α-haloenol acetates: Versatile reactants for oxetan-2-one, azetidin-2-one and isoxazolidin-5-one synthesis

Article abstract of DOI:10.1002/ejoc.200600708

New ketene equivalents, namely α-haloenol acetates, are investigated as both nucleophilic and electrophilic reactants in a tandem aldol-lactonization reaction. Diethylaluminum ethoxide proves to be an efficient promoter for the aldol reaction with a wide

Full text of DOI:10.1002/ejoc.200600708

FULL PAPER
DOI: 10.1002/ejoc.200600708
α-Haloenol Acetates: Versatile Reactants for Oxetan-2-one, Azetidin-2-one and
Isoxazolidin-5-one Synthesis
Romain Bejot,[a] Siddam Anjaiah,[b] J. R. Falck,*[b] and Charles Mioskowski*[a]
Keywords: Aldol reaction / Aluminum / Heterocycles / Lactonization / Tandem reaction
New ketene equivalents, namely α-haloenol acetates, are in-
vestigated as both nucleophilic and electrophilic reactants in
etan-2-ones, azetidin-2-ones and isoxazolidin-5-ones. The
resultant heterocyclic adducts are common structural ele-
ments in numerous compounds of interest as well as key in-
termediates in the preparation of other functionalities.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
a
tandem aldol–lactonization reaction. Diethylaluminum
ethoxide proves to be an efficient promoter for the aldol reac-
tion with a wide range of substrates, including inter alia, al-
dehydes, ketones, imines, nitrones and oximes, leading to ox-
ported.[8] Recently, Mukaiyama et al. explored a new and
effective catalyst, diethylaluminum ethoxide, which pro-
motes aldol reactions starting from enol esters.[9,10] As part
of our investigation of organochromium methodology, we
described an efficient synthesis of α-haloenol acetates 1 by
using chromous chloride.[11] The use of diethylaluminum
ethoxide brought us to report herein a tandem aldol–lac-
tonization reaction starting from α-haloenol acetates 1 that
behave as a ketene equivalent (2; Scheme 1).
Introduction
Oxetan-2-ones, azetidin-2-ones and isoxazolidin-5-ones
are witnessing a great deal of interest because of their syn-
thetic applications and their potential use as therapeutic
agents.[1] Useful reactions exploiting the inherent strain in
the four-membered rings and their transformation into β-
hydroxy and β-amino acids have been widely developed.[2,3]
As units present in many natural products, β-amino acids,
β-hydroxy acids, β-lactones and β-lactams are of great im-
portance. Since the first preparation of β-lactams by Staud-
inger et al. in 1907 by a [2+2] cycloaddition between ketenes
and imines,[4] many synthetic methods for the preparation
of β-lactones and β-lactams have been investigated.[5]
Amongst these methods, the tandem aldol–lactonization re-
action has been applied to a wide variety of carbon skeleton
constructions.[6] Though the aldol reaction with silyl enol
ethers generally takes place smoothly and gives the adducts
in satisfactory yields,[7] typical Lewis acid catalysts some-
times induce side reactions such as cleavage of protecting
groups, isomerization and rearrangement. The formation of
side reactions is more or less avoided with more stable reac-
tants such as enol esters. There are many reports of aldol
reactions that employ enol esters under basic conditions;
however, to date, only a few aldol reactions proceeding un-
der weakly acidic or neutral conditions have been re-
Scheme 1. α-Haloenol acetates 1 and their synthetic equivalence
with ketenes.
Results and Discussion
Besides the expected reactions of a ketene equivalent
with nucleophilic moieties,[12] such as hydrolysis (Scheme 2,
Reaction a), alcoholysis (Reaction b)[11] and aminolysis
(Reaction c), α-haloenol acetates 1 are capable of under-
going aldol reactions with electrophilic moieties such as al-
dehydes and ketones (Scheme 3, Reactions d, e and f), im-
[a] Laboratoire de Synthèse Bio-Organique, UMR 7175 – LC1, Fa- ines (Reaction g), nitrones (Reaction h) and oximes (Reac-
tion i).[13] We found that freshly prepared diethylaluminum
culté de Pharmacie, Université Louis Pasteur de Strasbourg,
74 Route du Rhin, B. P. 24, 67 401 Illkirch, France
ethoxide was an efficient promoter for the aldol reaction
starting from α-haloenol acetates 1.
When the aliphatic derivative of α-chloroenol ester, (Z)-
1-chloro-4-phenylbutenylacetate (1a), and aliphatic alde-
hydes or ketones 3 are reacted with diethylaluminum ethox-
ide in anhydrous THF, di- and tri-substituted β-lactones 4
were obtained in moderate-to-good yields (Table 1, Entries
Fax: +33-3-9024-4306
E-mail: mioskow@aspirine.u-strasbg.fr
[b] Department of Biochemistry, University of Texas Southwestern
Medical Center,
5323 Harry Hines Blvd., Dallas, TX 75390-9038, USA
Fax: +1-214-648-6455
E-mail: j.falck@utsouthwestern.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 101–107
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
101

R. Bejot, S. Anjaiah, J. R. Falck, C. Mioskowski
Table 1. Reaction of 1 with carbonyl compounds.
