Tertiary Amine Promoted Aziridination: Preparation of NH-Aziridines from Aliphatic α,β-Unsaturated Ketones

Article abstract of DOI:10.1055/s-0035-1560583

trans-NH-Aziridines were prepared from aliphatic α,β-unsaturated ketones using a tertiary amine promoted reaction via in situ generated N,N-ylides. Through use of modified conditions the reaction proved to be applicable for the diastereoselective aziridination of a range of enolisable aliphatic α,β-unsaturated ketones of varying substitution patterns.

Full text of DOI:10.1055/s-0035-1560583

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 151–155
letter
151
A. Armstrong et al.
Letter
Synlett
Tertiary Amine Promoted Aziridination: Preparation of NH-Aziri-
dines from Aliphatic α,β-Unsaturated Ketones
Alan Armstrong*a
O
Robert D. C. Pullina,1
James N. Scuttb
O
P
NH2
Ph
Ph
O
O
H
O
N
,
N
R1
R2
R1
R2
base
a Department of Chemistry, Imperial College London, South Kensington,
London, SW7 2AZ, UK
a.armstrong@imperial.ac.uk
b Syngenta Ltd., Jealott’s Hill International Research Centre, Bracknell,
Berkshire, RG42 6EY, UK
R1 = alkyl, aryl
R2 = alkyl
trans-NH-aziridines
9 examples, up to 90%
Dedicated to Professor Steven V. Ley on the occasion of his 70th birthday
Received: 02.10.2015
Accepted after revision: 09.10.2015
Published online: 03.11.2015
demonstrated that a nucleophilic nitrene equivalent, in
combination with a primary aminocatalyst, can allow both
aliphatic acyclic and cyclic α,β-unsaturated ketones to be
aziridinated enantioselectively,9,10 to deliver N-carbamate
aziridines. However, to the best of our knowledge, the direct
aziridination of any aliphatic α,β-unsaturated ketones to
form NH-aziridines has not been reported.
DOI: 10.1055/s-0035-1560583; Art ID: st-2015-d0787-l
Abstract trans-NH-Aziridines were prepared from aliphatic α,β-unsat-
urated ketones using a tertiary amine promoted reaction via in situ
generated N,N-ylides. Through use of modified conditions the reaction
proved to be applicable for the diastereoselective aziridination of a
range of enolisable aliphatic α,β-unsaturated ketones of varying substi-
tution patterns.
We and others have demonstrated that N,N-ylides
(termed aminimines or aminimides, Scheme 1) can act as
nucleophilic nitrene equivalents to deliver NH-aziridines;
the formation of the NH-aziridine permits flexibility in the
subsequent choice of N-functionality. The use of N,N-ylides
to effect aziridination was first reported by Ikeda in 1980,11
and studies, by both Xu12 and ourselves,13 have shown that
isolated hydrazinium salts, as stoichiometric ylide precur-
sors, can facilitate the aziridination of a variety of aromatic
α,β-unsaturated ketones in high yields. Later this concept
was further developed, and we have demonstrated the in
situ generation of aminimes, by means of the amination of
tertiary amines under basic conditions (Scheme 1).14a,15 We
have shown this method to be applicable for the diastereo-
selective formation of unsubstituted trans-NH-aziridines
from a range of α,β-unsaturated carbonyl compounds.14 We
now report, via modification of the reaction parameters,
the extension of this method to the successful aziridination
of a range of aliphatic α,β-unsaturated ketones.
In our originally developed system aliphatic α,β-unsatu-
rated ketones, which possess α-enolisable protons, had pre-
viously demonstrated poor reactivity.14a However, we sub-
sequently demonstrated that enones possessing alkyl
groups at the β-position, and later α,β,γ,δ-unsaturated ke-
tones (dienones) with alkyl substituents at the δ-position,
both substrate classes with allylic protons, could undergo
successful aziridination in good yields. Therefore we envis-
aged that it may be possible to extend the scope of our
aziridination methodology to encompass substrates that
Key words aziridines, organocatalysis, enones, aminimine, ylides, ste-
reoselective
Aziridines, the smallest saturated azaheterocycles, rep-
resent an important amine motif. Not only are several aziri-
dine-containing natural products known, frequently pos-
sessing significant biological activity,2 but aziridines consti-
tute a versatile building block for synthetic manipulation
through exploitation of their strained ring system.3 As a re-
sult of their significance, aziridines receive widespread in-
terest and their stereoselective preparation remains an im-
portant challenge. Whilst several strategies for aziridine
synthesis are in principle available,4 one potentially power-
ful approach involves the direct transfer of a nitrene equiva-
lent to an alkene precursor. This can be achieved either via
the use of a metal nitrenoid or use of a nucleophilic nitrene
equivalent, and these approaches can allow the preparation
of aziridines with high stereoselectivity from a range of im-
portant alkene classes, including α,β-unsaturated carbonyl
compounds, which encompasses cinnamate esters,5 aro-
matic ketones,6 and more recently aldehydes.7 It is notable,
however, that whilst the aziridination of aromatic α,β-un-
saturated ketones (chalcones) can be achieved by several
methods,6 significantly fewer reports exist concerning the
aziridination of simple acyclic aliphatic α,β-unsaturated ke-
tones.8 One notable study, however, by Melchiorre has
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A. Armstrong et al.
