y. Sawama and T.
Maegawa, Chem. Commun., 2010, 46, 3976.
5 For the oxidation of phosphorus ylides and phosphinoxide carbanions
leading to carbonyl compounds in an oxygen atmosphere, see: (a) H. J.
5650 | Org. Biomol. Chem., 2011, 9, 5648–5651
This journal is
The Royal Society of Chemistry 2011
©

View Article Online
Bestmann, Angew. Chem., 1960, 72, 34; (b) H. J. Bestmann and E. Kranz,
Chem. Ber., 1963, 96, 1899; (c) H. J. Bestmann and E. Kranz, Angew.
Chem., Int. Ed. Engl., 1967, 6, 81; (d) H. J. Bestmann and E. Kranz,
Chem. Ber., 1969, 102, 1802; (e) H. Zimmer, R. E. Koenigkramer, R. L.
Cepulis and D. M. Nene, J. Org. Chem., 1980, 45, 2018; (f) E. Vedejs,
G. P. Meier, D. W. Powell and H. Mastalerz, J. Org. Chem., 1981, 46,
5253; (g) M. Mikołajaczyk, W. Midura and S. Grzejszczak, Tetrahedron
Lett., 1984, 25, 2489; (h) O. Tsuge, S. Nanemasa and H. Suga, Chem.
Lett., 1986, 183; (i) O. Tsuge, S. Nanemasa, H. Suga and N. Nakagawa,
Bull. Chem. Soc. Jpn., 1987, 60, 2463; (j) F. A. Davis and B. Chen, J. Org.
Chem., 1990, 55, 360; (k) H. J. Bestmann and A. Groß, Tetrahedron Lett.,
1997, 38, 4765; (l) J. Sandri, T. Soto, J.-L. Gras and J. Viala, Tetrahedron
Lett., 1997, 38, 6611.
7 For the regioselective oxygenation of unsymmetrical cyclic acetals, the
choice of the silyltriflate is critical. When we examined the oxida-
tion reaction with TMSOTf instead of TESOTf, the regioselectivity
decreased.
6 No other regioisomer was detected, and the O,P-acetal remained in the
reaction.
.
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 5648–5651 | 5651
©