Efficient and chemoselective conversion of carbonyl compounds to 1,3-dioxanes catalyzed with N-bromosuccinimide under almost neutral reaction conditions

Article abstract of DOI:10.1021/ol9909987

(formula presented) Various types of carbonyl compounds were converted to the corresponding 1,3-dioxanes in the presence of ethyl orthoformate, 1,3-propanediol, and a catalytic amount of NBS via an in situ acetal exchange process. In contrast to conventional acid-catalyzed acetalization reactions, acid-sensitive substrates such as THP ethers and TBDMS ethers remain intact under described reaction conditions.

Full text of DOI:10.1021/ol9909987

ORGANIC
LETTERS
1999
Vol. 1, No. 11
1737-1739
Efficient and Chemoselective
Conversion of Carbonyl Compounds to
1,3-Dioxanes Catalyzed with
N-Bromosuccinimide under Almost
Neutral Reaction Conditions
Babak Karimi,* G. Reza Ebrahimian,† and Hassan Seradj†
Department of Chemistry, Institute for AdVanced Studies in Basic Sciences (IASBS),
P.O. Box 45195-159, GaVa Zang, Zanjan, Iran, and Department of Chemistry and
Medicinal Chemistry, School of Pharmacy, Shiraz UniVersity of Medical Sciences,
Shiraz 71345, Iran
karimi@iasbs.ac.ir
Received September 1, 1999
ABSTRACT
Various types of carbonyl compounds were converted to the corresponding 1,3-dioxanes in the presence of ethyl orthoformate, 1,3-propanediol,
and a catalytic amount of NBS via an in situ acetal exchange process. In contrast to conventional acid-catalyzed acetalization reactions,
acid-sensitive substrates such as THP ethers and TBDMS ethers remain intact under described reaction conditions.
Acetals are among the most popular protecting groups for
carbonyl compounds.1 In addition, chiral acetals are particu-
larly important for the preparation of enantiomerically pure
compounds.2 Although the formation of acetals is generally
achieved with protic acid catalysts, it has been shown that
the use of Lewis acids in these transformations may be
advantageous in some cases.3 Very recently, we have shown
that WCl6 and ZrCl4 are highly efficient catalysts for
chemoselective acetalization of various types of carbonyl
compounds.4 However, these two catalysts were not suitable
for the acetalization of carbonyl compounds containing other
acid-sensitive functionalities, such THP ethers. We thus
researched a milder catalytic system that would allow
survival of other acid-sensitive groups.
NBS has already been known as a mild oxidizing reagent
for chemoselective oxidative deprotection of S,S-acetals. A
brief survey of the literature shows that free hydroxyl groups,
disubstituted alkenes, and acid-sensitive functional groups
such as MEM ethers, TBDPS ethers, 1,3-dioxanes, and
phenolic benzyl ethers survive intact in the presence of NBS.5
In our development of new methods for functional group
† Shiraz University of Medical Sciences.
(1) (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 2nd ed.; Wiley: New York, 1991; pp 175-198. (b) Kocienski,
P. J. ProtectiVe Groups; Enders, R., Noyori, R., Trost, B. M., Eds.;
Thieme: Stuttgart, 1994; Chapter 4.
(2) Seebach, D.; Imwinkelried, R.; Weber, T. Modern Synthetic Methods
1986; Scheffold, R., Ed.; Springer-Verlag: Berlin, 1986; Vol. 4, pp 125-
259.
(3) (a) Luche, J. L.; Gemal, A. L. J. Chem. Soc., Chem. Commun. 1978,
976. (b) Hwu, J. R.; Leu, L. C.; Robl, J. A.; Anderson, D. A.; Wetzel, J.
M. J. Org. Chem. 1987, 52, 188. (c) Tsunoda, T.; Suzuki, M.; Noyori, R.
Tetrahedron Lett. 1980, 21, 1357. (d) Ott, J.; Ramos Tombo, G. M.; Schmid,
B.; Venanzi, L. M.; Wang, G.; Ward, T. R. Tetrahedron Lett. 1989, 30,
6151. (e) Otera, J.; Mizutani, T.; Nozaki, H. Organometallics 1989, 8, 2063.
(f) Ma, S.; Venanzi, L. M. Synlett 1993, 751. (g) Fukuzawa, S. I.;
Tsuchimoto, T.; Hotaka, T.; Hiyama, T. Synlett 1995, 1077. (h) Ishihara,
K.; Karumi, Y.; Kubota, M.; Yamamoto, H. Synlett 1996, 839.
(4) (a) Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synlett 1999, 321. (b)
Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synth. Commun. 1999, 29, 2255.
10.1021/ol9909987 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/04/1999

