CeCl3·7H2O-Nal Catalyzed Hydrooxacyclization of Unsaturated 3-Hydroxy Esters

Article abstract of DOI:10.1021/ol026955z

(Matrix Presented) Cerium(III) chloride heptahydrate and sodium iodide in boiling acetonitrile promote cyclization of 3-hydroxyalkenoic acids esters giving 5-substituted tetrahydrofuranacetic acid esters and 6-substituted tetrahydropyranacetic acid esters

Full text of DOI:10.1021/ol026955z

ORGANIC
LETTERS
2002
Vol. 4, No. 25
4451-4453
CeCl3‚7H O−NaI Catalyzed
2
Hydrooxacyclization of Unsaturated
3-Hydroxy Esters
Emanuela Marotta, Elisabetta Foresti,† Tommaso Marcelli, Francesca Peri,
Paolo Righi, Noemi Scardovi, and Goffredo Rosini*
Dipartimento di Chimica Organica “A. Mangini” and Dipartimento di Chimica
“G. Ciamician”, Alma Mater Studiorum, UniVersita` di Bologna, Italy
rosini@ms.fci.unibo.it
Received September 25, 2002
ABSTRACT
Cerium(III) chloride heptahydrate and sodium iodide in boiling acetonitrile promote cyclization of 3-hydroxyalkenoic acids esters giving
5-substituted tetrahydrofuranacetic acid esters and 6-substituted tetrahydropyranacetic acid esters in fair to good yield and with complete
retention of the absolute configuration of the starting 3-hydroxy ester.
Cerium(III) chloride heptahydrate1 has emerged as a very
cheap, water-tolerant, and “friendly” reagent, able to promote
a variety of selective functional group transformations.2,3 It
was found that the presence of sodium iodide reinforces its
activity.4 Our attention was drawn to the dehydration of
â-hydroxy ketones and esters that selectively give the
corresponding (E)-R,â-unsaturated derivatives.5
Herein, we report the results that originated from the
attempts to apply this method to the dehydration of 3-
hydroxyalkenoic acid esters.6 When 3-hydroxy-3,6-dimethyl-
6-heptenoic acid ethyl ester was subjected to the reported
protocols1.5 equiv of CeCl3‚7H2O and 1.5 equiv of NaI in
boiling acetonitrilesno doubly unsaturated ester was formed,
instead (2,5,5-trimethyltetrahydrofuran-2-yl)acetic acid ethyl
ester was isolated in 91% yield (eq 1).
† Dipartimento di Chimica “G. Ciamician”.
(1) Imamoto, T. Lanthanides in Organic Synthesis; Academic Press: New
York, 1994.
(2) (a) Denmark, S. E.; Nicaise, O. Synlett 1993, 359. (b) Ballini, R.;
Marcantoni, E.; Perrella, S. J. Org. Chem. 1999, 64, 2954. (c) Alessandrini,
S.; Bartoli, G.; Bellucci, M. C.; Dalpozzo, R.; Malavolta, M.; Marcantoni,
E.; Sambri, L. J. Org. Chem. 1999, 64, 1986. (d) Liu, H.-J.; Shia, K.-S.;
Shang, X.; Zhu, B.-Y. Tetrahedron 1999, 55, 3803. (e) Di Deo, M.;
Marcantoni, E.; Torreggiani, E.; Bartoli, G.; Bellucci, M. C.; Bosco, M.;
Sambri, L. J. Org. Chem. 2000, 65, 2830.
Several different substrates and conditions were then
studied. From the results reported in Table 1, it is rather
interesting to note the following: (i) the use of only 10%
equiv of CeCl3‚7H2O-NaI gave better results in terms of
both yields and practicality; (ii) it is the more substituted
(3) Sabitha, G.; Babu, R.-S.; Rajkumar, M.; Srividia, R.; Yadav, J. S.
Org. Lett. 2001, 3, 1149.
(4) (a) Bartoli, G.; Bellucci, M. C.; Bosco, M.; Cappa, A.; Marcantoni,
E.; Sambri, L.; Torreggiani, E. J. Org. Chem. 1999, 64, 5696. (b) Bartoli,
G.; Bosco, M.; Marcantoni, E.; Nobili, F.; Sambri, L. J. Org. Chem. 1997,
62, 4183. (c) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.; Torreggiani,
L. Synlett 1998, 209. (d) Marcantoni, E.; Massaccesi, M.; Torreggiani, E.;
Bartoli, G.; Bosco, M.; Sambri, L. J. Org. Chem. 2001, 66, 4430. (e) Sabitha,
G.; Babu, R.-S.; Rajkumar, M.; Reddy, C. S.; Yadav, J. S. Tetrahedron
Lett. 2001, 42, 3955. (f) Reddy, L. R.; Reddy, A. M.; Bhanumathi, N.;
Rao, K. R. Synthesis 2001, 831.
(6) (a) Marotta, E.; Righi, P.; Rosini, G. Org. Lett. 2000, 2, 4145. (b)
Marotta, E.; Righi, P.; Rosini, G. Org. Proc. Res. DeV. 1999, 3, 206. (c)
Rosini, G.; Confalonieri, G.; Marotta, E.; Rama, F.; Righi, P. Organic
Syntheses; Wiley: New York, 1997; Collect. Vol. IX, p 275 and references
therein.
(5) Bartoli, G.; Bellucci, M. C.; Petrini, M.; Marcantoni, E.; Sambri, L.;
Torreggiani, E. Org. Lett. 2000, 2, 1791.
10.1021/ol026955z CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/16/2002

