Aziridination of alkenes using 2-substituted-3-acetoxyamino-quinazolin-4(3H)-ones: Changes in transition state geometry resulting from addition of trifluoroacetic acid or by an electron-withdrawing 2-substituent

Article abstract of DOI:10.1039/a809703h

The effects of TFA on the competitive reactions of 3-acetoxyaminoquinazolinones 2 and 10 with methyl acrylate and with tert-butyl acrylate are interpreted as supporting a change in transition state geometry from one where (Q)C=O/ (ester)C=O overlap 7b is

Full text of DOI:10.1039/a809703h

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Aziridination of alkenes using 2-substituted-3-acetoxyamino-
quinazolin-4(3H)-ones: changes in transition state geometry
resulting from addition of trifluoroacetic acid or by an electron-
withdrawing 2-substituent
Robert S. Atkinson* and Sabri Ulukanli
Department of Chemistry, The University, Leicester, UK LE1 7RH
Received (in Cambridge) 14th December 1998, Accepted 4th February 1999
The effects of TFA on the competitive reactions of 3-acetoxyaminoquinazolinones 2 and 10 with methyl acrylate and
with tert-butyl acrylate are interpreted as supporting a change in transition state geometry from one where (Q)C᎐O/
᎐
(ester)C᎐O overlap 7b is replaced by (Q)C᎐NϩH/(ester)C᎐O overlap 7c (Q = quinazolinone). Aziridinations of methyl
᎐
᎐
᎐
or tert-butyl acrylate using 2-trifluoromethyl-substituted 3-acetoxyaminoquinazolinones 20 and 21 take place with
(Q)C᎐N/(ester)C᎐O overlap 22 even in the absence of TFA.
᎐
᎐
3-Acetoxyaminoquinazolinones e.g. 2 (Q1NHOAc), prepared as
tions with alkenes bearing electron-donating substituents to
form the corresponding three-membered rings are presumably
similar.4 However, unlike peroxyacids, compounds 2 and 6 react
with e.g. α,β-unsaturated esters to give the corresponding azirid-
ines in good yields (see above). We have suggested a mechanism
for aziridination in this latter case which involves (a) Michael
addition by the acetoxyamino nitrogen to the β-position of the
α,β-unsaturated ester followed by (b) SN2-type substitution of
the acetoxy group on the exocyclic nitrogen by the develop-
ing negative charge at Cα (see 7b Scheme 3). Activation of the
shown in Scheme 1, are aziridinating agents for alkenes.1
Scheme 1 Reagents: i, Pb(OAc)4 CH2Cl2, 20 ЊC; ii, hex-1-ene; iii,
hex-1-ene, TFA (3.4 equiv.).
The presence of trifluoroacetic acid (TFA) in these aziridin-
ations has a profound effect both upon the yield of aziridine
and upon the stereoselectivity of the reaction. Thus, for
example, hex-1-ene is a relatively unreactive alkene towards
Q1NHOAc 2 and the yield of aziridine 3 is less than 15% even in
the presence of excess of alkene: the major product of the reac-
tion is quinazolin-4(3H)-one 4. In the presence of TFA (3 mol
equiv.) the combined yield of aziridine 3 and its ring-opened
product 5 rises to 75%.2
The diastereomer ratio in reagent-controlled aziridination of
α,β-unsaturated esters e.g. for methyl acrylate with Q2NHOAc
6 is increased from 2.4:1 in the absence of TFA to 1:8.7 in
its presence i.e. the preferred sense of diastereoselectivity is
inverted (Scheme 2).3
Scheme 3
α,β-unsaturated ester towards Michael addition is brought
about by overlap of the ester carbonyl oxygen with the quin-
azolinone carbonyl carbon: such an overlap requires the s-cis
conformation of the ester (see 7b).5
To account for the increase and the change in the preferred
sense of stereoselectivity in Scheme 2 brought about by TFA,
we proposed3 that this acid protonated the (Q)N-1 and changed
the transition state geometry from one in which (Q)C᎐O/
(ester)C᎐O overlap 7b is replaced by (Q)C᎐N/(ester)C᎐O over-
lap 7c except that at the time the aziridinating species was
thought to be the N-nitrene. Because a minimum of 3 equiv. of
TFA must be used for the effect produced in Scheme 2, it is
᎐
᎐
᎐
᎐
possible that protonation of the (Q)C᎐O oxygen also occurs in
᎐
the aziridinating species in Scheme 3.
In this paper we present evidence which supports this pro-
posed change in transition state geometry from 7b to 7c not
only in the presence of TFA but also when the quinazolinone
2-substituent is strongly electron-withdrawing, e.g. a trifluoro-
methyl group.
3-Amino-2-ethyl-5-methylquinazolin-4(3H)-one
9 is pre-
pared from the commercially available 6-methylanthranilic acid
8 by the route shown in Scheme 4.
Competitive aziridination of methyl acrylate (1 equiv.) by a
mixture of 3-acetoxyaminoquinazolinones 2 and 10, prepared
Scheme 2
These 3-acetoxyaminoquinazolinones 2 and 6 are nitrogen
equivalents of peroxyacids and the mechanisms of their reac-
J. Chem. Soc., Perkin Trans. 2, 1999, 771–776
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Scheme 4 Reagents: i, (CH3CH2CO)2O; ii, Ac2O; iii, NH2NH2, EtOH.
in situ by acetoxylation with lead tetraacetate (LTA) (2.1 mol
equiv.) of the corresponding 3-aminoquinazolinones 1 (1
equiv.) and 9 (1 equiv.) gave a 3:2 ratio of aziridines 11 and 12
(Scheme 5).
