1-(3,4-Dihydro-4-oxoquinazolin-3-yl)aziridines (Q-substituted aziridines): Ring-opening reactions with C-N bond cleavage and preparation of Q-free chirons

Article abstract of DOI:10.1039/b004798h

The presence of the Q group in ring-opening reactions of N-(Q)-aziridines 3, 4, 5 and 6 has been found to be advantageous in the following ways, (i) nucleophilic ring-opening by cuprate or by azide with inversion of configuration is assisted by the electron-withdrawing character of the Q group, (ii) ring-opening of aziridines 5 or 6 to the corresponding alcohols 36 and 23 with retention of configuration can be accomplished by participation of the Q group: the Q carbonyl oxygen becomes the hydroxy oxygen in the alcohol product, (iii) the combined effects of the electron-withdrawing Q group and ring strain allow preparation of individual aziridine N-invertomers 3 and 4 whose ring-opening with hydrogen chloride in dichloromethane proceeds with complementary stereochemistry. The Q group is also believed to be involved in ring-opening of aziridines 5 and 6 mediated by samarium(III) nitrate hexahydrate with predominant retention of configuration. Reductive removal of the Q group from these ring-opened products gave chirons 12, 19 and 21. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b004798h

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1-(3,4-Dihydro-4-oxoquinazolin-3-yl)aziridines (Q-substituted
aziridines): ring-opening reactions with C–N bond cleavage
and preparation of Q-free chirons
1
Robert S. Atkinson,a Andrew P. Ayscough,b William T. Gattrella and Tony M. Raynhamc
a Department of Chemistry, Leicester University, Leicester, UK LE1 7RH
b British Biotech Pharmaceuticals Limited, Watlington Road, Oxford, UK OX4 5LY
c Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Hertfordshire,
UK AC7 3AY
Received (in Cambridge, UK) 15th June 2000, Accepted 27th July 2000
Published on the Web 31st August 2000
The presence of the Q group in ring-opening reactions of N-(Q)-aziridines 3, 4, 5 and 6 has been found to be
advantageous in the following ways, (i) nucleophilic ring-opening by cuprate or by azide with inversion of
configuration is assisted by the electron-withdrawing character of the Q group, (ii) ring-opening of aziridines
5 or 6 to the corresponding alcohols 36 and 23 with retention of configuration can be accomplished by
participation of the Q group: the Q carbonyl oxygen becomes the hydroxy oxygen in the alcohol product,
(iii) the combined effects of the electron-withdrawing Q group and ring strain allow preparation of individual
aziridine N-invertomers 3 and 4 whose ring-opening with hydrogen chloride in dichloromethane proceeds
with complementary stereochemistry. The Q group is also believed to be involved in ring-opening of aziridines
5 and 6 mediated by samarium() nitrate hexahydrate with predominant retention of configuration. Reductive
removal of the Q group from these ring-opened products gave chirons 12, 19 and 21.
The dearth of general and stereoselective methods for aziridine
synthesis means that these three-membered rings enjoy far less
use than epoxides as synthetic relay intermediates.1,2
We have shown that enantiopure 3-acetoxyaminoquinazol-
inones e.g. 2 are aziridinating agents for a variety of alkenes.1
Aziridination of styrene, butadiene and indene with 3-acetoxy-
aminoquinazolinone 2 (QNHOAc) in the presence of titan-
ium() tert-butoxide is highly diastereoselective (Scheme 1).3
influence the ring-opening of the aziridine would be by affect-
ing the rate, the stereochemistry or the regiochemistry.
Ring-opening of aziridines typically involves protonation or
Lewis acid coordination of the ring-nitrogen combined with
nucleophilic assistance to C–N bond breaking [Scheme 2(i)].
Scheme 2
Two variants on this mechanism are ring-opening without prior
protonation or activation of the ring nitrogen [Scheme 2(ii)]
and ring-opening leading to carbocation formation with only
subsequent reaction with the nucleophile [Scheme 2(iii)].
Whereas (i) and (ii) lead to inversion of configuration at the
ring carbon, (iii) generally results in some loss in its configur-
ational purity.
Scheme 1 (i) LTA, CH2Cl2, Ϫ20 ЊC; (ii) Ti(OBut)4; (iii) indene; (iv)
CH2᎐᎐C(H)R.
To make use of the aziridine products in Scheme 1, removal
of the Q substituent is required. Although reductive cleavage of
the Q group without ring-opening of the aziridine ring has been
accomplished by Coates et al.,4 we were particularly interested
in studying ring-opening methods on aziridines 3–6 before N–Q
bond cleavage. The expectation here was that the Q group could
be used to control or assist in the ring-opening of the 3-
membered ring in ways not available using the corresponding
NH-aziridines. Three ways in which the Q group might, a priori,
Substituents R in Scheme 2(ii) which activate5 the aziridine
towards nucleophilic attack include sulfonyl,6 alkoxycarbonyl7
and phosphinyl.8 However, these groups have no obvious effect
on either the stereo- or the regio-chemistry of ring-opening.9
The barriers to N-inversion in these aziridines are relatively
low10 and the geometry at their ring nitrogens, although pyram-
idal, would be expected to be flatter than N-(3,4-dihydro-4-
oxoquinazolin-3-yl) substituted (N-(Q)-substituted) aziridines.
We have some evidence to support this conclusion from a
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This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b004798h

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comparison of N-sulfonyl-substituted and N(QЈ)-substituted
aziridines in the Cambridge Crystallographic Data File. The
N-sulfonyl-substituted aziridine structures clearly fall into two
categories when the pyramidality at the ring nitrogen, as meas-
ured by the sum of angles (Σφ) at this nitrogen, is considered.
One category (13 structures) has the sulfonyl group cis to only
hydrogens on the 2- and 3-positions of the aziridine ring
(2-substituted or 2,3-cis-disubstituted) and has an average
Σφ of 292Њ. The other category has a substituent cis to the N-
sulfonyl group (2,3-trans or 2,2-disubstituted) with an average
Σφ of 300Њ. Clearly the presence of a substituent cis to the
sulfonyl group brings about a significant flattening of the
nitrogen pyramid. For the 7 N-(QЈ-substituted) aziridines in the
Data File the corresponding angles were 285Њ (2 examples)
and 291Њ (7 examples), i.e. the N-(QЈ-substituted) aziridines
have more steeply pyramidal nitrogens than the N-sulfonyl-
substituted analogues.
Along with the steeper pyramidal nitrogen of N-(QЈ)-
substituted aziridines goes a larger barrier to N-inversion. For
the particular case of the indene-derived aziridine, the rate of
N-inversion is sufficiently retarded to allow isolation of the
kinetically formed N-invertomer 3 and to observe its conversion
into the thermodynamically more stable N-invertomer 4.3
The Q substituent is certainly electron-withdrawing and
might, therefore, be expected to also activate the aziridine
ring towards attack by nucleophiles [Scheme 2(ii)]. At the same
time, the inductively electron-withdrawing Q group might be
expected to further reduce the basicity of the aziridine ring
nitrogen and hence discourage ring-opening via (i) or (iii) in
Scheme 2. On the other hand, the Q group itself contains two
In this paper we examine the ring-opening of aziridines 3, 4,
5 and 6 with particular attention to the role played by the Q
substituent.11
Results and discussion
Aziridine 4 was reacted with excess methylmagnesium bromide
in the presence of cuprous bromide–dimethyl sulfide complex
to give the ring-opened product 9 in 57% yield (Scheme 4)
confirming that this Q group was able to stabilise the develop-
ing negative charge on nitrogen in the transition state for
ring-opening. The presence of the hydroxy group in the Q side
chain is not vital for the success of the reaction since ring-
opening of aziridine 10 which lacks this hydroxy group also
takes place under the same conditions to give the corresponding
product 11 in 48% yield.
Confirmation that attack of the cuprate took place as
expected with inversion of configuration was provided by an
X-ray crystal structure of the ring-opened product11a 11 and
it is assumed that inversion also occurs in ring-opening of
aziridine 4.
Conversion of the ring-opened product 9 to the Q-free amide
chiron 12 was accomplished by samarium diiodide in the
presence of tert-butyl alcohol12 and reaction with its 3,5-dinitro-
benzoyl chloride; 4-oxo-3H-quinazolin-2-yl 3,5-dinitrobenzoate
13 was also isolated by chromatography.
Endo et al. have shown13 that in reductions using samarium
diiodide, submolar quantities of this reagent can be used in
the presence of magnesium metal which reduces Sm3ϩ→Sm2ϩ
in situ. Applying this procedure to the N–Q bond reduction in
conversion of amine 9 to amide 12 was successful with only a
small loss in yield by comparison with reduction using excess
samarium diiodide (see Scheme 4).
basic sites available for protonation at N-1 or C᎐O. The positive
᎐
charge resulting from protonation at either of these sites can be
resonance stabilised by involving N-3 leading to the possibility
of ring-opening in the presence of acid via an initially formed
ylide species, e.g. 7: rapid tautomerism to the more stable
isolated product 8 would be anticipated (Scheme 3).
A further example of the ability of the Q group to facilitate
nucleophilic attack without the necessity for prior protonation
[Scheme 2(ii)] was the reaction of aziridine 5 with azide ion.
Reaction takes place on heating in dimethyl sulfoxide at 70 ЊC
to give a mixture of products from which the ring-opened azide
14 was separated but in only 9% yield (Scheme 5). Inclusion of
acetic acid (1 eq.) in the reaction mixture (WARNING)†
however, resulted in azide 14 as the only product. It appears
that the function of the acetic acid is to protonate the anionic
nitrogen formed in the rate-determining aziridine ring-
opening step since the effect of increased concentration of
acetic acid on the rate of disappearance of aziridine 5 was so
small (Table 1).
† Sodium azide in the presence of acid can give rise to hydrogen azide:
this reaction has not been carried out on more than 200 mg of sodium
azide.
Scheme 3
Scheme 4 Reagents: (i) MeMgBr, CuBrSMe2; (ii) SmI2, ButOH, THF; (iii) 3,5-diNO2C6H3COCl, Et3N; (iv) SmI2 (0.5 eq.), ButOH, THF, Mg.
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Scheme 5 Reagents: (i) NaN3, AcOH, DMSO; (ii) Pd/C, H2; (iii) BOC-ON, Et3N; (iv) SmI2, ButOH, THF; (v) NaH, THF; (vi) HCl, Et2O; (vii) NaN3,
DMSO.
