N-amino-N-methylmorpholinium salts: Highly active aziridination reagents for chalcones

Article abstract of DOI:10.1055/s-2006-950425

A highly effective aziridination reagent, based on N-methylmorpholine, is reported which effects rapid conversion of chalcones to N-unfunctionalised aziridines at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950425

2
504
LETTER
N-Amino-N-methylmorpholinium Salts: Highly Active Aziridination Reagents
for Chalcones
a
a,1
b
b
a
N
A
-Amino-
N
-methy
l
lmorph
a
olinium Sa
n
lts Armstrong,* David R. Carbery, Scott G. Lamont, Andrew R. Pape, Richard Wincewicz
a
Department of Chemistry, Imperial College London, South Kensington, London SW7 2AZ, UK
Fax +44(20)75945804; E-mail: A.Armstrong@imperial.ac.uk
b
AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK
Received 25 May 2006
NaOH in MeCN, but the yield of aziridine was low (17%
after 18 h). Therefore we prepared alternative hydrazini-
um nitrate salts by amination of several cyclic amines.
While the hydrazinium salts derived from N-methylpyr-
rolidine and N-methylpiperidine gave comparable or
lower yields of aziridine, we were delighted to find that
the N-methylmorpholinium nitrate salt 2a (Scheme 2),
prepared by amination of N-methylmorpholine
Abstract: A highly effective aziridination reagent, based on N-
methylmorpholine, is reported which effects rapid conversion of
chalcones to N-unfunctionalised aziridines at room temperature.
Key words: aziridine, hydrazinium salts, chalcone, aminimine
Aziridines are highly attractive synthetic intermediates,2
largely because they can undergo ring opening with a
variety of nucleophiles to give functionalised amine
(
Scheme 2), effected aziridination of chalcone in 95%
yield after only three hours under the NaOH/MeCN con-
ditions (Scheme 3). While this result was encouraging,
particularly in identifying the reactivity of the morpholine
framework, we felt that the procedure used to prepare
the hydrazinium nitrate salt 2a from N-methylmorpholine
was inconvenient since it required reaction with hydroxyl-
amine-O-sulfonic acid (HOSA) and Ba(NO ) over ex-
3
,4
products. However, alkene aziridination, particularly
asymmetric aziridination, is far less well developed than
the closely related epoxidation.5 We were attracted by
the report of Xu in 2002 that enones can be aziridinated by9
hydrazinium salt 1 in the presence of NaH (Scheme 1).
–8
1
0
By analogy with an earlier study, this chemistry was as-
sumed to proceed by deprotonation of 1 to give an N–N
ylid (aminimine), which then undergoes Michael addition
to the enone followed by ring closure to give the aziridine.
An advantage of the method is that it affords N-unsubsti-
tuted aziridines which allows flexibility in further func-
tionalising the nitrogen with a choice of activating group.
We reasoned that this process had potential for asymmet-
ric aziridination if chiral hydrazinium salts were em-
ployed. However, the strong base and carcinogenic
solvent employed in this work were unattractive, as were
the relatively long reaction times. Therefore, we under-
took a study of alternative reaction conditions and report
here the discovery of two new base systems as well as a
more reactive hydrazinium salt that is particularly conve-
nient to prepare.
3
2
tended time periods at raised temperatures. Therefore, we
were pleased to find that the corresponding iodide salt
could be more readily prepared simply by treatment of
commercially available N-aminomorpholine 3 with one
equivalent of iodomethane in THF at 0 °C. The hydrazin-
ium iodide salt 2b was isolated after filtration as a white
solid in 77% yield and can be further purified by re-
crystallisation from EtOH. Under the same NaOH/MeCN
conditions, the iodide 2b afforded a slightly lower yield of
aziridine than nitrate 2a (Scheme 3). This, along with the
fact that the chemistry still required two equivalents of 2,
prompted us to screen further bases with the more readily
accessed iodide 2b.
O
N
O
O
N
H2NOSO3H
MeI, THF
0 °C to r.t., 30 min
Ba(NO3)2, Ba(OH)2
X–
NH2
NaH,
H
N
2
H O, reflux, 18 h
X = I 77%
N
N
i-PrOH–C6H6
H2N
a X = NO3
Ph
Ph
NO3–
NH2
X = NO3 93%
2
N
Ph
2
3
16 h, r.t.