Scheme 6
(Q)C᎐N (as in 17) removes the methyl or tert-butyl group from
the vicinity of this 5-methyl substituent.
᎐
We have also prepared the 3-amino-5-methyl-2-trifluoro-
methylquinazolinone 19 (Scheme 7) by a route analogous to
Scheme 5 Reagents: i, LTA, CH2Cl2, Ϫ20 ЊC; ii, methyl acrylate; iii,
tert-butyl acrylate.
This ratio of aziridines 11:12 was measured directly from
the NMR spectrum of the crude reaction product by inte-
gration of signals at δ 3.58 and 3.41 from the aziridine ring
protons adjacent to the ester groups in 11 and 12 respectively
(from comparison with the authentic samples). In contrast,
an analogous competitive aziridination of tert-butyl acrylate
with 3-acetoxyaminoquinazolinones 2 and 10 gave only azirid-
ine 13: none of the aziridine 14 was detectable when the
NMR spectrum of the crude reaction mixture was compared
with that from a sample of authentic aziridine 14. The 3-
acetoxyaminoquinazolinone 10 is converted to quinazolin-
4(3H)-one 15 which was isolated from the reaction mixture in
40% yield.
However, when these competitive reactions of compounds 2
and 10 with either methyl acrylate or with tert-butyl acrylate
were carried out in the presence of TFA (3 equiv.) a 1:1 ratio of
aziridines 11:12 and 13:14 was obtained in each case.
Scheme 7 Reagents: i, (CF3CO)2O; ii, NH2NH2, EtOH; iii, LTA,
CH2Cl2, Ϫ20 ЊC; iv, methyl acrylate; v, tert-butyl acrylate.
These changes in aziridine ratios are in agreement with those
predicted from a change in mechanism from 7b to 7c (Scheme
3) and correspond to a change from endo(Q)C᎐O/(ester)C᎐O
that in Scheme 4. Its 3-acetoxyamino derivative 21 shows a
similar stability at room temperature to that of the previously
prepared 5-H analogue 20.6 Competitive aziridination of
methyl acrylate (1 equiv.) with a mixture of the compounds 20
(1 equiv.) and 21 (1 equiv.) gave a 1:1 ratio of the correspond-
ing aziridines 23 and 24 (Scheme 7) from examination of the
NMR spectrum of the crude reaction mixture and by com-
parison with the spectra of authentic samples.
The corresponding competitive reaction of tert-butyl acryl-
ate with Q4NHOAc 20 and Q5NHOAc 21 likewise gave a 1:1
ratio of aziridines 25 and 26. It appears, therefore, that even in
the absence of TFA, the presence of a trifluoromethyl group as
the 2-substituent on the quinazolinone favours an aziridination
᎐
᎐
overlap 16 to endo(Q)C᎐N/(ester)C᎐O overlap 17 (Scheme 6)
᎐
᎐
mediated by TFA. Thus even with methyl acrylate there is a
small steric interaction between the methyl group of the ester
and the 5-methyl group which favours formation of aziridine
11. The augmented interaction of the 5-methyl group with the
tert-butyl group is responsible for the absence of any aziridine
14 from the reaction of tert-butyl acrylate with compound 10.
However, in the presence of TFA, the 5-methyl substituent
is without effect in competitive aziridination of both methyl
acrylate and tert-butyl acrylate because endo interaction of
the ester carbonyl oxygen and the quinazolinone imine carbon
transition state 22 having (Q)C᎐N/(ester)C᎐O overlap as
᎐
᎐
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illustrated in Scheme 7. The increase in electrophilicity at the
(Q)C᎐N carbon brought about either by protonation of (Q)N-1
᎐
or by trifluoromethyl substitution at (Q)C-2 is most likely
responsible for the change in transition state geometry.
In an attempt to discover just how electron-withdrawing
this quinazolinone 2-substituent needs to be for a transition
state resembling 22 to be favoured we synthesised the 2-(1,1-
dichloro)ethyl-substituted 3-amino-5-methylquinazolinone 28
(Scheme 8) from 6-methylanthranilic acid 8 by a route analo-
Scheme 8 Reagents: i, CH3CCl2COCl, pyr; ii, NH2NH2, EtOH; iii,
heat; iv, LTA, CH2Cl2, Ϫ20 ЊC; v, methyl acrylate or tert-butyl acrylate.
gous to that in Scheme 4. Competitive reactions of the corre-
sponding 3-acetoxyamino derivative 30 and the known 5-H
analogue 29 for methyl acrylate gave aziridines 32 and 31 in a
1:1.1 ratio from integration of the respective aziridine H-3
proton signals in the NMR spectrum of the crude reaction
product. However, competitive reaction of Q6NHOAc 29 and
Q7NHOAc 30 with tert-butyl acrylate gave aziridines 33 and 34
in a 3:2 ratio respectively from comparison of signals from the
corresponding aziridine ring protons.
Scheme 9
Preferential aziridination of tert-butyl acrylate by Q6NHOAc
29 may be the result of the reduced electrophilicity and greater
bulk of the dichloroethyl group by comparison with the tri-
fluoromethyl group. Thus, whereas Q7NHOAc 30 reacts via a
transition state 35 analogous to 22, competitive reaction by
Q6NHOAc 29 occurs by both transition states 36 and 37 lead-
ing to more of aziridine 33 than 34 (Scheme 9). If this interpret-
ation is correct, the aziridination of e.g. methyl acrylate via a
transition state resembling 22 may be possible with a chiral
2-substituent on the quinazolinone less electron-withdrawing,
if also less bulky, than the 1,1-dichloroethyl group. Diastereo-
selectivity in aziridination via the two competing transition
states represented by 22 (CF3 replaced by chiral group) would
be expected to be greater than via the two transition states
represented by 7b (R the same chiral group).