Scheme 6 Reagents: (i) dil. H2SO4, dioxane; (ii) AcOH, 70 ЊC, 17 h; (iii) AcOH, H2O, 70 ЊC, 5 h; (iv) HCl, dioxane; (v) HCl, ether; (vi) NaH–THF;
(vii) AcOH, 70 ЊC, 12 h; (viii) NaOH, H2O.
Table 1 Effect of acetic acid on rate of disappearance of aziridine 5 in
separable mixture of diol stereoisomers 22 and 23 (Scheme 6).
The same 3:1 ratio of diols 22 and 23 was obtained by reaction
of aziridine 6 with hydrochloric acid in dioxane but, in
addition, the chloride 24 (20%) was isolated, which appeared to
be a single diastereoisomer. The same chloride 24 was obtained
in quantitative yield when aziridine 6 was treated with hydrogen
chloride gas in ether and was shown to be formed with inver-
sion of configuration by its reconversion to aziridine 6 (79%) on
treatment with sodium hydride in THF.
DMSO containing sodium azide determined by NMR spectroscopya
Entry
AcOH added (eq.)
Unchanged isolated aziridine 5 (%)
1
2
3
0
1
2
35
31
31
a See Experimental for conditions.
Reaction of aziridine 6 with glacial acetic acid at 70 ЊC
overnight gave diacetate 25 (67%) and monoacetate 26 (7%).
Reaction of aziridine 6 with glacial acetic acid containing water
(20 eq.) and for a shorter time (5 h) resulted in the formation of
diol 23 (38%) together with the allylic monoacetate 27 (36%)
showing that acetylation of the Q side-chain hydroxy group
occurs after aziridine ring-opening. Further treatment of allylic
acetate 27 with the hot acetic acid solution above yielded
diacetate 25 but no monoacetate 26, showing that the latter was
not formed from 25 or 27 in situ.
Azide 14 is very likely formed with complete inversion of
configuration since it was found to be different from, and not
contaminated with, the diastereoisomeric azide 16 prepared
from aziridine 5 by ring-opening with hydrogen chloride
followed by displacement of the chloride in 15 by azide. Proof
that chloride 15 was formed from aziridine 5 with inversion of
configuration came from its reconversion back to aziridine 5 in
high yield by the action of sodium hydride in tetrahydrofuran
(THF).
Diacetate 25, monoacetates 26 and 27 and the two diols 22
and 23 were interrelated and their stereostructures identified
by the chemical correlations in Scheme 6 together with an
X-ray crystal structure determination on diacetate 25.11b Thus
diacetate 25 and the major diol 22 are formed with inversion of
configuration and monoacetate 26 and diol 23 with retention of
configuration. The proportion of diacetate 25 (inversion) to
monoacetate 26 (retention) was increased to 38:1 by carrying
out the reaction of aziridine 6 with glacial acetic acid in the
presence of molecular sieves to scavenge any water.
Conversion of diastereoisomeric azides 14 and 16 into their
respective Q-free, BOC-protected diamine enantiomers 19 and
21, was accomplished as shown in Scheme 5 by reagents not
affecting the configuration at the chiral centres. The almost
equal but opposite optical rotations for 19 and 21, separated by
chromatography from QH 20 in each case, support stereo-
specific inversion in each of the three substitution steps in
Scheme 5 and the absolute configurations assigned follow from
the known absolute configuration of aziridine 5.3
A mechanism to account for the retention of configuration in
formation of diol 23 and hence monoacetate 26 in the reaction
of aziridine 6 with acetic acid–water involves participation by
the quinazolinone ring as outlined in Scheme 7.
Involvement of the Q group in the stereochemistry of aziridine
ring-opening
Reaction of aziridine 6 with sulfuric acid in dioxane gives a
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Scheme 7
In Scheme 7, the allylic cation 28 formed by ring-opening,
version to the diol 23 by treatment with basic hydrogen
possibly via the Q-protonated intermediate 31 (see Scheme 3)
must be trapped by the quinazolinone carbonyl oxygen from
the syn-face, i.e. before rotation around the C2–C3 bond can
occur. This C2–C3 bond rotation might be more retarded in
carbocation 31 as a result of the formal negative charge on the
exocyclic nitrogen than in carbocation 28 with its neutral
exocyclic NH.‡ Further acetylation of only the more hindered
hydroxy group in the Q side-chain on heating for 17 h (Scheme
6) is assumed to result from ‘protection’ of the allylic hydroxy
group as the cyclic amide hemiacetal 30 and liberation of the
free hydroxy group only on aqueous work up.
peroxide. The isolation of quinazolinone diacetate 25 in the
reaction in Scheme 8 is important because it shows that without
the intervention of the amide hemiacetal 30, exchange of the
Q-carbonyl oxygen for sulfur in diol 23 or monoacetate 26 as a
route to quinazoline-4-thione 32, is not occurring.
The formation of quinazoline-4-thione 32 is consistent with
the mechanism in Scheme 7 with interception of the quinazo-
linium species 29 by hydrogen sulfide.
Aziridine ring-opening with retention of configuration at
the ring carbon has been reported in the conversion of N-
acylaziridine 34 into oxazoline 35 by boron trifluoride–diethyl
ether: theoretical results support an SNi mechanism.14
The acetate 27 and hence diacetate 25, formed from aziridine
6 with inversion of configuration, could arise from capture of
allylic carbocation 28 by acetic acid.
Aziridine ring-opening mediated by samarium(III) salts
In this mechanism in Scheme 7, the allylic oxygen in diol 23 is
derived from the quinazolinone carbonyl oxygen. As a test for
this mechanism we repeated the reaction in acetic acid saturated
with hydrogen sulfide. Further acetylation of the crude product
with acetic anhydride and pyridine gave a separable mixture of
diacetate 25 and the quinazoline-4-thione 32 (Scheme 8).
We have found that the ring-opening of these Q-substituted
aziridines is catalysed by samarium() salts. Treatment of
aziridine 6 with samarium trinitrate hexahydrate (1 eq.) in
acetonitrile (Scheme 8) gave the diols 23 and 22 in a ratio of
13:1. A by-product (7%) in this reaction was the nitrate ester
33 (of unknown relative configuration). A mechanism involving
coordination of the highly oxophilic Sm() to the Q-carbonyl
group and double inversion as shown in Scheme 9 could account
for the predominant overall retention of configuration.
Scheme 8 Reagents: (i) AcOH, H2S, 70 ЊC, 17 h; (ii) Ac2O, pyr.; (iii)
H2O2, NaOH, EtOH; (iv) Sm(NO3)3ؒ6H2O, CH3CN.
The lowest field aromatic proton in the NMR spectrum of
the quinazolinone ring is H-5 at ~δ 8.2 and the replacement of
the carbonyl group by a thione causes a downfield shift of this
H-5 proton to δ 8.6–8.7. As expected, this product 32 was
formed with retention of configuration as shown by its con-
Scheme 9
Thus, overall since the diacetate 25 is efficiently converted
into the diol 22 by hydrolysis (see Scheme 6), methods for ring-
opening of aziridine 6, formally by water, either with inversion
or with retention of configuration are available.
‡ We cannot exclude the possibility that this aziridine ring-opening in
fact proceeds by a route analogous to that in Scheme 7 but involving the
cis-N-invertomer of aziridine 6.
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Ring-opening of aziridine 5 with ethanol
[propan-2-ol (pKa 16.5) is less acidic than ethanol (pKa 16)]
with a reaction mechanism analogous to that for conversion
of aziridine 6 into allylic alcohol 23 (Scheme 7). To test this
mechanism we heated aziridine 5 in a Young’s tube with
hydrogen sulfide-saturated ethanol for 94 h at 78 ЊC. The N-(4-
thiocarbonylquinazolin-3-yl)-substituted benzyl alcohol 39
(46%) was separated from ether 37 (34%) by chromatography.
As expected, treatment of this alcohol 39 with basic hydrogen
peroxide gave the corresponding N-(oxoquinazolinyl) analogue
36. Benzyl ether 37 had not undergone any (Q)-carbonyl→(Q)-
thione conversion¶ which excludes a mechanism for formation
of alcohol 39 by direct attack on the Q-carbonyl of 36 by
hydrogen sulfide followed by oxygen/sulfur exchange via a
hemithioacetal.
When aziridine 5 was heated in boiling ethanol containing two
drops of water for 34 h, ring-opening occurred to give benzyl
alcohol 36 and a benzylic ethyl ether 37 of unknown configur-
ation (Scheme 10).
Ring-opening of indene-derived aziridines 3 and 4 with hydrogen
chloride
In contrast to the ring-opening of styrene- and butadiene-
derived aziridines 5 and 6 with hydrogen chloride, reaction of
the thermodynamically more stable N-invertomer of indene-
derived aziridine 4 with a solution of hydrogen chloride gas in
ether yielded a ~1:1 mixture of chlorides 40 and 41 (Scheme
11). This loss of stereospecificity could be ascribed to the
presence of a longer-lived carbocation intermediate [Scheme
2(iii)] which is trapped from both faces by chloride anion.
However, when hydrogen chloride gas was bubbled into an
ice-cold dichloromethane solution of aziridine 3 (prepared
directly by aziridination of indene, see Scheme 1) only chloride
40 was isolated in 62% yield from indene. The trans-
configuration of chloride 40 was confirmed by its re-conversion
to aziridine 4 in excellent yield by treatment with sodium
hydride–THF; in contrast, reaction of chloride 41 under the
same conditions gave a mixture of unidentified products.
To confirm that the change in stereochemistry in reactions of
the two aziridine N-invertomers 3 and 4 with hydrogen chloride
was not the result of the difference in solvent used (dichloro-
methane and ether), aziridine 4 was ring-opened with hydrogen
chloride in dichloromethane using the same conditions applied
to aziridine 3 above. Unexpectedly, this ring-opening gave a 4:1
mixture of chloride diastereoisomers 41 and 40 i.e. the major
product is formed with retention of configuration.
Scheme 10 Reagents: (i) EtOH, H2O, 78 ЊC, 34 h; (ii) Sm(NO3)3ؒ6H2O,
CH3CN; (iii) EtOH, H2S, 78 ЊC; (iv) H2O2, NaOH, EtOH.
Evidence for the benzylic alcohol 36 having been formed
with retention of configuration came from the ring-opening of
aziridine 5 with samarium() nitrate hexahydrate. In a reaction
analogous to that described previously (Scheme 8), benzyl
alcohol 36 together with nitrate ester 38 were isolated§ (Scheme
10) in comparable yields to the corresponding products from
ring-opening of vinylaziridine 6. Since the allylic alcohol 23
from this latter reaction is formed with retention of config-
uration, the configuration of benzyl alcohol 36 is assigned
accordingly.
