Synthesis of optically active 3-amino-2,3-dihydrobenzopyran-4-ones by ring transformation of aziridinecarboxamides

Article abstract of DOI:10.1055/s-2000-7101

Weinreb amides 1 of aziridinecarboxylic acids react with o-lithiated O-methoxymethylphenols 2 to 2-benzoylaziridines 3 which, after O-deprotection, undergo ring transformation by attack of the phenolic hydroxy group at 3-position of the aziridine ring affording optically active 3-aminodihydrobenzopyran-4-ones 5 under acidic conditions. Alternatively, 5-membered benzofuran-3-ones 6 and 7 can be obtained under basic conditions.

Full text of DOI:10.1055/s-2000-7101

1444
PAPER
Synthesis of Optically Active 3-Amino-2,3-dihydrobenzopyran-4-ones by Ring
Transformation of Aziridinecarboxamides
Karsten Woydowski, Jürgen Liebscher*
Institut für Chemie, Humboldt-Universität Berlin, Hessische Straße 1-2, 10115 Berlin, Germany
Fax +49(30)20938907; E-mail: liebscher@chemie.hu-berlin.de
Received 3 March 2000; revised 8 May 2000
Dedicated to Professor Richard Neidlein on the occasion of his 70th birthday
followed by Mitsunobu-conditions as reported for azri-
Abstract: Weinreb amides 1 of aziridinecarboxylic acids react with
dine carboxylates.9
o-lithiated O-methoxymethylphenols 2 to 2-benzoylaziridines 3
which, after O-deprotection, undergo ring transformation by attack
of the phenolic hydroxy group at 3-position of the aziridine ring af-
fording optically active 3-aminodihydrobenzopyran-4-ones 5 under
acidic conditions. Alternatively, 5-membered benzofuran-3-ones 6
and 7 can be obtained under basic conditions.
With these three Weinreb amides 1 in hand, we tried the
ring transformation with o-lithiated O-MOM-protected
phenols 2 (Scheme). The expected benzoylaziridines 3
were obtained in acceptable yields in the trans-series (3a-
3c) and in the 3-unsubstituted case 3e, while the cis-prod-
uct 3d was formed in modest yield (36%). This trend was
also observed in the following ring transformation of the
benzoylaziridines 3 into 3-tosylamino-benzopyrane-4-
ones 5 by heating in HClO4/EtOH/water (Method A),
where the O-MOM protective group is split off and the ap-
pearing phenolic OH-group attacks the 3-position of the
(o-hydroxy)benzoylaziridine 4. Again, higher yields were
obtained in the trans-series (Table). Remarkably, the
3-unsubstituted 2-(o-methoxymethoxybenzoyl)aziridine
3e (R1 = R2 = H) resisted the transformation into the cor-
responding 3-aminobenzopyranone 5 and gave only the
O-deprotected product 4e. This demonstrates that sub-
stituents at position 3 of the aziridine ring exert an effect
on the success of the ring transformation of 3 or 4 into 5.
Key words: 2,3-dihydrobenzopyran-3-ones, aziridines, ring trans-
formation, benzofuran-3-one, asymmetric synthesis
Ring transformation of chiral glycidic acid derivatives
with binucleophiles turned out to be a useful methodology
for the synthesis of optically active a-hydroxyalkyl or hy-
droxy 5-, 6-, and 7-ring heterocycles with a carbonyl car-
bon atom as ring atom.1-6 For example, we developed a
novel synthesis of enantiopure 3-hydroxy-2,3-dihy-
drobenzopyran-4-ones with 2-alkyl substituents by the re-
action of Weinreb amides of oxiranecarboxylic acids
(corresponding to 1 with O instead of TsN) with O-MOM-
protected o-lithiated phenols 2 as C-C-O-building
blocks.1 The o-hydroxybenzoyloxiranes initially formed
were O-deprotected under acidic conditions allowing a
ring transformation by attack of the evolving phenolic hy-
droxy group at the ß-position of the starting oxirane ring
as long as its substituents are in trans arrangement. When
cis-oxiranecarboxamides were used as starting materials,
an alternative attack at the a-position occurred resulting in
the formation of 2-alkylidenebenzofuranones. Both types
of products are alkyl analogues of naturally occurring fla-
vonoids.
