A synthesis of aziridines from α-iodoenones

Article abstract of DOI:10.1016/S0040-4039(02)00791-8

Aziridines were prepared from α-iodocycloenones in very good yield, by a Michael addition/cyclisation (Gabriel-Cromwell) process employing a slight excess of primary amine and Cs₂CO₃ as base at 95°C. Using chiral amines it was possible to prepare optically pure aziridines. The same method was also efficient for the synthesis of aziridines from acyclic α-halounsaturated compounds. 2-Oxoazabicycles reacted with several nucleophiles to afford α-heteroatom substituted cyclic enones in excellent yield.

Full text of DOI:10.1016/S0040-4039(02)00791-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4329–4331
A synthesis of aziridines from a-iodoenones
M. Teresa Barros,a Christopher D. Maycockb,* and M. Rita Venturab
aFaculdade de Cieˆncias e Tecnologia da Universidade Nova de Lisboa, Departamento de Qu´ımica, 2825 Monte da Caparica,
Portugal
bInstituto de Tecnologia Qu´ımica e Biolo´gica, Universidade Nova de Lisboa, Apartado 127, Rua de Quinta Grande 6,
2780-156 Oeiras, Portugal
Received 15 March 2002; revised 22 April 2002; accepted 23 April 2002
Abstract—Aziridines were prepared from a-iodocycloenones in very good yield, by a Michael addition/cyclisation (Gabriel–
Cromwell) process employing a slight excess of primary amine and Cs2CO3 as base at 95°C. Using chiral amines it was possible
to prepare optically pure aziridines. The same method was also efficient for the synthesis of aziridines from acyclic a-halounsat-
urated compounds. 2-Oxoazabicycles reacted with several nucleophiles to afford a-heteroatom substituted cyclic enones in
excellent yield. © 2002 Elsevier Science Ltd. All rights reserved.
Aziridines display great potential and versatility as
chiral substrates, auxiliaries, reagents and ligands in
stereoselective synthesis.1 Several natural molecules
possessing an aziridine ring have been found which
exhibit potent biological activity.2 One of the most
convenient methods for the formation of aziridines is
exemplified by their direct construction from a,b-
dibromo acyclic esters and ketones simply by reaction
with an excess of a suitable primary amine (Gabriel–
Cromwell reaction).3 The excess of amine employed has
the triple role of eliminating HBr, to form an a-bromo-
enone, performing conjugated addition, and deproto-
nating the cyclised product to afford the aziridine. To
our knowledge this procedure has not been employed
for cyclic substrates other than lactones4 and lactams.5
We have no reference to this reaction using a-
haloenones within carbocyclic systems. Previous
studies6 indicate that the cyclisation step requires the
leaving group to be trans to the adjacent amino group,
and thus the reprotonation of the enolate to form an
a-halo-b-aminoketone is fundamental. This requires
that the equilibrium between the starting compound
and the amine addition intermediate is favourable and
that conditions do not exist for the overall reverse
reaction.
part as intermediates in stereoselective synthesis.8 Thus,
we anticipated that they could be employed as sub-
strates for aziridination, and the presence of an adja-
cent asymmetric centre could induce stereoselectivity
during the process. The bicyclic products would be of
value in organic synthesis, due to the ability of aziridi-
nes to undergo highly regio- and stereoselective ring
opening reactions, and to induce stereoselectivity in
subsequent reactions at adjacent functional groups.
Table 1.
O
O
RNH2, Cs2CO3, phen,
xylene, 95 °C, 2h
I
N
R
n
n
1-3
4-13
n
1
1
1
Amine
Products
Yield %
92
4 R=Bn
BnNH2
CH2=CHCH2NH2
5 R=allyl
94
6 and 7 R=(R)-MeBn
2 diastereoisomers
d.r.=1:1
91
Ph
NH2
8 R=Bn
88
96
89
2
2
2
BnNH2
9 R=allyl
CH2=CHCH2NH2
a-Iodocycloenones are readily prepared from the corre-
sponding cycloenone,7 and have played an important
10 and 11 R=(R)-MeBn
2 diastereoisomers
d.r.=1:1
Ph
NH2
12 R=Bn
92
87
3
3
BnNH2
13 R=allyl
CH2=CHCH2NH2
* Corresponding author. Fax: +351 214469789; e-mail: maycock@
itqb.unl.pt
Phen = 1,10-phenantroline (1 eq)
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00791-8

