Cyclobutanones through SNi′ ring closure, a mechanistic study

Article abstract of DOI:10.1021/jo062264v

Mechanistic studies on the intramolecular nucleophilic substitution with allylic rearrangement (S_Ni′ reaction) and a new stereoselective access to substituted cyclobutanones are reported. 4,4-Dialkyl-5-oxohex-2E-en- 1-yl ethanesulfonates 4 were

Full text of DOI:10.1021/jo062264v

Cyclobutanones through SNi′ Ring Closure, a Mechanistic Study
Martin A. Lovchik,† Andreas Goeke,‡,§ and Georg Fra´ter*,†,‡
UniVersity of Zurich, 8057 Zurich, Switzerland, GiVaudan Schweiz AG, 8600 Duebendorf, Switzerland, and
Shanghai GiVaudan Ltd., 201203 Shanghai, China
georg.frater@giVaudan.com
ReceiVed NoVember 2, 2006
Mechanistic studies on the intramolecular nucleophilic substitution with allylic rearrangement (SNi′ reaction)
and a new stereoselective access to substituted cyclobutanones are reported. 4,4-Dialkyl-5-oxohex-2E-
en-1-yl methanesulfonates 4 were converted to 2,2-dialkyl-3-vinylcyclobutanones 6 by SNi′ ring closure.
The stereochemical analysis of the reaction was achieved through ring closure of (6S)-6-chloro-3,3-
diethylhept-4E-en-2-one (S)-17, defined by the absolute configuration of C(6), leading to (3S)-2,2-diethyl-
3-(prop-1E-en-1-yl)cyclobutanone (S)-(E)-18 and (3R)-2,2-diethyl-3-(prop-1Z-en-1-yl)cyclobutanone (R)-
(Z)-18, in a ratio of 85:15, with almost complete transfer of chirality (>97%). The absolute configuration
of (S)-17 was determined by X-ray diffraction analysis of the camphanoate derivative 16. The absolute
configuration of the cyclobutanone products (S)-(E)-18 and (R)-(Z)-18 was determined by Raman optical
activity spectroscopy. Comparison of the absolute configuration of (S)-17 and the resulting (E)- and
(Z)-cyclobutanones 18 allowed the conclusion that the SNi′ reaction proceeds with syn geometry relative
to the leaving group.
Introduction
addition of olefins.5 Cyclobutanones are frequently prepared by
the thermal [2+2] addition of olefins with ketenes.6 A diaste-
reoselective variant was developed by Ghosez et al. involving
chiral keteniminium salts.7 Another asymmetric route to cy-
clobutanones was reported by Fra´ter et al. who employed a chiral
ketene in the synthesis of (-)-blastmycinone.8 Only few other
methods for the enantioselective preparation of cyclobutanones
can be found in the literature.9
The SN2′ reaction (bimolecular nucleophilic substitution with
allylic rearrangement) was first postulated independently by
Hughes and Winstein.1 The regio- and stereoselectivity of the
displacement was found to depend on both the nature of the
nucleophiles and that of the leaving groups.2 The intramolecular
variant, the SNi′ reaction, is strongly related to the SN2′ reaction,
and the results from the stereochemical analysis of the SN2′
reaction apply to the intramolecular version as well.3 Herein
we discuss the results of our own mechanistic studies on the
SNi′ reaction and report a new enantioselective access to
substituted cyclobutanones.4
During research on the stereoselective R-alkylation of chiral
â-hydroxy esters, Fra´ter et al. reported the preparation of a 4:3
mixture of (R)-2 and (S)-3 via a base induced SNi reaction
(intramolecular, nucleophilic substitution) of (R)-1′ (′ indicates
The construction of four membered carbocycles is commonly
achieved by the inter- or intramolecular photochemical [2+2]
(5) (a) Dilling, W. L. Chem. ReV. 1969, 69, 845-877. (b) Demuth, M.;
Mikhail, G. Synthesis 1989, 145-162.
(6) Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159-646.
(7) (a) Sidani, A.; Marchand-Brynaert, J.; Ghosez, L. Angew. Chem. 1974,
86, 272. (b) Houge, C.; Frisque-Hesbain, A. M.; Mockel, A.; Ghosez, L.;
Declercq, J. P.; Germain, G.; Van Meerssche, M. J. Am. Chem. Soc. 1982,
104, 2920-2921. (c) Ghosez, L.; Mahuteau-Betzer, F.; Genicot, C.;
Vallribera, A.; Cordier, J.-F. Chem.-Eur. J. 2002, 8, 3411-3422.
(8) Fra´ter, G.; Mu¨ller, U.; Gu¨nther, W. HelV. Chim. Acta 1986, 69, 1858-
1861.
* Corresponding author. Phone: +41(0) 44/824 2371.
† University of Zurich.
‡ Givaudan Schweiz AG.
§ Shanghai Givaudan Ltd.
(1) (a) Hughes, E. D. Trans. Faraday Soc. 1938, 34, 185-202. (b)
Winstein S. Dissertation, California Institute of Technology, 1938.
(2) Magid, R. M. Tetrahedron 1980, 36, 1901-1930.
(3) Paquette, L. A.; Stirling, C. J. M. Tetrahedron 1992, 48, 7383-7423.
(4) (a) Lovchik, M. A. Dissertation, University of Zu¨rich, 2006. (b)
Preliminary results were presented at the fall meeting of the Swiss Chemical
Society: Lovchik, M. A.; Fra´ter, G.; Goeke, A. Chimia 2004, 58, 506.
(9) (a) Trost, B. M.; Yasukata, T. J. Am. Chem. Soc. 2001, 123, 7162-
7163. (b) Yoshida, M.; Abdel-Hamid Ismail, M.; Nemoto, H.; Ihara, M. J.
Chem. Soc. Perkin Trans. 1 2000, 2629-2635.
10.1021/jo062264v CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/03/2007
J. Org. Chem. 2007, 72, 2427-2433
2427

Lovchik et al.