FULL PAPER
Scheme 2. Reactivities of α-haloenol acetates with nucleophiles.
Scheme 3. Reactivities of α-haloenol acetates with electrophiles.
1–7).[14] The range of suitable α-haloenol acetates encom-
passed (Z)-1-fluoro-4-phenylbut-1-enyl acetate (1b) that
provide access to β-lactones, though in lower but acceptable
yield (Entry 8). When reacted under the same conditions,
the aryl derivative of the α-chloroenol ester, 1-chloro-2-
phenylethenyl acetate (1c), affords β-hydroxy ester 5e (Entry
9). The reaction of aliphatic derivatives of the α-chloroenol
ester also gives rise to β-hydroxy esters 5 when the reaction
is carried out in a mixture of THF and alcohol (Entry 10).
Interestingly, the aldol reaction can take place in protic sol-
vents. Finally, reaction of 1a with α,β-unsaturated carbonyl
compounds led to di- and tri-substituted olefins 5 (Entries
11–14).
When reacted with imines, (Z)-1-chloro-4-phenylbutenyl
acetate (1a) gives rise to β-lactams 7 and β-amino esters 9
(Table 2, Entries 1–4). Unfortunately, bicyclic azetidin-2-
one derivative 8d (Entry 4) could not be isolated, but could
be detected by H NMR analysis of the crude material: it
decomposes to acyclic amide 10d. Unexpectedly, tricyclic
compound 11d could be isolated as a byproduct. The α-
[a] Isolated yield after SiO2 chromatographic purification. Stereo-
chemistries have been deduced from 1H NMR analysis. [b] Cor-
rected yield based on conversion of α-haloenol acetate. [c] Unre-
acted 1c was recovered as a mixture of isomers Z/E 67:33. [d] Sol-
vent: THF/EtOH. [e] Unstable adduct.
1
haloenol esters proved also to be reactive with nitrones and (Entries 6 and 7). Alkoxy-substituted isoxazolidin-5-one
oximes 12. Under standard conditions, 1a affords isoxazol- 13c also decomposed on silica gel to give the isoxazol-
idin-5-ones 13 in good yields (Entries 5–7). Interestingly, 5(2H)-one derivative through β-elimination of ethanol (En-
from oximes, N-acetyl-isoxazolidin-5-ones are obtained try 7).
102
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Tandem Aldol–Lactonization Reaction Starting from α-Haloenol Acetates
FULL PAPER
Table 2. Reaction of 1 with imines, nitrones and oximes.
tionalized by a simple stereochemical model. Mukayama et
al. postulated that enol esters can be activated by nucleo-
philic attack of the acetyl group by the ethoxy group of
Et2AlOEt after coordination of the aluminum reagent to
the ketone or the aldehyde (Scheme 4).[9] Thus, a one-,[15]
or two-step acylation can give ethyl acetate as a byproduct.
An aldol reaction followed by lactonization may then give
rise to the β-lactone with elimination of diethylhaloalane.
The conversion of the carboxylic acid halide enolate to the
corresponding ketene may also give the β-lactone by a [2+2]
cycloaddition.[16] Results obtained from α-fluoroenol ace-
tate 1b seem to exclude a common nucleophile, such as ke-
tene 2, if the reaction is not catalyzed by Et2AlX or if it is
in both cases irreversible. Alkylhaloalanes and alkylethoxy-
alanes readily form complexes of associated units through
reversible and rather weak interactions.[17] Thus, several
transition states may be involved depending on the steric
interactions between the substituents. A transesterification
of the aldol adduct or the conversion of the ketene to an
ester enolate may explain the formation of β-hydroxy esters
When α-haloenol acetates are reacted with α,β-unsatu-
rated aldehydes and ketones under standard conditions, di-
and tri-substituted olefins 6 are obtained. A decarboxyl-
ation of the transcient β-lactone probably occurs, promoted
by dialkylethoxyalane and dialkylhaloalane. β-Lactone
could actually be detected by 1H NMR analysis of the
crude materials. Treatment of β-lactone 4k with diethylalu-
minum ethoxide or dimethylaluminum chloride led to a
mixture of β-lactone, β-hydroxy ester and olefin (Scheme 5).
Decarboxylation occurs with aryl derivatives because of the
electron density of the aryl group: it was actually demon-
strated that electron-rich groups at the C-4 position of 2-
oxetanones facilitate the decarboxylation reaction.[2a,18] Fi-
nally, the mechanism probably involves a stepwise fragmen-
tation through a zwitterionic intermediate because both β-
lactone fragmentations are nonstereoselective.
Besides the aldol reactions with electrophilic moieties, we
finally observed the formation of a β-keto ester adduct
formed by a Claisen-type condensation in the presence of
DMSO (Scheme 6). The mechanism is not clear but can be
interpreted as the Claisen condensation of two ethyl car-
boxylates, as the treatment of α-haloenol acetates with Et2-
AlOEt may give rise to ethyl carboxylate derivatives.
[a] Isolated yield after SiO2 chromatographic purification. Stereo-
chemistries have been deduced from 1H NMR analysis. [b] Cor-
rected yield based on conversion of α-haloenol acetate. [c] Yield
calculated from 1H NMR of the crude material. [d] Compound
8d could not be isolated. It gives quantitatively N-(4-oxopentyl)-4-
phenylbutanamide. [e] Compound 13c undergoes a β-elimination
on SiO2 to give 5(2H)-isoxazolone as a byproduct.
