Novel stereoselective synthesis of 1,2,3-trisubstituted azetidines

Article abstract of DOI:10.1016/j.tetasy.2012.10.014

A novel, superbase induced diastereoselective transformation of benzylamino groups containing oxiranes has provided a series of trans-1,2,3-trisubstituted azetidines in good yields. The reaction of the corresponding optically active cis-2,3-disubstituted

Full text of DOI:10.1016/j.tetasy.2012.10.014

Tetrahedron: Asymmetry 23 (2012) 1607–1614
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Tetrahedron: Asymmetry
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Novel stereoselective synthesis of 1,2,3-trisubstituted azetidines
Ferenc Faigl a, , Ervin Kovács , Gábor Turczel , Áron Szöllosy , Alessandro Mordini , László Balázs ,
⇑
a
a
b
c
d
}
Tamás Holczbauer e, Mátyás Czugler e
a MTA-BME Organic Chemical Technology Research Group, Budapest University of Technology and Economics, Budafoki út 8, H-1111 Budapest, Hungary
b Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, Gellért tér 4, H-1111 Budapest, Hungary
c CNR Istituto di Chimica dei Composti Organometallici, Dipt.Chim. Org., Universite di Firenze. Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italy
d R&D of Chinoin Ltd, External Pharmaceutical Department, Budapest University of Technology and Economics, Tó utca 1-5, H-1045 Budapest, Hungary
e Institute of Structural Chemistry, Hungarian Academy of Sciences, Pusztaszeri út 59-67, H-1025 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 October 2012
Accepted 19 October 2012
A novel, superbase induced diastereoselective transformation of benzylamino groups containing oxiranes
has provided a series of trans-1,2,3-trisubstituted azetidines in good yields. The reaction of the corre-
sponding optically active cis-2,3-disubstituted oxirane yielded the azetidine derivative as a single enan-
tiomer. The structures of the new azetidines were confirmed by NMR spectroscopic methods and, in one
case, by single crystal diffraction measurements.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
conclusions of these papers were that multisubstituted chiral
azetidines are often challenging to prepare.18
Azetidines are the members of an important class of heterocy-
clic compounds with remarkable biological activities.1–3 There
are cholesterol level decreasing agents,4 antiinflammatory,5 anti-
depressant6 compounds and selective neuronal nicotinic receptor
agonists7 among the known azetidine derivatives. In addition,
these compounds have also been used as ligands in metal-
catalysed transformations8 and as chiral auxiliaries in enantiose-
lective reactions.9,10
Recently, efficient kinetic resolution methods were developed
in our laboratory for the preparation of optically active 3-substi-
tuted cis-2-benzyloxymethyloxiranes and these compounds were
rearranged enantioselectively into the corresponding 3-substituted
trans-2-phenyl-oxetanes in the presence of an alkaliamide type
superbase.20,21 The aforementioned results were achieved by
extension of the first article on the superbase induced rearrange-
ment of benzyl–oxiranyl ethers into oxetanes.22 In addition, the
Diastereoisomeric mixtures of 2,3- and 2,4-disubstituted as
well as 2,3,4-trisubstituted azetidines were synthesised by the lith-
ium hexamethyldisilazane initiated intramolecular ring closure on
N-protected glycine derivatives.11–13 Low diastereoselectivities
were observed when optically active N-benzyl-N-(2-chloro-2-
phenylethyl)glycine ester was transformed into the corresponding
trans-N-benzyl-2-ethoxycarbonyl-3-phenylazetidine, but only one
diastereoisomer formed when the phosphaglycine analogue was
treated with the lithium base.14 Chiral bicyclic azetidines were also
prepared from N-(1-benzyloxymethyl-2-chloroethyl)proline esters
in satisfactory yields using lithium hexamethyldisilazane as the
deprotonating agent in the presence of HMPA.15 Optically active
2,3-bis-(benzyloxymethyl)azetidine was prepared in moderate
yield via a multistep synthesis starting from (+)-diethyltartrate
and the product was used as an intermediate for oxetanocin-A
analogues.16 With regard to their practical importance, reviews
on azetidine synthesis have also been published,17–19 but the
enzyme
catalysed
resolution
of
cis-2-hydroxymethyl-3-
trityloxymethyloxirane 1 was also accomplished by our group.23
With racemic and optically active forms of compound 1 in hand,
we decided to study the preparation of cis-N-substituted-2-benzyl-
amino-3-trityloxymethyloxiranes and cis-N-substituted-2-ally-
laminomethyl-3-trityloxymethyloxiranes and investigate the
superbase induced transformation of these compounds into the
corresponding azetidine derivatives. Herein, we report our findings
on a promising and highly stereoselective route to chiral 1,2,3-tri-
substituted azetidines.
2. Results and discussion
Amino groups containing key intermediates 3–8 were prepared
from cis-2,3-epoxy-4-trityloxybutanol 1 via tosylation of the pri-
mary hydroxyl group followed by reaction with different second-
ary amines (Scheme 1). Each amino containing oxirane derivative
was obtained in pure form and with good yields after column
chromatography.
In order to extend the applicability of our target compounds, a
tert-butoxycarbonyl group (Boc) protected benzylamine derivative
⇑
Corresponding author. Tel.: +36 1 463 3652; fax: +36 1 463 3648.
E-mail address: ffaigl@mail.bme.hu (F. Faigl).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.10.014

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F. Faigl et al. / Tetrahedron: Asymmetry 23 (2012) 1607–1614
and the protecting group (Boc) was introduced in a separate
reaction.
In the next, the amino containing oxirane derivatives 3–5 and 9
were treated with an excess of potassium tert-butoxide activated
lithium diisopropylamide (LiDA-KOR superbase) in tetrahydrofu-
ran at ꢀ75 °C and the azetidine derivatives 10–13 formed were iso-
lated, after aqueous hydrolysis and purification, with satisfactory
yields (Schemes 3).
O
O
O
TsCl
HNRR'
pyridine
KI, DMF
OTr
OTs
OTr
OH
OTr
N
R
R'
1
2
R
R'
Compd. Yield
Next, trans-2-(N-benzyl-N-methylaminomethyl)-3-propyloxi-
rane 14 was treated with LiDA-KOR superbase to give the corre-
sponding azetidine derivative 15. The starting material of this
reaction was synthesised from trans-3-propyl-2-hydroxymethy-
loxirane 1624 via tosylation 17, which was followed by reaction
with N-methylbenzylamine (Scheme 4).
The alkali amide type superbase (LiDA-KOR) induced transfor-
mation of the oxirane containing tetrahydroisoquinoline deriva-
tives 7 and 8 was also attempted. The reaction of compound 7
provided 1-(1-hydroxy-2-triphenylmethoxyethyl)-1,4,5,9b-tetra-
hydro-7,8-dimethoxy-1-methyl-2H-azeto[2,1-a] isoquinoline 18
(Scheme 5).
However, compound 8 failed to react under these conditions.
