Addition reactions to chiral aziridine-2-carboxaldimine toward various enantiopure nitrogen-containing heterocycles

Article abstract of DOI:10.1016/j.tet.2005.07.064

Chiral (2R,1′R)-(1′-phenylethyl)aziridine-2-carboxaldimine was utilized as a nitrogen-containing starting substrate for the preparation of various enantiopure nitrogen-containing heterocycles. The additions of nucleophiles including organomagnesium reagen

Full text of DOI:10.1016/j.tet.2005.07.064

Tetrahedron 61 (2005) 9281–9290
Addition reactions to chiral aziridine-2-carboxaldimine toward
various enantiopure nitrogen-containing heterocycles
c
Heui-Yoon Noh,a Sang-Woo Kim,a,b Seong In Paek,a Hyun-Joon Ha,a,b, Hoseop Yun
*
and Won Koo Leed,
*
aDepartment of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-719, South Korea
bCenter for Bioactive Molecular Hybrids, Yonsei University, Seoul 120-749, South Korea
cDepartment of Molecular Science and Technology, Ajou University, Suwon, 442-749, South Korea
dDepartment of Chemistry, Interdisciplinary Program of Integrated Biotechnology, Sogang University, Seoul 121-742, South Korea
Received 26 May 2005; revised 20 July 2005; accepted 20 July 2005
Available online 10 August 2005
Abstract—Chiral (2R,10R)-(10-phenylethyl)aziridine-2-carboxaldimine was utilized as a nitrogen-containing starting substrate for the
preparation of various enantiopure nitrogen-containing heterocycles. The additions of nucleophiles including organomagnesium reagents,
cyanotrimethylsilane and ketene acetal to the chiral (2R,10R)-(10-phenylethyl)aziridine-2-carboxaldimine proceeded in highly stereoselective
manner via chelation controlled transition states. Subsequent treatment of adducts with triphosgene and NaH yielded 5-substituted-4-
chloromethylimidazolidin-2-ones. This imine was also served as either aza-diene or aza-dienophile with olefin or diene to provide hetero-
Diels–Alder adducts 2-aziridinylpiperidines or 1,2,3,4-tetrahydroquinolines.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
governing the stereochemical pathways of the addition
reactions.
Commercial success to produce both enantiomers of
aziridine-2-carboxylates in optically pure forms enables us
to provide enantiomerically pure a- or b-amino ester and
their derivatives.1,2 We would like to extend their synthetic
utilities for the construction of enantiopure diamine
compounds based on the reaction of the substrate aziridin-
2-carboxaldimine that is readily available from aziridine-2-
carboxylate. The additions to the chiral (20R,100R)-(4-
methoxyphenyl){[1-(100-phenylethyl)aziridin-20-yl]methyl-
ene}amine (1) would afford amino alkyl aziridines (2 and
3), 2-aziridinylpiperidines (4) and 1,2,3,4-tetrahydroquino-
lines (5) via many different reaction pathways including
nucleophilic additions and Diels–Alder reactions shown in
Scheme 1. The subsequent chemical transformations of
aziridine ring of the adduct by the known methods1 can
afford various enantiopure nitrogen-containing cyclic and
acyclic molecules.
2. Results and discussion
(20R,100R)-(4-Methoxyphenyl){[1-(100-phenylethyl)aziridin-
20-yl]methylene}amine (1) was prepared from the conden-
sation of (2R,10R)-(10-phenylethyl)aziridine-2-carboxalde-
hyde and p-anisidine. p-Methoxyphenyl moiety is readily
removed to give free amine after the reaction with
cerium(IV) ammonium nitrate.3 Nucleophilic addition to
imines4 is a useful synthetic route toward the amines with
expectation of certain degree of stereoselectivity. Addition
of organometallic compounds including MeMgBr and MeLi
without any additive did not provide the addition product
even at room temperature for 15 h and all the starting imine
was recovered unreacted. This suggests that the starting
imine is not reactive enough toward alkyl metal compounds
whose reactivity can be increased by the addition of a
suitable Lewis acid. Among all tested Lewis acids
BF3$OEt2 was the best to promote the reactivity without
breaking the aziridine ring. The best result was obtained
with the addition of four equivalents of MeMgBr at K10 8C
with BF3$OEt2 to give the methylated product 2a in 86%
yield5 (entry 5). Lower temperatures or smaller amounts of
MeMgBr resulted in either no reaction or lower yield
Throughout the study we had an insight into the transition
state conformation with better understanding the factors
Keywords: Aziridine-2-carboxaldimine; Addition; Nucleophiles; Hetero-
Diels–Alder reaction.
*
Corresponding authors. Tel.: C 82 31 3304369; fax: C82 31 3304566
(H.-J.H.); tel.: C82 705 8449 (W.K.L.); e-mail addresses:
hjha@hufs.ac.kr; wonkoo@sogang.ac.kr
2
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.064

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H.-Y. Noh et al. / Tetrahedron 61 (2005) 9281–9290
Scheme 1.
(entries 1–4). Addition of MeLi provided a slightly lower
yield (76%, entry 6). The addition of a methyl group
proceeded in a completely stereoselective manner to give a
single isomer judging from H NMR and HPLC regardless
of the source of the organometallic reagents.
carboxaldimine, was inert without any additives. However,
reaction with cyanotrimethylsilane in CH2Cl2 with 50 mol%
of BF3$OEt2 at room temperature for 3 h yielded the
products 3a and 3a0 as a diastereomeric mixture with
the ratio of 69:31 in 91% yield with threo isomer 3a as the
major product (entry 1). Trials to improve the diastereo-
selectivity by changing Lewis acids such as ZnCl2,
Sc(OTf)3, Ti(Oi-Pr)4, TMSTf, CeCl3 were not successful
to show similar stereoselectivity in a little lower yield.
When we used CsF that is known to be a good catalyst7c in
the addition of imine, the reaction showed a little better ratio
of 78:22 in 85% yield (entry 2). It is also noteworthy that the
reaction with TMSCl as an additive gave products 3a and
3a0 with the ratio of 45:55 in 62% yield (entry 3).
1
Under the same reaction conditions were added various
alkyl and arylmagnesium reagents (Table 1). Ethyl
magnesium bromide gave 2b in a similar yield (82%) in a
completely stereoselective manner (entry 7). This was
further tested by addition of vinyl magnesium bromide
resulting 2c in 71% yield with diastereoselectivity of 97:3
based on 1H NMR integration (entry 8). Much lower
stereoselectivity was observed in the addition of allyl- and
n-butylmagnesium bromide with diastereoselectivities of
62:38 (2d and 2d0) and 91:9 (2e and 2e0), even though the
reaction yields were 82 and 72%, respectively (entries 9 and
10). Changing the alkylating agent to n-butyllithium form
n-butylmagnesium bromide showed lower selectivity of
84:16 in 63% yield (entry 11). Addition of aryl magnesium
reagents such as PhMgBr, p-tolyl-MgBr, p-FPhMgBr was
completely stereoselective to give products 2f, 2g, and 2h in
75, 68, and 71% yields, respectively (entries 12–14).
Another nucleophile ketene silyl acetal (7)8 was added to
(2R,10R)-(10-phenylethyl)aziridine-2-carboxaldimine (1) in
the presence of 50 mol% of BF3$OEt2 to afford b-amino-
carboxylated 3b as a single isomer with aziridine ring
conserved in 87% yield (entry 4).
