On the synthesis and reactivity of enantiopure azetidines

Article abstract of DOI:10.1002/ejoc.200700283

β-Amino alcohols with an (E)-vinylsilane moiety were cyclized in the presence of N-bromosuccinimide to afford diastereomerically pure azetidines. The chemo- and stereoselectivities of this bromocyclization are discussed. AM1 calculations support the obser

Full text of DOI:10.1002/ejoc.200700283

FULL PAPER
DOI: 10.1002/ejoc.200700283
On the Synthesis and Reactivity of Enantiopure Azetidines
Emilie Banide,[a] Vincent Lemau de Talancé,[a] Grégory Schmidt,[a] Hodney Lubin,[a]
Sébastien Comesse,[a][‡] Luc Dechoux,[a] Louis Hamon,[a] and Catherine Kadouri-Puchot*[a]
Keywords: Azetidines / Bromocyclization / Amino alcohols / Vinylsilane / Vinyl bromide / Cyclization
β-Amino alcohols with an (E)-vinylsilane moiety were cy-
clized in the presence of N-bromosuccinimide to afford dia-
stereomerically pure azetidines. The chemo- and stereoselec-
tivities of this bromocyclization are discussed. AM1 calcula-
tions support the observed chemoselectivity. The reactivity of
the azetidines towards fluorinated reagents was studied.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
reagent. We also describe the transformations of the re-
sulting azetidines into various heterocycles and new amino
alcohols.
Introduction
The electrophile-induced intramolecular cyclization be-
tween a heteroatom and an olefin is a well-known process
to synthesize various oxygen[1] or nitrogen[2] heterocycles. It
was expected that the presence of a silyl substituent on the
double bond could influence the regioselectivity of such
cyclizations. Thus, functionalized vinylsilanes are recog-
nized to favour exo processes for the formation of cyclic
ethers[3] and amines.[4] Indeed, the cyclization of homoal-
lylic alcohols substituted by a vinylsilane terminator led to
the regioselective formation of oxetanes,[3f] and the cycliza-
tion of δ-amino vinylsilanes allowed the regioselective syn-
thesis of pyrrolidines.[4a] To date, electrophile-induced intra-
molecular cyclizations of homoallylic amino vinylsilanes to
obtain azetidine rings have not been reported.
In the course of our studies about the enantioselective
synthesis of pipecolic acid[5a] and proline[5b] derivatives
from unsaturated and silylated β-amino alcohols,[5c] we fo-
cused on the use of these electrophile-induced cyclizations
to produce azetidines.[6] These molecules are attractive syn-
thetic targets because of their use as ligands, their presence
in natural products and their potent biological and pharma-
ceutical activities.[7] As a consequence, the asymmetric syn-
thesis of these compounds has attracted much attention in
recent years.[8]
Results and Discussion
Formation of Azetidines
Amino alcohols 1a–d and their O-methyl derivatives 2a–
d were cyclized by their treatment with N-bromosuc-
cinimide to afford azetidines 3a–d and 4a–d, respectively,
and some recovered starting material (Scheme 1). These re-
actions occurred in a regio- and diastereoselective manner,
and the configurations of the resulting stereogenic centres
have been established by X-ray analysis of compound 3d[6]
and 4d.[9] The best experimental conditions were: addition
of 1.05 equiv. of N-bromosuccinimide to a 0.1 M solution
of 1 or 2 at 0 °C in acetonitrile.[10]
In the present study, we explored the scope and the limits
of the cyclizations of amino alcohols with a γ-vinylsilane
group by using N-bromosuccinimide as the electrophilic
Scheme 1.
[a] Université Pierre et Marie Curie-Paris 6 Laboratoire de Chimie
Organique UMR 7611, Institut de Chimie Moléculaire FR
2769, Equipe Synthèse Asymétrique,
Azetidines 3 and 4 were formed in moderate to good
yields as single diastereomers. The diastereoselective forma-
tions of azetidines 3 and 4 were interpreted by considering
the intramolecular attack of the nitrogen atom on the bro-
monium intermediate A, affording a 4-exo-tet cyclization
product (Scheme 2).[11]
4 place Jussieu, case courrier 47, 75005 Paris, France
Fax: +33-1-4427-2620
E-mail: kadouri@ccr.jussieu.fr
[‡] Present address: URCOM, Université du Havre,
76600 Le Havre
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 4517–4524
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C. Kadouri-Puchot et al.
FULL PAPER
Scheme 2.
Calculations have been performed to obtain some infor- on the side of the C=C bond opposite the incoming nitrogen
mation on the site selectivity of the bromination with respect atom. As a result, two conformations of the vinylsilane cor-
to the two faces of the vinylsilane. Although ab initio calcula- responding to the two different diastereomeric cations A and
tions (STO3G) ascertained the traditional almost symmetri- B showed different steric interactions particularly with the
cal alkene-bromonium structure, semi-empirical AM1 calcu- α-(hydroxymethyl)benzyl moiety.[15] Moreover, progress
lations[12,13] led to a very unsymmetrical α-bromo-β-cationic towards the cyclized products did not show any further steric
structure (Figure 1). Such a situation seemed to account for hindrance. Indeed, calculations still confirmed an energy dif-
the strong hyperconjugation between the Cα–Si bond and the ference of 2.9 kcal/mol between the cyclized azetidinium
empty p orbital on the cationic Cβ atom.[14] Evidence for this compounds C and D (Figure 2). The energy difference may
well-known effect was given by the unusual length (ca. be explained by the pyramidalisation of Cβ, spreading the
2.37 Å) of the Cα–Si bond. Discrimination between the at- CαHBr–SiMe3 and phenyl groups apart and decreasing the
tack of Br+ on either side of the double bond arose from a associated steric hindrance.
quite important (3.4 kcal/mol) energy difference between the
Because of the presence of different heteroatoms (bro-
two stereoisomers; the attack on the bromine atom occurred mine, silicon, oxygen and nitrogen), these azetidines dis-
Figure 1. AM1-calculated structures for both A (favored) and B (disfavored) bromonium ions.
Figure 2. AM1-calculated structures for both C (favored) and D (disfavored) azetidinium ions.
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Eur. J. Org. Chem. 2007, 4517–4524

On the Synthesis and Reactivity of Enantiopure Azetidines
closed a very intriguing reactivity upon their interaction Reaction of Azetidines with HF/Pyridine
with fluorinated reagents.
Surprisingly, azetidines 3 and 4 reacted with a mixture
HF/pyridine to lead to the amino alcohols 6 and 7, respec-
tively, bearing a (Z)-bromovinyl function, in good to excel-
lent yields (Scheme 5).
Reaction of Azetidines with Tetrabutylammonium Fluoride
Compounds 3 and 4 were treated with tetrabutylammo-
nium fluoride in dry THF. Whereas amino ethers 4 were
desilylated to afford a complex mixture of products,[16,17]
azetidines 3, under the same conditions gave bicyclic com-
pounds 5. The product 5a (R = Ph) was recrystallized and
an X-ray analysis[18] of this compound (Figure 3) showed a
cis relative configuration for each heterocycle, thus estab-
lishing an (S) absolute configuration at the ring junction
(Scheme 3).
Scheme 5.
