Zinc metal-promoted nucleophilic addition of azetidin-2-ones to aldehydes and nitriles

Article abstract of DOI:10.1055/s-2004-834897

The reactivity of in situ generated organozinc reagents of 3-alkenyl-3-bromoazetidin-2-ones with aromatic and aliphatic aldehydes to give the corresponding alcohol derivatives has been studied. The effect of solvent and Lewis acids has been explored in or

Full text of DOI:10.1055/s-2004-834897

PAPER
61
Zinc Metal-Promoted Nucleophilic Addition of Azetidin-2-ones to Aldehydes
and Nitriles
N
ucleophilic
A
i
ddition
d
of Azetidin
e
-2-ones to
s
A
ldehydes and
N
B
itrile
s
enfatti, Giuliana Cardillo,* Serena Fabbroni, Luca Gentilucci, Rossana Perciaccante, Fabio Piccinelli,
Alessandra Tolomelli
Dipartimento di Chimica ‘G. Ciamician’, Università di Bologna, Via Selmi 2, 40126 Bologna, Italy
Fax +39(051)2099456; E-mail: giuliana.cardillo@unibo.it
Received 27 July 2004; revised 6 September 2004
regio- and stereochemistry of the nucleophilic attack of C-
Abstract: The reactivity of in situ generated organozinc reagents of
3-alkenyl-3-bromoazetidin-2-ones with aromatic and aliphatic al-
dehydes to give the corresponding alcohol derivatives has been
studied. The effect of solvent and Lewis acids has been explored in
order to improve the reaction yields. The application of this meth-
odology to nitriles and acyl chlorides allowed the preparation of the
corresponding keto derivatives. The products of these reactions
could be of interest on account of their structural similarity with the
already known cholesterol adsorption inhibitors.
3 zinc organometallic derivatives, obtained from a-bro-
mo- a-alkenyl-b-lactams, on aldehydes and nitriles
(Scheme 1, b).
b)
a)
ZnBr
N
R2
O
O
R
R
N
Key words: zinc, aldehydes, condensation, azetidinones, allylic or-
ganozinc reagents, Lewis acids
R1
R1
O
MBr
R3CHO
R2
OH
Organozinc reagents are very useful and versatile com-
pounds for the carbon–carbon bond formation.1 The Re-
formatsky and Barbier reactions2 have been widely used
due to the easy availability of these carbanions through
the oxidative addition of metallic zinc to activated organic
halides such as a-halo esters, a-halo amides and allyl ha-
lides. Recently, a class of b-lactam based structures, con-
taining hydroxy and keto functions in the C-3 side chain,
were found to be very potent cholesterol adsorption inhib-
itors (CAI) (Figure 1).3
R2
O
HO
O
R3
R
R2
R
N
N
R1
R1
Scheme 1 Different reaction pathways for the synthesis of hydro-
xyazetidinone derivatives.
The starting 3-alkenyl-3-bromoazetidin-2-ones 1 were di-
rectly prepared in a one-pot synthesis through the
Staudinger reaction5 of 2-bromoalkenyl chlorides6 and the
appropriate imines with triethylamine as reported by Bose
and Manhas for the synthesis of a-vinyl-b-lactams.7 The
b-lactams could be obtained in 50–60% yields, preferen-
tially in the cis configuration. Recently, densely substitut-
ed b-lactams have been recognized as useful
intermediates for a variety of further transformations as
well as biologically active molecules. To the best of our
knowledge, among the examples of substituted b-lac-
tams,3,8 3-alkenyl-3-bromoazetidin-2-ones have not been
described.
OMe
OH
O
O
H
Ph
N
N
O
SCH 56524
Figure 1 Representative examples of cholesterol adsorption inhibi-
tors containing hydroxy and keto functions in the side carbon chain.
In a program directed towards the synthesis of potential
protease inhibitors, we became interested in the introduc-
tion of oxygenated substituents at the C-3 position of 3-
alkenylazetidin-2-ones. In most cases, azetidin-2,3-diones
have been regarded as starting materials for the introduc-
tion of functionalized side chain at C-3 position via con-
densation with organometallic allylic reagents (Scheme 1,
a).4 Following a different approach, we investigated the
In the course of our investigation on the reactivity of this
class of compounds, the easy preparation of organozinc
derivatives 2 and their reactivity with aldehydes and ni-
triles was studied (Scheme 2). Although the transforma-
tion of C-3 substituted and unsubstituted azetidin-2-ones
to the corresponding anions is well known; anions as 2
have not been reported yet, as far as we know.
The organozinc 2 was easily prepared by stirring a cis/
trans mixture of 1 with zinc powder in anhydrous THF at
room temperature. The complete insertion of the metal
was checked by quenching the reaction with water. The
debrominated compound was quantitatively obtained af-
SYNTHESIS 2005, No. 1, pp 0061–0070
x
x
.
x
x
.2
0
0
4
Advanced online publication: 02.11.2004
DOI: 10.1055/s-2004-834897; Art ID: Z15104SS
© Georg Thieme Verlag Stuttgart · New York

62
F. Benfatti et al.
PAPER
ter 30 minutes as a cis/trans mixture of E-alkenyl b-lac- tained. However, an improvement in the yield was ob-
tams.
served under Barbier-type conditions, by directly mixing
azetidinone 1, zinc, the aldehyde, and one equivalent of
AlMe2Cl in THF at room temperature.
The addition of benzaldehyde to the preformed enolate at
room temperature did not afford any condensation prod-
uct even after stirring the mixture overnight. In order to Detailed studies of the reaction showed a considerable in-
activate the electrophile, a solution of benzaldehyde/ fluence of the solvent. THF and MeCN were found to be
AlMe2Cl in 1:1 ratio was added at 0 °C. The conversion better solvents than other aprotic solvents. This Refor-
of 2 into 3 and 4 proceeded within two hours at room tem- matsky reaction was tested with some aromatic and ali-
perature in good yield (Scheme 2).9 A detectable amount phatic aldehydes and the corresponding hydroxy
of debrominated compound (about 15%) was also ob- derivatives 3 and 4 were always obtained in good yields
and with complete trans diastereoselectivity at the ring
substitution. The phenyl substituent at C-4 of the orga-
nozinc enolate blocks the approach of the electrophile on
ZnBr
Br
the more hindered face of the azetidin-2-one and a trans
relationship between the newly introduced group and the
phenyl substituent in C-4 was observed in the final prod-
uct.10 Unfortunately 1:1 mixtures of diastereomers 3 and
4 were obtained with aromatic aldehydes, while aliphatic
aldehydes, such as isopropyl or cyclohexylcarbaldehyde
gave increased yields and 70:30 diastereomeric ratios.
The diastereomeric mixtures were easily separated by
flash chromatography. Compounds 3a and 3b, with lower
Rf, are solid products, which can be crystallized from
EtOH. Their relative stereochemistry was assigned by X-
ray crystallographic analysis (Figures 2 and 3).11 The ste-
reochemical assignments of the products 3c–e and 4c–e,
R1
Ph
Ph
R1
Ph
Ph
Zn, THF
N
N
R2CHO, AlMe2Cl
O
O
1a (R1 = H)
1b (R1 = Et)
2
HO
O
R2
HO
O
R2
R1
Ph
R1
Ph
Ph
+
N
N
Ph
3
4
a: R1 = H, R2 = Ph
b: R1 = Et, R2 = Ph
64% d.r. 50/50
63% d.r. 50/50
1
were established on the basis of a detailed H chemical
c: R1 = Et, R2 = PMP 64% d.r. 50/50
shift comparison.
d: R1 = Et, R2 = i-Pr
e: R1 = Et, R2 = Cyclohexyl 70% d.r. 70/30
86% d.r. 70/30
Further applications of this reaction were studied by react-
ing the substrates 1f–i (Figure 4) with benzaldehyde
(Table 1).
Scheme 2 Generation of zinc-enolate 2 and reaction with aldehy-
des.
Figure 2 X-ray crystallographic analysis and assignments of the proton signals in the 1H NMR spectra for 3a.
Synthesis 2005, No. 1, 61–70 © Thieme Stuttgart · New York

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Nucleophilic Addition of Azetidin-2-ones to Aldehydes and Nitriles
63
Figure 3 X-ray crystallographic analysis and assignments of the proton signals in the 1H NMR spectra for 3b.