This was probably due to the mesomeric electron donating effect
of the methoxy groups decreasing the acidity of the benzylic pro-
tons in the tetrahydroisoquinoline moiety. A similar phenomenon
was also observed in the aforementioned synthesis of oxetanes.22
The N-allyl substituted oxirane derivative 6 remained intact in
the presence of the LiDA-KOR reagent; however the corresponding
2-vinyl substituted azetidine 19 formed when Schlosser’s base
(LiC-KOR: a mixed aggregate of butyllithium and potassium-tert-
butoxide)25 was used (Scheme 6). Under these conditions, a small
Bn
Me
Et
3
4
5
6
96%
77%
85%
86%
Bn
Bn
Me
Bn
allyl
R
N
N
=
=
7
8
89%
77%
R'
OMe
OMe
R
N
N
R'
Scheme 1. Synthesis of compounds 3–8 (Tr = triphenylmethyl, Ts = p-toluenesul-
fonyl, Bn = benzyl group).
Ph
NBoc
O
O
Na
DMF
58%
NBoc
Ph
OTr
OTs
OTr
9
2
O
Scheme 2. Synthesis of compound
9
(Boc = tert-butoxycarbonyl, Ph = phenyl
group).
OH
LiDA-KOR
-78 oC, THF
25%
TrO
OTr
N
OH
O
N
LiDA-KOR
TrO
-78 oC, THF
7
10
OTr
N
Ph
N
R
R
Scheme 5. Synthesis of compound 16.
Yield
3
R = Me
10
11
12
13
75%
62%
48%
40%
4
5
9
R = Et
OH
R = Bn
O
R = tert-butoxycarbonyl
TrO
Scheme 3. Superbase induced transformation of oxiranes 3–5 and 9 into azetidines
10–13.
-78 oC, THF
42%
N
OTr
N
19
6
9 was also synthesised from tosylate 2 (Scheme 2). It should be
noted that lower yields were achieved when the secondary amine
was prepared in the first step from benzylamine and compound 2
Scheme 6. Synthesis of 3-(1-hydroxy-2-triphenylmethoxyethyl)-1-methyl-2-ethe-
nylazetidine 19.
Ph
O
O
O
OH
HN
LiDA-KOR
Ph
p-TsCl
Pr
Pr
Pr
Pr
THF,
-78 oC
86%
KI, DMF,
25 oC
86%
pyridine,
-10 oC
81%
OTs
N
OH
Ph
N
16
17
15
14
Scheme 4. Synthesis and superbase induced transformation of oxirane 14 into azetidine 15.

F. Faigl et al. / Tetrahedron: Asymmetry 23 (2012) 1607–1614
1609
O-M+
Tr
Ph
R
M
Ph
R
Tr
O
Tr
O
O
Ph
R
O
O
N
N
N
Scheme 7. Proposed reaction mechanism of azetidine formation via superbase induced transformation of benzylaminomethyl group containing oxiranes (M = K or Li).
TrO
OH
H y
O
O
O
H
H
i) TsCl, pyridine
H
H
kinetic
d
d
c
a
b
H y
a
a
c
H x
c
N
Ph
b
resolution
ii) HN
Ph
d
OTr
( )-1
OH
OTr
OH
OTr
N
Ph
H x
Ph
(+)-(2R,3S)-1
(+)-(2R,3S)-3
ee 98.9%
81%, ee 98.9%
HO
O
H
H
H
Ph
LiDA-KOR
-78 oC, THF
TrO
H
H
N
OTr
N
Ph
(+)-(1'R,2R,3R)-10
(+)-(2R,3S)-3
63%, ee 98.9%
ee 98.9%
Scheme 9. Synthesis of (10R,2R,3R)-10 from (2R,3S)-3.
Figure 1. ROESY spectrum of compound 10. The missing correlation between Hx
and Hy is highlighted by a red circle.
in simultaneous ring opening of the three membered heterocycle
and the formation of the azetidine ring (4-exo ring closure,
Scheme 5). The proposed reaction mechanism is analogous with
the transformations of the benzyloxymethyl group containing oxir-
anes into oxetanes21,22 and provides such azetidines in which the
C2 and C3 substituents are positioned (Scheme 7) on the opposite
side of the ring (in a trans-position to each other).
Spectroscopic investigations of products 10–13 confirmed that
the C2 and C3 substituents were always situated in a trans-position
around the azetidine ring, that is, the new azetidine forming reac-
tion is stereoselective.
TMS
OH
O
1. BuLi/THF
2. TMSCl/THF
TrO
Ph
TrO
Ph
-78 oC
93%
r.t.
N
N
10
20
For example, in the two dimensional (1H–1H ROESY: rotating
frame nuclear Overhauser effect spectroscopy) spectrum of 10
(Fig. 1), the missing correlation between the Hx and Hy protons
demonstrates that the bulky substituents of the C2 and C3 carbon
atoms of the azetidine ring are on the opposite sides of the ring.
Further experimental evidence for the highly diastereoselective
formation of product 10 was obtained by single crystal X-ray dif-
fraction measurements of its O-trimethylsilyl derivative 20, which
was prepared via the reaction of the lithium alcoholate with tri-
methylsilyl chloride (Scheme 8).
Scheme 8. Synthesis of trans-1-methyl-2-phenyl-3-[1-(trimethylsilyloxy)-2-(tri-
tyloxy)ethyl]azetidine (20).
The ORTEP diagram (Fig. 2) of a pair of compounds 20 shows
that the C2 and C3 substituents of the azetidine are on the opposite
sides of the ring. While the positions of the phenyl rings are quite
stable in the crystal, rotation of the trimethylsilyl group could be
observed. This is indicated by the dotted lines in the structure on
the right hand side.
In order to demonstrate the high diastereoselectivity of the
azetidine forming reaction, the superbase induced reaction was re-
peated by starting from (+)-(2R,3S)-2-(N-benzyl-N-methylami-
nomethyl)-3-(trityloxymethyl)oxirane (2R,3S)-3 (Scheme 9). The
optically active starting material was prepared from (+)-(2R,3S)-
2-hydroxymethyl-3-(trityloxymethyl)oxirane (2R,3S)-1, a product
of the recently developed enzyme catalysed kinetic resolution of
racemic 1.22
Figure 2. ORTEP diagram of a pair of compounds 20 as situated in the unit cell of a
single crystal (red: O, blue: N, yellow: Si, black: C, small empty circles: H).
amount of triphenylmethanol was also detected in the crude prod-
uct. This side product is probably formed via superbase induced
ether cleavage.
The first step of the superbase induced transformation is prob-
ably the metallation of the benzylic position. Next, an intramolec-
ular nucleophilic reaction occurs between the alkalibenzyl moiety
and the electrophilic C2 carbon atom of the oxirane ring resulting
The enantiomeric excess (ee) and diastereoisomeric composi-
tion of the starting material and the product were controlled by
HPLC using chiral stationary phase containing columns. We started

1610
F. Faigl et al. / Tetrahedron: Asymmetry 23 (2012) 1607–1614
from the (2R,3S)-3 enantiomer (ee: 98.9%) and, after the rearrange-
ment, we obtained (10R,2R,3R)-10 as the sole product (with the
same ee: 98.9%). These results confirm the complete diastereose-
lectivity of the new rearrangement reaction.