6-exo-trig, and 6-endo-trig) according to the Baldwin’s rules;7
(iv) 1c and 1f undergo a stereospecific cyclization and afford
the corresponding products 2c and 2f as only one stereo-
isomer; and (v) the ester group seems to play an important
role (entries 9 and 10). However, substrates such as 1k and
1l were recovered unchanged after treatment with CeCl3‚
7H2O-NaI in boiling acetonitrile (entries 11 and 12).
Table 1. Hydrooxacyclization of Unsaturated â-Hydroxy
Derivatives by CeCl3‚7H2O-NaI in Boilng Acetonitrile
Tetrahydrofurans and tetrahydropyrans8 are found in many
natural products of biological interest and the preparation
of such important subunits is still a challenge for synthetic
chemists in order to find safer and milder conditions utilizing
more “friendly” reagents as well as to have good selectivity
and efficiency. Therefore, several experiments with Ce(III)
halides have been performed to gain more insights on the
cyclization of these three-functionalized substrates. The main
results are summarized in Table 2.
Table 2. Results Observed with a Variety of CeX3 in Different
Reaction Conditions
Ce(III) halide
entry
(0.1 equiv)
CH3CN,a ∆
yield (%)
1
2
3
4
5
6
7
CeCl3‚7H2O-NaI
CeCl3 + NaI
CeCl3‚7H2O
CeBr3
CeI3
CeI3
74
24
traceb
44
22
62
60
dried-dist.
dried-dist.
CeI3
dried-dist. + H2O
(0.7 equiv)
a Freshly opened bottle of ACS reagent-grade acetonitrile for 21 h used
in N2 atmosphere when not otherwise specified. b With recovery of 1d.
They indicate the following: (i) both CeCl3‚7H2O and NaI
are necessary (entries 1 and 3); (ii) CeCl3‚7H2O alone gave
only a trace amount of the oxacyclic product with almost
complete recovery of the starting material (entry 3); (iii) a
dramatic drop in yield has been observed when anhydrous
CeCl3 and NaI were used in anhydrous boiling acetonitrile
(entry 2); (iv) anhydrous CeI3 is able to promote cyclization
in the absence of NaI and is more efficient when used in
boiling wet acetonitrile (entries 5, 6, and 7); and (iv)
similarly, CeBr3 induces cyclization in the same reaction
conditions but is less effective when compared with CeI3
(entry 4).
The CeCl3‚7H2O-NaI (10% equiv) cyclization of (R)-3-
hydroxy-6-octenoate 1h9 in boiling acetonitrile gave, after
ester hydrolysis, the carboxylic acid (-)-3 (Scheme 1).
(7) Baldwin, J. E.; Kruse, L. I. Chem. Commun. 1977, 233.
(8) For recent reviews, see: (a) Faulkner, D. J. Nat. Prod. Rep. 2001,
18, 1. (b) Koert, U. Synthesis 1995, 115. (c) Harmange, J. C.; Figadere, B.
Tetrahedron: Asymmetry 1993, 4, 1711. (d) Boivin, T. L. B. Tetrahedron
1987, 43, 3309.
olefinic carbon atom to undergo cyclization; (iii) all the
cyclization processes gave faVored ring closures (5-exo-trig,
4452
Org. Lett., Vol. 4, No. 25, 2002