All of adducts aminomethylaziridines 2 and 3 were
converted to other cyclic or acyclic dinitrogen containing
compounds by the known methods.1 We wished to convert
them to the valuable enantiopure 4,5-disubstituted imida-
zolin-2-ones, some of which have important biological
activities.9 This was achieved with triphosgene and NaH to
give 5-alkyl or 5-aryl-4-chloromethylimidazolidin-2-one
(9) in good yield (Scheme 2 and Table 3).10 The reaction
The utility of imines can be expanded by the addition of
nucleophile other than organometallic reagents as shown in
Table 2.6 The addition of nitrile to imine as in Strecker
reaction was studied using cyanotrimethylsilane (6).7 The
substrate we used, (2R,10R)-(10-phenylethyl)aziridine-2-
Table 1. The addition of organometallic reagents to chiral (20R,100R)-(4-methoxyphenyl){[1-(100-phenylethyl)aziridin-20-yl]methylene}amine (1)
Entries
Reagents
Equiv
Temperature
(8C)
Time (h)
Yield
Product
Ratio
1
2
3
4
5
6
7
8
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeLi
2
2
4
2
4
4
4
4
4
4
4
3
3
3
K78
K10
K78
K10
K10
K78
K10
K10
K10
K10
K10
K10
K10
K10
10
10
4
3
3
5
4
3
3
3
3
3
3
No rxn
40 (60)
45 (55)
65 (10)
86
76
82
71
82
72
63
75
68
2a
2a
2a
2a
O99:!1
O99:!1
O99:!1
O99:!1
O99:!1
97:3
62:38
91:9
84:16
EtMgBr
2b
2c, 2c0
2d, 2d0
2e, 2e0
2e, 2e0
2f
VinylMgBr
AllylMgBr
n-BuMgBr
n-BuLi
PhMgBr
p-TolylMgBr
p-FPhMgBr
9
10
11
12
13
14
O99:!1
O99:!1
O99:!1
2g
2h
3
71
All reactions were carried out in the presence of 1 mol equiv of BF3$OEt2. Isolated yield. Determined by 1H NMR.

H.-Y. Noh et al. / Tetrahedron 61 (2005) 9281–9290
9283
Table 2. The addition of nucleophiles to chiral (20R,100R)-(4-methoxyphenyl){[1-(100-phenylethyl)aziridin-20-yl]methylene}amine
Entry
Nucleophile
Lewis acida
Products (% yield, ratio)b,c
1
TMSCN (6)
BF3$OEt2
3a0
3a
(91%, 69:31)
(85%, 78:22)
(62%, 45:55)
2
3
TMSCN (6)
TMSCN (6)
CsF
TMSCI
4
5
BF3$OEt2
BF3$OEt2
7
8
3b
3c0
3c
(81%, 71:29)
a Lewis acid (0.5 mol equiv) was added.
b Yields were not optimized.
1
c The ratio was determined by H NMR spectrum.
proceeded smoothly with the formation of the aziridium ion
intermediate shown in the bracket of Scheme 2 that was
known from our early observations. All of the alkyl or aryl
addition products (2a–2h) yielded the corresponding
chloromethylimidazolidin-2-ones (9a–9h) in high yields
between 97 and 71% yields regardless of the stereochem-
istry as either threo or erythro. This reaction also worked
with other addition products 3a, 3a0, and 3b to afford
chloromethylimidazolidin-2-ones 10a, 10a0, and 10b in 75,
82, and 67% yields, respectively. These transformations
from aminomethylaziridine (2 or 3) to 4-chloromethyl-
imidazolidin-2-one (9) provide a useful tool to determine
the initial stereochemical outcomes of the original adducts 2
or 3 with nucleophlies whether they are threo or erythro.
The stereochemistry of the addition product 2a (R1ZMe,
R2ZH) was identified after its conversion to 5-methyl-4-
chloromethylimidazolidin-2-one (9a) by treatment with
triphosgene and NaH in THF. The coupling constant of
the two adjacent imidazolidinone ring protons at C-4 and
C-5 was measured to be 3.2 Hz (entry 1), which corresponds
to trans-relationship. This implies that methyl addition
occurred from re-face via a chelation controlled transition
state. The stereochemistry of the initial addition products 2b
Scheme 2.
Table 3. Preparation of 5-alkyl or 5-aryl-4-chloromethylimidazolidin-2-one (9) from the reactions of the corresponding 2-aminomethylaziridine (2 and 3) with
triphosgene and NaH
Entry
Substrate
R1
R2
Product
Yield (%)a
J (Hz)b
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2d0
2e
2e0
2f
2g
2h
3a
3a0
3b
Me
Et
Vinyl
Allyl
H
n-Bu
H
Ph
Tolyl
p-FPh
CN
H
CMe2CO2Me
H
H
H
H
Allyl
H
n-Bu
H
H
H
9a
9b
9c
94
91
87
79
71
96
83
97
92
89
75
82
67
3.2
3.0
3.4
2.6
6.4
3.2
6.6
3.0
3.2
2.6
3.0
7.1
3.4
9d
9d0
9e
9e0
9f
9
9g
9h
10a
10a0
10b
10
11
12
13
H
CN
H
a All reactions were carried out at K78 8C for 2 h.
b Coupling constants of the imidazoline ring protons at C-4 and C-5.

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H.-Y. Noh et al. / Tetrahedron 61 (2005) 9281–9290
and 2c were identified as threo by judging the coupling
constants of the two imidazolidinone ring protons at C-4 and
C-5 of 9b and 9c as 3.0 and 3.4 Hz, respectively (entries 2
and 3). The stereochemistry of all major products 2d, 2e, 2f,
2g and 2h were confirmed to be threo from the observed
coupling constants of 2.6–3.2 Hz corresponding to trans
relationship of two neighboring imidazolidinone ring
protons of compounds 9d, 9e, 9f, 9g, 9h 0(entries 4, 6, 8, 9,
and 10). The minor erythro isomers 2d and 2e0 isolated
from the addition of allyl- and n-butylMgBr were converted
by the same method to cis-5-chloromethylimidazolidin-2-
ones 9d0 and 9e0 whose coupling constants between two ring
protons at C-4 and C-5 were 6.4 and 6.6 Hz, respectively
(entries 5 and 7). The initial adduct of nitrile to imine was
obtained as inseparable diastreomeric mixture of 3a and 3a0,
which were also converted to 5-chloromethylimidazolidin-
2-ones 10a and 10a0 at which stage two diastereomers were
separated by column chromatography. The similar stereo-
chemical relationship was observed from the coupling
constants between two protons at C-4 and C-5 as 3.0 Hz for
the major isomer and 7.1 Hz for the minor isomer,
respectively (entries 11 and 12). The single isomer 10b
showed 3.4 Hz of coupling constant to indicate that the
original adduct of ketene acetal 3b was threo as expected.
intramolecular cyclization.11 The same reaction product
can be formed from aza-Diels–Alder reaction between the
imine (1) and 3-methoxytrimethylsilyloxybutadiene (8) as
an aza-dienophile and a diene, respectively.12 This
prompted us to expand the utility of the imine substrate
(100R,20R)-(4-methoxyphenyl){[1-(100-phenylethyl)aziridin-
20-yl]methylene}amine (1) for aza-Diels–Alder reactions
with a different diene to provide 2-aziridinylpiperidines 4
(Schemes 1 and 3). Addition of 2-trimethylsilyloxybuta-
diene (11) to the imine in the presence of 50 mol%
BF3$OEt2 yielded cycloadducts as an inseparable mixture.
