Stereospecific aziridination of olefins via electrophile-induced cyclization of γ,δ-unsaturated imines and subsequent hydrolytic rearrangement

Article abstract of DOI:10.1039/b703147e

The olefinic bond of γ,δ-unsaturated aldehydes underwent a net aziridination through electrophile-induced cyclization and subsequent rearrangement of the resulting cyclic iminium salts: this methodology allows the stereospecific introduction of aziridine

Full text of DOI:10.1039/b703147e

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Stereospecific aziridination of olefins via electrophile-induced
cyclization of c,d-unsaturated imines and subsequent hydrolytic
rearrangement{
Matthias D’hooghe, Mark Boelens, Johan Piqueur and Norbert De Kimpe*
Received (in Cambridge, UK) 1st March 2007, Accepted 27th March 2007
First published as an Advance Article on the web 13th April 2007
DOI: 10.1039/b703147e
aziridination of olefins by means of copper-catalyzed reactions of
intermediate oxaziridines.11
The olefinic bond of c,d-unsaturated aldehydes underwent a net
aziridination through electrophile-induced cyclization and
subsequent rearrangement of the resulting cyclic iminium salts:
this methodology allows the stereospecific introduction of
aziridine moieties into cyclic systems.
N-(2,2-Dimethyl-4-penten-1-ylidene)amines 5, prepared from
2,2-dimethyl-4-pentenal 412 upon treatment with 1 equiv. of a
primary amine in dichloromethane in the presence of MgSO4,
react very smoothly with bromine in dichloromethane at 0 uC for
10 min to afford cyclic iminium salts 6 in essentially quantitative
yields (Scheme 2).13 The functionalized 1-pyrrolinium salts 6 are
easily converted into aziridines 8 by a two-step process, involving
(i) hydrolysis of the iminium function with aqueous hydrogen
chloride in a two-phase system with dichloromethane as a co-
solvent, and (ii) ring closure of the resulting intermediate
b-bromoammonium salts 7 with potassium carbonate in dichloro-
methane (Scheme 2).14 The functionalized aziridines 8 were
isolated, after distillation, in 53–89% overall yields from the
starting a-allylisobutyraldimines 5 (Scheme 2, Route 1). This
initially followed route could be improved considerably by
treatment of the iminium salts 6 with aqueous sodium hydroxide,
directly affording the rearranged end-products 8 in 89–93% yield
(Scheme 2, Route 2).
Due to the well-known synthetic flexibility of aziridines,1 the
aziridination of olefins 1 towards azaheterocycles 2 is a highly
useful transformation in synthetic organic chemistry (Scheme 1).2
One-step procedures include, among others, the reaction of olefins
with nitrenes,2,3 with N(,N)-(di)halogenated amines,4 with palla-
dium complexes and bromine,5 with [N-(4-toluenesulfonyl)imino]-
phenyliodinane6 and related species.7 The formation of aziridines
from olefins and nitrenes, the latter generally synthesized from
azides, by a-elimination reactions and by oxidation of primary
amines, is well studied.2a,8 When azides serve as precursors,
the alternative of 1,3-dipolar cycloaddition must be envisaged. The
aziridination works well for certain aminonitrenes, in which the
amino group apparently stabilizes the singlet state, but the nature
of the amino substituent is crucial.2a Additionally, such N-amino
aziridines have most often an undesirable substituent which is
difficult to remove or replace by more general substituents.2a,8 An
alternative method for the synthesis of aziridines from olefins
consists of the regio- and stereospecific reaction with halo azides or
iodo isocyanate, the resulting b-halo azides9 and b-iodo isocya-
nates10 being ring closed subsequently.
The net result of this rearrangement constitutes a transfer of an
alkylamino group to the olefinic double bond with concomitant
generation of an aldehyde functionality. Because of the fact that
enimine 5 is easily accessible from 2,2-dimethyl-4-pentenal 4 by a
simple imination procedure in nearly quantitative yields, the net
transformation of pentenal 4 to aziridines 8 comprises an
aziridination of the olefinic double bond by primary amines under
mild conditions, ie via electrophile-induced cyclization of enimines
5 and subsequent hydrolysis and ring closure.
In the present report, a new and efficient method is disclosed for
the intramolecular aziridination of olefins by transfer of alkyl-
amine moieties (N–R) from a remote position in the molecule (see
compound 3) to the alkene, the net result being the conversion of
an unactivated carbon–carbon double bond into an aziridine 2
(Scheme 1). This approach offers a suitable alternative for the
Scheme 1
Department of Organic Chemistry, Faculty of Bioscience Engineering,
Ghent University, Belgium. E-mail: norbert.dekimpe@UGent.be;
Fax: +32 9 264 6243; Tel: +32 9 264 5951
{ Electronic supplementary information (ESI) available: Characterization
data. See DOI: 10.1039/b703147e
Scheme 2
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This intramolecular aziridination was extended to other imines
such as a-allylcyclohexanecarbaldimine 9, isobutyraldimines 11