This totally stereoselective reaction might take place, by
an E2 mechanism; protonation of the nitrogen atom would
give the ammonium intermediate E, and opening of the az-
etidine ring in an anti elimination by attack of the fluoride
ion on the TMS group would result in the selective forma-
tion of the (Z) isomer (Schemes 5 and 6).[19] Likewise, the
[20]
[21]
β-elimination of N3SiMe3 and BrSiMe3 are known to
take place with anti stereochemistry. In contrast, ring-open-
ing elimination[22] or substitution[23] of four-membered cy-
clic ammonium ions have been only scarcely described.
Figure 3. X-ray structure of 5a.
Scheme 6.
Scheme 3.
Next, in order to obtain the free azetidines, we focused
on their hydrogenolysis. This reaction was tested on com-
pound 3d, which reacted with hydrogen to afford product
8. Two reactions occurred under these conditions: a deben-
From a mechanistic point of view, the intramolecular
cyclization described above can be viewed as a simple desi-
lylation by the fluoride ion, generating a negative charge on
the carbon atom. The resulting carbenoid may evolve
through a subsequent acid/base reaction in an inter- or in-
tramolecular manner with the hydroxy group, and further
displacement of the bromine atom by the alcoholate in an
SN2-type reaction can occur. The integrity of the stereo-
genic centre at the ring junction was not altered by this
process. (Scheme 4).
zylation and
a hydrodehalogenation, as indicated in
Scheme 7.
Interestingly, when the hydroxy function of the starting
material was protected in 4 (RЈ = CH3), no cyclization
could occur; a mixture of products resulting probably from
the non-selective reactivity of the carbenoid species at the
Scheme 7.
This result shows that it is possible to synthesize in four
workup stage was observed. We decided then to test the steps, starting from phenyl glycinol, enantiopure cis-2,4-di-
desilylation under acidic conditions.
alkylated azetidines.
Scheme 4.
Eur. J. Org. Chem. 2007, 4517–4524
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C. Kadouri-Puchot et al.
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ppm. C19H33NOSi (319.56): calcd. C 71.41, H 10.41, N 4.38; found
C 71.12, H 10.65, N 4.14.
Conclusions
We have described the one-pot formation of polysubsti-
tuted enantiopure azetidines by a totally regio- and dia-
stereoselective N-bromosuccinimide-induced intramolecu-
lar cyclization. These compounds show their highly stimu-
lating reactivity when submitted to various reagents. The
new β-amino alcohols possessing a bromovinyl function are
potential intermediates for the synthesis of new heterocy-
cles. Studies are underway to elucidate the mechanistic pe-
culiarities of the behaviour of these azetidines.
[(1R,3E)-1-Isopropyl-4-(trimethylsilyl)but-3-en-1-yl][(1R)-2-meth-
oxy-1-phenylethyl]amine (2c): Oil (434 mg, 85% yield). [α]2D0 = –87
1
(c = 0.9, CHCl3). H NMR (250 MHz, CDCl3): δ = 7.34–7.14 (m,
5 H, Ar), 5.94 (dt, J = 7.5 and 17.5 Hz, 1 H, CH=CHTMS), 5.67
(d, J = 17.5 Hz, 1 H, CH=CHTMS), 3.98 (t, J = 7.5 Hz, 1 H,
NCHPh), 3.33–3.28 (m, 2 H, CH2O), 3.27 (s, 3 H, OCH3), 2.24–
2.15 (m, 3 H, NCH-iPr and CH2), 1.69 (s, 1 H, NH), 1.52–1.45 [m,
1 H, CH(CH3)2], 0.78 (d, J = 10 Hz, 3 H, CH3), 0.75 (d, J = 10 Hz,
3 H, CH3), 0.0 (s, 9 H, TMS) ppm. 13C NMR (62.9 MHz, CDCl3):
δ = 144.4 (CH=CHTMS), 142.0 (Ar), 133.0 (CH=CHTMS), 128.2,
128.1, 127.3 (Ar), 78.3 (CH2O), 60.3 (NCHPh), 59.6 (NCHiPr),
58.8 (OCH3), 37.8 (CH2), 31.0 (CHMe2), 19.2 (CH3), 18.6 (CH3),
–1.0 (TMS) ppm. C19H33NOSi (319.56): calcd. C 71.41, H 10.41,
N 4.38; found C 70.61, H 10.47, N 4.13.
Experimental Section
General Methods: 1H and 13C NMR spectra (CDCl3 solution) were
recorded with a Bruker ARX 250 spectrometer at 250 MHz and
62.9 MHz, respectively; chemical shifts are reported in ppm from
TMS. Optical rotations were determined with a Perkin–Elmer 141
instrument. All reactions were carried out under argon. Column
chromatography was performed with silica gel (230–400 mesh) by
using various mixtures of ethyl acetate (AcOEt) or diethyl ether
(Et2O) and cyclohexane (CH). Melting points are uncorrected.
THF was distilled from sodium/benzophenone ketyl. Compositions
of stereoisomeric mixtures were determined by NMR analysis of
crude products before any purification.
[(1R,3E)-1-tert-Butyl-4-(trimethylsilyl)but-3-en-1-yl][(1R)-2-meth-
oxy-1-phenylethyl]amine (2d): Oil (469 mg, 88% yield). [α]2D0 = –101
1
(c = 1.0, CHCl3). H NMR (250 MHz, CDCl3): δ = 7.15–7.32 (m,
5 H, Ar), 6.06 (dt, J = 6.5 and 18.5 Hz, 1 H, CH=CHTMS), 5.63
(d, J = 18.5 Hz, 1 H, CH=CHTMS), 4.07 (dd, J = 4.5 and 8.5 Hz,
1 H, NCHPh), 3.43–3.32 (m, 2 H, CH2O), 3.31 (s, 3 H, OCH3),
2.50–2.42 (m, 1 H, CHH C=C), 2.21–1.94 (m, 2 H, CHHC=C and
tBuCH), 1.59 (s, 1 H, NH), 0.77 (s, 9 H, tBu), 0.0 (s, 9 H, TMS)
ppm. 13C NMR (62.9 MHz, CDCl3): δ = 146.9 (CH=CHTMS),
141.6 (Ar), 130.9 (CH=CHTMS), 128.6, 128.2, 127.4 (Ar), 78.4
(CH2O), 62.2 (NCHtBu), 60.1 (NCHPh), 58.9 (OCH3), 39.0 (CH2),
35.4 (CMe3), 27.4 (CMe3), –1.1 (TMS) ppm. C20H35NOSi (333.58):
calcd. C 72.01, H 10.58, N 4.20; found C 71.98, H 10.59, N 4.39.
General Procedure for the Methylation of Amino Alcohols: A solu-
tion of amino alcohol (1.6 mmol) in anhydrous THF (3 mL) was
added to a solution of sodium hydride (2 mmol) in THF (12 mL)
at 0 °C. After stirring at room temp. for 1.5 h, iodomethane
(4.1 mmol) was added dropwise and the mixture was stirred until
the complete disappearance of the starting material. After addition
of water, extraction with Et2O was followed by drying the organic
layers with MgSO4. After concentration under reduced pressure,
the crude material was purified by chromatography with silica gel
(CH/AcOEt, 95:5) to give the amino ethers.
General Procedure for the Syntheses of Azetidines 3 and 4: N-Bro-
mosuccinimide (0.23 mmol) was added at 0 °C to a solution of the
required amino alcohol (0.21 mmol) in acetonitrile (4 mL). The
mixture was stirred at 0 °C for 15 min, and aqueous NaOH (10%,
3 mL) was added. The aqueous layer was extracted with Et2O, and
the organic layers were combined, dried with MgSO4 and concen-
trated under reduced pressure. The residue was then chromato-
graphed on silica gel.