SCHEME 1
the enolate of the corresponding compound) (Scheme 1).10 The
efficient approach to chiral cyclobutanones prompted us to apply
these findings in the synthesis of cyclobutanones by the SNi′
reaction of an allylic analogue (Scheme 1). Several requirements
must be met for this reaction to proceed: according to Baldwin’s
rules of ring closure, the 4-exo-trig mechanism is a favored
process.11 The double bond in 4 must have an E configuration,
to prevent the reaction from following the allowed 6-exo-tet
mechanism, leading to six-membered rings. In addition, disub-
stitution at C(3) prevents the formation of the alternative 2,3-
enolate, which will provoke simple E2 elimination leading to
hexa-3,5-dien-2-one. The allylic nucleophilic displacement of
the leaving group may proceed either by attack of the oxygen
anion (i) leading to oxetane 5 or by attack of the carbanion (ii)
leading to cyclobutanone 6.
Apart from the chemoselectivity of the reaction, it was of
particular interest to determine whether the allylic nucleophilic
displacement by the enolate takes place syn or anti with respect
to the leaving group. Since its discovery, the mechanism of the
SN2′ reaction has led to many disputes concerning its mechanism
and the preferred trajectory of the incoming nucleophile. Today,
the SN2′ reaction is commonly believed to involve a concerted
allylic syn displacement of the nucleofuge by the incoming
nucleophile. However, several examples exist in the literature
that report selective anti displacements, especially when ap-
plying organometallic nucleophiles.12 Stork and Kreft reported
that SN2′ and SNi′ reactions with thiolate nucleophiles led to
predominant or even exclusive anti displacement of the nucle-
ofuge in allylic systems.13a The authors reported a similar
example to our SNi′ ring closure where nucleophilic attack of a
thiolate anion led to the formation of a tetrahydrothiophen ring
by selective anti displacement of the leaving group.13b It was
the objective of the current research to investigate the scope
and limitations of the SNi′ reaction for the synthesis of
cyclobutanones and to determine the exact mechanistic course
of the reaction.
Results and Discussion
The general feasibility and chemoselectivity of the SNi′
reaction leading to cyclobutanones was explored by performing
the reaction with 4a,b, leading to cyclobutanones 6a,b and/or
oxetanes 5a,b upon SNi′ ring closure (Scheme 1). Stork enamine
synthesis of 2-ethylbutanal 7a and cyclohexanecarbaldehyde 7b
with morpholine,14 followed by acetylation of the resulting
enamines 8a,b with acetyl chloride and hydrolysis of the
resulting quaternary ammonium salt, led to the key intermediates
9a,b (Scheme 2).15 Subsequent reaction with triethyl phospho-
noacetate at 0 °C selectively afforded (E)-10a,b.
Conversion of 10a,b to the silyl-enol ether 11a,b, followed
by reduction of the ester group with LiAlH4, led to the allylic
alcohol 12a,b, which was then converted to the corresponding
methanesulfonate 4a,b. Treatment of 4a with 5% excess tBuOK
1 M in THF led to cyclobutanone 6a in 45% yield. Formation
of compound 13a, the product of a formal ketene elimination,
t
was indicated by the presence of BuOAc, identified by gas
chromatography mass spectroscopy (GC/MS). Accordingly, SNi′
cyclization of 4b under the same conditions led to a mixture of
cyclobutanone 6b in 56% yield and the ketene elimination
product 13b was isolated in 11% yield. In contrast to the SNi
reaction reported by Fra´ter et al., the SNi′ reactions did not lead
to any detectable amount of oxetane 5a,b, which would result
from nucleophilic attack of the oxygen anion.10 The observed
trend can be rationalized by the HSAB rule: the allylic system
in 4a,b exhibits softer acid properties and is therefore prone to
be attacked by the soft nucleophilic enolate-carbon rather than
the hard oxygen anion.16 The formal ketene-elimination reaction
leading to 13, found to be the major side reaction in the 4-exo-
trig SNi′ reaction, was not reported by Fra´ter et al. in the SNi
reaction.
However, the analysis of the reaction mechanism and
geometry of the transition state of the SNi′ reaction leading to
cyclobutanones requires more information than that which can
(10) Fra´ter, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40, 1269-
1277.
(13) (a) Stork, G.; Kreft, A. F. J. Am. Chem. Soc. 1977, 99, 3850-
3851. (b) Stork, G.; Kreft, A. F. J. Am. Chem. Soc. 1977, 99, 3851-3853.
(14) Benzing, E. Angew. Chem. 1959, 15, 521.
(15) Inukai, T.; Yoshizawa, R. J. Org. Chem. 1967, 32, 404-407 and
references cited therein.
(16) (a) Pearson, R. G. J. Chem. Educ. 1968, 45, 581-587. (b) Pearson,
R. G. J. Chem. Educ. 1968, 45, 643-648.
(11) Baldwin, J. E. JCS Chem. Comm. 1976, 734-736.
(12) (a) Staroscik, J.; Rickborn, B. J. Am. Chem. Soc. 1971, 93, 3046-
3047. (b) Johnson, C. R.; Wieland, D. M. J. Am. Chem. Soc. 1971, 93,
3047-3049. (c) Tanigawa, Y.; Ohta, H.; Sonoda, A.; Murahashi, S.-I. J.
Am. Chem. Soc. 1978, 100, 4610-4612.
2428 J. Org. Chem., Vol. 72, No. 7, 2007

Cyclobutanones through SNi′ Ring Closure
SCHEME 2a
FIGURE 1. (a) Calculated ROA spectrum of (S)-(E)-18. (b) Measured
spectrum of (S)-(E)-18. (c) Measured spectrum of (R)-(Z)-18.
procedure17a using (+)-diisopinocampheylchloroborane ((+)-
Ipc2BCl), derived from (-)-R-pinene and BH3‚SMe2.17b,c (R)-
15 was obtained in 77% yield with 48% ee (for the determi-
nation of the enantiomeric excess, see Supporting Information).
The enantiomerically pure product was obtained by reacting the
enriched product with (S)-(-)-camphanic acid chloride, to give
a solid camphanoate derivative 16. Fractional crystallization of
16 from hexane/ether led to the pure diastereomer. X-ray
crystallography of 16 allowed us to deduce the absolute
configuration of (R)-15.
a Reagents and conditions: (i) morpholine (1 mol. equiv), TsOH, -H2O,
8a 86% 8b 89%. (ii) AcCl, CH2Cl2, 9a 39%, 9b 32%. (iii) (Et2O)2P(O)-
CH2CO2Et, NaH, 10a 84%, 10b 62%. (iv) TMSCl, Et3N, 11a 82%, 11b
66%. (v) LiAlH4, THF, 12a 80%, 12b 45%. (vi) MsCl, pyridine, 4a 47%,
t
4b 40%. (vii) BuOK, THF, 6a 45%, 6b 56%, 13b 11%.
