Substrate-controlled diastereoselective aziridination of alkenes using 3-acetoxyaminoquinazolinone in the presence of hexamethyldisilazane

Article abstract of DOI:10.1016/j.tetlet.2004.11.080

8-Phenylmenthol derived α,β-unsaturated esters were aziridinated highly diastereoselectively using 3-acetoxyamino-2-ethylquinazolinone. The yields of these aziridines were greatly improved in the presence of hexamethyldisilazane.

Full text of DOI:10.1016/j.tetlet.2004.11.080

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 197–199
Substrate-controlled diastereoselective aziridination of
alkenes using 3-acetoxyaminoquinazolinone in the presence of
hexamethyldisilazane
Sabri Ulukanli,a,* Semistan Karabuga,a Ayhan Celikb and Cavit Kazazc
aDepartment of Chemistry, Faculty of Science and Letters, University of Kafkas, 36100 Kars, Turkey
bEdinburgh Center for Protein Technology, Chemistry Department, University of Edinburgh, King’s
Buildings, West Mains Road, Edinburgh, EH9 3JJ, UK
cDepartment of Chemistry, Faculty of Science and Letters, Ataturk University, 25240 Erzurum, Turkey
Received 10 October 2004; revised 10 November 2004; accepted 16 November 2004
Available online 30 November 2004
Abstract—8-Phenylmenthol derived a,b-unsaturated esters were aziridinated highly diastereoselectively using 3-acetoxyamino-2-
ethylquinazolinone. The yields of these aziridines were greatly improved in the presence of hexamethyldisilazane.
Ó 2004 Elsevier Ltd. All rights reserved.
3-Acetoxyaminoquinazolinones, for example, QNHOAc
2 are well known aziridinating agents for alkenes
through the mechanism shown in1,2 A (Scheme 1). The
mechanism for 3-membered ring formation, at least
for electron-rich alkenes (R = Ph) as in B resembles that
by which peroxyacetic acid converts alkenes into epox-
ides (Bartlett mechanism).3,4 Although peroxyacids do
not convert a,b-unsaturated esters to epoxides, their
counterpart, QNHOAc 2 reacts with a,b-unsaturated es-
ters to give the corresponding aziridines in good yields
(see below). The mechanism in this case has been sug-
gested to involve Michael addition of the exocyclic
nitrogen onto the b-position of the a,b-unsaturated ester
followed by an SN2 type displacement of the acetoxy
group by the developing partially negative charge at
Ca (see C in Scheme 1). In aziridine formation for both
methyl acrylate and styrene, endo overlap between the
carbonyl or the phenyl group and the quinazolinone car-
bonyl is also required (see B and C).
stereoselectivity (>50:1) (reagent-controlled) in the azir-
idination of alkenes, for example, styrene in the presence
of Ti(OBut)4 (Scheme 2).
Despite the usefulness of aziridines for accessing a- and
b-amino acids, 1,2-diamines and 1,2-aminoalcohols,
there are few methods, especially diastereoselective ones,
for the conversion of alkenes into aziridines.1,7,8 Here we
present our results on the substrate-controlled diastereo-
selective aziridination of a,b-unsaturated esters derived
from the easily prepared alcohol (À)-phenylmenthol9
(R*) using QNHOAc 2.
The chiral esters used in our work were converted into
their aziridines using lead tetraacetate (LTA) acetoxyla-
tion of 3-amino-2-ethylquinazolinone 1 (R = Et) in
CH2Cl2 at À18 to À20 °C under various conditions
(see Schemes 1 and 3 and Table 1).
During decomposition of QNHOAc 2, or the analogous
N-aminophthalimide derivative PNHOAc, in the pres-
ence of electron deficient alkenes, or in the absence of
alkenes, the main product is deaminated quinazolinone
9 (QH) or phthalimide (PH).10–12 However, 2 molequiv
of hexamethyldisilazane (HMDS) scavenges the acetic
acid formed in the acetoxylation as well as in the aziri-
dination steps, so prolonging the lifetime of the aziridi-
nating agent, for example, QNHOAc 2 (stable at <0 °C),
and increases the aziridine yield.13
Additionally, the quinazolinone ring in the aziridinating
agent offers a number of advantages: in particular, the
presence of a stereogenic centre at its 2-position, as in
QNHOAc 4,5,6 can result in high or even complete dia-
Keywords: Aziridination; 3-Acetoxyaminoquinazolinone; 8-Phenyl-
menthol; Substrate-controlled diastereoselective aziridination.
*
Corresponding author. Tel.: +90 4742120201/128; fax: +90
4742122706; e-mail: ulukanli@kafkas.edu.tr
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.080