[(1R)-2-Methoxy-1-phenylethyl][(1R,3E)-1-phenyl-4-(trimethylsilyl)-
but-3-en-1-yl]amine (2a): Oil (384 mg, 68% yield). 1H NMR
(250 MHz, CDCl3): δ = 7.22–7.06 (m, 10 H, Ar), 5.87 (dt, J =
6.5 and 18.5 Hz, 1 H, CH=CHTMS), 5.70 (d, J = 18.5 Hz, 1 H,
CH=CHTMS), 3.92 (dd, J = 4.5 and 7.0 Hz, 1 H, NCHPh), 3.72
(t, J = 6.5 Hz, 1 H, NCHPh), 3.50–3.40 (m, 2 H, CH2O), 3.23 (s,
3 H, OCH3), 2.46 (dt, J = 3.5 and 6.5 Hz, 2 H, CH2), 2.26 (s, 1 H,
NH), 0.0 (s, 9 H, TMS) ppm. 13C NMR (62.9 MHz, CDCl3):
(2R)-2-{(2S,4R)-2-[(1S)-(Bromo)(trimethylsilyl)methyl]-4-phenyl-
azetidin-1-yl}-2-phenylethanol (3a): White solid (66 mg, 75% yield).
M.p. 87 °C. [α]2D0 = 20 (c = 2.5, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 7.38–7.35 (m, 2 H, Ar), 7.19–7.04 (m, 6 H, Ar), 6.91–
6.85 (m, 2 H, Ar), 3.75–3.67 (m, 2 H, CHBr and CHHO), 3.49 (dd,
J = 4.5 and 8.3 Hz, 1 H, CHHO), 3.36–3.06 (m, 4 H, NCHCBr, 2
NCHPh and OH), 2.12–1.86 (m, 2 H, CCH2C), 0.0 (s, 9 H, TMS)
ppm. 13C NMR (62.9 MHz, CDCl3): δ = 143.8, 135.6, 129.4, 128.5,
128.4, 128.1, 127.7, 127.6 (Ar), 67.3 (NCHPh), 62.6 (CH2O), 60.8
(CHCBr), 58.7 (NCHPh), 49.1 (CBr), 32.1 (CH2), –2.1 (TMS)
ppm. C21H28BrNOSi (418.44): calcd. C 60.28, H 6.74, N 3.35;
found C 60.25, H 6.82, N 3.31.
δ
= 144.5 (Ar), 143.3 (CH=CHTMS), 141.7 5 (Ar), 133.8
(CH=CHTMS), 128.1, 128.0, 127.7, 127.1, 127.0, 126.6 (Ar), 77.0
(CH2O), 60.6 (OCH3), 60.2 (NCHPh), 58.9 (NCHPh), 44.7 (CH2),
–1.2 (TMS) ppm. C22H31NOSi (353.57): calcd. C 74.73, H 8.84, N
3.96; found C 74.63, H 10.22, N 3.37.
[(1R)-2-Methoxy-1-phenylethyl][(1S,3E)-1-propyl-4-(trimethylsilyl)-
but-3-en-1-yl]amine (2b): Oil (306 mg, 60% yield). [α]2D0 = –83 (c =
1.0, CHCl3). 1H NMR (250 MHz, CDCl3): δ = 7.34–7.15 (m, 5 H,
Ar), 5.92 (dt, J = 7.0 and 18.5 Hz, 1 H, CH=CHTMS), 5.67 (d, J
= 18.5 Hz, 1 H, CH=CHTMS), 4.00 (dd, J = 5.0 and 7.5 Hz, 1 H,
(2R)-2-{(2S,4S)-2-[(1S)-(Bromo)(trimethylsilyl)methyl]-4-propyl-
azetidin-1-yl}-2-phenylethanol (3b): White solid (36.3 mg, 45%
yield). M.p. 58 °C. [α]2D0 = –36 (c = 1.15, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 7.32–7.09 (m, 5 H, Ar), 3.75–3.52 (m, 3 H,
CHBr and CH2O), 3.52–3.35 (m, 1 H, NCHPh), 3.25–3.05 (m, 1
NCHPh), 3.33 (m, 2 H, CH2O), 3.27 (s, 3 H, OCH3), 2.38 (dt, J = H, NCHCBr), 3.05–2.85 (m, 1 H, NCHPr), 1.73 (t, J = 7.8 Hz, 2
7.5 and 17.5 Hz, 1 H, NCH-Pr), 2.19 (t, J = 5.0 Hz, 2 H,
CH2C=C), 1.75 (s, 1 H, NH), 1.40–1.23 (m, 1 H, CHHCH2), 1.23–
H, CHCH2CH), 1.50–0.85 (m, 4 H, 2 CH2), 0.71 (t, J = 7.3 Hz, 3
H, CH3), 0.0 (s, 9 H, TMS) ppm. 13C NMR (62.9 MHz, CDCl3):
1.14 (m, 3 H, CHHCH2), 0.71 (t, J = 6.0 Hz, 3 H, CH3), 0.0 (s, 9 δ = 136.9, 129.2, 128.5, 128.1 (Ar), 67.4 (NCHPh), 63.4 (CH2O),
H, TMS) ppm. 13C NMR (62.9 MHz, CDCl3):
δ
=
143.5 59.6 (CHBr), 58.2 (NCHCBr), 48.9 (NCHPr), 38.5 (CH2), 27.5
(CH=CHTMS), 141.8 (Ar), 133.6 (CH=CHTMS), 128.4, 127.9,
127.4 (Ar), 78.3 (CH2O), 59.8 (NCHPh), 58.8 (OCH3), 53.3 (NCH-
Pr), 40.5 (CH2), 37.7 (CH2), 19.2 (CH2), 14.3 (CH3), –1.1 (TMS)
(CH2), 18.3 (CH2), 14.2 (Me), –2.0 (TMS) ppm. C18H30BrNOSi
(384.43): calcd. C 56.24, H 7.87, N 3.64; found C 56.44, H 8.15, N
3.65.
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On the Synthesis and Reactivity of Enantiopure Azetidines
(2R)-2-{(2S,4S)-2-[(1S)-(Bromo)(trimethylsilyl)methyl]-4-isopropyl-
azetidin-1-yl}-2-phenylethanol (3c): White solid (44.4 mg, 55%
yield). M.p. 63 °C. [α]2D0 = –44 (c = 1.18, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 7.56–7.03 (m, 5 H, Ar), 3.66–3.51 (m, 3 H,
0.73 (d, J = 7.5 Hz, 3 H, Me), 0.70–0.50 (m, 1 H, CHMe2), 0.31
(d, J = 7.5 Hz, 3 H, Me), 0.0 (s, 9 H, TMS) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 141.0, 128.4, 128.2, 127.6 (Ar), 77.2
(CH2O), 71.3 (NCHPh), 68.0 (NCHCBr), 61.0 (NCHiPr), 58.6
CHBr and CH2O), 3.37–3.28 (m, 2 H, NCHPh and OH), 3.02 (td, (OMe), 51.5 (CHBr), 30.0 (CHMe2), 21.7 (CH2), 18.4 (Me), 16.7
J = 2.3 and 8.0 Hz, 1 H, NCHCBr), 2.84–2.76 (m, 1 H, NCHiPr), (Me), –2.0 (TMS) ppm. C19H32BrNOSi (398.45): calcd. C 57.27, H
1.81 (q, J = 7.5 Hz, 1 H, CHCHHCH), 1.46–1.23 (m, 2 H, 8.10, N 3.52; found C 57.32, H 8.71, N 3.82.
