Amine-promoted, organocatalytic aziridination of enones

Article abstract of DOI:10.1021/ol062852v

(Chemical Equation Presented) A novel method is presented using N-N ylides (prepared by in situ amination of a tertiary amine) for the aziridination of a range of enone systems. The amine may be used sub-stoichiometrically, and promising levels of enantioselectivity are observed with quinine as promoter.

Full text of DOI:10.1021/ol062852v

ORGANIC
LETTERS
2007
Vol. 9, No. 2
351-353
Amine-Promoted, Organocatalytic
Aziridination of Enones
Alan Armstrong,*,† Carl A. Baxter,† Scott G. Lamont,‡ Andrew R. Pape,‡ and
Richard Wincewicz†
Department of Chemistry, Imperial College London, South Kensington,
London, SW7 2AZ, United Kingdom, and AstraZeneca, Mereside, Alderley Park,
Macclesfield, Cheshire, SK10 4TG, United Kingdom
a.armstrong@imperial.ac.uk
Received November 23, 2006
ABSTRACT
A novel method is presented using N
−N ylides (prepared by in situ amination of a tertiary amine) for the aziridination of a range of enone
systems. The amine may be used sub-stoichiometrically, and promising levels of enantioselectivity are observed with quinine as promoter.
Aziridines are extremely important synthetic building blocks1
that can be opened in a stereocontrolled manner with various
nucleophiles,2 providing access to a wide range of important
nitrogen-containing products. However, they are less widely
used in synthesis than their oxygen counterparts, the ep-
oxides, partly because there are fewer efficient methods for
alkene aziridination relative to epoxidation.3 This is particu-
larly true when enantioselective methods are considered.4
Most of the catalytic methods involve transition metal
nitrenoid species and are often inefficient, requiring the
alkene substrate to be used in excess relative to the nitrogen
source, and afford good yields and enantioselectivities only
for a restricted range of alkenes. Additionally, many methods
provide aziridines protected as N-tosyl derivatives, a protect-
ing group that can prove difficult to remove. Currently, the
rapidly developing area of organocatalysis5 is revealing that
small organic molecules can offer valuable alternatives to
transition metal catalysts, often with the advantages that
reactions can be performed without the need for rigorous
exclusion of air or water. Progress in organocatalytic alkene
aziridination has been limited to asymmetric phase-transfer
catalysis, which provides acceptable results only for tert-
butyl acrylate.6 In considering possible novel organocatalytic
methods, we were attracted to a report that bishydrazinium
(4) For recent examples of asymmetric metal-catalyzed chalcone aziri-
dination see: (a) Ma, L. G.; Jiao, P.; Zhang, Q. H.; Xu, J. X. Tetrahedron:
Asymmetry 2005, 16, 3718-3734. (b) Ma, L. G.; Du, D. M.; Xu, J. X. J.
Org. Chem. 2005, 70, 10155-10158. (c) Xu, J. X.; Ma, L. G.; Jiao, P.
Chem. Commun. 2004, 1616-1617. For a two-step asymmetric aziridination
of chalcones by using chiral rare-earth metal catalyzed Michael addition of
hydroxylamines, see: (d) Jin, X. L.; Sugihara, H.; Daikai, K.; Tateishi, H.;
Jin, Y. Z.; Furuno, H.; Inanaga, J. Tetrahedron 2002, 58, 8321-8329. (e)
Sugihara, H.; Daikai, K.; Jin, X. L.; Furuno, H.; Inanaga, J. Tetrahedron
Lett. 2002, 43, 2735-2739.
† Imperial College London.
‡ AstraZeneca.
(1) For an overview of aziridine chemistry, see: Sweeney, J. B. Chem.
Soc. ReV. 2002, 31, 247-258.
(2) For review of aziridine openings, see: (a) Hu, X. E. Tetrahedron
2004, 60, 2701-2743. (b) McCoull, W.; Davis, F. A. Synthesis 2000, 1347-
1365.
(3) For reviews on aziridine synthesis, see: (a) Halfen, J. A. Curr. Org.
Chem. 2005, 9, 657-669. (b) Muller, P.; Fruit, C. Chem. ReV. 2003, 103,
2905-2919. (c) Osborn, H. M. I.; Sweeney, J. B Tetrahedron: Asymmetry
1997, 8, 1693-1715.
(5) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138-
5175.
(6) (a) Murugan, E.; Siva, A. Synthesis, 2005, 2022-2028. (b) Aires-
de-Sousa, J.; Prabhakar, S.; Lobo, A. M.; Rosa, A. M.; Gomes, M. J. S.;
Corvo, M. C.; Williams, D. J.; White, A. J. P. Tetrahedron: Asymmetry
2001, 12, 3349-3365. (c) Aires-de-Sousa, J.; Lobo, A. M.; Prabhakar, S.
Tetrahedron Lett. 1996, 37, 3183-3186. (d) Pereira, M. M.; Santos, P. P.
O.; Reis, L. V.; Lobo, A. M.; Prabhakar, S. J. Chem. Soc., Chem. Commun.
1993, 38-40.
10.1021/ol062852v CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/16/2006