Br
Br
hand, the introduction of a further stereogenic centre into
the starting azetidinone (entries 3 and 4), did not change
the stereochemical outcome of the reaction, affording de-
rivatives 3h/4h and 3i/4i in an 1:1 diastereomeric ratio.
Ph
Ph
Et
Et
Et
N
N
O
O
COOEt
1g
Br
1f
Br
Lewis acids have been used to promote a variety of differ-
ent reactions12 and many attempts to classify them have
been reported in the literature.13 The reactivity of orga-
nozinc derivatives with aldehydes in the presence of metal
salts has been recently reported in the literature. In order
to establish the effect of Lewis acids on the reactivity of
organozincs 2, relatively oxophilic metals13a,b were inves-
tigated in the reaction of 2b and benzaldehyde (Table 2).
Ph
Ph
Ph
Ph
Et
N
N
O
O
1i
1h
Figure 4 Azetidinones 1f–i
Table 1 Reaction of Azetidinones 1f–i with Benzaldehyde
Table 2 Lewis Acid Catalyzed Reaction of Azetidinones 1b with
Zinc and Benzaldehyde
Entry
Azetidinone N-Substituent
Yield of 3 + 4 (%)
Entry
Lewis Acid (1 equiv) Time (h) Yield of 3b + 4b (%)
1
2
3
4
1f
1g
1h
1i
CH2CH2CO2Et
CH2CH=CH2
85
1
2
3
4
5
6
Sc(OTf)2
ZrCl4
24
6
–
91 (dr = 68:32)
30
79
65
76
80
(S)-CH(CH3)Ph
(S)-CH(CH3)Ph
87
72
BF3·OEt2
Ti(Oi-Pr)4
TMSCl
2
2
72
2
The results reported show that the reaction is not influ-
enced by the nature of the N-substituent, giving good
yields for all the different starting azetidinones. When the
reaction was performed on azetidinone 1g, moderate dia-
stereoselectivity was observed in the formation of hydrox-
yphenyl carbon centre (Table 1, entry 2). On the other
TMSCl + AlMe2Cl
(10%)
While the addition of scandium triflate to the reaction
mixture did not afford any product (Table 2, entry 1), the
use of zirconium chloride allowed to obtain compounds
Synthesis 2005, No. 1, 61–70 © Thieme Stuttgart · New York

64
F. Benfatti et al.
PAPER
3b/4b in 30% yield (entry 2). By activating the reaction
with Ti(Oi-Pr)4 and BF3·OEt2, good yields were observed
within two hours (entries 3,4). Furthermore, the titanium-
catalyzed reaction showed a moderate diastereoselectivity
at the hydroxyphenyl carbon, affording compounds 3b/4b
in a 70:30 diastereomeric ratio.
Silicon Lewis acids14 afford some advantages over tradi-
tional metal-centered activators. For example, they are
compatible with many synthetically valuable carbon nu-
cleophiles, such as silyl enol ethers, allyl organometallic
reagents and cuprates. For these reasons, the Reformatsky
reaction of 1b was performed in the presence of 1 equiva-
lent of trimethylsilyl chloride (entry 5). This condensation
was very sluggish (72 h) and derivatives 3b/4b were iso-
lated in 76% yield, after treatment of the silyl intermedi-
ates with 6 N HCl during the workup (entry 5). Finally,
good yield and a faster reaction were observed by adding
ZnBr
N
Br
Ph
R1
Ph
R1
Et
Et
Zn, THF
N
O
O
1b R1 = CH2Ph
1i
1 = (S)-CH(CH3)Ph
2b
2i
R
R2
O
O
Method A: R2CN
Ph
R1
Et
N
Method B: R2COCl
5b R1 = CH2Ph, R2 = Ph
5i R1 = (S)-CH(CH3)Ph, R2 = Ph
6b
R
1 = CH2Ph, R2 = CH2Ph
Scheme 4 Blaise reaction of 1b–i with zinc and nitriles and reaction
10% of AlMe2Cl to the TMSCl-catalyzed reaction (entry of organozinc 2 with acyl chlorides.
6).
The reaction was sluggish (72 h), even in the presence of
Oxidation of each diastereomeric hydroxyphenylazetidi-
none 3b and 4b with chromic acid on anion exchange res-
in,15 furnished in each case a single keto derivative 5b, in
quantitative yield, thereby confirming that the hydroxy-
phenylazetidinones differed only in the stereochemistry
of the side chain (Scheme 3).
two equivalents of nitrile derivative (Table 3). Any at-
tempt to improve the yield and to decrease the reaction
time by adding a Lewis acid failed. Some selected results
are reported in Table 3.
Table 3 Blaise Reaction of Azetidinones 1b with Zinc and Nitriles
HO
Ph
HO
Ph
Entry
Azetidinone
R2
Product
5b
Yield (%)
Ph
Ph
Ph
Ph
Et
Et
1
2
5
1b
1b
1i
Ph
50
60
60
or
N
N
O
O
CH2Ph
Ph
5i
3b
4b
CrO4H- resin
6b
> 95%
Benzene, reflux
In an alternative pathway (Scheme 4, Method B), anion
2b was reacted with benzoyl chloride under the same con-
ditions and ketone 5b was obtained in 60% yield.
Ph
O
Ph
Et
In summary, we have demonstrated that the in situ gener-
ated organozinc reagents, derived from 3-alkenyl-3-bro-
moazetidin-2-ones, react with aromatic and aliphatic
aldehydes with complete regioselectivity and stereoselec-
tivity on the ring substitution. The effect of solvent and
the addition of Lewis acids have been studied in order to
improve the reaction yields. The application of this meth-
odology to nitriles and acyl chlorides also allowed the
preparation of keto derivatives.
N
O
Ph
5b
Scheme 3 Oxidation of 3b or 4b to ketone 5b with CrO4H– resin.
The oxidation was simply performed by stirring 3 or 4 in
the presence of an excess of CrO4H– resin in refluxing
benzene. The product was isolated by removing the resins
by filtration and evaporating the solvent under reduced
pressure.
Unless stated otherwise, solvents and chemicals were obtained from
commercial sources and used without further purification. Flash
chromatography was performed on silica gel (230–400 mesh).
NMR Spectra were recorded with 300 MHz or 600 MHz spectro-
meters. Chemical shifts were reported as d values (ppm) relative to
the solvent peak of CDCl3 set at d = 7.27 (1H NMR) or d = 77.0 (13C
NMR). IR spectra were recorded with an FT-IR spectrometer. Melt-
ing points are uncorrected. MS analyses were performed on a liquid
chromatograph coupled with an electrospray ionization-mass spec-
trometer (LC-ESI-MS), using H2O–MeCN as solvent at 25 °C (pos-
itive scan 100–500 m/z, fragmentor 70 eV).
In an effort to evaluate the ability of anion 2 to react in the
Blaise reaction with nitriles,16 the alternative synthesis of
b,g-unsaturated ketones was performed by treating 2b
with benzonitrile and phenylacetonitrile in THF under
Barbier conditions (Scheme 4, Method A).
Synthesis 2005, No. 1, 61–70 © Thieme Stuttgart · New York

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Nucleophilic Addition of Azetidin-2-ones to Aldehydes and Nitriles
65
3-Alkenyl-3-bromoazetidin-2-ones 1; General Procedure
To a refluxing solution of a respective imine (1 mmol) and Et3N (2
mmol, 2 equiv, 0.280 mL) in CH2Cl2 (10 mL) under N2, was added
dropwise the corresponding acyl chloride (1.25 mmol, 1.25 equiv)
in CH2Cl2 (2 mL) very slowly. The solution was refluxed for 4 h and
then allowed to reach r.t. After quenching with 0.1 M HCl (5 mL),
the mixture was diluted with CH2Cl2 (10 mL) and washed with H2O
(2 ×). The organic layer was dried (Na2SO4) and the solvent was re-
moved under reduced pressure. The products were obtained, after
purification by flash chromatography on silica gel (cyclohexane–
Et2O, 95:5 or benzene as eluent).