We also tried to isolate o-hydroxybenzoylaziridines 4 af-
ter shorter heating using Method A and to run the ring
transformation under basic conditions (Method B). In
these cases, however, the ring transformation resulted in
the connection of the phenolic OH-group to position 2 of
the starting 2-(o-hydroxybenzoyl)aziridine 4 rather than
to position 3 thus forming either racemic 2-tosylami-
nobenzofuran-3-ones 6 or 2-alkylidenebenzofuran-3-ones
7. The latter case resembles the reaction of the corre-
sponding 3-alkyl-2-(o-hydroxybenzoyl)oxiranes. It is
probably attributed to ß-elimination of tosylamide from
the intermediate 2-(a-tosylaminoalkyl)-benzofuran-3-
ones 8, which could be isolated in our preliminary inves-
tigations of the reaction of 1a with O-MOM-protected
1-naphthol. The formation of the 2-amino-benzofuran-3-
one 6e is unexpected since the phenolic O-atom and the
tosylamino group are found at the same C-atom and anal-
ogous reactions were not observed in the o-hydroxyben-
zoyloxirane series.1 The product 6e could be formed by
opening of the aziridine ring of the 2-(o-hydroxyben-
zoyl)aziridine 4 (R1 = R2 = H) by ß-elimination caused by
attack of the base at position 3 of the aziridine ring. The
resulting intermediates 9 would close the ring by addition
of the phenolic OH-group to the enamine moiety or the
corresponding imine. Intermediates structurally related to
Corresponding ring transformations of optically active
aziridinecarboxylic acid derivatives are rare.7 We report
here, first results in the synthesis of novel optically active
3-amino-2,3-dihydrobenzopyran-4-ones 4 by ring trans-
formation of Weinreb amides 1 of aziridinecarboxylic ac-
ids with o-lithiated MOM-protected phenols 2. 3-trans-
Propyl, 3-cis-methyl and the 3-unsubstituted aziridines 1
were used as representative starting materials. The first
could be obtained in enantiomerically pure form from
Weinreb amides of the corresponding oxiranecarboxam-
ides by ring opening with azide, Staudinger reaction of the
resulting azidoalcohol with triphenylphosphine and final
N-tosylation of the resulting aziridine according to
Zwanenburg et al.8 Compounds 1d and 1e were prepared
from N-tosylated L-threonine or L-serine, respectively,
by transformation to the corresponding Weinreb amide
Synthesis 2000, No. 10, 1444–1448 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active 3-Amino-2,3-dihydrobenzopyran-4-ones
1445
Scheme
9 were proposed in the ring contraction of 3-amino-2-aryl- zopyran-4-ones were obtained by three principal routes.
benzopyran-4-ones to 2-aminobenzofuran-3-ones10 re- Thus the amino group was introduced into the benzo-
sembling the transformation of 5 into 6, which also has to pyrane-ring by Neber rearrangement,11,13-17 nitrosation/
be taken into consideration as another possible pathway to reduction,12,13,15-17 or nucleophilic substitution.18-20
the 2-tosylaminobenzofuran-3-one 6e.
3-Amino-dihydrobenzopyran-4-ones were further synthe-
sised by ring formation of o-hydroxychalcones or corre-
sponding bromo-adducts in the presence of amines and
iodine,21,22 trimethylsilylazide,23 or azide in the presence
of TFA.24 Last, but not least, racemic 3-amino-dihy-
drobenzopyran-4-ones were accessible by ring transfor-
mation of 3-aryl-2-(o-hydroxybenzoyl)aziridines, which
were obtained from chalcones or corresponding dibro-
mides.24,25 Although those ring transformations resemble
the synthesis of our compounds 5 as far as the last step is
concerned, important differences are found. Thus, com-
pounds 5 are optically active and bear 2-alkyl rather than
2-aryl substituents. In light of the fact that cis-2-(o-hy-
droxybenzoyl)-3-phenylaziridine afforded mainly 2-ben-
zylidene-benzofuran-3-one25 (similar to 7) rather than the
3-amino-2-phenylbenzopyran-4-one the transformation
of the cis-aziridine 3d into the cis-3-amino-2-methylben-
zopyran-4-one 5d is worth mentioning. Obviously, the
3-methyl-substituent in the 2-(o-hydroxybenzoyl)aziri-
dine affects the mode of cyclisation as compared with
2-aryl-substituents favouring the attack of the phenolic
hydroxy group at position 3 rather than at position 2 of the
aziridine.