CHCHHCH and CHMe2), 0.86 (d, J = 5.0 Hz, 3 H, Me), 0.47 (d,
(2S,4R)-2-[(1S)-(Bromo)(trimethylsilyl)methyl]-4-tert-butyl-1-[(1R)-
J = 5.0 Hz, 3 H, Me), 0.0 (s, 9 H, TMS) ppm. 13 C NMR
(62.9 MHz, CDCl3): δ = 137.2, 129.1, 128.5, 128.1 (Ar), 68.3
(NCHPh), 64.1 (NCHiPr), 63.8 (CH2O), 59.3 (NCH), 49.1 (CHBr),
31.0 [CH(Me)2], 21.8 (CH2), 18.8 (Me), 17.0 (Me), –2.0 (TMS)
ppm. C18H30BrNOSi (384.43): calcd. C 56.24, H 7.87, N 3.64;
found C 56.74, H 8.08, N 3.07.
2-methoxy-1-phenylethyl)]azetidine (4d): Oil (57 mg, 66% yield).
[α]2D0 = –54 (c = 0.9, CHCl3). 1H NMR (250 MHz, CDCl3): δ =
7.41–7.37 (m, 2 H, Ar), 7.25–7.05 (m, 3 H, Ar), 3.72 (dd, J = 1.8
and 7.8 Hz, 1 H, NCHCBr), 3.66 (dd, J = 2.5 and 8.0 Hz, 1 H,
NCHPh), 3.54 (dd, J = 8.0 and 10.0 Hz, 1 H, CHHO), 3.36 (dd, J
= 3.5 and 10.3 Hz, 1 H, CHHO), 3.34 (d, J = 2.0 Hz, 1 H, CHBr),
3.23 (s, 3 H, OMe), 2.88 (t, J = 8.3 Hz, 1 H, NCHtBu), 1.89–1.78
(m, 1 H, CHCHHCH), 1.69–1.58 (m, 1 H, CHCHHCH), 0.52 (s,
9 H, tBu), 0.0 (s, 9 H, TMS) ppm. 13C NMR (62.9 MHz, CDCl3):
δ = 142.7, 128.4, 128.1, 127.0 (Ar), 75.8 (CH2O), 73.5 (NCHtBu),
68.4 (NCHPh), 58.6 (OMe), 57.4 (NCHCBr), 52.2 (CHBr), 34.4
( CMe3 ) , 2 6 . 5 ( CMe3 ) , 2 3 . 8 ( CH2 ) , – 2 . 0 ( T M S ) p p m .
C20H34BrNOSi (412.48): calcd. C 58.24, H 8.31, N 3.40; found C
58.11, H 8.03, N 3.21.
(2R)-2-{(2S,4S)-2-[(1S)-(Bromo)(trimethylsilyl)methyl]-4-tert-butyl-
azetidin-1-yl}-2-phenylethanol (3d): White solid (44.3 mg, 53%
yield). M.p. 71 °C. [α]2D0 = –106 (c = 0.8, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 7.25–6.95 (m, 5 H, Ar), 3.75 (t, J =
10.5 Hz, 1 H, CHHO), 3.55 (m, 2 H, CHBr and OH), 3.43–3.28
(m, 2 H, CHHO and NCHPh), 3.21 (td, J = 2.3 and 8.0 Hz, 1 H,
NCHCBr), 2.66 (t, J = 8.3 Hz, 1 H, CHtBu), 1.80 (q, J = 7.5 Hz,
1 H, CHCH2CH), 1.53–1.43 (m, 1 H, CHCH2CH), 0.67 (s, 9 H,
tBu), 0.0 (s, 9 H, TMS) ppm. 13C NMR (62.9 MHz, CDCl3): δ =
136.6, 129.6, 128.5, 128.1 (Ar), 68.2 (NCHtBu), 66.3 (NCHPh),
62.7 (CH2O), 58.0 (NCH), 48.5 (CHBr), 34.1 (CMe3), 27.0 (CMe3),
24.0 (CH2), –2.0 (TMS) ppm. C19H32BrNOSi (398.45): calcd. C
57.27, H 8.09, N 3.52; found C 57.33, H 8.23, N 3.41.
General Procedure for the Preparation of the Bicyclic Compounds 5:
A solution of tetrabutylammonium fluoride (1  in THF,
0.45 mmol) was added dropwise to a solution of compound 3
(0.37 mmol) in THF (4 mL). The mixture was stirred at room tem-
perature for 24 h. After the addition of water (5 mL), the solution
was extracted with Et2O. The organic layers were dried with
MgSO4, filtered, and concentrated, and the crude product was
flash-chromatographed.
(2S,4R)-2-[(1S)-(Bromo)(trimethylsilyl)methyl]-1-[(1R)-2-methoxy-
1-phenylethyl)]-4-phenylazetidine (4a): Oil (47.2 mg, 52% yield). 1H
NMR (250 MHz, CDCl3): δ = 7.15–7.11 (m, 2 H, Ar), 6.92–6.81
(m, 8 H, Ar), 3.75–3.53 (m, 4 H, NCHPh, CHHO, NCHCBr and
CHBr), 3.32 (dt, J = 2.5 and 7.5 Hz, 1 H, NCHPh), 3.17 (dd, J =
5.0 and 10.0 Hz, 1 H, CHHO), 3.11 (s, 3 H, OMe), 2.04 (t, J =
7.5 Hz, 2 H, CHCH2CH), 0.0 (s, 9 H, TMS) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 144.4, 137.8, 128.9, 127.9, 127.7, 127.5,
127.3, 126.6 (Ar), 76.6 (CH2O), 70.2 (NCHPh), 64.2 (NCHCBr),
61.6 (NCHPh), 58.6 (OMe), 50.9 (CHBr), 31.9 (CH2), –2.0 (TMS)
ppm. C22H30BrNOSi (432.47): calcd. C 61.10, H 6.99, N 3.24;
found C 60.82, H 7.78, N 2.68.
(2R,6S,8R)-2,8-Diphenyl-4-oxa-1-azabicyclo[4.2.0]octane (5a): Oil
(53 mg, 54% yield). [α]2D0 = –44 (c = 2.0, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 7.17–6.89 (m, 10 H, Ar), 4.04 (t, J =
6.7 Hz, 1 H, CHHO), 3.82 (dd, J = 2.7 and 9.5 Hz, 1 H, CHHO),
3.72–3.63 (m, 3 H, CHHO, CHHO and NCHPh), 3.56–3.51 (m, 1
H, NCHPh), 3.20–3.05 (m, 1 H, NCH), 2.31–2.23 (m, 2 H, CH2)
ppm. 13C NMR (62.9 MHz, CDCl3): δ = 141.4, 137.4, 128.6, 128.3,
127.9, 127.8, 127.7, 127.3 (Ar), 73.6 (CH2O), 70.7 (NCHPh), 69.6
(NCHPh), 69.4 (CH2O), 61.5 (NCH), 35.4 (CH2) ppm. C18H19NO
(265.35): calcd. C 81.47, H 7.22, N 5.28; found C 80.76, H 7.47, N
5.02.
(2S,4S)-2-[(1S)-(Bromo)(trimethylsilyl)methyl]-1-[(1R)-2-methoxy-
1-phenylethyl)]-4-propylazetidine (4b): Solid (32.6 mg, 39% yield).