4330
M. T. Barros et al. / Tetrahedron Letters 43 (2002) 4329–4331
Table 2.
Attempts to carry out the aziridination reaction on
a-iodocycloenones using an excess of benzylamine
under standard Gabriel–Cromwell conditions resulted
in the recovery of starting material. It appeared that the
failure of these compounds to undergo aziridination
was due to the rapid collapse of the intermediate eno-
late, to reform the starting material, before any cyclisa-
tion to the aziridine could occur. We anticipated that
the addition of an inorganic base would absorb irre-
versibly any acid formed and perhaps reprotonation of
the enolate would occur cis to the amino group via a
1,3-proton transfer. This would set the system up for
ring closure.
O
O
O
O
I
a
R
N
O
O
OMe
OMe
OMe
OMe
15
14
a) Reaction conditions
Amine
Phen Product
Yield %
Cs2CO3
14
15 R=Bn
15 R=Bn
BnNH2
No
Yes
"
No
"
Yes
80
94
90
"
"
CH2=CHCH2NH2
"
"
"
"
"
"
15 R=allyl
On adding cesium carbonate9 to a mixture of benzyl-
amine (1.5 equiv.) and a-iodocycloalkenone at 95°C in
xylene, the reaction proceeded in good yield to afford
the corresponding aziridine. The addition of the biden-
tate ligand 1,10-phenanthroline to this mixture
increased the reaction rate and the yield (Table 1
exemplified in Table 2), perhaps by serving as a ligand
for Cs+ ions. In fact, this reaction was very clean and
the product only needed to be filtered through a pad of
silica gel to be purified.
15 R=CMe3 95
Me3CNH2
BnONH2
15 R=OBn
88
R
N
Br
RNH2, Cs2CO3,
CO2Et
CO2Et
phen, xylene, 95 °C, 1h
20 R=Bn, 96%
21 R=allyl, 90%
16
CO Me
+
2
CO2Me
RNH2, Cs2CO3,
Br
17
Br
18
phen, xylene, 95 °C, 1h
For all three substrates, a-iodocyclopentenone 1, a-
iodocyclohexenone 2 and a-iodocycloheptenone 3, the
yields of the respective aziridines were very good. When
(R)-methylbenzylamine was the reagent, the two
diastereoisomeric pairs, 6 and 7, 10 and 11 (Table 1),
were easily chromatographically separated and each
compound obtained optically pure. Surprisingly no
diastereomer preference was observed.
R
R
N
N
+
CO2Me
CO2Me
22 R=Bn
24 R=allyl
23 R=Bn, 90%
25 R=allyl, +
RNH2, Cs2CO3,
CO2Me
Ph
Br
19
phen, xylene, 95 °C, 1h
The asymmetric enone 14, when treated under the
above conditions, afforded excellent yields of only one
diastereoisomer to which we have tentatively assigned
the configuration depicted in structure 15. The effect of
changing the reaction conditions for this transforma-
tion was also obvious from the results depicted in Table
2. Similar selectivities have been obtained during nucle-
ophilic epoxidation of this compound.
R
R
N
N
+
Ph
CO2Me Ph
26 R=Bn
28 R=allyl
CO2Me
27 R=Bn, 93%
29 R=allyl, 90%
+yield not evaluated due to the high volatility of the products
Scheme 1.
In order to demonstrate that these reaction conditions
could equally be applied to the aziridination of acyclic
esters, aziridination was performed on esters 16, 17, 18
(mixture), and 19 (Scheme 1). All the reactions gave
good to excellent yields, comparable with those already
reported.3,10 The aziridines 26–29 derived from cinna-
mate 19 appear not to have been previously reported.
O
O
O
O
AcO
Br
O
O
OMe
OMe
OMe
OMe
Exploratory studies on the reduction of 2-oxoazabicy-
cloalkanes with borohydride were carried out.
Diastereoisomers 6 and 7 and compounds 4 and 12
were reduced by NaBH4 with very high stereoselectivity
with all affording only one diastereoisomer of the
respective alcohol. The alcohols derived from reduction
of 6 and 7 were optically pure. Two diastereoisomeric
alcohols were formed from the reduction of 2-oxoazabi-
cycloheptane 8, d.r.=2.8:1. The configuration of these
alcohols is not obvious from the spectroscopic data
available although we suspect that the OH is cis with
30
31
Figure 1.
respect to the aziridine ring in the major product. More
results on this study will be forthcoming.
Preliminary studies on the acid-catalysed aziridine ring
opening reactions of the azabicycloalkane 15 (R=Bn)
with AcOH and MgBr2 afforded the a-acetoxy and
a-bromoenones 30 (94%) and 3111 (89%), respectively