7.0 Hz, 1 H, NCH2), 4.31 (dd, J = 15.2, 5.2 Hz, 1 H, NCH2), 4.81
(br s, 1 H, CHPh), 5.08–5.23 (m, 2 H, CH=CH2), 5.78 (m, 1 H,
CH=CH2), 5.91 (dt, J1,2 = 15.4 Hz, J1,3 = 1.5 Hz,
H,
CH=CHCH2), 6.20 (dt, J = 15.4, 6.2 Hz, 1 H, CH=CHCH2), 7.23–
7.28 (m, 2 H, C6H5), 7.38–7.45 (m, 3 H, C6H5).
13C NMR (CDCl3): d = 12.8, 25.3, 43.2, 67.3, 69.6, 119.1, 127.8,
128.3, 128.9, 130.3, 134.7, 136.7, 144.6, 165.5.
1
LC-ESI-MS (Rt 12.40 min): m/z = 320/322 (M + 1), 342/344 (M +
Na).
Anal. Calcd for C16H18BrNO: C, 60.01; H, 5.67; N, 4.37. Found: C,
60.00; H, 5.69; N, 4.34.
1-Benzyl-3-bromo-4-phenyl-3-vinylazetidin-2-one (1a)
Yield: 30%; cis/trans = 90:10; pale yellow oil.
3-Bromo-3-but-1-enyl-4-phenyl-1-(1-phenylethyl)azetidin-2-
1H NMR (CDCl3): d = 3.92 (d, J = 14.8 Hz, 1 H, PhCH2), 4.61 (br
s, 1 H, CCHPh), 5.02 (d, J = 14.8 Hz, 1 H, PhCH2), 5.35 (d, J = 10.7
Hz, 1 H, CH=CH2), 5.65 (d, J = 16.8 Hz, 1 H, CH=CH2), 6.18 (dd,
J = 10.7, 16.8 Hz, 1 H, CH=CH2), 7.1–7.5 (m, 10 H, C6H5).
13C NMR (CDCl3): d = 44.7, 66.1, 69.5, 120.4, 127.6, 127.9, 128.2,
128.3, 128.7, 128.9, 131.8, 134.0, 134.3, 165.3.
ones
Yield: 55%; cis/trans >99/1; dr = 75:25
(1S¢,3R,4S)-1h
Pale yellow oil; [a]D +3 (c = 1, CHCl3).
1H NMR (CDCl3): d =1.02 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.50 (d,
J = 7.2 Hz, 3 H, CHCH3), 2.05–2.22 (m, 2 H, CH2CH3), 4.50 (s, 1
H, CCHPh), 5.10 (q, J = 7.2 Hz, 1 H, CHCH3), 5.74 (dt, J1,2 = 15.4
Hz, J1,3 = 1.2 Hz, 1 H, CH=CHCH2), 6.03 (dt, J = 15.4, 6.6 Hz, 1 H,
CH=CHCH2), 7.25–7.42 (m, 10 H, C6H5).
13C NMR (CDCl3): d = 13.0, 18.8, 25.4, 53.1, 67.5, 68.8, 125.4,
127.3, 128.0, 128.3, 128.4, 128.7, 129.0, 136.0, 136.5, 139.3, 166.2.
LC-ESI-MS (Rt 12.2 min): m/z = 342/344 (M + 1), 364/366 (M +
Na).
Anal. Calcd for C18H16BrNO: C, 63.17; H, 4.71; N, 4.09. Found: C,
63.15; H, 4.69; N, 4.11.
1-Benzyl-3-bromo-3-but-1-enyl-4-phenylazetidin-2-one (1b)
Yield: 60%; cis/trans = 84:16; pale yellow oil.
LC-ESI-MS (Rt 15.57 min): m/z = 384/386 (M + 1), 406/408 (M +
Na).
1H NMR (CDCl3): d = 1.02 (t, J = 7.6 Hz, 3 H, CH2CH3), 2.13
(pseudo quintet, J = 6.4 Hz, 2 H, CH2CH3), 3.89 (d, J = 15.0 Hz, 1
H, PhCH2), 4.55 (s, 1 H, CCHPh), 4.98 (d, J = 15.0 Hz, 1 H,
PhCH2), 5.80 (dt, J1,2 = 15.4 Hz, J1,3 = 1.6 Hz, 1 H, CH=CHCH2),
6.13 (dt, J = 15.4, 6.4 Hz, 1 H, CH=CHCH2), 7.10–7.44 (m, 10 H,
C6H5).
Anal. Calcd for C21H22BrNO: C, 65.63; H, 5.77; N, 3.64. Found: C,
65.60; H, 5.78; N, 3.66.
(1S¢,3S,4R)-1i
White solid, mp 83–85 °C; [a]D –10 (c = 1.2, CHCl3).
1H NMR (CDCl3): d = 1.07 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.95 (d,
J = 7.0 Hz, 3 H, CHCH3), 2.10–2.22 (m, 2 H, CH2CH3), 4.33 (q,
J = 7.0 Hz, 1 H, CHCH3), 4.53 (s, 1 H), 5.83 (dt, J1,2 = 15.4 Hz,
J1,3 = 1.5 Hz, 1 H, CH=CHCH2), 6.18 (dt, J = 15.4, 4.4 Hz, 1 H,
CH=CHCH2), 7.22–7.43 (m, 10 H, C6H5).
13C NMR (CDCl3): d = 12.9, 25.4, 44.8, 66.9, 69.7, 125.5, 127.7,
127.9, 128.3, 128.4, 128.8, 128.9, 134.6, 136.8, 141.3, 165.7.
LC-ESI-MS (Rt 14.4 min): m/z = 370/372 (M + 1), 392/394 (M +
Na).
Anal. Calcd for C20H20BrNO: C, 64.87; H, 5.44; N, 3.78. Found: C,
64.88; H, 5.43; N, 3.76.
13C NMR (CDCl3): d =13.0, 20.3, 25.3, 55.4, 67.0, 69.1, 125.8,
126.7, 127.9, 128.0, 128.5, 128.8, 128.9, 135.0, 136.7, 140.8, 165.8.
LC-ESI-MS (Rt 15.76 min): m/z = 384/386 (M + 1), 406/408 (M +
Na).
3-(3-Bromo-3-but-1-enyl-2-oxo-4-phenylazetidin-1-yl)propion-
ic Acid Ethyl Ester (1f)
Yield 55%; cis/trans = 93:7; pale yellow oil.
Anal. Calcd for C21H22BrNO: C, 65.63; H, 5.77; N, 3.64. Found: C,
65.61; H, 5.75; N, 3.67.
1H NMR (CDCl3): d = 1.06 (t, J = 7.4 Hz, 3 H, CH2CH3), 1.22 (t,
J = 7.5 Hz, 3 H, OCH2CH3), 2.17 (dq, J = 7.4, 6.3 Hz, 2 H,
CH2CH3), 2.58 (dt, J = 16.8, 6.9 Hz, 1 H, CH2CO2Et), 2.73 (dt,
J = 16.8, 6.9 Hz, 1 H, CH2CO2Et), 3.28 (dt, J = 14.4, 6.9 Hz, 1 H,
NCH2), 3.85 (dt, J = 14.4, 6.9 Hz, 1 H, NCH2), 4.05 (q, J = 7.5 Hz,
2 H, OCH2CH3), 4.82 (br s, 1 H, CHPh), 5.85 (d, J = 15.3 Hz, 1 H,
CH=CHCH2), 6.14 (dt, J = 15.3, 6.3 Hz, 1 H, CH=CHCH2), 7.21–
7.45 (m, 5 H, C6H5).
Reformatski-Type Reaction on 1; General Procedure
Method A: To a stirred solution of 1 (1 mmol) in anhyd THF (5 mL),
under N2 at r.t., was added zinc powder (1.5 mmol, 1.5 equiv, 65
mg.) in one portion. After 20 min, the temperature was lowered to
0 °C and a solution of benzaldehyde (1.5 mmol, 1.5 equiv, 0.15 mL)
and AlMe2Cl (1.5 mmol, 1.5 equiv, 1.5 mL 1 M solution in hexane)
in anhyd THF (3 mL) was added dropwise under inert atmosphere
by means of a Teflon cannula. The reaction was monitored by TLC
and stopped after 2 h by adding an aq sat. solution of Seignette salts
(sodium potassium tartrate, 2 mL). The mixture was then filtered on
a Celite pad and the organic solvent was concentrated under re-
duced pressure. The residue, diluted with CH2Cl2 (10 mL) was
washed with H2O (2 ×). The organic layer was dried (Na2SO4) and
the solvent was removed. Compounds 3 and 4 were isolated by flash
chromatography on silica gel (cyclohexane–EtOAc, 9:1 as eluent).