salt 1 (2 equiv), in the presence of NaH/i-PrOH as base, could
effect aziridination of enones.7 This salt was prepared by
reaction of diazabicyclo[2.2.2]octane (DABCO) with hy-
droxylamine-O-sulfonic acid (HOSA) at elevated tempera-
ture. By analogy to an earlier study,8 the aziridination reaction
was assumed to proceed by deprotonation of 1 to give an
N-N ylide (aminimine), which then effects aziridination by
a Michael addition-ring closure mechanism. Recently, we
have shown that the N-methylmorpholinium salts 2 effect
aziridination of chalcones at room temperature.9 Since the
coproduct of the aziridination reaction is a tertiary amine,
we reasoned that it should be possible to construct a catalytic
system (Scheme 1), provided that the aminimine 3 could be
Scheme 2. Amine-Promoted Aziridination
ments established that aziridination does not occur in the
absence of the tertiary amine and that a secondary amine
(morpholine) does not promote aziridination, lending support
to the proposed aminimine pathway. A screen of several
tertiary amines and solvents (see the Supporting Information)
revealed NMM, N-methylpyrrolidine (NMP), and quinucli-
dine to be the most effective promoters, with fastest reactions
in MeCN, CH2Cl2, or DMF.
Scheme 1. Proposed Catalytic Cycle for Amine-Promoted
Aziridination
We next examined the scope of this novel aziridination
procedure. We were pleased to find that the chemistry was
Table 1. Aziridination of Râ-unsaturated Ketone Derivativesa
prepared from a tertiary amine in the presence of the alkene
substrate. A further exciting possibility was asymmetric
induction if a chiral tertiary amine was employed. Here we
describe our preliminary work demonstrating the feasibility
of these aims.10
Our initial studies attempted to effect in situ aziridination
of E-chalcone by reaction with N-methylmorpholine (NMM),
HOSA, and various bases at room temperature. However,
none of the desired aziridine product was obtained. In some
cases, reduction of the chalcone was observed, presumably
due to formation of diimide from the HOSA and base. The
apparent failure to aminate the tertiary amine mediator at
room temperature is perhaps not surprising given that HOSA
generally requires elevated temperatures to accomplish this
transformation. We reasoned that a neutral source of elec-
trophilic nitrogen might give faster amination, and were
pleased to accomplish our first in situ aziridination (Scheme
2) by using O-(diphenylphosphinyl)hydroxylamine (Dp-
pONH2) 4, which can be readily prepared in good yield in
one step from commercial hydroxylamine hydrochloride and
diphenylphosphinyl chloride.11 Importantly, control experi-
(7) Xu, J.; Jiao, P. J. Chem. Soc., Perkin Trans. 1 2002, 1491-1493.
(8) Ikeda, I.; Machii, Y.; Okahara, M. Synthesis 1980, 650-651.
(9) Armstrong, A.; Carbery, D. R.; Lamont, S. G.; Pape, A. R.;
Wincewicz, R. Synlett 2006, 2504-2506.
(10) After initial submission of this work, we became aware of closely
related results by Shi and co-workers: Shen, Y.-M.; Zhao, M.-X.; Xu, J.;
Shi, Y. Angew. Chem., Int. Ed. 2006, 45, 8005-8008.
(11) Colvin, E. W.; Kirby, G. W.; Wilson, A. C. Tetrahedron Lett. 1982,
23, 3835-3836.
a Reaction performed on a 0.240 mmol scale. See the Supporting
Information for details. b Isolated yields after column chromatography.
c Reaction performed on a 0.120 mmol scale. NMM ) N-methylmorpholine.
NMP ) N-methylpyrrolidine.
352
Org. Lett., Vol. 9, No. 2, 2007