Those adducts were subsequently treated with n-Bu4F to
remove TMS to afford separable adducts 4a, 4b, and 5a. The
ratio of two diasteromers 4a and 4b was 83:17 in 48% yield
while unexpected product 5a also obtained in 32% yield as a
single stereoisomer. Formation of 4-oxopiperidines (4a and
4b) can be explained by aza-Diels–Alder reactions between
the imine (1) and 2-trimethylsilyloxybutadiene (11) in the
same manner as observed in the formation of the ring
compound in entry 5 of the Table 2, followed by
desilylation. However, formation of 1,2,3,4-tetrahydro-
quinolines (5) bearing aziridine ring at C-2 indicates that
the imine substrate can perform as an azadiene with an
electron rich olefin in a reverse electron demand aza-Diels–
Alder reaction.12,13 Reactions with electron rich olefins such
as 2,3-dimethyl-1,3-butadiene (12) and bis-1,2-trimethyl-
silyloxycyclobutene (13) afforded 1,2,3,4-tetrahydroquino-
lines 5b and 5c in 62 and 68% yields, respectively
(Scheme 3). Even though 1,2,3,4-tetrahydroquinoline 5b
was obtained as a single stereoisomer, the absolute
stereochemistry of newly formed C–C bonds could not be
identified. Fortunately adduct 5c coming from the reaction
with bis-1,2-trimethylsilyloxycyclobutene was obtained as a
single crystal whose structure was fully identified by X-ray
crystallography as shown in Figure 1.14 The configuration of
C-2 of 1,2,3,4-tetrahydroquinoline in 5c showed R, which
The success of the addition of ketene silyl acetal 7 in entry 4
of the Table 2 prompted us to expand the reaction with
another electron rich nucleophile 3-methoxytrimethylsilyl-
oxybutadiene (8) known as the Danishefsky diene. The
reaction with the additive, 50 mol% BF3$OEt2, was
successful to give 4-oxopiperidines (3c and 3c0) as a
diastereomeric mixture with the ratio of 71:29 in 81% yields
(entry 5 of Table 2). Formation of cyclic adducts
4-oxopiperidines would be explained by the addition of
3-methoxytrimethylsilyloxybutadiene (8) as a nucleophile
to the imine like Mannich-type reaction followed by
Scheme 3.

H.-Y. Noh et al. / Tetrahedron 61 (2005) 9281–9290
9285
structure of dicyano[[(1R)-(1-phenylethyl)-aziridin-2-
yl]methanolato-O,N]boron (15) shown in Figure 2.17 This
crystalline structure features that there is a quite strong
chelation between boron and nitrogen without altering the
aziridine ring conformation. Therefore, we assume that the
transition state conformation of the addition reaction is quite
similar to the structure 15 and is rigid enough for the coming
nucleophile or olefin to approach from the re-face more
favorably.
The same stereochemical pathway was observed during the
reduction of 2-acylaziridine with NaBH4 and ZnCl2 in
methanol. High stereoselectivity was observed from the
tight binding between the nitrogen of aziridine ring and the
carbonyl oxygen by ZnC2 metal.18
In conclusion, the enantiomerically pure (20R,100R)-(4-
methoxyphenyl){[1-(100-phenylethyl)aziridin-20-yl]methyl-
ene}amine plays a multi-role substrate for the reactions with
nucleophiles, dienes and olefins to yield aminomethyl-
aziridines, 2-aziridinylpiperidines and 1,2,3,4-tetrahydro-
quinolines, respectively. High stereoselectivity was
observed throughout these addition reactions via a chelation
controlled transition state with re-face preference.
Figure 1.
came from the same facial selectivity as in the nucleophilic
addition reactions for the preparation of 2 and 3 in the
Scheme 1. This draws a conclusion that initial bond
formation on the imine carbon and the coming counterpart
approaches from re-face via a chelation controlled transition
state. All of these successful reactions informed us that
(20R,100R)-(4-methoxyphenyl){[1-(100-phenylethyl)aziridin-
20-yl]methylene}amine (1) may have dual role as an
azadiene and also an azadienophile in the reactions with
proper dienophiles and dienes to yield either 2-aziridinyl-
piperidines (4) or 1,2,3,4-tetrahydroquinolines (5).
3. Experimental
3.1. General methods
1H and 13C NMR spectra were recorded on a Varian 200 or
500 (300 or 500 MHz for 1H and 50.3 or 125.7 MHz for 13C).
Chemical shifts were given in ppm using TMS as an
internal standard. Mass spectra were obtained using a
Hewlett Packard Model 5985B spectrometer or a Kratos
Concept 1-S double focusing mass spectrometer. Elemental
analysis was taken on a Perkin-Elmer 240 DS elemental
analyzer. Melting point was measured by Mel-II capillary
melting point apparatus. Optical rotation was measured with
Rudolph Research Autopole 3 polarimeter. The silica gel
used for column chromatography was Merck 230–400
mesh. Thin-layer chromatography was carried out with
Merck 60F-254 plates with 0.25 mm thickness.
All of the addition reactions to (2R,10R)-(10-phenylethyl)
aziridine-2-carboxaldimine with various nucleophiles,
dienes and dienophiles yielded threo products with
chelation controlled transition state that is quite general
for the addition reaction of alkyl metal reagents to a,b-
epoxyimine without any additives.15 However, in the
presence of BF3$OEt2 as a Lewis acid non-chelation
controled product was dominant on the addition reaction
of alkyl Grignard to a,b-epoxyimine.15a,16 We have learned
that the same addition reaction of a,b-aziridinylimine (1)
led chelation controlled product. Because the Lewis acid
BF3$OEt2 we used in the reactions has dual roles, that is,
activating the imine and chelating the two nitrogens of the
substrate as shown in 14 of Figure 2. Therefore, the
transition state becomes quite rigid and the coming
nucleophile attacks the substrate from re-face more
favorably than from si-face. The rigidity of the transition
state is supported by the observation of the strong binding
between boron and aziridine ring nitrogen in a single crystal
3.1.1. (20R,100R)-(4-Methoxyphenyl){[1-(1000-phenylethyl)
aziridin-20-yl]methylene}amine (1). (2R,1 R)-(10-phenyl-
ethyl)aziridine-2-carboxaldehyde (175 mg, 1 mmol) in
5 mL CH2Cl2 was added dropwise into p-anisidine solution
(123 mg, 1 mmol) in 20 mL CH2Cl2 with anhydrous MgSO4
(1.20 g, 10 mmol). This solution was stirred for 5 h at room
temperature until all the starting material was consumed.
The reaction mixture was filtered and the filtrate was
evaporated under reduced pressure. The product was
purified by recrystallization from EtOH to give 272 mg of
product in 97% yield. This product should be kept under dry
condition not for longer than a week.
Yellowish solid. Mp 68–69 8C. 1H NMR (200 MHz, CDCl3)
d 1.46 (d, JZ6.2 Hz, 3H), 1.73 (d, JZ6.6 Hz, 1H), 1.92 (d,
JZ1.8 Hz, 1H), 2.48–2.52 (m, 1H), 2.56 (q, JZ6.2 Hz, 1H),
3.79 (s, 3H), 6.84–7.13 (m, 4H), 7.24–7.43 (m, 6H). 13C
NMR (50.3 MHz, CDCl3) d 23.0, 33.4, 42.8, 55.4, 69.7,
Figure 2. The possible transition state (14) to lead the major isomer of the
nucleophilic addition from re-face to (2R,10R)-(10-phenylethyl)aziridine-2-
carboxaldimine and the X-ray structure (15) of dicyano[[(1R)-(1-
phenylethyl)-aziridin-2-yl]methanolato-O,N]boron.

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H.-Y. Noh et al. / Tetrahedron 61 (2005) 9281–9290
114.2, 122.0, 126.7, 127.2, 128.4, 143.8, 143.9, 159.2, 162.9.
HRMS (EI) calcd for C18H20N2O: 280.1576, found 280.1572.
114.5, 114.7, 115.7, 126.7, 126.9, 128.2, 138.7, 141.7,
144.4, 151.8. HRMS (EI) calcd for C21H26N2O: 322.2045,
found 322.2038.
3.2. General procedure for addition reactions of alkyl or
aryl magnesium bromide
3.2.5. (1S,20R,100R)-(4-Methoxyphenyl){1-[10-(100-phenyl-
ethyl)aziridin-20-yl]but-3-enyl}amine (2d0). Liquid. [a]D
40.1 (c 3.0 in EtOAc); 1H NMR (200 MHz, CDCl3) d 1.30–
1.41 (m, 1H), 1.65 (d, JZ6.6 Hz, 3H), 1.68–1.72 (m, 2H),
2.35–2.40 (m, 3H), 3.30 (q, JZ6.6 Hz, 1H), 3.72 (s, 3H),
5.15 (d, JZ10 Hz, 1H), 5.18 (d, JZ16 Hz, 1H), 5.80–6.01
(m, 1H), 6.61–6.79 (m, 4H), 7.21–7.40 (m, 5H). 13C NMR
(50.3 MHz, CDCl3) d 14.1, 23.5, 30.5, 34.3, 42.5, 53.6, 55.7,
69.4, 114.6, 114.7, 117.3, 126.7, 126.8, 128.2, 135.4, 142.2,
144.6, 151.7. HRMS (EI) calcd for C21H26N2O: 322.2045,
found 322.2044.
