An efficient procedure for the preparation of (E)-α-alkylidenecycloalkanones mediated by a CeCl3·7H2O-NaI system. Novel methodology for the synthesis of (S)-(-)-pulegone

Article abstract of DOI:10.1021/jo026418s

2-Alkylidenecycloalkanones are powerful synthons used as the key intermediates in many important syntheses. Because of their potential, a general method of preparation from readily available starting materials, under very mild conditions, was considered to be worthwhile. Cerium(III) chloride heptahydrate in combination with sodium iodide in refluxing acetonitrile promotes a regio- and stereoselective β-elimination reaction to (E)-2-alkylidenecycloalkanones in 2-(1-hydroxyalkyl)cycloalkanones. The synthetic value of the present procedure is demonstrated by the synthesis of monoterpene (S)-(-)-pulegone (8) in its optically active form.

Full text of DOI:10.1021/jo026418s

â-hydroxy ketones to the corresponding R,â-unsaturated
compounds.8 Thus, given the importance of this bifunc-
tional moiety present in many biologically important
compounds,9 we considered the possibility of using our
procedure as a versatile and practical system for promot-
ing the formation of 2-alkylidenecycloalkanones. In fact,
2-alkylidenecycloalkanones are frequently present in the
skeleton of biologically active natural products,10 and
during the past decade many efforts have been devoted
to the development of efficient methodologies for their
preparation.11 The acid- or base-activated dehydration
reaction of 2-(1-hydroxyalkyl)cycloalkanones is the clas-
sical method for the preparation of these derivatives.12
Many reported procedures suffer from one or more
drawbacks: lack of selectivity, unsatisfactory yields,
costly or toxic reagents, need for anhydrous conditions,
and, in some cases, unavoidable side reactions such as
double-bond isomerization and Michael-type reaction.
Thus, there is still the need to devise an alternative
method that is simultaneously friendly and inexpensive
and affords good-to-excellent yields for carrying out the
conversion of hydroxy cycloalkanones into 2-alkylidenecy-
cloalkanones. We report now the CeCl3‚7H2O-NaI-
promoted dehydration of 2-(1-hydroxyalkyl)cycloalkanones,
devoid of exo-endo isomerization, as an attractive strat-
egy, as an alternative to existing methods for the
synthesis of 2-alkylidene cyclic carbonyl compounds. As
well, we report the application of this reaction to a new
and short asymmetric total synthesis of the (S)-(-)-
pulegone, a monoterpene utilized as a particularly ac-
tractive chiral starting material for the synthesis of more
complex natural products.13
An Efficien t P r oced u r e for th e P r ep a r a tion
of (E)-r-Alk ylid en ecycloa lk a n on es
Med ia ted by a CeCl3‚7H2O-Na I System .
Novel Meth od ology for th e Syn th esis of
(S)-(-)-P u legon e1
Giuseppe Bartoli,† Marcella Bosco,† Renato Dalpozzo,‡
Arianna Giuliani,§ Enrico Marcantoni,*,§
Tiziana Mecozzi,§ Letizia Sambri,† and
Elisabetta Torregiani§
Department of Chemical Sciences, University of Camerino,
via S. Agostino 1, I-62032 Camerino (MC), Italy,
Department of Organic Chemistry “A. Mangini”, University
of Bologna, viale Risorgimento 4, I-40136 Bologna, Italy,
and Department of Chemistry, University of Calabria,
I-87030 Arcavacata di Rende (CS), Italy
enrico.marcantoni@unicam.it
Received September 8, 2002
Abstr a ct: 2-Alkylidenecycloalkanones are powerful syn-
thons used as the key intermediates in many important
syntheses. Because of their potential, a general method of
preparation from readily available starting materials, under
very mild conditions, was considered to be worthwhile.
Cerium(III) chloride heptahydrate in combination with
sodium iodide in refluxing acetonitrile promotes a regio- and
stereoselective â-elimination reaction to (E)-2-alkylidenecy-
cloalkanones in 2-(1-hydroxyalkyl)cycloalkanones. The syn-
thetic value of the present procedure is demonstrated by the
synthesis of monoterpene (S)-(-)-pulegone (8) in its optically
active form.
