Preparation of imino lactones by electrophilic cyclization of β,γ-unsaturated hydroxamates: Formation of 3-cyanoprop-2-en-1-ones through fragmentation reactions

Article abstract of DOI:10.1002/ejoc.201000376

Treatment of γ-disubstituted β,γ-unsaturated hydroxamates with bis(collidine)bromine(I) hexafluorophosphate led mainly to the formation of cyclic bromo imidates - the thermodynamic products. Unsaturated cyclic imidates were then obtained by treatment with

Full text of DOI:10.1002/ejoc.201000376

FULL PAPER
DOI: 10.1002/ejoc.201000376
Preparation of Imino Lactones by Electrophilic Cyclization of β,γ-Unsaturated
Hydroxamates: Formation of 3-Cyanoprop-2-en-1-ones through Fragmentation
Reactions
Houssam Trabulsi,[a] Régis Guillot,[b] and Gérard Rousseau*[a]
Keywords: Nitriles / Lactams / Lactones / Bromonium ions / Electrophilic cyclization
Treatment of γ-disubstituted β,γ-unsaturated hydroxamates
with bis(collidine)bromine(I) hexafluorophosphate led
mainly to the formation of cyclic bromo imidates – the
thermodynamic products. Unsaturated cyclic imidates were
then obtained by treatment with triethylamine. With γ-aryl
β,γ-unsaturated hydroxamates, the corresponding cyclic
bromo imidates were also obtained. On treatment with trieth-
ylamine, however, these compounds led to the formation of
3-cyanoprop-2-en-1-ones in good yields through fragmenta-
tion reactions.
Introduction
were prepared from the corresponding acids either by treat-
ment of the corresponding acid chlorides with hydroxyl- or
O-alkylhydroxylamines or by direct treatment of the acids
with the O-alkylhydroxylamines. We first examined the re-
activities of the hydroxamic acid 3 and the hydroxamates 4,
5a and 5b, obtained from 3-cyclohexylidenepropanoic acid
(1).[7] These compounds were prepared as reported in
Scheme 1. The hydroxamate 4 was obtained by treatment
of 3-cyclohexylidenepropanoyl chloride (2) with aqueous
hydroxylamine, followed by acylation with acetyl chloride.
The hydroxamates 5a and 5b were formed by coupling of
the acid function of compound 1 with the corresponding
O-alkylhydroxylamines by a reported method.[8] These
compounds were easily characterized by their NMR and
IR spectra. Table 1 lists the results of their treatment with
bis(collidine)bromine(I) hexafluorophosphate. No reaction
was observed with the hydroxamic acid 3, although decom-
position of the bromo reagent due to the high acidity of
this compound was observed. To avoid this drawback, hy-
Electrophilic cyclization of unsaturated amides has been
reported to lead to the formation either of imino lactones
(or the corresponding immonium salts) or of lactams, de-
pending on the structures of the amides, the substituents on
the nitrogen and (or) the natures of the electrophiles.[1] Our
research into the reactivity of bis(collidine)bromine(I) hexa-
fluorophosphate[2] led us to examine the case of unsaturated
hydroxamates. Their reaction behaviour with electrophiles
has been briefly reported on in the literature. With bromine
or N-bromosuccinimide the formation of lactams was ob-
served,[3] whereas with selenium reagents, on the other hand,
mixtures of γ-butyrolactams and immonium salts were gen-
erally obtained.[4] These immonium salts rearranged to the
thermodynamically more stable lactams on heating.
We recently reported the synthesis of enantiomerically
pure γ-butyrolactones through diastereoselective halo-
lactonization of β,γ-unsaturated acids.[5] These results
prompted us to study the possible application of this cycli-
zation methodology for the preparation of optically pure γ-
butyrolactams. Indeed, there are still no efficient syntheses
of optically γ-butyrolactams possessing a tetrasubstituted C
atom in α position to the N atom.[6]
Results and Discussion
a) Reactivities of γ-Disubstituted β,γ-Unsaturated
Hydroxamates
We first decided to examine the reactivity of γ-disubsti-
tuted β,γ-unsaturated hydroxamates. These compounds
[a] Laboratoire de Synthèse Organique et Méthodologie, ICMMO,
Univ. Paris-Sud,
91405 Orsay, France
Fax: +33-1-69156278
E-mail: gerard.rousseau@u-psud.fr
[b] ICMMO, Univ. Paris-Sud,
91405 Orsay, France
Scheme 1. Preparation of the hydroxamates 4, 5a and 5b.
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Preparation of Imino Lactones and 3-Cyanoprop-2-en-1-ones
Table 1. Treatment of the hydroxamic acid 3 and the hydroxamates 4, 5a and 5b with bis(collidine)bromine(I) hexafluorophosphate.
[a] Global yield. [b] Proportion (1H NMR) of the products in the crude reaction mixture (%).
droxamates were examined. With the hydroxamate 4 (En-
try b), in dichloromethane at room temperature a mixture
of three products was obtained: one lactam (compound 6)
and two cyclic imidates (compounds 7 and 8). The unsatu-
rated compounds 6 and 8 were probably formed by elimi-
nation of HBr from the initially formed bromo products.
The structures of these different compounds were estab-
lished from their NMR and IR spectra, and the structure
of the unsaturated cyclic imidate 8 was confirmed from its
single-crystal X-ray data (Figure 1).
More interestingly, in toluene at –20 °C only the cyclic
bromo imidate 7 was isolated (Entry c). This bromo com- Figure 1. ORTEP drawing of the unsaturated imino lactone 8 and
the bromo imino lactone 41.
pound 7 appeared to be unstable, and partial elimination of
HBr could be observed during its purification over silica.
After standing at room temperature, rearrangement of the
compound 6 into the cyclic imidate 8 was observed.
no HBr elimination was observed in dichloromethane. Re-
Mixtures of bromo lactams and cyclic bromo imidates arrangement of the bromo lactams 9 and 11 into the cyclic
were also observed from the N-methoxy hydroxamate 5a bromo imidates and/or unsaturated cyclic imidates was ob-
and the N-benzyloxy hydroxamate 5b when the cyclizations served during purification or on standing at room tempera-
were carried out in dichloromethane at room temperature ture. Our study shows only small variation – probably due
(Table 1, Entries d, i). With these cyclic imidates 10 and 12, to the electronic effects of the substituents – in the N- and
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O-cyclization ratios as a function of the group on the nitro-
gen atom (Entries b, d and i).
We also examined the reactivity of hydroxamate 5a in
chloroform, toluene and pentane. Formation of the bromo
imino lactone 10 was mainly observed. Lowering the tem-
perature of the reaction enhanced its selectivity (Entries e,
f). Otherwise, heating of the unsaturated lactam 6 in chloro-
form for 30 min led to its quantitative transformation into
the cyclic imidate 8. Such rearrangements have been re-
ported in the literature, and in some cases have been shown
Scheme 2. Preparation of the oxime 13.
In a next step, we examined the behaviour of hydroxam-
to be equilibria.[9] The reverse transformation reaction has ates possessing various substituents on the C=C bond or
also been reported.[4] These results indicated that this re- substituted on the carbon α to the hydroxamate function.
arrangement is related to the relative thermodynamic sta- These compounds were prepared as shown in Scheme 3,
bilities of the N-alkoxylactam and of the cyclic imidate. either by direct treatment of the acid with alkoxyamine
This relative stability seems to be influenced by the hetero- (compound 21), or by treatment of the corresponding acid
atom attached to the carbon β to the carbonyl or imine chloride with hydroxylamine, followed by acylation of the
group.
hydroxamic acid (compounds 16, 19, 24, 30 and 33). The
Treatment of the cyclic bromo imidate 7 with triethyl- preparation of the optically active hydroxamates 24, 30 and
amine in dichloromethane led to the formation of the un- 33 was carried out from the corresponding optically active
saturated cyclic imidate 8. Treatment of this in turn with acids by the Evans methodology, as previously reported.[5]
lithium aluminium hydride led to the formation of the ox-
Subsequent treatment of these hydroxamates with bis-
ime 13 (Scheme 2).
(collidine)bromine(I) hexafluorophosphate were then car-
Scheme 3. Preparation of the hydroxamates 16, 19, 21, 24, 30 and 33.
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Preparation of Imino Lactones and 3-Cyanoprop-2-en-1-ones
ried out as reported in the cases of compounds 4, 5a and 5b. formation of imino lactones due to the steric hindrance in-
Our results are reported in Table 2. In all cases cyclizations troduced by the substituent α to the amide function.
occurred in satisfactory yields. Except in the case of the
As in the cases of unsaturated acids,[5] these cyclizations
hydroxamate 16 in dichloromethane (Entry a), only cyclic were diastereoselective. The structures of the different com-
imidates were formed under the studied conditions. In tolu- pounds were determined from their NMR, IR and mass
ene at –20 °C, the exclusive formation of cyclic bromo imid- spectra. The stereochemistry assigned to the cyclic bromo
ates was observed in the cases of hydroxamates 16, 19 and imidate 40 was also based on our previous results relating
21 (Table 2, Entries b, d and e). When a substituent was to the diastereoselective bromocyclization of (2R,4E)-2-
present α to the hydroxamate function (Entries f–h), only methyl-5-phenylhex-4-enoic acid (22) in the presence of
the bromo imidates 40, 41 and 42 were isolated, even at bis(collidine)bromine(I) hexafluorophosphate as electro-
room temperature in dichloromethane. This result indicates phile.[5] The structure of the cyclic bromo imidate 42 was
that the formation of lactams is disfavoured relative to the confirmed by its single-crystal X-ray data (Figure 1).
Table 2. Treatment of the hydroxamates 16, 19, 21, 24, 30 and 33 with bis(collidine)bromine(I) hexafluorophosphate.
[a] Global yield after purification by liquid chromatography. [b] Proportion (1H NMR) of the products in the crude reaction mixture (%).
Eur. J. Org. Chem. 2010, 5884–5896
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b) Reactivities of γ-Aryl β,γ-Unsaturated Hydroxamates
hydroxamate, formed from (3E)-hex-3-enoic acid, with bis-
(collidine)bromine(I) hexafluorophosphate and triethyl-
amine.
The different examples reported in Tables 1 and 2 led us
to reexamine the case previously reported by Miller, in
which the formation of a mixture of two diastereoisomeric
bromo lactams was claimed for the reaction between a hy-
droxamate derived from trans-styrylacetic acid and bro-
mine.[3b] The hydroxamate 44 (Scheme 4) was prepared in
two steps in good yield from the commercially available
trans-styrylacetic acid, by treatment of the acid chloride
with hydroxylamine, followed by acetylation. Treatment of
this compound with bis(collidine)bromine(I) hexafluoro-
phosphate in dichloromethane at room temperature led to
the formation of a mixture of the bromo imine 45, the
stereochemistry of which can be reasonably postulated to be
trans, the HBr elimination product 46 and the unsaturated
β-cyano-α,β-enone 47. No lactam derivatives were detected.
Significant degradation of these products was observed dur-
ing their attempted purification over silica gel. These prod-
ucts were characterized from their spectroscopic data. To
avoid the yield loss during their purification, the crude reac-
tion product was treated with one equivalent of triethyl-
amine. Contrary to our expectations, the unsaturated imino
lactone 46 was not isolated, but (Z)-4-oxo-4-phenylbut-2-
enenitrile (47) was obtained as a unique product in high
yield. This compound was characterized from its NMR and
IR spectra and by comparison of its spectra with those re-
ported in the literature.[10,11] Compound 47 was also formed
on starting from (E)-N-(benzyloxy)-4-phenylbut-3-enamide.