Conclusions
α-Haloenol acetates proved to be versatile reactants and
The scope of the reaction was explored by using various diethylaluminum ethoxide demonstrated a powerful pro-
aliphatic carbonyl derivatives and the results indicate intri- motion of aldol and tandem aldol–lactonization reactions
guing stereoselectivity. A reversal of stereoselectivity was with formal [2+2] and [2+3] cycloadditions. Thus, the reac-
observed between a few linear and branched aldehydes tion of aldehydes and ketones under the described condi-
(Table 1, Entries 1 and 2). A better selectivity was observed tions provide access to β-lactones, β-hydroxy esters and ole-
with ketones with respect to aldehydes (Entries 2 and 7) and fins according to the substitution pattern. Under the same
a bulky substituent did not lead to any selectivity (Entry 3). conditions, imines give rise to β-amino esters and β-lactams,
In addition, the stereoselectivity of β-lactones obtained and isoxazolidin-5-ones could be obtained starting from
from α-fluoroenol esters is lower than that obtained from nitrones and oximes. Further extensions are underway in
α-chloroenol (Entries 7 and 8). These results cannot be ra- our laboratory, including the enantioselective synthesis of
Eur. J. Org. Chem. 2007, 101–107
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103

R. Bejot, S. Anjaiah, J. R. Falck, C. Mioskowski
FULL PAPER
Scheme 4. Activation of the enol acetate by Et2AlOEt.
layers were separated, and the aqueous phase was extracted twice
with AcOEt. The combined organic extracts were washed with
brine and then dried with Na2SO4. After concentration under vac-
uum, the crude product was purified by chromatography on silica
gel to afford 37 mg (63%) of 4-butyl-3-(2-phenylethyl)oxetan-2-one
(4a) (cis/trans 70:30) as a colorless oil. 4a: 1H NMR (200 MHz,
CDCl3): δ = 7.33–7.18 (m, 5 H), 4.56–4.46 (m, 0.7 Hcis), 4.24–4.15
(m, 0.3 Htrans), 3.69–3.57 (m, 0.7 Hcis), 3.24.3.13 (m, 0.3 Htrans),
2.98–2.65 (m, 2 H), 2.30–1.34 (m, 8 H), 0.93 (t, J = 6.8 Hz, 3 H)
ppm. 13C NMR (CDCl3, 50 MHz): δ = 172.2 (cis), 171.5 (trans),
140.7 (cis), 140.4 (trans), 128.7, 128.6, 128.5, 126.6 (trans), 126.5
(cis), 78.5 (trans), 75.8 (cis), 55.5 (trans), 51.8 (cis), 34.1 (trans),
33.5 (cis), 33.2 (trans), 30.1 (cis), 29.7 (trans), 27.8 (cis), 27.2 (trans),
Scheme 5. Decarboxylation of 2-oxetanones promoted by Et2Al-
OEt and Me2AlCl.
25.9 (cis), 22.5 (cis), 22.4 (trans), 14.0 ppm. IR: ν = 1821 cm–1.
˜
HRMS (IE): calcd. for C15H20O2 [M]+ 232.1463; found 232.1467.
1
4-Isopropyl-3-(2-phenylethyl)oxetan-2-one (4b): (trans/cis 65:35). H
Scheme 6. Claisen condensation.
NMR (300 MHz, CDCl3): δ = 7.32–7.19 (m, 5 H), 4.09 (dd, J1 =
10.6 Hz, J2 = 6.2 Hz, 0.35 Hcis), 3.96 (dd, J1 = 7.8 Hz, J2 = 4.1 Hz,
0.65 Htrans), 3.62 (m, 0.35 Hcis), 3.25 (td, J1 = 7.8 Hz, J2 = 4.1 Hz,
0.65 Htrans), 3.07–2.97 (m, 0.35 Hcis), 2.88–2.70 (m, 1.65 H), 2.27–
1.84 (m, 3 H), 1.07 (d, J = 6.9 Hz, 1.05 Hcis), 1.04 (d, J = 6.9 Hz,
1.95 Htrans), 0.95 (d, J = 6.9 Hz, 1.95 Htrans), 0.92 (d, J = 6.9 Hz,
1.05 Hcis) ppm. 13C NMR (CDCl3, 75 MHz): δ = 172.1 (cis), 171.4
(trans), 140.8 (cis), 140.4 (trans), 128.7, 128.4, 126.5 (cis), 126.4
(trans), 82.9 (trans), 80.3 (cis), 53.5 (trans), 51.1 (cis), 33.2 (cis),
33.1 (trans), 32.3 (trans), 30.0 (trans), 29.0 (cis), 26.3 (cis), 19.2 (cis),
oxetan-2-ones, azetidin-2-ones and isoxazolidin-5-ones
through optically active dialkylaluminum alkoxide, which is
readily accessible from chiral alcohols.
Experimental Section
Triethylaluminum (25% in toluene) was purchased from Aldrich.
Tetrahydrofuran (THF) was distilled from Na/benzophenone ketyl.