All products 1, 3, 4, 5, and 6 are new. Their structure could
be confirmed by spectroscopic methods, in particular by
1H and 13C NMR spectroscopy. The vicinal couplings of
the protons in the 3-amino-dihydrobenzopyran-4-ones 5
clearly prove the relative configuration. The structure of
the unexpected 2-aminobenzofuran-3-one 6e is in agree-
ment with the observation of a quaternary carbon atom at
d = 92.5 ppm. No sign of the formation of diastereomers
was found in the NMR-spectra of the crude products 3, 4,
and 5. Since we started from enantiopure starting materi-
als 1 with two asymmetric carbon atoms, both of which
cannot invert configuration at the same time, products 5
obtained must be enantiomerically pure.
The overall transformation of aziridine-2-carboxamides 1
into benzopyranones 5 represents the first asymmetric
synthesis of 3-amino-2,3-dihydrobenzopyran-4-ones.
Previously, only racemic products, mostly with 2-arylsub-
stituents (3-aminochromanones) or 2-unsubstituted com-
pounds, had been prepared (v. i.). Some of them were
further reduced to 3-amino-4-hydroxytetrahydrobenzopy-
ranes exhibiting bronchiadilating and antispasmolytic
properties.11-13 The known racemic 3-amino-dihydroben-
Synthesis 2000, No. 10, 1444–1448 ISSN 0039-7881 © Thieme Stuttgart · New York

1446
K. Woydowski, J. Liebscher
PAPER
Table Starting Materials 1 and Products 3, 4, 5, 6 and 7
Yield
(%)
Mp (°C)
Rf
Solvent
[a]2D0
(c, CHCl3)
1H NMR (CDCl3)
d (ppm), J (Hz)
13C NMR (CDCl3)
d (ppm), J (Hz)
1a
86
colourless oil 0.48
CH2Cl2/
+27.9
0.91 (t, 3 H, J = 7.4, CH3), 1.45-2.15 13.7 (CH3), 21.1 (CH2), 21.6 (CH3),
(m, 4 H, 2CH2), 2.35 (s, 3 H, CH3), 29.9 (CH2), 32.5 (NCH3), 41.7 (CH),
Me2CO
95:5
3.07 (m, 1 H, CH), 3.12 (s, 3 H, NCH3), 48.6 (CH), 62.0 (CH3O), 127.6 (CHar),
3.68 (s, CH3-O), 3.72 (d, 1 H, J = 3.9, 129.6 (CHar), 137.1 (Car), 144.3 (Car),
CH), 7.23 (d, 2 H, J = 8.2, Aryl), 7.79 162.0 (C=O)
(d, 2 H, J = 8.2, Aryl)
1d
1e
3a
93
78
58
colourless oil 0.56
-34.7
-8.5
1.23 (d, 3 H, J = 5.7, CH3), 2.37 (s, 3 H, 12.4 (CH3), 21.7 (CH3), 32.5 (CH3-N),
CH3) 3.08 (m, 1 H, CH), 3.12 (s, 3 H, 40.0 (CH), 41.0 (CH), 61.8 (CH3-O),