SCHEME 3a
The chloride ion was found to be a suitable leaving group
for the SNi′ reaction, and (R)-15 was converted to (S)-17 with
hexachloroacetone in the presence of triphenylphosphine.18
Although the reaction was reported to proceed with complete
inversion of configuration, some loss of enantiomeric purity
(77% ee) was observed in chloride (S)-17, possibly caused by
partial formation of an allyl cation intermediate (SN1).
Chloro-ketone (S)-17 was cyclized using 1 M tBuOK in THF
at 0 °C following the procedure by Fra´ter et al.10 The reaction
afforded a mixture of 85% (E)-18 and 15% (Z)-18 in 49%
isolated yield together with 16% (GC) of the formal ketene
elimination product 19, as well as the dehydrochlorination
product 20. Analysis by chiral GC showed that the enantiomeric
excesses of (E)- and (Z)-18 was 75% for both isomers, indicating
that the SNi′ reaction proceeded with almost complete stereo-
selectivity.
To precisely analyze the mechanism of the SNi′ reaction, it
was necessary to separate (E)- and (Z)-18 and to determine the
absolute configuration of both products. The separation was
accomplished by chromatography over silica gel impregnated
with AgNO3 (pentane/Et2O 97.5:2.5).19 The separated products
were submitted for Raman optical activity (ROA) spectroscopy
(Figure 1, spectrum b and c).20 The absolute configuration of
both isomers was determined by comparing the vibration at 988
a Reagents and conditions: (i) Ph3PCH2COCH3, NaH, 72%. (ii) (+)-
Ipc2BCl, 77%. (iii) (-)-Camphanic acid chloride, crystallization. (iv) NaOH,
t
H2O, EtOH. (v) (CCl3)2CO, Ph3P, 85%. (vi) BuOK, THF.
(17) (a) Midland, M. M. Chem. ReV. 1989, 89, 1553-1561. (b) Brown,
H. C.; Chandrasekharan, J.; Ramachandran, P. V. J. Am. Chem. Soc. 1988,
110, 1539-1546. (c) Brown, H. C.; Singaram, B. J. Org. Chem. 1984, 49,
945-947.
(18) Magid, R. M.; Thally, B. G.; Souther, S. K. J. Org. Chem. 1981,
46, 824-825.
be deduced from the cyclization of 4a,b. Application of (S)-
17, defined by the absolute configuration at the carbon bearing
the leaving group, allows the analysis of the exact stereochem-
ical route of the reaction.
(19) Loev, B.; Bender, P. E.; Smith, R. Synthesis 1973, 6, 362-363.
(20) Extensive analysis of all the conformers contributing to the ROA
spectrum of (E)- and (Z)-18 will be published shortly by W. Hug and D.
Dudenko from the University of Fribourg, Switzerland.
Diketone (E)-14 was prepared by Wittig reaction of 1-triph-
enyl-propan-2-one on 9a (Scheme 3). The ketone function was
reduced chemo- and enantioselectively by a modified Midland
J. Org. Chem, Vol. 72, No. 7, 2007 2429

Lovchik et al.
SCHEME 4
FIGURE 2. Vibration at 988 cm-1 in the ROA spectrum of
(S)-(E)-18.
mechanistic course of the reaction, based on the conformational
analysis of the possible reaction pathways. The reactive enolate
(S)-17′ can adopt 4 different conformations A-D (Scheme 4).
Intramolecular displacement of the chloride ion in conformers
A and C would proceed in a syn fashion, but conformer A is
assumed to be lower in energy, because of a minor A1,3 strain.
However, both conformers interchange by a rapid equilibrium,
as the energy difference between them is small (∼12 kJ/mol)
at reaction temperature. Therefore, (S)-(E)-18 derives from
conformation A, where enolate attack at the re face of the
molecule leads to the (E)-configured product upon syn displace-
ment of the nucleofuge. The minor product is not only (Z)-
configured but also displays the opposite absolute configura-
tion: it results from conformation C in which the enolate attacks
the allylchloride unit from the si face. The E/Z ratio of 85:15
represents the selectivity by which (S)-17′ reacts through
conformation A or C. As the enantiomeric purity of 18 was
preserved to at least 97%, the anti displacements via conforma-
tions B and D are negligible, for they would lead to the
formation of (R)-(E)-18 and (S)-(Z)-18, respectively.
FIGURE 3.
cm-1, marked with an asterisk, with that of the theoretical
spectrum of (S)-(E)-18 calculated at the B3LYP/6-311++G**
level with the Gaussian program (Figure 1, spectrum a.). ROA
calculation at the TDHF/rDP level was carried out with the
Dalton program.21
The relevant vibration at 988 cm-1 was visualized as a
3-dimensional image (Figure 2). The image must be interpreted
as follows: The size (volume) of the spheres represents the total
vibration energy (kinetic and potential) of the corresponding
atom. The direction of the movement of the atoms in the
molecule is indicated by the two colored surfaces of the spheres.
The atoms vibrate on an axis perpendicular to the colored
surfaces, e.g., from blue to yellow or vice versa. The actual
excursion of the motion of the nuclei is not represented by this
delineation, which favors visibility of the motion of the heavier
nuclei in comparison to that of the lighter ones. The ROA is
proportional to the effective motion of the nuclei and to the
gradients of the relevant optical tensors at their site, and not to
vibrational energy. Despite the larger gradients at the site of
the heavier nuclei, the hydrogen atoms therefore tend to
contribute more to the computed ROA than implied by this
delineation (Figure 2).22 On the basis of the ROA analysis and
the fact that (E)-18 and (Z)-18 show the opposite sign of optical
rotation, the absolute configuration was assigned (S) for (E)-18
and (R) for (Z)-18.
Conclusions
The current research has shown that substituted cyclobu-
tanones 6a,b can be prepared by a SNi′ reaction of â,γ-
unsaturated ketones of type 4a,b (Scheme 1). Mechanistic
studies with chloro-ketone (S)-17 led to the conclusion that the
nucleophilic displacement of the chloride ion by the ketone
enolate proceeds exclusively with syn stereochemistry leading
to (E)- and (Z)-18 of opposite absolute configurations at C(3)
of the cyclobutanone ring (Scheme 4). These findings were in
accord with the results from Stork and White, who found that
nucleophilic SN2′ displacement with enolates in sterically
unbiased systems will take place syn to the leaving group.23
Now that the absolute configurations of the chloro-ketone
(S)-17 and the resulting cyclobutanones (S)-(E)-18 and (R)-(Z)-
18 had been determined, it was possible to establish the
(21) Zuber, G.; Hug, W. J. Phys. Chem. A 2004, 108, 2108-2118.