GC–MS analyses were carried out with a Shimadzu GCMS-
QP5050A instrument with a SGE silica capillary, 25 mϫ0.22 mm
BPX5 column (5% phenyl polysilphenylene-siloxane/95% methyl-
polysiloxane), helium carrier gas (29 mL/min; 113 kPa), 260 °C
interface, 80 °C column temp., 320 °C detector, programmed for
2 min at 80 °C, then heating.
18.0, 17.2 (trans) ppm. IR: ν = 1821 cm–1. HRMS (EI): calcd. for
˜
C14H18O2 [M]+ 218.1307; found 218.1305.
4-tert-Butyl-3-(2-phenylethyl)oxetan-2-one (4c): (cis/trans 1:1). 1H
NMR (300 MHz, CDCl3): δ = 7.35–7.20 (m, 10 H), 4.21 (d, J =
6.8 Hz, 1 Hcis), 4.01 (J = 3.8 Hz, 1 Htrans), 3.67 (td, J1 = 7.2 Hz, J2
= 6.8 Hz, 1 Hcis), 3.33 (td, J1 = 7.2 Hz, J2 = 3.8 Hz, 1 Htrans), 3.07–
2.97 (m, 1 Hcis), 2.86–2.68 (m, 3 Hcis+trans), 2.42–1.95 (m, 4 H), 1.06
(s, 9 Hcis), 1.00 (s, 9 Htrans) ppm. 13C NMR (CDCl3, 75 MHz): δ =
172.4 (cis), 171.4 (trans), 140.7 (cis), 140.5 (trans), 128.7, 128.4,
126.4, 85.2 (trans), 82.3 (cis), 51.5 (cis), 50.5 (trans), 34.2, (cis), 33.9
(trans), 33.1 (cis), 32.9 (trans), 30.4 (trans), 27.4 (cis), 26.0 (cis),
4-Butyl-3-(2-phenylethyl)oxetan-2-one (4a) (Representative Pro-
cedure): To a solution of triethylaluminum (25% in toluene,
0.75 mL) was carefully added anhydrous ethanol (73 µL,
1.25 mmol) at –78 °C under an argon atmosphere. The solution was
warmed to room temp. and diluted with anhydrous THF (2.0 mL).
(Z)-1-Chloro-4-phenylbut-1-enyl acetate (1a) (50 µL, 0.25 mmol)
and valeraldehyde (3a) (54 µL, 0.5 mmol) were then added to the
solution of diethylaluminum ethoxide, at 0 °C under an argon at-
mosphere. After the reaction mixture was stirred for 15 h from 0 °C
to room temp., aqueous Rochelle salt and AcOEt were added, and
the mixture was stirred for an additional 30 min at room temp. The
24.5 (trans) ppm. IR: ν = 1820 cm–1. HRMS (IE): calcd. for
˜
C15H20O2 [M]+ 232.1463; found 232.1445.
4,4-Dimethyl-3-(2-phenylethyl)oxetan-2-one (4d): 1H NMR (200
MHz, CDCl3): δ = 7.37–7.19 (m, 5 H), 3.23 (dd, J1 = 8.3 Hz, J2 =
8.0 Hz, 1 H), 2.93–2.60 (m, 2 H), 2.30–1.85 (m, 2 H), 1.56 (s, 3 H),
1.48 ppm (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 171.4,
140.5, 128.7, 128.6, 126.5, 80.2, 57.3, 33.4, 27.9, 26.9, 22.0 ppm.
104
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Tandem Aldol–Lactonization Reaction Starting from α-Haloenol Acetates
IR: ν = 1812 cm–1. HRMS (IE): calcd. for C H O [M]+
FULL PAPER
4-Phenyl-1-p-tolylbut-1-ene (6h): (E/Z 86:14). (E)-6h: 1H NMR
(200 MHz, CDCl3): δ = 7.36–7.09 (m, 9 H), 6.41 (d, J = 15.9 Hz,
1 H), 6.22 (dt, J1 = 15.9 Hz, J2 = 6.4 Hz, 1 H), 2.85–2.76 (m, 2 H),
2.60–2.48 (m, 2 H), 2.34 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 142.0, 136.7, 135.1, 130.3, 129.3, 129.0, 128.6, 128.5, 126.0,
36.1, 35.0, 21.3 ppm. (Z)-6h: 1H NMR (200 MHz, CDCl3): δ =
˜
13 16
2
204.1150; found 204.1172.
4,4-Diethyl-3-(2-phenylethyl)oxetan-2-one (4e): 1H NMR (300
MHz, CDCl3): δ = 7.34–7.21 (m, 5 H), 3.24 (dd, J1 = 9.0 Hz, J2 =
7.2 Hz, 1 H), 2.95–2.84 (m, 1 H), 2.79–2.68 (m, 1 H), 2.22–2.10 (m,
1 H), 2.04–1.67 (m, 5 H), 1.02 (t, J = 7.5 Hz, 3 H), 0.92 (t, J =
7.5 Hz, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 172.0, 140.7,
128.7, 128.5, 126.5, 85.0, 56.0, 33.7, 29.3, 26.3, 24.9, 8.2, 7.6 ppm.