As previously reported, CeCl3‚7H2O-NaI system pro-
motes the dehydration of acyclic â-hydroxy carbonyl
compounds in refluxing acetonitrile.8 Accordingly, we
wanted to apply the same â-dehydration conditions to the
conversion of 2-(1-hydroxyalkyl)cycloalkanones 1 into
2-alkylidenecycloalkanones 2 (Scheme 1). The 2-(1-hy-
droxypropyl)cyclohexanone (1a ) was examined as the
model substrate. A ca. 0.1 M solution of 1a in acetonitrile
The development of new and general strategies for the
synthesis of biologically important natural and unnatural
substances constitutes an outstanding field of interest
in organic chemistry. In this context, we have been
recently engaged in the chemistry of cerium(III) chloride
to affect a facile construction of various biologically active
molecules.2,3 In the past decade, in fact, cerium trichloride
has attracted recent attention for its low toxicity, low cost,
and water-tolerance as a reagent.4 We recently reported
the use of this trivalent lanthanide salt in reactions that
need the presence of a Lewis acid activator.2,3,5 Moreover,
we have found that CeCl3‚7H2O combined with sodium
iodide acts as an efficient reagent in the cleavage of
carbon-oxygen6 and silicon-oxygen7 bond under neutral
conditions. In particular, we recently reported an efficient
procedure for the diastereoselective dehydration of acyclic
(5) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Petrini, M.; Sambri,
L.; Torregiani, E. J . Org. Chem. 2001, 66, 9052-9055. (b) Badioli, M.;
Ballini, R.; Bartolacci, M.; Bosica, G.; Marcantoni, E. Torregiani, E. J .
Org. Chem. 2002, submitted for publication, and references therein.
(6) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Nobili, F.; Sambri, L.
J . Org. Chem. 1997, 62, 4183-4184. (b) Bartoli, G.; Bellucci, M. C.;
Bosco, M.; Cappa, A.; Marcantoni, E.; Torregiani, E. J . Org. Chem.
1999, 64, 5696-5699. (c) Bartoli, G.; Bellucci, M. C.; Bosco, M.; Di Deo,
M.; Marcantoni, E.; Sambri, L.; Torregiani, E. J . Org. Chem. 2000,
65, 2830-2833. (d) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi,
M.; Sambri, L.; Torregiani, E. J . Org. Chem. 2001, 66, 4430-4432.
(7) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.; Torregiani,
E. Synlett 1998, 209-211.
* To whom correspondence should be addressed. Phone: +39 0737
402255. Fax: +39 0737 637345.
(8) Bartoli, G. Bellucci, D. C.; Marcantoni, E.; Petrini, M.; Sambri,
L.; Torregiani, E. Org. Lett. 2000, 2, 1791-1793.
† University of Bologna.
‡ University of Calabria.
(9) (a) Corey, E. J .; Li, W.; Reichard, G. A. J . Am. Chem. Soc. 1998,
120, 2330-2336. (b) Panek, J . S.; Masse, C. E. Angew. Chem., Int. Ed.
1999, 38, 1093-1095.
§ University of Camerino.
(1) (a) The IUPAC name for (S)-pulegone is (5S)-5-methyl-2-(1-
methylethylidene)cyclohexanone. (b) Presented in part at the XXVII
Organic Chemistry Division National Meeting, Trieste; Italian Chemi-
cal Society: Rome, 2001; P080.
(2) Marcantoni, E.; Bartoli, G.; Bosco, M.; Sambri, L.; Dalpozzo, R.;
De Nino, A. J . Org. Chem. 1998, 63, 3745-3747.
(3) Marcantoni, E.; Massaccesi, M.; Petrini, M.; Bartoli, G.; Bellucci,
M. C.; Bosco, M.; Sambri, L. J . Org. Chem. 2000, 65, 4553-4559.
(4) (a) Imamoto, T. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I, Screiber, S. L., Eds.; Pergamon Press: Oxford, 1991;
Vol. 4, pp 231-250. (b) Molander, G. A. Chem. Rev. 1992, 92, 29-68.
(c) Imamoto, T. Lanthanides in Organic Synthesis; Academic Press:
London, 1994.
(10) Liebeskind, L. S.; Chidambaram, R.; Mitchell, D. Pure Appl.