Its formation can be explained by a Beckman fragmenta-
tion.[12] Two different mechanisms can be proposed: either
a concerted mechanism (A, Scheme 5), or the intermediate
formation of a ketenimine followed by acetoxy elimination
(B, Scheme 5).[13] Literature results relating to the Beckman
fragmentation prompted us to favour the first mechanism.
A similar reaction leading to the formation of 2-bromocy-
clohexanone and acetonitrile has been reported.[14] The ab-
straction of the mobile hydrogen α to the oxygen atom
seems to be the key step of this reaction. Indeed, we did
not observe this fragmentation on successive treatment of
Scheme 5. Proposed mechanisms for the formation of 47.
The reactivities of compound 47 and its E isomer have
been briefly reported on in the literature.[11,15] In addition,
we found that Michael additions were observed in good
yields with soft carbanions formed from dimethyl malonate,
β-keto ester and methyl (phenylsulfonyl)acetate (Scheme 6).
The regiospecificities of these additions were deduced from
the NMR spectra of the compounds and were consistent
with previously published results.[11,15] With butyllithium,
addition at the ketone function of 47 was observed and
alcohol 51 was obtained. With other lithium derivatives
(MeLi, tBuLi) and with Grignard reagents, complex reac-
tion mixtures were observed [formation of alcohols and (or)
Scheme 4. Preparation of hydroxamate 44 and treatment with bis-
(collidine)bromine(I) hexafluorophosphate.
Scheme 6. Reactivity of the unsaturated nitrile 47.
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Preparation of Imino Lactones and 3-Cyanoprop-2-en-1-ones
Michael products and probably products corresponding to be isolated when the unsaturated hydroxamates are γ-disub-
the addition on the nitrile function].
stituted. In the case of γ-aryl β,γ-unsaturated hydroxamates
We then studied the scope of this fragmentation. As indi- the cyclic bromo imidates were unstable, and their subse-
cated above, the presence of an aryl group in the γ-position quent treatment with triethylamine led to the formation of
seemed necessary to increase the mobility of the hydrogen 3-cyanoprop-2-en-1-ones through fragmentation reactions.
α to the oxygen atom. The hydroxamates 56 and 57 were These results lead us to comment on the results of Miller
prepared as shown in Scheme 7 by hydroxy amidation and et al. concerning the reaction of (3E)-N-(benzyloxycarb-
acylation of the corresponding known acids. Their reactions onyl)-4-phenylbut-3-enamide in the presence of NBS, which
with bis(collidine)bromine(I) hexafluorophosphate led to was reported lo lead to a mixture of the two diastereomers
the formation of the corresponding unstable cyclic imidates, of the bromo lactam.[3b] Under our conditions this sub-
which could not be purified by liquid chromatography over strate gave the same result as that found with hydroxamate
silica gel, so the crude reaction products were treated with 44. This suggests that Miller et al. in fact obtained a mix-
triethylamine to lead to the formation of compounds 58[15] ture of a bromo lactam (minor compound) and a cyclic
and 59.[16] The structures of these compounds were deter- bromo imidate (major compound).
mined from their NMR and IR spectra and by comparison
with those reported in the literature. For compound 59 the
Experimental Section
stereochemistry of the C=C bond was Z, whereas for com-
pound 58 the E stereochemistry was observed. This latter
result is probably due to the isomerization of the C=C bond
in the reaction mixture. There are precedents in the litera-
ture concerning the low stability of (Z)-α-alkylidenecyclo-
pentanones, and their isomerization into the corresponding
E isomers.[17] Compounds 47 (see the Exp. Section) and 59
were unstable and were easily isomerized to their E isomers
through the action of light, heat or nucleophiles.
General: All reactions were carried out under argon. Purification
of products was carried out by normal-phase flash chromatog-
raphy. 3-Cyclohexylidenepropanoic acid (1, 81%)[7] and bis(collid-
ine)bromine(I) hexafluorophosphate[18] were prepared as reported
previously.
3-Cyclohexylidene-N-hydroxypropanamide (3): Oxalyl chloride
(1.75 equiv., 2.275 mmol, 0.2 mL) was added dropwise to a CH2Cl2
solution (5 mL) of 3-cyclohexylidenepropanoic acid (1, 200 mg,
1.3 mmol) cooled to 0 °C. The solution was stirred overnight at
room temp. and was then concentrated under vacuum. An aqueous
solution of hydroxyamine (7 equiv., 4.5 mL of a 2.5  solution pre-
pared from an equimolar mixture of N+H3OH Cl– and NaOH) was
added to the acid chloride 2. There was formation of a white solid,
which was isolated by filtration. The filtrate was extracted twice
with CH2Cl2 (10 mL). The organic phases were dried (MgSO4), and
concentrated under vacuum. The residue was added to the previous
1
solid. 0.148 g (68%). H NMR (CDCl3; 300 MHz): δ = 9.00 (br. s,
2 H, –NHOH), 5.17 (s, 1 H, C=CH–), 2.97 (s, 2 H, –CH2–CON),
2.11 [br. s, 4 H, 2ϫ(CH2)C=], 1.41 [br. s, 6 H, 3ϫ(CH2) cyclo-
hexyl] ppm. 13C NMR (CDCl3, 90 MHz): δ = 170.2, 145.7, 111.5,
36.9, 31.9, 29.1, 28.7, 27.3, 26.5 ppm. IR (CH Cl ): ν = 3054, 2987,
˜
2
2
2305, 1421, 1265, 896 cm–1. LRMS: m/z = 170.0 [M + H]+, 187.2
[M + NH4]+. HRMS (ESI): calcd. for C18H30N2NaO4 (dimer):
361.2103; found 361.2098.
N-(Acetoxy)-3-cyclohexylidenepropanamide (4): Pyridine (1.06 equiv.,
30 µL) was added over 10 min to a THF solution (10 mL) of hy-
droxamic acid 2 (66 mg, 0.39 mmol), cooled to 0 °C. The solution
was stirred for 20 min at room temp., and acetyl chloride
(1.06 equiv., 40 µL) was added dropwise. After the system had been
kept for 2 h at room temp., diethyl ether (5 mL) was added and the
homogeneous organic solution was washed successively with water
(5 mL), aqueous HCl solution (0.5 , 5 mL) and saturated NaCl
solution (5 mL). The organic phase was dried (MgSO4) and con-
centrated under vacuum to give a colourless oil (66 mg, 80%),
Scheme 7. Preparation of the unsaturated nitriles 58 and 59.
1
which was used without further purification for the next step. H
NMR (CDCl3, 360 MHz): δ = 8.99 (br. s, 1 H, –NH–), 5.28 (t,
3JH,H = 7.5 Hz, 1 H, C=CH–), 3.04 (d, 3JH,H = 7.5 Hz, 2 H, –CH2–
CON), 2.25 [s, 3 H, O–(C=O)–CH3], 2.18 [br. s, 4 H, 2(CH2)C=],
1.59 [br. s, 6 H, 3ϫ(CH2) cyclohexyl] ppm. 13C NMR (CDCl3,
90 MHz): δ = 168.7, 168.5, 145.7, 111.2, 36.8, 32.1, 29.0, 28.7, 28.4,
Conclusions
Treatment of β,γ-unsaturated hydroxamates with bis(col-
lidine)bromine(I) hexafluorophosphate led mainly to the
formation of cyclic bromo imidates rather than the bromo
lactams expected from literature results.[3,4] These cyclic im-
28.2, 18.1 ppm. IR (CH Cl ): ν = 3054.5, 2987.1, 2305.8, 1792.0,
˜
2
2
1712.4, 1421.8, 1267.0, 896.0, 753 cm–1. LRMS: m/z = 212.0 [M +
H]+, 229.0 [M + NH4]+. HRMS: calcd. for C11H17NNaO3:
idates, which are the thermodynamic reaction products, can 234.1106 [M + Na]+; found 234.1106.
Eur. J. Org. Chem. 2010, 5884–5896
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3-Cyclohexylidene-N-methoxypropanamide (5a): Triethylamine
(1.2 mL, 8.7 mmol) was added to a dichloromethane solution
(50 mL) of cyclohexylidenepropanoic acid 1 (262 mg, 1.7 mmol), 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide (498 mg, 2.6 mmol),
hydroxybenzotriazole (280 mg, 2 mmol) and O-methylhydroxyl-
amine hydrochloride (171 mg, 2 mmol) and the mixture was stirred
for 4 d at room temp. The solution was then washed with an aque-
ous saturated solution of NaHCO3 (20 mL), aqueous HCl solution
(1 , 20 mL) and saturated NaCl solution (10 mL). After concen-
tration under vacuum, the residue was purified by liquid
chromatography over silica gel (elution: diethyl ether) to give pure
b) In Toluene at –20 °C: Bis(collidine)bromine(I) hexafluorophos-
phate[15] (0.66 mmol, 307 mg) was added to a toluene solution
(10 mL) of hydroxamate 4 (127 mg, 0.6 mmol), cooled to –20 °C.
After 2 h at –20 °C, the solution was allowed to warm to room
temp. and the solvent was removed under vacuum. The crude reac-
tion mixture was purified by liquid chromatography over silica gel
to give compound 7 (133 mg, 77%).
c) Preparation of (2Z)-1-Oxaspiro[4.5]dec-3-en-2-one O-Acetyl-
oxime (8): After treatment of the hydroxamate 4 with bis(collidine)-
bromine(I) hexafluorophosphate as indicated in paragraph a), tri-
ethylamine (1.12 mmol) was added to the crude reaction mixture.
After 1 h at room temp., the solution was concentrated under vac-
uum, and the residue was purified by liquid chromatography over
silica gel to give compound 8 (109 mg, 80%).
1
5a (200 mg, 64%). H NMR (CDCl3, 360 MHz): δ = 9.80 (br. s, 1
3
H, –NH–), 5.17 (t, JH,H = 7.0 Hz, 1 H, C=CH–), 3.68 (s, 3 H,
3
OCH3), 2.88 (d, JH,H = 7.0 Hz, 2 H, –CH2–CON), 2.06 [br. s, 4
H, 2ϫ(CH2)C=], 1.48 [br. s, 6 H, 3ϫ(CH2) cyclohexyl] ppm. 13C
NMR (CDCl3, 90 MHz): δ = 169.5, 144.3, 112.2, 63.8, 36.8, 32.0,
28.7, 28.1, 27.4, 26.4 ppm. LRMS: m/z = 184.0 [M + H]+. HRMS:
calcd. for C10H17NNaO2: 206.1157; found 206.1156.
Treatment of the Hydroxamate 5a with Bis(collidine)bromine(I)
Hexafluorophosphate: The reactions were carried out in dichloro-
methane and in toluene as reported for the hydroxamate 4, starting
from 5a (0.6 mmol, 110 mg). In dichloromethane, compounds 9
and 10 were characterized from the crude reaction mixture
(102 mg, 65%). Compound 9, however, was not isolated after liquid
chromatography over silica gel, due to its transformation into a
mixture of compound 10 and (2Z)-1-oxaspiro[4.5]dec-3-en-2-one O-
methyloxime, the HBr elimination product. In toluene at –20 °C,
only compound 10 was formed (115 mg of crude reaction product,
68%, Table 1).