4.2. Preparation of cis-2-tosyloxymethyl-3-trityloxymethyloxi-
rane 2
Compound 1 (24.5 mmol, 8.48 g) was dissolved in dry pyridine
(20 ml) under a dry nitrogen atmosphere. The solution was cooled
to ꢀ15 °C and a solution of tosyl chloride (61.0 mmol, 11.6 g) in
pyridine (22 ml) was added dropwise. The reaction mixture was
kept in ꢀ15 °C for 24 h, then it was poured into ice water (about
110 g) and the mixture was acidified with a 1 M aqueous solution
of sulfuric acid (200 ml). The aqueous mixture was extracted with
dichloromethane (4 ꢁ 60 ml), and the combined organic solution
was washed with a 5% aqueous solution of hydrochloric acid
(2 ꢁ 60 ml), and brine (1 ꢁ 60 ml), then dried over sodium sulfate.
The product 2 was isolated after evaporation of the solvent as a
white solid (11.3 g, 92%). mp: 120–122 °C. 1H NMR (CDCl3,
500 MHz) dH: 7.71 (2H, d, J = 8.5 Hz, aromatic H), 7.39 (6H, d,
J = 7.5 Hz, aromatic H), 7.31–7.24 (11H, m, aromatic H), 4.14 (1H,
dd, J = 11.0, 3.0 Hz, CHaHbOSO2), 3.91 (1H, dd, J = 11.5, 7.0 Hz,
CHaHbOSO2), 3.31 (1H, dd, J = 11.0, 5.5 Hz, CHaHbOTr), 3.20 (2H,
m, oxirane CH), 3.07 (1H, dd, J = 10.5, 4.0 Hz, CHaHbOTr), 2.43
(3H, s, ArCH3). 13C NMR (CDCl3, 75 MHz), dC: 145.2, 143.6, 132.9,
130.1, 128.7, 128.2, 127.5, 87.4, 68.6, 61.9, 54.9, 53.1, 21.9. IR (film)
mmax (cmꢀ1): 2906, 1359, 1178, 968, 704. MS (m/z): 518.2
([M+NH4]+), 243.1, (Ph3C+). HRMS C30H32NO5S ([M+NH4]+) requires
518.1996, found 518.2001.
3. Conclusion
On the basis of our experimental results, we can conclude that a
wide range of N-benzylaminomethyl or N-allylaminomethyl
containing oxirane derivatives can be transformed into the
corresponding 1,2,3-trisubstituted azetidines independent of the
electron donating (e.g., methyl or ethyl) or electron withdrawing
(tert-butoxycarbonyl) effect of the third substituent situated on
the nitrogen atom. Complete diastereoselective rearrangements
could be initiated at ꢀ75 °C in the most cases with an excess of
superbases such as LiDA-KOR or LiC-KOR in tetrahydrofuran.
New trans-1,2,3-trisubstituted azetidines were formed in these
reactions, due to the intramolecular 4-exo-tet ring closure reaction
of the organometallic intermediate (formed via the superbase in-
duced metallation in the benzylic or allylic position). The reaction
of an optically active oxirane derivative provided the correspond-
ing azetidine derivative as a single enantiomer. This experimental
result confirmed the highly diastereoselective formation of the
new (the third) stereogenic centre in the product.
The new products are valuable intermediates for a wide range
of organic synthesis projects because these compounds can be
easily transformed into other derivatives by removing the
N-protecting group in 13 or the trityl group in the side chain and
modification of the hydroxylic functions in compounds 10–13,
15, 18 and 19. Furthermore, the vinyl group makes 19 suitable
for further chemical transformations at that position.
4.2.1. (+)-(2R,3S)-2-Tosyloxymethyl-3-trityloxymethyloxirane
(2R,3S)-2
The optically active tosylate (2R,3S)-2 was prepared from
(+)-(2R,3S)-2-hydroxymethyl-3-trityloxymethyloxirane23 (2R,3S)-
1 {ee 98,9% (HPLC), ½a D25
¼ þ33:8 (c 2.1, CHCl3)} according to the
ꢂ
above described method. Product (2S,3R)-2 was isolated in 91%
yield, ½a 2D5
¼ þ23:8 (c 1.6, CHCl3).
ꢂ
4. Experimental section
4.1. General comments
4.3. General procedure for the preparation of aminooxiranes 3–
8
All commercial starting materials were purchased from Sigma–
Aldrich and Merck Hungary Ltd. and were used without further
purification. Tetrahydrofuran and diethylether were obtained in
anhydrous form by distillation from sodium wire after the charac-
teristic blue colour of the in situ generated sodium diphenylketyl
had been found to persist. The organometallic reactions were car-
ried out in Schlenk-flasks under a dry nitrogen atmosphere. TLC
was carried out on Kieselgel 60 F254 (Merck) sheets [the spots
Compound 2 (10.0 mmol) was dissolved in dry dimethylform-
amide under dry nitrogen atmosphere and potassium iodide
(5.00 mmol) was added into it. The solution was cooled down to
0 °C and the secondary amine (HNRR0, see Scheme
1 and
21.00 mmol,) was added into the solution. The reaction mixture
was stirred for 7 days at room temperature, then it was poured into
a mixture of ice, saturated sodium hydrogencarbonate solution
(200 ml) and diethyl ether (50 ml) after which the phases were
separated and the aqueous mixture was extracted with diethyl
ether (4 ꢁ 60 ml). The ether solution was washed with brine
(50 ml), dried over sodium sulfate and concentrated in vacuo.
The residue was purified by flash chromatography in order to yield
the products 3–8 as colourless oils (eluents, yields and spectro-
scopic parameters are given below).
were developed with UV or the aqueous solution of (NH4)6Mo7O24
,
Ce(SO4)2 and sulfuric acid). Routine 1H and 13C and spectra were
recorded in CDCl3 solution on a BRUKER AV 300 or DRX 500 spec-
trometer. Proton chemical shifts are reported in ppm relative to the
internal standard (dTMS = 0 ppm); carbon chemical shifts are re-
ported in ppm relative to the solvent (dChloroform = 77.0). Proton
peaks of the hydroxylic groups are not specified in the spectro-
scopic data because the positions of these broad singlets depend
on the samples’ concentration and usually appear below the other
proton signals. IR spectra were recorded on an appliance type PER-
KIN ELMER 1600 with a Fourier Transformer. Data are given in
cmꢀ1. The specific rotation of the optically active sample was
determined on a PERKIN ELMER 245 MC polarimeter using sodium
lamp (589 nm). Melting points were determined on a Gallenkamp
Melting Point Apparatus (in capillaries). High resolution mass
spectra (HRMS) were recorded on Waters LCT Premier XE spec-
trometer in electrospray ionization (ESI, 2.5 kV) mode using water
(0.035% trifluoroacetic acid)/acetonitrile as eluent in gradients (5–
95% acetonitrile); samples were made up in acetonitrile. Racemic
and optically active oxiranols ( )-1 and (2S,3R)-1 were prepared
according to the literature.23
4.3.1. cis-N-Benzyl-N-methyl-2-aminomethyl-3-(trityloxymeth-
yl)oxirane 3
Eluent for flash chromatography: hexane/ethyl acetate = 4/1;
oil, yield 96%. 1H NMR (CDCl3, 500 MHz) dH: 7.45–7.43 (6H, m, aro-
matic H), 7.30–7.21 (14H, m, aromatic H), 3.54 (1H, d, J = 13.0 Hz,
CHaHbPh), 3.40 (1H, d, J = 13.0 Hz, CHaHbPh), 3.32 (1H, dd,
J = 10.5, 6.0 Hz, CHaHbOTr), 3.18 (2H, m, oxirane CH), 3.10 (1H,
dd, J = 10.5, 4.5 Hz, CHaHbOTr), 2.57 (1H, dd, J = 13.5, 3.5 Hz,
CHaHbN), 2.18 (4H, m, CHaHbN and CH3N). 13C NMR (CDCl3,
75 MHz), dC: 143.9, 138.8, 129.2, 128.9, 128.5, 128.1, 87.1, 62.6,
62.4, 55.6, 55.4, 54.4, 42.9. IR mmax (cmꢀ1): 2906, 1492, 1443,
1359, 1178, 968, 704. MS (m/z): 450.2 ([M+H]+), 437.2, 243.1
(Ph3C+). HRMS C31H32NO2 ([M+H]+) requires 450.2433, found
450.2443.

