Highly Stereoselective Addition of Organomagnesium Reagents to Aziridinyl-2-carboxaldimine: Preparation of Enantiopure 2-Aminomethylaziridines and 4,5-Disubstituted Imidazolidin-2-ones

Article abstract of DOI:10.1055/s-2004-815444

The addition of alkyl- and arylmagnesium reagents to chiral [1′(R)-α-methylbenzyl]aziridine-2(R)-carboxaldimines was carried out in a highly stereoselective manner to give 2-aminomethylaziridine. Further treatment of 2-aminomethylaziridines with triphosge

Full text of DOI:10.1055/s-2004-815444

LETTER
489
Highly Stereoselective Addition of Organomagnesium Reagents to Aziridinyl-
2-carboxaldimine: Preparation of Enantiopure 2-Aminomethylaziridines and
4,5-Disubstituted Imidazolidin-2-ones
A
ddition of Organoma
a
gnesiumto
n
Aziridinyl-2
-
-carboxa
J
ldimine in Suh,a Sang Woo Kim,a,b Seong In Beak,a Hyun-Joon Ha,*a,b Won Koo Lee*c
a
Department of Chemistry, Hankuk University of Foreign Studies, Yongin, Kyunggi-Do 449-719, Korea
Fax +82(31)3304566; E-mail: hjha@hufs.ac.kr
b
c
Center for Bioactive Molecular Hybrids, Yonsei University, Seoul 120-749, Korea
Department of Chemistry, Sogang University, Seoul 121-742, Korea
Fax +82(2)7010967.; E-mail: +wonkoo@sogang.ac.kr
Received 3 December 2003
Dedicated to Professor Dong H. Kim on the occasion of his 70th birthday.
alkyl- or arylmetallic reagents to aziridinyl-2-carboxald-
imine5 will give us a better understanding of the transition
state and the role of coordination on the reaction of aziri-
dine compounds. The addition products extend the utility
Abstract: The addition of alkyl- and arylmagnesium reagents to
chiral [1¢(R)-a-methylbenzyl]aziridine-2(R)-carboxaldimines was
carried out in a highly stereoselective manner to give 2-aminometh-
ylaziridine. Further treatment of 2-aminomethylaziridines with
triphosgene and NaH afforded enantiopure 5-alkyl- or 5-aryl-4- scope of aziridines for the synthesis of diamine deriva-
tives.6 Thereby, we studied the addition reactions of orga-
chloromethylimidazolidin-2-ones.
nometallic reagents to chiral (p-methoxyphenyl)-{[1¢(R)-
a-methylbenzyl]aziridin-2(R)-ylmethylene}amine to af-
ford 2-aminomethylaziridines. The adducts were convert-
ed to the orthogonally protected enantiopure 4,5-
disubstituted imidazolindin-2-ones
Key words: stereoselectivity, addition reactions, organometallic
reagents, aziridines, imines
Aziridine is a unique nitrogen containing three membered
cyclic molecule with ring strain that prompts ring opening
reactions with various nucleophiles.1 This provides a fac-
ile route to nitrogen containing acyclic compounds. We
have studied chiral aziridine-2-carboxylates for many
years as a means of producing enantiomerically pure a- or
b-amino ester and their derivatives.2 The study includes
the addition reaction of alkylmetal compounds to aziridi-
nyl-2-carboxaldehyde to provide enantiomerically pure
hydroxylamine compounds. Diastereoselectivity of the
addition reaction of organometallic reagents varies from
1:1 to 33:1 in favor of the threo-isomer depending on the
reagents and the reaction conditions.3 Addition of aryllith-
ium in the presence of lithium salt as an extra coordinating
agent gave carbonyl addition products in high stereoselec-
tivity while most other alkylmetal compounds showed
poor stereoselectivity (Scheme 1).