N-(Benzyloxy)-3-cyclohexylidenepropanamide (5b): This compound
was prepared by the method reported for the preparation of com-
pound 5a. From 1.19 g (7.71 mmol) of acid 1 we isolated 1.02 g
1
(51%) of hydroxamate 5b. H NMR (CDCl3, 360 MHz): δ = 9.00
3
(s, 1 H, –NH–), 7.35–7.31 (m, 5 H, Ph), 5.14 (t, JH,H = 7.0 Hz, 1
3
H, C=CH–), 4.87 (s, 2 H, O-CH2-Ph), 2.87 (d, JH,H = 7.0 Hz, 2
H, –CH2–CON), 2.05 [br. s, 4 H, 2ϫ(CH2)C=], 1.48 [br. s, 6 H,
3ϫ(CH2) cyclohexyl] ppm. 13C NMR (CDCl3, 90 MHz): δ =
169.2, 144.7, 135.2, 129.0, 128.3, 112.0, 77.8, 36.7, 28.6, 28.1, 28.1,
4-Bromo-1-methoxy-1-azaspiro[4.5]dec-3-en-2-one (9): Crude reac-
1
27.3, 26.4 ppm. IR (film): ν = 3435, 2928, 1655, 1448, 749,
˜
tion mixture: H NMR (CDCl3, 360 MHz): δ = 4.24 (dd, J = 4.4
697 cm–1. LRMS: m/z = 260.1 [M + H]+, 277.1 [M + NH4]+.
and 7.3 Hz, 1 H, –CHBr), 3.70 (s, 3 H, OCH3), 3.45 [dd, J = 7.0
and 18.8 Hz, 1 H, –CH–(C=O)–], 3.20 [dd, J = 4.4 and 18.7, 1 H,
–CH–(C=O)–], 1.93–1.45 (m, 10H, cyclohexyl) ppm.
HRMS: calcd. for C16H22NO2: 260.1645; found 260.1657.
Treatment of Hydroxamate 4 with Bis(collidine)bromine(I) Hexa-
fluorophosphate
(2Z)-4-Bromo-1-oxaspiro[4.5]decan-2-one O-Methyloxime (10): Oil.
1H NMR (CDCl3, 360 MHz): δ = 4.33 (dd, 3JH,H = 6.7 and 3.5 Hz,
a) In Dichloromethane at Room Temp.: Bis(collidine)bromine(I)
hexafluorophosphate[18] (0.66 mmol, 307 mg) was added to a
dichloromethane solution (10 mL) of the hydroxamate 4 (127 mg,
0.6 mmol). After 2 h at room temp., the solvent was removed under
vacuum. The NMR spectra of the residue show the presence of
three products (compounds 6–8; see Table 1). After purification by
liquid chromatography over silica gel only two products were iso-
lated: the cyclic bromo imidate 7 (73 mg) and the unsaturated cyclic
imidate 8 (33 mg).
3
1 H, –CHBr), 3.78 (s, 3 H, OCH3), 3.40 (dd, JH,H = 17.5 and
3
6.7 Hz, 1 H, CH-C=N), 2.99 (dd, JH,H = 17.5 and 3.5 Hz, 1 H,
CH-C=N), 1.93–1.45 (m, 10 H, cyclohexyl) ppm. 13C NMR
(CDCl3, 90 MHz): δ = 152.4, 90.4, 62.3, 51.4, 38.0, 34.7, 34.6, 24.8,
23.2, 22.6 ppm. HRMS: calcd. for C10H17BrNO2: 262.0443 [M +
H]+; found 262.0445.
(2Z)-1-Oxaspiro[4.5]dec-3-en-2-one O-Methyloxime: 1H NMR
3
(CDCl3, 360 MHz): δ = 6.78 (d, JH,H = 6.0 Hz, 1 H, =CH-C=N),
3
1-(Acetoxy)-1-azaspiro[4.5]dec-3-en-2-one (6): (From the crude re-
6.07 (d, JH,H = 6.0 Hz, 1 H, CH=CH-C=N), 3.77 (s, 3 H, OCH3),
1
3
1.98–1.25 (m, 10 H, cyclohexyl) ppm. 13C NMR (CDCl3, 90 MHz):
δ = 160.6, 146.4, 119.4, 87.2, 62.5, 35.0, 34.7, 24.8, 23.1, 22.6 ppm.
action mixture) H NMR (CDCl3, 360 MHz): δ = 6.90 (d, JH,H
=
3
6.0 Hz, 1 H, =CH-C=O), 6.5 (d, JH,H = 6.0 Hz, 1 H, –CH=CH-
C=O), 2.10 [s, 3 H, O–(C=O)–CH3], 1.80–1.30 (m, 10H, cyclo-
hexyl) ppm. 13C NMR (CDCl3, 90 MHz): δ = 168.2, 161.2, 152.6,
115.2, 94.5, 35.2 (2 C), 29.7, 24.7, 23.0, 18.7 ppm.
Treatment of Hydroxamate 5b with Bis(collidine)bromine(I) Hexa-
fluorophosphate: The reaction was carried out in dichloromethane
as reported for the hydroxamate 4. From hydroxamate 5b (166 mg,
0.6 mmol) we isolated a mixture of compounds 11 and 12 (186 mg,
92%). Compound 11 was not isolated after liquid chromatography
over silica gel, due to its transformation into a mixture of com-
pound 12 (Table 1) and (2Z)-1-oxaspiro[4.5]dec-3-en-2-one O-benz-
yloxime, the HBr elimination product.
(2Z)-4-Bromo-1-oxaspiro[4.5]decan-2-one O-Acetyloxime (7): Oil.
1H NMR (CDCl3, 360 MHz): δ = 4.30 (dd, 3JH,H = 3.0 and 7.0 Hz,
1 H, –CHBr–), 3.50 (dd, 3JH,H = 7.0 and 18.0 Hz, 1 H, –CH-C=N),
3
3.00 (dd, JH,H = 3.0 and 18.0 Hz, 1 H, –CH-C=N), 2.05 [s, 3 H,
O–(C=O)–CH3], 1.83–1.43 (m, 10 H, cyclohexyl) ppm. 13C NMR
(CDCl3, 90 MHz): δ = 168.3, 161.7, 92.4, 50.8, 38.4, 34.5, 24.7,
23.0, 22.5, 22.0, 19.4 ppm.
1-Benzyloxy-4-bromo-1-azaspiro[4.5]dec-3-en-2-one (11): Crude re-
1
action mixture: H NMR (CDCl3, 360 MHz): δ = 7.41–7.28 (m, 5
(2Z)-1-Oxaspiro[4.5]dec-3-en-2-one O-Acetyloxime (8): White solid.
3
H, Ph), 4.96 (s, 2 H, O–CH2Ph), 4.20 (dd, JH,H = 4.7 and 7.3 Hz,
1
3
M.p. 106.7 °C. H NMR (CDCl3, 300 MHz): δ = 6.84 (d, JH,H
=
1 H, –CHBr), 3.47 (dd, 3JH,H = 7.3 and 18.8 Hz, 1 H, –CH-C=O),
3
6.0 Hz, 1 H, =CH-C=O), 6.08 (d, JH,H = 6.0 Hz, 1 H, –CH=CH-
C=O), 2.08 (s, 3 H, O-C=O-CH3), 1.83–1.43 (m, 10 H, cyclo-
hexyl) ppm. 13C NMR (CDCl3, 90 MHz) δ: 168.6, 165.1, 149.6,
119.4, 96.6, 35.2 (2 C), 29.7, 24.7, 22.9, 19.5 ppm. LRMS: m/z =
210.1, BRMS [M + H]+, 227.1. HRMS: calcd. for C11H16NO3:
210.1130 [M + H]+; found 210.1128.
3
3.22 (dd, JH,H = 4.7 and 18.8 Hz, 1 H, –CH-C=O), 1.83–1.43 (m,
10H, cyclohexyl) ppm.
(2Z)-4-Bromo-1-oxaspiro[4.5]decan-2-one O-Benzyloxime (12): 1H
NMR (CDCl3, 360 MHz): δ = 7.41–7.28 (m, 5 H, Ph), 5.02 (s, 2
3
H, O–CH2Ph), 4.32 (dd, JH,H = 3.5 and 6.7 Hz, 1 H, –CHBr),
5890
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5884–5896

Preparation of Imino Lactones and 3-Cyanoprop-2-en-1-ones
3.39 (dd, 3JH,H = 6.7 and 17.5 Hz, 1 H, –CH-C=N), 3.00 (dd, 3JH,H
= 3.5 and 17.5 Hz, 1 H, CH-C=N), 1.83–1.43 (m, 10 H, cyclo-
N-(Acetoxy)-4-methylpent-3-enamide (19): The procedure reported
for the preparation of the hydroxamate 4 was used. From the hy-
hexyl) ppm. 13C NMR (CDCl3, 90 MHz): δ = 155.1, 138.2, 128.1 droxamic acid 18 (1.03 g, 8 mmol), the hydroxamate 19 (0.96 g,
(2 C), 127.8 (2 C), 127.7, 90.2, 75.8, 51.3, 38.0, 35.6, 34.5, 24.7,
23.1, 22.1 ppm. HRMS: calcd. for C16H21BrNO2: 338.0756 [M +
H]+; found 338.0759.
70%) was obtained as an oil. 1H NMR (CDCl3, 250 MHz): δ =
3
9.94 (br. s, 1 H, –NH–), 5.22 (tt, JH,H = 1.0 and 7.5 Hz, 1 H,
3
C=CH–), 2.94 [d, JH,H = 7.5 Hz, 2 H, –CH2(C=O)–], 2.13 [s,
3 H, O–(C=O)–CH3], 1.69 (s, 3 H, =CCH3–), 1.60 (s, 3 H,
(2Z)-1-Oxaspiro[4.5]dec-3-en-2-one O-Benzyloxime: 1H NMR
=CCH3–) ppm. 13C NMR (CDCl3, 62.9 MHz): δ = 168.4 (2 C),
3
(CDCl3, 360 MHz): δ = 7,44–7.26 (m, 5 H, Ph), 6.75 (d, JH,H
=
137.2, 114.8, 32.6, 25.4, 18.0, 17.7 ppm. IR (film): ν = 3145, 2969,
˜
3
6.0 Hz, 1 H, =CH-C=N), 6.01 (d, JH,H = 6.0 Hz, 1 H, –CH=CH-
C=N), 5.07 (s, 2 H, O–CH2Ph), 1.85–1.51 (m, 10 H, cyclo-
hexyl) ppm. 13C NMR (CDCl3, 90 MHz): δ = 160.3, 145.6, 138.3,
128.1, 127.9, 127.4, 119.6, 94.9, 76.0, 35.6, 24.8, 23.1 ppm. IR
1793, 1655, 1533, 1427, 1373, 1189, 1048, 979, 856 cm–1. HRMS:
calcd. for C8H14NO3: 172.0974 [M + H]+; found 172.0976.
N-Methoxy-4,4-diphenylbut-3-enamide (21): The procedure re-
ported for the preparation of compound 5a was used. From 4,4-
diphenylbut-3-enoic acid (20, 1.90 g, 8 mmol), the hydroxamate 21
(0.77 g, 36%) was obtained as a white solid (m.p. 110 °C, CH2Cl2).
1H NMR (CDCl3, 360 MHz): δ = 8.68 (br. s, 1 H, –NH–), 7.43–
(film): ν = 3062 2981 2869 1759 1652 1453 1275 1052 698 cm–1.