Ph
H2N
O
2b X = I
O
1
Scheme 2
(2 equiv)
Scheme 1
O
O
2
equiv 2
We began by testing the Xu nitrate salt 1 (2 equiv) for
aziridination of chalcone with alternative bases and sol-
vents. Early studies showed that it was possible to use
Ph
Ph
Ph
Ph
2
equiv NaOH,
HN
MeCN, r.t., 3 h
With 2a (X = NO3): 95%
With 2b (X = I): 73%
Scheme 3
SYNLETT 2006, No. 15, pp 2504–2506
1
8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950425; Art ID: D15006ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
N-Amino-N-methylmorpholinium Salts
2505
Reasoning that a homogeneous system may lead to im-
Table 1 Enone Aziridination13
proved reaction rates, we were pleased to find that t-
O
X–
1
1
BuOK in DMSO allowed extremely rapid aziridination:
consumption of chalcone was complete in five minutes,
and the aziridine was isolated in 61% yield. Moreover, we
could now use about one equivalent of 2b. In view of the
ease of preparation of 2b and the rapid reaction times, we
tested these new conditions with a range of enone sub-
strates (Table 1, Method A). For some substrates, the
NaOH/MeCN conditions were also tested for comparison
N
O
O
H3C
NH2
Ar
Ar'
Ar
Ar'
HN
Methoda
Entry Ar
Ar¢
Isolated
yield (%)
1
2
3
4
5
6
7
8
9
0
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
A
B
A
A
A
A
A
B
A
A
B
A
B
A
A
B
A
A
A
B
61
95
68
65
55
60
56
2
(
Table 1, Method B). Good yields of aziridine could be
obtained for chalcone itself (Table 1, entries 1 and 2) and
for a range of substituted derivatives (Table 1, entries 3–
o-MeC H
6
4
1
7). In all cases, the trans-aziridine was obtained pre-
dominantly (>90:10). Interestingly, Methods A and B dis-
played potentially useful differences in reactivity.
Chalcones with the electron-donating MeO substituent
gave better results with 2b and t-BuOK/DMSO (Table 1,
entry 7 vs 8; entry 15 vs 16), while some electron-poor
chalcones afforded higher yields with the 2a/NaOH/
MeCN system (Table 1; entry 10 vs 11, entry 12 vs 13).
This may indicate mechanistic differences between the
two systems: indeed, intense colour changes were ob-
served during the successful reactions with 2b/t-BuOK/
DMSO, and electron-transfer processes have been report-
o-MeOC H
6
4
o-ClC H
6
4
p-MeC H
6
4
p-MeOC H
6
4
4
p-MeOC H
6
p-ClC H
42
0
6
4
1
p-CNC H
6
4
4
1
2
ed under similar conditions. Such mechanistic detail will 11
be the subject of future investigations. Pleasingly, we
p-CNC
H
17
0
6
1
2
m-NO C H
2 6
4
4
were also able to extend the methodology to other aromat-
ic systems such as 1-napthyl and 3-furyl chalcones in 13
comparable yield (Table 1, entries 18 and 19), with Meth-
od A again giving better results for the latter, electron-rich
substrate (Table 1, entry 19 vs 20). Unfortunately, howev- 15
er, we have so far not been able to extend the substrate
scope to include alkyl-substituted enones: no aziridine has
been obtained from cyclohexenone, benzylidene acetone
or 1-phenylbut-2-en-1-one.
m-NO C H
83
58
67
9
2
6
1
4
Ph
Ph
Ph
Ph
p-MeC H
6 4
p-MeOC H
6
4
4
1
1
1
6
7
8
p-MeOC H
6
p-ClC H
48
59
64
7
6
4
1-naphthyl
3-furyl
Ph
Ph
Ph
In conclusion, we have developed a convenient new
reagent system for aziridination of chalcones. Efforts to 19
extend the scope and mechanistic detail of the chemistry,
to develop an asymmetric variant by use of chiral
hydrazinium salts, and to explore synthetic applications of
the aziridine products are currently underway.