At first (p-methoxyphenyl)-{[1¢(R)-a-methylbenzyl]-
aziridine-2(R)-ylmethylene}amine (1) was prepared from
[1¢(R)-a-methylbenzyl]aziridine-2(R)-carboxaldehyde
and p-anisidine. p-Methoxyphenyl moiety is readily re-
moved to give free amine after the reaction with ceri-
um(IV) ammonium nitrate.7 Addition of either MeMgBr
or MeLi did not give any product even at room tempera-
ture after a reaction time of 15 hours, all starting imine
was recovered unreacted. This suggests that the starting
imine is not reactive enough toward alkyl metal com-
pounds whose reactivity may increase by the addition of a
suitable Lewis acid.5b,8
Among all tested Lewis acids BF3·OEt2 was the best to
promote the reactivity without breaking the aziridine ring
C-N bond. The best result was obtained with the addition
of four equivalents of MeMgBr at –10 °C to give the me-
thylated product in 86% yield (entry 5), lower tempera-
tures and larger amounts of MeMgBr were of no benefit
(entries 1–4).9 Addition of MeLi resulted in a slightly low-
er yield (76%, entry 6). The addition of a methyl group
proceeded in a completely stereoselective manner to give
a single isomer ( by 1H NMR and HPLC) regardless of the
source of the organometallic reagents. The stereochemis-
try of the addition product 2a was identified after its con-
version to 5-methyl-4-chloromethylimidazolidin-2-one
(6a) by treatment with triphosgene and NaH in THF.10
The coupling constant of two imidazolidinone ring pro-
tons at C-4 and C-5 was measured to be 3.2 Hz, which cor-
responds to a trans-relationship implying that methyl
addition occurred from re-face via a chelation controlled
transition state as expected from the earlier observation
Ph
Ph
Ph
OH
RLi
OH
O
Me
N
Me
+
N
Me
N
81–89 %
R
R
erythro
de = 1:1–33:1
threo
H
H
H
Scheme 1
Recently we found that addition of a coordinating agent
greatly improved the stereoselectivity of the reduction of
2-acylaziridines by NaBH4.4 Studies on the addition of
SYNLETT 2004, No. 3, pp 0489–0492
1
8.
0
2.
2
0
0
4
Advanced online publication: 06.02.2004
DOI: 10.1055/s-2004-815444; Art ID: U26803ST
© Georg Thieme Verlag Stuttgart · New York

490
M.-J. Suh et al.
LETTER
from the reaction of aziridinyl-2-carboxaldehyde.3 When added to the imine that should be properly activated by
the aryllithium was added to aziridinyl-2-carboxaldehyde BF3·OEt2. We observed the existence of strong binding
relatively poor stereoselectivity of 84:16 was improved up between BF3·OEt2 and aziridine ring nitrogen in the crys-
to 99:1 by the addition of a lithium salt. This extra chelat- talline structure of dicyano{[(1R)-(a-methylbenzyl)-aziri-
ing agent seems to make the reaction proceed through the din-2-yl]-methanolato-O,N}boron.13 Strong binding by
chelating controlled transition state.3 The same strategy BF3·OEt2 makes the substrate structure rigid, resulting in
was applied for the reduction of the 2-acylaziridine by high stereoselectivity with enhancement of imine reactiv-
NaBH4. The stereoselectivity was highly improved from ity toward the organomagnesium reagents.