M. T. Barros et al. / Tetrahedron Letters 43 (2002) 4329–4331
4331
(Fig. 1). This indicated that these aziridines were
regioselectively opened and that the amine function was
then lost to produce a new enone. This is the reverse
equivalent to the aziridine formation reaction. Nor-
mally, ring opening produces vicinally bifunctional
compounds. Further studies are required in order to
determine the scope of this reaction.
7. (a) Johnson, C. R.; Adams, J. P.; Braun, M. P.;
Senanayake, C. B. W.; Wovkulich, P. M.; Uskokovic, M.
R. Tetrahedron Lett. 1992, 33, 917; (b) Jonhson, C. R.;
Adams, J. P.; Braun, M. P.; Senanayake, C. B. W.;
Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron Lett.
1992, 33, 919.
8. (a) Barros, M. T.; Maycock, C. D.; Ventura, M. R.
Tetrahedron Lett. 1999, 40, 557; (b) Barros, M. T.; May-
cock, C. D.; Ventura, M. R. Chem. Eur. J. 2000, 6, 3991;
(c) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J.
Chem. Soc., Perkin Trans. 1 2001, 166.
9. All reagents were dried carefully before use. Potassium
carbonate could be used instead of cesium carbonate in
some cases.
10. Ley, S. V.; Middleton, B. J. Chem. Soc., Chem. Commun.
1998, 1995.
The aziridination method described afforded very good
yields of easily purified products using only a slight
excess of amine. High stereoselectivity was observed
with a chiral substrate. Oxoazabicycloalkanes were
available by this method and not by the classical
Gabriel–Cromwell procedure. Using a chiral amine it
was possible to produce chiral, easily separable aziridi-
nes from achiral iodocycloenones. This method was
also applicable to acyclic substrates, producing the
same products in similar or higher yields than those
previously described in the literature. The scope of this
reaction appears to be large both for the enone and
amine. These previously unknown 2-oxoazabicycloalka-
nes undergo novel aziridine ring-opening reactions
which are under study.
11. All compounds afforded spectral data consistent with the
structure proposed. NMR data for representative com-
pounds (assignments for 13C spectra supported by DEPT
experiments): Compound 4: 13C NMR (CDCl3), 75 MHz:
l 212.0 (CꢀO); 138.1 (quaternary Ar); 128.4, 127.6, 127.2
(Ar); 61.4 (C
C-5). Compound 5: 13C NMR (CDCl3), 75 MHz: l 212.0
(CꢀO); 134.2 (CH2CHꢀCH2); 116.9 (CH2CHꢀCH2); 60.3
(C
6 H2Ph); 46.9, 46.1 (C-2, C-3); 32.8, 24.0 (C-4,
6
6
6
H2CHꢀCH2); 46.8, 45.9 (C-2, C-3); 32.8, 24.0 (C-4,
Acknowledgements
C-5). Compound 8: 13C NMR (CDCl3), 75 MHz: l 207.6
(CꢀO); 138.4 (quaternary Ar); 128.4, 127.5, 127.2 (Ar);
63.3 (C
(C-4, C-5). Compound 9: 13C NMR (CDCl3), 75 MHz: l
207.5 (CꢀO); 134.5 (CH2CHꢀCH2); 116.6 (CH2CHꢀCH2);
62.1 (C
6 H2Ph); 46.3, 43.8 (C-2, C-3); 37.0 (C-6); 23.2, 18.8
We thank Fundac¸a˜o para a Cieˆncia e a Tecnologia for
generous financial support and a grant to M.R.V.
6
6
6
H2CHꢀCH2); 46.0, 43.6 (C-2, C-3); 36.9 (C-6);
23.2, 18.8 (C-4, C-5). Compound 12: 13C NMR (CDCl3),
75 MHz: l 212.1 (CꢀO); 138.6 (quaternary Ar); 128.4,
References
127.5, 127.1 (Ar); 64.0 (C6 H2Ph); 51.0, 44.8 (C-2, C-3);
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41.0 (C-7); 28.3, 24.1, 23.6 (C-4, C-5, C-6). Compound 13:
13C NMR (CDCl3), 75 MHz: l 212.1 (CꢀO); 134.7
(CH2C6 HꢀCH2); 116.2 (CH2CHꢀC6 H2); 62.6 (C6 H2CHꢀ
CH2); 50.8, 44.5 (C-2, C-3); 41.0 (C-7); 28.4, 24.0, 23.5
(C-4, C-5, C-6). Compound 30: 1H NMR (CDCl3), 300
MHz: l 6.50 (1H, s, H-3); 4.64 (1H, d, J=8.9 Hz, H-4);
4.17–4.08 (1H, ddd, J=13.5 Hz, J=8.9 Hz, J=4.8 Hz,
H-5); 3.31 (3H, s, OMe); 3.27 (3H, s, OMe); 2.83 (1H, dd,
J=16.4 Hz, J=4.8 Hz, H-6); 2.55 (1H, dd, J=16.4 Hz,
J=13.4 Hz, H-6); 2.23 (3H, s, OAc); 1.36 (3H, s, Me);
1
1.33 (3H, s, Me). Compound 31: H NMR (CDCl3), 300
MHz: l 7.31 (1H, d, J=1.9 Hz, H-3); 4.49 (1H, dd,
J=8.9 Hz, J=1.9 Hz, H-4); 4.07 (1H, ddd, J=13.8 Hz,
J=9.1 Hz, J=4.8 Hz, H-5); 3.32 (3H, s, OMe); 3.26 (3H,
s, OMe); 2.95 (1H, dd, J=16.6 Hz, J=4.8 Hz, H-6); 2.60
(1H, dd, J=16.6 Hz, J=13.7 Hz, H-6); 1.36 (3H, s, Me);
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(CꢀO); 148.7 (C-3); 124.3 (C-2); 100.9, 99.8 (2×C6 OMe);
70.3, 67.4 (C-4, C-5); 48.3, 48.2 (2×OMe); 41.1 (C-6);
17.6, 17.5 (2×Me).
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