Into the solution of (20R,100R)-(4-methoxyphenyl){[1-(100-
phenylethyl)aziridin-20-yl]methylene}amine (1, 280 mg,
1 mmol) in 10 mL of ethyl ether was added ethereal
solution of alkyl or aryl magnesium bromide (3 mmol)
and BF3$OEt2 (0.15 mL, 1.0 mmol). The resultant solution
was stirred under K10 8C for the completion before the
reaction was quenched by adding ice-water. The reaction
product was isolated with ethyl ether (15 mL!4). The
ethereal solution was washed with brine twice. The organic
layer was dried over anhydrous MgSO4, filtered and
concentrated under reduced pressure. Purification by silica
gel flash column chromatography provided the analytically
pure addition product.
3.2.6. (1R,20R,100R)-(4-Methoxyphenyl){1-[10-(100-phenyl-
ethyl)aziridin-20-yl]pentyl}amine (2e). Viscous oil. 1H
NMR (200 MHz, CDCl3) d 0.79 (t, JZ7.0 Hz, 3H), 1.09–
1.42 (m, 7H), 1.27 (d, JZ6.6 Hz, 3H), 1.43–1.68 (m, 2H),
2.33 (q, JZ6.6 Hz, 1H), 3.12 (q, JZ6.4 Hz, 1H), 3.64 (s,
3H), 6.50–6.80 (m, 4H), 7.15–7.30 (m, 5H). 13C NMR
(50.3 MHz, CDCl3) d 14.1, 22.8, 23.5, 28.6, 32.2, 33.8, 44.1,
53.7, 55.9, 69.4, 114.3, 114.7, 126.7, 126.8, 128.2, 142.7,
144.7, 151.4. HRMS (EI) calcd for C22H30N2O: 338.2358,
found 338.2364.
3.2.1. (1R,20R,100R)-(4-Methoxyphenyl){1-[10-(100-phenyl-
ethyl)aziridin-20-yl]ethyl}amine (2a). Liquid. [a]D 33.5 (c
2.0 in EtOAc); 1H NMR (200 MHz, CDCl3) d 1.14 (d, JZ
4.2 Hz, 3H), 1.28 (d, JZ6.2 Hz, 3H), 1.24–1.62 (m, 2H),
2.36 (q, JZ6.6 Hz, 1H), 3.32–3.41 (m, 1H), 3.40 (q, JZ
6.8 Hz, 1H), 3.63 (s, 3H), 6.52–6.71 (m, 4H), 7.14–7.31 (m,
5H). 13C NMR (50.3 MHz, CDCl3) d 19.5, 23.49, 30.37,
44.2, 48.9, 55.6, 69.3, 114.6, 114.6, 126.6, 126.7, 128.1,
141.8, 144.8, 151.6. HRMS (EI) calcd for C19H24N2O:
296.1889, found 296.1883. Anal. Calcd for C19H24N2O: C,
77.0; H, 8.16; N, 9.45. Found: C, 76.8; H, 8.09; N, 9.42.
3.2.7. (1S,20R,100R)-(4-Methoxyphenyl){1-[10-(100-phenyl-
ethyl)aziridin-20-yl]pentyl}amine (2e0). Viscous oil. 1H
NMR (200 MHz, CDCl3) d 0.78 (t, JZ7.0 Hz, 3H), 1.08–
1.45 (m, 7H), 1.26 (d, JZ6.6 Hz, 3H), 1.50–1.72 (m, 2H),
2.36 (q, JZ6.6 Hz, 1H), 3.12–3.21 (m, 1H), 3.64 (s, 3H),
6.48–6.68 (m, 4H), 7.16–7.25 (m, 5H). 13C NMR
(50.3 MHz, CDCl3) d 14.1, 22.8, 23.3, 28.0, 32.6, 33.0,
44.0, 53.7, 55.8, 69.7, 114.7, 114.9, 126.7, 126.9, 128.2,
142.1, 144.4, 151.8. HRMS (EI) calcd for C22H30N2O:
338.2358, found 338.2360.
3.2.2. (1R,20R,100R)-(4-Methoxyphenyl){1-[10-(100-phenyl-
ethyl)aziridin-20-yl]propyl}amine (2b). Liquid. [a]D 70.0
(c 0.2 in EtOAc); 1H NMR (200 MHz, CDCl3) d 1.06 (t, JZ
7.2 Hz, 3H), 1.19 (d, JZ5.8 Hz 1H), 1.38 (d, JZ6.6 Hz,
3H), 1.51–1.68 (m, 4H), 2.45 (q, JZ6.6 Hz, 1H), 3.17 (td,
JZ6.6 Hz, 3.4 Hz, 1H), 3.72 (s, 3H), 6.61–6.78 (m, 4H),
7.24–7.41 (m, 5H). 13C NMR (50.3 MHz, CDCl3) d 10.8,
23.4, 27.4, 30.4, 42.7, 55.3, 55.6, 69.3, 114.3, 114.6, 126.6,
126.7, 128.1, 142.6, 144.6, 151.4. HRMS (EI) calcd for
C20H26N2O: 310.2045, found 310.2042.
3.2.8. (1R,20R,100R)-(4-Methoxyphenyl){1-[10-(100-phenyl-
ethyl)aziridin-20-yl]-1-[phenyl]methyl}amine
(2f).
1
Liquid. [a]D 18.9 (c 3.0 in EtOAc); H NMR (200 MHz,
CDCl3) d 1.08 (d, JZ6.8 Hz, 3H), 1.19 (d, JZ6.2 Hz, 1H),
1.66–1.78 (m, 2H), 2.25 (q, JZ6.6 Hz, 1H), 3.55 (s, 3H),
4.04–4.08 (m, 1H), 6.35–6.57 (m, 4H), 7.10–7.33 (m, 10H).
13C NMR (50.3 MHz, CDCl3) d 23.6, 31.5, 45.4, 55.6, 58.9,
69.1, 114.6, 114.8, 126.5, 126.7, 127.0, 127.1, 128.3, 128.5,
141.5, 142.8, 144.3, 151.7. HRMS (EI) calcd for
C24H26N2O: 358.2045, found 358.2049.
3.2.3. (1R,20R,100R)-(4-Methoxyphenyl){1-[10-(100-phenyl-
ethyl)aziridin-20-yl]prop-2-enyl}amine (2c). Liquid. [a]D
34.5 (c 0.5 in EtOAc); 1H NMR (200 MHz, CDCl3) d 1.21–
1.25 (m, 1H), 1.38 (d, JZ6.6 Hz, 3H), 1.58–1.71 (m, 2H),
2.42 (q, JZ6.6 Hz, 1H), 3.70 (s, 3H), 3.2–3.76 (m, 1H), 5.20
(d, JZ9 Hz, 1H), 5.26 (d, JZ16 Hz, 1H), 5.81 (ddd, JZ
16.0, 9.0, 6.0 Hz, 1H), 6.56–6.79 (m, 4H), 7.16–7.41 (m,
5H). 13C NMR (50.3 MHz, CDCl3) d 23.6, 30.3, 37.3, 42.8,
56.5, 69.0, 114.5, 114.7, 115.6, 126.6, 126.8, 128.1, 134.8,
141.5, 144.4, 151.7. HRMS (EI) calcd for C20H24N2O:
308.1889, found 308.1892.