M.p. 44 °C. [α]2D0 = –45 (c = 1.0, CHCl3). 1H NMR (250 MHz,
CDCl3): δ = 7.19–7.12 (m, 5 H, Ar), 3.58–3.47 (m, 3 H, NCHPh,
CHHO and CHBr), 3.30 (dt, J = 1.5 and 9.5 Hz, 1 H, NCHCBr),
3.19 (dd, J = 2.0 and 7.2 Hz, 1 H, CHHO), 3.15 (s, 3 H, OMe),
2.81 (dq, J = 3.0 and 7.5 Hz, 1 H, NCHPr), 1.81 (dq, J = 2.0 and
7.5 Hz, 1 H, CHCHHCH), 1.67 (q, J = 7.5 Hz, 1 H, CHCHHCH),
1.00–0.80 (m, 2 H, CH2CH3), 0.78–0.67 (m, 2 H, CH2CH2CH3),
0.49 (t, J = 7.0 Hz, 3 H, CH3), 0.0 (s, 9 H, TMS) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 140.7, 128.7, 128.2, 127.6 (Ar), 77.5
(CH2O), 71.0 (NCHPh), 62.2 (NCHCBr), 61.9 (NCHPr), 58.7
(OMe), 51.7 (CHBr), 37.8 (CH2CH2CH3), 27.3 (CH2), 18.0
(CH2CH2CH3), 14.1 (CH3), –2.0 (TMS) ppm. C19H32BrNOSi
(398.45): calcd. C 57.27, H 8.10; found C 57.89, H 8.30.
(2R,6S,8S)-2-Phenyl-8-propyl-4-oxa-1-azabicyclo[4.2.0]octane (5b):
1
Oil (46.2 mg, 54% yield). [α]2D0 = –93 (c = 1.8, CHCl3). H NMR
(250 MHz, CDCl3): δ = 7.21–7.06 (m, 5 H, Ar), 3.61 (dd, J = 2.7
and 9.5 Hz, 1 H, CHHO), 3.55 (dd, J = 2.0 and 9.7 Hz, 1 H,
CHHO), 3.42 (t, J = 9.7 Hz, 1 H, CHHO), 3.38–3.28 (m, 2 H,
NCHPh and CHHO), 3.04–2.93 (m, 1 H, NCHPr), 2.88–2.75 (m,
1 H, NCH), 1.91 (td, J = 5.5 and 8.7 Hz, 1 H, CHH), 1.63 (q, J =
8.8 Hz, 1 H, CHH), 1.15–0.50 (m, 4 H, CH2CH2CH3), 0.53 (t, J =
7.0 Hz, 3 H, CH3) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 139.4,
128.3, 128.2, 127.8 (Ar), 73.6 (CH20), 70.7 (CH20), 68.9 (NCHPh),
67.5 (NCHPr), 61.7 (NCH), 38.1 (CH2CH2CH3), 32.9 (CH2), 18.8
(CH2CH2CH3), 14.2 (CH3) ppm. C15H21NO (231.33): calcd. C
77.88, H 9.15, N 6.05; found C 77.82, H 9.51, N .29.
(2S,4R)-2-[(1S)-(Bromo)(trimethylsilyl)methyl]-4-isopropyl-1-[(1R)-
2-methoxy-1-phenylethyl)]azetidine (4c): Solid (36 mg, 43% yield).
M.p. 63 °C. [α]2D0 = –41 (c = 1.0, CHCl3). 1H NMR (250 MHz,
(2R,6S,8R)-8-Isopropyl-2-phenyl-4-oxa-1-azabicyclo[4.2.0]octane
(5c): Oil (47 mg, 55% yield). [α]2D0 = –90 (c = 1.5, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 7.32–7.18 (m, 5 H, Ar), 3.73 (dd, J = 2.5
CDCl3): δ = 7.30–7.00 (m, 5 H, Ar), 3.61–3.54 (m, 2 H, CHHO and 9.5 Hz, 1 H, CHHO), 3.67–3.48 (m, 4 H, CH2O, NCHPh and
and CHBr), 3.45 (dd, J = 3.5 and 7.7 Hz, 1 H, NCHCBr), 3.28–
3.17 (m, 2 H, CHHO and NCHPh), 3.15 (s, 3 H, OMe), 2.79 (dt,
CHHO), 2.97–2.84 (m, 2 H, NCH and NCHiPr), 1.85–1.78 (m, 2
H, CH2), 1.25–1.16 (m, 1 H, CHMe2), 0.71 (d, J = 6.7 Hz, 3 H,
J = 3.7 and 8.5 Hz, 1 H, NCHiPr), 1.81 (q, J = 10 Hz, 1 H, Me), 0.33 (d, J = 6.7 Hz, 3 H, Me) ppm. 13C NMR (62.9 MHz,
CHCHHCH), 1.52 (dq, J = 3.7 and 10.0 Hz, 1 H, CHCHHCH),
CDCl3): δ = 139.8, 128.4, 128.3, 128.0 (Ar), 73.8 (NCHiPr), 73.5
Eur. J. Org. Chem. 2007, 4517–4524
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4521

C. Kadouri-Puchot et al.
(CH2O), 70.6 (CH2O), 69.7 (NCHPh), 61.3 (NCH), 30.5 (CHMe2), (2R)-2-{[(1R,3Z)-4-Bromo-1-tert-butylbut-3-en-1-yl]amino}-2-phen-
FULL PAPER
27.8 (CH2), 19.5 (Me), 17.6 (Me) ppm.
ylethanol (6d): Oil (36.4 mg, 86% yield). [α]2D0 = –99 (c = 0.9,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 7.30–7.16 (m, 5 H, Ar),
6.17 (q, J = 6.7 Hz, 1 H, CH=CHBr), 6.10 (d, J = 7.2 Hz, 1 H,
CH=CHBr), 3.83 (dd, J = 4.5 and 8.5 Hz, 1 H, NCHPh), 3.60 (dd,
J = 4.7 and 10.7 Hz, 1 H, CHHO), 3.46 (dd, J = 8.5 and 10.7 Hz,
1 H, CHHO), 2.43–2.25 (m, 2 H, CH2C=C), 2.21 (t, J = 4.7 Hz, 1
H, NCHtBu), 2.08 (br. s, 2 H, NH and OH), 0.79 (s, 9 H, tBu)
ppm. 13C NMR (62.9 MHz, CDCl3): δ = 141.1 (Ar), 134.2
(CH=CHBr), 128.7, 127.7 (Ar), 108.0 (CH=CHBr), 67.2
(NCHPh), 62.5 (NCHtBu), 62.3 (CH2O), 35.2 (CMe3), 31.7
(CH2C=C), 27.1 (CMe3) ppm. C16H24BrNO (326.27): calcd. C
58.90, H 7.41, N 4.29; found C 58.61, H 7.48, N 4.07.
(2R,6S,8R)-8-tert-Butyl-2-phenyl-4-oxa-1-azabicyclo[4.2.0]octane
(5d): Oil (49 mg, 54% yield). [α]2D0 = –99 (c = 1.4, CHCl3). 1H NMR
(250 MHz, CDCl3): δ = 7.21–7.18 (m, 5 H, Ar), 3.70 (dd, J = 2.5
and 9.5 Hz, 1 H, CHHO), 3.66–3.40 (m, 4 H, CHHO, CH2O and
NCHPh), 2.85–2.74 (m, 2 H, NCHtBu and NCHCH2), 1.78–1.70
(m, 2 H, CH2), 0.36 (s, 9 H, tBu) ppm. 13C NMR (62.9 MHz,
CDCl3): δ = 139.7, 128.6, 127.8, 127.6 (Ar), 78.3 (NCHtBu), 72.7
(CH2O), 70.1 (NCHPh), 69.9 (CH2O), 60.6 (NCH), 31.6 (CtBu),
27.1 (CH2), 25.8 (CtBu) ppm. C16H23NO (245.36): calcd. C 78.32,
H 9.45, N 5.71; found C 78.02, H 9.61, N 5.42.