7.31–7.15 (m, 9 H), 6.43 (d, J = 11.7 Hz, 1 H), 5.67 (dt, J1
=
11.7 Hz, J2 = 6.6 Hz, 1 H), 2.84–2.64 (m, 4 H), 2.36 (s, 3 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 141.9, 136.4, 134.8, 131.3, 129.4,
129.0, 128.8, 128.6, 128.5, 126.0, 36.3, 30.6, 21.3 ppm.
IR: ν = 1814 cm–1. HRMS (IE): calcd. for C H O [M]+
˜
15 20
2
232.1463; found 232.1467.
2,5-Diphenylprop-2-ene (6i): (E/Z 70:30). 1H NMR (200 MHz,
CDCl3): δ = 7.43–7.13 (m, 10 H), 5.86 (t, J = 7.0 Hz, 0.7 HE), 5.54
(t, J = 7.2 Hz, 0.3 HZ), 2.86–2.77 (m, 1.4 HE), 2.73–2.50 (m, 2
HE+Z), 2.39–2.27 (m, 0.6 HZ), 2.06 (s, 0.9 HZ), 2.02 (s, 2.1 HE) ppm.
13C NMR (50 MHz, CDCl3): δ = 144.0 (Z), 142.1 (E), 137.0 (Z),
135.6 (E), 128.62, 128.59, 128.5, 128.33, 128.28, 128.2, 128.0, 127.5,
126.8, 126.7, 126.6, 126.0, 125.83, 125.76, 36.5 (Z), 36.0 (E), 31.1
(Z), 30.9 (E), 25.7 (Z), 15.9 (E) ppm.
4-Methyl-3-(2-phenylethyl)-4-propyloxetan-2-one (4f): (trans/cis
66:33). trans-4f: H NMR (300 MHz, CDCl3): δ = 7.35–7.19 (m, 5
1
H), 3.21 (dd, J1 = 8.1 Hz, J2 = 7.9 Hz, 1 H), 2.90–2.79 (m, 1 H),
2.76–2.65 (m, 1 H), 2.20–2.07 (m, 1 H), 1.97–1.66 (m, 3 H), 1.46
(s, 3 H), 1.43–1.27 (m, 2 H), 0.96 (t, J = 7.3 Hz, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 171.8, 140.6, 128.7, 128.6, 126.5, 82.4,
56.2, 43.1, 33.5, 27.0, 19.7, 17.7, 14.3 ppm. cis-4f: 1H NMR
(300 MHz, CDCl3): δ = 7.33–7.19 (m, 5 H), 3.22 (dd, J1 = 8.9 Hz,
J2 = 7.3 Hz, 1 H), 2.92–2.82 (m, 1 H), 2.77–2.66 (m, 1 H), 2.20–
2.07 (m, 1 H), 2.02–1.89 (m, 1 H), 1.84–1.70 (m, 1 H), 1.68–1.57
(m, 1 H), 1.52 (s, 3 H), 1.49–1.42 (m, 2 H), 0.97 ppm (t, J = 7.3 Hz,
3 H). 13C NMR (50 MHz, CDCl3): δ = 171.9, 140.7, 128.7, 128.6,
(E)-(4-Methyl-3,5-hexadienyl)benzene [(E)-6j]: 1H NMR (300 MHz,
CDCl3): δ = 7.32–7.19 (m, 5 H), 6.38 (dd, J1 = 17.3 Hz, J2
=
10.6 Hz, 1 H), 5.55 (t, J = 7.2 Hz, 1 H), 5.10 (d, J = 17.3 Hz, 1 H),
4.95 (d, J = 10.6 Hz, 1 H), 2.79–2.66 (m, 2 H), 2.54–2.43 (m, 2 H),
1
126.5, 82.3, 58.3, 37.4, 33.6, 26.3, 24.9, 17.2, 14.5 ppm. IR: ν =
˜
1.71 (s, 3 H) ppm. (Z)-6j: H NMR (300 MHz, CDCl3): δ = 7.32–
1815 cm–1. HRMS (EI): calcd. for C15H20O2 [M]+ 232.1463; found
7.19 (m, 5 H), 6.77 (dd, J1 = 17.3 Hz, J2 = 10.9 Hz, 1 H), 5.45 (t,
J = 7.5 Hz), 5.21 (d, J = 17.3 Hz, 1 H), 5.09 (d, J = 10.9 Hz, 1 H),
2.79–2.66 (m, 2 H), 2.54–2.43 (m, 2 H), 1.83 (s, 3 H) ppm.
232.1467; calcd. for C14H20 [M – CO2]+ 188.1565; found 188.1551.