3.2.9. (1R,20R,100R)-(4-Methoxyphenyl){1-[10-(100-phenyl-
ethyl)aziridin-20-yl]-1-[p-tolyl]methyl}amine
(2g).
1
Liquid. [a]D 5.3 (c 5.0 in EtOAc); H NMR (200 MHz,
CDCl3) d 1.23–1.29 (m, 4H), 1.82–1.94 (m, 2H), 2.26 (s,
3H), 2.28–2.41 (m, H), 3.59 (s, 3H), 4.08 (bs, 1H), 6.45–
6.66 (m, 4H), 7.05–7.33 (m, 9H). 13C NMR (50.3 MHz,
CDCl3) d 20.9, 23.5, 31.4, 45.5, 55.4, 58.8, 69.0, 114.4,
114.8, 126.6, 126.8, 128.1, 129.1, 136.5, 138.5, 139.5,
140.5, 141.5, 144.1, 151.6. HRMS (EI) calcd for
C25H28N2O: 372.2202, found 372.2204.
3.2.4. (1R,20R,100R)-(4-Methoxyphenyl){1-[10-(100-phenyl-
ethyl)aziridin-20-yl]but-3-enyl}amine (2d). Liquid. [a]D
2.98 (c 3.0 in EtOAc); 1H NMR (200 MHz, CDCl3) d 1.29–
1.33 (m, 1H), 1.41 (d, JZ6.6 Hz, 3H), 1.61–1.77 (m, 2H),
2.38–2.54 (m, 3H), 3.14 (q, JZ6.6 Hz, 1H), 3.72 (s, 3H),
5.16 (d, JZ10 Hz, 1H), 5.18 (d, JZ16 Hz, 1H), 5.80–6.10
(m, 1H), 6.57–6.76 (m, 4H), 7.24–7.33 (m, 5H). 13C NMR
(50.3 MHz, CDCl3) d 14.1, 23.4, 32.7, 42.1, 55.5, 56.7, 68.0,
3.2.10.
(1R,20R,100R)-(4-Methoxyphenyl){1-[10-(100-
phenylethyl)aziridin-20-yl]-1-[p-fluorophenyl]methyl}-
amine (2h). Liquid. [a]D 30.8 (c 2.0 in EtOAc); H NMR
1

H.-Y. Noh et al. / Tetrahedron 61 (2005) 9281–9290
9287
1
(200 MHz, CDCl3) d 1.12 (d, JZ6.6 Hz, 3H), 1.23 (d, JZ
6.4 Hz, 1H), 1.71–1.80 (m, 2H), 2.33 (q, JZ6.6 Hz, 1H),
3.59 (s, 3H), 4.11 (d, JZ4.4 Hz, 1H), 6.36–6.62 (m, 4H),
6.90–7.34 (m, 9H). 13C NMR (50.3 MHz, CDCl3) d 23.6,
31.3, 45.2, 55.6, 58.0, 69.0, 114.6, 114.8, 115.2, 115.6,
126.7, 127.0, 127.9, 128.0, 128.2, 128.3, 138.4, 138.5,
141.2, 144.2, 151.8, 159.5, 164.3. HRMS (EI) calcd for
C24H25FN2O: 376.1951, found 376.1948.
one (3c0). Liquid. H NMR (200 MHz, CDCl3) d 1.23 (d,
JZ6.5 Hz, 3H), 1.47 (d, JZ6.5 Hz, 1H), 1.62 (d, JZ
3.0 Hz, 1H), 2.37–2.46 (m, 2H), 3.02 (dd, JZ16.5, 6.0 Hz,
1H), 3.59 (t, JZ7.5 Hz, 1H), 3.83 (s, 3H), 4.12 (q, JZ
6.5 Hz, 1H), 5.28 (dd, JZ6.5, 1.0 Hz, 1H), 6.94 (d, JZ
9.0 Hz, 2H), 7.26–7.30 (m, 1H), 7.33–7.38 (m, 4H), 7.45
(dd, JZ7.0, 1.5 Hz, 1H), 7.59 (d, JZ8.5 Hz, 2H). 13C NMR
(50.3 MHz, CDCl3) d 23.7, 32.3, 39.1, 39.3, 55.8, 63.2, 70.1,
102.0, 114.6, 121.6, 126.9, 127.4, 128.6, 138.4, 144.3,
147.5, 156.9, 191.3. HRMS (EI) calcd for C22H24N2O2:
348.1838, found 348.1840.
3.3. General Procedure for the preparation of 3
To a solution of (200R,100R)-(4-methoxyphenyl){[1-(100-
phenylethyl)aziridin-2 -yl]methylene}amine (1, 414 mg,
1.48 mmol) in 20 mL of CH2Cl2 under nitrogen atmosphere
was added the nucleophile (1.48 mmol) at K10 8C. The
mixture was stirred at room temperature for 2–3 h until the
reaction was completed. Then the reaction was quenched by
adding water at 0 8C and warmed to room temperature. The
aqueous layer was extracted with CH2Cl2 (15 mL!5). The
combined extracts was dried over anhydrous MgSO4 and the
solvent was evaporated to give the crude product, which was
purified by silica gel flash chromatography to obtain
analytically pure product.
3.4. General procedure for 5-alkyl or 5-aryl-4-chloro-
methylimidazolidin-2-one (9 and 10)
To a solution of (20R,100R)-(4-methoxyphenyl){[1-(100-
phenylethyl)aziridin-20-yl]alkyl}amine (2 or 3, 310 mg,
1.05 mmol) in 15 mL of THF under nitrogen atmosphere
was added NaH (144 mg, 6 mmol) at K10 8C. The mixture
was stirred for 1 h at K10 8C. To the mixture was slowly
added triphosgene solution (0.356 g, 1.2 mmol) in THF
(5 mL) at K10 8C. The mixture was stirred for 2 h at
K10 8C. The reaction was quenched with water at K10 8C
and warmed to room temperature. The aqueous layer was
extracted with CH2Cl2 (10 mL!5). The combined organic
extracts was dried over MgSO4 and the solvent was
evaporated in vacuo to give the crude product as a white
solid, which was purified by silica gel flash chromatography
to give analytically pure product.
3.3.1. (2R,20R,100R)-2-(p-Methoxyphenylamino)-2-[10-
(100-phenylethyl)aziridin-20-yl]acetonitrile (3a). Liquid.
1H NMR (200 MHz, CDCl3) d 1.39–1.49 (m, 1H), 1.47
(d, JZ6.6 Hz, 3H), 1.90 (d, JZ4.0 Hz, 1H), 2.09 (dd, JZ
5.8, 2.2 Hz, 1H), 2.55 (d, JZ6.6 Hz, 1H), 3.70 (s, 3H), 4.29
(q, JZ6.6 Hz, 1H), 6.60–6.87 (m, 4H), 7.18–7.32 (m, 5H).
13C NMR (50.3 MHz, CDCl3) d 23.6, 29.7, 39.2, 46.6, 55.6,
68.8, 114.9, 115.9, 119.0, 126.7, 127.3, 128.4, 138.3, 143.6,
153.6. HRMS (EI) calcd for C19H21N3O: 307.1685, found
307.1691.
3.4.1. (4S,5R,10R)-4-Chloromethyl-1-(4-methoxyphenyl)-
5-methyl-3-(10-phenylethyl)imidazolidin-2-one (9a).
1
Liquid. H NMR (200 MHz, CDCl3) d 0.82 (d, JZ6.2 Hz,
3H), 1.50 (d, JZ7.4 Hz, 3H), 2.92 (dt, JZ7.0, 3.2 Hz, 1H),
3.32 (dd, JZ11.4, 7.6 Hz, 1H), 3.42 (dd, JZ11.4, 3.2 Hz,
1H), 3.65 (s, 3H), 3.90 (qd, JZ6.2, 3.2 Hz, 1H), 5.25 (q, JZ
7.4 Hz, 1H), 6.72–6.78 (m, 2H), 7.11–7.27 (m, 7H). 13C
NMR (50.3 MHz, CDCl3) d 18.7, 19.4, 45.5, 51.2, 54.6,
55.4, 58.8, 114.1, 123.1, 127.3, 127.7, 128.6, 131.4, 139.8,
156.2, 156.8. HRMS (EI) calcd for C20H23ClN2O2:
358.1448, found 358.1453.