198
S. Ulukanli et al. / Tetrahedron Letters 46 (2005) 197–199
O
Q
H
R
H
H
Q
N
H
O
LTA, CH2Cl2
N
N
N
H
R
H
H
-20ºC to -25ºC
H
H
H
N
O
O
N
R
NH2
NHOAc
3
2
QNHOAc
1
QNH2
A
R=Ph
R=CO2Me
N
H
N
N
OAc
N
OAc
H
N
N
H
H
H
H
Me
O
H
H
B
C
Scheme 1.
H
H
slight excess of N-aminophthalimide (1.5 equiv) in the
presence of LTA gave up to 94% of the aziridine. There-
fore, we carried out aziridination of the alkenes using an
excess of the aziridinating agent QNHOAc 2 (2 equiv) in
the presence of HMDS (see Table 2).
Ph
H
N
t
N
Ti(OBu )
CH Cl
4
t Bu
t Bu
2
2
N
N
O
N
O
o
o
-20 C to -25
C
OH
OH NHOAc
H
H
Ph
In the aziridination of chiral acrylate 8a with QNHOAc
2, the product was shown to be a single diastereoisomer
present as a mixture of N-invertomers (13:1) from care-
H
4
1
5 dr:>50:1
ful H NMR examination of the C-5 proton of the qui-
nazolinone ring. This ratio of N-invertomers was not
Scheme 2.
affected by chromatotron purification of the crude
product as shown by re-examination of the H NMR
1
spectrum of the resulting oily product. The ratio of N-
invertomers was not affected by chromatography be-
cause interconversion is fast on the real timescale in
solution.15 In the case of the crotonate derived aziridine
8b, the ratio of N-invertomers (3.5:1), before and after
chromatographic purification was again determined
measuring the signals of the C-5 proton of the Q ring.
No minor diastereoisomer was detectable 1H NMR
The yields of aziridine from acrylate, crotonate and
methacrylate using QNHOAc 2 were 27%, 28% and
17%, respectively, (Table 1 entries 1, 5 and 7) and were
raised to 72%, 79% and 66%, respectively, (Table 1, en-
tries 3, 6 and 9) in the presence of 2 equiv of HMDS (rel-
ative to the quinazolinone). Yang and Chen14 reported
that aziridination of N-enoylpyrazolidinones using a
R3
R'2
CO2R*
R1
Q
N
8
N
R3
R2
CO2R*
R1
N
HMDS, CH2Cl2
+
-18 oC to -20 o
C
N
O
N
H
O
NHOAc
2
7
9
8a R1, R2, R3=H
8b R2=CH3, R1 and R3=H
8c R1=CH3, R2 and R3=H
8d R2=Et, R1 and R3=H
8e R2=Ph, R1 and R3=H
R*= 8-phenylmenthol
Scheme 3.

S. Ulukanli et al. / Tetrahedron Letters 46 (2005) 197–199
Table 1. Reactions under various conditions (absence or presence of HMDS)
199
Entry
Alkenes
Moleequiv of quinazolinone
Moleequiv of alkene
Moleequiv of HMDS
Yield (%)
1
2
3
4
5
6
7
8
9
Acrylate
Acrylate
Acrylate
2
1
2
1
2
2
2
1
2
1
2
1
2
1
1
1
2
1
—
2
27
68
4
72
Crotonate
Crotonate
Crotonate
Methacrylate
Methacrylate
Methacrylate
—
—
4
<15
<28
79
—
2
17
48
4
66
Table 2. All aziridinations were carried out using QNHOAc 2 (2equiv)
and alkenes (1equiv) in the presence of HMDS (4equiv) in dichlo-
romethane at À18 °C to À20 °C
In conclusion, we have presented herein the highly sub-
strate-controlled diastereoselective aziridination of 8-
phenylmenthol derived olefinic alkenes using 3-acet-
oxyamino-2-ethylquinazolinone 2 (QNHOAc). Yields
obtained in these reactions were greatly improved in
the presence of hexamethyldisilazane.
Entry
Substrate
Yield (%)a
Drb
1
2
3
4
5
8a
8b
8c
8d
8e
72
79
73
71
66
>50:1
>50:1
>50:1
>50:1
>50:1
Acknowledgements
a Isolated yield (after chromatography).
b Determined by 1H NMR and LCMS (C18-RP column with
EPS + MS detection).
We acknowledge Dr. R. S. Atkinson for his comments
on this manuscript. We wish to thank the Turkish Scien-
tific Research Council (Grant TBAG 2322 (103T071))
for generous support of this work. We are also grateful
to the Departments of Chemistry at Ataturk University
and Karadeniz Teknik University for use of the
400 MHz NMR facility and LCMS analysis.
H
AcO
H
N
H
O
O
N
O
N
References and notes
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1
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The high diastereoselectivity using QNHOAc 2 in the
aziridination of esters 8a–e can be ascribed to the p-
stacking effect16 between the phenyl group and/or the
double bond of the alkene in the unsaturated ester. This
blocks one face of the alkene directing the exocyclic
nitrogen in QNHOAc 2 to attack the other face of the
alkene as in Figure 1.
Although other methods for high reagent-controlled
diastereoselective aziridination of a,b-unsaturated esters
or amides are known,14 none shows the generality of the
present method. It is noteworthy that crotonate and
methacrylate esters give poor diastereoselectivity in re-
agent-controlled aziridination using QNHOAc 4.5
16. Jones, G. B.; Chapman, B. J. Synthesis 1995, 475.