13C NMR (CDCl3): d = 11.3, 14.0, 25.2, 32.3, 46.6, 60.8, 64.7, 68.3,
125.9, 127.8, 128.5, 128.9, 136.7, 144.6, 165.6, 171.8.
LC-ESI-MS (Rt 13.40 min): m/z = 380/382 (M + 1), 402/404 (M +
Na).
Anal. Calcd for C18H22BrNO3: C, 56.85; H, 5.83; N, 3.68. Found: C,
56.84; H, 5.86; N, 3.68.
1-Allyl-3-bromo-3-but-1-enyl-4-phenylazetidin-2-one (1g)
Yield: 50%; cis/trans = 80:20; pale yellow oil.
Method B: To a stirred solution of 1 (1 mmol) in anhyd THF (5 mL),
were added zinc powder (1.5 mmol, 1.5 equiv, 65 mg.), benzalde-
hyde (1.5 mmol, 1.5 equiv., 0.15 mL) and AlMe2Cl (1.5 mmol, 1.5
equiv, 1.5 mL 1 M solution in hexane) were added under N2 at r.t.
1H NMR (CDCl3): d = 1.07 (t, J = 7.8 Hz, 3 H, CH2CH3), 2.19 (ddq,
J1,2 = 6.2, 7.8 Hz, J1,3 = 1.5 Hz, 2 H, CH2CH3), 3.48 (dd, J = 15.2,
Synthesis 2005, No. 1, 61–70 © Thieme Stuttgart · New York

66
F. Benfatti et al.
PAPER
The reaction was monitored by TLC and stopped after 2 h by adding
an aq sat. solution of Seignette salts (sodium potassium tartrate, 2
mL). The mixture was then filtered on a Celite pad and the organic
solvent was concentrated under reduced pressure. The residue, di-
luted with CH2Cl2 (10 mL) was washed with H2O (2 ×). The organic
layer was dried (Na2SO4) and the solvent was removed. Compounds
3 and 4 were isolated by flash chromatography on silica gel (cyclo-
hexane–EtOAc, 9:1 as eluent).
1-Benzyl-3-but-1-enyl-3-(hydroxyphenylmethyl)-4-phenylaze-
tidin-2-ones
3b
Yield: 64%; white solid; mp 159–161 °C; dr = 50:50.
IR (Nujol): 3364, 2959, 2933, 2853, 1733, 1461, 1375, 1063 cm–1.
1H NMR (CDCl3): d = 0.81 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.8–2.0
(m, 2 H, CH2CH3), 3.39 (d, J = 1.8 Hz, 1 H, OH), 3.90 (d, J = 15.3
Hz, 1 H, PhCH2), 4.45 (d, J = 15.9 Hz, 1 H, CH=CHCH2), 4.88 (s,
1 H, CHPh); 4.92 (d, J = 15.3 Hz, 1, PhCH2), 5.00 (s, 1 H, CHOH),
6.13 (dt, J = 15.9, 6.6 Hz, 1 H, CH=CHCH2), 6.9–7.0 (m, 2 H,
C6H5), 7.20–7.60 (m, 13 H, C6H5).
1-Benzyl-3-(hydroxyphenylmethyl)-4-phenyl-3-vinylazetidin-
2-ones
3a
13C NMR (CDCl3): d = 13.2, 25.6, 43.9, 59.3, 70.7, 75.4, 123.1,
127.2, 127.3, 127.6, 127.8, 127.9, 128.0, 128.3, 128.4, 134.9, 135.2,
136.4, 139.8, 170.2.
White solid; yield: 64%; mp 158–160 °C; dr = 50:50.
IR (Nujol): 3383, 2919, 2853, 1726, 1474, 1375, 1049, 1023 cm–1.
1H NMR (CDCl3): d = 3.45 (d, J = 3.8 Hz, 1 H, OH), 3.98 (d,
J = 15.0 Hz, 1 H, PhCH2), 4.88 (dd, J = 11.3, 17.5 Hz, 1 H,
CH=CH2), 4.96 (d, J = 15.0 Hz, 1 H, PhCH2), 4.98 (s, 1 H, CHPh),
5.05 (s, 1 H, CHOH), 5.17 (dd, J = 1.5, 11.3 Hz, 1 H, CH=CH2),
5.70 (dd, J = 1.5, 17.5 Hz, 1 H, CH=CH2), 6.90–6.98 (m, 2 H,
C6H5), 7.2–7.5 (m, 13 H, C6H5).
LC-ESI-MS (Rt 14.63 min): m/z = 379 (M – H2O + 1), 398 (M + 1),
420 (M + Na).
Anal. Calcd for C27H27NO2: C, 81.58; H, 6.85; N, 3.52. Found: C,
81.59; H, 6.87; N, 3.51.
13C NMR (CDCl3): d = 44.4, 59.4, 71.8, 75.5, 119.2, 127.5, 127.8,
128.1, 128.2, 128.3, 128.4, 128.5, 128.7, 128.8, 132.7, 135.1, 135.5,
140.0, 170.2.
Single Crystal X-ray Diffraction Data of 3b
MF C27H27NO2, Fw: 397.50, colorless parallelepiped, size:
0.35 × 0.25 × 0.20 mm, triclinic, space group P –1, a = 10.134(3)
Å, b = 12.498(3) Å, c = 19.626(5) Å, a = 82.360(6)°
b = 87.201(6)°, g = 68.077(6)°, V = 2285.5(10) Å3, theta range for
data collection is from 1.05 to 30.11°, T = 293(2) K, Z = 4,
F(000) = 848, Dx = 1.155 Mg/m3, m = 0.072 mm–1, data collected
LC-ESI-MS (Rt 13.19 min): m/z = 352 (M – H2O + 1), 370 (M + 1),
392 (M + Na).
Anal. Calcd for C25H23NO2: C, 81.27; H, 6.27; N, 3.79. Found: C,
81.26; H, 6.27; N, 3.81.
on
a Bruker AXS CCD diffractometer (Mo-Ka radiation,
l = 0.71073 Å) at 293(2) K, total of 29731 reflections, of which
13315 unique [R(int) = 0.0843]; 3400 reflections I > 2s (I). Empiri-
cal absorption correction was applied, initial structure model by di-
rect methods. Anisotropic full-matrix least-squares refinement on
F2 for all non-hydrogen atoms yielded R1 = 0.0653 and
wR2 = 0.1465 for 3400 [I > 2s (I)] and R1 = 0.2529 and
wR2 = 0.1994 for all (13315) intensity data. Goodness-of-
fit = 0.784, the max/mean shift/esd is 0.00 and 0.00, max/min.
CCDC number is 245013.
Single Crystal X-ray Diffraction Data of 3a
MF C25H23NO2, Fw 369.44, colorless parallelepiped, size:
0.30 × 0.23 × 0.20 mm, monoclinic, space group P21/n,
a = 12.4900(7) Å, b = 10.7157(5) Å, c = 15.5174(8) Å,
b = 92.288(2)°, V = 2075.18(19) Å3, theta range for data collection
is from 2.05 to 30.00°, T = 293(2) K, Z = 4, F(000) = 784,
Dx = 1.183 Mg/m3, m = 0.074 mm–1, data collected on a Bruker
AXS CCD diffractometer (Mo-Ka radiation, l = 0.71073 Å) at
293(2) K, total of 23637 reflections, of which 6053 unique
[R(int) = 0.1147]; 2191reflections I > 2s (I). Empirical absorption
correction was applied, initial structure model by direct methods.
Anisotropic full-matrix least-squares refinement on F2 for all non-
hydrogen atoms yielded R1 = 0.0606 and wR2 = 0.1382 for 2191
[I > 2s (I)] and R1 = 0.1824 and wR2 = 0.1812 for all (6053) inten-
sity data. Goodness-of-fit = 0.851, the max/mean shift/esd is 0.00
and 0.00, max/min, CCDC number is 245012.
4b
Yellow oil.
IR (neat): 3423, 2965, 2913, 1739, 1653, 1448, 1408, 1355 cm–1.