(+)-dimethyl tartrate in the presence of 2 and 3 mol % of
NBS also furnished the corresponding optically active acetals
in high yields (Table 1, entries 12 and 13). Moreover,
acetalization of relatively hindered ketones such as (-)-
camphor, benzophenone, and 3-â-acetoxyandrost-5-en-17-
one was also achieved in low yields in the presence of 5
mol % of NBS after prolonged reaction times (Table 1,
entries 14-16). On the other hand, 4-hydroxybenzaldehyde
was recovered intact even after 7 days under similar reaction
conditions.
Because ketones undergo acetalization considerably slower
than aldehydes, it seemed plausible that our system could
promote chemoselective protection of aldehydes in the
presence of ketones. Indeed, benzaldehyde and butanal were
converted to the acetals in the presence of acetophenone and
benzylacetone with complete selectivity (Scheme 2).8 This
Scheme 1
transformations, we are especially interested in exploring the
potential use of various types of neutral catalyst.6 Along this
line, we have found that various aldehydes are converted to
the corresponding 1,3-dioxanes in excellent yields upon
treatment with (EtO)3CH (1 equiv), dry MeOH (2 equiv),
1,3-propanediol (3 equiv), and a catalytic amount of NBS
(0.01-0.02 equiv) (Scheme 1, Table 1, entries 1-6)7
Table 1. Acetalization of Carbonyl Compounds in the
Presence of NBS
Scheme 2
result suggests that our method may be generally useful for
the conduction of similar chemoselective acetalization reac-
tions. It is also worthy of note that acid-sensitive substrates
such as THP ethers and TBDMS ethers remain intact under
these conditions (Scheme 3).9
Scheme 3
a Yields refer to isolated pure product unless otherwise stated. b (+)-
Dimethyl tartrate was used instead of 1,3-propanediol. c Yields are based
on NMR of the crude products. d No reaction.
Aliphatic and aromatic ketones also formed the respective
acetals under these conditions, although long reaction times
were required to obtain satisfactory yields (Table 1, entries
7-11). The reaction of benzaldehyde and acetophenone with
(5) (a) Williams, D. R.; Jass, P. A.; Allan Tse, H. L.; Gaston, R. D. J.
Am. Chem. Soc. 1990, 112, 4552. (b) Schmidt, U.; Meyer, R.; Leitemberger,
V.; Grisser, H.; Lieberknecht, A. Synthesis 1992, 1025.
(6) (a) Firouzabadi, H.; Iranpoor, N.; Karimi, B. Synthesis 1999, 58. (b)
Firouzabadi, H.; Karimi, B.; Eslami, S. Tetrahedron Lett. 1999, 40, 4055.
1738
Org. Lett., Vol. 1, No. 11, 1999

The precise role of NBS is not clear in this method. One
explanation for this process is that NBS probably generates
small quantities of HBr, which may be the actual catalyst
for the acetalization reactions. However, when we conduct
similar acetalization reactions with benzaldehyde in the
presence of a catalytic amount of a saturated HBr solution
in benzene instead of NBS, a drastic rate enhancement was
observed and the reaction was completed within minutes (15
min). This observation may be due to the fact that HBr is
produced in smaller amounts in the NBS protocol than from
the saturated solution of HBr. Another explanation is that
NBS could act as a precursor for the formation of Br+, which
in turn could behave as a Lewis acid in the reaction medium.
Nevertheless, at this time we have obtained no experimental
evidence for these two features of NBS, and the actual role
of this reagent should be further studied in detail.
In summary, we have demonstrated that NBS is a new,
efficient, and practically neutral catalyst for 1,3-dioxanation
of aldehydes and ketones. Work on other reactions promoted
by NBS and related compounds is currently underway in
our laboratory.
(7) General procedure for acetalization of carbonyl compounds
catalyzed with NBS: To a solution of carbonyl compound (10 mmol),
(EtO)3CH (10-13 mmol), anhydrous methanol (20-50 mmol), and dry
1,3-propanediol (30-50 mmol) in CH2Cl2 (50 mL) was added NBS (0.1-
0.5 mmol), and the resulting solution was stirred at room temperature. After
completion of the reaction (TLC or GC), a cold aqueous solution of NaHCO3
(10%, 25 mL) was added and the mixture was extracted with CH2Cl2 (3 ×
50 mL). The organic extracts were washed with water (2 × 15 mL) and
dried over anhydrous Na2SO4. Evaporation of the solvent under reduced
pressure gave almost pure product(s). Further purification was proceeded
by vacuum distillation or recrystalization to afford pure acetals (Table 1).
(8) The product ratios were determined by NMR spectroscopy.
Acknowledgment. The authors thank the IASBS Re-
search Council for support of this work. G.R.E. and H.S.
thank Dr. S. M. H. Tabaei from the Department of Chemistry,
School of Pharmacy, Shiraz University of Medical Sciences,
for his kind assistance.
(9) The product ratios were determined by GC and NMR.
OL9909987
Org. Lett., Vol. 1, No. 11, 1999
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