An efficient procedure for the diastereoselective dehydration of β-hydroxy carbonyl compounds by CeCl3·7H2O/Nal system

Article abstract of DOI:10.1021/ol005766i

(Formula presented) The dehydration of β-hydroxy ketones and β-hydroxy esters is a synthetically useful method for the conversion of these compounds to the corresponding α,β-unsaturated derivatives. Cerium(III) chloride heptahydrate in combination with sodium iodide in refluxing acetonitrile acts as an efficient reagent for this conversion. The present procedure, which utilizes cheap and "friendly" reagents, offers the corresponding (E)-enones in good yields as the only isolable products.

Full text of DOI:10.1021/ol005766i

ORGANIC
LETTERS
2000
Vol. 2, No. 13
1791-1793
An Efficient Procedure for the
Diastereoselective Dehydration of
â-Hydroxy Carbonyl Compounds by
CeCl3‚7H O/NaI System
2
,†
,‡
Giuseppe Bartoli,* Maria C. Bellucci,† Marino Petrini,‡ Enrico Marcantoni,*
Letizia Sambri,† and Elisabetta Torregiani‡
Dipartimento di Scienze Chimiche, UniVersita` di Camerino, Via S. Agostino 1,
I-62032 Camerino, Italy, and Dipartimento di Chimica Organica “A. Mangini”,
UniVersita` di Bologna, Viale Risorgimento 4, I-40136 Bologna, Italy
enricom@camserV.unicam.it
Received March 7, 2000
ABSTRACT
The dehydration of â-hydroxy ketones and â-hydroxy esters is a synthetically useful method for the conversion of these compounds to the
corresponding r,â-unsaturated derivatives. Cerium(III) chloride heptahydrate in combination with sodium iodide in refluxing acetonitrile acts
as an efficient reagent for this conversion. The present procedure, which utilizes cheap and “friendly” reagents, offers the corresponding
(E)-enones in good yields as the only isolable products.
In the past decade we have been engaged in the chemistry
of cerium(III) chloride1 and, more recently, we have devel-
oped the combination of cerium(III) chloride heptahydrate
and sodium iodide as a promoter that facilitates a variety of
useful organic transformations. For example, the CeCl3‚
7H2O/NaI system in acetonitrile is an efficient reagent for
the cleavage of p-methoxybenzyl ethers in the presence of
benzyl ethers2 and for the deprotection of 1,3-dioxolanes3
and trialkylsilyl ethers.4 The nontoxic and water tolerant
features,5 the low cost and efficient activity in combination
with sodium iodide, make CeCl3 an attractive alternative to
classical Lewis acids such as TiCl4. Thus, recently, we have
discovered that CeCl3 is also an ideal Lewis acid for affecting
one-pot conversion of a hydroxy group into an iodo group.6
The synthesis of conjugated unsaturated carbonyl com-
pounds is of great importance since this functionality is one
of the most alluring structural units for synthetic organic
chemists.7 This bifunctional moiety is present in a large
number of molecules that are particularly important due to
their widespread occurrence in biologically essential com-
pounds.8 Moreover, the R,â-enones are important as inter-
mediates in many addition reactions of nucleophiles at the
† Universita` di Bologna.
‡ Universita` di Camerino.
(1) (a) Bartoli, G.; Marcantoni, E.; Petrini, M. Angew. Chem., Int. Ed.
Engl. 1993, 32, 1061-1062. (b) Bartoli, G.; Marcantoni, E.; Sambri, L.;
Tamburini, M. Angew. Chem., Int. Ed. Engl. 1995, 34, 2046-2048. (c)
Bartoli, G.; Marcantoni, E.; Petrini, M.; Sambri, L. Chem. Eur. J. 1996, 2,
913-918. (d) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Sambri,
L. Chem. Eur. J. 1997, 3, 1941-1950. (e) Bartoli, G.; Bosco, M.; Cingolani,
S.; Marcantoni, E.; Sambri, L. J. Org. Chem. 1998, 63, 3624-3630. (f)
Ballini, R.; Marcantoni, E.; Perrella, S. J. Org. Chem. 1999, 64, 2954-
2956. (g) Alessandrini, S.; Bartoli, G.; Bellucci, M. C.; Dalpozzo, R.;
Malavolta, M.; Marcantoni, E.; Sambri, L. J. Org. Chem. 1999, 64, 1986-
1993.
(4) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.; Torregiani, L.
Synlett 1998, 209-211.
(5) Imamoto, T. Lanthanides in Organic Synthesis; Academic Press: New
York, 1994.
(6) Bartoli, G.; Bellucci, M. C.; Bosco, M.; Di Deo, M.; Marcantoni,
E.; Sambri, L.; Torregiani, E. J. Org. Chem. 2000, 65, 2830-2833.
(7) (a) Perlmutter, P. Conjugated Addition Reactions in Organic Syn-
thesis; Pergamon Press: Oxford, 1992. (b) Ebenezer, W. J.; Wight, P. In
ComprehensiVe Organic Functional Group Transformation; Katritzky, A.
R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon Press: Oxford, 1995;
Vol. 3, pp 206-276.
(2) Bartoli, G.; Bellucci, M. C.; Bosco, M.; Cappa, A.; Marcantoni, E.;
Sambri, L.; Torregiani, E. J. Org. Chem. 1999, 64, 5696-5699.
(3) Bartoli, G. Bosco, M.; Marcantoni, E. Nobili, F.; Sambri, L. J. Org.
Chem. 1997, 62, 4183-4184.
10.1021/ol005766i CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/01/2000