General Procedure for the Preparation of the Brominated β-Amino
Alcohols 6 and β-Amino Ethers 7: A solution of hydrofluoric
acid in pyridine (35 µL) was added to a solution of azetidine
(0.13 mmol) in THF (1.5 mL) at 0 °C. The mixture was stirred until
the complete disappearance of the starting material. After the ad-
dition of saturated aq. NaHCO3 (3 mL), the aqueous layer was
extracted with Et2O (3ϫ3 mL). The organic layers were dried with
MgSO4, concentrated under reduced pressure, and compounds 6
and 7 were isolated.
[(1R,3Z)-4-Bromo-1-phenylbut-3-en-1-yl][(1R)-2-methoxy-1-phenyl-
ethyl]amine (7a): Oil (45.4 mg, 97% yield). [α]2D0 = –35 (c = 2.1,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 7.26–7.08 (m, 10 H,
Ar), 6.06 (dt, J = 1.5 and 6.7 Hz, 1 H, CH=CHBr), 5.85 (q, J =
6.7 Hz, 1 H, CH=CHBr), 3.94 (dd, J = 5.0 and 6.5 Hz, 1 H,
NCHPh), 3.69 (dd, J = 5.7 and 7.5 Hz, 1 H, NCHPh), 3.35–3.28
(m, 2 H, CH2O), 3.26 (s, 3 H, OMe), 2.70–2.68 (m, 1 H,
CHHC=C), 2.52–2.48 (m, 1 H, CHHC=C), 2.30 (br. s, 1 H, NH)
ppm. 13C NMR (62.9 MHz, CDCl3): δ = 143.4, 141.1 (Ar), 131.6
(CH=CHBr), 128.5, 127.8, 127.5, 127.4, 127.2 (Ar), 109.6
(CH=CHBr), 77.2 (CH2O), 60.2 (NCHPh), 59.1 (NCHPh), 59.0
(OMe), 36.6 (CH2C=C) ppm. C19H22BrNO (360.29): calcd. C
63.34, H 6.15, N 3.89; found C 63.39, H 7.07, N 4.04.
(2R)-2-{[(1R,3Z)-4-Bromo-1-phenylbut-3-en-1-yl]amino}-2-phenyl-
ethanol (6a): Oil (42.7 mg, 95% yield). [α]2D0 = –47 (c = 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): δ = 7.26–7.12 (m, 10 H, Ar), 6.08
(d, J = 7.0 Hz, 1 H, CH=CHBr), 5.85 (q, J = 7.0 Hz, 1 H,
CH=CHBr), 3.83 (dd, J = 4.7 and 7.2 Hz, 1 H, NCHPh), 3.72–
3.64 (m, 2 H, NCHPh and CHHO), 3.46 (dd, J = 4.7 and 7.2 Hz,
1 H, CHHO), 2.74–2.62 (m, 1 H, CHHC=C), 2.56–2.44 (m, 3 H,
CHHC=C, OH and NH) ppm. 13C NMR (62.9 MHz, CDCl3): δ =
143.2, 140.9 (Ar), 131.3 (CH=CHBr), 128.7, 128.6, 127.7, 127.6,
127.3, 127.1 (Ar), 109.9 (CH=CHBr), 65.9 (CH20), 61.6 (NCHPh),
58.9 (NCHPh), 36.8 (CH2C=C) ppm. C18H20BrNO (346.26): calcd.
C 62.44, H 5.82, N 4.05; found C 62.82, H 5.96, N 3.84.
[(1S,3Z)-4-Bromo-1-propylbut-3-en-1-yl][(1R)-2-methoxy-1-phenyl-
ethyl]amine (7b): Oil (39 mg, 92% yield). [α]2D0 = –83 (c = 1.0,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 7.33–7.18 (m, 5 H, Ar),
6.16 (dd, J = 1.2 and 6.2 Hz, 1 H, CH=CHBr), 6.06 (q, J = 6.2 Hz,
1 H, CH=CHBr), 4.01 (t, J = 6.2 Hz, 1 H, NCHPh), 3.38–3.31 (m,
2 H, CH2O), 3.27 (s, 3 H, OMe), 2.46–2.39 (m, 1 H, NCHPr), 2.27–
2 . 2 3 ( m , 3 H , CH2 C = C a n d N H ), 1 . 3 6 – 1 . 1 8 ( m , 4 H,
CH2CH2CH3), 0.72 (t, J = 7.5 Hz, 3 H, CH3) ppm. 13C NMR
(62.9 MHz, CDCl3): δ = 141.1 (Ar), 131.7 (CH=CHBr), 128.5,
127.9, 127.5 (Ar), 109.5 (CH=CHBr), 78.0 (CH2O), 59.5 (NCHPh),
58.9 (OMe), 52.9 (NCHPr), 37.6 (CH2C=C), 33.5 (CH2CH2CH3),
19.3 (CH2CH2CH3), 14.2 (CH3) ppm. C16H24BrNO (326.27): calcd.
C 58.90, H 7.41, N 4.29; found C 59.31, H 7.53, N 4.14.
(2R)-2-{[(1S,3Z)-4-Bromo-1-propylbut-3-en-1-yl]amino}-2-phenyl-
ethanol (6b): Oil (33.3 mg, 82% yield). [α]2D0 = –93 (c = 1.0, CHCl3).
1H NMR (250 MHz, CDCl3): δ = 7.35–7.21 (m, 5 H, Ar), 6.19 (d,
J = 7.0 Hz, 1 H, CH=CHBr), 6.10 (q, J = 7.0 Hz, 1 H, CH=CHBr),
3.86 (dd, J = 4.5 and 8.7 Hz, 1 H, NCHPh), 3.62 (dd, J = 4.5 and
10.7 Hz, 1 H, CHHO), 3.45 (dd, J = 8.7 and 10.7 Hz, 1 H, CHHO),
2.58–2.54 (m, 1 H, NCHPr), 2.30–2.25 (m, 4 H, CH2C=C, OH and
NH), 1.37–1.19 (m, 4 H, CH2CH2CH3), 0.73 (t, J = 6.0 Hz, 3 H,
CH3) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 141.1 (Ar), 131.6
(CH=CHBr), 128.8, 127.8, 127.3 (Ar), 109.7 (CH=CHBr), 67.0
(CH20), 61.8 (NHCHPh), 53.2 (NHCHPr), 37.4 (CH2CH2CH3),
33.8 (CH2C=C), 19.3 (CH2CH2CH3), 14.2 (CH2CH2CH3) ppm.
C15H22BrNO (312.25): calcd. C 57.70, H 7.10, N 4.49; found C
58.19, H 7.40, N 4.34.