3.3.2. (3R,20R,100R)-2,2-Dimethyl-3-(4-methoxyphenyl-
amino)-3-[10-(100-phenylethyl)aziridin-20-yl]propionic
acid methyl ester (3b). Liquid. 1H NMR (200 MHz,
CDCl3) d 1.07 (d, JZ6.2 Hz, 1H), 1.31 (s, 9H), 1.43 (d,
JZ2.4 Hz, 1H), 1.58–1.62 (m, 1H), 2.47 (q, JZ6.6 Hz, 1H),
3.38 (s, 1H), 3.59 (s, 3H), 3.64 (s, 3H), 3.98 (s, 1H), 6.63–
6.73 (m, 4H), 7.14–7.26 (m, 5H). 13C NMR (50.3 MHz,
CDCl3) d 21.6, 22.9, 30.2, 40.2, 47.4, 51.4, 55.2, 61.6, 69.0,
114.3, 114.4, 126.6, 128.0, 143.2, 144.2, 151.5, 177.0.
HRMS (EI) calcd for C23H30N2O3: 382.2256, found
382.2251.
3.4.2. (4S,5R,10R)-4-Chloromethyl-5-ethyl-1-(4-methoxy-
phenyl)-3-(10-phenylethyl)imidazolidin-2-one (9b).
1
Liquid. H NMR (200 MHz, CDCl3) d 0.45 (t, vZ6.6 Hz,
3H), 1.01–1.53 (m, 2H), 1.50 (d, JZ6.2 Hz, 3H), 3.05 (q,
JZ2.8 Hz, 1H), 3.29–3.55 (m, 2H), 3.63 (s, 3H), 3.78 (dt,
JZ7.8, 3.0 Hz, 1H), 5.23 (q, JZ6.6 Hz, 1H), 6.61–6.76 (m,
2H), 7.11–7.27 (m, 7H). 13C NMR (50.3 MHz, CDCl3) d
7.61, 18.7, 24.6, 46.1, 51.4, 55.3, 55.6, 59.4, 114.0, 123.2,
127.3, 127.7, 128.5, 131.4, 139.6, 156.1, 156.8. HRMS (EI)
calcd for C21H25ClN2O2: 372.1605, found 372.1594.
3.3.3. (2R,20R,100R)-1-(4-Methoxyphenyl)-2-[10-(100-
phenylethyl)aziridin-20-yl]-2,3-dihydro-1H-pyridin-4-
one (3c). Liquid. 1H NMR (500 MHz, CDCl3) d 1.28 (d, JZ
6.5 Hz, 1H), 1.36 (d, JZ3.5 Hz, 1H), 1.44 (d, JZ6.5 Hz,
3H), 2.00–2.04 (m, 1H), 2.41 (q, JZ6.5 Hz, 1H), 2.84 (dd,
JZ16.5, 2.5 Hz, 1H), 3.05 (dd, JZ16.5, 7.0 Hz, 1H), 3.62
(td, JZ7.0, 2.5 Hz, 1H), 3.80 (s, 3H), 5.21 (d, JZ8.0 Hz,
1H), 6.87 (d, JZ7.0 Hz, 2H), 7.11 (d, JZ9.0 Hz, 2H), 7.21–
7.23 (m, 1H), 7.26–7.30 (m, 5H). 13C NMR (125.7 MHz,
CDCl3) d 23.5, 34.1, 38.5, 39.7, 55.7, 62.6, 69.5, 100.8,
114.8, 124.0, 126.8, 127.2, 128.5, 138.5, 144.2, 149.8,
157.8, 191.1. HRMS (EI) calcd for C22H24N2O2: 348.1838,
found 348.1834.
3.4.3. (4S,5R,10R)-4-Chloromethyl-1-(4-methoxyphenyl)-
3-(10-phenylethyl)-5-vinylimidazolidin-2-one
(9c).
1
Liquid. H NMR (200 MHz, CDCl3) d 1.59 (d, JZ7.4 Hz,
3H), 3.11 (td, JZ4.4, 3.4 Hz, 1H), 3.45 (d, JZ4.4 Hz, 3H),
3.70 (s, 3H), 4.31 (dd, JZ6.0, 3.4 Hz, 1H), 5.01 (d, JZ
8.2 Hz, 1H), 5.15 (d, JZ18.0 Hz, 1H), 5.21–5.45 (m, 1H),
6.76–6.81 (m, 2H), 7.18–7.35 (m, 7H). 13C NMR
(50.3 MHz, CDCl3) d 18.5, 45.1, 51.3, 55.3, 58.0, 61.0,
113.9, 118.3, 122.3, 127.3, 127.7, 128.6, 132.1, 135.8,
3.3.4.
phenylethyl)aziridin-20-yl]-2,3-dihydro-1H-pyridin-4-
(2S,20R,100R)-1-(4-Methoxyphenyl)-2-[10-(100-

9288
H.-Y. Noh et al. / Tetrahedron 61 (2005) 9281–9290
139.4, 155.9, 157.1. HRMS (EI) calcd for C21H23ClN2O2:
370.1448, found 370.1441.
20.9, 45.4, 51.5, 55.2, 60.9, 62.0, 113.8, 121.8, 125.8, 127.1,
127.6, 128.5, 129.4, 132.1, 136.9, 137.7, 139.4, 155.6,
157.3. HRMS (EI) calcd for C26H27ClN2O2: 434.1761,
found 434.1762.
3.4.4. (4S,5R,10R)-5-Allyl-4-chloromethyl-1-(4-methoxy-
phenyl)-3-(10-phenylethyl)imidazolidin-2-one (9d).
1
Liquid. H NMR (200 MHz, CDCl3) d 1.51 (d, JZ7.0 Hz,
3.4.10. (4S,5R,10R)-4-Chloromethyl-5-(4-fluorophenyl)-
1-(4-methoxyphenyl)-3-(10-phenylethyl)imidazolidin-2-
one (9h). Liquid. 1H NMR (200 MHz, CDCl3) d 1.57 (d, JZ
7.8 Hz, 3H), 3.19–3.34 (m, 1H), 3.59 (s, 3H), 3.64 (d, JZ
3.4 Hz, 2H), 4.83 (d, JZ2.6 Hz, 1H), 5.32 (q, JZ7.4 Hz,
1H), 6.58–6.88 (m, 4H), 6.89–7.21 (m, 9H). 13C NMR
(50.3 MHz, CDCl3) d 18.6, 45.5, 51.6, 56.9, 60.7, 61.7,
114.0, 115.5, 121.7, 126.9, 127.1, 127.4, 127.6, 128.1,
128.6, 128.8, 135.7, 138.2, 139.5, 155.8, 157.9. HRMS (EI)
calcd for C25H24ClFN2O2: 438.1510, found 438.1513.
3H), 2.47 (d, JZ7.2 Hz, 2H), 3.47–3.71 (m, 3H), 3.76 (s,
3H), 4.12 (dt, JZ7.2, 2.6 Hz, 1H), 4.93–5.02 (m, 2H), 5.38
(q, JZ7.0 Hz, 1H), 5.50–5.57 (m, 1H), 6.85 (d, JZ8.8 Hz,
2H), 7.20–7.31 (m, 7H). 13C NMR (50.3 MHz, CDCl3) d
18.4, 31.1, 41.8, 50.7, 55.4, 55.6, 56.7, 114.1, 118.0, 125.1,
127.3, 127.6, 128.7, 130.9, 133.4, 139.1, 156.8, 158.7.
HRMS (EI) calcd for C22H25ClN2O2: 384.1605, found
384.1603.