trans-4-Isopropyl-4-methyl-3-(2-phenylethyl)oxetan-2one: (trans/cis
1
94:6). trans-4g: H NMR (300 MHz, CDCl3): δ = 7.35–7.20 (m, 5
1-Benzyl-4-phenyl-3-(2-phenylethyl)azetidin-2-one (8a): (trans/cis
88:12) 1H NMR (200 MHz, CDCl3): δ = 7.30–6.89 (m, 15 H), 4.92
(d, J = 14.9 Hz, 0.12 Hcis), 4.86 (d, J = 14.9 Hz, 0.88 Htrans), 4.62
(d, J = 5.4 Hz, 0.12 Hcis), 4.07 (d, J = 2.0 Hz, 0.88 Htrans), 3.90 (d,
J = 14.9 Hz, 0.12 Hcis), 3.75 (d, J = 14.9 Hz, 0.88 Htrans), 3.47–3.36
(m, 0.12 Hcis), 3.14–3.05 (m, 0.88 Htrans), 2.74 (t, J = 7.8 Hz, 1.76
H), 2.55–1.76 (m, 2.24 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
170.3, 141.1, 137.8, 135.8, 129.1, 128.9, 128.6, 128.5, 127.8, 126.7,
H), 3.19 (dd, J1 = 9.2 Hz, J2 = 7.4 Hz, 1 H), 2.92–2.82 (m, 1 H),
2.77–2.66 (m, 1 H), 2.22–2.09 (m, 1 H), 2.03–1.81 (m, 2 H), 1.40
(s, 3 H), 1.02 (d, J = 6.9 Hz, 3 H), 0.91 (d, J = 7.2 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 171.8, 140.7, 128.7, 128.5, 126.4,
85.1, 55.5, 37.6, 33.5, 27.1, 17.1, 16.6, 15.2 ppm. IR: ν = 1813 cm–1.
˜
GC (heating at 10 °C/min): tR = 9.20 min. HRMS (IE): calcd. for
C15H20O2 [M]+ 232.1463; found 232.1467. cis-4g: GC (heating at
10 °C/min): tR = 9.04 min.
126.1, 60.8, 60.0, 44.4, 33.4, 30.6 ppm. IR: ν = 1751 cm–1. HRMS
˜
(ESI-TOF): calcd. for C24H24N1O1 [M]+ 342.1852; found 342.1872.
trans-8a: GC (heating at 25 °C/min): tR = 12.42 min. cis-8a: GC
(heating at 25 °C/min): tR = 12.60 min.
Ethyl 3-Ethyl-3-hydroxy-2-phenylpentanoate (5e): M.p. 58–60 °C.
1H NMR (300 MHz, CDCl3): δ = 7.48–7.44 (m, 2 H), 7.36–7.29
(m, 3 H), 4.22 (dq, J1 = 10.9 Hz, J2 = 7.2 Hz, 1 H), 4.07 (dq, J1 =
10.9 Hz, J2 = 7.2 Hz, 1 H), 3.77 (br. s, 1 H), 3.67 (s, 1 H), 1.65 (qd,
J1 = 7.5 Hz, J2 = 2.8 Hz, 2 H), 1.33–1.07 (m, 2 H), 1.22 (t, J =
7.2 Hz, 3 H), 0.96 (t, J = 7.5 Hz, 3 H), 0.78 (t, J = 7.5 Hz, 3
H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 174.9, 135.2, 129.9,
128.4, 127.6, 77.4, 76.1, 61.1, 56.8, 32.0, 30.5, 29.1, 27.0, 22.8, 14.2,
1-(4-Methoxyphenyl)-4-phenyl-3-(2-phenylethyl)azetidin-2-one (8b):
(trans/cis 95:5): 1H NMR (300 MHz, CDCl3): δ = 7.38–7.13 (m, 12
H), 6.79 (d, J = 9.1 Hz, 2 H), 5.17 (d, J = 5.9 Hz, 0.05 Hcis), 4.63
(d, J = 2.2 Hz, 0.95 Htrans), 3.75 (s, 3 H), 3.14 (td, J2 = 6.5 Hz, J2
= 2.2 Hz, 0.95 Htrans), 2.85 (t, J = 7.2 Hz, 1.9 Htrans), 2.36–2.12 (m,
1.9 Htrans) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.2, 156.0,
141.0, 138.1, 131.5, 129.2, 128.6, 126.3, 126.1, 61.6, 60.1, 55.5, 33.5,
14.1, 8.3, 7.6 ppm. IR: ν = 3508, 1710 cm–1. HRMS (ESI-TOF):
˜
calcd. for C15H23O3 [M]+ 251.1642; found 251.1639.
30.9 ppm. IR: ν = 1745 cm–1. MS (CI, NH ): m/z = 358 [M +
Ethyl 2-(Hydroxy-p-tolylmethyl)-4-phenylbutanoate (5h): According
to the general procedure using (Z)-1-chloro-4-phenylbut-1-enyl ace-
tate (1a) (50 µL, 0.25 mmol) and 3h (60 µL, 0.5 mmol) in THF
(1.0 mL) and EtOH (1.0 mL), the title compound 5h (66 mg, 85%)
was obtained as a mixture of isomers (syn/anti = 70:30). syn-5h: 1H
NMR (200 MHz, CDCl3): δ = 7.30–7.10 (m, 9 H), 4.94 (d, J =
5.9 Hz, 1 H), 4.08 (q, J = 7.1 Hz, 2 H), 2.79–2.44 (m, 4 H), 2.35
(s, 3 H), 2.12–1.96 (m, 2 H), 1.18 (t, J = 7.1 Hz, 3 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = 174.8, 141.6, 138.6, 137.4, 129.1,
˜
3
H]+. HRMS (ESI-TOF): calcd. for C24H24N1O2 [M]+ 358.1802;
found 358.1812. trans-8b: GC (heating at 25 °C/min): tR
13.60 min. cis-8b: GC (heating at 25 °C/min): tR = 13.82 min.