Chem. 1988, 60, 27-35 and references therein.
(11) (a) Ijima, A.; Takahashi, K. Chem. Pharm. Bull. 1973, 21, 215-
219. (b) Ksander, G. M.; McMurry, J . E.; J ohnson, M. J . Org. Chem.
1977, 42, 1180-1185. (c) Renvers, J . T. A.; De Groot, A. Synthesis 1982,
1105-1107. (d) Nakano, T.; Irifune, S.; Umano, S.; Inada, A.; Ishii,
Y.; Ogawa, M. J . Org. Chem. 1987, 52, 2239-2244. (e) Enholm, E. J .;
Whitley, P. E.; Xie, Y. J . Org. Chem. 1996, 61, 5384-5390. (f) Clive,
D. L. J .; Huang, X. Tetrahedron 2001, 57, 3845-3858.
(12) Ebenezer, W. J .; Wight, P. In Comprehensive Organic Func-
tional Group Transformation; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Eds.; Pergamon Press: Oxford, 1995; Vol. 3, pp 219-220.
10.1021/jo026418s CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/20/2002
J . Org. Chem. 2002, 67, 9111-9114
9111

TABLE 1. Deh yd r a tion of
SCHEME 1
2-(1-Hyd r oxya lk yl)cycloa lk a n on es by CeCl3‚7H2O-Na I
System in Reflu xin g Aceton itr ile
containing 1.5 equiv of CeCl3‚7H2O and 1.5 equiv of NaI
was heated at reflux temperature. After 24 h at reflux
temperature, only 35% dehydration was detected. Un-
fortunately, attempts to extend reactions times allowed
only little improvement in yield of the desired product
2a , which resulted in contamination by impurities after
even longer reaction times (72 h at reflux). In an effort
to improve the dehydration by increasing the solubility
of CeCl3‚7H2O in acetonitrile (ca. 3 g/100 mL), the CeCl3‚
7H2O-NaI mixture was refluxed in acetonitrile for 24
h. When this mixture was added to substrate 1a and
refluxed for 24 h, a 58% yield of the desired of R-alkyl-
idenecyclohexanone 2a was obtained. We repeated this
procedure with different [CeCl3‚7H2O]/[NaI]/[1a ] ratios.
Complete conversion was obtained after 1.5 h of refluxing
in acetonitrile and using 3.2 equiv of CeCl3‚7H2O and 3.2
equiv of NaI (entry 1, Table 1). A quite simple procedure
for dehydration of â-hydroxy cyclohexanone 1a was then
setup. A suspension of CeCl3‚7H2O-NaI in acetonitrile
was refluxed for 24 h; after the mixture was cooled, the
substrate was added and this mixture stirred at reflux
temperature until TLC or GC indicated the disappear-
ance of starting materials. Usual workup and evaporation
of solvent followed by purification through a short silica
gel column chromatography14 furnished the pure 2-pro-
pylidenecyclohexanone (2a ).
This procedure was applied to a wide range of â-hy-
droxy cycloalkanones (1b-j, Table 1), easily prepared by
aldol condensation of cycloalkanones with various alde-
hydes or ketones.15 In all cases the reaction works well,
leading to the desired 2-alkylidenecycloalkanones (2b-
j, Table 1) in very high yields without the occurrence of
complicating retroaldol reactions. The conversion pro-
ceeds smoothly, but if the reaction is carried out with
less than 3.2 equiv of the CeCl3‚7H2O-NaI system, the
process becomes slower and the dehydration is not
complete even for prolonged reaction times. This ac-
celeration effect caused by addition of more than a
stoichiometric quantity is in agreement with Fukuzawa’s
results.16 We believe, in fact, that in our conditions of a
halogen exchange reaction (eq 1), the species CeCl(3 - n)In
formed shows an enhanced activity in dehydration.
a
All starting materials were prepared by aldol condensation of
cycloalkanones with various carbonyl compounds according to ref
b
22. All products were identified by their IR, NMR, and GC/MS
spectra. c Yields of products isolated by column chromatography.
d
No selectivity was obtained, and the migration of the double bond
CeCl3 + nNaI f CeCl(3 - n)In + nNaI
(1)
also occurred. e E/ Z ) 88:12 as determined by NMR.