3.4.5. (4S,5S,10R)-5-Allyl-4-chloromethyl-1-(4-methoxy-
phenyl)-3-(10-phenylethyl)imidazolidin-2-one (9d0).
3.4.11. (4S,5S,10R)-4-Chloromethyl-5-cyano-3-(4-meth-
1
oxyphenyl)-1-(10-phenylethyl)imidazolidin-2-one (10a).
Liquid. H NMR (200 MHz, CDCl3) d 1.52 (d, JZ7.4 Hz,
1
3H), 1.60–1.75 (m, 1H), 2.02–2.09 (m, 1H), 3.10–3.13 (m,
1H), 3.35–3.41 (m, 2H), 3.37 (s, 3H), 3.85 (dt, JZ6.4,
3.4 Hz, 1H), 4.52 (d, JZ17.0 Hz, 1H), 4.78 (d, JZ8.4 Hz,
1H), 5.16–5.33 (m, 2H), 6.77 (d, JZ8.8 Hz, 2H), 7.11–7.27
(m, 7H). 13C NMR (50.3 MHz, CDCl3) d 18.7, 36.5, 45.9,
51.4, 55.1, 55.4, 58.0, 114.2, 119.5, 123.5, 127.5, 127.8,
128.6, 131.2, 131.5, 139.7, 156.3, 156.8. HRMS (EI) calcd
for C22H25ClN2O2: 384.1605, found 384.1611.
Liquid. H NMR (200 MHz, CDCl3) d 1.50 (d, JZ7.0 Hz,
3H), 3.28–3.40 (m, 1H), 3.51–3.63 (m, 2H), 3.61 (s, 3H),
4.50 (d, JZ3.0 Hz, 1H), 5.17 (q, JZ7.0 Hz, 1H), 6.78 (d,
JZ8.8 Hz, 4H), 7.10–7.30 (m, 5H). 13C NMR (50.3 MHz,
CDCl3) d 18.4, 44.4, 49.9, 51.7, 55.2, 56.3, 114.3, 116.4,
124.0, 127.1, 128.1, 128.7, 129.5, 138.2, 155.6, 157.5. Anal.
Calcd HRMS (EI) calcd for C20H20ClN3O2: 369.1244,
found 369.1241.
3.4.6. (4S,5R,10R)-5-n-Butyl-4-chloromethyl-1-(4-meth-
3.4.12. (40S,50R,100R)-2-[40-Chloromethyl-10-(4-methoxy-
phenyl)-2-oxo-3- (100-phenylethyl)imidazolidin-50-yl]-2,
2-dimethylpropionate acid methyl ester (10b). Liquid.
1H NMR (200 MHz, CDCl3) d 0.74 (s, 3H), 0.82 (s, 3H),
1.58 (d, JZ7.2 Hz, 3H), 3.10–3.19 (m, 1H), 3.12 (s, 3H),
3.45 (dd, JZ11.0, 1.8 Hz, 1H), 3.55 (dd, JZ11.0, 4.2 Hz,
1H), 3.65 (s, 3H), 4.27 (d, JZ2.2 Hz, 1H), 5.13 (q, JZ
7.2 Hz, 1H), 6.75 (d, JZ8.8 Hz, 2H), 7.20–7.34 (m, 7H).
13C NMR (50.3 MHz, CDCl3) d 18.6, 19.9, 20.1, 46.2, 47.9,
51.3, 52.1, 54.2, 55.0, 63.6, 113.5, 126.7, 127.4, 127.7,
128.4, 131.4, 139.0, 157.1, 157.2, 175.3. HRMS (EI) calcd
for C24H29ClN2O4: 444.1816, found 444.1823.
oxyphenyl)-3-(10-phenylethyl)imidazolidin-2-one (9e).
1
Liquid. H NMR (200 MHz, CDCl3) d 0.47 (t, JZ7.0 Hz,
3H), 0.65–1.13 (m, 4H), 1.35–1.45 (m, 2H), 1.38 (d, JZ
6.4 Hz, 3H), 3.09 (dt, JZ7.4, 3.2 Hz, 1H), 3.28–3.47 (m,
2H), 3.61 (s, 3H), 3.69–3.77 (m, 1H), 5.15 (q, JZ6.4 Hz,
1H), 6.69–6.73 (m, 2H), 7.05–7.19 (m, 7H). HRMS (EI)
calcd for C23H29ClN2O2: 400.1918, found 400.1916.
3.4.7. (4S,5S,10R)-5-n-Butyl-4-chloromethyl-1-(4-meth-
oxyphenyl)-3-(10-phenylethyl)imidazolidin-2-one (9e0).
1
Liquid. H NMR (200 MHz, CDCl3) d 0.44 (t, JZ7.0 Hz,
3H), 0.78–1.20 (m, 4H), 1.46–1.49 (m, 2H), 1.49 (d, JZ
6.4 Hz, 3H), 3.06 (td, JZ7.0, 6.6 Hz, 1H), 3.25–3.52 (m,
2H), 3.65 (s, 3H), 3.71–3.82 (m, 1H), 5.16 (q, JZ6.4 Hz,
1H), 6.71–6.78 (m, 2H), 7.11–7.27 (m, 7H). HRMS (EI)
calcd for C23H29ClN2O2: 400.1918, found 400.1921.
3.5. Cycloaddition reaction with 2-trimethylsilyloxy-1,3-
butadiene (4a, 4b and 5a)
Into the solution of (20R,100R)-(4-methoxyphenyl){[1-(100-
phenylethyl)aziridin-20-yl]methylene}amine (1, 280 mg,
1.0 mmol) in 10 mL of CH2Cl2 were added 2-trimethyl-
silyloxy-1,3-butadiene (11, 142 mg, 1.0 mmol) and
BF3$OEt2 (56 mg, 0.4 mmol) at room temperature. The
resultant solution was stirred for 0.5 h until all the starting
material was consumed. Then the reaction was quenched by
adding water. The reaction product was isolated with
CH2Cl2 (20 mL!4). The solution was washed with brine
twice. The organic layer was dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure. The
residue was dissolved in 10 mL THF. Into this solution
was added ethereal solution n-Bu4NF (4 mmol). The
reaction mixture was stirred for 30 min and quenched by
adding water. The organic layer was treated in the standard
protocol. The crude reaction mixture was obtained after
removal of solvent under reduced pressure. Careful
chromatographic separation and purification yielded the
analytically pure products 4a (137 mg), 4b (21 mg) and 5a
(13 mg).
3.4.8. (4S,5R,10R)-4-Chloromethyl-1-(4-methoxyphenyl)-
5-phenyl-3-(10-phenylethyl)imidazolidin-2-one (9f).
1
Liquid. H NMR (200 MHz, CDCl3) d 1.58 (d, JZ7.0 Hz,
3H), 3.21–3.27 (m, 1H), 3.50–3.64 (m, 1H), 3.64 (s, 3H),
4.85 (d, JZ3.0 Hz, 2H), 5.33 (q, JZ7.0 Hz, 1H), 6.66–7.00
(m, 4H), 7.12–7.27 (m, 10H). 13C NMR (50.3 MHz, CDCl3)
d 18.6, 45.5, 51.5, 55.3, 60.8, 62.2, 113.9, 121.7, 125.8,
127.1, 128.0, 128.2, 128.8, 129.4, 132.1, 139.4, 139.9,
155.6, 157.3. HRMS (EI) calcd for C25H25ClN2O2:
420.1605, found 420.1602.