Since aziridine 5 was not affected by heating in wet propan-
2-ol or wet dioxane, it appeared that the ring-opening in
Scheme 10 was probably catalysed by ethanol acting as an acid
It is possible that the inversion of configuration which
accompanies ring-opening of aziridine 3 may be the result of
§ None of the ring-opened alcohol with inversion of configuration was
identified in this reaction.
¶ This result suggests that ether 37 is very likely formed with inversion
of configuration.
Scheme 11 Reagents: (i) HCl, ether; (ii) NaH, THF; (iii) HCl, CH2Cl2, 0 ЊC.
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shielding of one face of the carbocation by the Q group.
The retention of configuration in reaction of aziridine 4 with
hydrogen chloride may arise via a transition state resembling 42
where an un-ionised hydrogen chloride molecule suffers depro-
tonation leaving the chloride to attack from the syn face. In
ether solution, the concentration of chloride anions will be
higher and syn and anti attack will become competitive.
The lower barriers for cis→trans N-inversion in other N-(QЈ)-
aziridines limit the number of pairs of aziridine N-invertomers
available for further study: the barrier for conversion of azir-
idine 3 to 4 is abnormally high because of the ring-strain
associated with the 5,3-ring-fusion in addition to the effect of
the electron-withdrawing Q group.
reduced pressure to give a brown residue. Column chrom-
atography (eluent 4:1 light petroleum–ethyl acetate) yielded
amine 9 (Rf 0.35) (60 mg, 57%) as a colourless oil (Found: MHϩ
378.2182. C23H27N3O2 requires MHϩ 378.2182); αD 177.1 (c 3.5,
ethanol); νmax/cmϪ1 3480w, 1660s and 1595s; δH (400 MHz)
0.89 [(9H, s, C(CH3)3], 1.21 (3H, d, J 6.9, CH3), 2.91 (1H, dd,
J 6.2 and 15.8, CHH), 3.13 (1H, struct. m, CHCH3), 3.18 (1H,
dd, J 6.6 and 15.8, CHH), 3.58 (1H, d, J 10.2, OH), 3.74 (1H,
struct. m, CHNH), 4.94 (1H, d, J 10.2, CHOH), 5.60 (1H, d,
J 5.6, NH), 7.18 [4H, struct. m, 4 × CH(Ar)], 7.50 [1H, ddd,
J 1.1, 7.0 and 8.0, 6-H(Q)], 7.71 [1H, br d, J ~8, 8-H(Q)], 7.78
[1H, ddd, J 1.5, 7.0 and 8.2, 7-H(Q)] and 8.28 [1H, dd, J 1.5 and
8.0, 5-H(Q)]; δC 18.3 (CH3), 25.8 [C(CH3)3], 37.1 (CH2), 37.8
[C(CH3)3], 43.5 (CH), 69.0 (CH), 74.1 (CH), 120.7 [CCO(Q)],
123.5, 124.5, 126.7, 126.9, 127.3, 134.6 [6 × CH(Q), CH(Ar)],
Summary
139.9, 145.7, 146.0 [2 × C(Ar), CN᎐C(Q)], 159.2 [C᎐N(Q)]
᎐
᎐
The Q group in N-(Q)-aziridines 4, 5 and 6 activates the ring
towards nucleophilic attack by cuprates and by azide.
and 161.7 [CO(Q)]; m/z (%) 378 (100, MHϩ), 248 (83) and
191 (20).
Involvement of the Q group in ring-opening of aziridines 5
and 6 gives the corresponding alcohols 23 (in acetic acid) and
36 (in ethanol) respectively, with retention of configuration.
The carbonyl oxygen of the Q ring becomes the oxygen of the
hydroxy group. Better yields of ring-opened alcohols 23 and
36 are obtained by ring-opening using samarium() nitrate
hexahydrate in acetonitrile. Since ring-opening of aziridine 6 by
acetic acid can be accomplished with inversion of configuration
and the derived acetate 25 can be hydrolysed to the alcohol 22,
access to either alcohol stereoisomers 22 or 23 is possible start-
ing from a single stereoisomer of the aziridine 6.
Aziridine N-invertomers 3 and 4 are isolable because of the
enhanced barrier to N-inversion: stereochemically comple-
mentary modes of ring-opening are obtained by use of
hydrogen chloride in dichloromethane giving inversion of con-
figuration (for 3) and mainly retention (for 4).
Ring-opening of aziridine 10 with methylmagnesium bromide–
copper(I) bromide–dimethyl sulfide
To a flame-dried, 3-necked flask equipped with a stirrer bar and
under an argon atmosphere a solution of aziridine 10 (163 mg,
0.454 mmol) in THF (3 cm3) was added via a septum cap,
followed by a solution of methylmagnesium bromide in THF
(0.4 cm3, 3.0 mol dmϪ3). After effervescence had ceased copper
bromide–dimethyl sulfide complex (93 mg, 0.45 mmol) was
quickly added and the reaction vessel flushed with argon. The
resulting deep red solution was stirred at room temperature for
1.5 h under argon before being syringed into a stirred saturated
aqueous ammonium chloride solution (5 cm3) maintained at
0 ЊC. The resulting deep blue aqueous solution was extracted
with ethyl acetate (10 cm3) and the organic layer separated,
dried and evaporated under reduced pressure to give a brown
oil. Chromatography (eluent 9:1 light petroleum–ethyl acetate)
yielded amine 11 (Rf 0.35) (82 mg, 48%) as a colourless crystal-
line solid; mp 136–137 ЊC (from light petroleum–ethyl acetate).
(Found: MHϩ 376.2389. C24H30N3O requires MHϩ 376.2389);
νmax/cmϪ1 3290w, 1665s and 1580s; δH (400 MHz) 0.91 [9H, s,
C(CH3)3], 1.30 (6H, 2 × d, J 6.9, 2 × CH3), 2.96 (1H, dd, J 6.7
and 15.7, CHH), 3.08 (1H, br s, CHNH), 3.12 (1H, dd, J 6.7
and 15.7, CHH), 3.60 (2H, struct. m, 2 × CHCH3), 5.87 (1H, d,
J 6.6, NH), 7.13–7.22 [4H, struct. m, CH(Ar)], 7.45 [1H, ddd,
J 1.6, 6.7 and 8.0, 6-H(Q)], 7.67–7.78 [2H, struct. m, 7-H and 8-
H(Q)] and 8.26 [1H, dd, J 1.2 and 8.0, 5-H(Q)]; δC 14.5, 18.0
(2 × CH3), 27.4 [C(CH3)3], 35.4 [C(CH3)3], 37.2 (CH2), 42.1,
43.5, 69.1 [CHNH, CHC(CH3)3, CHCH3], 120.3 [CCO(Q)],
123.2, 124.5, 126.0, 126.4, 126.7, 126.8, 127.5, 134.0
[4 × CH(Ar), 4 × CH(Q)], 140.2, 145.5, 146.8 [2 × C(Ar),
Experimental
General
Unless otherwise indicated 1H NMR spectra were recorded
at 250 MHz and 13C at 63 MHz using a Bruker ARX 250
spectrometer. 1H NMR spectra at 400 MHz were recorded
using a Bruker DRX 400 spectrometer. IR spectra of crystalline
compounds were recorded at room temperature in dichloro-
methane and of liquids as thin films using a Perkin-Elmer
298 spectrometer. Optical rotations were determined on a
Perkin-Elmer 341 Polarimeter at 589 nm and are given in 10Ϫ1
deg cm2 gϪ1
.
All NMR spectra were recorded at room temperature in
deuterated chloroform unless otherwise indicated. For other
general experimental details see ref. 3.
BOC-ON refers to [2-(tert-butoxycarbonyloxyimino)-2-phen-
ylacetonitrile and was supplied by Aldrich. LTA refers to lead
tetraacetate.
CN᎐C(Q)] and 161.3, 162.0 [CO(Q), C᎐N(Q)]; m/z (%) 376
᎐
᎐
(MHϩ, 100), 246 (21) and 189 (45). A crystal for X-ray structure
determination was grown from light petroleum–ethyl acetate.11a
Ring-opening of aziridine 4 with methylmagnesium bromide–
copper(I) bromide–dimethyl sulfide
Q–N bond reduction and 3,5-dinitrobenzoylation of N-(Q)-amine
9
To a flame-dried 3-necked flask equipped with a stirrer bar and
under an argon atmosphere was added a solution of aziridine
4 (100 mg, 0.277 mmol) in freshly distilled THF (2 cm3) via
a septum cap, followed by a solution of methylmagnesium
bromide in THF (0.35 cm3, 3.0 mol dmϪ3). After effervescence
had ceased, copper bromide–dimethyl sulfide complex (57 mg,
0.33 mmol) was quickly added and then the reaction vessel
again flushed with argon. The resulting deep red solution was
stirred under argon for 4 h at room temperature before being
syringed into a stirred aqueous saturated ammonium chloride
solution (5 cm3) maintained at 0 ЊC. The resulting deep blue
aqueous solution was extracted with ethyl acetate (10 cm3) and
the organic layer separated, dried and evaporated under
Amine 9 (206 mg, 0.55 mmol) in THF (8 cm3) containing tert-
butyl alcohol (1 cm3) was reduced with a solution of samarium
diiodide in THF (33 cm3, 0.1 mol dmϪ3). After the solution had
decolourised (~80 min), triethylamine (1 cm3) was added,
followed by 3,5-dinitrobenzoyl chloride (264 mg, 1.14 mmol)
and the resulting red solution stirred for 2 h. Saturated sodium
hydrogen carbonate solution (10 cm3) was added, the solution
filtered and ethyl acetate (20 cm3) added to the filtrate. After
shaking, the organic layer was separated, washed with brine
(10 cm3), dried and evaporated under reduced pressure. Chrom-
atography (eluent 5:1 light petroleum–ethyl acetate) yielded
amide 12 (Rf 0.23) (151 mg, 81%) mp 172–174 ЊC (from light
petroleum–ethyl acetate) (Found: C, 60.1; H, 4.5; N, 12.2.