=
3-(2-Phenylethyl)-4-p-tolyl-1-(p-tolylsulfonyl)azetidin-2-one
(8c):
(cis/trans 1:1): The β-lactam cannot be separated from N-(4-methyl-
benzylidene)-p-toluenesulfonamide by column chromatography.
1
Characteristic peaks: H NMR (200 MHz, CDCl3): δ = 5.17 (d, J
= 6.6 Hz, 1 Hcis), 4.66 (d, J = 2.9 Hz, 1 Htrans), 3.43 (td, J1 = 8.3 Hz,
J2 = 6.6 Hz, 1 Hcis), 3.12 (td, J1 = 7.7 Hz, J2 = 2.9 Hz, 1
Htrans) ppm.
128.5, 128.4, 126.2, 126.0, 74.2, 60.7, 52.6, 33.8, 28.9, 21.2,
1
14.2 ppm. IR: ν = 3455, 1729 cm–1. anti-5h: H NMR (200 MHz,
˜
CDCl3): δ = 7.29–7.06 (m, 9 H), 4.80 (dd, J1 = 8.1 Hz, J2 = 5.1 Hz,
1 H), 4.16 (q, J = 7.1 Hz, 2 H), 2.86–2.50 (m, 4 H), 2.34 (s, 3 H),
Ethyl
4-Phenyl-2-[p-Tolyl(p-tolylsulfonylamino)methyl]butanoate
1
2.02–1.82 (m, 1 H), 1.73–1.58 (m, 1 H), 1.27 (t, J = 7.1 Hz, 3 (9c): (syn/anti 1:1): H NMR (300 MHz, CDCl3): δ = 7.50 (d, J =
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 175.2, 141.3, 138.9,
8.1 Hz, 2 H), 7.30–7.18 (m, 3 H), 7.11–7.01 (m, 4 H), 6.92–6.82 (m,
4 H), 6.06 (d, J = 9.0 Hz, 0.5 H), 5.51 (d, J = 8.7 Hz, 0.5 H), 4.59
(dd, J1 = 9.0 Hz, J2 = 6.2 Hz, 0.5 H), 4.47 (dd, J1 = 8.7 Hz, J2 =
137.9, 129.4, 128.5, 126.5, 126.1, 75.4, 60.8, 52.7, 33.5, 31.2, 21.3,
14.4 ppm. IR: ν = 3455, 1706 cm–1.
˜
Eur. J. Org. Chem. 2007, 101–107
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
105

R. Bejot, S. Anjaiah, J. R. Falck, C. Mioskowski
FULL PAPER
8.4 Hz, 0.5 H), 4.02 (q, J = 7.2 Hz, 1 H), 3.89 (q, J = 7.2 Hz, 1 H),
2.76–2.43 (m, 3 H), 2.33 (s, 1.5 H), 2.30 (s, 1.5 H), 2.25 (s, 3 H),
condensation, Ti(OiPr)4-mediated aldolization, commercial Et2Al-
OEt-mediated aldolization, Ti(OiPr)3Cl-mediated aldolization and
2.06–1.94 (m, 1 H), 1.80–1.67 (m, 1 H), 1.13 (t, J = 7.2 Hz, 1.5 H), decarboxylation reactions. Full characterization of isolated prod-
1.02 (t, J = 7.2 Hz, 1.5 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
174.3, 172.8, 143.1, 142.8, 141.1, 140.8, 138.1, 137.49, 137.45,
137.1, 136.0, 135.4, 129.3, 129.2, 129.02, 128.95, 128.5, 127.2,
127.0, 126.9, 126.4, 126.2, 126.1, 61.0, 60.8, 59.2, 58.5, 51.7, 51.4,
33.5, 33.2, 31.8, 30.4, 21.5, 21.1, 14.2, 14.0 ppm.
ucts and byproducts.
Acknowledgments
We are grateful to the Ministère délégué à l’Enseignement supérieur
et à la Recherche, the Robert A. Welch Foundation and NIH
(GM31278, DK38226) for financial support of this work.
5-Methyl-6-(2-phenylethyl)-1-azabicyclo[3.2.0]heptan-7-one
(8d):
GC (heating at 25 °C/min): tR = 9.43 min. MS (CI, NH3): m/z =
230.
N-(4-Oxopentyl)-4-phenylbutanamide (10d): 1H NMR (200 MHz,
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CDCl3): δ = 7.33–7.16 (m, 5 H), 5.67 (br. s, 1 H), 3.24 (td, J1
=
6.8 Hz, J2 = 5.9 Hz, 2 H), 2.65 (t, J = 7.3 Hz, 2 H), 2.50 (t, J =
6.8 Hz, 2 H), 2.21–2.13 (m, 2 H), 2.15 (s, 3 H), 2.04–1.88 (m, 2 H),
1.84–1.70 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 208.9,
173.0, 141.6, 128.6, 128.5, 126.1, 41.2, 39.1, 36.0, 35.3, 30.2, 27.2,
23.5 ppm. IR: ν = 1715, 1647 cm1. GC (heating at 25 °C/min): t
˜
R
= 10.10 min. MS (CI, NH3): m/z = 248, 230. HRMS (ESI-TOF):
calcd. for C15H22N1O2 [M]+ 248.1645; found 248.1630.
