The conversion of an aziridine plus an iminium salt to a 1,2-diamine

Article abstract of DOI:10.1016/S0040-4039(03)01833-1

The conversion of an aziridine to a 1,2-diamine using lithium iodide and an iminium salt is discussed. We have found that when the aziridine is substituted by only alkyl groups, it is the less substituted carbon-nitrogen bond that is broken; whereas, when the aziridine is substituted by a phenyl group at either the nitrogen or the carbon, it is the more substituted carbon-nitrogen bond that is broken. For a 2,3-disubstituted aziridine, the reaction sequence goes with net retention of stereochemistry.

Full text of DOI:10.1016/S0040-4039(03)01833-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7125–7128
The conversion of an aziridine plus an iminium salt to a
1,2-diamine
Matthew T. Hancock and Allan R. Pinhas*
Department of Chemistry, University of Cincinnati, PO Box 210172, Cincinnati, OH 45221-0172, USA
Received 17 June 2003; revised 23 July 2003; accepted 28 July 2003
Abstract—The conversion of an aziridine to a 1,2-diamine using lithium iodide and an iminium salt is discussed. We have found
that when the aziridine is substituted by only alkyl groups, it is the less substituted carbonꢀnitrogen bond that is broken; whereas,
when the aziridine is substituted by a phenyl group at either the nitrogen or the carbon, it is the more substituted carbonꢀnitrogen
bond that is broken. For a 2,3-disubstituted aziridine, the reaction sequence goes with net retention of stereochemistry.
© 2003 Elsevier Ltd. All rights reserved.
1,2-Diamines, also known as vicinal diamines, are bio-
logically and medically important compounds. In addi-
tion, they are prominent in organic synthesis as starting
materials, as chiral auxiliaries, and as chiral ligands to
a variety of metal complexes.1–5
Previously, we have shown that a ring-opened aziridine
will react with a metal carbonyl complex, such as
Fe(CO)5, to generate a metallacyclic complex,15 and will
react with CO2 to generate an oxazolidinone.16 In this
manuscript, we will show that a ring-opened aziridine
will react with a readily available17 iminium salt to
generate, after an aqueous work-up, a 1,2-diamine. We
have studied the regiochemistry and the stereochemistry
of this reaction.
Although there are known conversions of aziridines to
1,2-diamines, the number is rather small.1,6–11 In addi-
tion, to open the ring, most of these conversions require
electron-withdrawing groups on the nitrogen and a
strong nucleophile, such as azide. Alternatively, the
aziridine can be converted to an aziridinium ion, which
can then be ring-opened with a large variety of
nucleophiles.12–14
As shown in Scheme 1, we used (CH3)2N+ꢁCH2 as the
iminium salt and varied the substituents on the
aziridine. These reactions were run by heating aziridine
1 with LiI in THF to affect a ring opening, and then,
Scheme 1.
* Corresponding author. Tel.: 513-556-9255; fax: 513-556-9239; e-mail: allan.pinhas@uc.edu
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01833-1

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M. T. Hancock, A. R. Pinhas / Tetrahedron Letters 44 (2003) 7125–7128
adding the iminium salt and stirring at room tempera-
ture. For compounds 1a and 1b, in which the nitrogen
and a carbon are both substituted by alkyl groups, it is
the less substituted carbonꢀnitrogen bond which is bro-
ken to give products 2a and 2b, respectively, in 70–80%
yield. Only a trace of regioisomer 3 can be detected by
1H NMR spectroscopy or gas chromatography/mass
spectrometry.
reasons that are unknown to us,16 the ring opening
reaction does not occur.
Next, as shown in Scheme 2, we used aziridine 1a and
varied the iminium salt (4). These reactions were done
to determine the variety of substituents that could be
used.
In all cases, the methylene is lost and the two alkyl
groups are retained in the product diamine (5). This
result implies that the iminium salts are stable to hydro-
gen scrambling under our reaction conditions. All reac-
tions proceed in good yield (65–85%) except for the
di-isopropyl case (4f), which does not react at all. We
suspect this lack of reactivity is due to the large size of
the two isopropyl groups.
When carbon-2 is substituted by a phenyl group as in
1c, it is the more substituted carbonꢀnitrogen bond that
is broken to give 3c in over 70% isolated yield. When
R1=Ph, as in 1d and 1e, the more substituted car-
bonꢀnitrogen bond is broken to give 3d and 3e, but
unfortunately in very low isolated yield (about 20%).
Next, we wanted to determine the stereochemistry of
this transformation. Aziridine 1f gives 1,2-diaminocy-
clohexane 2f as the product. If the two amine groups
are trans, a large diaxial coupling between H1 and H2
should be observed. In contrast, if the two amines are
cis, the J value will be small.18 A J value of 2.4 Hz was
obtained, which indicates that the two amino groups
are cis. Thus, this transformation goes with net reten-
tion of stereochemistry.
Because a gem-aminoether is the immediate precursor
to each iminium salt, we were curious if a gem-
aminoether would undergo a similar reaction with a LiI
ring-opened aziridine. Although the aminoethers have
the advantage of being less air-sensitive than the
iminium salts, in most cases, they were very difficult to
isolate due to their volatility. The exception is the
aminoether corresponding to iminium salt 4d, which
has a benzyl substituent. For this reaction, the yield
was higher when using the iminium salt than when
using the aminoether.
For aziridine 1g, the reaction is stereospecific, i.e. the
cis stereoisomer of the starting material gives one
stereoisomer of the product and the trans stereoisomer
of the starting material gives the other stereoisomer of
the product. This was determined by the differences in
the chemical shifts of the two products. (The product
from cis-1g has its methyl groups at 1.09 and 1.14 ppm
and H1 and H2 at 2.3 and 2.9 ppm. The product from
trans-1g has its methyl groups at 0.8 and 1.0 ppm and
H1 and H2 at 2.2 and 2.3 ppm.) The stereochemistry of
the product diamine was determined by the chemical
shifts and coupling constants of H1 and H2.19 We found
that cis-1g generates erythro-2g and that trans-1g gen-
erates threo-2g. Thus, as above, this reaction goes with
net retention of stereochemistry.
Taking into account the above data, we propose the
mechanism shown in Scheme 3, which is drawn for the
conversion of aziridine 1a to diamine 2a. As mentioned
previously,16 in the first step, LiI opens the aziridine
ring to give 6. (Although we have no spectroscopic data
for 6, we believe it is present because when the solution
is concentrated, we isolate a six-membered ring dimer
of 6. This dimer is not observed upon concentration of
1.) Compound 6 then reacts with the iminium salt to
give 7, which immediately ring closes to give 8. We
have NMR data consistent with compound 8. Upon
hydrolysis of the reaction solution, diamine 2a is
generated.
When the aziridine ring is substituted by two phenyl
groups as in 1h, as we have shown previously, for
Scheme 2.