1:1 to >99: 1 with the assistance of a bidentate metal
This compound 2a was utilized as a precursor of the nitro-
gen containing acyclic compound by aziridine ring open-
additive ZnCl2 in the reaction medium.4
Compared with aziridinyl-2-carboxaldehyde this imine ing reactions. Acid catalyzed ring opening with acetic
has better chelating ability toward the metal through nitro- acid did not yield the expected acetyloxymethylaniline2
gen instead of oxygen, a greater selectivity results be- but a complex mixture was obtained. Catalytic hydroge-
tween threo-2 and erythro-3 up to >99:1. This observation nation in the presence of Pd/C as a catalyst with H2 at 30
is solid evidence that the proper selection of the chelating psi afforded the product that was identified as 2-(p-meth-
agent may improve the stereoselectivity. More than two oxylpheny)aminobutane 5 in 82% yield (Scheme 2). This
equivalents of organomagnesium reagents may be re- was quite surprising that both of carbon and nitrogen
quired due to the high affinity of metal for nitrogen not bonds in the aziridine ring were reduced simultaneously
only at imine11 but also at the aziridine ring.12 For the best with the removal of a-methylbenzylamine. Normally ei-
results four equivalents of organomagnesium reagents are ther one of two bonds was selectively reduced by catalytic
needed. The transition state can be drawn as 4 with oligo- hydrogenation depending on the substituent at C-2 of the
meric association of organomagnesium reagents being aziridine ring. When hydroxymethyl is a substituent as in
Table 1 Addition of Organometallic Reagents to Chiral (p-methoxyphenyl)-{[1¢(R)-a-methylbenzyl]aziridin-2(R)-ylmethylene}aminea
H
H
Re face
Ph
C6H4-pOMe
BF3
C6H4-pOMe
Ph
Ph
N
C6H4-pOMe
N
C6H4-pOMe
HN
RM
HN
Me
N
N
Me
threo
N
R
Me
N
R
Mg
71–86 %
R
R
*Bn
Br
Mg
H
erythro
H
H
Br
4
1
2
3
Entry
1
Reagents
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeMgBr
MeLi
Equiv
Temp (°C)
–78
Time (h)
Yieldb
Ratioc
2
2
4
2
4
4
4
4
4
4
4
3
3
3
10
10
4
No reaction
2
–10
40 (60)
45 (55)
65 (10)
86
3
–78
>99:<1
>99:<1
>99:<1
>99:<1
>99:<1
97:3
4
–10
3
5
–10
3
6
–78
5
76
7
EtMgBr
–10
4
82
8
VinylMgBr
AllylMgBr
n-BuMgBr
n-BuLi
–10
3
71
9
–10
3
82
62:38
10
11
12
13
14
–10
3
72
91:9
–10
3
63
84:16
PhMgBr
–10
3
75
>99:<1
>99:<1
>99:<1
p-TolylMgBr
p-FPhBgBr
–10
3
68
–10
3
71
a All reactions were carried out in the presence of BF3·OEt2.
b Isolated, not optimized yield. Yield in the brackets were unreacted starting material recovered.
c Determined by 1H NMR.
Synlett 2004, No. 3, 489–492 © Thieme Stuttgart · New York

LETTER
Addition of Organomagnesium to Aziridinyl-2-carboxaldimine
491
Table 2 Preparation of 5-Alkyl or 5-Aryl-4-chloromethylimidazoli-
din-2-one from Alkylated or Arylated Products
2-hydroxymethyl-[1¢(R)-a-methylbenzyl]aziridine, the
bond between nitrogen and C-3 was cleaved to yield b-
amino alcohol. While 2-carboalkoxycarbonyl substituent
as in alkyl [1¢(R)-a-methylbenzyl]aziridine-2-carboxylate
afforded the b-amino carboxylate with the breakage of ni-
trogen and C-2 bond.2 Formation of 2-(p-methoxylanil-
no)butane from 2a suggests that the bond strength of both
bonds between nitrogen and C-2 and C-3 in the aziridine
ring is similar.