â-position due to the inductive polarization of a carbonyl
group for organic synthesis.9 Therefore, several methods for
synthesis of these systems based on the formation of double
carbon-carbon bonds have been reported, and among them
the direct aldol condensation and related processes still
occupy a prominent position.10 However, many of these
methods require harsh reaction conditions or expensive and
toxic reagents or give poor yields and low selectivity. Thus,
although several subsequent modifications and alternatives
have alleviated many of these problems, there is still a need
for the development of selective and better strategies for the
dehydration of â-hydroxy carbonyl compounds.
Table 1. Dehydration of â-Hydroxy Carbonyl Compounds by
CeCl3‚7H2O/NaI System in Acetonitrile
We report herein a new and efficient combination of
reagents for the dehydration of â-hydroxy carbonyl com-
pounds by the use of the CeCl3‚7H2O/NaI system in
acetonitrile (Scheme 1).
Scheme 1
The reaction proceeds with excellent yields at reflux to
give R,â-enones of (E)-configuration as summarized in Table
1.11 Recently, we observed that during the conversion of
alcohols into the corresponding iodides by the CeCl3‚7H2O/
NaI system, a â-hydroxy carbonyl compound (1a) was
transformed into the corresponding R,â-unsaturated deriva-
tive via dehydration.12 Particularly interesting, this reaction
of dehydration also occurred when the carbonyl moiety was
protected as a 1,3-dioxolane (1b). Very probably the cleavage
of acetal3 is faster than hydroxyl substitution and the
â-hydroxy ketone intermediate immediately gives the cor-
(8) (a) Maehr, H.; Liu, C.-M.; Palleroni, N. J.; Smalleheer, J.; Todan,
L.; Williams, T. H.; Blount, J. F. J. Antibiot. 1986, 39, 17-21. (b) Corey,
E. J.; Li, W.; Nagamitsu, T. Angew. Chem., Int. Ed. 1998, 37, 1676-1679.
(c) Corey, E. J.; Li, W.; Reichard, G. A. J. Am. Chem. Soc. 1998, 120,
2330-2336. (d) Panek, J. S.; Masse, C. E. Angew. Chem., Int. Ed. 1999,
38, 1093-1096.
(9) Ji, S.-J.; Takahashi, E.; Takahashi, T. T.; Horiuchi, C. A. Tetrahedron
Lett. 1999, 40, 9263-9266.
(10) (a) Heathcock, C. H. In ComprehensiVe Carbanion Chemistry;
Buncel E., Durst, T., Eds.; Elsevier: Amsterdam 1984. (b) Mukaiyama, T.
Org. React. 1992, 28, 203-331.
a All starting materials were commercially available or were prepared
by conventional methods. b All products were identified by their IR, NMR,
and GC/MS spectra. c Yields of products isolated by column chromatog-
raphy.
(11) Representative experimental procedure: To a stirred suspension
of 4-hydroxy-4-phenylbutan-2-one (1c; 82 mg, 0.5 mmol) and cerium(III)
chloride heptahydrate (0.28 g, 0.75 mmol) in acetonitrile (5 mL) was added
sodium iodide (0.11 g, 0.75 mmol), and the resulting mixture was stirred
for 10 h at reflux. The reaction progress was monitored by withdrawing
aliquots which were analyzed by GC, and the products were identified by
GC-MS. The reaction mixture was diluted with ether and treated with 0.5
N HCl (10 mL). The organic layer was separated, and the aqueous layer
was extracted with ether (3 × 25 mL). The combined organic layers were
washed twice with an aqueous saturated NaHCO3 solution and a saturated
NaCl solution and dried over anhydrous Na2SO4. The extracts were then
concetrated under reduced pressure, and the residue was chromatographed
on a silica gel column (eluent: hexanes-ethyl acetate, 8:2) to give 65 mg
(89% yield) of the corresponding R,â-unsaturated enone as an oil.
(12) (a) Furstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 8746-
8749. (b) Larock, R. C. ComprehensiVe Organic Transformation; VCH
Publishers: New York, 1989; pp 167-172.
responding R,â-unsaturated ketone. Encouraged by these
results, we prepared and investigated a number of other
â-hydroxy carbonyl compounds to probe their behavior under
the current dehydration conditions. As shown in Table 1,
this simple methodology can be successfully applied to a
variety of â-hydroxy ketones and â-hydroxy esters, and in
particular, the relative increase in steric bulk of the carbo-
alkoxy moiety does not hamper their conversions to the
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Org. Lett., Vol. 2, No. 13, 2000