[(1R,3Z)-4-Bromo-1-isopropylbut-3-en-1-yl][(1R)-2-methoxy-1-phen-
ylethyl]amine (7c): Oil (21.2 mg, 50% yield). [α]2D0 = –87 (c = 1.0,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 7.33–7.15 (m, 5 H, Ar),
6.12 (td, J = 1.2 and 7.0 Hz, 1 H, CH=CHBr), 6.03 (q, J = 6.5 Hz,
1 H, CH=CHBr), 3.99 (t, J = 6.5 Hz, 1 H, NCHPh), 3.34 (d, J =
6.5 Hz, 2 H, CH2O), 3.28 (s, 3 H, OMe), 2.35–2.18 (m, 3 H,
CH2C=C and NCHiPr), 1.56 (br. s, 1 H, NH), 1.54–1.47 (m, 1 H,
CHMe2), 0.82 (d, J = 6.7 Hz, 3 H, Me), 0.77 (d, J = 6.7 Hz, 3 H,
Me) ppm. 13C NMR (62.9 MHz, CDCl3): δ = 141.5 (Ar), 132.5
(CH=CHBr), 128.3, 128.1, 127.5 (Ar), 108.9 (CH=CHBr), 78.2
(CH2O), 59.8 (NCHPh), 58.9 (NCHiPr), 58.7 (OMe), 31.3
(CH2C=C and CHMe2), 19.7 (Me), 18.0 (Me) ppm. C16H24BrNO
(326.27): calcd. C 58.90, H 7.41, N 4.29; found C 58.49, H 7.64, N
3.77.
(2R)-2-{[(1R,3Z)-4-Bromo-1-isopropylbut-3-en-1-yl]amino}-2-phen-
ylethanol (6c): Oil (38.1 mg, 94% yield). [α]2D0 = –109 (c = 1.0,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 7.31–7.16 (m, 5 H, Ar),
6.16 (dt, J = 1.0 and 7.0 Hz, 1 H, CH=CHBr), 6.09 (q, J = 6.7 Hz,
1 H, CH=CHBr), 3.82 (dd, J = 4.5 and 8.5 Hz, 1 H, NCHPh), 3.60
(dd, J = 4.5 and 10.5 Hz, 1 H, CHHO), 3.45 (dd, J = 8.7 and
10.7 Hz, 1 H, CHHO), 2.38–2.26 (m, 3 H, NCHiPr and CH2C=C),
2.22 (br. s, 2 H, NH and OH), 1.64–1.51 (m, 1 H, CHMe2), 0.82
(d, J = 6.7 Hz, 3 H, Me), 0.74 (d, J = 6.7 Hz, 3 H, Me) ppm. 13C
[(1R,3Z)-4-Bromo-1-tert-butylbut-3-en-1-yl][(1R)-2-methoxy-1-phen-
ylethyl]amine (7d): Oil (42 mg, 95% yield). [α]2D0 = –100 (c = 1.0,
CHCl3). 1H NMR (250 MHz, CDCl3): δ = 7.36–7.19 (m, 5 H, Ar),
6.19 (q, J = 7.0 Hz, 1 H, CH=CHBr), 6.11 (d, J = 7.0 Hz, 1 H,
NMR (62.9 MHz, CDCl3): δ = 141.1 (Ar), 132.3 (CH=CHBr), CH=CHBr), 4.01 (dd, J = 4.7 and 8.0 Hz, 1 H, NCHPh), 3.41–
128.7, 127.7, 127.5 (Ar), 109.3 (CH=CHBr), 67.0 (CH2O), 62.0 3.37 (m, 2 H, CH2O), 3.33 (s, 3 H, OMe), 2.51–2.41 (m, 1 H,
(NCHPh), 59.1 (NCHiPr), 31.3 (CH2C=C), 31.1 (CHMe2), 19.0 CHHC=C), 2.38–2.25 (m, 1 H, CHHC=C), 2.13 (t, J = 5.0 Hz, 1
(Me), 18.4 (Me) ppm. C15H22BrNO (312.25): calcd. C 57.70, H
7.10, N 4.49; found C 58.43, H 7.20, N 4.19.
H, NCHtBu), 1.68 (br. s, 1 H, NH), 0.84 (s, 9 H, tBu) ppm. 13C
NMR (62.9 MHz, CDCl3): δ = 141.2 (Ar), 134.5 (CH=CHBr),
4522
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4517–4524

On the Synthesis and Reactivity of Enantiopure Azetidines
Lett. 2000, 2, 385; b) H. Hasegawa, H. Senboku, Y. Kajizuka,
K. Orito, M. Tokuda, Tetrahedron 2003, 59, 827; c) K. Miura,
T. Takahashi, T. Hondo, A. Hosomi, Chirality 2003, 15, 41.
[5] a) C. Agami, S. Comesse, C. Kadouri-Puchot, J. Org. Chem.
2002, 67, 2424; b) C. Agami, S. Comesse, S. Guesné, C. Ka-
douri-Puchot, L. Martinon, Synlett 2003, 1058; c) C. Agami,
S. Comesse, C. Kadouri-Puchot, J. Org. Chem. 2002, 67, 1496.
[6] Preliminary communication: V. Lemau de Talancé, E. Banide,
B. Bertin, S. Comesse, C. Kadouri-Puchot, Tetrahedron Lett.
2005, 46, 8023.
[7] For reviews, see: a) N. De Kimpe, in Comprehensive Heterocy-
clic Chemistry II (Eds.: A. Padwa), Elsevier, Oxford, 1996, vol.
1B, chapter 1.18, pp. 507–589; b) F. Couty, G. Evano, D. Prim,
Mini-Rev. Org. Chem. 2004, 1, 133; c) S. Robin, G. Rousseau,
Eur. J. Org. Chem. 2002, 3099.
[8] a) R. Pedrosa, C. Andrés, J. Nieto, S. del Pozo, J. Org. Chem.
2005, 70, 1408; b) S. Mangelinckx, M. Boeykens, M. Vliegen,
J. Van der Eycken, N. De Kimpe, Tetrahedron Lett. 2005, 46,
525; c) D. Enders, J. Gries, Z.-S. Kim, Eur. J. Org. Chem. 2004,
4471; d) F. Couty, G. Evano, N. Rabasso, Tetrahedron: Asym-
metry 2003, 14, 2407; e) A. C. B. Burtoloso, C. R. D. Correia,
Tetrahedron Lett. 2004, 45, 3355; f) D. Enders, J. Gries, Synthe-
sis 2005, 3508; g) S.-H. Ma, D. H. Yoon, H.-J. Ha, W. K. Lee,
Tetrahedron Lett. 2007, 48, 269; h) R. Marcia de Figueredo, R.
Frölich, M. Christmann, J. Org. Chem. 2006, 71, 4147; i) A.
Marinetti, P. Hubert, J.-P. Genêt, Eur. J. Org. Chem. 2000,
1815.
128.4, 128.3, 127.5 (Ar), 107.5 (CH=CHBr), 78.2 (CH2O), 61.9
(NCHtBu), 60.1 (NCHPh), 58.9 (OMe), 35.5 (CMe3), 31.6
(CH2C=C), 27.2 (CMe3) ppm.