Ph
Ph
PMP
R
O
N
HN
Me
N
Me
Cl
N
(CCl3)2CO
PMP
NaH
H
79–97%
R
6
2
Entry
Compound
R
Yield (%)a J (Hz)b
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
Me
94
91
87
79
96
97
92
89
3.2
Et
3.0
Vinyl
Allyl
n-Bu
Ph
3.4
2.6 (6.4)c
3.2 (6.6)c
3.0
Scheme 2
With reaction conditions in hand we added various alkyl-
and arylmagnesium reagents (Table 1). Ethyl magnesium
bromide gave a similar yield (82%) in a completely ste-
reoselective manner (entry 7). This was further tested by
addition of vinyl magnesium bromide resulting in 71%
yield with diastereoselectivity of 97:3 by 1H NMR (entry
8). Much lower stereoselectivity was observed – 62:38
and 91:9 – when allyl magnesium bromide and n-butyl
magnesium bromide were added in 82% and 72% yield,
respectively (entries 9 and 10). Changing the alkylating
agent to n-BuLi gave worse selectivity of 84:16, in 63%
yield (entry 11). Addition of aryl magnesium reagents
such as PhMgBr, p-tolyl-MgBr, p-FPhMgBr was com-
pletely stereoselective to give products in 75%, 68% and
71% yield respectively (entries 12–14).
2g
2h
Tolyl
p-FPh
3.2
2.6
a All reactions were carried out at –78 °C for 2 h.
b Coupling constants at the imidazolidin-2-one ring protons at C-4 and
C-5.
c The values in the brackets were the coupling constants at the imida-
zolidin-2-one ring protons prepared from the minor erythro products
after alkylation reactions.
din-2-ones 7a and 8a by the treatment with
methansulfonic acid10 or cerium(IV) ammonium nitrate
(CAN),7 respectively (Scheme 3).
In conclusion, the addition of organomagnesium reagents
to the enantiomerically pure (p-methoxyphenyl)-{[1¢(R)-
a-methylbenzyl]aziridin-2(R)-ylmethylene}amine pro-
ceeded in highly stereoselective manner to give 2-ami-
nomethylaziridine in the presence of BF3·OEt2. Treatment
of alkyl or arylated 2-aminomethylaziridines with triphos-
gene and NaH yielded 5-alkyl or 5-aryl-4-chlorometh-
ylimidazolidin-2-ones efficiently.
All of these compounds were converted to 5-alkyl or 5-
aryl-4-chloromethylimidazolidin-2-one (6) in high yields
by treatment with triphosgene and NaH (Table 2).14
This is a facile route for the preparation of 5-alkyl or 5-
aryl-4-chloromethylimidazolin-2-ones with orthogonally
protected nitrogens by a-methylbenzyl and p-methox-
yphenyl. Enantiomerically pure imidazolidin-2-ones are
found as essential structural elements of many biological-
ly important molecules.15 Chemical libraries derived from
imidazolidin-2-ones were used for screening and some of
which were developed as a potential drug candidate.
O
CH3SO3H
76%
HN
N
C6H4pOH
Cl
The stereochemistry of all major products 6 were con-
firmed by the observed coupling constants of the imidazo-
line ring protons at C-4 and C-5 to be 2.6–3.4 Hz
corresponding to trans relationship.10 The minor erythro
isomers isolated from the addition of allyl- and n-butyl
magnesium bromide were converted by the same method
to cis-5-chloromethylimidazolidin-2-ones whose cou-
pling constants between two protons at C-4 and C-5 were
6.4 Hz and 6.6 Hz respectively (entries 4 and 5).
Ph
O
Me
7a
Me
Cl
N
N
PMP
Ph
O
Me
Cl
N
Me
6a
NH
Me
CAN
53%
8a
Scheme 3
Selective removal of either a-methylbenzyl or p-meth-
oxyphenyl from 6a provided mono-protected imidazoli-
Synlett 2004, No. 3, 489–492 © Thieme Stuttgart · New York

492
M.-J. Suh et al.