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H
N
O
O
P
H
N
O
O
NH2
previous work:
R1
R2
Ph
O
R3N
Ph
DppONH2 (1)
R1
R2
R2
R1
R2
O
Ot-Bu
=
R
N
R3N = NMM, (2)
Ph2PO2
R3N NH2
H
N
O
O
this work:
R1
R2
R1
R2
R
base
O
R2
alkyl
=
R3N-NH
H
R1
R2
aminimine
DppONH2 = O-diphenylphosphinyl hydroxylamine (1), NMM = 4-methylmorpholine (2)
Scheme 1 Tertiary amine promoted aziridination
possessed enolisable groups via an appropriate set of reac-
tion conditions. This prompted us to select an initial sub-
strate, commercially available (E)-4-phenylbut-3-en-2-one
(3a), as a model substrate for examination (Table 1).
the tertiary amine promoter, gave only low levels of aziri-
dine 4a (Table 1, entries 1 and 2). However, we had previ-
ously found that for lower reactivity substrates, such as di-
enones,14b a second equivalent of aminating agent was re-
quired in order to achieve good levels of reactivity, ra-
tionalised by promoting quantitative levels of the hydraz-
inium intermediate (Scheme 1). On application of these
conditions (2 equiv DppONH2, 3 equiv base), pleasingly the
desired aziridine 4a was isolated in a high yield of 80%.
Aziridine 4a was formed with exclusive trans diastereose-
lectivity (3J = 2.1 Hz, Table 1, entry 3).16 Various bases were
then screened. Whilst NaOH did not prove efficient for this
transformation (Table 1, entry 4), various alkoxide bases
provided uniformly high yields of the aziridine (Table 1, en-
tries 5–7). Continuing with isopropoxide as the base, vari-
ous polar aprotic solvents were subsequently screened to
see if any further improvements in the yield could be ob-
tained. In MeCN and 1,4-dioxane moderate levels of aziri-
dine were observed (Table 1, entries 8 and 9) but in DMSO
only trace amounts of the aziridine were detected (Table 1,
entry 10), with the optimal solvent remaining CH2Cl2 (Table
1, entry 3).
With an effective set of reaction conditions in hand (Ta-
ble 1, entry 3) we sought to investigate the aziridination of
a range of different enolisable enones (Table 2). Initially, we
explored enones with various degrees of steric bulk at the
carbonyl. As identified methyl derivative 3a gave high
yields of aziridine 4a (80%, Table 2, entry 1). Isopropyl de-
rivative 3b gave only a moderate yield of aziridine 4b (51%),
despite excellent conversion of the substrate (Table 2, entry
2). Whilst no further products could be isolated from the
reaction mixture, the moderate yield proved reproducible
(three reactions, 46–51%). tert-Butyl enone 3c was aziridi-
nated in excellent yield (91%, Table 2, entry 3). Various oth-
er enolisable substrates were also identified for investiga-
Table 1 Optimisation of the Conditions for the Aziridination of Enone
3a
i. NMM (1.05 equiv), DppONH2
solvent, r.t., 30 min
H
N
O
O
Ph
Ph
ii. base, then 3a (1 equiv), 16 h
3a
Entrya Base
4a
Base
(equiv)
DppONH2 Solvent
(equiv)
Yield (%)b,c
1
2
NaOH
2
2
3
3
3
3
3
3
3
3
1.05
1.05
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
traces
45
i-PrOH/NaH
i-PrOH/NaH
NaOH
3
85 (80)
28
4
5
MeOH/NaH
EtOH/NaH
t-BuOH/NaH
i-PrOH/NaH
i-PrOH/NaH
i-PrOH/NaH
79
6
85
7
80
8
55
9
1,4-dioxane 69
DMSO traces
10
a Reaction performed on a 0.12 mmol scale.
b Determined by 1H NMR spectroscopy using Bn2O as the internal standard.
c Isolated yield in parentheses.