The effect of addition of TFA on aziridination of methyl
acrylate with Q2NHOAc 6 (Scheme 2)3 can be accounted for by
a change in transition state geometry from 38 to 39 (Scheme
10): the acetoxy group on the exocyclic nitrogen is syn to
the chiral centre in 38 and anti in 39 and, we believe, plays
an important role in determining the preferred sense of
diastereoselectivity in the reaction with or without the presence
of TFA.
Thus the relative configuration of the major aziridine
diastereoisomer formed in the absence of TFA was previously
assigned as 40 by analogy with the relative configuration of
the preferred diastereoisomer from aziridination of methyl
crotonate with Q2NHOAc 6. The sites occupied by the methyl
and tert-butyl in transition state 38 presumably reflect the
unfavourable interaction between the tert-butyl and N-acetoxy
group which is present in the transition state 42 for formation
of the minor aziridine diastereoisomer 41. There is a change in
the preferred sense of diastereoselectivity in the TFA-catalysed
reaction giving aziridine 41 because the opposite face of the
α,β-unsaturated ester is attacked in transition state 39 by com-
parison with 38 with the same configuration at the (Q)C-2
Scheme 10
chiral centre in both cases. The methyl group can be better
accommodated “inside” in transition state 39 to avoid
unfavourable interaction with the ester OMe and because the
N-acetoxy group is now anti to the chiral centre.
Experimental
1H NMR spectra were recorded on a Bruker ARX 250 NMR
spectrometer. Chemical shifts are reported as δ in units of parts
per million (ppm) relative to tetramethylsilane (δ 0.00 singlet)
in deuterated chloroform (CDCl3); J values are given in Hz.
Melting points were obtained on a Kofler hot stage and are
uncorrected. Infrared spectra (IR) of all compounds were
recorded in dichloromethane (CH2Cl2) using a Perkin-Elmer
J. Chem. Soc., Perkin Trans. 2, 1999, 771–776
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PE 298 spectrometer. Mass spectra were recorded on a Kratos
Concept 1H Magnetic Sector Mass spectrometer and all spec-
tra were determined in units of mass relative to charge (m/z)
with electron impact (EI) ionisation or fast atomic bombard-
ment (FAB); only peaks ≥20% of the base peak are given.
Dichloromethane was distilled from CaH2 and stored over 4 Å
molecular sieves. Lead tetraacetate was freed from acetic acid
under reduced pressure prior to use. All other reactants were
reagent grade and were used as received.
61%) mp 142–144 ЊC (from ethanol) (Found: C, 65.25; H, 6.45;
N, 20.65. C11H13N3O requires C, 65.0; H, 6.45; N, 20.65%);
δH 1.29 (t, J 7.2, CH2CH3), 2.83 [s, 5-CH3 (Q)], 2.96 (q, J 7.2,
CH2CH3), 4.72 (s, NH2) and 7.55–7.11 [m, H-6, H-7 and H-8
(Q)]; νmax/cmϪ1 3320w, 2965w, 1665s, 1595s and 1570m; m/z (%)
204 (MHϩ, 100), 154 (58), 137 (29) and 136 (43).
Aziridination of methyl acrylate using Q1NHOAc 2
The general procedure 1 was followed using 1 (0.1 g, 0.53
mmol), LTA (0.26 g, 0.58 mmol) and methyl acrylate (0.05 g,
0.63 mmol) in dichloromethane (2 cm3). An NMR spectrum of
the crude product showed that a mixture of aziridine 11 and
quinazolin-4(3H)-one 4 was present in a ratio 4.4:1 from the
integration of signals at δ 8.15 and 8.22 ppm respectively. The
crude product crystallised on addition of ethanol to give azirid-
ine 11 as a colourless solid (0.1 g, 71%) mp 116–118 ЊC (from
ethanol) (lit.1 mp 116–118 ЊC) δH 1.42 (t, J 6.9, CH2CH3), 2.85
(d, J 5.0, azir. H-3 trans to Q), 3.02 (m, CH2CH3), 3.12 (d, J 7.5,
azir. H-3 cis to Q), 3.58 (dd, J 7.5 and 5.0 azir. H-2), 3.80 (s,
OCH3), 7.32–7.76 [m, 6-H, 7-H, 8-H (Q)] and 8.15 [d, J 8.2, 5-H
(Q)].
General procedure (1) for the aziridination of á,â-unsaturated
esters
3-Aminoquinazolinone (1 equiv.) and acetic acid-free lead
tetraacetate (LTA) (1.1 mol equiv.) were added alternately and
continuously in very small portions over 15 min to a vigorously
stirred solution of dry dichloromethane (1 cm3/100 mg of
3-aminoquinazolinone) cooled with a dry ice–acetone bath held
at Ϫ20 to Ϫ25 ЊC. The mixture was then stirred for a further
5 min before dropwise addition of the α,β-unsaturated ester
(1.5–3.5 equiv.) as a solution in dichloromethane (1 cm3/500
mg) over 2 min and the temperature of the solution was then
allowed to rise to ambient over 20–25 min with stirring
throughout. Lead diacetate was separated, dichloromethane
(15 cm3) added, the organic solution washed successively with
saturated aqueous sodium hydrogen carbonate and water, dried
with magnesium sulfate and the solvent removed by evapor-
ation under reduced pressure.