LETTER
114.6, 126.6, 126.7, 128.1, 141.8, 144.6, 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. Compound 2f: colorless oil, [a]D 18.9
(c 3.0 in EtOAc). 1H NMR (200 MHz, CDCl3): d = 1.08 (d,
J = 6.8 Hz, 3 H), 1.19 (d, J = 6.2 Hz, 1 H), 1.66–1.78 (m, 2
H), 2.25 (q, J = 6.6 Hz, 1 H), 3.55 (s, 3 H), 4.04–4.08 (m, 1
H), 6.35–6.57 (m, 4 H), 7.10–7.33 (m, 10 H). 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.
Acknowledgment
We gratefully acknowledge the financial support of the following
institutions: The Korea Science and Engineering Foundation (R01-
2000-000-00048-0 and CBMH to HJH and R14-2002-045-010020
to WKL), and the Korea Research Foundation (KRF-2002-070-
C00060 to WKL and HJH).
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(9) General Procedure for the Addition Reactions of Alkyl
or Aryl Magnesium Bromide: Into the solution of (p-
methoxyphenyl)-{[1¢(R)-a-methylbenzyl]aziridine-2(R)-
ylmethylene}amine (280 mg, 1 mmol) in of Et2O (10 mL)
was added ethereal solution of alkyl or aryl magnesium
bromide (3 mmol) and BF3·OEt2 (0.15 mL, 0.8 mmol) under
N2 atmosphere. The resultant solution was stirred at –10 °C
for the reaction to be completed before being quenched by
adding ice-water. The reaction product was isolated with
Et2O (15 mL × 4). The ethereal solution was washed with
brine twice. The organic layer was dried over anhyd MgSO4,
filtered and concentrated under reduced pressure.
Purification by silica gel flash column chromatography
provided the analytically pure addition product. Compound
2a: colorless oil, [a]D 33.5 (c 2.0 in EtOAc). 1H NMR (200
MHz, CDCl3): d = 1.12 (d, J = 6.0 Hz, 1 H), 1.14 (d, J = 4.2
Hz, 3 H), 1.22 (d, J = 6.2 Hz, 3 H), 1.54–1.62 (m, 2 H), 2.36
(q, J = 6.6 Hz, 1 H), 3.32–3.41 (m, 1 H), 3.63 (s, 3 H), 6.52–
6.71 (m, 4 H), 7.14–7.31 (m, 5 H). 13C NMR (50.3 MHz,
CDCl3): d = 19.5, 23.5, 30.4, 44.2, 48.9, 55.6, 69.3, 114.6,
(14) General Procedure for the Synthesis of 5-Aalkyl or 5-
Aryl-4-chloromethylimidazolidin-2-one: To a solution of
{1-[1¢(R)-a-methylbenzyl]aziridin-2(R)-yl}-methylamine
(310 mg, 1.05 mmol) in 15 mL of THF under nitrogen
atmosphere was added NaH (144 mg, 6 mmol) at –10 °C.
The mixture was stirred for 1 h at –10 °C. To the mixture
was slowly added triphosgene solution (0.356 g, 1.2 mmol)
in THF (5 mL) at –10 °C. The mixture was stirred for 2 h at
–10 °C. The reaction was quenched with H2O at –10 °C and
warmed to r.t. The aqueous layer was extracted with CH2Cl2
(10 mL × 5). The combined organic extract 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.
Compound 6a: colorless oil. 1H NMR (200 MHz, CDCl3):
d = 0.82 (d, J = 6.2 Hz, 3 H), 1.50 (d, J = 7.4 Hz, 3 H), 2.92
(dt, J = 7.0 Hz, 3.2 Hz, 1 H), 3.32 (dd, J = 11.4 Hz, 7.6 Hz,
1 H), 3.42 (dd, J = 11.4 Hz, 3.2 Hz, 1 H), 3.65 (s, 3 H), 3.90
(qd, J = 6.2 Hz, J = 3.2 Hz, 1 H), 5.25 (q, J = 7.4 Hz, 1 H),
6.72–6.78 (m, 2 H), 7.11–7.27 (m, 7 H). 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.
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Synlett 2004, No. 3, 489–492 © Thieme Stuttgart · New York