˜
HRMS: calcd. for C16H20NO2: 258.1494 [M
258.1495.
+
H]+; found
(2Z)-1-Oxaspiro[4.5]dec-3-en-2-one Oxime (13): An ethereal solu-
tion (8 mL) of LiAlH4 (9.4 mg) was added dropwise to a diethyl
ether solution (10 mL) of the acetyloxime 8 (50 mg, 0.24 mmol).
After the system had been kept for one night at room temp., solid
hydrated Na2SO4 was added. The mixture was stirred for two hours
at room temp. and was then filtered through Celite. The filtrate was
concentrated under vacuum and the residue was purified by liquid
chromatography over silica gel to give the oxime 13 as an oil
(38 mg, 95%). 1H NMR (CDCl3, 360 MHz) δ: 8.18 (br. s, 1 H,
3
7.20 (m, 10 H, 2ϫPh), 6.26 (t, JH,H = 7.4 Hz, 1 H, C=CH–), 3.74
(br. s, 3 H, OCH3), 2.99 [br. s, 2 H, –CH2(C=O)–] ppm. 13C NMR
(CDCl3, 62.9 MHz): δ = 168.7, 145.5, 141.5, 139.0, 129.7 (2 C),
128.5 (2 C), 128.2 (2 C), 127.6 (2 C), 127.4 (2 C), 119.9, 64.4,
30.1 ppm.
(2R,4E)-N-Hydroxy-2-methyl-5-phenylhex-4-enamide (23): The pro-
cedure reported for the preparation of the hydroxamate 4 was used.
From (2R,4E)-2-methyl-5-phenylhex-4-enoic acid (22,[5] 0.50 g,
2.45 mmol), the hydroxamate 23 (0.44 g, 82%) was obtained as an
3
–OH), 6.74 [d, JH,H = 6.0 Hz, 1 H, –CH=CH–(C=N)–], 6.07 [d,
3JH,H = 6.0 Hz, 1 H, –CH=CH–(C=N)–], 1.83–1.43 (m, 10 H, cy-
clohexyl) ppm. 13C NMR (CDCl3, 100 MHz): δ = 161.3, 146.1,
1
oil. H NMR (CDCl3, 360 MHz): δ = 9.24 (br. s, 2 H, –NHOH),
3
7.43–7.22 (m, 5 H, Ph), 5.77 (d, JH,H = 8.6 Hz, 1 H, C=CH–),
3
119.4, 94.9, 35.6 (2 C), 24.8, 23.0 (2 C) ppm. IR (CH Cl ): ν =
˜
2
2
3.39 (m, 1 H, –CHCH3–), 2.10 (s, 3 H, =CCH3–), 1.33 (d, JH,H
=
6.5 Hz, 3 H, –CHCH3–) ppm. 13C NMR (CDCl3, 100 MHz): δ =
3247.0 3135.5 2934.8 2860.3 1670.1 1449.4 1286.8 1241.4
979.0 cm–1. HRMS: calcd. for C9H14NO2: 168.1025 [M + H]+;
found 168.1025.
168.5, 142.5, 138.0, 128.6 (2 C), 127.2, 125.9 (2 C), 125.7, 38.0,
18.0, 16.0 ppm. IR (CH Cl ): ν = 3202, 2925, 1658, 1450, 1016,
˜
2
2
759 cm–1. LRMS: m/z = 206.2 [M + H]+, 223.2 [M + NH4]+.
(3E)-N-Hydroxy-4-phenylpent-3-enamide (15): The procedure used
for the preparation of the hydroxamic acid 3 was used. From (E)-
4-phenylpent-3-enoic acid (14,[19] 1.76 g, 10 mmol), the hydroxamic
acid 15 (1.80 g, 94%) was obtained as a white solid (m.p. 112 °C,
MeOH). 1H NMR (CD3OD, 250 MHz): δ = 7.36–7.18 (m, 5 H,
Ph), 5.86 (t, 3JH,H = 6.5 Hz, 1 H, C=CH–), 3.05 [d, 3JH,H = 6.5 Hz,
2 H, –CH2(C=O)–], 2.02 (s, 3 H, –CH3) ppm. 13C NMR (CD3OD,
62.9 MHz) δ : = 171.1, 144.2, 139.6, 129.1, 128.0 (2 C), 126.6 (2
(2R,4E)-N-(Acetoxy)-2-methyl-5-phenylhex-4-enamide (24): The
procedure reported for the preparation of the hydroxamate 4 was
used. From the hydroxamic acid 23 (0.548 g, 2.5 mmol), the hydro-
xamate 24 (0.588 g, 90%) was obtained as a white solid (m.p. 122–
1
123 °C, Et2O). H NMR (CDCl3, 250 MHz): δ = 9.27 (br. s, 1 H,
3
–NH–), 7.44–7.26 (m, 5 H, Ph), 5.83 (d, JH,H = 9.2 Hz, 1 H,
C=CH–), 3.52 (m, 1 H, –CHCH3–), 2.23 [s, 3 H, –O(CO)CH3],
C), 120.6, 33.9, 16.2 ppm. IR (MeOH): ν = 3369, 3056, 2944, 2832,
3
˜
2.15 (s,
3
H, =CCH3–), 1.42 (d, JH,H
=
6.7 Hz,
3
H,
1644 cm–1. HRMS: calcd. for C11H13NNaO2: 214.0844 [M + Na]
+; found 214.0845.
–CHCH3–) ppm. 13C NMR (CDCl3, 62.9 MHz): δ = 168.8 (2 C),
142.4, 138.6, 128.3 (2 C), 127.4, 126.9 (2 C), 125.8, 38.5, 18.2, 17.7,
16.2 ppm. IR (CH Cl ): ν = 3139, 2960, 1794, 1656, 1179, 1021,
˜
(3E)-N-(Acetoxy)-4-phenylpent-3-enamide (16): The procedure used
for the preparation of hydroxamate 4 was used. From the hy-
droxamic acid 15 (1.53 g, 8 mmol), the hydroxamate 16 (1.49 g,
2
2
849, 755, 696 cm–1. HRMS: calcd. for C14H18NO3: 248.1287 [M +
H]+; found 248.1288.
80%) was obtained as an oil. 1H NMR (CDCl3, 250 MHz): δ =
(4R)-3-(3-Cyclohexylidenepropanoyl)-4-phenyl-1,3-oxazolidin-2-one
(25): Triethylamine (121 mg, 1.2 mmol) and pivaloyl chloride
(144 mg, 1.2 mmol) were added successively at –78 °C to a THF
solution (20 mL) of 3-cyclohexylidenepropanoic acid (1, 0.154 g,
1 mmol). After 15 min at this temperature, the solution was allowed
to warm to 0 °C for 45 min and was then cooled again at –78 °C.
In a second flask, n-butyllithium (1 mmol, 1.6  hexane solution)
was added to a THF solution (3.5 mL) of (R)-4-phenyloxazolidin-
2-one[20] (163.2 mg, 1 mmol) cooled to –78 °C. The solution from
the first flask was cannulated at –78 °C into the oxazolidine solu-
tion. After 20 min at –78 °C, the resulting mixture was allowed to
warm to room temperature for 2 h. A saturated aqueous solution
3
9.07 (br. s, 1 H, –NH–), 7.42–7.24 (m, 5 H, Ph), 5.91 (t, JH,H
=
3
7.5 Hz, 1 H, C=CH–), 3.28 [d, JH,H = 7.5 Hz, 2 H, –CH2(C=O)–
], 2.22 [s, 3 H, O–(C=O)–CH3], 2.11 (s, 3 H, –CH3) ppm. 13C NMR
(CDCl3, 62.9 MHz): δ = 169.2, 168.6, 142.4, 139.7, 128.1 (2 C),
127.2 (2 C), 125.6, 117.9, 33.2, 18.0, 16.1 ppm. IR (film): ν = 3155,
˜
2985, 1793, 1709 cm–1. HRMS: calcd. for C13H15NNaO3: 256.0950
[M + Na]+; found 256.0944.
N-Hydroxy-4-methylpent-3-enamide (18): The procedure reported
for the preparation of the hydroxamic acid 3 was used. From 4-
methylpent-3-enoic acid 1 (7, 1.03 g, 9 mmol), the hydroxamic acid
18 (1.16 g, 80%) was obtained as a white solid (m.p. 69 °C, Et2O).
1H NMR (CDCl3, 250 MHz): δ = 8.60–8.10 (br. s, 2 H, –NHOH), (30 mL) of ammonium chloride was added, and the aqueous phase
3
3
5.23 (tt, JH,H = 1.0 and 7.5 Hz, 1 H, C=CH–), 2.98 [d, JH,H
=
was extracted with dichloromethane (3 ϫ20 mL). After drying
7.5 Hz, 2 H, –CH2(C=O)–], 1.77 (s, 3 H, =CCH3–), 1.66 (s, 3 H, (MgSO4), the organic phase was concentrated under vacuum, and
=CCH3–) ppm. 13C NMR (CDCl3, 100 MHz): δ = 170.3, 137.8, the residue was purified by liquid chromatography over silica gel
115.1, 32.7, 25.6, 17.8 ppm.
(pentane/Et2O). The oxazolidine 25 (245 mg, 82%) was obtained
5891
Eur. J. Org. Chem. 2010, 5884–5896
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org

H. Trabulsi, R. Guillot, G. Rousseau
FULL PAPER
as white crystals (m.p. 67 °C, CH2Cl2). [α]D = –102.4 (c = 0.167,
(2R)-2-Benzyl-3-cyclohexylidenepropanoic Acid (28): Hydrogen per-
MeOH). 1H NMR (CDCl3, 360 MHz): δ = 7.40–7.20 (m, 5 H, Ph), oxide (0.68 mL of a 33% solution, 7.8 mmol, 6 equiv.) was added
3
5.36 (dd, 3JH,H = 3.8 and 10.5 Hz, 1 H, –CHPhN), 5.27 (dd, JH,H
dropwise to oxazolidine 26 (0.410 g, 1.3 mmol) in solution in a
THF/H2O mixture (12 and 4 mL, respectively) cooled to 0 °C, fol-
lowed by LiOH (0.138 g, 3.35 mmol, 2.5 equiv.). After the system
3
= 7.0 Hz, 1 H, C=CH–), 4.70 [t, JH,H = 8.8 Hz, 1 H, CCH2O-
(CO)–], 4.29 [dd, 3JH,H = 3.8 and 8.8 Hz, 1 H, CCH2O(CO)–], 3.67
3
[d, JH,H = 7.0 Hz, 2 H, –CH2(CO)N–], 2.10 [br. s, 4 H, 2 ϫ had been stirred at this temperature for 3.5 h, Na2SO3 (10 mL of
–CH2C=(cyclohexyl)], 1.50 [m, 6 H, 3ϫCH2 (cyclohexyl)] ppm.
a 1.3  solution) was added and the mixture was stirred for 30 min.
13C NMR (CDCl3, 100 MHz): δ = 171.3, 153.7, 144.4, 139.1, 129.4 After concentration under vacuum, the aqueous phase was ex-
(2 C), 129.1, 126.0 (2 C), 111.4, 70.0, 57.6, 37.0, 34.3, 29.1, 28.4,
tracted with dichloromethane (3 ϫ 10 mL) and acidified (pH 1)
with 1  HCl. The acidic phase was extracted with dichlorometh-
ane (3 ϫ 10 mL) and the combined organic phases were dried
(MgSO4) and concentrated under vacuum to give the acid 28
(0.154 g, 60%), which was used without further purification. [α]D
27.5, 26.7 ppm. IR (CH Cl ): ν = 2928.6, 2853.3, 1782.2, 1706.7,
˜
2
2
1385.5, 1327.7, 1202.2, 705.0 cm– 1 . HRMS: calcd. for
C18H21NNaO3: 322.1419 [M + Na]+; found 322.1414.