In line with our previous observations, our original re-
action conditions, which utilise one equivalent of aminat-
ing agent O-diphenylphosphinyl hydroxylamine (1,
DppONH2, Scheme 1) and two equivalents of either NaOH
or i-PrOH/NaH as the base, with N-methylmorpholine (2) as
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A. Armstrong et al.
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tion, including trisubstituted enone 3d, which allowed in-
vestigation of the tolerance of the reaction to α-substitution
on the alkene. Pleasingly enone 3d could be aziridinated in
good yield (63%), allowing the formation of two stereogenic
centres, one quaternary, with the remainder of the material
being unreacted substrate (Table 2, entry 4). The aziridine
4d was formed exclusively as the isomer depicted (as con-
firmed by NOESY analysis). We were also keen to screen di-
alkyl-substituted enones in the reaction, which, containing
both allylic and α-enolisable protons, may be anticipated to
be most sensitive to the basic reaction conditions. Three
substrates (3e–g) were thus selected for screening, which
possessed aromatic, olefinic, and also heteroatom function-
alities in the β-alkyl chain, respectively. Pleasingly aziridi-
nation of each of these dialkyl-substituted enones proceed-
ed in good yield (58–61%), albeit that each reaction showed
almost complete substrate conversion (Table 2, entries 5–
7). The regioselective aziridination of dialkyl-substituted
Table 2 Aziridination of Aliphatic α,β-Unsaturated Ketones 3a–i
H
N
O
O
i. NMM (1.05 equiv), DppONH2 (2.0 equiv)
CH2Cl2, r.t., 30 min
R1
R2
R1
R2
ii. i-PrOH/NaH (3.0 equiv), substrate, 16 h
R3
R3
4a–i
3a–i
Entrya
1
Substrate
Product
Conversion (%)b
>95
Yield (%)c
80
H
N
O
O
O
O
3a
4a
4b
Ph
Ph
Ph
Ph
H
N
2
3
3b
3c
>95
>95
51
91
O
O
H
N
O
O
4c
Ph
Ph
Ph
Ph
H
N
4
3d
4d
70
63
H
N
O
O
5
6
3e
3f
4e
4f
>95
>95
60
61
Ph
Ph
O
H
N
O
O
O
H
O
N
BnO
7
8
3g
3h
4g
4h
>95
83
58
70
BnO
4
4
H
N
O
O
O
9
3i
4i
>95
35
HN
a Reactions performed on a 0.11–0.56 mmol scale.
b Determined by 1H NMR spectroscopy using Bn2O as the internal standard.
c Isolated by flash column chromatography.
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dienone 3h could also be effected, which pleasingly afford-
ed a good yield of vinyl aziridine 4h (70%), with the remain-
der of material being unreacted substrate (Table 2, entry 8).
Whilst both metal nitrenoids and nucleophilic nitrene
equivalents have previously been employed for the aziridi-
nation of cyclic enones, generally this has provided only
moderate yields for a limited substrate scope,8a,b,17 but more
recently a broader scope of cyclic enones have been aziridi-
nated in high enantioselectivities via aminocatalysis.10,18 In
terms of our own methodology, our originally reported
conditions for aziridination had previously shown no evi-
dence of aziridine formation for cyclic substrates. Pleasing-
ly, we could apply the now-modified conditions to the
aziridination of cyclohexenone 3i, albeit with moderate
yield of aziridine 4i (35%). Nevertheless, this represents the
first successful example of aziridine formation from a cyclic
enone utilising our amine-promoted methodology (Table 2,
entry 9).19
Whilst the developed conditions for the aziridination of
enolisable substrates had proved applicable to a range of
examples, with generally moderate-to-good yields ob-
tained, high substrate conversions were often observed
which did not always reflect the isolated yield of aziridine.