J. Chem. Soc., Perkin Trans. 1, 2000, 3096–3106
3101

View Article Online
C17H15N3O5 requires C, 59.8; H, 4.4; N, 12.3%); αD Ϫ40.18
(c 1.12, CHCl3); νmax/cmϪ1 3430w, 1735m, 1675s and 1545s; δH
1.41 (3H, d, J 6.9, CH3), 2.89 (1H, dd, J 6.3, 16.0, CHH), 3.23
(1H, quintet, J 6.9, CHCH3), 3.51 (1H, dd, J 7.5, 16.0, CHH),
4.56 (1H, struct. m, J 6.3 and 7.5 visible, CHNH), 6.56 (1H, br
d, J 7.5, NH), 7.24 [4H, s, 4 × H(Ph)], 8.94 [2H, d, J 2.2, H-2,
H-6 ((NO2)2Ar)] and 9.16 [1H, s br, H-4 ((NO2)2Ar)]; m/z (%)
342 (MHϩ, 69), 259 (48) and 147 (33).
Further elution with the same solvent yielded QH-O-(3,5-
dinitrobenzoate) 13 (Rf 0.10) (72 mg, 31%) (Found: MHϩ
427.1254. C20H19N4O7 requires MHϩ 427.1254); νmax/cmϪ1
1740m, 1670s, 1610m and 1550s; δH 1.18 (9H, s, C(CH3)3), 5.47
(1H, s, CHO), 7.39 [1H, ddd, J 1.3, 7.0 and 8.0, 6-H(Q)], 7.63
[1H, dd, J 1.3 and 8.2, 8-H(Q)], 7.72 [1H, ddd, J 1.0, 7.0 and
8.2, 7-H(Q)], 8.08 [1H, dd, J 1.0 and 8.0, 5-H(Q)], 8.98 [1H, t,
J 2.2, H-4 (NO2)2Ar], 9.21 [2H, d, J 1.9, H-2, H-6 (NO2)2Ar]
and 11.95 (1H, s, NH); δC 26.5 [C(CH3)3], 35.7 [C(CH3)3], 83.9
(CHO), 120.7 [CCO(Q)], 122.6, 126.0, 127.2, 127.8, 129.7
[5 × CH(Q), CH(Ar)], 132.8 [C(Ar)], 135.2 [CH(Q)], 148.2,
Effect of acetic acid concentration on ring-opening of aziridine 5
with sodium azide
Three 5 cm3 round-bottom flasks (a), (b) and (c) were each
charged with aziridine 5 (100 mg, 0.286 mmol) and sodium
azide (56 mg, 0.86 mmol). To flask (a) was added DMSO
(1 cm3); to flask (b) 1 cm3 of a solution of acetic acid (0.164 cm3,
2.86 mmol made up to 10 cm3 with DMSO) and to flask (c)
1 cm3 of a solution of acetic acid (0.33 cm3, 5.76 mmol, made
up to 10 cm3 with DMSO). The flasks were then heated in the
same oil bath at 70 ЊC for 5 h. After this time the oil bath was
removed, each reaction poured into saturated aqueous sodium
hydrogen carbonate solution (5 cm3) and worked up in the
following way. The solution was extracted with ethyl acetate
(3 × 5 cm3) and the combined organic extracts were washed
with water (3 × 5 cm3), then saturated brine (5 cm3), dried and
the solvent evaporated under reduced pressure. The NMR
spectra of the crude products were recorded and the results
shown in Table 1.
148.6, 151.5 [CN᎐C(Q), 2 × C(Ar)], 162.4 [C᎐N(Q)] and 163.9
᎐
᎐
Ring-opening of aziridine 5 with a solution of hydrogen chloride
in ether
[CO(Q)] [CO, (CH(Ar) missing]; m/z (%) 427 (MHϩ, 51), 307
(20) and 215 (47).
Hydrogen chloride gas was slowly bubbled into a rapidly stirred
solution of aziridine 5 (500 mg, 1.43 mmol) in diethyl ether
(10 cm3) for 20 s and a white solid was immediately precipitated.
The reaction mixture was carefully washed with excess satur-
ated aqueous sodium hydrogen carbonate, the organic layer
separated, dried and evaporated under reduced pressure to give
chloride 15 as a colourless solid (388 mg, 70%), mp 153–155 ЊC
(ethanol) (Found: C, 65.65; H, 6.3; N, 10.9. C21H24ClN3O2
requires C, 65.55; H, 6.25 and N, 10.9%); αD 126.0 (c 1.0,
chloroform); νmax/cmϪ1 3500w, 3280w, 1640s and 1590s; δH (400
MHz) 0.95 [9H, s, C(CH3)3], 3.22 (1H, struct. m, CHH), 3.59
(1H, d, J 10.2, OH), 3.84 (1H, struct. m, CHH), 4.91 (1H, d,
J 10.2, CHOH), 5.09 (1H, dd, J 6.0 and 7.0, CHCl), 5.31 (1H,
dd, J 4.6 and 9.8, NH), 7.29–7.53 [6H, struct. m, 6-H(Q),
5 × CH(Ph)], 7.67 [1H, br d, J 7.0, 8-H(Q)], 7.75 [1H, ddd, J 1.5,
7.0 and 8.1, 7-H(Q)] and 8.22 [1H, dd, J 1.5 and 8.0, 5-H(Q)];
m/z (%) 386 (MHϩ, 100) and 215 (26).
Q–N bond reduction and 3,5-dinitrobenzoylation of N-(Q)-amine
9 using samarium(II) iodide and magnesium
Magnesium turnings (305 mg, 12.7 mmol) were stirred vigor-
ously overnight in a flame-dried 3-necked flask under an argon
atmosphere. The amine 9 (150 mg, 0.4 mmol) dissolved in
freshly distilled THF (2 cm3) and tert-butyl alcohol (1 cm3) was
added via a septum cap and the solution de-gassed 5 times with
argon using a 3-way tap. A solution of samarium diiodide in
THF (2 cm3, 0.1 mol dmϪ3) was added via the septum cap to the
vigorously stirred solution and the disappearance of the amine
monitored by TLC. After 2.5 h the solution was transferred via
a cannula into a round-bottom flask under an argon atmos-
phere and triethylamine (1 cm3) and 3,5-dinitrobenzoyl chloride
(193 mg, 0.84 mmol) were added aqueous with stirring. After
2 h the solution was filtered, saturated sodium hydrogen
carbonate solution (5 cm3) added and the mixture extracted
with ethyl acetate (20 cm3). The organic layer was separated,
washed with brine, dried and evaporated under reduced
pressure. Chromatography of this residue (eluent 5:1 light-
petroleum–ethyl acetate) yielded the amide 12 (Rf 0.23) (94 mg,
69%). Further elution with the same solvent yielded QH-O-3,5-
dinitrobenzoate 13 (Rf 0.10) (87 mg, 51%).
Reconversion of chloride 15 to aziridine 5 with sodium hydride
The chloride 15 (100 mg, 0.26 mmol) was dissolved in dry THF
(2 cm3) and sodium hydride (31 mg of a 60% dispersion in oil,
0.77 mmol) added. After stirring at room temperature for 70
min the reaction was quenched with ice–water and extracted
with ethyl acetate (3 × 5 cm3). The combined organic fractions
were separated, dried and the solvent was evaporated to give
aziridine 5 (90 mg, 99%).
Ring-opening of aziridine 5 with sodium azide
To a solution of aziridine 5 (300 mg, 0.86 mmol) in DMSO
(3 cm3) containing acetic acid (52 mg, 0.87 mmol) was added
sodium azide (167 mg, 0.26 mmol) and the mixture heated at
70 ЊC for 17 h with stirring behind a screen (WARNING—
hydrogen azide present). Water (5 cm3) was then added, the solu-
tion extracted with ethyl acetate (3 × 10 cm3) and the combined
organic extracts were washed with water (3 × 5 cm3), then
saturated brine (5 cm3), dried and the solvent removed under
reduced pressure to give azide 14 (336 mg, 94%) as a colourless
oil (Found: MHϩ 393.2039. C21H25N6O2 requires MHϩ
393.2039); νmax/cmϪ1 3490w, 3290w, 2100s, 1675s and 1595s;
δH (400 MHz) 0.88 (9H, s, C(CH3)3), 3.02 (1H, br m, CHH),
3.50 (2H, br d, OH, CHH), 4.72 (1H, dd, J 5.0 and 7.3, CHN3),
4.78 (1H, d, J 10.2, CHOH), 5.49 (1H, dd, J 4.7 and 9.5, NH),
7.27–7.38 [5H, struct. m, 5 × CH(Ph)], 7.42 [1H, ddd, J ~1, ~7
and ~8, 6-H(Q)], 7.61 [1H, dd, J 1.0 and ~7, 8-H(Q)], 7.70 [1H,
ddd, J 1.5, 7.0 and ~8, 7-H(Q)], 8.17 [1H, dd, J 1.5 and ~7,
5-H(Q)]; δC 25.6 [C(CH3)3], 37.5 [C(CH3)3], 55.1 (CH2), 64.1
(CH), 74.1 (CH), 120.4 [CCO(Q)], 126.4, 126.7, 126.8, 127.1,
128.6, 128.8, 134.4 [CH(Ar), CH(Q)], 136.6 [C(Ar)], 145.8
[CN᎐C(Q)], 158.1 [C᎐N(Q)] and 161.1 [CO(Q)]; m/z (%) 393
Displacement of chloride in 15 by azide
A solution of chloride 15 (381 mg, 0.99 mmol) in DMSO (3
cm3) was stirred rapidly with sodium azide (193 mg, 2.97 mmol)
overnight at room temperature. The reaction mixture was then
diluted with water (5 cm3), extracted with ethyl acetate (3 × 5
cm3), the combined organic extracts were washed with water
(3 × 5 cm3) then brine (5 cm3), dried and the solvent was
removed under reduced pressure to give a crystalline solid.
Recrystallisation gave azide 16 as a colourless solid (246 mg,
63%), mp 110–112 ЊC (from 4:1 light petroleum–ethyl acetate)
(Found: C, 64.35; H, 6.25; N, 21.15. C21H24N6O2 requires C,
64.25; H, 6.15; N, 21.15%); αD 262.0 (c 1.0, ethanol); νmax/cmϪ1
3480w, 3270m, 2095s, 1675s and 1590s; δH (400 MHz) 0.90 [9H,
s, C(CH3)3], 2.94 (1H, br s, CHH), 3.78 (2H, br m, CHH, OH),
4.69 (1H, dd, J 4.7 and 8.9, CHN3), 4.83 (1H, d, J 10, CHOH),
5.64 (1H, dd, J 3.9 and 10.0, NH), 7.25–7.34 (5H, struct. m,
ArH), 7.40 [1H, ddd, J 1.0, ~8 and ~8, 6-H(Q)], 7.59 [1H, br d,
J 7.5, 8-H (Q)], 7.68 [1H, ddd, J 1.5, 7.5 and ~8, 7-H(Q)] and
8.17 [1H, dd, J 1.5 and 8.1, 5-H(Q)]; m/z (%) 393 (MHϩ, 100),
260 (32) and 215 (20).