CH3-N), 3.65 (s, 3 H, CH3-O), 3.74 (d, 127.9 (CHar), 129.7 (CHar), 134.8 (Car),
1 H, J = 7.7, CH), 7.26 (d, 2 H, J = 8.2, 144.7 (Car), 165.2 (CO)
Aryl ), 7.80 (d, 2 H, J = 8.2, Aryl)
CH2Cl2/
Me2CO
95:5
70-73
(C6H14/
EtOAc
9:1)
0.53
2.38 (s, 3 H, CH3), 2.57 (d, 1 H, J = 4.2, 21.7 (CH3), 31.9 (CH2), 32.5 (CH3-N),
CH2), 2.63 (d, 1 H, J = 6.9, CH2)3.16 33.1 (CH), 62.2 (CH3-O), 128.2 (CHar),
(s, 3 H, CH3-N), 3.73 (s, 3 H, CH3-O), 129.8 (CHar), 134.2 (Car), 145.1 (Car),
3.85 (m, 1 H, CH), 7.27 (d, 2 H, J = 8.2, 166.1 (CO)
CH2Cl2/
Me2CO
95:5
Aryl), 7.78 (d, 2 H, J = 8.2, Aryl)
colourless oil 0.76
CH2Cl2/
0.91 (t, 3 H, J = 7.4, CH3), 1.46-2.12 13.7 (CH3), 21.2 (CH2), 21.6 (CH3),
(m, 4 H, 2CH2), 2.33 (s, 3 H, CH3),
30.2 (CH2), 49.7 (CH), 50.8 (CH), 56.6
Me2CO
95:5
3.06 (m, 1 H, CH), 3.44 (s, 3 H, CH3- (CH3-O), 94.6 (CH2), 114.8 (CHar),
O), 4.26 (d, 1 H, J = 4.2, CH), 5.21 (s, 116.2 (CHar), 121.9 (CHar), 127.3
2 H, CH2), 6.93-7.76 (8H, Aryl)
(CHar), 127.4 (Car), 129.5 (CHar), 134.5
(CHar), 137.3 (Car), 144.1 (Car), 156.7
(Car), 194.3 (CO)
3b
3c
53
63
colourless oil 0.49
0.91 (t, 3 H, J = 7.4, CH3), 1.48-2.10 13.7 (CH3), 20.2 (CH3), 21.2 (CH2),
(m, 4 H, 2CH2), 2.20 (s, 3 H, CH3), 21.6 (CH3), 49.7, 50.9 (CH), 56.5
2.33 (s, 3 H, CH3), 3.05 (m, 1 H, CH), (CH3O), 94.6 (CH2), 114.8 (CHar), 127.1
3.43 (s, 3 H, CH3-O), 4.26 (d, 1 H, J = (Car), 127.3 (CHar), 129.5 (CHar), 130.6
4.2, CH), 5.18 (s, 2 H, CH2), 7.03-7.77 (CHar), 131.4 (Car), 135.1 (CHar), 137.4
C5H12/
Et2O
1:1
(m, 7 H, Aryl)
(Car), 144.1 (Car), 154.7 (Car), 194.4
(CO)
colourless oil 0.72
0.92 (t, 3 H, J = 7.4, CH3), 1.44-2.12 13.8 (CH3), 21.2 (CH2), 21.6 (CH3),
(m, 4 H, 2CH2), 2.33 (s, 3 H, CH3), 30.4 (CH2), 50.2, 50.9 (CH), 55.8, 56.0
3.06 (m, 1 H, CH), 3.41 (s, 3 H, CH3O), (CH3O), 95.1 (CH2), 112.7 (CHar), 114.6
3.70 (s, 3 H, CH3O), 4.28 (d, 1 H, J = (CHar), 117.6 (CHar), 123.3 (CHar),
4.1, CH), 5.03 (s, 2 H, CH2), 6.76-7.76 126.8 (Car), 127.3 (CHar), 129.5 (CHar),
C5H12/
Et2O
1:1
(m, 7 H, Aryl)
137.4 (Car), 151.0 (Car), 154.3 (Car),
193.2 (CO)
3d
3e
4d
36
72
75
colourless oil 0.76
1.16 (d, 3 H, J = 5.8, CH3), 2.36 (s, 3 H, 12.2 (CH3), 21.7 (CH3), 41.8 (CH), 49.0
CH3), 3.22 (m, 1 H, CH), 3.45 (s, 3 H, (CH), 56.7 (CH3-O), 94.5 (CH2), 114.6