1
(4R)-3-[(2R)-2-Benzyl-3-cyclohexylidenepropanoyl]-4-phenyl-1,3-
oxazolidin-2-one (26): Diisopropylamine (0.54 mL, 3.86 mmol,
1.2 equiv.), n-butyllithium (2.4 mL of a 1.6  hexane solution,
1.2 equiv.) and HMPA (0.8 mL) were added to THF (10 mL), co-
oled to 0 °C. After 30 min at this temperature, the solution was
cooled to –78 °C and a THF solution (10 mL) of oxazolidine 25
(0.963 g, 3.22 mmol, 1 equiv.) was added over 10 min. After 1 h at
–78 °C, the solution was allowed to warm to –50 °C for 50 min and
then to –15 °C. A saturated aqueous solution of ammonium chlo-
ride (20 mL) was added and the mixture was concentrated under
vacuum. The resulting aqueous phase was extracted with diethyl
ether (3ϫ 5 mL). The organic phases were then washed with HCl
(0.5 , 5 mL), water (5 mL) and saturated NaCl (5 mL). After dry-
ing (MgSO4), the solution was concentrated under vacuum, and
the residue was purified by liquid chromatography over silica gel
(ether/pentane 40–60) to give compound 26 (0.800 g, 64%). The
crude reaction product, before chromatography, showed a 99:1 ra-
tio of the two diastereomers. The minor isomer was not isolated
= –109.4 (c = 0.059, CH2Cl2). H NMR (CDCl3, 360 MHz): δ =
3
11.66 (s, 1 H, CO2H), 7.32 (m, 5 H, Ph), 5.21 (d, JH,H = 9.7 Hz,
3
1 H, C=CH–), 3.66 (m, 1 H, –CHCH2Ph), 3.20 (dd, JH,H = 6.5
3
and 13.5 Hz, 1 H, –CH2Ph), 2.80 (dd, JH,H = 8.3 Hz, 1 H, and
13.5, –CH2Ph), 2.09 [m, 4 H, 2ϫ–CH2C=(cyclohexyl)], 1.55 [m, 6
H, 3ϫCH2 (cyclohexyl)] ppm. 13C NMR (CDCl3, 100 MHz): δ =
180.9, 144.1, 138.7, 129.2 (2 C), 128.2 (2 C), 126.2, 117.6, 45.8,
38.8, 37.1, 29.1, 28.3, 27.2, 26.5 ppm. IR (CH Cl ): ν = 3030, 2931,
˜
2
2
2855, 1705, 1448, 1265, 909, 739, 701 cm–1. HRMS: calcd. for
C16H24NO2: 262.1807 [M + NH4]+; found 262.1809.
(2R)-2-Benzyl-3-cyclohexylidene-N-hydroxypropanamide (29): The
procedure reported for the preparation of the hydroxamic acid 3
was used. From (2R)-2-benzyl-3-cyclohexylidenepropanoic acid
(28, 0.140 g, 0.573 mmol), the hydroxamic acid 29 (0.134 g, 90%)
was obtained as a white solid. 1H NMR (CDCl3, 360 MHz): δ =
3
8.40 (br. s, 2 H, –NHOH), 7.22 (m, 5 H, Ph), 5.11 (d, JH,H
=
3
9.5 Hz, 1 H, C=CH–), 3.35 (m, 1 H, –CHCH2Ph), 3.20 (dd, JH,H
= 5.5 and 13.5 Hz, 1 H, –CH2Ph), 2.70 (dd, JH,H = 8.7 Hz, 1 H,
3
after chromatography. White crystals, m.p. 83 °C (Et2O). [α]D
=
and 13.4, –CH2Ph), 2.33 [m, 4 H, 2ϫ –CH2C=(cyclohexyl)], 1.40
[m, 6 H, 3ϫCH2 (cyclohexyl)] ppm. 13C NMR (CDCl3, 100 MHz):
δ = 170.2, 145.2, 139.0, 129.3 (2 C), 128.2 (2 C), 126.3, 117.3, 44.2,
–12.9 (c = 0.029, CH2Cl2). 1H NMR (CDCl3, 360 MHz): δ = 7.40–
7.29 (m, 10 H, 2ϫPh), 5.43 (dd, 3JH,H = 3.6 and 8.6 Hz, –CHPhN),
3
5.15 (m, 2 H, C=CH- and –CHCH2Ph), 4.66 [t, JH,H = 8.8 Hz, 1
38.6, 37.2, 29.2, 28.3, 27.3, 26.5 ppm. IR (CH Cl ): ν = 3345, 2924,
3
˜
2
2
H, CCHHO(CO)–], 4.22 [dd, JH,H = 3.6 and 8.8 Hz, 1 H,
2851, 16.77, 1619, 1446, 1023, 700 cm–1. HRMS: calcd. for
CCHHO(CO)–], 3.10 (m, 1 H, –CHHPh), 2.60 (m, 1 H, –CHHPh),
2.07 [m, 4 H, 2ϫ –CH2C=(cyclohexyl)], 1.40 [m, 6 H, 3ϫCH2
(cyclohexyl)] ppm. 13C NMR (CDCl3, 100 MHz): δ = 174.4, 153.2,
144.2, 139.0, 139.0, 138.5, 129.5 (2 C), 129.0 (2 C), 128.1, 128.4,
126.1, 125.6 (2 C), 117.9, 69.7, 57.8, 43.5, 39.8, 37.1, 29.4, 28.4,
C16H25N2O2: 277.1916 [M + NH4]+; found 277.1919.
(2R)-N-(Acetoxy)-2-benzyl-3-cyclohexylidenepropanamide (30): The
procedure reported for the preparation of the hydroxamate 4 was
used. From the hydroxamic acid 29 (0.120 g,0.463 mmol), the hy-
droxamate 30 (0.140 g, 90%) was obtained as an oil. [α]D = –83.0
27.3, 26.6 ppm. IR (CH Cl ): ν = 2928, 2853, 1781, 1702, 1384,
˜
2
2
1196, 1104, 700 cm–1. HRMS: calcd. for C25H28NO3: 390.2069 [M
1
(c = 0.0324, CH2Cl2). H NMR (CDCl3, 250 MHz): δ = 8.40 (br.
+ H]+; found 390.2071.
3
s, 1 H, –NH–), 7.22 (m, 5 H, Ph), 5.11 (d, JH,H = 9.5 Hz, 1 H,
3
C=CH–), 3.35 (m, 1 H, –CHCH2Ph), 3.20 (dd, JH,H = 5.5 and
(4R)-3-[(2R)-3-Cyclohexylidene-2-methylpropanoyl]-4-phenyl-1,3-
oxazolidin-2-one (27): This reaction was carried out as reported for
the preparation of compound 26, with methyl iodide as alkylation
agent. From compound 25 (1.10 g, 3.34 mmol), a mixture of two
diastereomers (70:30, 0.732 g, 70%) was obtained. Only the major
diastereomer (2R) was characterized after chromatography over sil-
ica gel. [α]D = –14.0 (c = 0.043, CH2Cl2). 1H NMR (CDCl3,
3
13.4 Hz, 1 H, –CH2Ph), 2.70 (dd, JH,H = 8.7 Hz and 13.4, 1 H,
–CH2Ph), 2.23 [s, 3 H, –O(CO)–CH3 ], 2.00 [m, 4 H, 2 ϫ
–CH2C=(cyclohexyl)], 1.40 [m, 6 H, 3ϫCH2 (cyclohexyl)] ppm.
13C NMR (CDCl3, 62.9 MHz): δ = 168.5 (2 C), 145.2, 139.0, 129.2
(2 C), 128.2 (2 C), 126.2, 117.3, 44.5, 38.4, 37.1, 29.1, 28.2, 27.2,
26.4, 18.2 ppm. IR (CH Cl ): ν = 3170 3929 2853 1797 1667 1448
˜
2
2
1367 1177 1030 690 cm–1. HRMS: calcd. for C18H27N2O3: 319.2022
3
360 MHz): δ = 7.40–7.29 (m, 5 H, Ph), 5.40 (dd, JH,H = 3.6 and
[M + NH4]+; found 319.2028.
3
8.6 Hz, 1 H, –CHPhN), 5.19 (d, JH,H = 9.3 Hz, 1 H, C=CH–),
3
4.74 [dq, JH,H = 6.9 and 13.8 Hz, 1 H, CCH2O(CO)–], 4.64 (q,
(2R)-3-Cyclohexylidene-2-methylpropanoic Acid (31): This com-
pound was obtained by the method reported for the preparation
of acid 28. From the oxazolidine 27 (0.52 g), the acid 31 (0.254 g,
3
3JH,H = 8.7 Hz, 1 H, –CHCH3), 4.21 [dd, JH,H = 3.6 and 8.7 Hz,
1 H, CCH2O(CO)–], 2.20 [m, 2 H, –CH2C=(cyclohexyl)], 2.18 [br.
s, 2 H, –CH2C=(cyclohexyl)], 1.53 [br. s, 6 H, 3 ϫ CH2 (cyclo-
91%) was isolated. [α]D = –138.6 (c = 0.060, CH2Cl2). 1H NMR
hexyl)], 1.17 (d, J = 6.9 Hz, 3 H, CHCH3) ppm. 13C NMR (CDCl3, (CDCl3, 250 MHz): δ = 12.09 (s, 1 H, CO2H), 5.09 (d, JH,H
=
3
3
100 MHz): δ = 175.5, 153.3, 142.3, 139.4, 129.1 (2 C), 128.6 (2 C),
125.7, 119.9, 69.8, 57.8, 37.1, 36.4, 29.3, 28.5, 27.9, 26.8, 19.1 ppm.
9.1 Hz, 1 H, C=CH–), 3.38 (qd, JH,H = 7.0 and 9.0 Hz, 1 H,
–CHCH3), 2.11 [d, 3JH,H = 19.2 Hz, 4 H, 2ϫ-CH2C=(cyclohexyl)],
3
IR (CH Cl ): ν = 2925, 2842, 1785, 1698, 1456, 1309, 1236, 1.53 [br. s, 6 H, 3ϫCH2 (cyclohexyl)], 1.21 (d, JH,H = 7.0 Hz, 3
˜
2
2
703 cm–1. HRMS: calcd. for C19H23NNaO3: 336.1576 [M + Na]+;
H, CHCH3) ppm. 13C NMR (CDCl3, 62.9 MHz): δ = 182.4, 142.6,
119.8, 37.8, 36.9, 29.1, 28.3, 27.6, 26.6, 18.1 ppm. IR (CH Cl ): ν
found 336.1574.
˜
2
2
5892
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5884–5896

Preparation of Imino Lactones and 3-Cyanoprop-2-en-1-ones
= 2931, 2854, 1708, 1448, 1415, 1287, 1237, 1220, 934 cm–1
.
CH=), 6.16 [d, 3JH,H = 8.0 Hz, 1 H, =CH–(C=N)O–], 2.18 [s, 3 H,
CH3–(CO)O–], 1.52 (s, 6 H, –OCMe2) ppm. 13C NMR (CDCl3,
100 MHz): δ = 168.4, 165.0, 150.7, 119.1, 94.5, 25.9, 23.2,
19.5 ppm. HRMS: calcd. for C8H12NO3: 170.0817 [M + H]+; found
170.0817.