successful for a range of aromatic enones (Table 1). In all
cases, the product was obtained exclusively (>95:5) as the
trans-aziridine. It is especially noteworthy that high yields
were obtained for both electron-rich (entries 4 and 7) and
electron-poor enones (e.g., entries 1, 2, and 5), since the
isolated hydrazinium nitrate salt derived from NMM (2a)
was restricted to the electron-poor substrates.9 While the aryl
aziridine products in Table 1 are of high synthetic value,12
the successful extension to alkyl enones is gratifying (entries
10-12), as is the demonstration for the first time that R,â-
unsaturated esters can be successfully aziridinated by using
this chemistry (entries 13 and 14). Overall, the in situ
chemistry appears to have considerably higher scope than
the use of isolated hydrazinium salts, as well as being more
convenient. An advantage of the method is that it affords
N-unsubstituted aziridines, which allows flexibility in further
functionalizing the nitrogen with a choice of activating group.
With an efficient one-pot aziridination procedure in hand,
we now addressed the possibility of using substoichiometric
quantities of the amine promoter. Using 50 mol % of NMM
under the standard conditions of MeCN/NaOH, we found
that a 75% yield of aziridine could be isolated (Table 2, entry
stable to base, and this will be the subject of further
optimization.
As well as the use of substoichiometric amine, another
important question is whether asymmetric induction is
possible when a chiral tertiary amine is used. Building on
the earlier successful use of quinuclidine as promoter, the
readily available chiral analogue quinine was an attractive
starting point. While rates and enantiomeric excesses are
highly solvent dependent (see the Supporting Information),
promising levels of asymmetric induction can be observed.
In the best compromise of yield and enantioselectivity,
E-chalcone can be aziridinated in 56% ee and 64% yield
(Scheme 3).
Scheme 3. Quinine-Mediated Enantioselective Aziridination
Table 2. Organocatalytic Aziridination of Chalcone
Derivativesa
In conclusion, we have demonstrated that tertiary amines
can promote aziridination of enones using Dpp-ONH2 4 as
the stoichiometric nitrogen source, believed to proceed via
in situ formation of an N-N ylide (aminimine). We have
demonstrated turnover, leading to an organocatalytic enone
aziridination, and we have also shown that use of a chiral
amine can lead to asymmetric induction. Although the levels
of turnover and ee are moderate at present, the strong track
record of chiral amines in asymmetric catalysis13 and the
large number of possibilities for screening suggest that a
highly enantioselective catalytic system may well be attain-
able. Further efforts toward this goal along with mechanistic
studies and synthetic applications of the aziridine products
are underway. In addition to the highly synthetically valuable
aziridination process, the demonstration that N-N ylides can
be generated in situ from a substoichiometric amine may
also have wider synthetic applications.
Acknowledgment. We thank the EPSRC (GR/S58508)
and AstraZeneca (CASE award to R.W.) for their support
of this work. We are grateful to Bristol-Myers Squibb and
Merck Sharpe and Dohme for generous support of our
research programs. We acknowledge Dr. D. R. Carbery for
preliminary experiments on in situ aziridination.
a Reaction performed on a 0.120 mmol scale. See the Supporting
Information for details. b Based on 1H NMR analysis of the crude reaction
mixture. c Isolated yields after column chromatography. NMM ) N-
methylmorpholine. NMP ) N-methylpyrrolidine.
1). A solvent screen indicated that in general best results
with substoichiometric amine are obtained in DMF (entries
3-5). These results are noteworthy as they demonstrate the
feasibility of using substoichiometric amine as aziridination
promoter. We believe that the key to further improvement
in turnover is the discovery of a nitrogen source that is more
Supporting Information Available: General experimen-
tal procedures and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062852V
(12) Recent example: Xiong, C.; Wang, W.; Cai, C.; Hruby, V. J. J.
Org. Chem. 2002, 67, 1399-1402.
(13) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003,
103, 2985-3012.
Org. Lett., Vol. 9, No. 2, 2007
353