᎐
᎐
(MHϩ, 100), 260 (28), 215 (32) and 175 (22).
3102 J. Chem. Soc., Perkin Trans. 1, 2000, 3096–3106

View Article Online
Conversion of azide 14 to N-BOC,NЈ-(Q)-diamine 17
arated, washed with brine (10 cm3), dried and evaporated to
dryness under reduced pressure. Chromatography (eluent 4:1
light petroleum–ethyl acetate) yielded DIBOC-diamine 21
(Rf 0.18, visualised with phosphomolybdic acid) (99 mg, 73%).
Crystallisation gave colourless needles, mp 150–152 ЊC (from
light petroleum–ethyl acetate) (Found: C, 64.2; H, 8.25; N, 8.3.
C18H28N2O4 requires C, 64.25; H, 8.4; N, 8.3%); αD 29.2 (c 1.20,
CHCl3); νmax/cmϪ1 3450m and 1710s; δH (Ϫ40 ЊC, 9.4:1 ratio
of rotamers) major rotamer 1.41 [9H, s, C(CH3)3], 1.45 [9H, s,
C(CH3)3], 3.31 (1H, struct. m, CHH), 3.49 (1H, struct. m,
CHH), 4.72 (1H, struct. m, CHAr), 4.96 (1H, t, J 5.7,
CH2NH), 5.83 (1H, d, J 7.3, CHNH) and 7.27–7.42 [5H, struct.
m, 5 × CH(Ar)]; minor rotamer observable signals δH 3.12 (1H,
struct. m, CHH), 4.59 (1H, struct. m, CHAr), 5.12 (1H, struct.
m, CH2NH) and 5.68 (1H, d, J 7.3, CHNH); m/z (%) 359
(MNaϩ, 10), 337 (MHϩ, 33), 281 (21), 225 (100), 181 (87), 164
(60) and 150 (39).
Azide 14 (418 mg, 1.06 mmol) was dissolved in ethyl acetate
(10 cm3), 5% palladium on charcoal (40 mg) added and the
mixture stirred rapidly for 48 h under an atmosphere of
hydrogen. The solution was then filtered through a plug of
Celite, the solvent removed under reduced pressure and the
residue dissolved in a mixture of 1:1 THF–water (10 cm3). To
the stirred solution was then added triethylamine (0.2 cm3) and
BOC-ON (Aldrich) (289 mg, 1.17 mmol). After stirring at room
temperature for 45 min a solid had precipitated and was filtered
off and washed with cold ethanol. Crystallisation yielded
N-BOC, NЈ-(Q)-diamine 17 (206 mg, 41%), mp 225–227 ЊC
(from ethanol–dichloromethane) (Found: C, 66.5; H, 7.25; N,
12.2. C26H34N4O4 requires C, 66.9; H, 7.35; N, 12.0%); αD 105.5
(c 0.36, CHCl3); νmax/cmϪ1 1710s, 1680s and 1595s; δH 1.00 [9H,
s, C(CH3)3], 1.44 [9H, s, OC(CH3)3], 3.11 (1H, struct. m, CHH),
3.57 (1H, struct. m, CHH), 3.62 (1H, d, J 10.1, OH), 4.94 (1H,
d, J 10.1, CHOH), 4.98–5.08 (2H, br m, CHNH, NHCO), 5.40
(1H, dd, J 4.1 and 10.0, NH), 7.27–7.41 [5H, struct. m,
5 × H(Ph)], 7.47 [1H, ddd, J 1.2, 6.9 and 7.9, 6-H(Q)], 7.67 [1H,
br d, J 8.2, 8-H(Q)], 7.76 [1H, ddd, J 1.2, 6.9 and 8.2, 7-H(Q)]
and 8.23 [1H, dd, J 1.2 and 7.9, 5-H(Q)]; m/z (%) 467 (MHϩ,
49), 260 (39) and 215 (20).
Q–N bond reduction of N-BOC,NЈ-(Q)-diamine 17
Amine 17 (196 mg, 0.42 mmol) was reduced and reacted with
BOC-ON as described above using dry, distilled THF (3 cm3),
tert-butyl alcohol (1 cm3), samarium diiodide in THF (10 cm3,
0.1 mol dmϪ3), water (10 cm3), triethylamine (0.2 cm3) and
BOC-ON (114 mg, 0.46 mmol). Chromatography (eluent 4:1
light petroleum–ethyl acetate) eluted unchanged starting
amine (Rf 0.2, 19 mg) followed by DIBOC-diamine 19 (Rf 0.18,
visualised with phosphomolybdic acid), 96 mg, 75% (based on
recovered starting material); αD Ϫ28.0 (c 1.0, CHCl3), otherwise
identical to the DIBOC-diamine as isolated above. Further
elution with 2:1 light petroleum–ethyl acetate yielded 3H-
quinazolinone 20 (78 mg, 89%) identical with that isolated
previously.3
Conversion of azide 16 to N-BOC,NЈ-(Q)-diamine 18
Azide 16 (246 mg, 0.63 mmol) was dissolved in ethyl acetate
(10 cm3), 5% palladium on charcoal (25 mg) added and reduc-
tion with hydrogen effected as described above. After the
same work-up, the residue was dissolved in a mixture of 1:1
THF–water (10 cm3) and triethylamine (0.13 cm3) and BOC-
ON (185 mg, 0.75 mmol) were added to the stirred solution.
After stirring at room temperature for 2 h the solution was
extracted with ethyl acetate (3 × 10 cm3), the combined extracts
were washed with brine (10 cm3), dried and the solvent was
evaporated under reduced pressure. Chromatography (eluent
4:1 light petroleum–ethyl acetate) yielded N-BOC,NЈ-(Q)-
diamine 18 (Rf 0.26) (230 mg, 79%) which crystallised as colour-
less needles, mp 183–187 ЊC (from ethanol) (Found: MHϩ
467.2658. C26H35N4O4 requires MHϩ 467.2658); αD 151.5
(c 0.68, CHCl3); νmax/cmϪ1 3450m, 3300w, 1720s and 1680s;
δH 0.99 [9H, s, C(CH3)3], 1.46 [9H, s, OC(CH3)3], 3.15 (1H, ddd,
J 5.0, 5.0 and 10.5, CHH), 3.47 (1H, br m, CHH), 3.57 (1H,
d, J 10.0, OH), 4.89 (1H, d, J 10.0, CHOH), 4.99 (1H, br s,
CHPh), 5.43 (1H, br d, J 7.5, NHCO), 5.57 (1H, dd, J 3.1 and
10.5, NH), 7.30–7.37 [5H, struct. m, 5 × CH(Ph)], 7.48 [1H,
ddd, J 1.2, 6.9 and 8.0, 6-H(Q)], 7.67 [1H, br d, J 8.1, 8-H(Q)],
7.76 [1H, ddd, J 1.2, 6.9 and 8.1, 7-H(Q)] and 8.23 [1H,
dd, J 1.2 and 8.0, 5-H(Q)]; δC 25.9, 28.3 [2 × C(CH3)3], 37.8
[C(CH3)3], 55.3 (CH2), 74.4 (CHOH), 80.1 (OC(CH3)3), 120.6
(CCO(Q)), 126.1, 126.6, 126.9, 127.4, 127.8, 128.9, 134.6
Ring-opening of 2-vinylaziridine 6 with dilute sulfuric acid
Aziridine 6 (50 mg, 0.167 mmol) was dissolved in 1,4-dioxane
(1 cm3) and dilute sulfuric acid (1 cm3, 0.2 mol dmϪ3) was
added. After 15 min the reaction solution was poured into
aqueous saturated sodium hydrogen carbonate (5 cm3) and
extracted with ethyl acetate (3 × 3 cm3). The combined organic
extracts were dried and the solvent was removed under reduced
pressure to give a clear residue (50 mg.) By NMR spectroscopy
this residue comprised a 3:1 mixture of allylic alcohol diastereo-
isomers 22 and 23 (94%) from comparison of the signals at
δ 5.03 and 4.32 ppm respectively (see below).
Ring-opening of 2-vinylaziridine 6 with dilute hydrochloric acid
Aziridine 6 (147 mg, 0.492 mmol) was dissolved in 1,4-dioxane
(4 cm3) and dilute hydrochloric acid (3 cm3, 0.2 mol dmϪ3
)
added. After stirring for 15 min the reaction was poured into
aqueous saturated sodium hydrogen carbonate (5 cm3) and
extracted with ethyl acetate (3 × 5 cm3). The organic extracts
were combined, dried and the solvent was removed under
reduced pressure to give a clear oil. Chromatography (eluent
2:1 light petroleum–ethyl acetate) yielded the allylic chloride 24
(Rf 0.33), (32 mg, 20%) (Found: MHϩ 336.1479. C17H23ClN3O2
requires MHϩ 336.1479); αD 165.0 (c 1.0, ethanol); νmax/cmϪ1
3480w, 3380w, 1675s and 1590s; δH 1.03 [9H, s, C(CH3)3], 3.11
(1H, struct. m, CHH), 3.62 (2H, struct. m, CHH, OH), 4.58
(1H, struct. m, CHCl), 5.04 (1H, br s, CHOH), 5.32 (1H, d,
J 10.1, HTHCC), 5.46 (1H, d, J 17.0, HTHCC), 5.64 (1H, dd,
(7 × CH), 146.0 [CN᎐C(Q)], 155.4, 158.3 and 161.2 [C᎐N(Q),
᎐
᎐
CO(Q), CO] (CH, C missing); m/z (%) 467 (MHϩ, 100), 411
(32), 260 (50), 215 (42) and 175 (30).
