Amine-promoted synthesis of vinyl aziridines

Article abstract of DOI:10.1021/jo100407s

N-Unsubstituted vinyl aziridines were synthesized via an amine-promoted regioselective nucleophilic aziridination of α,β,γ,δ- unsaturated carbonyl compounds. The reaction is completely regioselective (>95: 5) for the α,β-alkene and completely diastereosel

Full text of DOI:10.1021/jo100407s

pubs.acs.org/joc
products, including piperidines,8 pyrrolines,9 imidazolidi-
Amine-Promoted Synthesis of Vinyl Aziridines
nones,10 β-lactams,11 and azepines.12 Strategies for their
synthesis include guanidinium ylide addition to R,β-unsatu-
rated aldehydes,13 nitrenoid additions to 1,3-dienes,14 elimi-
nation from amino- or azido-alcohols,15 and Wittig reac-
tions of aziridine-2-carbaldehydes,16 with the most common
strategy involving allyl ylide addition to imines.17 However,
it is notable that few methods provide the desired vinyl
aziridines with consistently high levels of cis/trans diaster-
eoselectivity for a broad range of substrates.
Alan Armstrong,*,† Robert D. C. Pullin,† Chloe R. Jenner,†
and James N. Scutt‡
†Department of Chemistry, Imperial College London, South
Kensington, London, SW7 2AZ, United Kingdom, and
‡Syngenta Ltd., Jealott’s Hill International Research Centre,
Bracknell, Berkshire, RG42 6EY, United Kingdom
We have previously reported18 a diastereoselective aziri-
dination of R,β-unsaturated carbonyl compounds to afford
trans-aziridines in good to excellent yield (Scheme 1).19 Our
method involves the amination of a tertiary amine, which in
the presence of base is presumed to form a reactive N-N ylide
(referred to as an aminimine or aminimide), which subse-
quently undergoes conjugate addition to R,β-unsaturated
carbonyl compounds, followed by ring-closure to afford the
NH-aziridine. The tertiary amine mediator is regenerated in
this step, and can in principle be used in substoichiometric
quantities. The reaction proved broad in scope allowing the
aziridination of R,β-unsaturated ketones bearing either
β-alkyl, aromatic, or heterocyclic aromatic substituents, and
significantly also allowed the aziridination of R,β-unsatu-
rated esters, a challenge not possible via iminium ion organo-
catalytic aziridination methods.20 We were also able to
a.armstrong@imperial.ac.uk
Received March 4, 2010
N-Unsubstituted vinyl aziridines were synthesized via an
amine-promoted regioselective nucleophilic aziridination
of R,β,γ,δ-unsaturated carbonyl compounds. The reac-
tion is completely regioselective (>95: 5) for the R,β-
alkene and completely diastereoselective, affording the
trans-vinyl aziridine in moderate-to-good yields.
(11) (a) Ley, S. V.; Middleton, B. Chem. Commun. 1998, 1995. (b) Spears,
G. W.; Nakanishi, K.; Ohfune, Y. Synlett 1991, 91. (c) Fontana, F.; Tron,
G. C.; Barbero, N.; Ferrini, S.; Thomas, S. P.; Aggarwal, V. K. Chem.
Commun. 2010, 46, 267.
(12) (a) Fantauzzi, S.; Gallo, E.; Caselli, A.; Piangiolino, C.; Ragaini, F.; Re,
N.;Cenini, S. Chem.—Eur. J.2009, 15, 1241. (b) Scheiner, P. J. Org. Chem. 1967,
32, 2628. (c) Stogryn, E. L.; Brois, S. J. J. Am. Chem. Soc. 1967, 89, 605.
(13) Disadee, W.; Ishikawa, T. J. Org. Chem. 2005, 70, 9399.
(14) (a) Knight, J. G.; Muldowney, M. P. Synlett 1995, 949. (b) Nishimura,
M.; Minakata, S.; Thongchant, S.; Ryu, I.; Komatsu, M. Tetrahedron Lett.
2000, 41, 7089.
(15) (a) Lindstrom, U. M.; Somfai, P. Synthesis 1998, 109. (b) Zamboni,
R.; Rokach, J. Tetrahedron Lett. 1983, 24, 331. (c) Olofsson, B.; Wijtmans,
R.; Somfai, P. Tetrahedron 2002, 58, 5979.
(16) Baktharaman, S.; Afagh, N.; Vandersteen, A.; Yudin, A. K. Org.