2
0
3-furyl
a
Method A: enone (1 equiv), 2b (1.1 equiv), DMSO, t-BuOK (1.1
equiv), 5 min, r.t. Method B: enone (1 equiv), 2a (2 equiv), MeCN,
NaOH (2 equiv), 18 h, r.t.
Acknowledgment
(
6) For a two-step asymmetric aziridination of chalcones using
chiral rare-earth-metal-catalysed Michael addition of
hydroxylamines, see: Jin, X. L.; Sugihara, H.; Daikai, K.;
Tateishi, H.; Jin, Y. Z.; Furuno, H.; Inanaga, J. Tetrahedron
We thank the EPSRC (GR/S58508) and AstraZeneca (CASE award
to R.W.) for their support of this work.
2
002, 58, 8321.
References and Notes
(
7) Sugihara, H.; Daikai, K.; Jin, X. L.; Furuno, H.; Inanaga, J.
(1) Current address: Department of Chemistry, University of
Tetrahedron Lett. 2002, 43, 2735.
Bath, Bath BA2 7AY, UK.
(8) Recent examples of asymmetric chalcone aziridination:
(a) Ma, L. G.; Jiao, P.; Zhang, Q. H.; Xu, J. X. Tetrahedron:
Asymmetry 2005, 16, 3718. (b) Ma, L. G.; Du, D. M.; Xu, J.
X. J. Org. Chem. 2005, 70, 10155. (c) Xu, J. X.; Ma, L. G.;
Jiao, P. Chem. Commun. 2004, 1616.
(9) Xu, J.; Jiao, P. J. Chem. Soc., Perkin Trans. 1 2002, 1491.
(10) Ikeda, I.; Machii, Y.; Okahara, M. Synthesis 1980, 650.
(11) Appel, R.; Heinen, H.; Schollhorn, R. Chem. Ber. 1966, 99,
3118.
(
(
2) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247.
3) For a review of aziridine opening, see: Hu, X. E.
Tetrahedron 2004, 60, 2701.
4) McCoull, W.; Davis, F. A. Synthesis 2000, 1347.
5) For reviews on aziridine synthesis, see: (a) Halfen, J. A.
Curr. Org. Chem. 2005, 9, 657. (b) Muller, P.; Fruit, C.
Chem. Rev. 2003, 103, 2905. (c) Osborn, H. M. I.; Sweeney,
J. Tetrahedron: Asymmetry 1997, 8, 1693.
(
(
Synlett 2006, No. 15, 2504–2506 © Thieme Stuttgart · New York

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506
A. Armstrong et al.
LETTER
dissolved in DMSO (10 mL) at r.t. To this solution was
(
(
12) Donskaya, O. V.; Elokhina, V. N.; Nakhmanovich, A. S.;
Vakul’skaya, T. I.; Larina, L. I.; Vokin, A. I.; Albanov, A. I.;
Lopyrev, V. A. Tetrahedron Lett. 2002, 43, 6613.
added solid t-BuOK (0.12 g, 1.07 mmol, 1.1 equiv) in 10
portions over 1 min. During this addition a bright red colour
forms. After 5 min, H O (50 mL) and Et O (50 mL) were
13) Compound 2a: Ba(NO ) (10.3 g, 40 mmol), Ba(OH)
3
2
2
2
2
(
12.5 g, 40 mmol) and N-methyl morpholine (4.4 mL, 40
added. The reaction was extracted with Et O (100 mL) and
2
mmol) were added to H O (60 mL) to give a turbid white
mixture. This was added in 2-mL portions to a solution of
washed with H O (2 × 100 mL) and brine (50 mL). The
2
2
organic layer was dried over MgSO , filtered and the solvent
4
hydroxylamine-O-sulfonic acid (5.6 g, 50 mmol) in H O (50
removed in vacuo. The crude product was further purified on
2
mL) to give a white precipitate immediately. The mixture
was then heated at reflux for 18 h. The white precipitate was
filtered off and the filtrate was concentrated under reduced
pressure leaving a white crystalline solid. This solid was
silica gel (PE–Et O, 4:1) to give the aziridine (0.13 g, 61%)
2
as a fine white solid; mp 100–101 °C. IR (KBr): 3268 (NH),
–
1 1
1668 (C=O) cm . H NMR (250 MHz, CDCl ): d = 8.00–
3
7.20 (10 H, m, Ar), 3.52 (1 H, dd, J = 7.9, 2.4 Hz), 3.18 (1
H, dd, J = 9.2, 2.4 Hz), 2.68 (1 H, t, J = 8.5, NH). MS (CI):
m/z (%) = 224 (M + H, 100).