(22) Hug, W.; Haesler, J. Int. J. Quantum Chem. 2005, 104, 695-715.
2430 J. Org. Chem., Vol. 72, No. 7, 2007

Cyclobutanones through SNi′ Ring Closure
5.59 (d, J ) 16.2 Hz, 1 H), 4.01 (dd, J ) 7.1, 14.1 Hz, 2 H), 3.93
(dd, J ) 2.0, 29.6 Hz, 2 H), 1.48-1.30 (m, 4 H), 1.11 (t, J ) 7.1
Hz, 3 H), 0.64-0.54 (m, 6 H), 0.00 (s, 9 H). 13C NMR (75 MHz,
CDCl3; δ, ppm): 167.0, 160.1 (2 s), 153.5, 120.0 (2 d), 90.4, 60.1
(2 t), 50.0 (s), 26.7 (2 t), 14.2, 8.4, 0.0 (6 q). IR (CCl4, cm-1): ν
2968w, 1720m, 1650w, 1620w. MS (EI): m/z 284 (5, M+·), 269
(7, [M-CH3]+), 255 (19, [M-C2H5]+), 239 (3, [M-OC2H5]+), 227
(3), 75 (31, [C2H7OSi]+), 73 (100, [C3H9Si]+). HRMS (EI): calcd.
for C15H28O3Si (M+): 284.1808; found, 284.1798.
Experimental Section
1
The H and 13C NMR spectra were recorded at 500 and 300
MHz and 100 and 75 MHz, respectively. Chemical shifts are
expressed in parts per million (ppm). FTIR spectra were recorded
in solution (CDCl3) on Spectrum One FTIR and Bruker Vector 22
FTIR spectrometers. High-resolution mass spectra were recorded
on a Finnigan MAT 95 double-focusing magnetic sector mass
spectrometer. Thin layer chromatography was performed on com-
mercial 60 mesh silica gel plates, and visualization was effected
with short wavelength UV light (254 nm) and KMnO4 staining
reagent. Chromatography was carried out with hexane (hex) and
tert.-butyl methyl ether (MtBE) unless stated otherwise.
Ethyl 4,4-Diethyl-5-oxohex-2E-enoate (10a). Sodium hydride
in paraffin oil (60%, 1.70 g, 42.30 mmol) was suspended in THF
(40.0 mL). Triethyl phosphonoacetate (7.57 g, 33.80 mmol) was
added dropwise. The mixture slowly became homogeneous, and
the temperature rose to 35 °C. After stirring for 20 min, the mixture
was cooled to 0-5 °C using an ice/NaCl bath. Keto-aldehyde 9a
(4.00 g, 28.20 mmol) was added slowly while maintaining the
temperature at 0 °C. After the addition the cooling bath was
removed and the reaction mixture stirred for an additional 30 min.
The reaction mixture was poured onto ice/water and extracted with
hexane. The hexane layers were combined and washed with aq.
NaHCO3, dried, and concentrated. Short-path distillation (90 °C,
0.05 mbar) afforded 10a as a colorless oil (5.04 g, 84%). 1H NMR
(300 MHz, CDCl3; δ, ppm): 7.02 (d, J ) 16.3 Hz, 1 H), 5.87 (d,
J ) 16.3 Hz, 1 H), 4.21 (q, J ) 7.1 Hz, 2 H), 2.11 (s, 3 H), 1.82-
1.78 (m, 4 H), 1.30 (t, J ) 7,1 Hz, 3 H), 0.77 (t, J ) 7.5 Hz, 6 H).
13C NMR (75 MHz, CDCl3; δ, ppm): 208.6, 166.1 (2 s), 149.5,
122.0 (2 d), 60.3 (t), 58.3 (s), 26.4 (2 t), 26.1, 14.1 (2 q), 8.2 (2 q).
IR (CCl4, cm-1): ν 2971w, 1708s, 1646w. MS (EI): m/z 197 (1,
[M-CH3]+), 170 (100, [M-C2H4]+), 167 (7, [M-C2H5O]+), 113
(12, [M-C5H7O2]+), 99 (13, [M-C7H13O]+), 43 (80, [C2H3O]+).
Anal. Calcd. for C12H20O3 (212): C 67.89, H 9.50. Found: C 67.64,
H 9.31.
Ethyl 3-[1-(1-Trimethylsilanyloxyvinyl)cyclohexyl]acrylate
(11b). Prepared from 10b (2.00 g, 8.93 mmol) following the same
procedure reported for the synthesis of 11a. Chromatography over
silica gel with (hex/MtBE 95:5) afforded 11b as a colorless liquid
1
(1.75 g, 66%). H NMR (300 MHz, C6D6; δ, ppm): 6.64 (d, J )
16.0 Hz 1 H), 5.62 (d, J ) 16.0 Hz, 1 H), 4.00 (q, J ) 7.1 Hz, 2
H), 3.961 (dd, J ) 1.8, 11.1 Hz, 2H), 1.61-1.17 (m, 10 H), 1.10
(t, J ) 7.1 Hz, 3 H), 0.17 (s, 9 H). 13C NMR (100 MHz, CDCl3;
δ, ppm): 167.0, 161.3 (2 s), 154.6, 120.2 (2 d), 89.5, 60.0 (2 t),
46.3 (s), 33.3, 26.0, 22.3 (5 t), 14.2 (q), 0.0 (3 q). IR (CCl4, cm-1):
ν 2935m, 2860w, 1719m, 1648w, 1620w. MS (EI): m/z 296 (6,
M+·), 223 (17), 281 (2, [M-CH3]+), 267 (3, [M-C2H5]+), 253 (3,
[M-C3H7]+), 208 (19), 196 (15), 75 (31, [C2H7OSi]+), 73 (100,
[C3H9Si]+). HRMS (EI): calc. for C16H28O3Si (M+): 296.1808;
found, 296.1797.