Importantly, we determined that the aziridine products are
stable to the reaction conditions.20 It is likely that the basic
reaction conditions (we generally require a hydroxide or
alkoxide base) also promote unwanted side-reactions of the
substrate (such as dimer- or oligomerisation), and such de-
composition of the substrate likely accounts for any dis-
crepancy between substrate conversion and isolated yield
of aziridine. Current studies are focusing on assessment of
alternative aminating agents that may operate with the em-
ployment of weaker bases and therefore may permit great-
er tolerability to these enolisable substrates
References and Notes
(1) Current address: Dr. R. D. C. Pullin, Vertex Pharmaceuticals
(Europe) Ltd., 86-88 Jubilee Avenue, Milton Park, Abingdon,
Oxfordshire, OX14 4RW, UK.
(2) For a review, see: Lowden, P. A. S. In Aziridines and Epoxides in
Organic Synthesis; Yudin, A. K., Ed.; Wiley-VCH: Weinheim,
2006, 399.
(3) For reviews see: (a) McCoull, W.; Davis, F. A. Synthesis 2000,
1347. (b) Hu, X. E. Tetrahedron 2004, 60, 2701.
(4) For recent reviews, see: (a) Pellissier, H. Tetrahedron 2010, 66,
1509. (b) Pellissier, H. Adv. Synth. Catal. 2014, 356, 1899.
(c) Degennaro, L.; Trinchera, P.; Luisi, R. Chem. Rev. 2014, 114,
7881.
(5) For selected examples, see: (a) Evans, D. A.; Faul, M. M.;
Bilodeau, M. T.; Anderson, B. A.; Barnes, D. M. J. Am. Chem. Soc.
1993, 115, 5328. (b) Gillespie, K. M.; Sanders, C. J.;
O’Shaughnessy, P.; Westmoreland, I.; Thickitt, C. P.; Scott, P.
J. Org. Chem. 2002, 67, 3450. (c) Wang, X.; Ding, K. Chem. Eur. J.
2006, 12, 4568.
(6) For example: (a) Ma, L.; Du, D.-M.; Xu, J. J. Org. Chem. 2005, 70,
10155. (b) Ma, L.; Jiao, P.; Zhang, Q.; Xu, J. Tetrahedron: Asymme-
try 2005, 16, 3718.
(7) For examples, see: (a) Vesely, J.; Ibrahem, I.; Zhao, G. L.; Rios, R.;
Córdova, A. Angew. Chem. Int. Ed. 2007, 46, 778. (b) Arai, H.;
Sugaya, N.; Sasaki, N.; Makino, K.; Lectard, S.; Hamada, Y. Tetra-
hedron Lett. 2009, 50, 3329. (c) Deiana, L.; Zhao, G.-L.; Lin, S.;
Dziedzic, P.; Zhang, Q.; Leijonmarck, H.; Córdova, A. Adv. Synth.
Catal. 2010, 352, 3201. (d) Deiana, L.; Dziedzic, P.; Zhao, G.-L.;
Vesely, J.; Ibrahem, I.; Rios, R.; Sun, J.; Córdova, A. Chem. Eur. J.
2011, 17, 7904. (e) Desmarchelier, A.; Pereira de Sant’Ana, D.;
Terrasson, V.; Campagne, J. M.; Moreau, X.; Greck, C.; Marcia de
Figueiredo, R. Eur. J. Org. Chem. 2011, 4046. (f) Molnar, I. G.;
Tanzer, E.-M.; Daniliuc, C.; Gilmour, R. Chem. Eur. J. 2014, 20,
794.
(8) Isolated examples have been reported, examples include:
(a) Fioravanti, S.; Pellacani, L.; Tabanella, S.; Tardella, P. A. Tetra-
hedron 1998, 54, 14105. (b) Tung, S.; Yudin, A. K. J. Am. Chem.
Soc. 2002, 124, 530. (c) Chen, D.; Timmons, C.; Guo, L.; Xu, X.; Li,
G. Synthesis 2004, 2479. (d) Zibinsky, M.; Stewart, T.; Prakash, G.
K. S.; Kuznetsov, M. A. Eur. J. Org. Chem. 2009, 3635.
In summary, through modification of the reaction con-
ditions, we have demonstrated the applicability of our ter-
tiary amine promoted aziridination to a range of aliphatic
α,β-unsaturated ketones.21 A range of trans-NH-aziridines
were prepared from enolisable aliphatic α,β-unsaturated
ketones with a variety of substitution patterns in moderate
to good yields with exclusive diastereoselectivity.
(9) Pesciaioli, F.; De Vincentiis, F.; Galzerano, P.; Bencivenni, G.;
Bartoli, G.; Mazzanti, A.; Melchiorre, P. Angew. Chem. Int. Ed.
2008, 47, 8703.