Attempts to replace acetonitrile with several alterna-
tive solvents, including THF, ether, dichloromethane,
DMF, DME, and nitromethane invariably led to lower
yields. As shown in Table 1, the efficiency of the proce-
dure is not influenced of ring size of cycloalkanones
(entries 1, 3, and 4, Table 1). The reaction was success-
fully applied to secondary or tertiary hydroxyl derivatives
(entries 1 and 10, Table 1), while primary 2-(1-hydroxy-
alkyl)cycloalkanones presented problems due to the high
instability of R-methylenecycloalkanone derivatives, which
(13) (a) Walinsky, J .; Gibson, T.; Chan, D.; Wolf, H. Tetrahedron
1965, 21, 1247-1261. (b) Corey, E. J .; Eusley, H. E. J . Am. Chem.
Soc. 1975, 97, 6908-6909. (c) Corey, E. J .; Eusley, H. E.; Suggs, J . W.
J . Org. Chem. 1976, 41, 380-381. (d) Eusley, E. J .; Carr, R. V. C.
Tetrahedron Lett. 1977, 18, 513-516. (e) Wuest, J . D.; Madonik, A.
M.; Gordon, D. C. J . Org. Chem. 1977, 42, 2111-2113. (f) Sato, T.;
Kawara, T.; Nishizawa, A.; Fujisawa, T. Tetrahedron Lett. 1980, 21,
3377-3380. (g) Szabo, W. A.; Lee, H. T. Aldrichimica Acta 1980, 3,
13-21. (h) Caine, D.; Procter, K.; Cassell, R. A. J . Org. Chem. 1984,
49, 2647-2648. (i) Whitesell, J . K.; Liu, C.-L.; Buchanan, C. M.; Chen,
H.-H.; Minton, M. A. J . Org. Chem. 1986, 51, 551-553 (j) Ferna´ndez,
F.; Garcia-Mera, X.; Lo´pez, C.; Rodriguez, G.; Rodriguez-Borges, J . E.
Tetrahedron: Asymmetry 2000, 11, 4805-4815 and references therein.
(k) J ia, V. X.; Wu, B.; Li, X.; Ren, S. K.; Tu, Y. Q.; Chan, A. S. C.;
Kitching, W. Org. Lett. 2001, 3, 847-849.
(14) It is known that R-alkylidene cyclic carbonyl compounds are
isomerized to their R,â-unsatured cyclic isomers on slow silica gel
chromatography (McMurry, J . E.; Donovan, S. F. Tetrahedron Lett.
1977, 18, 2869-2872).
(15) Heathcock, C. H.; Buse, C. T.; Kleschick, W. A.; Pirrung, M.
C.; Sohn, J . E.; Lampe, J . J . Org. Chem. 1980, 45, 1066-1081.
(16) (a) Fukuzawa, S.; Fujinami, T.; Sakai, S. J . Chem. Soc., Chem.
Commun. 1985, 777-778. (b) Fukuzawa, S.; Tsuruta, T.; Fujinami,
T.; Sakai, S. J . Chem. Soc., Perkin Trans. 1 1987, 1473-1477.