HRMS: calcd. for C10H17O2: 169.1229 [M + H]+; found 169.1230.
(2R)-3-Cyclohexylidene-N-hydroxy-2-methylpropanamide (32): This
compound was prepared by the procedure reported for the forma-
tion of the hydroxamic acid 3. From the acid 31 (0.168 g,
1.31 mmol), the hydroxamic acid 32 (0.225 g, 94%) was obtained as
(2Z)-4-Bromo-5,5-dimethyldihydrofuran-2(3H)-one O-Acetyloxime
(38): Oil. 1H NMR (CDCl3, 360 MHz): δ = 4.22 (t, 3JH,H = 7.2 Hz,
1
a white solid. [α]D = –58.5 (c = 0.220, CH2Cl2). H NMR (CDCl3,
3
3
300 MHz): δ = 8.42 (br. s, 2 H, –NHOH), 5.06 (d, JH,H = 8.8 Hz,
1 H, –CHBr–), 3.43 [dd, JH , H = 7.2 and 18.0 Hz, 1 H,
3
1 H, C=CH–), 3.20 (m, 1 H, –CHCH3–), 2.11 [br. s, 4 H, 2ϫ
–CH2C=(cyclohexyl)], 1.41 [br. s, 6 H, 3ϫCH2 (cyclohexyl)], 1.25
–CH2 (C=N)–], 3.11 [dd, JH , H = 7.2 and 18.0 Hz, 1 H,
–CH2(C=N)–], 2.11 [s, 3 H, CH3–(CO)O–], 1.54 (s, 3 H,
–OCCH3CH3), 1.50 (s, 3 H, –OCCH3CH3) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 168.0, 161.2, 91.1, 49.8, 37.7, 25.5, 25.0,
19.2 ppm. HRMS: calcd. for C8H13BrNO3: 250.0079 [M + H]+;
found 250.0078.
3
(d, JH,H = 5.9 Hz, 3 H, CHCH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 173.3, 144.0, 119.6, 37.0, 36.5, 29.2, 28.4, 27.7, 26.6,
18.3 ppm. IR (CH Cl ): ν = 3191, 2928, 2853, 1629, 1533, 1270,
˜
2
2
957 cm–1. HRMS: calcd. for C10H18NO2: 184.1338 [M + H]+;
found 184.1338.
Treatment of the Hydroxamate 21 with Bis(collidine)bromine(I)
Hexafluorophosphate: This reaction was carried out in toluene at
–20 °C as reported in the case of the hydroxamate 4. From the
hydroxamate 21 (267 mg), the cyclic bromo imidate 39 (215 mg)
was obtained.
(2R)-N-(Acetoxy)-3-cyclohexylidene-2-methylpropanamide (33):
This compound was prepared by the procedure reported for the
formation of the hydroxamate 4. From compound 32 (0.150 g), the
hydroxamate 33 (0.147 g, 80%) was obtained. [α]D = –93.7 (c =
0.088, CH2Cl2). 1H NMR (CDCl3, 360 MHz): δ = 9.10 (br. s, 1
3
(2Z)-4-Bromo-5,5-diphenyldihydrofuran-2(3H)-one O-Methyloxime
(39): 1H NMR (CDCl3, 360 MHz): δ = 7.59–7.28 (m, 10 H, 2ϫPh),
5.30 (dd, J = 2.7 and 5.5 Hz, 1 H, –CHBr–), 3.94 (s, 3 H, –OCH3),
3.20 double AB System: 3.23 [part A, dd, J = 5.5 and 17.0, 1 H,
–CH2–(C=N)O-, part B, dd, J = 2.7 and 17.0 Hz, 1 H, –CH2–
(C=N)O–] ppm. 13C NMR (CDCl3, 62.9 MHz): δ = 153.9, 141.0,
140.8, 129.0 (2 C), 128.4 (2 C), 127.9 (2 C), 127.8 (2 C), 125.9,
125.2, 94.5, 62.6, 51.9, 38.4 ppm. HRMS: calcd. for C17H17BrNO2:
346.0443 [M + H]+; found 346.0444.
H, –NH–), 5.10 (d, J = 9.0 Hz, 1 H, C=CH–), 3.04 (dq, JH,H
=
6.7 and 9.0 Hz, 1 H, –CHMe–), 2.18 [s, 3 H, –O(CO)CH3], 2.00
[br. s, 4 H, 2ϫ –CH2C=(cyclohexyl)], 1.54 [br. s, 6 H, 3ϫCH2
3
(cyclohexyl)], 1.28 (d, JH,H = 9.0 Hz, 3 H, –CHCH3) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 168.7 (2 C), 144.3, 119.6, 37.0 (2 C),
29.2, 28.3, 27.6, 26.5, 18.3, 17.9 ppm. IR (CH Cl ): ν = 3583, 3183,
˜
2
2
2930, 2853, 1797, 1674, 1448, 1369, 1178, 1024, 850 cm–1. HRMS:
calcd. for C12H19NNaO3: 248.1263 [M + Na]+; found 248.1263.
Treatment of Hydroxamate 16 with Bis(collidine)bromine(I) Hexa-
fluorophosphate: This reaction was carried out in dichloromethane
as reported for the treatment of the hydroxamate 4. From the hy-
droxamate 16 (233 mg, 1 mmol) we obtained a mixture (265 mg)
composed of products 35 and 36 (50:50), together with a small
amount (Ͻ2%) of compound 34, which could not be characterized
(Table 2).
Treatment of the Hydroxamate 24 with Bis(collidine)bromine(I)
Hexafluorophosphate: This reaction was carried out in dichloro-
methane as reported in the case of the hydroxamate 4. From the
hydroxamate 24 (247 mg), the cyclic bromo imidate 40 (245 mg)
was obtained.
(2Z,3S,4R,5S)-4-Bromo-3,5-dimethyl-5-phenyldihydro-2(3H)-
furanone O-Acetyloxime (40): [α]D = –1.80 (c = 0.875, CH2Cl2). 1H
NMR (CDCl3, 360 MHz): δ = 7.56–7.37 (m, 5 H, Ph), 4.00 (d,
3JH,H = 10.5 Hz, 1 H, –CHBr–), 3.36 (dq, 3JH,H = 6.7 and 10.5 Hz,
1 H, –CHMe), 2.21 [s, 3 H, CH3–(CO)O–], 1.87 (s, 3 H, –CPhCH3),
(2Z,4S*,5R*)-4-Bromo-5-methyl-5-phenyldihydrofuran-2(3H)-one
O-Acetyloxime (35): 1H NMR (CDCl3, 360 MHz): δ = 7.42–7.31
(m, 5 H, Ph), 4.68 (dd, 3JH,H = 2.8 and 6.0 Hz, 1 H, –CHBr–), 3.26
3
3
[dd, JH,H = 6.0 and 17.6 Hz, 1 H, –CH2(C=N)–], 3.11 [dd, JH,H
= 2.8 and 17.6 Hz, 1 H, –CH2(C=N)–], 2.25 [s, 3 H, CH3–(CO)-
O–], 1.91 (s, 3 H, –OCPhCH3) ppm. 13C NMR (CDCl3, 90 MHz):
δ = 168.3, 161.7, 140.9, 129.1 (2 C), 128.6 (2 C), 124.1, 93.5, 53.1,
38.3, 27.5, 19.5 ppm. HRMS: calcd. for C13H14BrNNaO3: 334.0055
[M + Na]+; found 334.0052.
3
1.41 (d, JH,H = 6.7 Hz, 3 H, –CHCH3) ppm. 13C NMR (CDCl3,
100 MHz): δ = 168.2, 163.7, 141.6, 128.7 (2 C), 128.4 (2 C), 124.1,
90.5, 58.0, 43.8, 24.7, 19.4, 13.9 ppm. IR (CH Cl ): ν = 2983, 1771,
˜
2
2
1671, 1448, 1204, 1047, 984, 700 cm–1. HRMS: calcd. for
C14H16BrNNaO3 [M + Na]+: 348.0204; found 348.0211.
(2Z)-5-Methyl-5-phenyl-2(5H)-furanone O-Acetyloxime (36): White
solid. 1H NMR (CDCl3, 360 MHz): δ = 7.41–7.37 (m, 5 H, Ph),
7.00 (d, 3JH,H = 6.0 Hz, 1 H, cmePh–CH=), 6.29 [d, 3JH,H = 6.0 Hz,
1 H, =CH–(C=N)O–], 2.23 [s, 3 H, CH3–(CO)O–], 1.89 (s, 3 H,
–OCPhCH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 168.5, 165.0,
150.0, 139.4, 128.8 (2 C), 128.5 (2 C), 125.9, 119.0, 96.3, 26.0,
Treatment of the Hydroxamate 30 with Bis(collidine)bromine(I)
Hexafluorophosphate: This reaction was carried out in dichloro-
methane as reported in the case of the hydroxamate 4. From the
hydroxamate 30 (151 mg), the product 41 (143 mg) was isolated.
(2Z,3S,4R)-3-Benzyl-4-bromo-1-oxaspiro[4.5]decan-2-one O-Acet-
1
19.5 ppm. IR (CH Cl ): ν = 3155, 3091, 3066, 2987, 1762,
˜
yloxime (41): [α]D = –45.7 (c = 0.165, CH2Cl2). H NMR (CDCl3,
2
2
1654 cm–1. HRMS: calcd. for C13H14NO3: 232.0974 [M + H]+;
250 MHz): δ = 7.22 (m, 5 H, Ph), 3.50 (m, 2 H, –CHBr- and -
3
found 232.1337.
CHCH2Ph–), 3.28 (dd, JH,H = 4.5 and 14.3 Hz, 1 H, –CH2Ph),
3
3.10 (dd, JH,H = 5.2 and 14.3 Hz, 1 H, –CH2Ph), 2.15 [s, 3 H,
Treatment of the Hydroxamate 19 with Bis(collidine)bromine(I)
Hexafluorophosphate: These reactions were carried out in dichloro-
methane and in toluene as reported in the case of the hydroxamate
4. In dichloromethane, from the hydroxamate 19 (171 mg, 1 mmol),
compound 37 (150 mg) and compound 38 (12 mg) were obtained
after chromatography. In toluene at –20 °C, compound 38 (175 mg)
was isolated.
CH3–(CO)O–], 1.40 (m, 10 H, cyclohexyl) ppm. 13C NMR (CDCl3,
100 MHz): δ = 168.3, 162.4, 136.0, 130.1 (2 C), 128.4 (2 C), 127.0,
89.7, 53.0, 48.3, 34.4, 33.1, 31.6, 24.8, 22.2, 21.6, 19.4 ppm. IR
(CH Cl ): ν = 3507, 2936, 2865, 1768, 1667, 1450, 1366, 1199, 1017,
˜
2
2
794, 703 cm–1. HRMS: calcd. for C18H23BrNO3: 380.0861 [M + H]
+; found 380.0863.