F. Faigl et al. / Tetrahedron: Asymmetry 23 (2012) 1607–1614
1611
4.3.2. (+)-(2R,3S)-N-Benzyl-N-methyl-2-aminomethyl-3-(tritylo-
xymethyl)oxirane (2R,3S)-3
2247, 1598, 1491, 1449, 1222, 1071, 909, 735, 707. MS (m/z):
464 ([M+H]+), 317, 243 (Ph3C+), 142. HRMS C32H32NO2 ([M+H]+)
requires: 462.2433, found 462.2442.
The optically active benzylaminomethyl oxirane (2R,3S)-3 was
prepared from (2R,3S)-2 according to the above described method.
The product (2R,3S)-3 was obtained in 81% yield. ½a D25
¼ þ10:0 (c
ꢂ
4.3.7. cis-6,7-Dimethoxy-2-[(3-(trityloxymethyl)oxiran-2-ylmet-
hyl]-1,2,3,4-tetrahydroizoquinoline 8
1.4, CHCl3).
Eluent for flash chromatography: hexane/ethyl acetate = 1/1;
oil, yield 77%. 1H NMR (CDCl3, 300 MHz) dH: 7.48–7.46 (6H, m, aro-
matic H), 7.32–7.21 (9H, m, aromatic H), 6.57 (1H, s, aromatic H),
6.47 (1H, s, aromatic H), 3.83 (1H, s, CH3O), 3.79 (1H, s, CH3O),
3.61 (1H, d, 14.5 Hz, NCHaHbAr), 3.54 (1H, d, 14.5 Hz, NCHaHbAr)
3.56 (1H, m, CHaHbOTr) 3.25 (2H, s, oxirane CH), 3.12 (1H, m, CHaH-
bOTr), 2.74 (5H, m, 2xCH2 piperidine and NCHaHb), 2.31 (1H, m,
NCHaHb). 13C NMR (CDCl3, 75 MHz), dC: 147.6, 147.2, 143.7,
128.6, 127.9, 127.1, 126.1, 125.7, 111.4, 109.4, 86.9, 62.0, 56.3,
55.9, 55.8, 54.9, 54.1, 51.3, 28.4. IR mmax (cmꢀ1): 3084, 2932,
1610, 1518, 1490, 1448. MS (m/z): 522 ([M+H]+), 317, 243
(Ph3C+), 142. HRMS C34H36NO4 ([M+H]+) requires: 522.2644, found
522.2656.
4.3.3. cis-N-Benzyl-N-ethyl-2-aminomethyl-3-(trityloxymethyl)-
oxirane 4
Eluent for flash chromatography: hexane/ethyl acetate = 1/6;
oil, yield 77%. 1H NMR (CDCl3, 500 MHz) dH: 7.44–7.43 (6H, m, aro-
matic H), 7.30–7.22 (14H, m, aromatic H), 3.65 (1H, d, J = 14.0 Hz,
CHaHbPh), 3.48 (1H, d, J = 14.0 Hz, CHaHbPh), 3.28 (1H, dd,
J = 10.0, 6.0 Hz, CHaHbOTr), 3.17–3.11 (2H, m, oxirane CH), 3.08
(1H, dd, J = 10.5, 4.5 Hz, CHaHbOTr), 2.57 (2H, m, CH3CHaHbN and
CHaHbN), 2.49 (1H, m, CH3CHaHbN), 2.29 (1H, dd, J = 13.5, 6.0 Hz,
CHaHbN), 0.98 (3H, t, J = 7.0 Hz, CH3CH2N). 13C NMR (CDCl3,
75 MHz), dC: 143.7, 139.3, 128.8, 128.62, 128.1, 127.8, 127.1,
126.8, 86.9, 62.3, 58.3, 55.3, 54.3, 51.5, 47.9, 11.8. IR mmax (cmꢀ1):
3027, 2925, 2833, 1489, 1447. MS (m/z): 464 ([M+H]+), 317, 243
(Ph3C+), 142. HRMS C32H34NO2 ([M+H]+) requires 464.2590, found
464.2596.
4.4. cis-N-Benzyl-N-Boc-2-aminomethyl-3-(trityloxymethyl)oxi-
rane 9
4.3.4. cis-N,N-Dibenzyl-2-aminomethyl-3-(trityloxymethyl)oxi-
rane 5
The dispersion oil was washed out from sodium hydride 60%
dispersion (1.8 mmol, 72.2 mg) with dry hexane (3 ꢁ 3 ml) under
a dry nitrogen atmosphere, then it was dried in vacuo followed
by the addition of dry dimethylformamide (2 ml). A dimethylform-
amide solution (7 ml) of N-Boc-Benzylamine (1.20 mmol, 0.248 g)
was added dropwise to the cold (5 °C) suspension and the mixture
was stirred for 2 hours at room temperature. The yellow solution
obtained was slowly added into a dimethylformamide solution
(7 ml) of 2 (1.2 mmol, 0.60 g) at 5 °C under a dry nitrogen atmo-
sphere. The reaction mixture was stirred for 48 hours, then it
was poured into a mixture of ice (15 g) and saturated sodium
hydrogencarbonate solution (10 ml), and the aqueous mixture
was extracted with diethyl ether (5 ꢁ 10 ml). The organic solution
was washed with brine (10 ml), dried over sodium sulfate and con-
centrated in vacuo. The residue was purified by column chroma-
tography (eluent hexane/ethyl acetate = 7/1) to yield pure 9 as an
oil (0.375 g, 58%). 1H NMR (CDCl3, 300 MHz) dH: 7.43–7.06 (20H,
m, aromatic H), 4.59 (1H, d, J = 15.6 Hz, NCHaHbPh), 4.30 (1H, m,
NCHaHbPh), 3.67–3.25 (2H, m, CHaHbOTr, BnNCHaHb), 3.18–2.83
(4H, m, CHaHbOTr, 2 oxirane CH, BnNCHaHb), 1.44 (9H, s, (CH3)3).
13C NMR (CDCl3, 75 MHz), dC (ppm): 146.91, 143.86, 133.85,
128.82, 128.11, 127.34, 87.21, 85.38, 80.22, 62.47, 55.20, 54.61,
53.62, 45.39, 28.57. IR mmax (cmꢀ1): 3086, 3031, 3002, 2930,
1697, 1455. MS (m/z): 558 ([M+Na]+), 553, 536 ([M+H]+), 243
(Ph3C+), 146. HRMS C35H38NO4 ([M+H]+) requires: 536.2801, found
536.2816.