9112 J . Org. Chem., Vol. 67, No. 25, 2002

SCHEME 2
ylsilyl (TMS) ether was carried out by reaction of 4 with
trimethylchlorosilane in the presence of triethylamine in
THF at reflux temperature.20 To this point, the stereo-
chemical features of 4 suggest the possibility of using an
asymmetric conjugate addition to 5. In fact, it is reported
in the literature, that the conjugate addition of organo-
metallic reagents to electron-deficient olefins constitutes
one of the versatile methodologies for forming new
carbon-carbon bonds. Although considerable efforts have
been made to develop efficient chiral promoter systems
for asymmetric conjugate addition, successful examples
are rare in terms of enantioselectivity and generality.21
Nevertheless, in the past decade, Tomioka and co-
workers22 found that the conjugate addition of lithium
cuprates to R,â-unsaturated ketones to obtain â-substi-
tuted ketones is highly controllable using the chiral
bidentate amidophosphine ligands. Following this strat-
egy, we have planned to create the stereogenic center of
the target pulegone 8 through the addition of a methyl
organocopper reagent in the presence of a chiral phos-
phine. Thus, the asymmetric conjugate addition reaction
of lithium dimethylcyanocuprate, generated from 3.5
equiv of methyllithium and 1.5 equiv of copper cyanide
and in the presence of lithium bromide (12 equiv) in
ether, with cyclohexenone derivative 5 was carried out
in the presence of pivaloylamidophosphine 6. The usual
workup and purification by silica gel column chromatog-
raphy afforded (S)-methyl adduct 7 in 95% isolated
yield.23
Finally, the dehydration of 7 using our combination
system of CeCl3‚7H2O-NaI in acetonitrile at reflux
temperature for 1.5 h afforded (S)-(-)-pulegone (8) in 89%
yield. Under these simple conditions, the desilylation was
fast accomplished,7 and the â-hydroxycyclohexanone
intermediate immediately gave the corresponding 2-alkyl-
idenecyclohexanone 8. The absolute configuration was
determined by the specific rotation of the purified prod-
uct. The value found ([R]D -23° (c 2, abs. EtOH)) is almost
in agreement with the one reported in the literature ([R]D
-24° (c 2, abs. EtOH)),13d indicating a good enantiose-
lective conjugate addition of lithium organocuprate. The
enantiomeric excess (93% ee) was verified by GC analysis
of the corresponding diastereomeric ketal24 with (2S,3S)-
(-)-diethyl tartrate bis-trimethylsilyl ether25 by Noyori’s
method,26 under conditions where double-bond migration
is not usually observed. The diastereomeric purity of
ketal was assumed to be identical to the enantiomeric
purity of 5-methyl-2-(1-methylethylidene)cyclohexanone.
In conclusion, we have shown that the conversion of
2-(1-hydroxyalkyl)cycloalkanones, which are well recog-
nized as versatile and powerful synthons, into 2-alkyl-
a
Reagents and conditions: (a) (i) LDA, THF, -78 °C; (ii)
(CH3)2CO, CeCl3, THF, -78 °C, 74%. (b) Me3SiCl, Et3N, THF,
reflux 7.5 h, 88%. (c) CH3Li, CuCN, LiBr, pivaloylamidophosphine
19, Et2O, -78 °C, 95%. (d) CeCl3‚7H2O, NaI, CH3CN, reflux, 1 h,
89%.
are notoriously highly reactive and undergo facile Michael-
type reactions.17
The formation of the carbon-carbon double bond was
highly stereoconvergent, the (E)-isomer always being
obtained, independently from the stereochemistry of
substrate. Indeed, in all cases, the mixture of threo- and
erythro-â-hydroxy ketones 1, obtained by aldol condensa-
tion, gave only the corresponding enones 2 in (E)-
configuration. In fact, in the case where we separated
threo and erythro diastereomers of 2-(1-hydroxypropyl)-
cyclopentanone (1d ) by column chromatography, their
independent dehydration led to (E)-R,â-unsaturated cy-
clopentanone 2d as the unique product. In all cases, the
(E)-geometry was established by the characteristic chemi-
cal shifts of 13C NMR and by the H NMR signal of the
1
vinyl hydrogen.11f
It should be noted that the reaction is poorly efficient
for compound 1h (entry 8, Table 1), only 14% of expected
alkylidene derivative 2h being isolated after 1 h. In this
case, besides the 2h product, we observed the formation
of a mixture of endo-isomers that accounted for 62% of
the reaction. When pure 2h exo-compound is treated with
CeCl3‚7H2O-NaI at reflux in acetonitrile, a smooth
isomerization to the more stable endo-derivative occurs.
On the other hand, we never observed any isomerization
phenomena in structural isomers of 2h , without R′-alkyl
substituents (2f and 2g) as well as in the presence of two
methyl groups in R′-position (2i).
To better evaluate the usefulness of the present
methodology, we focused our attention on the synthesis
of a synthetically important alkylidene intermediate,
such as (S)-(-)-pulegone (8).18 For this purpose, we began
with the synthesis of 6-(1-hydroxy-1-methylethyl)cyclo-
hex-2-en-1-one (4), which was accomplished (Scheme 2)
by aldol condensation of cyclohexanone 3 with acetone.