Aziridination of methyl acrylate using Q3NHOAc 10
The general procedure 1 was followed using 9 (0.1 g, 0.49
mmol), LTA (0.24 g, 0.54 mmol), methyl acrylate (0.05 g,
0.59 mmol) and, in addition, HMDS (0.16 g, 0.98 mmol)7 in
dichloromethane (2 cm3) was added. An NMR spectrum of the
crude product showed a mixture of aziridine 12 and quinazolin-
4(3H)-one 15 present in a 3.5:1 ratio from the integration of
signals at δ 3.50 and 10.72 ppm respectively. The crude product
crystallised on addition of ethanol to give aziridine 12 as a
colourless solid (0.11 g, 78%) mp 132–134 ЊC (from ethanol)
(Found: Mϩ 287.126. C15H17N3O3 requires M 287.126); δH 1.40
(t, J 7.2, CH2CH3), 2.81 (s, 5-CH3), 2.92 (dd, J 5.0 and 1, azir.
H-3 trans to Q), 3.03 (m, CH2CH3 and azir. H-3 cis to Q), 3.41
(dd, J 7.5 and 5.0, azir. H-2), 3.85 (s, OCH3), 7.13 [d, J 7.2, 6-H
(Q)] and 7.49 [m, 7-H and 8-H (Q)]; νmax/cmϪ1 1750s, 1675s and
1600m; m/z (%) 287 (Mϩ, 85), 145 (100), 90 (24) and 89 (22).
General procedure (2) for the aziridination of á,â-unsaturated
esters in the presence of TFA
A solution of 3-acetoxyaminoquinazolinone at Ϫ20 ЊC was
prepared as described above, separated from lead diacetate at
this temperature (on a small scale a Pasteur pipette can be used)
and the cold solution added dropwise over 2 min to a stirred
solution of the alkene (1.5–3.5 equiv.) in dichloromethane (1
cm3/50 mg) containing TFA (3 equiv.) and held at Ϫ20 ЊC (bath
temp.). The temperature of the stirred solution was allowed to
rise to room temperature over 20–25 mins. After addition of
dichloromethane (15 cm3), the solution was washed successively
with aqueous saturated sodium hydrogen carbonate and water,
dried with magnesium sulfate and the solvent removed by evap-
oration under reduced pressure.
Aziridination of tert-butyl acrylate using Q1NHOAc 2
General procedure 1 was followed using 1 (0.1 g, 0.53 mmol),
LTA (0.26 g, 0.58 mmol) and tert-butyl acrylate (0.1 g, 0.79
mmol) in dichloromethane (2 cm3). An NMR spectrum of the
crude product showed a mixture of aziridine 13 and its corre-
sponding quinazolin-4(3H)-one 4 were present in a ratio 5.3:1
from integration of signals at δ 8.15 and 8.22 ppm respectively.
The crude product crystallised on addition of ethanol to give
aziridine 13 as a colourless solid (0.1 g, 70%) mp 88–89 ЊC
(from ethanol) (Found: Mϩ 315.158. C17H21N3O3 requires M
315.158); δH 1.42 (t, J 7.5, CH2CH3), 1.53 (s, But), 2.87 (dd, J 5.0
and 1.3, azir. H-3 trans to Q), 3.09 (q, J 7.5, CH2CH3), 3.26 (dd,
J 7.5 and 1.3, azir. H-3 cis to Q), 3.51 (dd, J 7.5 and 5.0 azir.
H-2), 7.37–7.72 [m, 6-H, 7-H, 8-H (Q)] and 8.15 [ddd, J 7.2, 1.3
and 0.6, 5-H (Q)]; νmax/cmϪ1 1725s, 1670s and 1595m; m/z (%)
315 (Mϩ, 33), 259 (100), 175 (23), 174 (42), 173 (32), 131 (90)
and 130 (48).
Preparation of 3-amino-2-ethyl-5-methylquinazolin-4(3H)-one 9
To 6-methylanthranilic acid 8 (Aldrich) (12.5 g, 82 mmol) was
added propionic anhydride (10.7 g, 82 mmol) and the mixture
was heated at 100 ЊC with stirring for 1 h. After cooling the
mixture was poured into water, dichloromethane (100 cm3) was
added and the organic layer separated, dried and concentrated
under reduced pressure to give an oil which was then cyclised by
heating under reflux in acetic anhydride (35 cm3) for 2.5 h. The
bulk of the acetic anhydride was removed by distillation under
reduced pressure (Kugelrohr) using a water pump. 2-Ethyl-5-
methyl-4H-3,1-benz[d]oxazin-4-one was obtained as a colour-
less solid by crystallisation of the residue from light petroleum
(13.4 g, 86%) mp 84–85 ЊC (Found: Mϩ 189.0789. C11H11NO2
requires M 189.0789); δH 1.54 (t, J 7.5, CH2CH3), 2.87 (q, J 7.5,
CH2CH3), 2.98 (s, 5-CH3), 7.45 (d, J 7.2, H-6), 7.58 (dd, J 7.5
and 0.6, H-8) and 7.80 (dd, J ~7.0 and 7.5, H-7); νmax/cmϪ1
2950w, 1750s, 1655s and 1600s; m/z (%) 189 (Mϩ, 71), 160 (100)
and 104 (22). 2-Ethyl-5-methyl-4H-3,1-benz[d]oxazinone (6.7 g,
35 mmol) and hydrazine hydrate (12.3 g, 246 mmol) were heated
under reflux for 6 h with ethanol (100 cm3) as solvent under
nitrogen. After cooling, the bulk of the ethanol was removed
under reduced pressure and the residue dissolved in dichloro-
methane (100 cm3) which was then washed with water (100
cm3), dried and concentrated to give 3-amino-2-ethyl-5-
methylquinazolin-4(3H)-one 9 as colourless crystals (4.36 g,
Aziridination of tert-butyl acrylate using Q3NHOAc 10
The general procedure 1 was followed using 9 (0.1 g, 0.49
mmol), LTA (0.24 g, 0.54 mmol) and tert-butyl acrylate (0.09 g,
0.74 mmol) in dichloromethane (2 cm3). The crude product
crystallised on addition of ethanol to give aziridine 14 as a
colourless solid (0.12 g, 74%) mp 121–123 ЊC (from ethanol)
(Found: C, 65.6; H, 7.0; N, 12.7. C18H23N3O3 requires C, 65.65;
H, 7.05; N, 12.75%); δH 1.47 (t, J 7.2, CH2CH3), 1.60 (s, But),
2.88 [s, 5-CH3 (Q)], 2.97 (dd, J 4.7 and 1.3, azir. H-3 trans to Q),
3.11 (q, J 7.2, CH2CH3), 3.21 (dd, J 7.5 and 1.3, azir. H-3 cis to
Q), 3.35 (dd, J 7.5 and 4.7 azir. H-2), 7.22 [d, J 7.2, 6-H (Q)] and
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7.56 [m, 7-H and 8-H (Q)]; νmax/cmϪ1 1735s, 1675s and 1595m;
m/z (%) 329 (Mϩ, 22), 273 (64), 188 (24) and 145 (100).