Eluent for flash chromatography: hexane/ethyl acetate = 9/1;
oil, yield 85%. 1H NMR (CDCl3, 500 MHz) dH: 7.41–7.40 (6H, m, aro-
matic H), 7.30–7.18 (19H, m, aromatic H), 3.71 (2H, d, J = 14.0 Hz,
CHaHbPh), 3.47 (2H, d, J = 14.0 Hz, CHaHbPh), 3.24 (1H, dd,
J = 10.5, 6.0 Hz, CHaHbOTr), 3.16–3.11 (2H, m, oxirane CH), 3.05
(1H, dd, J = 10.5, 4.5 Hz, CHaHbOTr), 2.59 (1H, dd, J = 13.5, 3.5 Hz,
CHaHbN), 2.28 (1H, dd, J = 13.5, 6.5 Hz, CHaHbN). 13C NMR (CDCl3,
75 MHz), dC: 143.7, 139.1, 128.7, 128.6, 128.2, 127.8, 127.0,
126.9, 86.9, 62.2, 58.6, 55.3, 54.2, 51.6. IR mmax (cmꢀ1): 2943,
2825, 1489, 1447, 1077. MS (m/z): 526 ([M+H]+), 317, 243
(Ph3C+), 142. HRMS C37H36NO2 ([M+H]+) requires: 526.2746, found
526.2733.
4.3.5. cis-N-Allyl-N-methyl-2-aminomethyl-3-(trityloxymethyl)-
oxirane 6
Eluent for flash chromatography: hexane/ethyl acetate = 3/2;
oil, yield 86%. 1H NMR (CDCl3, 500 MHz) dH: 7.46–7.45 (6H, m, aro-
matic H), 7.31–7.21 (9H, m, aromatic H), 5.78 (1H, m, vinyl CH),
5.11 (2H, dd, J = 18.0, 10.0 Hz, vinyl CH2), 3.34 (1H, dd, J = 10.0,
6.0 Hz, CHaHbOTr), 3.20 (1H, m, oxirane CH), 3.13–3.09 (2H, m, oxi-
rane CH and CHaHbOTr), 3.03 (1H, m, NCHaHbCH@CH2), 2.92 (1H,
m, NCHaHbCH@CH2), 2.56 (1H, dd, J = 13.5, 3.5 Hz, CHaHbN), 2.23
(3H, s, CH3N), 2.13 (1H, dd, J = 12.0, 6.5 Hz, CHaHbN). 13C NMR
(CDCl3, 75 MHz), dC: 143.9, 135.4, 128.9, 128.1, 127.3, 118.2, 87.1,
62.4, 61.3, 55.4, 55.2, 54.4, 42.8. IR mmax (cmꢀ1): 3084, 3023,
2787, 1736, 1491, 1448. MS (m/z): 400 ([M+H]+), 317, 243
(Ph3C+), 142. HRMS C27H30NO2 ([M+H]+) requires: 400.2277, found
400.2269.
4.5. Synthesis of trans-2-(N-benzyl-N-methylaminomethyl)-3-
propyloxirane 14
trans-(3-Propyloxiran-2-yl)methanol24 16 (16.4 mmol, 1.90 g)
was dissolved in dry pyridine (20 ml) under a dry nitrogen atmo-
sphere. The solution was cooled to ꢀ15 °C and a solution of tosyl
chloride (40.89 mmol, 7.79 g) in pyridine (30 ml) was added drop-
wise to it. The reaction mixture was kept in ꢀ15 °C for 24 h, then it
was poured into ice water (about 150 g) and the mixture was
acidified with a 1 M aqueous solution of sulfuric acid (200 ml).
The aqueous mixture was extracted with dichloromethane
(4 ꢁ 30 ml), then the combined organic solution was washed with
a 5% aqueous solution of hydrochloric acid (2 ꢁ 20 ml), and brine
(1 ꢁ 30 ml), then dried over sodium sulfate. The tosylate 17 was
purified by flash chromatography (eluent hexane, then ethyl
4.3.6. cis-2-[(3-(Trityloxymethyl)oxiran-2-ylmethyl]-1,2,3,4-
tetrahydroizoquinoline 7
Eluent for flash chromatography: hexane/ethyl acetate = 3/1;
oil, yield 89%. 1H NMR (CDCl3, 500 MHz) dH: 7.48–7.46 (6H, m,
aromatic H), 7.32–7.23 (9H, m, aromatic H), 7.10–7.08 (3H, m,
aromatic H), 6.97–6.95 (1H, m, aromatic H), 3.68 (1H, d, 15.0 Hz,
NCHaHbAr), 3.58 (1H, d, 15.0 Hz, NCHaHbAr) 3.41 (1H, dd, J = 17.5,
9.5 Hz, CHaHbOTr), 3.25 (2H, s, oxirane CH), 3.12 (1H, dd, J = 17.0,
7.5 Hz, CHaHbOTr), 2.76 (5H, m, 2 ꢁ CH2 piperidine and NCHaHb),
2.31 (1H, m, NCHaHb). 13C NMR (CDCl3, 75 MHz), dC: 142.7, 133.3,
132.9, 127.6, 126.9, 126.1, 125.5, 125.2, 124.6, 85.9, 61.0, 55.3,
55.2, 53.9, 53.1, 50.2, 27.9. IR (film) mmax (cmꢀ1): 3060, 3023,

1612
F. Faigl et al. / Tetrahedron: Asymmetry 23 (2012) 1607–1614
acetate) and isolated after evaporation of the solvent as a colour-
less oil (3.56 g, 81%).
J = 3.5 Hz, 9.5 Hz, CHaHbOTr), 2.85 (1H, m, CHaHbOTr), 2.70 (1H, t,
J = 7.0 Hz, CHaHbN), 2.50 (1H, m, (CH)2CHCH2), 2.29 (3H, s, CH3N).
13C NMR (CDCl3, 75 MHz), dC: 142.6, 140.7, 127.5, 127.3, 126.8,
126.3, 126.1, 85.7, 72.3, 71.3, 64.6, 53.4, 43.0, 41.9. IR (film) mmax
(cmꢀ1): 3154, 2930, 2778, 1449, 1068, 749, 699. MS (m/z): 450.2
([M+H]+), 243.1 (Ph3C+). HRMS C31H32NO2 ([M+H]+) requires:
450,2433, found 450,2424.
4.5.1. trans-3-Propyl-2-tosyloxymethyloxirane 17
1H NMR (CDCl3, 300 MHz) dH: 7.80 (2H, d, J = 8.1 Hz aromatic
H), 7.35 (2H, d, J = 8.1 Hz aromatic H), 4.18 (1H, dd, J = 11.4 Hz,
3.9 Hz, CHaHbOSO2), 3.98 (1H, dd, J = 11.4 Hz, 3.9 Hz, CHaHbOSO2),
2.95 (1H, m, oxirane CH), 2.79 (1H, m, oxirane CH), 2.45 (3H, s,
ArCH3), 1.55–1.38 (4H, m, CH2CH2), 0.93 (3H, t, J = 7.2 Hz,
CH2CH3). 13C NMR (CDCl3, 75 MHz), dC: 145.1, 132.8, 129.9,
128.0, 70.2, 56.6, 54.5, 33.3, 21.7, 19.1, 13.8. IR (film) mmax
(cmꢀ1): 2962, 2875, 1598, 1363, 1178, 962, 816, 666. MS (m/z):
271(M+H]+), 241, 198, 145. HRMS C13H19O4S (M+H]+) requires:
271.1004, found 271.1017
4.6.2. (+)-(10R,2R,3R)-3-(1-Hydroxy-2-trityloxyethyl)-2-phenyl-
1-methylazetidine (1’R,2R,3R)-10
The optically active form ((1’R,2R,3R)-10) of azetidine 10 was
prepared from (2R,3S)-3 using LiDA-KOR superbase as described
above. The product was obtained in 63% yield. ½a D25
¼ þ59:8 (c
ꢂ
3.1, CHCl3), ee 98.9% (HPLC, column: cellulose-2, eluent hexane/
ethanol = 93/7, 0.6 ml/min, UV detector 254 nm, retention times:
for (+)-10 10.55 min, for (ꢀ)-10 11.93 min.).