Q–N bond reduction of N-BOC,NЈ-(Q)-diamine 18 using
samarium(II) iodide
A flame-dried 3-necked flask equipped with stirrer bar under
an argon atmosphere was charged with amine 18 (184 mg, 0.30
mmol) dissolved in freshly distilled and dried THF (3 cm3)
containing tert-butyl alcohol (1 cm3) via septum cap and the
solution de-gassed 5 times with argon using a 3-way tap. A
J 4.1 and 9.8, NH), 6.03 (1H, ddd, J 7.9, 10.1 and 17.0, ᎐CH),
᎐
solution of samarium diiodide in THF (9 cm3, 0.1 mol dmϪ3
)
7.49 [1H, struct. m, 6-H(Q)], 7.69 [1H, d, J 7.2, 8-H(Q)],
7.77 [1H, struct. m, 7-H(Q)] and 8.25 [1H, dd, J 1.0 and 8.2,
5-H(Q)]; δC 25.8 [C(CH3)3], 37.7 [C(CH3)3], 55.9 (CH2),
59.0 (CH), 74.2 (CH), 118.9 (CH ᎐), 120.5 [CCO(Q)], 126.5,
was added slowly dropwise using a syringe via the septum cap
with stirring; discharge of the blue colour of Sm() occurred
almost instantaneously. Water (10 cm3) was added, followed by
triethylamine (0.2 cm3) and BOC-ON (107 mg, 0.43 mmol),
with stirring throughout. After 2 h the solution was filtered,
extracted with ethyl acetate (20 cm3), the organic layer sep-
᎐
2
126.9, 127.3, 134.6, 135.3 [4 × CH(Q), CH᎐], 145.8
᎐
[CN᎐C(Q)], 158.1 [C᎐N(Q)] and 161.0 [CO(Q)]; m/z (%) 336
᎐
᎐
(MHϩ, 100), 278 (20) and 215 (20). Further elution with the
J. Chem. Soc., Perkin Trans. 1, 2000, 3096–3106 3103

View Article Online
same solvent gave the allylic alcohol diastereoisomers 22 and 23
(Rf 0.13) as a 3:1 mixture (69 mg, 46%) identical with those
isolated above.
mg, 36%) (Found: MHϩ 360.1924. C19H26N3O4 requires MHϩ
360.1923); νmax/cmϪ1 3480w, 3290w, 1745s, 1650s and 1590s;
δH 0.94 [9H, s, C(CH3)3], 2.10 (3H, s, COCH3), 2.90 (1H, struct.
m, CHH), 3.40 (1H, unresolved ddd, J 4 and 8 visible, CHH),
3.57 (1H, br d, J 7.5, OH), 4.89 (1H, d, J 7.5, CHOH), 5.24
Ring-opening of aziridine 6 with a solution of hydrogen chloride
gas in ether
(1H, dd, J 10.7 and 1.0, H H C᎐), 5.32 (1H, dd, J 17.0 and 1.0,
᎐
T
C
H H C᎐), 5.45 (1H, struct. m, CHOAc), 5.51 (1H, dd, J 4.0
᎐
T
C
A suspension of aziridine 6 (93 mg, 0.31 mmol) was stirred
rapidly in sodium-dried ether (5 cm3) whilst hydrogen chloride
gas was slowly bubbled into the mixture. The suspended solid
dissolved before a white solid rapidly precipitated. The reaction
solution was neutralised by careful addition of excess saturated
sodium hydrogen carbonate; the organic layer was separated,
dried, and the solvent removed to give allylic chloride 24 (101
mg, 97%), identical with that isolated above.
and 10.4, NH), 5.82 (1H, ddd, J 5.9, 10.7 and 17.0, CH᎐), 7.43
᎐
[1H, ddd, J 1.0, 6.9 and 8.2, 6-H(Q)], 7.62 [1H, dd, J 1.0
and 8.2, 8-H(Q)], 7.71 [1H, ddd, J 1.6, 6.9 and 8.2, 7-H(Q)] and
8.18 [1H, dd, J 1.6 and 8.2, 5-H(Q)]; δC 21.0 (COCH3), 25.8
[C(CH3)3], 37.6 [C(CH3)3], 53.3 (CH2), 71.9, 74.3 (CHOH,
CHOAc), 118.3 (CH ᎐), 120.5 [CCO(Q)], 126.5, 126.8,
᎐
2
127.2, 133.4, 134.5 [4 × CH(Q), CH᎐], 145.9 (CN᎐C), 158.2
᎐
᎐
[C᎐N(Q)], 161.1 [CO(Q)] and 169.9 (COCH ); m/z (%) 360
᎐
3
(MHϩ 100), 215 (53) and 175 (37).
Further elution gave the allylic alcohol 23 (Rf 0.22), 40 mg,
38% (Found: MHϩ 318.1818. C17H24N3O3 requires MHϩ
318.1818); δH 0.96 [9H, s, C(CH3)3], 2.95 (1H, struct. m, CHH),
3.08 (1H, ddd, J 3.8, 8.8 and 12.0, CHH), 4.32 (1H, struct.
m, CHOHCH2), 5.00 (1H, br s, ButCHOH), 5.13 (1H, d,
J 10.7, H H C᎐), 5.32 (1H, d, J 17.3, H H C᎐), 5.73 (1H,
Re-conversion of chloride 24 to aziridine 6
To a solution of chloride 24 (175 mg, 0.52 mmol) in THF
(2 cm3) was added sodium hydride (23 mg of a 60% dispersion
in oil, 0.57 mmol) and the reaction stirred for 45 min. After
addition of water (5 cm3) the solution was extracted with ethyl
acetate (3 × 5 cm3), the organic extracts were dried and solvent
was removed under reduced pressure to give aziridine 6 (123
mg, 79%).
᎐
᎐
T
C
T
C
dd, J 3.8, 10.4, NH), 5.80 (1H, ddd, J 5.0, 10.7 and 17.3, CH᎐),
᎐
7.42 [1H, unresolved ddd, J ~8 visible, 6-H(Q)], 7.63 [1H,
d, J 7.9, 8-H(Q)], 7.71 [1H, unresolved ddd, J ~8 visible,
7-H(Q)] and 8.18 [1H, d, J 8.2, 5-H(Q)]; δC 25.9 [C(CH3)3],
37.6 [C(CH3)3], 55.9 (CH2), 70.2 (CH), 74.4 (CH), 116.0
Ring-opening of 2-vinylaziridine 6 with hot glacial acetic acid
(CH ᎐), 120.3 [CCO(Q)], 126.5, 126.7, 127.2, 134.4 [4 ×
᎐
2
Aziridine 6 (100 mg, 0.33 mmol) was dissolved in glacial acetic
(2 cm3) and heated at 70 ЊC for 17 h. After evaporating the bulk
of the acetic acid under reduced pressure, the residue was
dissolved in ethyl acetate (5 cm3) and remaining acetic acid
neutralised with excess aqueous saturated sodium hydrogen
carbonate. The organic layer was separated, washed with sat-
urated brine (1 cm3), dried and solvent removed under reduced
pressure. Chromatography (2:1 light petroleum–ethyl acetate)
yielded diacetate 25 (Rf 0.35) (90 mg, 67%) which crystallised
as a colourless solid, mp 118–121 ЊC (from light petroleum–
ethyl acetate) (Found: C, 62.8; H, 6.8; N, 10.45. C21H27N3O5
requires C, 62.8; H, 6.8; N, 10.5%); αD 154.0 (c 1.03, ethanol);
νmax/cmϪ1 3050m, 1740s, 1680s and 1595s; δH 1.00 [9H, s,
C(CH3)3], 2.09 (3H, s, COCH3), 2.11 (3H, s, COCH3), 3.46 (2H,
CH(Q)], 137.8 (CH᎐), 146.0 [CN᎐C(Q)], 158.1 [C᎐N(Q)] and
᎐ ᎐ ᎐
171.1 [CO(Q)]; m/z (%) 318 (MHϩ, 100), 260 (20), 215 (42)
and 147 (31).
Ring-opening of 2-vinylaziridine 6 in acetic acid in the presence
of hydrogen sulfide
Aziridine 6 (100 mg, 0.33 mmol) was dissolved in acetic acid
(2 cm3) saturated with hydrogen sulfide and the resulting solu-
tion heated at 70 ЊC for 17 h. After cooling the bulk of the
acetic acid was removed by evaporation under reduced pressure
and residual acid neutralised by addition of excess aqueous
saturated sodium hydrogen carbonate. The solution was
extracted with ethyl acetate (3 × 5 cm3) and the combined
organic extracts were washed with brine (5 cm3), dried and
evaporated under reduced pressure. The resulting colourless oil
was dissolved in pyridine (2 cm3), acetic anhydride (0.1 cm3,
1.06 mmol) added and the solution left to stand overnight at
room temperature. After addition of saturated aqueous sodium
hydrogen carbonate (5 cm3) the solution was extracted with
ethyl acetate (3 × 5 cm3), the combined organic fractions
washed with brine (5 cm3), dried and the solvent removed
under reduced pressure. Chromatography (eluent 4:1 light
petroleum–ethyl acetate) yielded quinazoline-4-thione diacetate
32 (Rf 0.31) (33 mg, 24%) (Found: MHϩ 418.1801. C21H28N3-
O4S requires MHϩ 418.1801); νmax/cmϪ1 1740s and 1590s;
δH 1.01 [9H, s, C(CH3)3], 2.09 (3H, s, COCH3), 2.10 (3H, s,
COCH3), 3.40 (1H, ddd, J 4.1, 11.6 and 11.6, CHH), 3.66 (1H,
struct. m, CH ), 5.23 (1H, dd, J 1.0 and 10.4, H H C᎐), 5.32
᎐
2
C
T
(1H, dd, J 1.0 and 17.3, H H C᎐), 5.50 (2H, struct. m, NH,
᎐
T
C
CHOAc), 5.85 (1H, ButCHOAc), 5.90 (1H, ddd, J 5.7, 10.4 and
17.3, CH᎐), 7.39 [1H, ddd, J 3.1, 5.7 and 8.0, 6-H(Q)], 7.65 [2H,
᎐
struct. m, 7-H, 8-H(Q)] and 8.16 [1H, d, J 8.0, 5-H(Q)]; δC 20.9,
21.2 (2 × COCH3), 26.1 [C(CH3)3], 35.9 [C(CH3)3], 51.9 (CH2),
72.2, 76.5 (2 × CHOCO), 117.8 (CH ᎐), 120.9 [CCO(Q)], 126.4,
᎐
2
126.8, 127.9, 134.0, 134.3 (4 × CH(Q), CH᎐), 146.6 [CN᎐C(Q)],
᎐
᎐
154.2 [C᎐N(Q)], 161.3 [CO(Q)], 170.0 and 171.3 (2 × CO CH );
᎐
2
3
m/z (%) 402 (MHϩ 100), 342 (47), 302 (43), 215 (92) and 175
(27). A crystal was grown from light petroleum–ethyl acetate for
X-ray structure determination.11b
Further elution with the same solvent gave acetoxy allylic
alcohol 26 (Rf 0.22) (9 mg, 7%) (Found: MHϩ 360.1923.