(Q)]; νmax/cmϪ1 1735s, 1690s and 1605m; m/z (%) 355 (Mϩ, 8),
299 (45), 214 (56), 84 (100) and 57 (40).
Aziridination of tert-butyl acrylate using Q5NHOAc 21
Preparation of 3-amino-2-trifluoromethyl-5-methylquinazolin-
4(3H)-one 19
The general procedure 1 was followed using 19 (0.1 g, 0.41
mmol), LTA (0.2 g, 0.45 mmol) and tert-butyl acrylate (0.11 g,
0.82 mmol) in dichloromethane (2 cm3) to afford aziridine 26
which crystallised on addition of ethanol as a colourless solid
(0.09 g, 57%) mp 164–165 ЊC (from ethanol) (Found: C, 55.2;
H, 4.95; N, 11.35. C16H16N3O3F3 requires C, 55.3; H, 4.9; N,
11.35%); δH 1.49 (s, But), 2.58 (d, J 4.4, azir. H-3 trans to Q),
2.79 (s, 5-CH3), 3.92 (d, J 7.2, azir. H-3 cis to Q), 4.16 (dd, J 7.2
and 4.4, azir. H-2) and 7.26–7.77 [m, 6-H, 7-H, 8-H (Q)];
νmax/cmϪ1 1745s, 1690s and 1605m; m/z (%) 369 (Mϩ, 24), 313
(100), 296 (30), 229 (20), 228 (74), 144 (39), 118 (96), 90 (30), 89
(22), 69 (21), 57 (93) and 55 (54).
To a suspension of 6-methylanthranilic acid (10.3 g, 68 mmol)
in CHCl3 (200 cm3) was added trifluoroacetic anhydride (43 g,
205 mmol) dropwise with stirring. The mixture was heated
under reflux for 1 h, then cooled and the excess trifluoroacetic
anhydride removed under reduced pressure to give a yellow
solid. 2-Trifluoromethyl-5-methyl-4H-3,1-benz[d]oxazin-4-one
was obtained as a colourless solid (13.4 g, 86%) mp 86–88 ЊC
(from light petroleum) (Found: C, 52.2; H, 2.7; N, 6.05.
C10H6NO2F3 requires C, 52.4; H, 2.65; N, 6.1%); δH 2.83 (s,
5-CH3), 7.48 (d, J 7.9, 6-H), 7.60 (d, J 7.5, 8-H) and 7.76 (app. t,
J ~7.5, 7-H); νmax/cmϪ1 1780s, 1680m and 1600m; m/z (%) 229
(Mϩ, 32), 160 (100) and 104 (38). 2-Trifluoromethyl-5-methyl-
4H-3,1-benz[d]oxazin-4-one (9.5 g, 41.5 mmol) and hydrazine
hydrate (12.3 g, 246 mmol) were stirred for 1 h at room temper-
ature in ethanol (50 cm3). The bulk of the ethanol was removed
under reduced pressure and the residue dissolved in ethyl acet-
ate (100 cm3) which was washed successively with hydrochloric
acid (2 M, 100 cm3) and brine (100 cm3), dried with magnesium
sulfate and evaporated to give 3-amino-2-trifluoromethyl-
quinazolin-4(3H)-one 19 as colourless crystals (6.4 g, 63%) mp
154–156 ЊC (from ethanol) (Found: C, 49.55; H, 3.4; N,
17.1. C10H8N3OF3 requires C, 49.4; H, 3.3; N, 17.3%); δH 2.83 [s,
5-CH3 (Q)], 4.83 (s, NH2) and 7.55–7.11 [m, H-6, H-7 and H-8
(Q)]; νmax/cmϪ1 3320w, 1680s, 1640s and 1600m; m/z (%) 243
(Mϩ, 100), 227 (32), 214 (61) and 144 (38).