C5H12/
Et2O
1:1
CH3-O), 4.24 (d, 1 H, J = 7.8, CH),
(CHar), 122.0 (CHar), 127.3 (Car), 127.8
5.23 (dd, 2 H, J = 6.9, 8.6, CH2), 6.85- (CHar), 129.7 (CHar), 130.5 (CHar),
7.82 (m, 8 H, Aryl)
134.7 (CHar), 135.0 (Car), 144.6 (Car),
156.7 (Car), 192.1 (CO)
colourless
crystals
0.72
C5H12/
Et2O
1:1
2.50 (s, 3 H, CH3), 2.74 (d, 1 H, J = 4.2, 21.7 (CH3), 33.4 (CH2), 41.4 (CH), 56.7
CH2), 2.79 (d, 1 H, J = 7.0, CH2), 3.62 (CH3O), 94.5 (CH2), 114.8 (CHar), 121.9
(s, 3 H, CH3O), 4.50 (dd, 1 H, J = 4.3, (CHar), 127.2 (Car), 128.1 (CHar), 129.8
7.0, CH), 5.43 (s, 2 H, CH2), 7.09-7.94 (CHar), 130.7 (CHar), 134.8 (CHar),
(m, 8 H, Aryl)
134.6 (Car), 144.9 (Car), 157.1 (Car),
193.7 (CO)
colourless
crystals
0.51
C6H14/
Et2O
11
1.15 (d, 3 H, J = 5.8, CH3), 2.38 (s, 3 H, 12.7 (CH3), 21.7 (CH3), 41.3 (CH), 45.3
CH3), 3.30 (m, 1 H, CH), 4.09 (d, 1 H, (CH), 118.7 (CHar), 119.0 (CHar), 115.4
J = 7.6 Hz, CH), 6.85-7,85 (m, 8 H, (CHar), 128.0 (2CHar), 129.8 (2CHar),
Aryl), 11.62 (s, 1 H, OH)
129.9 (CHar), 137.4 (CH), 145.1 (Car),
162.6 (Car), 195.4 (=O)
Synthesis 2000, No. 10, 1444–1448 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Optically Active 3-Amino-2,3-dihydrobenzopyran-4-ones
1447
Table (continued)
Yield
(%)
Mp (°C)
Rf
Solvent
[a]2D0
(c, CHCl3)
1H NMR (CDCl3)
d (ppm), J (Hz)
13C NMR (CDCl3)
d (ppm), J (Hz)
4e
75
colourless
crystals
0.67
2.37 (s, 3 H, CH3), 2.70 (d, 1 H, J = 4.1, 21.7 (CH3), 32.7 (CH2), 37.3 (CH),
CH2Cl2/
Me2CO
95:5
CH2), 2.83 (d, 1 H, J = 7 Hz, CH2), 4.14 118.6 (CHar), 119.0 (Car), 119.6 (CHar),
(dd, 1 H, J = 4.1, J = 7.0, CH), 6.86- 128.2 (CHar), 129.8 (CHar),
7.92 (m, 8 H, Aryl), 11.60 (s, 1 H, OH) 130.3 (CHar), 134.0 (Car), 137.7 (CHar),
145.4 (Car), 162.8 (Car), 195.9 (C=O)
5aa
80
131-32
(C6H14/
EtOAc
7:3)
0.78
+10.8
-15.9
-37.9
0.92 (t, 3 H, J = 7.4, CH3), 1.18-2.14 13.8 (CH3), 18.2 (CH2), 21.6 (CH3),
C6H14/
AcOEt
7:3
(m, 4 H, 2CH2), 2.32 (s, 3 H, CH3),
34.0 (CH2), 59.6 (CH), 82.0 (CH), 117.8
3.93 (m, 1 H, CH), 4.07 (m, 1 H, CH), (CHar), 119.1 (Car), 121.6 (CHar), 127.4
5.36 (d, 1 H, J = 6.4, NH), 6.87-7.73 (CHar), 127.5 (CHar), 129.7 (CHar),
(m, 8 H, Aryl)