C19H26N3O4 requires MHϩ 360.1923); νmax/cmϪ1 3450w, 3295w,
1740s, 1680s and 1590s; δH 1.10 [9H, s, C(CH3)3], 2.18 (3H, s,
COCH3), 3.22 (1H, ddd, J 3.8, 8.5 and 11.7, CHH), 3.45 (1H,
ddd, J 3.5, 10.0 and 11.7, CHH), 4.43 (1H, struct. m, CHOH),
ddd, J 4.4, 7.2, 11.6, CHH), 5.23 (1H, d, J 10.7, H H C᎐), 5.34
᎐
C
T
(1H, d, J 17.3, H H C᎐), 5.54 (1H, struct. m, CHOCOCH ),
᎐
C
T
3
5.83 (1H, ddd, J 5.7, 10.7, 17.3, CHC᎐), 6.05 [1H, s, CHC-
᎐
(CH3)], 6.88 (1H, dd, J 4.4, 11.6, NH), 7.44 [1H, br dd, J 8.2
visible, 6-H(Q)], 7.67 [2H, struct. m, 7-H, 8-H(Q)] and 8.60 [1H,
d, J 8.5, 5-H(Q)]; δC 20.9, 21.1 (2 × CH3), 26.1 [C(CH3)3], 36.5
5.19 (1H, ddd, J 1.3, 1.6 and 10.7, H H C᎐), 5.41 (1H, ddd,
᎐
T
C
J 1.3, 1.6 and 17.3, H H C᎐), 5.70 (1H, dd, J 3.8 and 10.0,
᎐
T
C
NH), 5.93 (1H, ddd, J 5.0, 10.7 and 17.3, CH᎐), 6.11 (1H, s,
[C(CH ) ], 49.8 (CH ), 72.5, 77.3 (2 × CHO), 117.9 (CH ᎐),
᎐
3 3 2 2
128.3, 128.5 [2 × CH(Q)], 128.7 [CCS(Q)], 130.9, 133.6, 134.4
᎐
ButCHOCOCH3), 7.48 [1H, struct. m, 6-H(Q)], 7.74 [2H,
struct. m, 7-H, 8-H(Q)] and 8.24 [1H, d, J 7.9, 5-H(Q)]; m/z (%)
360 (MHϩ, 100), 302 (39), 215 (73) and 175 (28).
[2 × CH(Q), CH᎐], 141.7 [CN᎐C(Q)], 153.3 [C᎐N(Q)], 170.2,
᎐
᎐
᎐
171.3 (2 × CO) and 186.3 [CS(Q)]; m/z (%) 418 (MHϩ, 83),
358 (77), 305 (24), 291 (48), 231 (100), 215 (32) and 191 (36).
Further elution with the same solvent mixture yielded
quinazoline-4-one diacetate 25 (Rf 0.18) 67 mg, 50% identical to
an authentic sample prepared previously.
The same reaction was carried out but with addition of water
(120 mg, 20 eq.) and heating for only 5 h at 70 ЊC. After the
same work up, chromatography of the crude product (3:2 light
petroleum–ethyl acetate) yielded allylic acetate 27 (Rf 0.38) (43
3104
J. Chem. Soc., Perkin Trans. 1, 2000, 3096–3106

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Conversion of quinazoline-4-thione diacetate 32 to quinazolin-4-
one diol 23
6-H(Q)], 7.66 [1H, d, J 7.5, 8-H(Q)], 7.74 [1H, ddd, J 1.3, 7.5
and 8.4, 7-H(Q)] and 8.24 [1H, dd, J 1.3 and 8.1, 5-H(Q)];
δC 15.3 (CH3), 25.9 [C(CH3)3], 37.5 [C(CH3)3], 53.4, 56.3
(2 × CH2), 74.4 (CHOH), 79.7 (CHPh), 120.7 [CCO(Q)], 126.6,
126.7, 127.3, 127.9, 128.5, 134.4 [6 × CH(Ph), CH(Q)], 139.9
Quinazoline-4-thione 32 (12 mg, 0.029 mmol) was dissolved in
a mixture of ethanol (0.5 cm3) and sodium hydroxide solution
(0.5 cm3, 1.0 mol dmϪ3) and hydrogen peroxide (20 volume,
3 drops) added. After 30 min the solution was extracted with
ethyl acetate (10 cm3), the organic layer separated and washed
successively with water (2 × 5 cm3) and brine (5 cm3), then dried
and evaporated to give quinazoline-4-one diol 23 (5 mg, 55%),
identical by comparison of its NMR spectrum with that of an
authentic sample prepared previously.
[C(Ph)], 146.1 (CN᎐C), 158.4 [C᎐N(Q)] and 161.4 [CO(Q)];
᎐
᎐
m/z (%) 396 (100 MHϩ), 260 (39) and 215 (50).
Further elution with the same solvent gave alcohol 36 (Rf 0.1)
(25 mg, 48%) identical with that isolated below.
Ring-opening of aziridine 5 with samarium nitrate hexahydrate
Aziridine 5 (100 mg, 0.28 mmol) was heated at 60 ЊC for 50 min
in acetonitrile (1 cm3) containing samarium nitrate hexahydrate
(127 mg, 0.28 mmol). Water (5 cm3) was added and the solution
extracted with ethyl acetate (5 cm3), the organic layer separated,
washed with brine, dried and evaporated under reduced
pressure. Chromatography (eluent 4:1 light petroleum–ethyl
acetate) yielded nitrate ester 38 (9 mg, 8%) (Found: MHϩ
413.1826. C21H25N4O5 requires MHϩ 413.1825); δH 0.90 [9H, s,
C(CH3)3], 3.25 (1H, s m, CHH), 3.45 (1H, d, J 10.4, OH), 3.59
(1H, s m, CHH), 4.82 (1H, d, J 10.4, CHOH), 5.57 (1H, dd,
J 5.3 and 8.2, CHPh), 5.99 (1H, dd, J 3.8 and 8.5, NH), 7.61
[5H, br s, 5 × CH(Ph)], 7.43 [1H, struct. m, 6-H(Q)], 7.70 [2H,
m, 7-H, 8-H(Q)] and 8.17 [1H, dd, J 1.2, 7.8, 5-H(Q)]; m/z (%)
413 (MHϩ, 100), 260 (35), 233 (33), 215 (48), 176 (100) and 147
(71).
Ring-opening of 2-vinylaziridine 6 with samarium nitrate
hexahydrate
Aziridine 6 (300 mg, 1.00 mmol) was heated at 60 ЊC for 50 min
in acetonitrile (4 cm3) containing samarium nitrate hexahydrate
(446 mg, 1.00 mmol). Water (5 cm3) was then added and the
solution extracted with ethyl acetate (10 cm3). The organic layer
was separated, washed with brine, dried and concentrated.
Chromatography (eluent 5:2 light petroleum–ethyl acetate)
yielded nitrate ester 33 as an oil (Rf 0.30) (26 mg, 7%) (Found:
MHϩ 363.1668. C17H23N4O5 requires MHϩ 363.1669); δH 0.93
[9H, s, C(CH3)3], 3.03 (1H, struct. m, CHH), 3.47 (2H, struct.
m, CHOH, CHH), 5.38 (1H, d, J 10.7, H H C᎐), 5.46 (1H,
᎐
T
C
d, J 17.3, H H C᎐), 5.55 (1H, struct. m, CHONO ), 5.80 (1H,
᎐
C
T
2
ddd, J 6.6, 10.7, 17.3, CH᎐), 7.43 [1H, ddd, J 1.0, 6.9, 8.1,
᎐
Further elution with 2:1 light petroleum–ethyl acetate gave
alcohol 36 (Rf 0.1) (72 mg, 68%) as colourless crystals mp 125–
128 ЊC (from 2:1 light petroleum–ethyl acetate) (Found: C,
68.75; H, 6.8; N, 11.4. C21H25N3O3 requires C, 68.65; H, 6.85;
N, 11.45%); νmax/cmϪ1 3600w, 3420w, 3300w, 1675s and 1590s;
δH 0.90 [9H, s, C(CH3)3], 2.86 (1H, d, J 4.7, CHOHPh), 3.01
(1H, struct. m, CHH), 3.30 (1H, struct. m, CHH), 3.54 (1H, d,
J 10.4, CHOH), 4.83 (1H, struct. m, CHPh), 4.91 (1H, d,
J 10.4, CHOH), 5.73 (1H, dd, J 3.7 and 9.4, NH), 7.09–7.30
[5H, struct. m, 5 × CH(Ph)], 7.36 [1H, ddd, J 1.2, 6.9 and 8.2,
6-H(Q)], 7.56 [1H, br d, J ~7, 8-H(Q)], 7.65 [1H, ddd, J 1.0,
6.9 and 8.2, 7-H(Q)] and 8.12 [1H, dd, J 1.0 and 8.2, 5-H(Q)];
m/z (%) 368 (MHϩ, 100), 260 (24), 215 (22) and 175 (20).
6-H(Q)], 7.63 [1H, br d, J ~8, 8-H(Q)], 7.71 [1H, ddd, J 1.0,
6.9, 8.5, 7-H(Q)] and 8.18 [1H, dd, J 1.0, 8.1, 5-H(Q)]; m/z (%)
363 (MHϩ, 100), 260 (33), 233 (52), 215 (47) and 176 (96).
Further elution with the same solvent yielded a mixture of
allylic alcohols 22 and 23 (Rf 0.1) (242 mg, 76%) in a 1:13 ratio
by comparison of the NMR signals at δ 5.03 and 4.32 ppm
respectively with those of authentic samples.