Preparation of 3-amino-2-(1,1-dichloroethyl)-5-methylquin-
azolin-4(3H)-one 28
To a solution of 6-methylanthranilic acid (3 g, 20 mmol) in
pyridine (30 cm3) was added 2,2-dichloropropanoyl chloride
(3.2 g, 20 mmol) dropwise with stirring. The mixture was stirred
for a further 16 h at room temperature, then ethyl acetate was
added (50 cm3), the solution washed successively with hydro-
chloric acid (2 M, 3 × 50 cm3), brine (50 cm3) and water (50
cm3), the organic layer was dried with magnesium sulfate and
then evaporated under reduced pressure to give 2-(1,1-dichloro-
ethyl)-5-methyl-4H-3,1-benz[d]oxazin-4-one as a brown solid
(2.5 g, 49%). δH 2.54 and 2.82 (2 × s, 5-CH3 and CH3CCl2), 7.38
(d, J 7.5, 6-H), 7.52 (d, J 7.9, 8-H) and 7.9 (dd, J 7.5 and 7.9,
7-H); νmax/cmϪ1 1770s, 1650s and 1600m. 2-(1,1-Dichloroethyl)-
5-methyl-4H-3,1-benz[d]oxazin-4-one (2.3 g, 8.5 mmol) and
hydrazine hydrate (0.5 g, 10 mmol) were heated under reflux for
3 h in ethanol (5 cm3). The bulk of the ethanol was removed
under reduced pressure and the residue dissolved in dichloro-
methane (30 cm3) which was washed with water (30 cm3) and
brine (30 cm3), dried with magnesium sulfate and evaporated
to give N-2,2-dichloropropanoyl-6-methylanthranilic acid
hydrazide as a brown solid (1 g, 40%). δH 2.27 and 2.3 (2 × s,
5-CH3 and CH3CCl2), 4.05 (s, br, NHNH2), 6.98 (d, J 7.9, 6-H),
7.22 (dd, J 8.2 and 7.9, 7-H), 7.34 (s, NHNH2), 7.74 (d, J 8.2,
8-H) and 9.5 (s, NH). The N-2,2-dichloropropanoyl-6-methyl-
anthranilic acid hydrazide (1 g, 3.4 mmol) was placed in a
Young’s tube with ethanol (3 cm3) and heated at 150 ЊC for
16 h. Excess ethanol was removed, the residue dissolved in
dichloromethane (30 cm3) which was then washed successively
with water (30 cm3) and brine (30 cm3), dried with magnesium
sulfate and evaporated to give 3-amino-2-(1,1-dichloroethyl)-5-
methylquinazolinone 28 as a colourless solid (0.8 g, 82%) mp
173–175 ЊC (from ethanol) (Found: Mϩ 271.027. C11H11N3OCl2
requires M 271.027); δH 2.67 and 2.9 [2 × s, 5-CH3 (Q) and
CH3CCl2], 5.15 (s, NH2), 7.31 [d, J 6.9, 6-H, (Q)] and 7.54–7.65
[m, H-7 and H-8 (Q)]; νmax/cmϪ1 3320w, 1675s and 1600m; m/z
(%) 271 (Mϩ, 100), 238 (23), 236 (74), 219 (51), 208 (26), 207
(30), 206 (62), 183 (20), 146 (21), 144 (26), 89 (24) and 77 (21).
Aziridination of methyl acrylate using Q4NHOAc 20
The general procedure 1 was followed using 18 (0.1 g, 0.87
mmol), LTA (0.43 g, 0.96 mmol) and methyl acrylate (0.15 g,
1.74 mmol) in dichloromethane (3 cm3) to give aziridine 23
which crystallised on addition of ethanol as a colourless solid
(0.15 g, 56%) mp 105–107 ЊC (from ethanol) (Found: Mϩ
313.067. C13H10F3N3O3 requires M 313.067); δH 2.63 (d, J 4.4,
azir. H-3 trans to Q), 3.74 (s, OMe), 3.93 (d, J 7.2, azir. H-3 cis
to Q), 4.26 (dd, J 4.4 and 7.2 azir. H-2), 7.81–7.52 [m, 6-H, 7-H,
8-H (Q)] and 8.13 [dd, J 7.9 and 1, 5-H (Q)]; νmax/cmϪ1 1750s,
1690s and 1605m; m/z (%) 313 (Mϩ, 62), 214 (100), 171 (27), 145
(46), 104 (88), 90 (39), 76 (51) and 55 (27).
Aziridination of methyl acrylate using Q5NHOAc 21
The general procedure 1 was followed using 19 (0.2 g, 0.87
mmol), LTA (0.43 g, 0.96 mmol) and methyl acrylate (0.15 g,
1.74 mmol) in dichloromethane (3 cm3) to afford aziridine 24
which crystallised on addition of ethanol as a colourless solid
(0.16 g, 58%) mp 130–132 ЊC (from ethanol) (Found: C, 51.45;
H, 3.75; N, 12.75. C14H12N3O3F3 requires C, 51.4; H, 3.7; N,
12.85%); δH 2.52 (d, J 4.4, azir. H-3 trans to Q), 2.64 (s, 5-CH3),
3.64 (s, OCH3), 3.74 (d, J 7.2, azir. H-3 cis to Q), 4.08 (dd, J 7.2
and 4.4, azir. H-2) and 7.16–7.60 [m, 6-H, 7-H, 8-H (Q)]; νmax
/
cmϪ1 1750s, 1690s and 1605m; m/z (%) 355 (Mϩ, 8), 299 (45),
Aziridination of methyl acrylate using Q6NHOAc 29
214 (56), 84 (100) and 57 (40).