have made. In particular it is not clear why an acid-catalyzed
mechanism should prevent substrates 1f and 1j-l from
cyclizing; and the crucial role of water is not understood
(Table 2, entries 5-7). The mechanism might involve an
oxyceriation of the double bond.12
Scheme 1. Asymmetric Synthesis of (R)-1h and (-)-3
In conclusion, the results reported here show that this
CeCl3‚7H2O-NaI catalyzed cyclization is of general ap-
plicability for 3-hydroxyalkenoic acid esters. This procedure
makes use of an inexpensive catalyst under mild reaction
conditions. Moreover, the ability to maintain the absolute
configuration of the starting 3-hydroxyalkenoate and the easy
availability of these substrates in enantiomerically pure form
are two important aspects. Additionally, this cyclization can
generate stereogenic centers with a high degree of control
(Table 1, entries 2, 3, and 6).
It is also worth noting that the starting 3-hydroxy alkenoic
acid esters could have undergone at least three different
known reactions promoted by CeCl3‚7H2O-NaI and claimed
as general the following: the conversion of the hydroxy
group into the corresponding iodine derivative,2e the ester
hydrolysis to a free carboxylic acid,4 and more important,
the 1,2-dehydratation of the 3-hydroxy ester to the R,â-
unsaturated ester.5 Instead, a new hydrooxacyclization took
place affording tetrahydrofurans and pyrans, without the
formation of any byproduct arising from the alternative
known transformations.
This latter was converted into the corresponding enan-
tiopure acetamide by reaction with (S)-phenylethylamine, in
the presence of cyanuric chloride10 and triethylamine. The
absolute configuration of compound A was assigned by X-ray
diffraction analysis11 (Figure 1). Therefore, the CeCl3‚7H2O-
These remarks call to mind the words of Professor R. B.
Woodward “...One finds, for example, that there are no
general reactions. And each case has to be studied, carefully,
experimentally. That’s the glory of chemistrysthat it is an
experimental science. And it will remain that for a long time
to come.”13
Figure 1. X-ray crystal structure of A.
Acknowledgment. This work was supported by the
Ministero dell’Istruzione, dell’Universita` e della Ricerca
(MIUR, Programma di Ricerca “Stereoselezione in Sintesi
Organica. Metodologie ed Applicazioni”), Italy, the Consiglio
Nazionale delle Ricerche (CNR), Italy, and the Universita`
di Bologna, Italy (Progetto d’Ateneo: Metodologie sintetiche
a basso impatto ambientale).
NaI catalyzed cyclization occurs with retention of the
absolute configuration of the starting 3-hydroxy esters.
Further studies are necessary to understand better the
possible mechanism of this CeCl3‚7H2O-NaI catalyzed
cyclization, and especially if the cerium plays an active role
in this process. However, a simple Broensted acid (HI)
catalyzed mechanism cannot explain all the observations we
Supporting Information Available: Descriptions of
experimental procedures and selected characterization data,
and X-ray crystal structures and data for compounds A and
B. This material is available free of charge via the Internet
at http://pubs.acs.org.
(9) (a) Hirama, M.; Shimizu, M.; Iwashita, M. Chem. Commun. 1983,
599. (b) Hirama, M.; Shimizu, M.; Iwashita, M. J. 2.1.12; Bakers’ yeast
reduction of â-keto carboxylic acids salt. In PreparatiVe Biotransformations;
Roberts, S. M., Ed; University of Exeter: Exeter, UK; Wiley ISBN 0 471
929867.
(10) Baccolini, G.; Caglioti, L.; Poloni, M.; Rosini, G. La Chim., l’Ind.
(Milano) 1969, 51, 287 (Chem. Abstr. 1970, 72, 3441s). For recent
utilizations of this method, see: (a) Rayle, H. L.; Fellmeth, L. Org. Proc.
Res. DeV. 1999, 3, 172. (b) Kaminski, Z. J.; Paneth, P.; Rudzinki, J. J.
Org. Chem. 1998, 63, 4248.
(11) Crystal data for A: orthorombic system, space group P212121, a )
9.4582(7) Å, b ) 11.2046(9) Å, c ) 15.389(1) Å, V ) 1630.8(2) Å3, Z )
4, Fcalc ) 1.122 Mg/m3, R ) 0.0559 (Rw ) 0.1142) for 1813 observed
reflections (170 parameters) with I > 2σI. Goodness of fit ) 0.975.
OL026955Z
(12) A similar process of “oxyindiation” and referred to “an additive
incorporation of an oxygen and indium across a double bond” has been
proposed recently: Loh, T.-P.; Hu, Q.-Y.; Ma, L.-T. J. Am. Chem. Soc.
2001, 123, 2450.
(13) Woodward, R. B. In Proceedings of the Robert A. Welch Foundation
Conference on Chemical Research, XII. Organic Synthesis; Milligan, W.
O., Ed.; Huston, TX, 1969; pp 3-6.
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