Thus, cyclohexenone 3 was converted to the R-lithium
enolate by reaction in THF with lithium diisopropylamide
(LDA) at -78 °C and transferred by cannula to a mixture
of acetone and anhydrous CeCl3 in THF at -78 °C19 to
afford the desired â-hydroxy ketone 4 in 74% yield. The
subsequent protection of the hydroxyl group as trimeth-
(19) (a) Imamoto, T.; Kusumoto, T.; Yokoyama, M. Tetrahedron Lett.
1983, 24, 5233-5236. (b) Imamoto, T.; Takiyama, N.; Nakamura, K.;
Hatajima, T.; Kamiya, Y. J . Am. Chem. Soc. 1989, 111, 4392-4398.
(c) Liu, H. J .; Al-Said, N. H. Tetrahedron Lett. 1991, 32, 5473-5476.
(d) Shang, X.; Liu, H. J . Synth. Commun. 1994, 24, 2485-2489. (e)
Shang, X.; Liu, H. J . Synth. Commun. 1995, 25, 2155-2159.
(20) (a) Maurer, P. J .; Kundsen, C. G.; Palkowitz, A. D.; Rapoport,
H. J . Org. Chem. 1985, 50, 325-332. (b) Ballester, P.; Capo, M.;
Garcias, X.; Saa, J . M. J . Org. Chem. 1993, 58, 328-334.
(21) For a pertinent review, see: Tomioka, K.; Nagaoka, Y. In
Comprehensive Asymmetric Catalysis; J acobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: New York, 1999; Vol. 3, pp
1105-1120.
(22) (a) Kanai, M.; Tomioka, K. Tetrahedron Lett. 1994, 35, 895-
898. (b) Nakagawa, Y.; Kanai, M.; Tomioka, K.; Nagaoka, Y. Tetrahe-
dron 1998, 54, 10295-10307. (c) Kanai, M.; Nakagawa, Y.; Tomioka,
K. Tetrahedron 1999, 55, 3831-3842. (d) Kanai, M.; Nakagawa, Y.;
Tomioka, K. Tetrahedron 1999, 55, 3843-3854.
(23) The absolute configuration was assigned on the basis of the
absolute configuration of the final (S)-(-)-pulegone (8).
(17) (a) Nakahira, H.; Ryu, I.; Ikebe, M.; Oku, Y.; Ogawa, A.; Kambe,
N.; Sonoda, N.; Murai, S. J . Org. Chem. 1992, 57, 17-28. (b) Magnus,
P.; Lan, S. Tetrahedron 1999, 55, 3553-3560.
(18) (a) Buschmann, H.; Scharf, H.-D. Synthesis 1988, 827-830. (b)
Wartheu, J . D.; Lee, C.-J .; J ang, E. B.; Lance, D. R.; Mcinnis, D. O. J .
Chem. Ecol. 1997, 23, 1891-1900. (c) Differences between (R)-pulegone
3 and (S)-pulegone 4 in methabolism in mammals are known too
(Madyastha, K. M.; Geikwad, N. W. Xenobiotica 1998, 28, 723-734).
J . Org. Chem, Vol. 67, No. 25, 2002 9113

(5S)-2-[1-(Tr im eth ylsilyloxy)-1-m eth yleth yl]-5-m eth ylcy-
cloh exa n on e (7). A solution of methyllithium (2.37 mL of 1.3
M ether, 3.08 mmol) was added to a suspension of CuCN (0.12
g, 1.32 mmol) and LiBr (0.92 g, 10.56 mmol) in ether (10 mL),
and the whole was stirred at -20 °C for 20 min. A solution of 6
(0.53 g, 1.51 mmol) in ether (4 mL) was added at -78 °C, and
the resulting mixture was stirred for 20 min at the same
temperature. Then, a solution of 5 (0.2 g, 0.88 mmol) in ether (6
mL) was added dropwise, and the mixture was stirred at -78
°C for 0.5 h. A mixture of 10 mL of saturated aqueous NH4Cl
and 10 mL of 23% NH4OH was added, and the mixture was
stirred for 30 min. After extraction with ether (3 × 25 mL), the
extracts were washed successively with a saturated solution of
NaHCO3 and brine and finally dried. The crude product 7 (0.20
g, 95%) was used in the next stage of preparation without
purification: IR (neat, cm-1) 1715; 1H NMR δ 0.14 (s, 6H), 0.16
(s, 3H), 1.06 (d, 3H, J ) 6,74 Hz), 1.32 (s, 6H), 1.38-1.45 (m,
2H), 1.78-1.86 (m, 1H), 2.00-2.56 (m, 5H); 13C NMR δ 14.75,
18.88, 20.88, 21.65, 25.82, 27.65, 33.78, 34.65, 47.81, 55.95, 80.34,
209.32; EI-MS m/z 227, 184, 169, 131 (100), 75, 73, 55, 43. Anal.