General procedure 1 was followed using 27 (0.1 g, 0.39 mmol),
LTA (0.19 g, 0.43 mmol) and methyl acrylate (0.07 g, 0.77
mmol) in dichloromethane (2 cm3). The crude product was
purified by chromatography over silica eluting with light
petroleum–ethyl acetate (6:1) and aziridine 31 (Rf 0.29) was
obtained as a colourless oil (0.04 g, 27%) (Found: Mϩ 341.033.
C14H13N3O3Cl2 requires M 341.033); δH 2.53 (d, J 3.8, azir. H-3
trans to Q), 2.55 (s, CH3CCl2), 3.65 (s, OCH3), 4.07 (d, J 6.6,
azir. H-3 cis to Q), 4.58 (dd, J 6.6 and 3.8 azir. H-2), 7.42 [ddd,
J 8.2, 6.9 and 1.3, 6-H (Q)], 7.64 [m, 7-H and 8-H (Q)] and 8.05
[dd, J 8.2 and 1.3, 5-H (Q)]; νmax/cmϪ1 1770s, 1680s and 1590s;
m/z (%) 341 (Mϩ, 6), 308 (34), 306 (100) and 207 (20).
Aziridination of tert-butyl acrylate using Q4NHOAc 20
The general procedure 1 was followed using 18 (0.2 g, 0.87
mmol), LTA (0.43 g, 0.96 mmol) and tert-butyl acrylate (0.22 g,
1.74 mmol) in dichloromethane (3 cm3) to afford aziridine 25
which crystallised on addition of ethanol to give a colourless
solid (0.2 g, 63%) mp 118–120 ЊC (from ethanol) (Found: C,
54.0; H, 4.55; N, 11.8. C16H16N3O3F3 requires C, 54.1; H, 4.55;
N, 11.85%); δH 1.50 (s, But), 2.60 (d, J 4.7, azir. H-3 trans to Q),
3.99 (d, J 7.2, azir. H-3 cis to Q), 4.20 (dd, J 7.2 and 4.4, azir.
H-2), 7.56–7.83 [m, 6-H, 7-H, 8-H (Q)] and 8.20 [d, J 8.2, 5-H
J. Chem. Soc., Perkin Trans. 2, 1999, 771–776
775

View Article Online
Aziridination of methyl acrylate using Q7NHOAc 30
tography over silica gel using light petroleum–ethyl acetate
(6:1) as eluent as a colourless solid (0.037 g, 40%) (sublimed
above 180 ЊC) (from light petroleum) (Found: C, 69.7; H, 6.4;
N, 14.65. C11H12N2O2 requires C, 70.2; H, 6.4; N, 14.9%);
δH 1.44 (t, J 7.2, CH2CH3), 2.78 (q, J 7.2, CH2CH3), 2.89 [s,
5-CH3 (Q)] and 7.19–7.8 [m, 6-H, 7-H and 8-H (Q)], 11.2 (s,
NH); νmax/cmϪ1 3000s, 1665s and 1600m; m/z (%) 189 (MHϩ,
100), 188 (32) and 176 (43).
When this reaction was repeated under the same conditions,
but with addition of TFA (361 mg, 3.18 mmol) (general pro-
cedure 2), the NMR spectrum of the crude reaction product
showed the presence of aziridines 13 and 14 in a 1:1 ratio from
the integration of signals at δ 3.51 and 3.35 ppm, respectively.
General procedure 1 was followed using 28 (0.07 g, 0.27 mmol),
LTA (0.13 g, 0.3 mmol) and methyl acrylate (0.05 g, 0.55 mmol)
in dichloromethane (2 cm3). The crude product was purified by
chromatography over silica eluting with light petroleum–ethyl
acetate (5:1) and aziridine 32 (Rf 0.35) was obtained as a
colourless solid, mp 161–163 ЊC (0.03 g, 31%) (from ethanol)
(Found: Mϩ 355.049. C15H15N3O3Cl2 requires M 355.049);
δH 2.53 (d, J 3.8, azir. H-3 trans to Q), 2.56 (s, CH3CCl2), 2.70 [s,
5-CH3 (Q)], 3.68 (s, OCH3), 4.05 (d, J 6.6, azir. H-3 cis to Q),
4.58 (dd, J 6.6 and 3.8 azir. H-2) and 7.16–7.54 [m, 6-H, 7-H
and 8-H (Q)]; νmax/cmϪ1 1770s, 1665s and 1600m; m/z (%) 355
(Mϩ, 13), 322 (30), 320 (88), 208 (32) and 206 (100).
Competitive aziridination of methyl acrylate and of tert-butyl
acrylate using 20 and 21
Aziridination of tert-butyl acrylate using Q6NHOAc 29
General procedure 1 was followed using 27 (0.1 g, 0.41 mmol),
LTA (0.2 g, 0.45 mmol) and tert-butyl acrylate (0.1 g, 0.82
mmol) in dichloromethane (2 cm3). The crude product was
purified by chromatography over silica eluting with light
petroleum–ethyl acetate (6:1) and aziridine 33 (Rf 0.32) was
obtained as a colourless solid (0.04 g, 25%) (Found: Mϩ
383.080. C17H19N3O3Cl2 requires M 383.080); δH 1.39 (s, But),
2.47 (d, J 4.1, azir. H-3 trans to Q), 2.59 (s, CH3CCl2), 3.99 (d,
J 6.6, azir. H-3 cis to Q), 4.49 (dd, J 6.6 and 4.1 azir. H-2), 7.43
[ddd, J 1.3, 6.9 and 8.2, 6-H (Q)], 7.63 [m, 7-H and 8-H (Q)] and
8.07 [dd, J 1.0 and 8.2, 8-H (Q)]; νmax/cmϪ1 1745s, 1660s and
1595s; m/z (%) 383 (Mϩ, 9), 294 (34), 292 (100), 207 (45), 146
(29) and 57 (31).