(2R,4S)-2-tert-Butyl-4-[(trimethylsilyl)methyl]azetidine Hydrobro-
mide (8): A solution of compound 3d (0.13 mmol) in absolute etha-
nol (1.5 mL) was injected into a hydrogenation flask containing a
suspension of palladium on charcoal (15 mg) in absolute ethanol
(1 mL). The reaction was complete in 3 h. The mixture was filtered
through Celite 545, and the residue was washed with ethanol. After
evaporation of the solvent, the resulting solid was triturated with
Et2O and dried to afford the azetidine 8. Solid (18.2 mg, 50 %
yield). M.p. 70 °C. [α]2D0 = –6 (c = 1.44, CHCl3). 1H NMR
(250 MHz, CD3OD): = 4.39–4.25 (m, 1 H, NCHCH2TMS), 3.99
(t, J = 10 Hz, 1 H, NCHtBu), 2.43 (dt, J = 8.0 and 11.8 Hz, 1 H,
CHCHHCH), 2.13–2.00 (m, 1 H, CHCHHCH), 1.19–1.04 (m, 2
H, CH2TMS), 0.90 (s, 9 H, tBu), 0.00 (s, 9 H, TMS) ppm. 13C
N M R ( 6 2 . 9 M H z , C D C l 3 ) : δ = 6 4 . 8 ( NC Ht B u ) , 5 4 . 7
(NCHCH2TMS), 32.5 (CMe3), 29.5 (CHCH2CH), 25.1 (CMe3),
23.7 (CH2TMS), –1.0 (TMS) ppm. C11H26BrNSi (280.32): calcd. C
47.13, H 9.35, N 5.00; found C 47.23, H 9.56, N 4.87.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra of obtained compounds and AM1-
calculated structures for bromonium and azetidinium ions.
[9] CCDC-641472 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
We thank Dr. Patrick Herson for X-ray analyses of compounds 4d
and 5a.
[10] This solvent was already reported as the more efficient solvent
for a 4-exo trig process: ref.[2b,2h]
[11] J. E. Baldwin, J. Chem. Soc. Chem. Commun. 1976, 734.
[12] AM1 calculations: The calculations on the bromonium inter-
mediate were carried out using the AM1 Hamiltonian[13] as
implemented in the AMPAC program version 4.0 QCPE
No527. The geometries were optimized by using the Davidson–
Fletcher–Powell algorithm (FLEPO procedure) that minimizes
the energy with respect to all internal coordinates.
[13] A. Sevin, J. Tortajada, M. Pfau, J. Org. Chem. 1986, 51, 2671.
[14] J. B. Lambert, Y. Zhao, R. W. Emblidge, L. A. Salvador, X.
Liu, J.-H. So, E. C. Chelius, Acc. Chem. Res. 1999, 32, 183.
[15] These calculations excluded any other configuration for the ni-
trogen atom. Any attempt at optimisation led to the stable con-
figuration proposed here.
[1] For recent examples of O-cyclizations, see: a) G. Fragale, T.
Wirth, Eur. J. Org. Chem. 1998, 1361; b) M. Gruttadauria, P.
Lo Meo, R. Noto, Tetrahedron 2001, 57, 1819; c) P.
Van de Weghe, S. Bourg, J. Eustache, Tetrahedron 2003, 59,
7365; d) S. Ma, L. Lu, J. Org. Chem. 2005, 70, 7629; e) L. A.
Paquette, I. H. Kim, N. Cunière, Org. Lett. 2003, 5, 221; f) R.
Pedrosa, C. Andrès, P. Mendiguchia, J. Nieto, J. Org. Chem.
2006, 71, 8854, and references therein.
[2] For recent examples of N-cyclizations, see: a) N. De Kimpe, D.
De Smaele, J. Heterocycl. Chem. 2000, 37, 607; b) X. Panneco-
ucke, F. Outurquin, C. Paulmier, Eur. J. Org. Chem. 2002, 995;
c) F. Outurquin, X. Pannecoucke, B. Berthe, C. Paulmier, Eur.
J. Org. Chem. 2002, 1007; d) D. W. Knight, A. L. Redfern, J.
Gilmore, J. Chem. Soc. Perkin Trans. 1 2001, 2874; e) D. W.
Knight, A. L. Redfern, J. Gilmore, J. Chem. Soc. Perkin Trans.
1 2002, 622; f) S. Robin, G. Rousseau, Eur. J. Org. Chem. 2000,
3007; g) E. J. Corey, T.-P. Loh, S. AchyuthaRao, D. C. Daley,
S. Sarshar, J. Org. Chem. 1993, 58, 5600; h) B. Berthe, F. Outur-
quin, C. Paulmier, Tetrahedron Lett. 1997, 38, 1393; i) S. Mi-
nakata, Y. Morino, Y. Oderaotoshi, M. Komatsu, Org. Lett.
2006, 8, 3335.
[16] In this mixture, a new product was isolated. The NMR spectra
are in accordance with either the brominated azetidine or pyr-
rolidine. As described in ref.[17], α-halo azetidines are known to
be unstable and rearrange to pyrrolidines:
[3] For examples of silicon-directed O-cyclizations, see: a) K. Mi-
ura, T. Hondo, H. Saito, H. Ito, A. Hosomi, J. Org. Chem.
1997, 62, 8292; b) K. Miura, T. Hondo, S. Okajima, A. Ho-
somi, Tetrahedron Lett. 1996, 37, 487; c) E. Schaumann, A.
Kirschning, J. Chem. Soc. Perkin Trans. 1 1990, 1481; d) K.
Miura, T. Hondo, S. Okajima, T. Nakagawa, T. Takahashi, A.
Hosomi, J. Am. Chem. Soc. 2000, 122, 11348; e) K. Miura, S.
Okajima, T. Hondo, T. Nakagawa, T. Takahashi, A. Hosomi,
[17] F. Couty, F. Durrat, D. Prim, Tetrahedron Lett. 2003, 44, 5209.
[18] CCDC-641473 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
J. Org. Chem. 2002, 67, 6082; f) M. Rofoo, M.-C. Roux, G. [19] The (Z) configuration was based upon the coupling (7.0 Hz)
Rousseau, Tetrahedron Lett. 2001, 42, 2481; g) G. Adiwidjaja,
H. Flörke, A. Kirschning, E. Schaumann, Liebigs Ann. Chem..
1995, 501; h) E. Ehlinger, P. Magnus, J. Am. Chem. Soc. 1980,
102, 5004; i) L. A. Paquette, I. H. Kim, N. Cunière, Org. Lett.
2003, 5, 221.
of the ethylene hydrogen atoms.
[20] For an anti elimination of β-silyl azides, see: L. Chabaud, Y.
Landais, Tetrahedron Lett. 2003, 44, 6995.
[21] For references concerning the utility of vinylsilanes as interme-
diates in the stereoselective synthesis of vinyl halides, see: a)
M. A. Brook, M. A. Hadi, A. Neuy, J. Chem. Soc. Chem. Com-
mun. 1989, 957; b) K. E. Koenig, W. P. Weber, Tetrahedron Lett.
[4] For examples of silicon-directed N-cyclizations, see: a) K. Mi-
ura, T. Hondo, T. Nakagawa, T. Takahashi, A. Hosomi, Org.
Eur. J. Org. Chem. 2007, 4517–4524
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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FULL PAPER
1973, 14, 2533; c) R. B. Miller, G. McGarvey, J. Org. Chem.
1978, 43, 4424.
[22] For an example of the ring opening of azetidinium ions by a
β-elimination, see: G. Gionta, C. Lillocci, J. Phys. Org. Chem.
1993, 6, 187.
[23] For a reference concerning the SN2Ј ring opening of four-mem-
bered cyclic ammonium ions, see: F. Couty, F. Durrat, G.
Evano, J. Marrot, Eur. J. Org. Chem. 2006, 4214.
Received: March 30, 2007
Published Online: July 12, 2007
4524
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4517–4524