Calcd for C13H26O2: Found: C, 72.84; H, 12.23. Found: C, 72.79;
H, 12.18.
idenecycloalkanones via â-dehydration is promoted by a
CeCl3‚7H2O-NaI system in acetonitrile. The mildness of
the reaction conditions avoids side reactions such as
carbon-carbon double-bond isomerization and Michael-
type reactions, which often follow this type of acid- or
base-catalyzed dehydration. The simplicity of our proce-
dure, the use of cerium(III) compounds as environmen-
tally friendly reagents,27 the low cost of reagents, and the
high yield of R,â-enone products make the present
reaction highly synthetically useful. Further investiga-
tions of our reagent system in new schemes of synthesis
for the preparation of other biologically important sub-
stances are in progress in our laboratories.
Exp er im en ta l Section
NMR spectra were recorded in CDCl3 solutions at 300 MHz
(1H) and 75.5 MHz (13C). Mass spectra were determined by
means of the EI technique (70 ev). IR absorption spectra were
recorded with thin films on NaCl plates, and only noteworthy
absorptions (cm-1) are listed. All air- or moisture-sensitive
reactions were carried out in flame-dried glassware under an
atmosphere of N2. All solvents were dried and distilled according
to standard procedures.
(5S)-5-Meth yl-2-(1-m eth yleth yliden e)cycloh exan on e [(S)-
(-)-P u legon e] (8). A suspension of CeCl3‚7H2O (0.6 g, 1.6
mmol) and NaI (0.24 g, 1.6 mmol) in acetonitrile (7.5 mL) was
stirred at reflux temperature for 24 h. Compound 7 (0.12 g, 0.5
mmol) was then added, and the resulting mixture was refluxed
under stirring for 1 h (until no starting material remained, as
monitored by TLC and GC). After being cooled to room temper-
ature, the reaction mixture was diluted with Et2O and treated
with 0.5 N HCl (20 mL). The organic layer was separated, and
the aqueous layer was extracted with Et2O (4 × 40 mL). The
combined organic layers were washed with water, a saturated
solution of NaHCO3, and brine and dried. The crude product
was purified by fast flash column chromatography (10% EtOAc-
6-(1-Hyd r oxy-1-m eth yleth yl)cycloh ex-2-en -1-on e (4). In
a 250 mL three-necked round-bottom flask equipped with a
magnetic stirrer and condenser, a dropping funnel of finely
ground CeCl3‚7H2O (2.60 g, 6.97 mmol) was dried by heating at
140 °C/0.2 mmHg for 2 h, and then it was suspended in 75 mL
of dry THF and left to stir overnight at room temperature. The
white suspension was cooled to -78 °C, and a solution of acetone
(0.41 g, 6.9 mmol) in 5 mL of THF was added and left to stir for
1 h. A THF (15 mL) solution of cyclohex-2-en-1-one 3 enolate
(0.5 g, 5.20 mmol) prepared by reaction of 3 with LDA at -78
°C was then added by cannula, and the resulting mixture was
left to stir until TLC indicated that no substrate 3 remained (1
h). The reaction mixture was quenched by the addition of
saturated aqueous NH4Cl (60 mL). A standard workup with CH2-
Cl2 extraction and water and brine washing gave an oil, which
was chromatographed on silica gel column using ethyl 3:7
acetate-hexane as an eluent to afford 0.6 g of 4 (74% yield): IR
hexane) giving 67 mg of (S)-pulegone (8) as an oil (89% yield):
1
[R]25 - 23° (c 2, abs. EtOH); IR (neat, cm-1) 1686; H NMR δ
D
0.99 (d, 3H, J ) 6.23 Hz), 1.22-1.42 (m, 2H), 1.77 (s, 3H), 1.85-
1.96 (m, 1H), 1.97 (s, 3H), 2.00-2.26 (m, 2H), 2.45-2.74 (m, 2H);
13C NMR δ 21.95, 22.28, 23.18, 28.81, 31.78, 32.38, 51.04, 132.05,
142.00, 204.48; EI-MS m/z 152 [M+], 137, 109, 81 (100), 67, 55,
43. Anal. Calcd for C10H16O2: C, 71.39; H, 9.59. Found: C, 71.26;
H, 9.45.