1H NMR (CDCl3): d = 0.83 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.9–2.0
(m, 2 H, CH2CH3), 3.39 (d, J = 1.5 Hz, 1 H, OH), 3.82 (d, J = 15.3
Hz, 1 H, PhCH2), 4.64 (s, 1 H, CHPh), 4.78 (dt, J1,2 = 15.8,
J1,3 = 1.5 Hz, 1 H, CH=CHCH2), 4.88 (d, J = 15.3 Hz, 1 H, PhCH2),
5.08 (d, J = 1.5 Hz, 1 H, CHOH), 6.04 (dt, J = 6.6, 15.8 Hz, 1 H,
CH=CHCH2), 6.8–7.6 (m, 15 H, C6H5).
4a
Pale yellow oil.
13C NMR (CDCl3): d = 13.2, 26.8, 43.7, 60.4, 70.1, 76.3, 121.9,
127.3, 127.4, 127.7, 127.8, 127.9, 128.1, 128.5, 134.8, 134.9, 136.9,
139.4, 169.7.
IR (neat): 3417, 3069, 3022, 2922, 2845, 1731, 1649, 1560, 1490,
1460, 1401 cm–1.
1H NMR (CDCl3): d = 2.64 (d, J = 2.1 Hz, 1 H, OH), 3.85 (d,
J = 15.0 Hz, 1 H, PhCH2), 4.65 (s, 1 H, CHPh), 4.88 (d, 1 H,
J = 15.0 Hz, PhCH2), 5.13 (d, J = 2.1 Hz, 1 H, CHOH), 5.15–5.22
(m, 2 H, CH=CH2), 5.59–5.67 (m, 1 H, CH=CH2), 6.80–6.90 (m, 2
H, C6H5), 7.00–7.10 (m, 2 H, C6H5), 7.20–7.40 (m, 9 H, C6H5),
7.50–7.60 (m, 2 H, C6H5).
LC-ESI-MS (Rt 14.17 min): m/z = 379 (M – H2O + 1), 420 (M +
Na).
Anal. Calcd for C27H27NO2: C, 81.58; H, 6.85; N, 3.52. Found: C,
81.61; H, 6.85; N, 3.49.
13C NMR (CDCl3): d = 43.9, 60.3, 70.9, 76.3, 119.5, 127.4, 127.5,
127.8, 128.0, 128.2, 128.3, 128.4, 128.5, 128.6, 131.2, 134.6, 134.8,
139.1, 169.2.
1-Benzyl-3-but-1-enyl-3-[hydroxy(4-methoxyphenyl)methyl]-
4-phenylazetidin-2-ones
3c
Yield: 64%; yellow waxy oil; dr = 50:50.
LC-ESI-MS (Rt 12.90 min): m/z = 352 (M – H2O + 1), 392 (M +
Na).
IR (neat): 3364, 3025, 3006, 2952, 1726, 1613, 1507, 1447, 1242,
1169, 1030 cm–1.
1H NMR (CDCl3): d = 0.81 (t, J = 7.2 Hz, 3 H, CH2CH3); 1.81–1.96
(m, 2 H, CH2CH3), 2.57 (br s, 1 H, OH), 3.83 (s, 3 H, OCH3), 3.88
(d, J = 15.3 Hz, 1 H, PhCH2), 4.48 (d, J = 15.4 Hz, 1 H,
Anal. Calcd for C25H23NO2: C, 81.27; H, 6.27; N, 3.79. Found: C,
81.28; H, 6.25; N, 3.80.
Synthesis 2005, No. 1, 61–70 © Thieme Stuttgart · New York

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Nucleophilic Addition of Azetidin-2-ones to Aldehydes and Nitriles
67
CH=CHCH2), 4.84 (s, 1 H, CHPh), 4.93 (d, J = 15.3 Hz, 1 H,
PhCH2), 4.94 (br s, 1 H, CHOH), 6.10 (dt, J = 15.4, 6.6 Hz, 1 H,
CH=CHCH2), 6.80–6.90 (m, 2 H, C6H5), 6.91–7.00 (m, 1 H, C6H5),
7.01–7.10 (m, 1 H, C6H5), 7.20–7.40 (m, 10 H, C6H5).
13C NMR (CDCl3): d = 13.2, 25.7, 43.8, 55.2, 59.5, 71.0, 75.2,
113.5, 123.1, 127.4, 127.8, 128.1, 128.2, 128.3, 128.4, 128.5, 131.7,
134.9, 135.2, 136.8, 159.3, 168.9.
Hz, 1 H, PhCH2), 6.09 (dt, J = 15.6, 6.6 Hz, 1 H, CH=CHCH2),
7.00–7.20 (m, 4 H, C6H5), 7.21–7.5 (m, 6 H, C6H5).
13C NMR (CDCl3): d = 13.2, 18.3, 19.7, 25.9, 30.8, 43.7, 63.0, 69.8,
80.0, 120.6, 127.5.127.7, 128.0, 128.1, 128.4, 128.5, 128.7, 129.0,
134.1, 135.5, 137.1, 168.9.
LC-ESI-MS (Rt 16.30 min): m/z = 346 (M - H2O + 1), 364 (M + 1),
386 (M + Na), 402 (M + K).
LC-ESI-MS (Rt 15.20 min): m/z = 410 (M – H2O + 1), 428 (M + 1),
450 (M + Na), 877 (2 M + Na).
Anal. Calcd for C24H29NO2: C, 79.30; H, 8.04; N, 3.85. Found: C,
79.30; H, 8.02; N, 3.84.
Anal. Calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C,
81.71; H, 7.08; N, 3.41.
1-Benzyl-3-but-1-enyl-3-(cyclohexylhydroxymethyl)-4-phenyl-
azetidin-2-ones
3e
4c
Yellow oil.
Yield: 67%; colorless oil; dr = 70:30.
IR (neat): 3430, 3025, 2966, 2926, 1726, 1600, 1514, 1454, 1235,
1169, 1036 cm–1.
IR (neat): 3436, 2959, 2926, 2853, 1739, 1666, 1441, 1387, 1341,
1069 cm–1.
1H NMR (CDCl3): d = 0.79 (t, J = 7.3 Hz, 3 H, CH2CH3), 1.81–1.96
(m, 2 H, CH2CH3), 2.61 (br s, 1 H, OH), 3.78 (d, J = 15.0 Hz, 1 H,
PhCH2), 3.84 (s, 3 H, OCH3), 4.59 (s, 1 H, CHPh), 4.77 (dt,
J1,2 = 15.8 Hz, J1,3 = 1.4 Hz, 1 H, CH=CHCH2), 4.86 (d, J = 15.0
Hz, 1 H, PhCH2), 5.02 (s, 1 H, CHOH), 6.00 (dt, J = 15.8, 6.6 Hz, 1
H, CH=CHCH2), 6.80–6.90 (m, 4 H, C6H5), 6.91–7.10 (m, 2 H,
C6H5), 7.11–7.30 (m, 6 H, C6H5), 7.31–7.40 (m, 2 H, C6H5).
13C NMR (CDCl3): d = 13.2, 25.8, 43.7, 55.2, 60.3, 70.4, 76.0,
113.4, 122.1, 127.4, 127.7, 127.8, 127.9, 128.2, 128.5, 128.6, 131.5,
134.8, 134.9, 136.9, 159.3, 169.7.
1H NMR (CDCl3): d = 0.88 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.00–1.10
(m, 2 H, CH2, cyclohexyl), 1.20–1.30 (m, 4 H, CH2, cyclohexyl),
1.40–1.50 (m, 2 H, CH2, cyclohexyl), 1.56 (m, 1 H, CH, cyclohex-
yl), 1.60–1.70 (m, 2 H, CH2, cyclohexyl), 1.90–2.00 (m, 2 H,
CH2CH3), 3.48 (br s, 1 H, OH), 3.80 (d, J = 15.0 Hz, 1 H, PhCH2),
3.85 (br s, 1 H, CHOH), 4.77 (s, 1 H, CHPh), 4.78 (d, J = 15.8 Hz,
1 H, CH=CHCH2), 4.84 (d, J = 15.0 Hz, 1 H, PhCH2), 6.05 (dt,
J = 15.8, 6.6 Hz, 1 H, CH=CHCH2), 7.10–7.40 (m, 10 H, C6H5).