Lett. 2010, 12, 240.
(17) (a) Li, A.-H.; Dai, L.-X.; Hou, X.-L.; Chen, M.-B. J. Org. Chem.
1996, 61, 4641. (b) Wang, D.-K.; Dai, L.-X.; Hou, X.-L. Chem. Commun.
1997, 1231. (c) Liao, W.-W.; Deng, X.-M.; Tang, Y. Chem. Commun. 2004,
1516. (d) Zheng, J.-C.; Liao, W.-W.; Sun, X.-X.; Sun, X.-L.; Tang, Y.; Dai,
L.-X.; Deng, J.-G. Org. Lett. 2005, 7, 5789. (e) Li, A.-H.; Dai, L.-X.; Hou,
X.-L. J. Chem. Soc., Perkin Trans. 1 1996, 867. (f) Zhu, B.-H.; Zheng, J.-C.;
Yu, C.-B.; Sun, X.-L.; Zhou, Y.-G.; Shen, Q.; Tang, Y. Org. Lett. 2010, 12,
504. (g) Iska, V. B. R.; Gais, H. J.; Tiwari, S. K.; Babu, G. S.; Adrien, A.
Tetrahedron Lett. 2007, 48, 7102. (h) Arini, L. G.; Sinclair, A.; Szeto, P.;
Stockman, R. A. Tetrahedron Lett. 2004, 45, 1589. (i) Morton, D.; Pearson,
D.; Field, R. A.; Stockman, R. A. Org. Lett. 2004, 6, 2377. (j) Chigboh, K.;
Nadin, A.; Stockman, R. A. Synlett 2007, 2879. (k) Chigboh, K.; Morton, D.;
Nadin, A.; Stockman, R. A. Tetrahedron Lett. 2008, 49, 4768. (l) Illa, O.;
Arshad, M.; Ros, A.; McGarrigle, E. M.; Aggarwal, V. K. J. Am. Chem. Soc.
2010, 132, 1828. (m) Aggarwal, V. K.; Alonso, E.; Fang, G. Y.; Ferrara, M.;
Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1433.
(18) (a) Armstrong, A.; Baxter, C. A.; Lamont, S. G.; Pape, A. R.;
Wincewicz, R. Org. Lett. 2007, 9, 351. (b) Armstrong, A.; Carbery, D. R.;
Lamont, S. G.; Pape, A. R.; Wincewicz, R. Synlett 2006, 2504.
(19) For a related approach see: Shen, Y.-M.; Zhao, M.-X.; Xu, J. X.;
Shi, Y. Angew. Chem., Int. Ed. 2006, 45, 8005.
Aziridines are versatile building blocks for the synthesis of
diverse nitrogen-containing products via ring-opening and
ring-expansion reactions.1-5 Vinyl aziridines are a particu-
larly interesting class of aziridine that lend themselves to a
host of highly useful synthetic transformations. They are
versatile electrophiles and notably undergo regioselective
ring-opening via addition at either the vinyl terminus6 or
directly at the aziridine depending on the reagents emplo-
yed.7 Moreover, vinyl aziridines can be exploited in a variety
of ring-expansion reactions to afford a range of heterocyclic
(1) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247.
(2) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
(3) Xu, X. E. Tetrahedron 2004, 60, 2701.
(4) McCoull, W.; Davis, F. A. Synthesis 2000, 1347–1365.
(5) Yudin, A. K., Ed. Aziridines and Epoxides in Organic Synthesis; Wiley-
VCH: Weinheim, Germany, 2006.
(6) (a) Crotti, S.; Bertolini, F.; Macchia, F.; Pineschi, M. Org. Lett. 2009,
11, 3762. (b) Fujii, N.; Nakai, K.; Tamamura, H.; Otaka, A.; Mimura, N.;
Miwa, Y.; Taga, T.; Yamamoto, Y.; Ibuka, T. J. Chem Soc., Perkin Trans. 1
1995, 1359. (c) Wipf, P.; Fritch, P. C. J. Org. Chem. 1994, 59, 4875. (d) Ibuka,
T.; Nakai, K.; Habashita, H.; Hotta, Y.; Fujii, N.; Mimura, N.; Miwa, Y.;
Taga, T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1994, 33, 652.