1
(neat, cm-1) 3469, 1658; H NMR δ 1.24 (s, 6H), 1.70-1.86 (m,
1H), 2.05-2.16 (m, 1H), 2.40-2.50 (m, 3H), 4.97 (bs, 1H, OH),
5.98-6.05 (m, 1H), 6.98-7.04 (m, 1H); 13C NMR δ 22.34, 23.97,
27.34, 28.05, 56.99, 76.01, 130.56, 146.85, 205.22; EI-MS m/z
96 (100), 95, 85, 55, 43. Anal. Calcd for C9H14O2: C, 70.10; H,
9.15. Found: C, 70.06; H, 9.06.
En a n tiom er ic Excess Ver ifica tion . Trimethylsilyl trifluo-
romethanesulfonate (17 µL, 0.09 mmol) was added to a solution
of (S)-(-)-pulegone (8) (27 mg, 0.18 mmol) and (2S,3S)-(-)-
diethyl tartrate bis-trimethylsilyl ether (67 mg, 0.19 mmol) in
CH2Cl2 (1 mL) and cooled to -78 °C. After stirring at room
temperature for 5 days, the mixture was partitioned between
CH2Cl2 and saturated NaHCO3. The organic layer was sepa-
rated, and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were washed with water and brine prior
to drying and filtering. This solution was concentrated to ca. 4
mL, and GC analysis showed ketals corresponding to 93% de.
6-[1-(Tr im eth ylsilyloxy)-1-m eth yleth yl]cycloh ex-2-en -1-
on e (5). To a solution of alcohol 8 (0.4 g, 2.6 mmol) in dry THF
(16 mL) cooled to 0 °C was added a solution of trimethylsilyl
chloride (0.42 g, 2.70 mmol) in 2 mL of THF followed by Et3N
(0.4 g, 2.9 mmol). The resulting mixture was stirred for 7.5 h at
reflux temperature and then distributed between Et2O (150 mL)
and 1 M NaH2PO4 solution (50 mL); the organic phase was
washed with saturated aqueous NaHCO3, dried, and evaporated,
and the resulting residue of 5 (0.57 g, 98% yield) was sufficiently
pure for further use: IR (neat, cm-1) 3012, 1655; 1H NMR δ 0.13
(s, 6H), 0.15 (s, 3H), 1.19 (s, 6H), 1.58-2.15 (m, 4H), 5.58-5.86
(m, 1H), 7.00-7.06 (m, 1H); 13C NMR δ 14.05, 18.12, 22.42,
24.05, 25.82, 27.76, 57.25, 79.65, 129.81, 145.95, 203.04; EI-MS
m/z 211, 168, 153, 131 (100), 75, 73, 55, 43. Anal. Calcd for
C12H22O2: C, 72.68; H, 11.18. Found: C, 75.45; H, 11.16.
Ack n ow led gm en t. The authors are grateful to Prof.
Alberto Brandi (University of Florence, Italy) for many
useful suggestions and to Dr. Giovanni Rafaiani for
performing NMR spectral analyses. This work was
carried out under the framework of the National Project
“Stereoselection in Organic Synthesis. Methodologies
and Applications” supported by MIUR, Rome, and by
the University of Camerino.
(24) (a) Miller, D.; Bilodeau, F.; Burnell, R. H. Can. J . Chem. 1991,
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903-909.
Su p p or tin g In for m a tion Ava ila ble: Detailed descrip-
tions of experimental procedures and conditions for the
synthesis of amidophosphine 6 and NMR spectra, MS spectra,
and other characterization data for new compounds, not
reported previously, designated by their entries in Table 1.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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