(10) De Vincentiis, F.; Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.;
Bartoli, G.; Galzerano, P.; Melchiorre, P. Chem. Asian. J. 2010, 5,
1652.
(11) Ikeda, I.; Machii, Y.; Okahara, M. Synthesis 1980, 650.
(12) Xu, J.; Jiao, P. J. Chem. Soc., Perkin Trans. 1 2002, 1491.
(13) Armstrong, A.; Carbery, D. R.; Lamont, S. G.; Pape, A. R.;
Wincewicz, R. Synlett 2006, 2504.
Acknowledgment
We thank the EPSRC and Syngenta (CASE award to RDCP) for their
support of this work.
(14) (a) Armstrong, A.; Baxter, C. A.; Lamont, S. G.; Pape, A. R.;
Wincewicz, R. Org. Lett. 2007, 9, 351. (b) Armstrong, A.; Pullin,
R. D. C.; Jenner, C. R.; Scutt, J. N. J. Org. Chem. 2010, 75, 3499.
(c) Armstrong, A.; Ferguson, A. Beilstein J. Org. Chem. 2012, 8,
1747. (d) Armstrong, A.; Pullin, R. D. C.; Jenner, C. R.; Foo, K.;
White, A. J. P.; Scutt, J. N. Tetrahedron: Asymmetry 2014, 25, 74.
(15) See also: (a) Shen, Y.-M.; Zhao, M.-X.; Xu, J.; Shi, Y. Angew. Chem.
Int. Ed. 2006, 45, 8005. (b) Page, P. C. B.; Bordogna, C.; Strutt, I.;
Chan, Y.; Buckley, B. R. Synlett 2013, 24, 2067.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560583.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(16) Diastereoselectivity determined to be >95:5 by 1H NMR spec-
troscopy. The cis and trans diastereoselectivity was determined
by analysis of the 3J coupling constants of the aziridine ring;
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A. Armstrong et al.
Letter
Synlett
generally trans-aziridines have 3J = 2–4 Hz, cis-aziridines 3J = 5–
9 Hz. All aziridines prepared were determined be a single dia-
stereoisomer.
at r.t., and the mixture was stirred for 0.5 h. i-PrOH (28 μL, 0.36
mmol) and NaH (60% dispersion in mineral oil, 14.4 mg, 0.36
mmol) were then added sequentially followed by addition of
trans-4-phenylbut-3-en-2-one (3a, 17.5 mg, 0.12 mmol) in
CH2Cl2 (1 mL) and the mixture allowed to stir at r.t. for 16 h. The
reaction was quenched by the addition of sat. aq NH4Cl solution
and the aqueous layer separated and extracted with CH2Cl2,
dried (Na2SO4), filtered and concentrated in vacuo. Purification
by flash column chromatography (15% EtOAc–n-hexane)
afforded (2R*,3S*)-1-(3-phenylaziridin-2-yl)ethanone (4a, 15.6
mg, 80%) as a colourless oil; Rf = 0.30 (15% EtOAc–n-hexane). 1H
NMR (400 MHz, CDCl3): δ = 7.38–7.27 (5 H, m, 5 × PhH), 3.04 (1
H, d, J = 2.0 Hz, 3-CHN), 2.86 (1 H, d, J = 2.1 Hz, 2-CHN), 2.38 (3
H, s, CH3), 2.29 (1 H, br, NH). 13C NMR (100 MHz, CDCl3): δ =
204.5, 138.2, 128.5, 127.8, 126.1, 46.8, 43.0, 29.6.
(17) Fioravanti, S.; Mascia, M. G.; Pellacani, L.; Tardella, P. A. Tetrahe-
dron 2004, 60, 8073.
(18) Menjo, Y.; Hamajima, A.; Sasaki, N.; Hamada, Y. Org. Lett. 2011,
13, 5744.
(19) For the aziridination certain cyclic enones using N,N-ylides, see:
(a) Oves, D.; Ferrero, M.; Fernandez, S.; Gotor, V. J. Org. Chem.
2002, 68, 1154. (b) De, S. R.; Ghorai, S. K.; Mal, D. J. Org. Chem.
2009, 74, 1598.
(20) Aziridine 4e was resubmitted to the reaction conditions in
place of the enone substrate and was recovered in quantitative
amounts.
(21) Representative Procedure for Enone Aziridination
N-Methylmorpholine (14 μL, 0.125 mmol) was added dropwise
to a solution of DppONH2 (56.0 mg, 0.24 mmol) in CH2Cl2 (2 mL)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 151–155