Compound 17 (6.66 mmol, 1.80 g) was dissolved in dry
dimethylformamide under a dry nitrogen atmosphere and then
potassium iodide (3.33 mmol, 0.55 g) was added to it. The solu-
tion was cooled to 0 °C and N-benzyl-N-methylamine (16.7 mmol,
2.01 g) was added to the solution. The reaction mixture was stir-
red for 5 days at room temperature, then poured into a mixture of
ice, saturated sodium hydrogencarbonate solution (200 ml) and
diethyl ether (50 ml), after which the phases were separated
and the aqueous mixture was extracted with diethyl ether
(3 ꢁ 50 ml). The ether solution was washed with brine (30 ml),
dried over sodium sulfate and concentrated in vacuo. The residue
was purified by flash chromatography (eluent hexane/ethyl ace-
tate in a gradient) in order to yield the product 14 as a yellowish
oil (1.62 g, 86%).
4.6.3. trans-1-Ethyl-2-phenyl-3-(1-hydroxy-2-trityloxyethyl)-
azetidine 11
The crude product was purified by column chromatography (sil-
ica gel, eluent hexane/ethyl acetate = 1/2), then it was recrystal-
lized from a hexane/diethyl ether mixture to yield compound 11
(62%), mp: 105–106 °C. 1H NMR (CDCl3, 500 MHz) dH: 7.35–7.17
(20H, m, aromatic H), 3.93 (1H, m, HOCH), 3.86 (1H, d, J = 8.0 Hz,
NCHPh), 3.39 (1H, t, J = 7.0 Hz, CHaHbN), 3.02 (1H, dd, J = 3.5 Hz,
9.5 Hz, CHaHbOTr), 2.90 (1H, m, CHaHbOTr), 2.58 (2H, m, CHaHbN
and CH3CHaHbN), 2.31 (2H, m, (CH)2CHCH2 and CH3CHaHbN), 0.86
(3H, t, J = 7.0 Hz, CH3CH2N). 13C NMR (CDCl3, 125 MHz), dC: 143.7,
143.1, 128.6, 128.2, 127.9, 127.0, 86.8, 72.8, 71.9, 65.7, 52.7, 52.4,
43.0, 12.7. IR mmax (cmꢀ1): 3027, 2925, 2833, 1489, 1447. MS (m/
z): 464 ([M+H]+), 317, 243 (Ph3C+), 142. HRMS C32H34NO2
([M+H]+) requires: 464.2590, found 464.2586.
4.5.2. trans-2-(N-Benzyl-N-methylaminomethyl)-3-propyloxi-
rane 14
1H NMR (CDCl3, 300 MHz) dH: 7.36–7.22 (5H, m, aromatic H),
3.63 (1H, d, J = 13.2 Hz, CHaHbPh), 3.50 (1H, d, J = 13.2 Hz,
CHaHbPh), 2.90–2.86 (1H, m), 2.71–2.64 (2H, m), 2.405 (1H, q,
J = 6.0 Hz) 2.30 (3H, s, CH3N), 1.56–1.38 (4H, m, CH2CH2), 0.95
(3H, t, J = 6.9 Hz, CH2CH3). 13C NMR (CDCl3, 300 MHz), dC: 138.7,
129.0, 128.2, 127.0, 62.6, 59.3, 57.0, 56.8, 42.9, 33.9, 19.3, 13.9. IR
(film) mmax (cmꢀ1): 3063, 3028, 2960, 2790, 1603, 1495, 1455,
1024, 907, 740, 699. MS (m/z): 220 ([M+H]+), 132. HRMS
4.6.4. trans-1-Benzyl-3-(1-hydroxy-2-trityloxyethyl)-2-phenyl-
azetidine 12
The crude product was purified by column chromatography
(Silica gel, eluent hexane/ethyl acetate = 3/1). The pure product
was recrystallized from hexane/diethyl ether mixture to yield com-
pound 12 (48%), mp: 121–122 °C. 1H NMR (CDCl3, 300 MHz) dH:
7.40–7.19 (25H, m, aromatic H), 4.06 (1H, d, J = 7.5 Hz, NCHPh),
3.93 (1H, m, HOCH), 3.79 (1H, d, J = 12.9 Hz, NCHaHbPh), 3.38
(1H, d, J = 12.9 Hz, NCHaHbPh), 3.27 (1H, t, NCHaHbPh), 3.00 (1H,
m, CHaHbOTr), 2.93 (1H, t, J = 4.5 Hz CHaHbOTr), 2.68 (1H, t,
J = 4.2 Hz NCHaHbPh), 2.42 (1H, m, (CH)2CHCH2). 13C NMR (CDCl3,
75 MHz), dC: 143.7, 142.6, 138.4, 128.8, 128.6, 128.2, 127.9,
127.2, 127.1, 126.9, 86.8, 72.8, 71.2, 65.7, 61.8, 52.6, 43.7. IR mmax
(cmꢀ1): 3059, 2943, 2825, 1489, 1447. MS (m/z): 526 ([M+H]+),
317, 243 (Ph3C+), 142. HRMS C37H36NO2 ([M+H]+) requires:
526.2746, found 526.2744.
C
14H22NO ([M+H]+) requires: 220.1701, found 220.1703.
4.6. General procedure for the preparation of azetidines
Potassium tert-butoxide (6.0 mmol, 0.67 g) was dissolved in dry
tetrahydrofuran (20 ml) then the solution was cooled down to
ꢀ75 °C and diizopropylamine (6.0 mmol, 0.61 g) followed by a
1.59 M hexane solution of butyllithium (9.0 mmol, 5.66 ml) were
added dropwise to the solution. The reaction mixture was stirred
for 20 min at ꢀ75 °C, then a tetrahydrofuran (20 ml) solution of
the oxirane 3–9 (3.0 mmol) was added and the mixture was stirred
at the same temperature for 2 hours. Water (20.0 ml) was then
added to the cold mixture after which it was allowed to warm
up to room temperature. The organic phase was separated and
the aqueous phase was extracted with diethyl ether (3 ꢁ 10 ml).
The collected organic solutions were washed with brine
(1 ꢁ 10 ml), dried over sodium sulfate and concentrated in vacuo.
The residue was purified by column chromatography.