(2Z)-5,5-Dimethyl-2(5H)furanone O-Acetyloxime (37): Oil. 1H Treatment of the Hydroxamate 33 with Bis(collidine)bromine(I)
3
NMR (CDCl3, 360 MHz): δ = 6.77 (d, JH,H = 8 Hz, 1 H, CMe2-
Hexafluorophosphate: This reaction was carried out in dichloro-
Eur. J. Org. Chem. 2010, 5884–5896
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5893

H. Trabulsi, R. Guillot, G. Rousseau
FULL PAPER
methane as reported in the case of the hydroxamate 4. From the
hydroxamate 33 (112 mg), the cyclic bromo imidate 42 (98 mg) was
isolated.
hexafluorophosphate, triethylamine (2 equiv.) was added to the re-
action mixture. After stirring for 2 h at room temp., the mixture
was concentrated under vacuum, and the residue was purified by
liquid chromatography over silica gel to give compound 47[10]
(125 mg, 87%) as a white solid (m.p. 77 °C, CH2Cl2). Heating at
reflux for three days in toluene caused isomerization to give the E
isomer (m.p. 72 °C). The isomerization of the pure product was
(2Z,3S,4R)-4-Bromo-3-methyl-1-oxaspiro[4.5]decan-2-one O-Acet-
1
yloxime (42): [α]D = –1.84 (c = 0.075, MeOH). H NMR (CDCl3,
360 MHz): δ= = 3.60 (d, 3JH,H = 11.3 Hz, 1 H, –CHBr–), 3.20 (dq,
3JH,H = 6.7 Hz and 11.3, 1 H, –CHMe), 2.17 [s, 3 H, CH3–(CO)-
also observed in 5 weeks at room temp. 1H NMR (CDCl3,
3
O–], 1,96–1.54 (m, 10 H, cyclohexyl), 1.41 (d, JH,H = 6.7 Hz, 3
3
360 MHz): δ = 7.97 (d, J = 7.2 Hz, 2 H, phenyl), 7.64 (d, JH,H
=
=
H, –CHCH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 168.4, 164.3,
89.8, 57.3, 42.6, 34.5, 31.9, 24.9, 22.2, 21.5, 19.4, 14.0 ppm. HRMS:
calcd. for C12H19BrNO3: 304.0548 [M + H]+; found 304.0549.
3
11.5 Hz, 1 H, PhCH=), 7.63 (m, 1 H, phenyl), 7.54 (t, JH,H
3
7.2 Hz, 2 H, phenyl), 6.00 (d, JH,H = 11.5 Hz, 1 H, =CH-
CN) ppm. For the E isomer, the vinylic protons were at 7.97 and
6.57 (d, J = 20 Hz) ppm. 13C NMR (CDCl3, 62.9 MHz): δ = 186.6,
141.7, 135.4, 134.2, 128.9 (2 C), 128.6 (2 C), 115.4, 108.8 ppm. IR
(E)-N-Hydroxy-4-phenylbut-3-enamide (43): This compound was
prepared by the procedure reported for the preparation of the hy-
droxamic acid 3. From commercially available (E)-4-phenylbut-3-
enoic acid (1.62 g, 10 mmol) we isolated compound 43 (1.70 g,
(CH Cl ): ν = 3084, 3054, 2965, 2928, 1671, 1603, 1579, 908,
˜
2
2
732 cm–1. HRMS: calcd. for C10H7NNaO: 180.0425 [M + Na]+;
96 %) as a white solid (m.p. 135–137 °C, MeOH). 1H NMR
found 180.0427.
3
(CD3OD, 250 MHz): δ = 7.33–7.11 (m, 5 H, Ph), 6.47 (d, JH,H
=
Dimethyl 2-(1-Cyano-3-oxo-3-phenylpropyl)malonate (48): n-Butyl-
lithium (0.375 mL of a 1.6  solution in hexanes, 0.60 mmol) was
added dropwise at –40 °C to a THF solution (5 mL) of dimethyl
malonate (76 µL, 0.66 mmol). After 30 min, a THF solution (1 mL)
of (Z)-4-oxo-4-phenylbut-2-enenitrile (47, 0.095 g, 0.60 mmol) was
added dropwise and the temperature was maintained at –40 °C for
1 h. A saturated aqueous solution of NH4Cl (5 mL) was added.
After separation, the aqueous phase was extracted with diethyl
ether (3 ϫ 5 mL) and the combined organic phases were dried
(MgSO4) and concentrated under vacuum. The residue was puri-
fied by liquid chromatography over silica gel, to give compound 48
as an oil (140 mg, 80%). 1H NMR (CDCl3, 300 MHz): δ = 7.93
3
16.0 Hz, 1 H, Ph–CH=CH), 6.23 (dt, JH,H = 7.0 and 16.0 Hz, 1
H, Ph–CH=CH–), 2.97 (d, J = 7.0 Hz, 2 H, CH2–CON) ppm. 13C
NMR (CD3OD, 62.9 MHz): δ = 169.6, 136.9, 133.4, 128.4 (2 C),
127.2 (2 C), 126.0, 122.0, 36.6 ppm. IR (CD OD): ν = 3344 3031
˜
3
1650 cm–1. HRMS: calcd. for C10H11NNaO2: 200.0687 [M + Na]
+; found 200.0690.
(3E)-N-(Acetoxy)-4-phenylbut-3-enamide (44): This compound was
obtained by the procedure reported for the preparation of com-
pound 4. From the hydroxamic acid 43 (1.1 g), compound 44
(1.05 g, 77%) was isolated as a white solid (m.p. 131–133 °C, Et2O).
1H NMR (CDCl3, 360 MHz): δ = 9.0 (br. s, 1 H, –NH–), 7.38–7.25
3
3
3
(m, 5 H, Ph), 6.59 (d, JH,H = 15.8 Hz, 1 H, Ph–CH=CH), 6.29
(d, JH,H = 8.4 Hz, 2 H, phenyl), 7.60 (t, JH,H = 7.2 Hz, 1 H,
3
(dt, 3JH,H = 15.8 and 7.4 Hz, 1 H, Ph–CH=CH–), 3.25 (d, JH,H
=
3
phenyl), 7.47 (t, JH,H = 7.2 Hz, 2 H, phenyl), 3.97–3.90 [m, 2 H,
7.3 Hz, 2 H, CH2–CON), 2.22 [s, 3 H, CH3–(CO)O–] ppm. 13C
NMR (CDCl3, 62.9 MHz): δ = 169.3, 168.7, 136.3, 135.0, 128.6 (2
–CHCN and CH(CO2Me)2–], 3.80 (s, 3 H, –OCH3), 3.79 (s, 3 H,
–OCH3), 3.54–3.50 [m, 2 H, CH2–(CO)Ph] ppm. 13C NMR
(CDCl3, 62.9 MHz): δ = 194.5, 166.6, 166.5, 135.3, 133.9, 128.7 (2
C), 127.9 (2 C), 118.8, 53.2 (2 C), 51.4, 38.1, 25.8 ppm. IR
C), 127.9 (2 C), 126.3, 120.4, 37.5, 18.2 ppm. IR (CH Cl ): ν =
˜
2
2
3148, 2964, 1792, 1662 cm–1. HRMS: calcd. for C12H13NNaO3:
242.0793 [M + Na]+; found 242.0803.
(CH Cl ): ν = 2957, 2249, 1741, 1739, 1687, 1598, 1449, 1437 cm–1.
˜
2
2
HRMS: calcd. for C15H19N2O5: 307.1294 [M + NH4]+; found
Treatment of the Hydroxamate 44 with Bis(collidine)bromine(I)
307.1297.
Hexafluorophosphate: This reaction was carried out in dichloro-
1
methane as reported in the case of hydroxamate 4. The H NMR
Methyl 3-Cyano-5-oxo-5-phenyl-2-(phenylsulfonyl)pentanoate (49):
Methyl (phenylsulfonyl)acetate (0.058 mL, 0.35 mmol) was added
dropwise at room temp. to a suspension of sodium hydride (17 mg
of a 50% dispersion in mineral oil, 0.35 mmol) in dry THF (3 mL).
After 30 min, the solution was cooled to –20 °C, a THF solution
(1 mL) of (Z)-4-oxo-4-phenylbut-2-enenitrile (47, 50 mg,
0.31 mmol) was added dropwise, and the temperature was main-
tained at –20 °C for 1 h. A saturated aqueous solution of NH4Cl
(5 mL) was added. After separation, the aqueous phase was ex-
tracted with diethyl ether (3ϫ 5 mL) and the combined organic
phases were dried (MgSO4) and concentrated under vacuum. The
residue was purified by liquid chromatography over silica gel, to
give compound 49 as a mixture of two diastereomers (60:40, 76 mg,
64%). Major diastereomer (from the crude reaction mixture): 1H
NMR (CDCl3, 300 MHz): δ = 7.99–7.49 (m, 10 H, 2ϫPh), 4.65
spectrum of the crude reaction mixture showed the presence of
three products: the cyclic bromo imidate 45 (47%), the unsaturated
cyclic imidate 46 (30%) and the β-cyano-α,β-enone 47 (23%). Puri-
fication of this mixture by liquid chromatography over silica gel led
to intensive degradation. Only small amounts of compounds 46
and 47 were isolated.
(2Z)-4-Bromo-5-phenyldihydrofuran-2(3H)-one O-Acetyloxime (45):
Oil. 1H NMR (CDCl3, 250 MHz): δ = 7.37–7.20 (m, 5 H, Ph), 5.66
3
(d, JH,H = 4.8 Hz, 1 H, –CHPh–), 4.29 (ddd, J = 4.8, 5.8 and
3
7.0 Hz, 1 H, –CHBr–), 3.40 [dd, JH,H = 17.5 and 7.0 Hz, 1 H,
3
–CH2(C=N)O–], 3.12 [dd, JH,H = 17.5 and 5.8 Hz, 1 H,
–CH2(C=N)O–], 2.17 [s, 3 H, CH3–(C=O)O–] ppm. 13C NMR
(CDCl3, 62.9 MHz): δ = 168.0, 162.2, 135.1, 129.5 (2 C), 129.1 (2
C), 125.4, 92.3, 46.1, 37.0, 19.3 ppm. IR (film): ν = 2902, 1767,
˜
3
1679 cm–1. HRMS: calcd. for C12H12BrNNaO3: 319.9898 [M + Na]
+; found 319.9899.
(d, JH,H = 6.9 Hz, 1 H, –CHSO2PhCO2Me), 4.17–4.12 (m, 1 H,
–CHCN–), 3.91–3.60 [m, 2 H, –CH2(CO)Ph], 3.64 (s, 3 H,
–OCH3) ppm. 13C NMR (CDCl3, 100 MHz): δ = 194.3, 163.9,
134.9, 134.0, 129.3, 129.1, 128.7 (2 C), 128.0 (2 C), 117.5, 68.8,
53.3, 38.1, 25.3 ppm. HRMS: calcd. for C19H21N2O5S: 389.1171
[M + NH4]+; found 389.1175. Minor diastereomer (from the crude
reaction mixture): 1H NMR (CDCl3, 300 MHz): δ = 7.99–7.49 (m,
(2Z)-5-Phenyl-2(5H)-furanone O-Acetyloxime (46): 1H NMR
3
(CDCl3, 250 MHz): δ = 7.37–7.20 (m, 5 H, Ph), 7.04 [d, JH,H
=
3
5.7 Hz, 1 H, –CH=CH(C=N)O–], 6.34 [d, JH,H = 5.7 Hz, 1 H,
=CH(C=N)O–], 6.29 (br. s, 1 H, –CHPh–), 2.15 [s, 3 H, CH3–
(C=O)O–] ppm.