corresponding R,â-unsaturated esters (entry 11). On the other
hand, we observed that if the carboalkoxy group is a tert-
butyl ester, no selectivity is obtained and the tert-butyl ester
is also removed (entries 12 and 13). It has been observed
that in the case of a tertiary carbinol carbon (1j) a longer
reaction time is necessary (entry 10). Table 1 indicates that
a â-hydroxy carbonyl compound is also dehydrated in the
presence of a furan ring (entries 7 and 13), and no ring
opening reaction has been revealed. Moreover, in all cases
examined, the recovered R,â-unsaturated carbonyl com-
pounds are isolated with good yields, and the geometry of
carbon-carbon double bond is obtained with high dia-
stereoselection. In fact, our dehydration of the â-hydroxy
compound affords the (E)-isomer as the unique form
(determined by NMR analysis of the crude reaction mixture).
It is well documented13 that when the enone system is singly
R- or â-substituted the trans coupling constant is larger than
the cis coupling constant between the two olefinic hydrogens.
In addition, the ranges of the trans and cis coupling constants
are separate enough to allow unambiguous structural assign-
ment even if only one isomer is available. When, instead,
the olefin is trisubstituted, the configuration is assigned by
NOE experiments. Consequently, the NMR chemical shifts
provide a reliable guide for the assignment of the olefin
configuration.
The mechanism of the reaction is not very clear. Un-
doubtely the presence of NaI is essential for the process; in
fact the reaction carried out in its absence does not work. In
addition, we have not detected traces of the â-iodo carbonyl
compound by GC/MS analysis of the crude reaction mixture
after acetonitrile reflux of the mixture of â-hydroxy ester 1f
and the CeCl3‚7H2O/NaI system.
In conclusion, we have developed an efficient procedure
for the diastereoselective dehydration of â-hydroxy ketones
and â-hydroxy esters to the corresponding R,â-unsaturated
compounds. Our method shows that there are many advan-
tages to the use of the cerium(III) chloride heptahydrate/
sodium iodide system in acetonitrile: no strongly basic or
acidic conditions are employed, no expensive reagents are
required, and no precautions need to be taken to exclude
moisture or oxygen from the reaction system. Additional
studies to extend this methodology to other highly function-
alized R,â-unsaturated systems are currently underway and
will be reported in due course.
Acknowledgment. This research was carried out within
the framework of the National Project Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni supported by
the Ministry of University and Technological Research
(MURST), Rome, and by the University of Camerino.
(13) Dieter, R. K.; Silks, L. A.; Fishpaugh, J. R.; Kastner, M. E.; J. Am.
Chem. Soc. 1985, 107, 4679-4692. (b) Kackman, L. M.; Sternhell, S.
Application of Nuclear Magnetic Resonance Spectroscopy in Organic
Chemistry, 2nd ed.; Pergamon Press: London, 1969; pp 221-224.
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