3,3-Diethyl-6-hydroxyhex-4E-en-2-one (12a). A solution of 11a
(250 mg, 0.88 mmol) in THF (5.0 mL) was cooled to -10 °C by
means of an ice/NaCl bath. LiAlH4 (21 mg, 0.55 mmol) was added
in portions keeping the temperature at -10 °C. Cooling was
removed, and the mixture was stirred for 1 h. The reaction was
quenched by carefully adding water. The mixture was extracted
with MtBE, the organic layers were combined, washed with water
and brine, and concentrated. Chromatography over silica gel (hex/
MtBE 3:7) and short-path distillation (0.05 mbar, 130 °C) gave
12a as a colorless viscous oil (120 mg, 80%). 1H NMR (300 MHz,
CDCl3; δ, ppm): 5.72-5.69 (m, 2 H), 4.19-4.16 (m, 2 H), 2.09
(s, 3 H), 1.88 (s, 1H), 1.85-1.61 (m, 4H), 0.76 (t, J ) 7.6 Hz, 6
H). 13C NMR (75 MHz, CDCl3; δ, ppm): 211.0 (s), 133.5, 130.3
(2 d), 63.5 (t), 57.5 (s), 26.0 (2 t), 25.8 (q), 8.2 (2 q). IR (CCl4,
cm-1): ν 3402br, 2967m, 2940m, 2880w, 1702s. MS (EI): m/z
170 (1, M+·), 152 (1 [M-H2O]+), 141 (4, [M-C2H4]+), 110 (52),
95 (26), 81 (64), 67 (33), 43 (100, [C2H3O]+). HRMS (EI): calcd.
for C9H15O2 ([M-CH3]+): 155.1072; found, 155.1080.
1-[1-(3-Hydroxyprop-1E-en-1-yl)cyclohexyl]ethanone (12b).
Prepared from 11b (1.00 g, 3.40 mmol) by the same procedure
reported for the synthesis of 12a. Because of higher steric hindrance,
the hydrolysis of the silylenolether was incomplete and a mixture
of 12b* and 12b was obtained (Figure 3). The crude product was
stirred in a 1 M solution of tetra-n-butylammonium fluoride in THF
(2 mL) to complete the hydrolysis. For details on the isolation and
characterization of 12b*, see Supporting Information. After puri-
fication by chromatography over silica gel (hex/MtBE 1:1) and
drying in vacuo 12b was obtained as a colorless oil (279 mg, 45%).
1H NMR (300 MHz, C6D6; δ, ppm): 5.75-5.54 (m, 2 H), 4.15
(dd, J ) 1.3, 5.3 Hz, 2 H), 2.53 (s 1 H), 2.10 (s, 3 H), 1.98-1.92
(m, 2 H), 1.57-1.53 (m, 4 H), 1.36-1.39 (m, 4 H). 13C NMR (100
MHz, CDCl3; δ, ppm): 210.9 (s), 134.4, 130.7 (2 d), 63.2 (t), 54.2
(s), 32.9, 25.7 (3t), 25.5 (q), 22.6 (2t). IR (CCl4, cm-1): ν 3420br,
2932s, 2856m, 1702vs. MS (EI): m/z 182 (1, M+·), 164 (3,
[M-H2O]+), 151 (5, [M-CH2OH]+), 122 (100), 107 (41), 93 (73),
79 (85).
Ethyl (2E)-3-(1-Acetylcyclohexyl)acrylate (10b). Prepared from
9b (11.50 g, 74.70 mmol) following the same procedure reported
for the synthesis of 10a. The crude product was purified by
distillation over a 15-cm Vigreux column (0.05 mbar, 112 °C) to
1
give 10b as a colorless oil (10.45 g, 62%). H NMR (300 MHz,
CDCl3; δ, ppm): 6.85 (d, J ) 16.1 Hz, 1 H), 5.87 (d, J ) 16.1 Hz,
1 H), 4.2 (q, J ) ?? 2 H), 2.11 (s, 3 H), 2.04-1.94 (m, 2 H),
1.72-1.61 (m, 2 H), 1.60-1.36 (m, 6 H), 1.30 (t, 3 H). 13C NMR
(75 MHz, CDCl3; δ, ppm): 208.0, 166.0 (2 s), 150.2, 122.3 (2 d),
60.4 (t), 55.1 (s), 32.5 (2 t), 25.8 (1 q), 25.4, 22.4 (2 t), 14.1 (q).
IR (CCl4, cm-1): ν 2935m, 2857w, 1707vs, 1643m. MS (EI): m/z
206(1,[M-H2O]+),182(100,[M-CH2CO]+),179(6,[M-C2H5O]+),
154 (10), 136 (15), 107 (44), 94 (16), 79 (31), 43 (65, [C2H3O]+).
HRMS (EI): calcd. for C13H21O3 ([M+H]+), 225.1491; found,
225.1496.
Ethyl 4,4-Diethyl-5-(trimethylsilanyloxy)hexa-2E,5-dienoate
(11a). A solution of 10a (26.46 g, 125.00 mmol) in of CH3CN
(50.0 mL) was prepared, and triethylamine (17.67 g, 175.00 mmol)
was added. Trichloromethylsilane (18.90 g, 175.00 mmol) was
added in portions to the stirred solution. A solution of NaI (26.26
g, 175.00 mmol) in CH3CN (140.0 mL) was prepared and added
dropwise at room temperature. After the addition was complete
the mixture was heated to 50-60 °C and stirred for 3 h. The reaction
mixture was poured onto a mixture of dilute NaHCO3, and ice and
was extracted with MtBE. The organic layers were washed with
water and brine. After concentration of the combined ether layers
the product was distilled over a 15-cm Vigreux column (97 °C,
0.05 mbar). 11a was obtained as a colorless oil (29.00 g, 82%). 1H
NMR (300 MHz, CDCl3; δ, ppm): 6.73 (d, J ) 16.2 Hz, 1 H),
2,2-Diethyl-3-vinylcyclobutanone (6a).24 A solution of 12a
(1.00 g, 6.50 mmol) in pyridine (12.0 mL) was cooled to -10 °C
by means of an ice/NaCl bath. Methanesulfonic acid chloride (0.55
mL, 7.15 mmol) was added dropwise, and the mixture was stirred
at -10 °C for a total of 1.5 h. The mixture was poured onto water
(50 mL) and extracted with MtBE. The combined organic layers
were washed with aq. CuSO4 solution until no more darkening of
the solution occurred, indicating that all of the residual pyridine
had been removed. The organic solutions were washed with water
(23) Stork, G.; White, W. N. J. Am. Chem. Soc. 1956, 78, 4609-4619.