4.6.5. trans-1-tert-Butoxycarbonyl-3-(1-hydroxy-2-trityloxy-
ethyl)-2-phenylazetidine 13
The crude product was purified by column chromatography
(Silica gel, eluent hexane/ethyl acetate = 4/1). The pure product
13 was obtained as an oil (40%). 1H NMR (CDCl3, 500 MHz) dH:
7.42–7.21 (20H, m, aromatic H), 5.06 (1H, d, J = 5.5 Hz, NCHPh),
4.00 (1H, s, HOCH), 3.88 (1H, t, J = 5.5 Hz, CHaHbN), 3.67 (1H, t,
J = 5.5 Hz, CHaHbN), 3.14 (1H, dd, J = 3.5 Hz, 9.5 Hz, CHaHbOTr),
3.01 (1H, t, J = 5.1 Hz CHaHbOTr), 2.40 (2H, m, (CH)2CHCH2 and
OH), 1.30 (9H, s, (CH3)3. 13C NMR (CDCl3, 75 MHz), dC (ppm):
156.54, 143.51, 141.78, 128.60, 128.55, 127.94, 127.23, 127.14,
125.95, 87.00, 79.55, 80.22, 65.28, 60.39, 41.63, 30.33, 28.42. IR
mmax (cmꢀ1): 3423, 3061, 3031, 2976, 1697, 1392, 1367, 1252,
1167, 1076, 900, 747, 700. MS (m/z): 536 ([M+H]+), 317, 243
(Ph3C+), 243, 165. HRMS C35H38NO4 ([M+H]+) requires: 536.2801,
found 536.2805.
4.6.1. trans-3-(1-Hydroxy-2-trityloxyethyl)-2-phenyl-1-methyl-
azetidine 10
The crude product was purified by column chromatography (sil-
ica gel, eluent hexane/ethyl acetate = 1/4). The pure product was
recrystallized from hexane/diethyl ether mixture to yield com-
pound 10 (75%), mp: 114–115 °C. 1H NMR (CDCl3, 500 MHz) dH:
7.35–7.21 (20H, m, aromatic H), 3.92 (1H, m, HOCH), 3.84 (1H, d,
J = 8.0 Hz, NCHPh), 3.28 (1H, t, J = 7.0 Hz, CHaHbN), 3.00 (1H, dd,

F. Faigl et al. / Tetrahedron: Asymmetry 23 (2012) 1607–1614
1613
4.6.6. trans-3-(1-Hydroxybutyl)-1-methyl-2-phenylazetidine 15
Potassium tert-butoxide (6.4 mmol, 0.72 g) was dissolved in dry
tetrahydrofuran (20 ml) after which the solution was cooled down
to ꢀ75 °C and diisopropylamine (6.4 mmol, 0.89 ml) followed by a
1.59 M hexane solution of butyllithium (9.6 mmol, 6.4 ml) were
added dropwise to the solution. The reaction mixture was stirred
for 20 min at ꢀ75 °C, then a tetrahydrofuran (5 ml) solution of 14
(3.2 mmol, 0.70 g) was added to it and the mixture was stirred at
the same temperature for 2 hours. Water (15 ml) was then added
to the cold mixture after which it was allowed to warm up to room
temperature. The organic phase was separated and the aqueous
phase was extracted with diethyl ether (5 ꢁ 15 ml) The collected
organic solutions were washed with distilled water (2 ꢁ 10 ml)
and brine (1 ꢁ 8 ml), dried over sodium sulfate and concentrated
in vacuo. The residue was purified by column chromatography
(eluent dichloromethane/methanol = 10/1) to yield pure 15 as an
oil (0.60 g, 86%). 1H NMR (CDCl3, 300 MHz) dH: 7.40–7.25 (5H, m,
aromatic H), 3.75 (1H, d, J = 8.1 Hz, NCHPh), 3.67 (1H, m, HOCH),
3.55 (1H, t, J = 6.6 Hz, CHaHbN), 2.83 (1H, dd, J = 8.7 Hz, 6.6 Hz,
CHaHbN), 2.55–2.44 (2H, m, CHCHPh, OH), 2.33 (3H, s, CH3N),
1.45–1.14 (4H, m, CH2CH2), 0.84 (3H, t, J = 6.6 Hz, CH2CH3). 13C
NMR (CDCl3, 75 MHz), dC: 141.7, 128.4, 128.5, 128.2, 72.8, 71.3,
54.4, 46.0, 44.2, 37.4, 18.6, 14.0. IR (film) mmax (cmꢀ1): 3394,
2958, 2871, 1494, 1454, 1146, 1068, 830, 750, 700. MS (m/z):
220 ([M+H]+), 159. HRMS C14H22NO ([M+H]+) requires: 220.1701,
found 220.1696.
143.7, 139.4, 128.6, 127.9, 127.1, 115.9, 86.8, 72.2, 72.2, 65.6,
54.8, 43.7, 41.0. IR (KBr) mmax (cmꢀ1): 3058, 2929, 1716, 1491,
1449, 1219, 1073, 765, 706, 632. MS (m/z): 400 ([M+H]+), 317,
243 (Ph3C+), 142. HRMS C27H30NO2 ([M+H]+) requires: 400.2277,
found 400.2290.
4.6.9. trans-1-Methyl-2-phenyl-3-[1-(trimethylsilyloxy)-2-(trity-
loxy)ethyl]azetidine 20
A
solution of 1-(1-methyl-2-phenylazetidin-3-yl)-2-(trityloxy)
ethanol 10 (1.00 g, 2.29 mmol) in THF (10 ml) was cooled down to
ꢀ75 °C under a nitrogen atmosphere, after which butyllithium in
hexane (2.10 ml, 3.34 mmol) was added to the mixture and stirred
for 30 minutes. After adding chlorotrimethylsilane (0.426 ml,
3.34 mmol), the reaction mixture was stirred for 60 minutes, then it
was warmed up to room temperature and stirred overnight. After-
wards it was diluted with diethyl ether (20 ml), distilled water
(20 ml) and saturated sodium hydrogen carbonate solution (20 ml)
and the two phases were separated. The aqueous phase was extracted
with diethyl ether (4 ꢁ 20 ml) and the combined ether extracts were
washed with brine (1 ꢁ 20 ml), then dried over sodium sulfate. After
evaporating the solvent, 1.21 g of crude product was obtained. This
was purified by column chromatography on florisil (eluent hexane/
ethyl acetate = 4:1) to give yellowish crystals of 20 (1.08 g, 93%), mp:
108–110 °C. 1H NMR (acetone-d6, 300 MHz) dH: 7.40–7.19 (20H, m,
aromatic H), 3.92 (1H, dd, J = 5.4 Hz, 11.4 Hz, HOCH), 3.79 (1H, d,
J = 6.9 Hz, NCHPh), 3.43 (1H, t, J = 6.0 Hz, CHaHbN), 3.03 (1H, dd,
J = 5.4 Hz, 9.6 Hz, CHaHbOTr), 2.90 (1H, dd, J = 6.0 Hz, 9.6 Hz, CHaH-
bOTr), 2.78–2.68 (2H, m, CHaHbN, (CH)2CHCH2), 2.22 (3H, s, CH3N),
0.04 (9H, s, Si(CH3)3). 13C NMR (acetone-d6, 75 MHz), dC: 146.0, 145.1,
130.5, 129.8, 129.6, 129.3, 128.8, 88.7, 74.1, 73.9, 68.4, 56.3, 45.9,
45.3, 1.6. IR (KBr) mmax (cmꢀ1): 3059, 2953, 2830, 1449, 1252, 1073,
876, 699. MS (m/z): 522 ([M+H]+), 243 (Ph3C+), 145. HRMS C34H40NO2Si
([M+H]+) requires: 522.2828, found 522.2826.