13C NMR (CDCl3): d = 13.4, 25.9, 26.0, 26.4, 26.9, 30.4, 30.6, 39.5,
43.8, 60.4, 70.1, 77.9, 122.5, 127.4, 127.9, 128.1, 128.2, 128.4,
128.5, 128.7, 129.3, 134.5, 134.9, 135.8, 170.8.
LC-ESI-MS (Rt 15.08 min): m/z = 410 (M – H2O + 1), 428 (M + 1),
450 (M + Na), 877 (2 M + Na).
LC-ESI-MS (Rt 19.40 min): m/z = 386 (M – H2O + 1), 404 (M + 1),
426 (M + Na), 442 (M + K).
Anal. Calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C,
81.74; H, 7.11; N, 3.38.
Anal. Calcd for C27H33NO2: C, 80.36; H, 8.24; N, 3.47. Found: C,
80.35; H, 8.22; N, 3.50.
1-Benzyl-3-but-1-enyl-3-(1-hydroxy-2-methylpropyl)-4-phe-
nylazetidin-2-ones
4e
3d
White solid; mp 100–102 °C.
Yield: 86%; colorless oil; dr = 70:30.
IR (neat): 3450, 2966, 2926, 2739, 1454, 1394, 1348, 1149 cm–1.
IR (Nujol): 3463, 3025, 2959, 2926, 2853, 1759, 1493, 1454, 1387,
1398, 1361, 1069 cm–1.
1H NMR (CDCl3): d = 0.90 (t, J = 7.3 Hz, 3 H, CH2CH3), 0.91 (d,
J = 6.0 Hz, 3 H, CH3CHCH3), 1.00 (d, J = 6.0 Hz, 3,H,
CH3CHCH3), 1.8–2.0 (m, 3 H, CH2CH3 + CH3CHCH3), 2.20 (br s,
1 H, OH), 3.85 (d, J = 15.0 Hz, 1 H, PhCH2), 3.91 (d, J = 3.6 Hz, 1
1H NMR (CDCl3): d = 0.91 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.05–1.10
(m, 4 H, CH2, cyclohexyl), 1.25–1.35 (m, 2 H, CH2, cyclohexyl),
1.60–1.80 (m, 4 H, CH2, cyclohexyl), 1.90–2.10 (m, 2 H, CH2CH3),
2.05–2.10 (m, 1 H, CH, cyclohexyl), 2.90 (br s, 1 H, OH), 3.64 (d,
J = 6.9 Hz, 1 H, CHOH), 3.78 (d, J = 15.0 Hz, 1 H, PhCH2), 4.37 (s,
1 H, CHPh), 4.75 (d, J = 15.6 Hz, 1 H, CH=CHCH2), 4.91 (d,
J = 15.0 Hz, 1 H, PhCH2), 6.11 (dt, 1 H, J = 15.6, 6.6 Hz,
CH=CHCH2), 7.10–7.20 (m, 4 H, C6H5), 7.30–7.40 (m, 6 H, C6H5).
H, CHOH), 4.81 (dt, J1,2 = 15.9 Hz, J1,3 = 1.4 Hz,
1 H,
CH=CHCH2), 4.85 (s, 1 H, CHPh), 4.87 (d, J = 15.0 Hz, 1 H,
PhCH2), 6.10 (dt, J = 15.9, 6.6 Hz, 1 H, CH=CHCH2), 7.10–7.50
(m, 10 H, C6H5).
13C NMR (CDCl3): d = 13.3, 16.5, 20.5, 25.8, 29.4, 43.8, 60.2, 70.2,
77.8, 122.6, 127.4, 128.0, 128.2, 128.5, 128.6, 129.3, 134.9, 135.6,
135.7, 170.9.
13C NMR (CDCl3): d = 13.3, 25.8, 25.9, 26.1, 26.2, 28.6, 29.6, 40.5,
43.7, 62.9, 69.6, 79.3, 120.6, 127.7, 128.1, 128.3, 128.4, 128.7,
129.0, 134.1, 135.3, 137.2, 170.4.
LC-ESI-MS (Rt 17.20 min): m/z = 346 (M – H2O + 1), 364 (M + 1),
LC-ESI-MS (Rt 19.50 min): m/z = 386 (M – H2O + 1), 404 (M + 1),
386 (M + Na), 402 (M + K).
426 (M + Na).
Anal. Calcd for C24H29NO2: C, 79.30; H, 8.04; N, 3.85. Found: C,
79.31; H, 8.01; N, 3.86.
Anal. Calcd for C27H33NO2: C, 80.36; H, 8.24; N, 3.47. Found: C,
80.38; H, 8.22; N, 3.49.
4d
3-[3-But-1-enyl-3-(hydroxyphenylmethyl)-2-oxo-4-phenylazeti-
din-1-yl]propionic Acid Ethyl Esters
3f
White solid; mp 85–87 °C.
IR (Nujol): 3463, 3032, 2966, 2933, 2873, 1752, 1494, 1454, 1388,
1355, 1063 cm–1.
Yield: 85%; white solid; mp 89–91 °C; dr = 50:50.
IR (neat): 3430, 3065, 3032, 2972, 2933, 1746, 1494, 1441, 1401,
1375, 1189, 1050, 1017 cm–1.
1H NMR (CDCl3): d = 0.79 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.25 (t,
J = 6.9 Hz, 3 H, OCH2CH3), 1.8–1.9 (m, 2 H, CH2CH3), 2.58 (br t,
J = 6.9 Hz, 2 H, CH2CO2Et), 3.23 (dt, J = 14.1, 6.9 Hz, 1 H, NCH2),
3.54 (br s, 1 H, OH), 3.84 (dt, J = 14.1, 6.9 Hz, 1 H, NCH2), 4.05–
1H NMR (CDCl3): d = 0.88 (t, J = 7.2 Hz, 3 H, CH2CH3), 0.89 (d,
J = 6.6 Hz, 3 H, CH3CHCH3), 1.05 (d, J = 6.6 Hz, 3 H,
CH3CHCH3), 1.6–1.8 (m, 1 H, CH3CHCH3), 1.85–2.00 (m, 2 H,
CH2CH3), 2.84 (br s, 1 H, OH), 3.60 (d, J = 7.0 Hz, 1 H, CHOH),
3.79 (d, J = 15.0 Hz, 1 H, PhCH2), 4.38 (s, 1 H, CHPh), 4.73 (dt,
J1,2 = 15.6 Hz, J1,3 = 1.4 Hz, 1 H, CH=CHCH2), 4.94 (d, J = 15.0
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68
F. Benfatti et al.
PAPER
4.15 (m, 2 H, OCH2CH3), 4.39 (dt, J1,2 = 15.9 Hz, J1,3 = 1.5 Hz, 1
H, CH=CH-CH2), 5.03 (s, 1 H, CHOH), 5.13 (br s, 1 H, CHPh), 6.03
(dt, J = 15.9, 6.6 Hz, 1 H, CH=CHCH2), 6.96–6.99 (m, 2 H, C6H5),
7.20–7.50 (m, 8 H, C6H5).
13C NMR (CDCl3): d = 13.1, 14.0, 25.6, 32.6, 36.1, 59.7, 60.7, 70.6,
75.2, 122.8, 127.1, 127.6, 127.8, 127.9, 128.0, 128.2, 135.3, 136.2,
139.8, 170.6, 171.2.
5.5 (m, 1 H, CH=CH2), 5.97 (dt, J = 15.6, 6.6 Hz, 1 H,
CH=CHCH2), 7.06 (d, J = 7.8 Hz, 2 H, C6H5), 7.2–7.5 (m, 6 H,
C6H5), 7.57 (d, J = 7.8 Hz, 2 H, C6H5).
13C NMR (CDCl3): d = 13.2, 26.8, 42.6, 60.6, 72.4, 74.2, 118.6,
122.9, 127.2, 127.6, 127.8, 127.9, 128.0, 128.0, 128.1, 128.2, 131.6,
135.6, 136.6, 139.8, 170.3.
LC-ESI-MS (Rt 13.34 min): m/z = 330 (M – H2O + 1), 370 (M +
LC-ESI-MS (Rt 13.40 min): m/z = 390 (M – H2O + 1), 408 (M + 1),
Na).
430 (M + Na).
Anal. Calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03. Found: C,
79.50; H, 7.26; N, 4.03.
Anal. Calcd for C25H29NO4: C, 73.68; H, 7.17; N, 3.44. Found: C,
73.66; H, 7.19; N, 3.44.