(24) Martin, J. C.; Gott, P. G. French Patent 1414457, priority,
15.10.1965, (to Eastman Kodak Co.).
J. Org. Chem, Vol. 72, No. 7, 2007 2431

Lovchik et al.
and brine and concentrated. Chromatography over silica gel with
(hex/MtBE 95:5) gave 4a as a colorless oil (750 mg, 47%). The
product is irritant and sensitive to air and humidity. A solution of
4a (180 mg, 0.73 mmol) in THF (1.5 mL) was cooled to 0-5 °C
by means of an ice/H2O bath and 1 M tBuOK in tBuOH (0.75 mL,
0.75 mmol) was added dropwise. The yellow solution was stirred
at 0 °C for 30 min. The mixture was poured onto water and
extracted with MtBE. The ether layers were washed with water
and brine, dried, and concentrated. The crude product was purified
by column chromatography over silica gel (pentane/ Et2O 9:1) and
short path distillation (100 mbar, 80 °C). Cyclobutanone 6a was
obtained as a colorless, volatile liquid (50 mg, 45%). 1H NMR (300
MHz, CDCl3; δ, ppm): 6.04-5.89 (m, 1 H), 5.20-5.09 (m, 2 H),
3.11-2.92 (m, 2 H), 2.87-2.76 (m, 1 H), 1.75-1.46 (m, 4 H),
0.93-0.85 (m, 6 H). 13C NMR (75 MHz, CDCl3; δ, ppm): 210.2
(s), 136.9 (d), 127.1 (t), 57.7 (s), 45.1 (t), 26.2 (2 t), 25.8 (d), 8.2
(2 q). IR (CCl4, cm-1): ν 2972m, 2941m, 1769s. MS (EI): m/z
110 (21, [M-CH2CO]+), 108 (21), 79 (67), 78 (49), 72 (60), 56
(47), 55 (100).
3-Vinylspiro[3.5]nonan-1-one (6b). Methanesulfonate 4b was
prepared from 12b (1.50 g, 8.24 mmol) by the same procedure as
4a. Purification of the crude product by chromatography over silica
gel (hex/MtBE 95:5) and drying in vacuo afforded 4b as a colorless
liquid (850 mg, 40%). The product is irritant and sensitive to air
and humidity. 4b (800 mg, 3.07 mmol) was converted to 6b by
the same procedure reported for 6a. After chromatography over
silica gel (hex/Et2O 8:2), cyclobutanone 6b (280 mg, 56%) and
the fragmentation product 13b (60 mg, 11%) were obtained as
colorless oils. Spectroscopic data for 6b: 1H NMR (300 MHz,
CDCl3; δ, ppm): 6.02-5.86 (m, 1 H), 5.17 (d, J ) 1.1 Hz, 1 H),
5.15-5.09 (m, 1 H), 3.14 (dd, J ) 17.5, 9.1 Hz, 1 H), 2.89 (dd, J
) 7.0, 17.6 Hz, 1 H), 2.69 (q, J ) 8.1 Hz, 1 H), 1.83-1.23 (m, 10
H). 13C NMR (75 MHz, CDCl3; δ, ppm): 214.0 (s), 137.2 (d),
116.2 (t), 67.6 (s), 46.5 (t), 39.8 (d), 33.7, 28.0, 25.5, 22.7, 22.4 (5
t). IR (CCl4, cm-1): ν 2928m, 2853w, 1769vs. MS (EI): m/z 164
(1, M+·), 136 (1, [M-CO]+), 122 (71), 110 (39), 107 (38), 93 (27),
79 (58), 67 (100), 54 (46, [C4H6]+). HRMS (EI): calc. for C11H16O
(M+): 164.1201; found, 164.1192. Spectroscopic data for 13b: 1H
NMR (300 MHz, CDCl3; δ, ppm): 6.62 (td, J ) 17.1 Hz, 1 H),
5.79 (d, J ) 11.0 Hz, 1 H), 5.09 (dd, J ) 16.8, 2.0 1 H), 4.95 (dd,
J ) 10.1, 2.0 Hz, 1 H), 2.28 (s, 2 H), 2.14 (s, 2 H), 1.57-1.55 (m,
6 H). IR (CCl4, cm-1): ν 2977vs, 2935vs, 2858m, 1767vs. MS
(EI): m/z 122 (40, M+·), 107 (45, [M-CH3]+), 93 (36, [M-C2H5]+),
79 (100, [M-C3H7]+). HRMS (EI): calcd. for C11H16O (M+),
164.1201; found, 164.1192.
added dropwise over 30 min. After stirring at 0 °C for 1 h the
solution was concentrated and dried in vacuo. The active reagent
(+)-Ipc2BCl was obtained as a colorless, viscous liquid and was
used without further purification. THF (25.0 mL) was added, and
the solution was cooled to -60 °C by means of a CO2/acetone
bath. A solution of 14 (8.58 g, 30.00 mmol) in 10.0 mL of THF
was added dropwise and stirring was continued at -60 °C for 1 h.
The mixture was allowed to reach room temperature and stirring
was continued for 16 h. The resulting dark-purple mixture was
treated with diethanol amine (7.00 g, 66.60 mmol). The solids were
removed by filtration and the orange liquid was diluted with MtBE,
washed with water and brine, and concentrated. After chromatog-
raphy over silica gel (hex/MtBE 1:1) and drying in vacuo, (R)-15
was obtained as colorless oil (3.87 g, 77%, 48% ee). The product
is sensitive to heat and cannot be distilled without decomposition.