M. T. Hancock, A. R. Pinhas / Tetrahedron Letters 44 (2003) 7125–7128
7127
Scheme 3.
Though we have no direct proof, our results are consis-
tent with compound 8 isomerizing to compound 9.
When the reaction solution is treated with LiAlH4 prior
to the aqueous work-up, diamine 10 is generated.
References
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This mechanism explains the net retention of stereo-
chemistry that is observed. In the first step, the stereo-
chemistry is inverted by the SN2 addition of I−, and in
the third step, the stereochemistry is again inverted by
the SN2 addition of an amine.
The conversion of an aziridine plus and an iminium salt
to a 1,2-diamine was studied. We found that the reac-
tion is regiospecific (when the aziridine is substituted by
only alkyl groups, it is the less substituted car-
bonꢀnitrogen bond that is broken; whereas, when the
aziridine is substituted by a phenyl group, it is the more
substituted carbonꢀnitrogen bond that is broken) and
stereospecific (a 2,3-disubstituted aziridine reacts with
net retention of stereochemistry). Although the yields
are not quantitative, they are usually between 70 and
80%. In addition, most products are very clean after
simple extractions, i.e. either no chromatography or a
short column in a disposable pipette is all that is
needed.20,21
6. Li, Z.; Fernandez, M.; Jacobsen, E. N. Org. Lett. 1999, 1,
1611.
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Acknowledgements
17. Rochin, C.; Babot, O.; Dunogues, J.; Duboudin, F. Syn-
thesis 1986, 228.
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M.T.H. thanks the Department of Chemistry of the
University of Cincinnati for a Laws-Shubert Fellow-
ship. The authors thank Professor Paul Lahti of the
University of Massachusetts for suggesting the LiAlH4
experiments.
19. Olofsson, B.; Somfai, P. Tetrahedron Lett. 2003, 44, 1279.

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M. T. Hancock, A. R. Pinhas / Tetrahedron Letters 44 (2003) 7125–7128
20. General procedure for the conversion of an aziridine to a
diamine. A mixture of the aziridine (1.0 mmol) and
lithium iodide (0.20 g, 1.5 mmol) in 30 mL of THF was
allowed to reflux for 15 min. This reaction was cooled to
room temperature. Then the iminium salt (1.0 mmol) was
added and the solution was stirred at 25°C. After at least
20 h, the reaction mixture was added to 50 mL of ether.
Then the mixture was treated with 100 mL of water and
made acidic (pH 2 or 3, as determined by pH paper) with
HCl. The water was removed and made basic (pH 10 or
11, as determined by pH paper) with NaOH. Finally, the
water was extracted with 150 mL of ether, in three
portions. The ether solutions were mixed together, dried
with anhydrous K2CO3, and evaporated to dryness. The
remaining oil easily was purified (when necessary) by
using a short alumina column in a disposable pipette,
eluting with methylene chloride and ethyl acetate, to give
the corresponding 1,2-diamine. Spectroscopic data for
compounds 2, 3 and 5 have been reported previously.15
21. Isolation of the reaction intermediate 8g. The reaction
using aziridine trans-1g and iminium salt 4a was run as
discussed in Ref. 20. After 20 h, the reaction mixture was
added to 50 mL of ether and the solid that precipitated
from the solution was collected: 1H NMR l 1.21 (d,
J=6.1 Hz, 3H), 1.38 (d, J=7.0 Hz, 3H), 2.87–2.93 (m,
1H), 2.96 (s, 3H), 3.10 (s, 3H), 3.41–3.47 (m, 1H), 3.71 (d,
J=14.2 Hz, 1H), 4.03 (d, J=8.6 Hz, 1H), 4.08 (d, J=14.4
Hz, 1H), 4.24 (d, J=8.3 Hz, 1H), 7.31–7.36 (m, 5H).