Hydrolysis of diacetate 25
Diacetate 25 (50 mg, 0.125 mmol) was dissolved in 1,4-dioxane
(1 cm3), sodium hydroxide solution (2 cm3, 2.0 mol dmϪ3) was
added and the resulting solution left to stand overnight. The
solution was then diluted with ethyl acetate (3 cm3), washed
with water (2 cm3) then brine (2 cm3), dried and evaporated
under reduced pressure to give diol 22 (34 mg, 86%) (Found:
Ring-opening of aziridine 5 in ethanol containing hydrogen
sulfide
MHϩ 318.1818. C17H24N3O3 requires MHϩ 318.1818); νmax
/
A Young’s tube was charged with aziridine 5 (100 mg, 0.29
mmol) dissolved in ethanol (4 cm3). The solution was saturated
with hydrogen sulfide and then heated under reflux for 94 h
before being evaporated under reduced pressure. Chroma-
tography (eluent 3.5:1 light petroleum–ethyl acetate) yielded
ether 37 (Rf 0.38) (39 mg, 34%), identical to a sample prepared
previously by comparison of their NMR spectra. Further
elution with the same solvent yielded quinazoline-4-thione diol
39 (Rf 0.25) as a yellow oil, (51 mg, 46%) (Found: MHϩ
384.1746. C21H26N3O2S requires MHϩ 384.1746); νmax/cmϪ1
3450s, 1735w, 1680s and 1590s; δH 0.98 [9H, s, C(CH3)3], 2.61
(1H, br s, CHPhOH), 3.01 (1H, ddd, J 3.5, 3.8 and 11.0, CHH),
3.55 (1H, d, J 10.0, CHOH), 3.60 (1H, ddd, J 3.5, 8.5 and 11.0,
CHH), 4.97 (1H, dd, J 3.5, 8.5, CHPh), 5.14 (1H, d, J 10.0,
CHOH), 7.18–7.43 [6H, struct. m, 5 × H(Ph), NH], 7.53 [1H,
ddd, J 1.0, 6.9 and 8.2, 6-H(Q)], 7.70 [1H, d, J 8.2, 8-H(Q)], 7.79
[1H, ddd, J 1.0, 6.9 and 8.2, 7-H(Q)] and 8.69 [1H, dd, J 1.0
and 8.2, 5-H(Q)]; δC 25.8 [C(CH3)3], 38.2 [C(CH3)3], 56.0 (CH2),
72.1, 75.2 (2 × CHOH), 125.9 [CCO(Q)], 127.9, 128.3, 128.4,
cmϪ1 3450m, 3290m, 1675s and 1590s; δH 1.03 [9H, s, C(CH3)3],
2.97 (1H, struct. m, CHH), 3.23 (1H, ddd, J 3.5, 7.2 and 10.8,
CHH), 3.69 (2H, br s, 2 × OH), 4.25 (1H, struct. m, CHCH᎐),
᎐
5.03 (1H, br s, CHOH), 5.20 (1H, dd, J 1.3 and 11.7, CH H ᎐),
᎐
T
C
5.34 (1H, dd, J 1.3 and 17.3, CH H ᎐), 5.88 (2H, struct. m,
᎐
T
C
CH᎐, NH), 7.49 [1H, ddd, J 1.3, 6.9, ~8, 6-H(Q)], 7.70 [1H, br
᎐
d, J ~8, 8-H(Q)], 7.78 [1H, ddd, J 1.0, 6.9, 8.2, 7-H(Q)] and 8.25
[1H, dd, J 1.0 and 8.2, 5-H(Q)]; δC 25.9 [C(CH3)3], 37.8
[C(CH ) ], 56.1 (CH ), 69.7, 74.6, (2 × CHOH), 116.4 (CH ᎐),
᎐
2
3
3
2
120.3 [CCO(Q)], 126.7, 126.9, 127.3, 134.7, 137.2 [4 × CH(Q),
CH᎐], 146.1 [CN᎐C(Q)], 158.3 [C᎐N(Q)] and 162.1 [CO(Q)];
᎐
᎐
᎐
m/z (%) 318 (MHϩ, 100), 260 (20), 215 (42) and 147 (30).
Ring-opening of aziridine 5 by ethanol–water
Aziridine 5 (50 mg, 0.14 mmol) was heated in a mixture of
ethanol (2 cm3) and water (2 drops) under reflux for 34 h. The
reaction mixture was cooled, diluted with ethanol (5 cm3), dried
and evaporated under reduced pressure. Chromatography
(eluent 2:1 light petroleum–ethyl acetate) gave the ether 37
(Rf 0.35), (14 mg, 25%) (Found: MHϩ 396.2287. C23H30N3O3
requires MHϩ 396.2287); νmax/cmϪ1 3375w, 3290w, 1680s and
1595s; δH (400 MHz) 0.90 [9H, s, C(CH3)3], 1.21 (3H, t, J 7.0,
CH3), 3.09 (1H, br s, CHH), 3.49 (3H, struct. m, CH2CH3,
OH), 3.72 (1H, br s, CHH), 4.54 (1H, dd, J 3.7 and 6.2, CHPh),
4.72 (1H, d, J 10.0, CHOH), 5.68 (1H, dd, J 4.8 and 8.5, NH),
7.35 [5H, struct. m, 5 × CH(Ar)], 7.46 [1H, br dd, J ~8 and ~8,
128.7, 128.9, 131.0, 134.8 (7 × CH), 141.1, 141.4 [CN᎐C(Q),
᎐
C(Ph)], 157.0 [C᎐N(Q)] and 185.9 [CS(Q)] (1 C missing);
᎐
m/z (%) 384 (MHϩ, 49), 267 (32), 231 (20) and 191 (22).
Conversion of quinazoline-4-thione diol 39 to quinazolin-4-one
diol 36
The quinazoline-4-thione diol 39 (25 mg, 0.065 mmol) was dis-
solved in a mixture of ethanol (0.5 cm3) and sodium hydroxide
J. Chem. Soc., Perkin Trans. 1, 2000, 3096–3106
3105

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(0.5 cm3, 1.0 mol dmϪ3) and hydrogen peroxide (3 drops, 20
volume) added. After 30 min the solution was diluted with ethyl
acetate (10 cm3), washed with water (2 × 5 cm3), brine (5 cm3),
dried and evaporated to give quinazolin-4-one diol 36 (12 mg,
50%), identical with an NMR spectrum of an authentic sample
prepared previously.
Ring-opening of indene-derived aziridine 4 with hydrogen
chloride in dichloromethane
The aziridine 4 (100 mg, 0.277 mmol) was dissolved in dichloro-
methane (5 cm3) and cooled to 0 ЊC in an ice–water bath.
Hydrogen chloride was bubbled in slowly for 20 s, the excess
acid then neutralised by careful addition of excess saturated
aqueous sodium hydrogen carbonate and the organic layer
separated, washed with saturated brine, dried and concentrated
to give a clear oil (105 mg). Examination by NMR spectroscopy
showed the product to consist of a 1:4 ratio of chloride dia-
stereoisomers 40 and 41 (95%) by comparison of the signals
at δ 5.57 and 5.99 ppm respectively (see above).
Ring-opening of aziridine 4 with a solution of hydrogen chloride
in diethyl ether
A suspension of aziridine (67 mg, 0.185 mmol) in sodium dried
ether (3 cm3) was stirred rapidly whilst hydrogen chloride gas
was bubbled in for ~30 s. The initially cloudy solution cleared
during the reaction before a white solid precipitated out.
Residual acid in the solution was neutralised by careful
addition of excess saturated aqueous sodium hydrogen carbon-
ate, then more ether (3 cm3) added before the organic layer was
separated, dried and evaporated to give a clear oil (80 mg, 90%).
Examination of the crude product by NMR spectroscopy
showed it to be a 1:1.2 mixture of chloride diastereoisomers 40
and 41, by comparison of the signals at δ 5.57 and 5.99 ppm,
respectively. δH (major diastereoisomer 41) 1.06 [9H, s,
C(CH3)3], 3.09 (1H, dd, J 6.6 and 15.4, CHH), 3.35 (1H, dd,
J 9.1 and 15.4, CHH), 3.62 (1H, br d, J 10.0, OH), 3.82 (1H,
struct. m, CHNH), 5.15 (1H, br d, J 10.0, CHOH), 5.47 (1H, d,
J 5.0, CHCl), 5.99 (1H, d, J 7.9, NH), 7.06–7.85 [7H, struct. m,
4 × CH(Ph), 6-H, 7-H, 8-H(Q)] and 8.26 [1H, dd, 1.2 and 8.5,
5-H(Q)]; for NMR data of minor diastereoisomer 40 see below.
Reconversion of chloride 40 to aziridine 4
To a solution of the chloride 40 (69 mg, 0.174 mmol) in THF
(2 cm3) was added sodium hydride (10 mg of a 60% dispersion
in oil, 0.25 mmol) and the solution stirred for 45 min. After
the addition of water (5 cm3) the solution was extracted with
ethyl acetate (3 × 5 cm3), the organic extracts were separated,
dried and solvent was removed under reduced pressure to give
aziridine 4, (65 mg, 91%).
Acknowledgements
We thank the Asymmetric Link Scheme for funding (to
W. T. G.), Drs J. Fawcett, D. R. Russell and C. Frampton for the
X-ray crystal structure determinations and Dr S. Ulukanli for
the preparation of aziridine 10.
Ring-opening of the cis-N-invertomer of aziridine 3 with
hydrogen chloride
A lead diacetate-free solution of quinazolinone 3 in dichloro-
methane (4 cm3) was prepared as described previously2 from 1
(200 mg, 0.81 mmol) and LTA (377 mg, 0.85 mmol) at Ϫ20 ЊC
and added to a stirred solution of titanium() tert-butoxide
(548 mg, 1.62 mmol), indene (0.13 cm3, 1.11 mmol) and dry
dichloromethane (1 cm3) held at Ϫ20 ЊC. The temperature of
the reaction mixture was held at Ϫ20 ЊC for 2 min and then
allowed to reach 0 ЊC over 10 min, with stirring throughout.
Hydrogen chloride gas was then bubbled into the reaction
solution for 10 s and the temperature of the solution then
allowed to reach ambient. Excess acid was then neutralised by
careful addition of excess aqueous saturated sodium hydrogen
carbonate solution, the resulting white gelatinous precipitate
was separated and the organic layer of the filtrate separated,
washed with saturated brine (2 × 5 cm3), dried, and the solvent
evaporated under reduced pressure to give a white crystalline
solid. Examination of the crude product by NMR spectroscopy
showed it to consist of a single diastereoisomer of the chloride
40 identical to the minor diastereoisomer from the previous
experiment. Crystallisation gave chloride 40 (100 mg, 62%) as
colourless crystals mp 163–165 ЊC (from ethanol) (Found:
MHϩ 398.1635. C22H25ClN3O2 requires MHϩ 398.1635);
αD 236.0 (c 0.5, ethanol); νmax/cmϪ1 3490w, 3290w, 1660s and
1595s; δH 0.89 [9H, s, C(CH3)3], 2.95 (1H, dd, J 5.7 and 16.0,
CHH), 3.46 (1H, dd, J 6.9 and 16.0, CHH), 3.56 (1H, d, J 10.0,
OH), 4.29 (1H, struct. m, CHNH), 4.96 (1H, d, J 10.0,
CHOH), 5.25 (1H, d, J 5.0, CHCl), 5.57 (1H, d, J 3.8, NH),
7.20–7.56 [5H, struct. m, 4 × CH(Ar), 6-H(Q)], 7.77 [2H, struct.
m, 7-H, 8-H(Q)] and 8.28 [1H, dd, J 1.2 and 7.9, 5-H(Q)];
m/z (%) 398 (MHϩ, 100), 215 (21) and 175 (32).
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3106
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