[R]25 ) -6.45 (c 0.945, MeOH). The product was treated with
D
(-)-camphanic acid chloride (6.84 g, 31.6 mmol) in pyridine
(35 mL) at 0 °C and then stirred at room temperature for 3 h. The
reaction mixture was diluted with MtBE and washed with water
and brine. The organic layer was dried over MgSO4 and concen-
trated. The solid residue was recrystallized (hex/MtBE 9:1) until
the value of the optical rotation remained constant. [R]25D ) +9.75
(c 1.005, MeOH). 16 was obtained as fine colorless crystals (1.64
g, 21.4%, 99% de). Mp 67-69 °C. The camphanoate 16 was
dissolved in EtOH (20 mL) and hydrolyzed with 3 M NaOH (5
mL). The mixture was stirred for 1 h and then diluted with water
(100 mL) and extracted with MtBE. The ether layers were
combined, washed with water and brine, dried over MgSO4, and
concentrated. The residue was dried in vacuo to afford enantio-
merically pure (R)-15 (824 mg, 99%, 99% ee). [R]25 ) -12.48
D
1
(c 1.307, MeOH). H NMR (300 MHz, CDCl3; δ, ppm): 5.56-
5.34 (m, 2 H), 4.08-3.97 (m 1 H), 1.80 (s, 3 H), 1.69-1.44 (m, 4
H), 1.26 (d, J ) 3.4 Hz, 1 H), 1.09 (d, J ) 6.5 Hz, 3 H), 0.66 (dt,
J ) 11.2, 3.6 Hz, 6 H). 13C NMR (75 MHz, CDCl3; δ, ppm): 211.1
(s), 135.4, 131.5, 68.7 (3 d), 57.3 (s), 26.0, 25.9 (2 t), 25.7, 23.4 (2
q), 8.1 (2 q). IR (CCl4, cm-1): ν 3430br, 2968m, 2940w, 2880w,
1703vs. MS (EI): m/z 169 (1, [M-CH3]+), 155 (1, [M-C2H5]+),
124 (40), 109 (12), 95 (59), 43 (100, [C2H3O]+). Anal. calcd. for
camphanoate 16 C21H32O5 (364): C 69.20, H 8.85. Found: C 69.29,
H 8.88.
(6S)-6-Chloro-3,3-diethylhept-4E-en-2-one ((S)-17). A mixture
of (R)-15 (280 mg, 1.52 mmol, 98% ee) and hexachloroacetone
(0.51 mL, 3.34 mmol) was cooled to 0 °C and triphenylphosphine
(420 mg, 1.60 mmol) was added at once. The mixture was stirred
at 0 °C for 1 h and then at room temperature for 15 h. The mixture
was diluted with MtBE and washed with water, sat. NaHCO3
solution, and brine. After drying and concentration of the combined
ether extracts the crude product was purified by chromatography
over silica gel (hex/MtBE 95:5) and short-path distillation (80 °C,
0.05 mbar). (S)-17 was obtained as a colorless liquid (260 mg, 85%,
77% ee). [R]25D ) +20.70 (c 1.145, CH2Cl2). 1H NMR (300 MHz,
CDCl3; δ, ppm): 5.49-5.40 (m, 2 H), 4.16-4.20 (m, 1 H), 1.75
(s, 3 H), 1.59-1. 36 (m, 4 H), 1.28 (d, J ) 6.6 Hz, 3 H), 0.60 (dd,
J ) 7.5, 7.9 Hz, 6 H). 13C NMR (75 MHz, CDCl3; δ, ppm): 210.2
(s), 133.5, 133.3, 57.9 (3 d), 57.3 (1 s), 26.2, 26.0 (2 t), 25.7, 25.2
(2 q), 8.1 (2 q). IR (CCl4, cm-1): ν 2969m, 2881w, 1706vs. MS
(EI): m/z 173 (3, [M-C2H5]+), 167 (2, [M-Cl]+), 159 (2,
[M-CH3CO]+), 124 (75), 109 (17), 95 (100), 81 (47), 67 (48).
HRMS (EI): calcd. for C10H16OCl ([M-CH3]+): 187.0890; found,
187.0881.
5,5-Diethylhept-3E-ene-2,6-dione (14). To a solution of 9a
(24.43 g, 0.17 mol) in xylene (250.0 mL) 1-(triphenyl-λ5-phospha-
nylidene)propan-2-one (60.42 g, 0.19 mol) was added, and the
suspension was heated to reflux. After 24 h the mixture was cooled
to room temperature, diluted with MtBE and washed with water
and brine. The organic solution was concentrated and the residue
distilled over a 20-cm Vigreux column (68 °C, 0.05 mbar). The
diketone 14 was obtained as a colorless oil (23.00 g, 74%). The
typical (E)-alkene absorption peaks at 1674 and 988 cm-1 in the
IR spectrum as well as the vinylic proton spin-coupling constant
1
of J ) 16.8 Hz in the H NMR (300 MHz, CDCl3, δ 6.94 and
6.12) spectrum are good indicators that the product possesses E
configuration. 1H NMR (300 MHz, CDCl3; δ, ppm): 6.94 (d, J )
16.8 Hz, 1 H), 6.12 (d, J ) 16.8 Hz, 1 H), 2.31 (s, 3 H), 2.13 (s,
3 H), 1.85-1.76 (m, 4 H), 0.78 (t, J ) 7.6 Hz, 6 H). 13C NMR (75
MHz, CDCl3; δ, ppm): 208.7, 198.0 (2 s), 148.4, 131.0 (2 d), 58.5
(1 s), 27.1 (2 t), 27.0, 25.9 (2 q), 8.4 (2 q). IR (CCl4, cm-1): ν
2969w, 2881w, 1703s, 1674s, 1619m, 988m. MS (EI): m/z 153
(1, [M-C2H5]+), 140 (37), 125 (15), 111 (46), 97 (13), 43 (100,
[C2H3O]+). Anal. calcd. for C11H18O2 (182): C 72.49, H 9.95.
Found: C 72.36, H 9.72.
2,2-Diethyl-3-(prop-1E/Z-en-1-yl)cyclobutanone ((E/Z)-18). A
solution of (S)-17 (1.00 g, 4.95 mmol, 77% ee) in THF (22.0 mL)
t
t
was cooled to 0 °C. BuOK 1 M in BuOH (5.00 mL, 5.00 mmol)
was added dropwise to the stirred solution over the period of 1 h.