136.0 (Car), 136.8 CHar), 144.0 (Car),
161.5 (Car), 190.2 (CO)
5b
5c
82
78
136-38
(C6H14/
EtOAc
8:2)
0.74
0.92 (t, 3 H, J = 7.4, CH3), 1.38-2.06 13.8 (CH3), 18.3 (CH2), 20.3, 21.6
(m, 4 H, 2CH2), 2.18 (s, 3 H, CH3), (CH3), 34.0 (CH2), 59.7 (CH), 82.0
2.33 (s, 3 H, CH3), 3.89 (m, 1 H, CH), (CH), 117.6 (CHar), 118.6 (Car), 126.9
CH2Cl2/
Me2CO
95:5
4.02 (m, 1 H, CH), 5.33 (d, 1 H, J = 6.3, (CHar), 127.5 (CHar), 129.7 (CHar),
NH), 6.77-7.77 (m, 7 H, Aryl)
131.1 (Car), 135.7 (Car), 137.9 (CHar),
143.9 (Car), 159.6 (Car), 190.4 (CO)
150-52
(C6H14/
EtOAc
6:4)
0.69
0.91 (t, 3 H, J = 7.4, CH3), 1.25-2.10 13.8 (CH3), 18.3 (CH2), 21.6 (CH3),
(m, 4 H, 2CH2), 2.33 (s, 3 H, CH3), 34.0 (CH2), 55.8 (CH3O), 59.8, 82.2
3.66 (s, 3 H, CH3O), 3.90 (m, 1 H, CH), (CH), 107.6 (CHar), 118.8 (Car), 119.1
CH2Cl2/
Me2CO
95:5
4.00 (m, 1 H, CH), 5.32 (d, 1 H, J = 6.4, (CHar), 126.1 (CHar), 127.5 (CHar),
NH), 6.80-7.73 (m, 7 H, Aryl)
129.7 (CHar), 136.1 (Car), 143.9 (Car),
154.2 (Car), 156.3 (Car), 190.4 (CO)
5d
6e
53
45
83
191-92
(C6H14/
EtOAc
1:1)
0.80
C6H14/
Et2O
1:1
+192.0
1.24 (d, 3 H, J = 6.7, CH3), 2.33 (s, 3 H, 11.9 (CH3), 21.5 (CH3), 58.5 (CH), 76.7
CH3), 4.19 (m, 1 H, CH), 5.06 (m, 1 H, (CH), 118.6 (CHar), 118.9 (Car), 121.4
CH), 5.73 (d, 1 H, J = 2.8, NH), 6.84- (CHar), 126.8 (CHar), 127.3 (CHar),
7.73 (m, 8 H, Aryl)
130.0 (CHar), 135.2 (Car), 137.2, (CHar),
144.1 (Car), 159.1, (Car), 188.1 (CO)
150-51
(C6H14/
EtOAc 6:4) Me2CO
95:5
0.53
CH2Cl2/
±0
1.52 (s, 3 H, CH3), 2.36 (s, 3 H, CH3), 21.6 (CH3), 23.1 (CH3), 92.5 (C), 113.0
6.15 (s, 1 H, NH), 6.83-7.67 (m, 8 H, (CHar), 119.3 (Car), 122.4 (CHar), 125.2
Aryl)
(CHar), 127.2 (CHar), 129.5 (CHar),
138.4, (CHar), 138.5 (Car), 143.8 (Car),
169.2 (Car), 196.9 (CO)
7db
a MS (70eV): m/z = 359 (M+, 1), 204 (24), 121 (45), 43 (86), 18 (100).
b Known compound.1
(2S,3R)-N-Methoxy-N-methyl-1-(4-tosyl)-3-propyl-2-aziridine-
carboxamide (1a)
In summary, our results demonstrate that the concept of
ring transformation of oxirane carboxylic acids with binu-
cleophiles can also be applied to their aza-analogues, i. e.
to aziridine carboxylic acid derivatives as a new route to
optically active amino-substituted heterocycles.