(7) (a) Disadee, W.; Ishikawa, T. J. Org. Chem. 2005, 70, 9399. (b) Trost,
B. M.; Fandrick, D. R.; Brodmann, T.; Stiles, D. T. Angew. Chem., Int. Ed.
2007, 46, 6123.
(8) (a) Coldham, I.; Collis, A. J.; Mould, R. J.; Rathmell, R. E. Tetrahedron
Lett. 1995, 36, 3557. (b) Ahman, J.; Somfai, P. Tetrahedron Lett. 1995, 36, 303.
(9) (a) Brichacek, M.; Lee, D.; Njardarson, J. T. Org. Lett. 2008, 10, 5023.
(b) Fugami, K.; Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett.
1985, 26, 857. (c) Atkinson, R. S.; Rees, C. W. Chem. Commun. 1967, 1232.
(10) Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836.
(20) (a) Pesciaioli, F.; De Vincentiis, F.; Galzerano, P.; Bencivenni, G.;
Bartoli, G.; Mazzanti, A.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47,
8703. (b) Vesely, J.; Ibrahem, I.; Zhao, G. L.; Rios, R.; Cordova, A. Angew.
Chem., Int. Ed. 2007, 46, 778. (c) Arai, H.; Sugaya, N.; Sasaki, N.; Makino,
K.; Lectard, S.; Hamada, Y. Tetrahedron Lett. 2009, 50, 3329.
DOI: 10.1021/jo100407s
r
Published on Web 04/07/2010
J. Org. Chem. 2010, 75, 3499–3502 3499
2010 American Chemical Society

Armstrong et al.
JOCNote
SCHEME 1. Approach to Organocatalytic Alkene
Aziridination
TABLE 1. Optimization of the Reaction Conditions for Aziridination of
Dienone 1a
NMR
base
(equiv) solvent
DppONH2
(equiv)
yieldb
(%)
entrya
base
NaOH
1
2
2
2
2
2
3
3
3
MeCN
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
1
1
1
1.5
1.5
2
42c
41
45
37
54
62
67
83
2d
3
NaOH
NaH/iPrOH
NaH/iPrOH
NaH/iPrOH
NaH/iPrOH
NaH/iPrOH
KOtBu/THFe
4d
5
6
7
8
2
aReactions performed at 0.06 M in substrate on a 0.12 mmol scale.
bYield determined by 1H NMR with Bn2O as the internal standard.
cIsolated yield after flash column chromatography. dReaction per-
formed at 0.12 M in substrate on 0.12 mmol scale. e1 M solution of
KOtBu in THF
between the carbonyl carbon and the CH protons of the
aziridine ring, and an absence of carbonyl carbon correla-
tions to either vinylic proton. The reaction was also com-
pletely diastereoselective (>95: 5 by NMR spectroscopy)
3
for the trans-aziridine as determined by J2H-3H coupling con-
stants of the aziridine ring (3J2H-3H = 2.6 Hz; generally the cis
value is ca. 7-9 Hz and the trans value is ca. 2-4 Hz).13-17
Keen to optimize the yield of the vinyl aziridine, we
screened alternative base and solvent combinations that
had afforded high product yields in our previous work with
amine-promoted aziridination (entries 3 and 4). Only a mini-
mal improvement in the yield of vinyl aziridine was observed,
including at a doubled concentration, but the majority
of remaining material was returned as unreacted starting
material. It was found the combination of NaH/iPrOH in
CH2Cl2 at a concentration of 0.06 M in substrate gave the
best combined yield of product (45%) and return of starting
material (entry 3) and optimization continued with these
conditions. We decided to investigate the effect of varying
the equivalents of aminating agent, DppONH2. Pleasingly, it
was found that an increase from 1.0 to 1.5 equiv, still with
2 equiv of base, increased the yield of vinyl aziridine to 54%
and this could be improved further to 62% by using 3.0 equiv
of base (entries 5 and 6). The yield could further be enhanced
(to 67%) utilizing 2.0 equiv of DppONH2 with 3.0 equiv of
base (entry 7). In earlier work, we had found KOtBu in
DMSO to be an effective base for aziridination using stoi-
chiometric hydrazinium salts.18b Preliminary attempts to
aziridinate 1a by using this base/solvent combination with
NMM and DppONH2 led only to very low yields of aziri-
dine. However, use of a commercial THF solution of KOtBu
in CH2Cl2 was more successful, and pleasingly gave an
increase to 83% (entry 8).