4.6.7. trans-1-(1-Hydroxy-2-trityloxyethyl)-2,4,5,9b-tetrahydro-
1H-azeto[2,1-a]izoquinoline 18
The crude product was purified by column chromatography (sil-
ica gel, eluent ethyl acetate). The pure product 13 was obtained as
an oil (25%). 1H NMR (CDCl3, 500 MHz) dH: 7.40–7.21 (15H, m, aro-
matic H), 7.11 (2H, m, aromatic H), 6.95 (2H, t, J = 7.0 Hz, aromatic
H), 4.42 (1H, d, J = 17.0 Hz), 3.79 (1H, d, J = 17.5 Hz), 3.59 (1H, m,
HOCH), 3.30 (1H, d, J = 2.5 Hz, NCHPh), 3.19 (2H, m), 3.07 (1H,
m), 2.96 (3H, m), 2.32 (1H, m, (CH)2CHCH2). 13C NMR (CDCl3,
75 MHz), dC: 143.7, 142.7, 130.7 128.6, 128.0, 127.3, 126.9, 126.8,
126.5, 126.4, 87.1, 71.8, 66.2, 58.7, 56.8, 54.5, 52. 8, 40.1. IR mmax
(cmꢀ1): 3352, 3058, 2924, 1710, 1596, 1490, 1449, 1073, 748,
707, 633. MS (m/z): 462 ([M+H]+), 317, 243 (Ph3C+), 142. HRMS
C32H32NO2 ([M+H]+) requires: 462.2433, found 462.2448.
4.7. Single crystal X-ray measurements
Crystal data of a single crystal of 20: colourless, block, size:
0.55 ꢁ 0.45 ꢁ 0.15 mm, triclinic, space group P ꢀ1, a = 11.6028(5) Å,
b = 13.6126(6) Å, c = 19.7452(11) Å,
a = 90.065(3)°, b = 90.128(3)°,
c
= 107.959(2)°, V = 2966.7(2) Å3, measured at T = 93(2) K, Z = 4,
F(000) = 1120, Dx = 1.168 Mg/m3,
l .
= 0.921 mmꢀ1
A crystal of 20 (CCDC 888073) was mounted on a loop. Cell
parameters were determined by least-squares using 19085
(6.73 6 h 6 71.63°) reflections. Intensity data were collected on a
Rigaku R-Axis RAPID diffractometer (graphite monochromator
4.6.8. trans-3-(1-Hydroxy-2-trityloxyethyl)-1-methyl-2-vinyl-
azetidine 19
Potassium tert-butoxide (1.45 mmol, 0.162 g) was dissolved in
dry tetrahydrofuran (3 ml) under a dry nitrogen atmosphere and
the solution was cooled down to ꢀ75 °C. A hexane solution of n-
butyllithium (1.59 M, 1.45 mmol, 0.86 ml) was added dropwise
and the reaction mixture was stirred for 20 min at ꢀ75 °C. At this
Cu-K
6.73 6 h 6 66.59.26 A total of 41907 reflections were collected of
which 8655 were unique [R(int) = 0.0590, R( ) = 0.0427]; intensi-
ties of 7199 reflections were greater than 2 (I). Completeness to
a radiation, k = 1.54187 Å) at 93(2) K in the range
r
r
temperature,
a
tetrahydrofuran solution (2 ml) of oxirane
6
h = 0.826. A numerical absorption correction was applied to the
data (the minimum and maximum transmission factors were
0.612 and 0.848). The structure was solved by direct methods27
(and subsequent difference syntheses). Anisotropic full-matrix
least-squares refinement27 on F2 for all non-hydrogen atoms
(0.36 mmol, 0.140 g) was added and the solution was stirred for
2 h at ꢀ75 °C, followed by the addition of distilled water (3 ml).
The intensively stirred mixture was allowed to warm up to room
temperature and the phases were separated. The aqueous phase
was extracted with diethyl ether (3 ꢁ 5 ml), and the organic solu-
tions were collected and washed with water (2 ꢁ 3 ml) and brine
(3 ml), and dried over sodium sulfate. The solvent was evaporated
in vacuo and the residue was purified by column chromatography
(silica gel, eluent ethyl acetate, then acetone). Pure product 15 was
obtained as an oil (0.060 g, 42%). 1H NMR (CDCl3, 500 MHz) dH:
7.39–7.21 (15H, m, aromatic H), 5.92 (1H, m, vinyl CH), 5.06 (1H,
dd, J = 10.5 Hz, J = 6.0 Hz, vinyl CH2), 5.04 (1H, dd, J = 10.5 Hz,
J = 6.0 Hz, vinyl CH2), 3.85 (1H, m, HOCH), 3.70 (1H, t, J = 8.0 Hz,
NCH-vinyl), 3.60 (1H, t, J = 8.0 Hz, CHaHbN), 3.02 (2H, m, CHaHbOTr
and CHaHbN), 2.94 (1H, t, J = 8.0 Hz, CHaHbOTr), 2.62 (1H, m,
(CH)2CHCH2), 2.36 (3H, s, CH3N). 13C NMR (CDCl3, 125 MHz), dC:
yielded R1 = 0.0515 and wR2 = 0.1217 for 1332 [I>2
r(I)] and
R1 = 0.0624 and wR2 = 0.1380 for all (8655) intensity data, (number
of parameters = 702, goodness-of-fit = 1.188, the maximum and
mean shift/esd is 0.000 and 0.000). The maximum and minimum
residual electron density in the final difference map was 0.297
and ꢀ0.338e Åꢀ3
.
The weighting scheme applied was w ¼
2
1=½r2ðF2oÞ þ ð0:0436PÞ þ 2:3879Pꢂ where P ¼ ðFo2 þ 2F2c Þ=3.
Hydrogen atomic positions were calculated from assumed
geometries. Hydrogen atoms were included in structure factor cal-
culations but were not refined. The isotropic displacement param-
eters of the hydrogen atoms were approximated from the U(eq)
value of the atom they were bonded to. CCDC 888073 contains

1614
F. Faigl et al. / Tetrahedron: Asymmetry 23 (2012) 1607–1614
8. Lee, Y. H.; Kim, H. H.; Thuéry, P.; Harrowfield, J. M.; Lim, W. T.; Kim, B. J.; Kim, Y.
J. Inclusion Phenom. Macrocyclic Chem. 2009, 65, 65–71.
9. Lee, D.-H.; Lee, Y. H.; Kim, D. I.; Kim, Y.; Lim, W. T.; Harrowfield, J. M.; Thuéry,
P.; Kim, M.-J.; Park, Y. C.; Lee, I.-M. Tetrahedron 2008, 64, 7178–7182.
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the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgment
The work is connected to the scientific program of the ‘Develop-
ment of quality-oriented and harmonized R+D+I strategy and func-
tional model at BME’ project in the framework of the New Hungary
Development Plan. (TÁMOP-4.2.1/B-09/1/KMR-2010–0002) and to
the ‘Synthesis of new chiral heterocycles using polar organometal-
lics’ project in the framework of the bilateral cooperation agree-
ment of CNR (Firenze) and MTA (Budapest) 2010–2012.
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Simándi, B. Tetrahedron: Asymmetry 2005, 16, 3841–3847.
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