3.4.9. (4S,5R,10R)-4-Chloromethyl-1-(4-methoxyphenyl)-
5-(4-methylphenyl)-3-(10-phenylethyl)imidazolidin-2-
one (9g). Liquid. 1H NMR (200 MHz, CDCl3) d 1.57 (d, JZ
6.6 Hz, 3H), 2.18 (s, 3H), 3.21–3.26 (m, 1H), 3.48 (d, JZ
4.4 Hz, 2H), 3.61 (s, 3H), 4.80 (d, JZ3.2 Hz, 1H), 5.32 (q,
JZ7.4 Hz, 1H), 6.67 (d, JZ8.6 Hz, 2H), 6.86–6.95 (m, 4H),
7.13–7.25 (m, 7H). 13C NMR (50.3 MHz, CDCl3) d 18.6,

H.-Y. Noh et al. / Tetrahedron 61 (2005) 9281–9290
9289
3.5.1. 1-4-Methoxyphenyl)-2-[10-(100-phenylethyl)aziri-
3.5.5. (2aR,3S,8bS,20R,100R)-7-Methoxy-3-[10-(100-phenyl-
ethyl)aziridin-20-yl]-2a,8b-bistrimethylsilyloxy-1,2,2a,3,
4,8b-hexahydrocyclobuta[c]quinoline (5c0)0. The starting
imine (200R,100R)-(4-methoxyphenyl){[1-(1 -phenylethyl)-
aziridin-2 -yl]methylene}amine (1, 350 mg, 1.25 mmol)
was dissolved in 15 mL of CH2Cl2 and then were added
bis-1,2-trimethylsilyloxycyclobutene (13, 290 mg,
1.25 mmol) and BF3$OEt2 (71 mg, 0.5 mmol) at K78 8C.
The resultant solution was stirred for 2 h at K78 8C. After
the reaction was completed according to TLC the reaction
was quenched by adding saturated NaHCO3 solution. The
reaction product was isolated with CH2Cl2 (15 mL!4),
which was washed with brine twice. The organic layer was
dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. Analytically pure product 433 mg
was obtained after flash column chromatography in 68%
yield.
din-20-yl]piperidin-4-one, major isomer (4a). Viscous
liquid. [a]D 3.85 (c 1.5 in EtOAc); H NMR (200 MHz,
1
CDCl3) d 1.23 (d, JZ6.2 Hz, 3H), 1.37–1.84 (m, 3H), 2.45–
2.87 (m, 5H), 3.34–3.97 (m, 3H), 3.76 (s, 3H), 6.81–7.02
(m, 4H), 7.21–7.30 (m, 5H). 13C NMR (50.3 MHz, CDCl3)
d 23.4, 33.9, 40.8, 41.2, 44.9, 47.4, 55.6, 63.8, 69.8, 114.4,
121.1, 126.8, 127.2, 128.4, 143.7, 144.3, 154.9, 208.9.
HRMS (EI) calcd for C22H26N2O2: 350.1994, found
350.1991.
3.5.2. 1-4-Methoxyphenyl)-2-[10-(100-phenylethyl)aziri-
din-20-yl]piperidin-4-one, minor isomer (4b). Viscous
liquid. [a]D 9.40 (c 5 in EtOAc); 1H NMR (200 MHz,
CDCl3) d 1.43 (d, JZ6.2 Hz, 3H), 1.27–1.84 (m, 3H), 2.39–
2.98 (m, 5H), 3.21–3.77 (m, 3H), 3.87 (s, 3H), 6.76–7.48
(m, 9H). 13C NMR (50.3 MHz, CDCl3) d 23.3, 31.4, 40.5,
41.6, 42.8, 44.9, 55.8, 59.1, 69.9, 114.7, 117.7, 126.9, 127.1,
128.4, 143.9, 144.5, 153.4, 209.4. HRMS (EI) calcd for
C22H26N2O2: 350.1994, found 350.1208.
White soild. Mp 140–141 8C. [a]D K2.30 (c 3.0 in EtOAc);
1H NMR (200 MHz, CDCl3) d 0.12–0.31 (s, 18H), 1.29 (d,
JZ4.2 Hz, 3H), 1.50 (d, JZ6.2 Hz, 2H), 1.72 (d, JZ
3.6 Hz, 1H), 1.88–2.16 (m, 4H), 2.33 (q, JZ6.6 Hz, 1H),
3.81 (s, 3H), 6.57 (d, JZ8.8 Hz, 1H), 6.72 (dd, JZ8.8 Hz,
2.1 Hz, 1H), 6.95 (d, JZ3.0 Hz, 1H), 7.24–7.37 (m, 5H).
13C NMR (50.3 MHz, CDCl3) d 2.39, 2.94, 23.6, 24.2, 34.7,
36.9, 40.9, 55.7, 59.7, 69.5, 74.7, 83.9, 112.9, 115.1, 116.8,
126.1, 127.1, 128.5, 131.0, 135.6, 144.5, 152.8. HRMS (EI)
calcd for C28H41N2O3Si2: 509.2656, found 509.2651. Anal.
Calcd for C28H41N2O3Si2: C, 66.0; H, 8.11; N, 5.49. Found:
C, 66.2; H, 8.03; N, 5.52.
3.5.3. 6-Methoxy-2-[10-(100-phenylethyl)aziridin-20-yl]-4-
trimethylsilanyloxy-4-vinyl-1,2,3,4-tetrahydroquinoline
(5a). Gummy liquid. [a]D 2.55 (c 1.0 in EtOAc); H NMR
1
(200 MHz, CDCl3) d 0.07 (s, 9H), 1.27 (d, JZ6.8 Hz, 3H),
1.31–1.87 (m, 4H), 1.57 (dd, 2H), 2.51 (q, JZ6.6 Hz, 1H),
3.57–3.83 (m, 2H), 3.75 (s, 3H), 5.30 (dd, JZ7.8, 1.8 Hz,
1H), 5.56 (dd, JZ15.2, 1.8 Hz, 1H), 6.06 (dd, JZ15.2,
7.8 Hz, 1H), 6.97–6.83 (m, 3H), 7.28–7.46 (m, 5H). 13C
NMR (50.3 MHz, CDCl3) d 1.93, 2.01, 23.6, 29.8, 41.6,
43.0, 47.8, 56.0, 56.1, 69.6, 74.0, 113.4, 114.9, 115.2, 116.5,
122.7, 126.9, 127.2, 128.5, 128.6, 139.1, 144.1, 144.8,
150.7. HRMS (EI) calcd for C25H34N2O2Si: 422.2390,
found 422.2383.
Acknowledgements
We gratefully acknowledge the financial supports from the
Korea Science and Engineering Foundation (Program
through the Center for Bioactive Molecular Hybrids and
R01-2000-000-00048-0 to H. J. H. and R14-2002-045-
01002-0 to W. K. L.), HUFS grant (2005 to H. J. H.), and the
Korea Research Foundation (KRF-2002-070-C00060 to
W. K. L.).
3.5.4. 6-Methoxy-4-methyl-4-(1-methylethenyl)-2-[10-
(100-phenylethyl)aziridin-20-yl]-1,2,3,4-tetrahydroquino-
line (5b). The starting imine (20R,100R)-(4-methoxy-
phenyl){[1-(100-phenylethyl)aziridin-20-yl]methylene}-
amine (1, 403 mg, 1.35 mmol) was dissolved in 10 mL of
CH2Cl2 and then were added excess amount of 2,3-
dimethyl-1,3-butadiene (12, 123 mg, 1.50 mmol) and
BF3$OEt2 (85 mg, 0.6 mmol) at 0 8C. T he resultant solution
was stirred for 2 h at room temperature. After the reaction
was completed according to TLC the reaction was quenched
by adding saturated NaHCO3 solution. The reaction product
was isolated with CH2Cl2 (15 mL!4), which was washed
with brine twice. The organic layer was dried over
anhydrous MgSO4, filtered and concentrated under reduced
pressure. Product was further purified by flash column
chromatography to afford the titled products 224 mg as a
diastereomeric mixture in 49% yield.
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1
Gummy liquid. H NMR (200 MHz, CDCl3) d 1.15–1.83
(m, 5H), 1.28 (s, 3H), 1.89–2.12 (m, 2H), 2.52 (q, JZ
6.7 Hz, 1H), 2.95 (tq, JZ6.7, 3.4 Hz, 1H), 3.74 (s, 3H),
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