induce promising levels of asymmetric induction via the use
of quinine and related cinchona alkaloid tertiary amines.18a
We were keen to extend the application of our developed
aziridination to the aziridination of dienones in order to
provide the vinyl aziridine motif. To the best of our know-
ledge there exist only two isolated instances of the regiose-
lective aziridination of R,β,γ,δ-unsaturated carbonyl com-
pounds. Ito presented complementary conditions for either
the cis- or trans-selective aziridination of an R,β,γ,δ-unsatu-
rated amide at the R,β-position, with stereoselectivity gover-
ned by choice of lithiated diaziridine reagent.21 Addition-
ally Xu has reported two examples of the aziridination
of R,β,γ,δ-unsaturated ketones, via a Cu-catalyzed nitrene
addition in the presence of a bisoxazoline ligand, with the
reaction selective for the γ,δ-alkene of the substrate and
providing the cis-aziridine.22 Herein, we describe the adapta-
tion of our own nucleophilic aziridination chemistry to
provide a novel method for the diastereoselective synthesis
of unprotected-NH-vinyl aziridines.
Initially we attempted to extend our reported reaction
conditions18a to the aziridination of the diphenyl-substituted
dienone cinnamylideneacetophenone 1a (Table 1, entry 1).
Pleasingly we were able to isolate the vinyl aziridine 2a in
moderate yield (42%), although it appeared that the reacti-
vity of the diene substrate was lower than that of the R,β-
unsaturated carbonyl compounds studied earlier. The reac-
tion was found to be selective for the R,β-alkene of the sub-
strate, as determined by strong 2J and 3J HMBC correlations
With two effective sets of reaction conditions in hand
(entries 7 and 8) we then sought to apply the conditions to a
range of different diene substrates, synthesized via either an
aldol condensation or a Wittig reaction (see the Supporting
Information) (Table 2). The reaction proved applicable to a
range of diene substrates providing the vinyl aziridines in
moderate to good yield. While either NaH/iPrOH or KOtBu
(21) Ishihara, H.; Hori, K.; Sugihara, H.; Ito, Y. N.; Katsuki, T. Helv.
Chim. Acta 2002, 85, 4272.
(22) Ma, L.; Du, D.-M.; Xu, J. Chirality 2006, 18, 575.
3500 J. Org. Chem. Vol. 75, No. 10, 2010

Armstrong et al.
JOCNote
TABLE 2. Investigation into the Substrate Tolerance of the Dienone Aziridination
aReactions performed at 0.06 M in substrate on a 0.12-0.24 mmol scale. bIsolated yield after flash column chromatography. cYield determined by 1H
NMR spectroscopy, using Bn2O as the internal standard. This product underwent decomposition on attempted purification (see Scheme 2).
was generally effective as a base, KOtBu gave slightly better
SCHEME 2. Rearrangement of Aziridine 2g to Diene 3
results with electron-deficient substrates and also those
possessing alkyl groups. Cinnamylideneacetophenone 1a
afforded the diphenyl-substituted vinyl aziridine 2a in very
good yield (79%) (entry 1), and a variety of heterocyclic
aromatics, including furyl 1b (entry 2) and thiophenyl-C1
substituents 1c-e (entries 3-5) also performed well
(64-70%). The reaction was also tolerant of electron-defi-
cient aromatics at C1, with p-F-substituted diene 1f afford-
ing vinyl aziridine 2f, albeit with a slight drop in yield (46%)
(entry 6). Various substituents at C5 were also tolerated. The
strongly electron-rich 4-methoxyphenyl diene 1g gave very
good conversion to vinyl aziridine 2g (78%) (entry 7).
Interestingly the product was found to rearrange to diene 3
upon attempted flash column chromatography purification,
using either silica gel or neutral alumina, presumably via
either a Bronsted or Lewis acid-promoted ring-opening via a
stabilized allyl cation (Scheme 2).
Strongly electron-withdrawing C5 substitution was also
permitted although the 4-nitrophenyl-substituted dienone 1h
did afford a lower yield of the aziridine and the reaction
appeared to benefit from a reduced amount of base (entry 8).