The mixture was allowed to reach room temperature and stirring
was continued for 4 h. The reaction was quenched with water and
extracted with MtBE. The organic layers were combined, washed
with water and brine, dried, and concentrated. The crude product
mixture was purified by chromatography over silica gel (hex/MtBE
(6R)-3,3-Diethyl-6-hydroxyhept-4E-en-2-one ((R)-15). A solu-
tion of (+)-Ipc2BH (5.00 g, 27.50 mmol) in Et2O (25.0 mL) was
cooled to -60 °C and HCl in Et2O (7.40 mL, 30.00 mmol) was
2432 J. Org. Chem., Vol. 72, No. 7, 2007

Cyclobutanones through SNi′ Ring Closure
9:1) and short-path distillation (10 mbar, 80 °C). (E/Z)-18 (ratio
the mixture and does therefore not necessarily correspond precisely
to that of the corresponding pure compounds. 1H NMR for (Z)-18
(500 MHz, C6D6; δ, ppm): 5.39 (dqd, J ) 10.7, 6.9, 1.0 Hz, 1 H),
5.24 (ddq, J ) 10.7, 9.6, 1.8 Hz, 1 H), 280.-2.69 (m, 2 H), 2.49-
2.47 (m, 1 H), 1.51-1.38 (m, 3 H), 1.42 (dd, J ) 6.9, 1.8 Hz, 3
H), 1.33 (dq, J ) 14.5, 7.5 Hz, 1 H), 0.82 (t, J ) 7.5 Hz, 3 H),
85:15, GC) was obtained as a colorless oil (402 mg, 49%). [R]25
D
) -5.42 (c 0.720, CH2Cl2). 1H NMR (300 MHz, CDCl3; δ, ppm):
5.36-5.18 (m, 2 H), 2.78-2.56 (m, 2 H), 2.49-2.36 (m, 1 H),
1.54 (d, J ) 4.9 Hz, 1 H), 1.52-1.25 (m, 4 H), 0.84 (t, J ) 7.4
Hz, 3 H), 0.73 (t, J ) 7.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3;
δ, ppm): 214.1 (s), 130.0, 127.1 (2 d), 70.6 (s), 47.5 (t), 36.9 (d),
25.0, 21.7 (2 t), 17.8, 13.2, 8.4, 7.7 (3 q). IR (CCl4, cm-1): ν 2967m,
2921w, 1771vs. MS (EI): m/z 166 (2, M+·), 151 (1, [M-CH3]+]),
138 (5, [M-C2H4]+), 124 (40), 109 (18), 98 (57), 95 (68), 83 (100),
67 (46). Anal. calcd. for C11H18O (166): C 79.46, H 10.91.
Found: C 79.44, H 10.72. HRMS (EI): calc. for C11H18O (M+):
166.1358. Found: 166.1356.
1
0.73 (t, J ) 7.5 Hz, 3 H). H NMR for 20 (500 MHz, C6D6; δ,
ppm): 6.22 (dtd, J ) 17.0, 10.1, 0.6 Hz, 1 H), 6.00 (dd, J ) 15.8,
10.3 Hz, 1 H), 5.51 (dd, J ) 15.8, 0.6 Hz, 1 H), 5.05 (d, J ) 17.0
Hz, 1 H), 4.95 (d, J ) 10.1 Hz, 1 H), 1.75 (s, 3 H), 1.60 (dq, J )
14.5, 7.5 Hz, 2 H), 1.51 (dq, J ) 14.8, 7.5 Hz, 2 H), 0.63 (t, J )
7.5 Hz, 6 H).
Separation of (E)-18 and (Z)-18. AgNO3 (6.00 g, 35.00 mmol)
was dissolved in acetonitrile (100.0 mL) and silica gel (50.00 g)
was added. The acetonitrile was removed by rotary evaporator (200
mbar) and the AgNO3 impregnated silica gel was dried in vacuo
(0.05 mbar) for 24 h. A chromatography column (12 × 1 cm) was
filled with the treated silica gel, and a mixture of (E)-18 and (Z)-
18 (E/Z ) 85:15, 45 mg, 0.27 mmol) was separated over 48
fractions (hex/MtBE 97.5 : 2.5). The Rf values for (E)-18 and (Z)-
18 on AgNO3-impregnated silica gel thin-layer chromatography
plates (hex/MtBE 95:5) were 0.3 and 0.2, respectively. The isolated
E and Z isomers were purified by microscale distillation (0.05 mbar,
40 °C) under dust-free conditions. Analysis by ROA spectroscopy
indicated (S)-configuration for (E)-18 (32 mg, 71%, 75% ee) and
Acknowledgment. Funding from Givaudan is gratefully
acknowledged. We would like to thank Prof. Dr. Heinz
Heimgartner and his group from the University of Zurich for
many valuable discussions. We thank Prof. Dr. Werner Hug
and Dmytro Dudenko from the University of Fribourg for
performing the ROA measurements and calculations. We also
thank Dr. Anthony Linden from the University of Zurich for
performing the X-ray crystallographic measurements and cal-
culations. We are grateful to Dr. Gerhard Brunner from
Givaudan for his help with various NMR related problems and
to Katarina Grman from Givaudan for performing the chiral
GC analysis.
(R)-configuration for (Z)-18 (3 mg, 7%, 75% ee). [R]25 (S)-(E)-
D
1
18 ) +0.96 (c 1.040, CH2Cl2). H NMR for (E)-18 (500 MHz,
Supporting Information Available: Experimental procedures
for the synthesis of 8a,b; 9a,b; 12b*, X-ray crystallographic data
C6D6; δ, ppm): 5.31-5.19 (m, 2 H), 2.71 (dd, J ) 17.3, 9.1 Hz,
1 H), 2.60 (dd, J ) 17.3, 7.9 Hz, 1 H), 2.39-2.37 (m, 1 H), 1.53
(d, J ) 5.7 Hz, 3 H), 1.52 (dq, J ) 14.3, 7.5 Hz, 1 H), 1.42 (dq,
J ) 14.4, 7.5 Hz, 1 H), 1.39 (dq, J ) 14.3, 7.5 Hz, 1 H), 1.31 (dq,
J ) 14.4, 7.5 Hz, 1 H), 0.83 (t, J ) 7.5 Hz, 3 H), 0.71 (t, J ) 7.5
1
for 16, the determination of the ee for (S)-15 by H NMR, chiral
1
GC analysis of (S)-17 and (E/Z)-18, as well as H and 13C NMR
data for 9a,b, 10a,b, 12a, 12b*, 6a,b, 14, (R)-15, (S)-17, and (E/
Z)-18. This material is available free of charge via the Internet at
http://pubs.acs.org.
Hz, 3 H). [R]25 (R)-(Z)-18 ) -5.94 (c 0.690, CH2Cl2). NMR
D
analysis showed that (Z)-18 contained 25% of the dehydrochlori-
nation product 20. The following NMR data was elaborated from
JO062264V
J. Org. Chem, Vol. 72, No. 7, 2007 2433