NaN3 (3.84, 60 mmol) and NH4Cl (3.19 g, 60 mmol) were added to
a solution of (2S,3R)-N-methoxy-N-methyl-3-propyl-2-oxirane-
carboxamide1 (3.45 g, 20 mmol) in MeOH (70 mL). After refluxing
for 5 h, the mixture was concentrated under vacuum, combined with
H2O (70 mL) and extracted with EtOAc (3 ¥ 30 mL). The combined
organic phases were washed with brine, dried (MgSO4), concentrat-
ed, and purified by flash chromatography (CHCl3/MeOH, 9:1) pro-
viding the corresponding azido alcohol (3.3 g, mixtures of
regioisomers, Rf = 0.52 and 0.38). This product (3.3 g, 15.3 mmol)
was dissolved in MeCN (70 mL) and combined with PPh3 (4.18 g,
15.9 mmol). The mixture was stirred at r.t. for 1 h, refluxed for 4 h,
and concentrated. The OPPh3 was filtered off and the solvent was
completely evaporated. Flash chromatography (CHCl3/MeOH, 9:1,
Rf = 0.23) gave (2S,3R)-N-methoxy-N-methyl-3-propyl-2-aziridin-
ecarboxamide (2.53 g, 14.7 mmol, 74% yield) which was dissolved
in dry CH2Cl2 (30 mL). p-Tosyl chloride (2.93 mL, 15.4 mmol) and
1H and 13C NMR spectra were recorded at 300 MHz and 75.5 MHz,
respectively, on a BRUKER AC-300 with TMS as internal standard
(CDCl3). Optical rotation was determined with a PERKIN ELMER
polarimeter 241. Silica gel (0.04-0.063 mm, MERCK) was used for
preparative column chromatography. If not otherwise mentioned,
chemicals were purchased from MERCK or ALDRICH. (2S,3R)-N-
Methoxy-N-methyl-3-propyl-2-oxiranecarboxamide was prepared
as reported before.1
Synthesis 2000, No. 10, 1444–1448 ISSN 0039-7881 © Thieme Stuttgart · New York

1448
K. Woydowski, J. Liebscher
PAPER
Et3N (2.14 mL, 15.4 mmol) were added under Ar and the mixture
was stirred at r.t. for 12 h. Concentration under vacuum and purifi-
cation by flash chromatography (CH2Cl2/Me2CO, 95:5, Rf = 0.48)
afforded 1a (3.83 g, 86%).
Acknowledgement
We gratefully acknowledge financial support from the Deutsche
Forschungsgemeinschaft and Fonds der Chemischen Industrie.
(2S,3S)-N-Methoxy-N,3-dimethyl-1-(4-tosyl)-2-aziridinecar-
boxamide (1d)
References
HN(Me)OMe.HCl (0.82 g, 8.39 mmol) and Et3N (1.18 mL,
8.39 mmol) were added to a suspension of (L)-N-tosylthreonine
(2.33 g, 8.39 mmol) in dry CH2Cl2 (50 mL) under stirring. After
cooling to 0 °C, DCC (1.73, 8.39 mmol) and DMAP (2 drops) were
added under Ar and stirring was continued at r.t. for 15 h. The re-
sulting mixture was diluted with Et2O (50 mL) and the dicyclohex-
ylurea was filtered off. Concentrating the filtrate and purifying by
flash chromatography (CHCl3/MeOH, 9:1, Rf = 0.23) provided the
Weinreb amide of L-N-tosylthreonine (1.56 g, 4.95 mmol, 59%
yield). This material was dissolved in dry CH2Cl2 (30 mL) and
combined with PPh3 (1.35 g, 5.2 mmol). A solution of DEAD
(0.824 mL, 5.20 mmol) in CH2Cl2 (2 mL) was added dropwise un-
der Ar at 0 °C and the mixture was stirred at r.t. for 15 h. Concen-
tration and flash chromatography (CH2Cl2/Me2CO, 95:5, Rf = 0.56)
gave the final product 1d (1.37 g, 93%).
(1) Woydowski, K.; Ziemer, B.; Liebscher, J. J. Org. Chem. 1999,
64, 3489.
(2) Woydowski, K.; Liebscher, J. Synthesis 1998, 1110.
(3) Woydowski, K.; Ziemer, B.; Liebscher, J. Tetrahedron:
Asymmetry 1998, 9, 1231.
(4) Woydowski, K.; Liebscher, J. J. Prakt. Chem. 1998, 340, 567.
(5) Woydowski, K.; Fleischhauer, J.; Schiffer, J.; Liebscher, J. J.
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(7) Funaki, I.; Thijs, L.; Zwanenburg, B. Tetrahedron 1996, 52,
9909.
(8) Legters, J.; Thijs, L.; Zwanenburg, B. Recl. Trav. Chim. Pay-
Bas 1992, 111, 1.
(9) Ibuka, T.; Nakai, K.; Habashita, H.; Hotta, Y.; Fujii, N.;
Mimura, N.; Miwa, Y.; Taga, T.; Yamamoto, Y. Angew.
Chem. Int. Ed. Engl. 1994, 33, 652.
(10) Patonay-Péli, E.; Litkei, G.; Patonay, T. Synthesis 1990, 511.