6a,10a-Dimethyl-6-(2-phenylethyl)octahydrodipyrrolo[1,2-a:1Ј,2Ј-c]-
pyrimidin-5(6H)-one (11d): 1H NMR (300 MHz, CDCl3): δ = 7.37–
7.16 (m, 5 H), 3.84–3.74 (m, 1 H), 3.52–3.43 (m, 1 H), 3.16–3.06
(m, 1 H), 2.93–2.88 (m, 2 H), 2.64–2.53 (m, 1 H), 2.29–2.16 (m, 2
H), 1.97–1.64 (m, 7 H), 1.46–1.32 (m, 2 H), 1.34 (s, 3 H), 0.84 (s,
3 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 170.8, 142.9, 128.8,
128.4, 125.8, 77.5, 65.1, 50.3, 47.4, 45.2, 43.2, 39.6, 35.8, 28.9, 25.2,
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24.5, 24.2, 21.3 ppm. IR: ν = 1655 cm–1. HRMS (ESI-TOF): calcd.
˜
for C20H29N2O1 [M]+ 313.2274; found 313.2284.
6,6-Dimethyl-3-(2-phenylethyl)tetrahydropyrrolo[1,2-b]isoxazol-
1
2(3H)-one (13a): (cis/trans 80:20). H NMR (300 MHz, CDCl3): δ
= 7.33–7.18 (m, 5 H), 4.13–4.05 (m, 0.8 H), 3.93–3.87 (m, 0.2 H),
3.21–3.12 (m, 0.8 H), 2.85–2.72 (m, 2 H), 2.71–2.61 (m, 0.2 H),
2.33–1.61 (m, 6 H), 1.41 (s, 3 H), 1.09 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 176.0, 140.6, 128.7, 128.5, 126.5, 69.9, 67.7,
45.5, 35.8, 33.9, 27.7, 25.9, 24.1, 23.9 ppm. IR: ν = 1768 cm–1
.
˜
HRMS (ESI-TOF): calcd. for C16H22N1O2 [M]+ 260.1645; found
260.1630. cis-13a: GC (heating at 25 °C/min): tR = 9.88 min. trans-
13a: GC (heating at 25 °C/min): tR = 10.10 min.
2-Acetyl-3,3-dimethyl-4-(2-phenylethyl)isoxazolidin-5-one (13b): 1H
NMR (300 MHz, CDCl3): δ = 7.35–7.21 (m, 5 H), 3.13–3.03 (m, 1
H), 2.86–2.75 (m, 1 H), 2.68 (dd, J1 = 9.7 Hz, J2 = 4.4 Hz, 1 H),
2.15 (s, 3 H), 2.14–1.97 (m, 1 H), 1.80–1.63 (m, 1 H), 1.65 (s, 3 H),
1.35 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.3, 171.4,
140.5, 128.7, 128.6, 126.5, 68.0, 50.9, 32.9, 26.3, 25.8, 23.1,
18.0 ppm. IR: ν = 1801, 1686 cm–1. GC (heating at 25 °C/min): t
˜
R
= 9.05 min. MS (CI, NH3): m/z = 262 [M + H]+. HRMS (IE):
calcd. for C15H19NO3 [M]+ 261.1365; found 261.1353; calcd. for
C13H17NO2 [M – CH2CO]+ 219.1259; found 219.1280.
2-Acetyl-3-ethoxy-3-methyl-4-(2-phenylethyl)isoxazolidin-5-one
(13c): (cis/trans Ͼ 98:2; trans isomer could not be detected). cis-
13c: 1H NMR (300 MHz, CDCl3): δ = 7.34–7.20 (m, 5 H), 3.67
(dq, J1 = 7.2 Hz, J2 = 6.9 Hz, 1 H), 3.54 (dq, J1 = 7.2 Hz, J2
=
6.9 Hz, 1 H), 3.08–2.97 (m, 1 H), 2.89–2.78 (m, 1 H), 2.69 (dd, J1
= 8.4 Hz, J2 = 4.7 Hz, 1 H), 2.18 (s, 3 H), 2.19–2.04 (m, 1 H), 1.98–
1.87 (m, 1 H), 1.88 (s, 3 H), 1.16 (t, J = 6.9 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 172.3, 168.9, 140.7, 128.8, 128.6,
126.5, 95.2, 60.5, 50.9, 32.9, 25.4, 22.8, 20.9, 15.3 ppm. IR: ν =
˜
1810, 1686 cm–1. HRMS (ESI-TOF): calcd. for C16H21N1Na1O4
[M]+ 314.1363; found 314.1360.
Supporting Informations (see footnote on the first page of this arti-
cle): Experimental procedures for hydrolysis, aminolysis, Claisen
[10] J. Shibata, I. Shiina, T. Mukaiyama, Chem. Lett. 1999, 28, 313–
314.
106
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Tandem Aldol–Lactonization Reaction Starting from α-Haloenol Acetates
FULL PAPER
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not efficient for lactonization: the formation of β-hydroxy ester
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lactonization reaction but much less efficient than Et2AlOEt.
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Published Online: November 9, 2006
Eur. J. Org. Chem. 2007, 101–107
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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