It seems the aziridination reaction appears to be less tolerant
of electron-deficient substrates (entries 6 and 8), which is in
contrast to the previously observed reactivity of R,β-unsa-
turated carbonyl compounds.18 In most cases it was possible
to recover unreacted starting material although this was not
possible with substrates 1f and 1h and we believe the lower
yields for these reactions are the result of partial decomposi-
tion of the more electron-deficient substrates. We were
pleased to extend the scope of the reaction to δ-alkyl-sub-
stituted dienes, with optimal yields achieved by utilizing 2
equiv of base. Indeed primary butyl C5-substituted diene 1i
and cyclic derivative 1k both underwent reaction to afford
vinyl aziridines 2i and 2k in good yield (60-62%) (entries 9
and 11). The reaction was also found to be tolerant of
branching at the C4-position with aziridines 2j and 2k
isolated in respectable yield (60-67%) (entries 10 and 11).
In all cases the aziridination was completely regioselective
for the R,β-alkene and also completely diastereoselective for
J. Org. Chem. Vol. 75, No. 10, 2010 3501

Armstrong et al.
JOCNote
the trans-aziridine. In no case was the cis-aziridine observed.
The complete control of diastereoselectivity observed is in
contrast with many of the current methods used to prepare
vinyl aziridines, where consistently high levels of diaster-
eocontrol are rare.16,17b-d,17f We are currently investi-
gating the utility of the aziridine products to provide
diastereocontrolled access to functional amine building
blocks.
In summary, we have developed a method for the synthe-
sis of trans-N-unprotected-vinyl aziridines utilizing an
amine-promoted nucleophilic aziridination of R,β,γ,δ-un-
saturated carbonyl compounds. The reaction was observed
to be completely regio- and diastereoselective and the scope
tolerant of a range of diene substrates. Current studies are
focused on the development of an asymmetric version of
the reaction and also applications of the methodology to
total synthesis. Further results will be reported in due
course.
for 0.5 h. Either KOtBu (0.36 mL, 1 M in THF, 0.36 mmol) or
iPrOH (27.6 μL, 0.36 mmol) and NaH (60% in mineral oil) (14.4
mg, 0.36 mmol) were then added followed by cinnamylidenea-
cetophenone (56 mg, 0.24 mmol) and the mixture was allowed to
stir at room temperature overnight. The reaction was quenched
by the addition of saturated aqueous NH4Cl solution (4 mL)
and the aqueous layer was separated and extracted with CH2Cl2,
dried (Na2SO4), filtered, and concentrated in vacuo. Purifica-
tion by flash column chromatography (20% EtOAc/ihexane)
afforded 2a (49.3 mg, 79%) as a yellow oil; Rf (20% EtOAc/
ihexane) 0.40; νmax (ATR) 3267, 1671, 1602, 1582, 1255, 966
cm-1; δH (400 MHz, CD3OD) 8.05-8.10 (2H, m, ArH),
7.63-7.69 (1H, m, ArH), 7.52-7.57 (2H, m, ArH), 7.40-7.45
(2H, m, ArH), 7.28-7.34 (2H, m, ArH), 7.21-7.26 (1H, m
ArH), 6.81 (1H, d, J = 16.0 Hz, PhCHd), 6.05 (1H, dd, J = 16.0
and 8.2 Hz, PhCHdCH-), 3.76 (1H, d, J = 2.6 Hz, 2-CHN),
2.86 (1H, dd, J = 8.2 and 2.6 Hz, 3-CHN); δC (100 MHz,
CD3OD) 197.1, 137.9, 137.4, 135.3, 135.2, 130.2, 129.8, 129.5,
129.2, 128.7, 127.6, 44.4, 42.1; m/z (ESþ) 250 (MHþ, 100%), 272
(MNaþ, 30); m/z HRMS (ESþ) MHþ calcd for C17H16NO
250.1232, observed 250.1241.
Experimental Section
Acknowledgment. We thank the EPSRC and Syngenta
(CASE award to RDCP) for their support of this work.
General Procedures for the Aziridination of Dienes 1a-k: Syn-
thesis of Vinyl Aziridines 2a-k: (E)-(2R*,3S*)-Phenyl[3-(styryl)-
aziridin-2-yl]methanone, 2a. N-Methylmorpholine (NMM)
(27.7 μL, 0.25 mmol) was added dropwise over 1 min to a
solution of O-diphenylphosphinyl hydroxylamine (DppONH2)
(112 mg, 0.48 mmol) and dibenzyl ether (11.4 μL, 0.06 mmol) in
CH2Cl2 (4 mL) at room temperature and the mixture was stirred
Supporting Information Available: Experimental procedu-
res, including full optimization studies, and characterization
data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
3502 J. Org. Chem. Vol. 75, No. 10, 2010