3
10 H, 2ϫPh), 4.61 (d, JH,H = 6.9 Hz, 1 H, –CHSO2PhCO2Me),
(Z)-4-Oxo-4-phenylbut-2-enenitrile (47): After treatment of the hy-
droxamate 44 (200 mg, 0.91 mmol) with bis(collidine)bromine(I)
4.17–4.12 (m, 1 H, –CHCN–), 3.91–3.60 [m, 2 H, –CH2(CO)Ph],
3.84 (s, 3 H, –OCH3) ppm. 13C NMR (CDCl3, 100 MHz): δ =
5894
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Preparation of Imino Lactones and 3-Cyanoprop-2-en-1-ones
194.5, 163.7, 134.9, 134.0, 129.3, 129.1, 128.7 (2 C), 128.0 (2 C), 3.16 [br. s, 2 H, –CH2–(CO)N], 2.87 (t, 3JH,H = 7.8 Hz, 2 H, –CH2–
3
117.7, 68.6, 53.4, 37.9, 25.1 ppm. IR (film, mixture of the two dia-
Car), 2.35 (t, JH,H = 7.8 Hz, 2 H, –CH2-CH2-C=), 1.80 (br. s, 1
H, –OH) ppm. 13C NMR (CD3OD, 62.9 MHz): δ = 170.2, 135.8,
135.5, 135.4, 126.8, 126.5, 126.1, 125.6, 125.5, 42.1, 28.8, 27.9 ppm.
HRMS: calcd. for C12H13NNaO2: 226.0844 [M + Na]+; found
226.0849.
stereomers): ν = 2955, 2251, 1747, 1686, 1598, 1449, 1329, 1151,
˜
1082, 911, 732 cm–1.
Methyl 2-Acetyl-3-cyano-5-oxo-5-phenylpentanoate (50): Methyl 3-
oxobutanoate (41 mg, 0.35 mmol) was added dropwise at room
temp. to a suspension of sodium hydride (17 mg of a 50% disper-
sion in mineral oil, 0.35 mmol) in dry THF (3 mL). After 30 min,
the solution was cooled to –20 °C, a THF solution (1 mL) of (Z)-
4-oxo-4-phenylbut-2-enenitrile (47, 50 mg, 0.31 mmol) was added
dropwise, and the temperature was maintained at –20 °C for 1 h.
A saturated aqueous solution of NH4Cl (5 mL) was added. After
separation, the aqueous phase was extracted with diethyl ether (3ϫ
5 mL) and the combined organic phases were dried (MgSO4) and
concentrated under vacuum. The residue was purified by liquid
chromatography over silica gel, to give compound 50 as a mixture
of two diastereomers (50:50, 74 mg, 77 %). 1H NMR (CDCl3,
N-Acetoxy-2-(1H-inden-2-yl)acetamide (56): This compound was
obtained by the procedure reported for the preparation of com-
pound 4. From the hydroxamic acid 53 (378 mg, 2 mmol), com-
pound 56 (347 mg, 75%) was isolated as a white solid (m.p. 95 °C,
CH2Cl2). 1H NMR (CDCl3, 250 MHz): δ = 9.20 (br. s, 1 H, –NH–
), 7.50–7.10 (m, 4 H, aromatic), 6.80 (br. s, 1 H, CH=), 3.54 [s, 2
H, –CH2– (ring)], 3.49 [s, 2 H, –CH2–(C=O)–], 2.23 [s, 3 H, CH3–
(CO)O–] ppm. 13C NMR (CDCl3, 62.9 MHz): δ = 168.7 (2 C),
144.5, 143.4, 140.2, 131.2, 126.5, 124.8, 123.7, 120.8, 41.3, 36.2,
18.3 ppm. HRMS: calcd. for C13H13NNaO3: 254.0793 [M + Na]+;
found 254.0798.
3
250 MHz, mixture): δ = 7.94 (d, JH,H = 8.7 Hz, 2 H, Ph), 7.62 (t,
2-(Acetoxy)-2-(3,4-dihydronaphthalen-2-yl)acetamide (57): This
compound was obtained by the procedure reported for the prepara-
tion of compound 4. From the hydroxamic acid 55 (1.10 g), the
hydroxamate 57 (1.13 g , 85%) was obtained as a white solid (m.p.
115 °C, CH2Cl2). 1H NMR (CDCl3, 250 MHz): δ = 9.00 (br. s, 1
H, –NH–), 7.20–7.00 (m, 4 H, aromatic), 6.48 (s, 1 H, –CH=), 3.26
3
3JH,H = 7.2 Hz, 1 H, Ph), 7.49 (t, JH,H = 7.2 Hz, 2 H, Ph), 4.11
(m, 1 H, –CHCN–), 3.95–3.84 [m, 1 H, –CH(COMe)CO2Me], 3.84
and 3.81 (2ϫs, 3 H, –OCH3), 3.50–3.45 [m, 2 H, –CH2(CO)Ph],
2.39 and 2.36 [2 ϫ s, 3 H, –(CO)CH3] ppm. 13C NMR (CDCl3,
62.9 MHz, mixture): δ = 199.3, 199.1, 194.9, 194.8, 166.8 (2 diast.),
135.4 (2 diast.), 133.9 (2 diast.), 128.7 (2 C for the 2 diast.), 127.9
(2 C for the 2 diast.), 119.3 (2 diast.), 58.5, 58.2, 53.2 (2 diast.),
3
[s, 2 H, –CH2–(CO)N], 2.90 (t, JH,H = 7.8 Hz, 2 H, –CH2–Car),
2.41 (t, 3JH,H = 7.8 Hz, 2 H, –CH2–CH2–C=), 2.26 [s, 3 H, –O(CO)-
CH3] ppm. 13C NMR ([D6]DMSO, 62.9 MHz): δ = 169.0, 167.4,
136.4, 135.4, 134.4, 127.6, 127.1, 126.9, 125.9, 125.7, 41.1, 27.7,
27.1, 18.5 ppm. HRMS: calcd. for C14H15NNaO3: 268.0950 [M +
Na]+; found 268.0948.
38.0, 37.9, 30.0, 29.7, 25.0 (2 diast.) ppm. IR (film, mixture): ν =
˜
2957, 2247, 1744, 1720, 1637, 1597, 1449, 1360, 1247, 1219, 1159,
913, 755, 690 cm–1. HRMS: calcd. for C15H19N2O4: 291.1345 [M
+ NH4]+; found 291.1346.
(Z)-4-Hydroxy-4-phenyloct-2-enenitrile (51): n-Butyllithium
(0.30 mL of 1.6  solution in hexanes, 0.478 mmol) was added
dropwise at –78 °C to a THF solution (5 mL) of (Z)-4-oxo-4-phen-
ylbut-2-enenitrile (47, 0.050 g, 0.32 mmol). After the system had
been kept for 1 h at this temperature, a saturated aqueous solution
of NH4Cl (5 mL) was added. After separation, the aqueous phase
was extracted with diethyl ether (3ϫ5 mL) and the combined or-
ganic phases were dried (MgSO4) and concentrated under vacuum.
The residue was purified by liquid chromatography over silica gel,
(E)-2-[1-Oxo-1H-inden-2(3H)-ylidene]acetonitrile (58): This com-
pound was prepared by the procedure reported for the preparation
of compound 47 (45 mg, 75%). White solid, m.p. 138 °C (CH2Cl2)
(ref.[16] m.p. 138 °C); see also ref.[15]
(Z)-2-[3,4-Dihydro-1-oxonaphthalen-2(1H)-ylidene]acetonitrile (59):
This compound was prepared by the procedure reported for the
preparation of compound 47 (120 mg, 74%). White solid, m.p. 88–
89 °C (CH2Cl2); see also ref.[16]
1
to give the alcohol 51 as an oil (52 mg, 75%). H NMR (CDCl3,
X-ray Crystallography: Data were collected with a Kappa X8 AP-
PEX II Bruker diffractometer with use of graphite-monochromated
3
360 MHz, mixture): δ = 7.44–7.31 (m, 5 H, Ph), 6.96 (d, JH,H
=
3
16.2 Hz, 1 H, NC–CH=CH–), 5.77 (d, JH,H = 16.2 Hz, 1 H, NC–
CH=CH–), 2.08 (br. s, 1 H, –OH), 2.00–1.94 (m, 2 H, HO–C–CH2–
), 1.38–1.23 (m, 4 H, –CH2–CH2–), 0.91 (t, JH,H = 6.8 Hz, 3 H,
Table 3. Crystallographic data for compounds 8 and 41.
3
–CH3) ppm. 13C NMR (CDCl3, 62.9 MHz): δ = 159.0, 142.9, 128.7
(2 C), 127.8 (2 C), 125.0, 117.8, 97.8, 72.7, 41.0, 25.4, 22.8,
13.9 ppm. HRMS: calcd. for C14H17NNaO: 238.1208 [M + Na]+;
found 238.1211.
41
8
Empirical formula
Formula wt. [g/mol]
Temp. [K]
C12H18BrNO3
304.17
290(2)
C11H15NO3
209.24
100(1)
Wavelength [Å]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
0.71073
monoclinic
P21
9.0816(12)
7.3831(9)
10.7751(12)
93.856(6)
720.84(15)
2
0.71073
monoclinic
P21/n
9.6440(17)
10.170(2)
11.373(2)
97.480(4)
1106.0(4)
4
N-Hydroxy-2-(1H-inden-2-yl)acetamide (53): This compound was
prepared by the procedure reported for the preparation of the hy-
droxamic acid 3 from 2-(1H-inden-2-yl)acetic acid (56, 348 mg).[21]
Yield 300 mg (79 %). White pasty solid. 1H NMR (CD3OD,
250 MHz): δ = 7.35–7.05 (m, 4 H, aromatic), 6.70 (br. s, 1 H, CH=),
4.97 [br. s, 2 H, –CH2– (ring)], 3.41 [br. s, 2 H, –CH2–(C=O)–] ppm.
13C NMR (CD3OD, 62.9 MHz): δ = 171.1, 147.0, 145.5, 144.3,
131.5, 128.1, 126.2, 125.2, 122.2, 42.8, 37.2 ppm. HRMS: calcd. for
C11H11NNaO2: 212.0682 [M + Na]+; found 212.0683.
β [°]
Cell volume [Å3]
Z
Density (calcd.)
Absor. coeff. [mm–1]
Reflections collected
Independent reflections
Final R indices [IϾ2σ(I)] 0.0375
Final wR indices [IϾ2σ(I)] 0.0756
1.401
2.848
16986
1.257
0.091
13119
2-(1,2-Dihydronaphthalen-3-yl)-N-hydroxyacetamide (55): This
compound was prepared by the procedure reported for the prepara-
tion of the hydroxamic acid 3, from the acid 54[21] (1.88 g). The
hydroxamic acid 55 (1.85 g, 91%) was isolated as a white solid (m.p.
4401 (Rint = 3.72%) 4199 (Rint = 3.50%)
0.0452
0.1161
1.034
–
Goodness of fit
Flack parameter
1.038
0.025(12)
1
180 °C, CH2Cl2). H NMR (CDCl3, 250 MHz): δ = 8.60–8.20 (br.
s, 1 H, –NH–), 7.25–7.00 (m, 4 H, aromatic), 6.42 (s, 1 H, –CH=),
Eur. J. Org. Chem. 2010, 5884–5896
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5895

H. Trabulsi, R. Guillot, G. Rousseau
FULL PAPER
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Received: March 18, 2010
Published Online: September 7, 2010
5896
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5884–5896