then recrystallised (H O) to give the hydrazinium nitrate salt
2
1
2
a (7.13 g, 99%) as a white solid. H NMR (400 MHz,
DMSO): d = 5.96 (2 H, br, NH ), 3.99–3.93 (2 H, m, OCH ),
Method B: N-Methyl-N-aminomorpholinium nitrate (2a,
0.17 g, 0.96 mmol) and NaOH (0.04 g, 0.96 mmol) were
added to MeCN (4 mL) and the resulting solution was stirred
at r.t. for 30 min. Chalcone (0.10 g, 0.48 mmol) was then
added and the mixture was stirred for a further 3 h. The
2
2
3
.87–3.82 (2 H, m, OCH ), 3.59–3.53 (2 H, m, NCH ), 3.44–
2
2
1
3
3
.52 (2 H, m, NCH ), 3.33 (3 H, s, NCH ). C NMR (100
2
3
MHz, DMSO): d = 62.2 (CH ), 60.4 (CH ), 56.6 (CH ).
2
2
3
Compound 2b: To a solution of N-aminomorpholine (8.9
mL, 92 mmol, 1.0 equiv) in THF (60 mL) at 0 °C was added
neat MeI (6.0 mL, 96 mmol, 1.05 equiv) dropwise over 5 min.
During this time, a white precipitate was observed to form
and after completion of the addition of MeI, the reaction
reaction was then quenched with a sat. solution of NH Cl (20
4
mL) and extracted with toluene (3 × 20 mL). The organic
layers were then washed with a sat. solution of NH Cl (20
4
mL), dried over Na SO and the solvent was removed in
2
4
mixture was warmed to r.t. for 30 min. Et O (100 mL) was
vacuo. The crude product was further purified on silica gel
2
added and the white solid was isolated by filtration and
(PE–Et O, 4:1) to give the aziridine (0.10 g, 95%); data as
2
subsequently washed with Et O (4 ×). The morpholinium
above.
2
9
iodide salt 2b (17.18 g, 77%) was isolated as a white powder
NMR data for aziridine products in Table entries 1, 2, 4–9,
6
9
which was recrystallised from hot EtOH–MeOH (3:1) to
10, 11, and 14–17 corresponded to those in the literature.
Other aziridines also gave satisfactory spectroscopic data in
accord with their assigned structures.
1
give clear plates. H NMR (400 MHz, DMSO): d = 5.97 (2
H, s, NH ), 3.96 (2 H, ddd, J = 13.2, 9.2, 3.9 Hz, CH ), 3.86
2
2
(
3
2 H, dt, J = 12.8, 3.2 Hz, CH ), 3.60 (2 H, ddd, J = 12.8, 9.2,
Caution. While no problems were encountered during our
work, hydrazinium salts should be considered as potentially
hazardous and should be handled with appropriate pre-
cautions. Differential scanning calorimetry studies indicated
an exotherm for iodide salt 2b at ca. 170 °C; no exotherm
was noted for nitrate 2a at temperatures up to 300 °C.
2
.2 Hz, CH ), 3.48 (2 H, br d, J = 12.4 Hz, CH ), 3.41 (3 H,
2
2
13
s, CH3). C NMR (100 MHz, DMSO): d = 62.4, 60.1, 56.4.
Aziridination of E-Chalcones; General Procedure
Method A: Chalcone (0.20 g, 0.96 mmol) and
morpholinium iodide 2b (0.24 g, 1.05 mmol, 1.1 equiv) were
Synlett 2006, No. 15, 2504–2506 © Thieme Stuttgart · New York