3-But-1¢¢-enyl-3-(hydroxyphenylmethyl)-4-phenyl-1-(1¢-phe-
nylethyl)azetidin-2-ones
(1¢S,1¢¢R,3R,4S)-3h
Yellow oil; yield: 87%, dr = 50:50; [a]D +85 (c = 1.1, CHCl3).
4f
Yellow oil.
IR (neat): 3423, 3059, 3032, 2966, 2926, 1726, 1501, 1441, 1375,
1189, 1056 cm–1.
IR (neat): 3396, 3064, 3031, 2958, 2932, 1725, 1493, 1453, 1340,
1201, 1055, 1022 cm–1.
1H NMR (CDCl3): d = 0.77 (t, 3 H, J = 7.5 Hz, CH2CH3), 1.24 (t,
J = 7.0 Hz, 3 H, OCH2CH3), 1.8–1.9 (m, 2 H, CH2CH3), 2.28 (br t,
J = 6.9 Hz, 2 H, CH2CO2Et), 2.81 (br s, 1 H, OH), 3.11 (dt, J = 14.1,
6.9 Hz, 1 H, NCH2), 3.76 (dt, J = 14.1, 6.9 Hz, 1 H, NCH2), 4.00–
4.20 (m, 2 H, OCH2CH3), 4.71 (dt, J1,2 = 15.9 Hz, J1,3 = 1.5 Hz, 1
H, CH=CHCH2), 4.85 (s, 1 H, CHPh), 5.11 (br s, 1 H, CHOH), 5.95
(dt, J = 15.9, 6.6 Hz, 1 H, CH=CHCH2), 7.00–7.10 (m, 2 H, C6H5),
7.20–7.60 (m, 8 H, C6H5).
1H NMR (CDCl3): d = 0.83 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.50 (d,
J = 7.2 Hz, 3 H, CHCH3), 1.8–2.0 (m, 2 H, CH2CH3), 3.03 (br s, 1
H, OH), 4.43 (dt, J1,2 = 15.9 Hz, J1,3 = 1.4 Hz, 1 H, CH=CHCH2),
4.88 (q, J = 7.2 Hz, 1 H, CHCH3), 4.89 (s, 1 H, CHPh), 4.97 (s, 1 H,
CHOH), 6.10 (dt, J = 15.9, 6.6 Hz, 1 H, CH=CHCH2), 6.95–6.99
(m, 2 H, C6H5), 7.1–7.4 (m, 13 H, C6H5).
13C NMR (CDCl3): d = 13.1, 19.8, 25.6, 53.1, 59.8, 69.2, 75.8,
123.4, 127.2, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.3, 128.5,
136.2, 136.4, 139.7, 140.1, 170.6.
13C NMR (CDCl3): d = 13.1, 14.0, 25.7, 32.4, 35.7, 60.7, 61.5, 70.2,
76.4, 121.4, 126.9, 127.0, 127.4, 127.7, 127.9, 128.0, 128.2, 128.4,
135.2, 137.1, 139.4, 169.9, 171.0.
LC-ESI-MS (Rt 21.40 min): m/z = 394 (M – H2O + 1), 412 (M + 1),
LC-ESI-MS (Rt 13.06 min): m/z = 390 (M – H2O + 1), 408 (M + 1),
434 (M + Na).
430 (M + Na).
Anal. Calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C,
81.70; H, 7.09; N, 3.42.
Anal. Calcd for C25H29NO4: C, 73.68; H, 7.17; N, 3.44. Found: C,
73.67; H, 7.17; N, 3.47.
(1¢S,1¢¢S,3R,4S)-4h
Yellow oil; [a]D +47 (c = 1.0, CHCl3).
1-Allyl-3-but-1-enyl-3-(hydroxyphenylmethyl)-4-phenylazeti-
din-2-ones
3g
IR (neat): 3423, 3065, 3032, 2972, 2932, 1719, 1646, 1494, 1461,
1381, 1208, 1043, 1023 cm–1.
Yield: 91%; colorless oil; dr = 68:32.
1H NMR (CDCl3): d = 0.82 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.36 (d, 3
H, J = 7.0 Hz, CHCH3), 1.8–2.0 (m, 2 H, CH2CH3), 2.90 (br s, 1 H,
OH), 4.14 (q, 1 H, J = 7.0 Hz, CHCH3), 4.49 (s, 1 H, CHPh), 4.66
(dt, J1,2 = 15.8 Hz, J1,3 = 1.4 Hz, 1 H, CH=CHCH2), 4.90 (br s, 1 H,
CHOH), 6.03 (dt, J = 15.8, 6.6 Hz, 1 H, CH=CHCH2), 7.0–7.5 (m,
15 H, C6H5).
13C NMR (CDCl3): d = 13.1, 19.2, 25.7, 52.6, 61.1, 68.7, 76.2,
121.6, 127.3, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.3, 128.4,
136.1, 137.1, 139.2, 139.7, 170.3.
IR (neat): 3403 3025 2952 2926 1733 1494 1454 1401 1355 1288
1050 cm–1.
1H NMR (CDCl3): d = 0.81 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.8–2.0
(m, 2 H, CH2CH3), 2.76 (br s, 1 H, OH), 3.44 (dd, J = 15.6, 6.9 Hz,
1 H, NCH2), 4.28 (dd, J = 15.6, 4.8 Hz, 1 H, NCH2), 4.45 (d,
J = 15.9 Hz, 1 H, CH=CHCH2), 5.07 (s, 1 H, CHPh), 5.13–5.22 (m,
2 H, CH=CH2), 5.16 (s, 1 H, CHOH), 5.60–5.80 (m, 1 H, CH=CH2),
6.08 (dt, J = 15.6, 6.6 Hz, 1 H, CH=CHCH2), 6.90–7.00 (m, 2 H,
C6H5), 7.20–7.50 (m, 8 H, C6H5).
13C NMR (CDCl3): d = 13.2, 25.6, 42.7, 59.2, 70.6, 75.2, 118.4,
123.0, 127.2, 127.6, 127.8, 127.9, 128.0, 128.1, 128.2,128.3, 131.5,
135.3, 136.3, 140.0, 170.3.
LC-ESI-MS (Rt 21.20 min): m/z = 394 (M – H2O + 1), 412 (M + 1),
434 (M + Na).
Anal. Calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C,
81.73; H, 7.10; N, 3.42.
LC-ESI-MS (Rt 13.52 min): m/z = 330 (M – H2O + 1), 370 (M +
Na).
3-But-1-enyl-3-(hydroxyphenylmethyl)-4-phenyl-1-(1-phenyl-
ethyl)azetidin-2-ones
(1¢S,1¢¢R,3S,4R)-3i
Anal. Calcd for C23H25NO2: C, 79.51; H, 7.25; N, 4.03. Found: C,
79.52; H, 7.28; N, 4.02.
Yield: 72%; yellow oil; dr = 50:50; [a]D –82.1 (c = 1.0, CHCl3).
4g
IR (neat): 3405 3063 3028 2969 2927 1731 1649 1566 1495 1454
1378 cm–1.
Colorless oil.
IR (neat): 3417 3063 3034 2969 2921 1725 1696 1649 1560 1448
1401 cm–1.
1H NMR (CDCl3): d = 0.83 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.82 (d,
J = 7.3 Hz, 3 H, CHCH3), 1.8–2.0 (m, 2 H, CH2CH3), 2.87 (br s, 1
H, OH), 4.45 (d, J = 15.7 Hz, 1 H, CH=CHCH2), 4.47 (q, J = 7.3
Hz, 1 H, CHCH3), 4.91 (s, 1 H, CHPh); 5.03 (br s, 1 H, CHOH),
6.13 (dt, J = 15.7, 6.6 Hz, 1 H, CH=CHCH2), 6.8–6.9 (m, 2 H,
C6H5), 7.1–7.5 (m, 13 H, C6H5).