(11) Sarda, N.; Grouiller, A.; Pacheco, H. Eur. J. Med. Chem.,
Chim. Ther. 1976, 11, 145.
(2S)-N-Methoxy-N-methyl-1-(4-tosyl)-2-aziridinecarboxamide
(1e)
The same procedure was used as for 1d. Intermediate Weinreb
amide of L-N-tosylserine: (Rf = 0.22, CHCl3/MeOH, 9:1, 43% yield;
1e (Rf = 0.53, CH2Cl2/Me2CO, 95:5, 78% yield).
Sarda, N.;Grouiller, A.; Pacheco, M; Cier, A., Genin, D. Bull.
Soc. Chim. Fr. 1972, 3183.
(12) auf dem Keller, H. H.; Zymalkowski, F. Arch. Pharm.
(Weinheim) 1971, 304, 543.
(13) Sugihara, H., Sanno, Y. Chem. Pharm. Bull. 1977, 25, 859.
(14) Kasahara, A. Nippon Kagaku Zasshi 1959, 80, 416; Chem.
Abstr. 1961, 55, 5481.
(15) O´Brien, C.; Philbin, E. M.; Ushioda, S.; Wheeler, T. S.
Tetrahedron 1963, 19, 373.
(16) Kidd, D. J. Chem. Soc. 1962, 5121.
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(20) Patonay, T.; Litkei, G.; Bognár, R. Acta Chim. Acad. Sci.
Hung. 1981, 108, 135.
o-Methoxymethoxybenzoylaziridines 3; General Procedure
A solution of t-BuLi in pentane (1.6 M, 0.66 mL, 1.05 mmol)
was added to a solution of the O-MOM-phenol corresponding to 2
(1 mmol) in dry THF (3 mL) at 0 °C under Ar. The mixture was
stirred at 0 °C for 3 h. After cooling to -30 °C, a solution of the
Weinreb amide 1 (1 mmol) in dry THF (1 mL) was added under stir-
ring. Stirring was continued at 0 °C for 10 min (1d, 1e) or 20 min
(1a). After quenching with sat. NH4Cl, the mixture was extracted
with Et2O (3 ¥ approx. 10 mL). The combined organic phases were
dried (MgSO4), concentrated and purified by flash chromatography
(CH2Cl2/Me2CO, 95:5).
(21) Bognár, R.; Litkei, G.; Szigeti, P. Acta Chim. Acad. Sci. Hung.
1971, 68, 421.
(22) Donnelly, J. A.; Emerson, G. M. Tetrahedron 1990, 46, 7227.
(23) Litkei, G.; Patonay, T. Acta Chim. Acad. Sci. Hung. 1983, 114,
47.
(24) Cacchi, S.; Palmieri, G. Misiti, D. J. Chem. Soc., Perkin
Trans. 1 1976, 2371.
(25) Litkei, G., Mester, T.; Patonay, T.; Bognár, R. Acta Chim.
Acad. Sci. Hung. 1979, 101, 53.
o-Hydroxybenzoylaziridines 4 and 3-(Tosylamino)dihydroben-
zopyran-4-ones 5; General Procedure (Method A)
70% HClO4 (19 mL, 0.17 mmol) were added to a solution of benzoy-
laziridine 3 (0.5 mmol) in EtOH/H2O (3 mL, 2:1). The mixture was
refluxed (45 min for 4d, 1 h for 4e, 1.5 h for 5a, b, c, 5 h for 5d).
After cooling to r.t., the mixture was extracted with CH2Cl2 (3 ¥ 5
mL). The combined organic layers were dried with MgSO4, concen-
trated and purified by flash chromatography (CH2Cl2/Me2CO, 95:5)
Benzofuran-3-ones 6 and 7; General Procedure (Method B)
DBU (0.05 mmol) was added to a solution of the o-hydroxybenz-
oylaziridine 4 (0.5 mmol) in dry EtOH (3 mL). After refluxing for
1 h the solution was concentrated and submitted to flash chromato-
graphy (CH2Cl2/Me2CO, 95:5).
Article Identifier:
1437-210X,E;2000,0,10,1444,1448,ftx,en;H01400SS.pdf
Synthesis 2000, No. 10, 1444–1448 ISSN 0039-7881 © Thieme Stuttgart · New York