General procedure 1 was followed using 3-aminoquinazolin-
4(3H)-ones 18 (0.1 g, 0.46 mmol) and 19 (0.106 g, 0.46 mmol),
LTA (0.449 g, 0.506 mmol) and methyl acrylate (0.049 g, 0.46
mmol) in dichloromethane (4 cm3). NMR spectroscopic exam-
ination of the crude product mixture showed that a 1:1 ratio of
23 and 24 was present from comparison of the signals at δ 4.26
and 4.08 and at δ 3.93 and 3.74 ppm.
Identical quantities of 3-aminoquinazolin-4(3H)-ones 18
and 19, LTA and dichloromethane were used for the aziridin-
ation of tert-butyl acrylate (0.06 g, 0.46 mmol) and yielded
aziridines 25 and 26. NMR spectroscopic examination of the
crude product mixture confirmed that a 1:1 ratio of 25 and 26
was present from comparison of signals at δ 4.20 and 4.16 and
at δ 3.99 and 3.92 ppm.
Aziridination of tert-butyl acrylate using Q7NHOAc 30
Competitive aziridination of methyl acrylate and of tert-butyl
acrylate using 29 and 30
General procedure 1 was followed using 28 (0.06 g, 0.22 mmol),
LTA (0.11 g, 0.24 mmol) and tert-butyl acrylate (0.06 g, 0.44
mmol) in dichloromethane (1 cm3). The crude product was
purified by chromatography over silica eluting with light
petroleum–ethyl acetate (6:1) and aziridine 34 (Rf 0.34) was
obtained as a colourless oil (0.02 g, 20%) (Found: Mϩ 397.096.
C18H21N3O3Cl2 requires M 397.096); δH 1.40 (s, But), 2.43 (d,
J 3.8, azir. H-3 trans to Q), 2.56 and 2.7 [2 × s, 5-CH3 (Q)
and CH3CCl2], 3.97 (dd, J 6.6 and 0.6, azir. H-3 cis to Q), 4.47
(dd, J 6.6 and 3.8, azir, H-2), 7.15–7.53 [m, 6-H, 7-H and 8-H
(Q)]; νmax/cmϪ1 1760s, 1665s and 1600m; m/z (%) 397 (Mϩ, 11),
308 (26), 221 (33), 208 (32) and 206 (100).
The general procedure 1 was followed using 3-aminoquin-
azolin-4(3H)-ones 27 (0.075 g, 0.30 mmol) and 28 (0.079 g, 0.30
mmol), LTA (0.145 g, 0.33 mmol) and methyl acrylate (0.026 g,
0.30 mmol) in dichloromethane (2 cm3). NMR spectroscopic
examination of the crude product mixture showed that a 1.1:1
ratio of 31 and 32 was present from comparison of signals at
δ 4.07 and 4.05 ppm (from cutting and weighing the (over-
lapping) peaks).
The 3-aminoquinazolin-4(3H)-ones 27 (0.1 g, 0.387 mmol)
and 28 (0.106 g, 0.387 mmol), LTA (0.361 g, 0.814 mmol) in
dichloromethane (3 cm3) were also used for the aziridination of
tert-butyl acrylate (0.05 g, 0.387 mmol) and yielded aziridines
33 and 34. NMR (400 MHz) spectroscopic examination of the
crude product mixture confirmed that a 3:2 ratio of 33 and 34
was present from comparison of signals at δ 3.99 and 3.97 ppm.
Competitive aziridination of methyl acrylate using 2 and 10 with
and without addition of TFA
General procedure 1 was followed but using a mixture of
3-aminoquinazolinones 1 (0.1 g, 0.53 mmol) and 9 (0.11 g, 0.53
mmol), LTA (0.52 g, 1.16 mmol) and methyl acrylate (0.045 g,
0.53 mmol) in dichloromethane (4 cm3). Examination of the
NMR spectrum of the crude product mixture after work-up
showed the presence of aziridines 11 and 12 in a 1.4:1 ratio
from the integration of signals at δ 3.58 and 3.41 ppm. When
the above reaction was carried out under the same conditions
but with addition of TFA (0.36 g, 3.18 mmol) (see general pro-
cedure 2) aziridines 10 and 11 were present in a 1:1 ratio in
the crude reaction product determined from the integration of
the same signals in the NMR spectrum as indicated above.
Acknowledgements
We thank the University of Kafkas (Turkey) for support (to
S. U.).
References
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M. J. Grimshire and B. J. Kelly, Tetrahedron, 1989, 45, 2875.
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3 R. S. Atkinson and G. Tughan, J. Chem. Soc., Perkin Trans. 1, 1987,
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4 R. S. Atkinson and B. J. Kelly, J. Chem. Soc., Perkin Trans. 1, 1989,
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Competitive aziridination of tert-butyl acrylate using 2 and 10
with and without addition of TFA
The same procedure described above was followed using the
same quantities of 3-aminoquinazolinones 1 and 9, LTA and
dichloromethane, but using tert-butyl acrylate (0.06 g, 0.53
mmol) instead of methyl acrylate. The NMR spectrum of the
crude reaction product showed the presence of aziridine 13 and
quinazolin-4(3H)-one 15 in a 1:1.7 ratio from integration
comparison of signals at δ 3.51 and 2.89 ppm. A pure sample
of 5-methylquinazolin-4(3H)-one 15 was isolated by chroma-
Paper 8/09703H
776
J. Chem. Soc., Perkin Trans. 2, 1999, 771–776