1H NMR (CDCl3): d = 0.78 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.8–2.0
(m, 2 H, CH2CH3), 2.60 (br s, 1 H, OH), 3.33 (dd, J = 15.3, 7.2 Hz,
1 H, NCH2), 4.20 (dd, J = 15.3, 4.8 Hz, 1 H, NCH2), 4.72 (dt,
J1,2 = 15.6 Hz, J1,3 = 1.5 Hz, 1 H, CH=CHCH2), 4.81 (s, 1 H,
CHPh), 4.93–5.06 (m, 2 H, CH=CH2), 5.14 (s, 1 H, CHOH), 5.3–
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PAPER
Nucleophilic Addition of Azetidin-2-ones to Aldehydes and Nitriles
69
13C NMR (CDCl3): d = 13.2, 20.0, 25.7, 54.0, 59.2, 69.5, 75.8,
123.3, 127.0, 127.3, 127.5, 127.8, 127.9, 128.0, 128.3, 128.4, 128.5,
135.3, 136.3, 139.8, 141.3, 170.3.
3-Benzoyl-3-but-1-enyl-4-phenyl-1-(1¢-phenylethyl)azetidin-2-
one (5i)
Yield: 60%; colorless oil; [a]D +117.8 (c = 0.5 CHCl3).
LC-ESI-MS (Rt 15.0 min): m/z = 394 (M – H2O + 1), 412 (M + 1),
434 (M + Na).
IR (neat): 3058, 3032, 2952, 2932, 1759, 1666, 1593, 1454, 1242,
1182 cm–1.
Anal. Calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C,
81.72; H, 7.12; N, 3.39.
1H NMR (CDCl3): d = 0.68 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.89 (d,
J = 7.2 Hz, 3 H, CHCH3), 1.7–1.9 (m, 2 H, CH2CH3), 4.48 (q,
J = 7.2 Hz, 1 H, CHCH3), 5.04 (dt, J1,2 = 15.8 Hz, J1,3 = 1.4 Hz, 1
H, CH=CHCH2), 5.33 (s, 1 H, CHPh), 5.88 (dt, J = 15.8, 6.6 Hz, 1
H, CH=CHCH2), 7.10–7.40 (m, 10 H, C6H5), 7.42–7.60 (m, 3 H,
C6H5), 8.25 (d, J = 7.0 Hz, 2 H, C6H5).
13C NMR (CDCl3): d = 12.7, 20.0, 25.6, 54.6, 61.5, 77.4, 122.6,
126.7, 127.6, 128.0, 128.1, 128.4, 128.6,130.7, 133.1, 134.7, 134.9,
138.6, 140.9, 165.6, 194.4.
(1¢S,1¢¢S,3S,4R)-4i
Yellow oil; [a]D –18.2 (c = 0.5 CHCl3).
HPLC-MS (Rt 14.8 min: m/z = 412 (M + 1), 434 (M + Na).
IR (neat): 3422 3063 3028 2957 2933 1731 1708 1649 1542 1448
cm–1.
1H NMR (CDCl3): d = 0.81 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.76 (d,
J = 6.9 Hz, 3 H, CHCH3), 1.85–1.95 (m, 2 H, CH2CH3), 2.76 (br s,
1 H, OH), 4.35 (q, J = 6.9 Hz, 1 H, CHCH3), 4.56 (s, 1 H, CHPh),
4.67 (d, J = 15.8 Hz, 1 H, CH=CHCH2), 5.07 (br s, 1 H, CHOH),
6.04 (dt, J = 15.8, 6.6 Hz, 1 H, CH=CHCH2), 6.90–6.93 (m, 2 H,
C6H5), 6.91–7.07 (m, 2 H, C6H5) 7.2-7.5 (m, 11 H, C6H5).
LC-ESI-MS (Rt 28.00 min): m/z = 410 (M + 1), 432 (M + Na), 841
(2 M + Na).
Anal. Calcd for C28H27NO2: C, 82.12; H, 6.65; N, 3.42. Found: C,
82.14; H, 6.66; N, 3.43.
3-But-1-enyl-3-phenylacetyl-4-phenyl-1-(1¢-phenylethyl)azeti-
din-2-one (6b)
Yield: 60%; colorless oil.
13C NMR (CDCl3): d = 13.2, 19.9, 25.8, 54.3, 60.8, 68.8, 76.6,
121.5, 126.8, 127.4, 127.5, 127.6, 127.8, 128.0, 128.1, 128.2, 128.3,
128.6, 128.7, 135.0, 137.2, 139.3, 141.1, 170.1.
IR (neat): 3063 3034 2957 2922 1761 1713 1501 1460 1401 1100
cm–1.
LC-ESI-MS (Rt 14.8 min): m/z = 394 (M – H2O + 1), 412 (M + 1),
434 (M + Na).
1H NMR (CDCl3): d= 0.83 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.80–2.00
(m, 2 H, CH2CH3), 3.96 (d, J = 14.9 Hz, 1 H, PhCH2N), 4.04 (s, 2
Anal. Calcd for C28H29NO2: C, 81.72; H, 7.10; N, 3.40. Found: C,
81.71; H, 7.07; N, 3.41.
H, PhCH2CO), 4.84 (dt, J1,2 = 15.8, J1,3 = 1.5 Hz,
1 H,
CH=CHCH2), 4.93 (d, J = 14.9 Hz, 1 H, PhCH2N), 5.08 (s,1 H,
CHPh), 6.20 (dt, J = 15.8, 6.6 Hz, 1 H, CH=CHCH2), 7.00–7.20 (m,
4 H, C6H5), 7.22–7.30 (m, 2 H, C6H5), 7.31–7.50 (m, 9 H, C6H5).
13C NMR (CDCl3): d= 12.9, 25.7, 44.4, 46.3, 61.0, 78.3, 120.4,
126.9, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3, 128.4, 128.8, 129.1,
129.7, 133.6, 134.0, 134.8, 139.2, 165.8, 202.0.
Reaction of 1 with Nitrile Derivatives or Acyl Chlorides; Gener-
al Procedure
To a stirred solution of 1 (1 mmol) in anhyd THF (5 mL), were add-
ed zinc powder (1.5 mmol, 1.5 equiv, 65 mg), the nitrile derivative
or acyl chloride (2 mmol, 2 equiv) under N2 at r.t. The reaction was
monitored by TLC and stopped after 2 h by adding H2O (2 mL). The
mixture was then filtered on a Celite pad to remove zinc powder and
the filtrate was concentrated under reduced pressure. The residue,
diluted with CH2Cl2 (10 mL) was washed with H2O (2 ×). The or-
ganic layer was separated, dried (Na2SO4) and the solvent was re-
moved on a rotary evaporator. Compound 5 or 6, was isolated by
flash chromatography on silica gel (cyclohexane–EtOAc, 9:1).
LC-ESI-MS (Rt 23.50 min): m/z = 410 (M + 1), 432 (M + Na).
Anal. Calcd for C28H27NO2: C, 82.12; H, 6.65; N, 3.42. Found: C,
82.10; H, 6.64; N, 3.41.
Acknowledgment
3-Benzoyl-1-benzyl-3-but-1-enyl-4-phenylazetidin-2-one (5b)
Yield: >95%; yellow oil.
We thank MURST (Cofin 2002 and FIRB 2001), ISOF-CNR and
the University of Bologna (funds for selected topics) for financial
support.
IR (neat): 2957, 2916, 2845, 1749, 1672, 1649, 1466, 1260, 1089
1024 cm–1.
1H NMR (CDCl3): d = 0.71 (t, J = 7.5 Hz, 3 H, CH2CH3), 1.7–1.9
(m, 2 H, CH2CH3), 4.02 (d, J = 15.0 Hz, 1 H, PhCH2), 4.98 (d,
J = 15.0 Hz, 1 H, PhCH2), 5.07 (dt, J1,2 = 15.9 Hz, J1,3 = 1.5 Hz, 1
H, CH=CHCH2), 5.41 (s, 1 H, CHPh), 5.95 (dt, J = 15.9, 6.6 Hz, 1
H, CH=CHCH2), 7.1–7.3 (m, 2 H, C6H5), 7.3–7.5 (m, 11 H, C6H5),
8.2–8.3 (m, 2 H, C6H5).
13C NMR (CDCl3): d = 12.8, 25.7, 44.5, 61.7, 78.2, 122.5, 126.1,
127.7, 127.8, 128.1, 128.2, 128.3, 128.4, 128.5, 128.6, 128.7, 128.9,
130.7, 133.2, 134.3, 134.8, 136.6, 138.8, 165.6, 194.3.
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Synthesis 2005, No. 1, 61–70 © Thieme Stuttgart · New York