and 13, and a-(2-cyclohexen-1-yl)isobutyraldimine 15, which were,
after electrophile-induced cyclization with bromine and hydrolytic
alkylamino transfer, converted into aziridines 10, 12, 14 and 16
(Scheme 3). Due to the nature of the cyclization process, the
conversion of 15 into 7-azabicyclo[4.1.0]heptane derivative 1615
occurs stereospecifically with the aziridino moiety positioned cis
with respect to the alkyl substituent.
In order to underline the synthetic potential of this stereospecific
construction of aziridines via an intramolecular rearrangement
process, 1-methyl-2-cyclohexenecarbaldehyde 17 was converted to
b,c-unsaturated imine 18 upon treatment with 1 equiv. of t-BuNH2
in dichloromethane in the presence of MgSO4. The latter imine
underwent smooth electrophile-induced cyclization with bromine
to afford the bicyclic iminium salt 19 in quantitative yield
(Scheme 4). Alkaline hydrolysis of this iminium salt 19 with
aqueous sodium hydroxide at room temperature produced the
rearranged 7-aza-7-t-butyl-2-methylbicyclo[4.1.0]heptane-2-carbal-
dehyde 20 in 86% yield (Scheme 4). Again, the conversion of 17
into 20 consists of a net aziridination process in which the aziridine
moiety is stereospecifically positioned cis with respect to the
carbaldehyde group. This stereospecific aziridination is a useful
synthetic procedure for the functionalization of cycloalkenes due
to the chemical behaviour of (non-activated) aziridines in ring
opening reactions.16
Scheme 4
By means of this methodology, a stereospecific introduction of
aziridine moieties in cyclic systems can be accomplished in an
efficient and straightforward manner.
Notes and references
1 (a) U. M. Lindstro¨m and P. Somfai, Synthesis, 1998, 109; (b)
B. Zwanenburg and P. ten Holte, Top. Curr. Chem., 2001, 94; (c)
J. B. Sweeney, Chem. Soc. Rev., 2002, 31, 247; (d) X. E. Hu,
Tetrahedron, 2004, 60, 2701; (e) D. Tanner, Angew. Chem., Int. Ed.
Engl., 1994, 33, 599; (f) H. M. I. Osborn and J. Sweeney, Tetrahedron:
Asymmetry, 1997, 8, 1693; (g) W. McCoull and F. A. Davis, Synthesis,
2000, 1347.
2 (a) J. A. Deyrup, Small Ring Heterocycles, Part 1, Aziridines, Azirines,
Thiiranes and Thiirenes, ed. A. Hassner, Wiley-Interscience, New York,
1983, chapter 1,; (b) C.-M. Che and W.-Y. Yu, Pure Appl. Chem., 1999,
71, 281; (c) G. Hilt, Angew. Chem., Int. Ed., 2002, 41, 3586; (d)
I. D. G. Watson, L. Yu and A. K. Yudin, Acc. Chem. Res., 2006, 39,
194; (e) S. Dalili and A. K. Yudin, Org. Lett., 2005, 7, 1161; (f)
C. E. Davis, J. L. Bailey, J. W. Lockner and R. M. Coates, J. Org.
Chem., 2003, 68, 75; (g) P. H. Di Chenna, F. Robert-Peillard, P. Dauban
and P. R. H. Dodd, Org. Lett., 2004, 6, 4503; (h) C. Fruit, F. Robert-
Peillard, G. Bernardinelli, P. Muller, R. H. Dodd and P. Dauban,
Tetrahedron: Asymmetry, 2005, 16, 3484.
In conclusion, a novel aziridination of olefins via electrophile-
induced cyclization of unsaturated imines towards cyclic iminium
salts and subsequent hydrolytic rearrangement has been presented.
3 (a) W. Lwowski Ed., Nitrenes, Wiley-Interscience, New York, (1970); (b)
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Scheme 3
1928 | Chem. Commun., 2007, 1927–1929
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12 (a) G. Salomon and S. Ghosh, Organic Synthesis, Collect. Vol. p.177,
Wiley, New York, (1990); (b) K. C. Brannock, J. Am. Chem. Soc., 1959,
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Chem., 1994, 59, 5485.
(55); 124 (18); 110 (46); 109 (45); 108 (55); 99 (27); 99 (27); 98 (27);
94 (18); 83 (23); 70 (18); 67 (18); 57(18); 56 (100); 55 (45). Anal.
Calcd for C13H23NO: C 74.59%; H 11.08%. Found: C 74.41%; H
11.19%.
15 General procedure (Route 2). To a stirred solution of imine 9, 11, 13 or
15 (1 mmol) in dry dichloromethane (3 mL) at 0 uC was added slowly an
equimolar amount of bromine (0.16 g, 1 mmol) in dichloromethane
(2 mL). After stirring for 10 min at 0 uC, the solvent was evaporated
in vacuo. Subsequently, an aqueous sodium hydroxide solution (5 mL,
2 M) was added to the residual oil, and the mixture was stirred for 1.5 h
at room temperature. The aqueous reaction mixture was then extracted
with chloroform (3 6 5 mL), and the combined organic layers were
dried over MgSO4. After filtration and evaporation, the nearly pure
reaction mixture was purified by Kugelrohr distillation, yielding
pure aziridine 10, 12, 14 or 16. Spectroscopic data of 2-(7-t-butyl-7-
azabicyclo[4.1.0]hept-2-yl)-2-methylpropanal 16. Yield 78%. Bp.
14 General procedure (Route 1). To a stirred solution of imine 5 (34 mmol)
in dry dichloromethane (60 mL) at 0 uC was added slowly an equimolar
amount of bromine (5.44 g, 34 mmol) in dichloromethane (20 mL).
After stirring for 10 min at 0 uC, an aqueous hydrogen chloride solution
(170 mL, 2 M) was added, and the resulting mixture was stirred for 4 h
at room temperature. Then, the reaction mixture was basified by adding
an aqueous sodium hydroxide solution (4 M), and the organic layer was
separated. The aqueous phase was extracted with dichloromethane (2 6
50 mL). The combined organic layers were dried (K2CO3), followed by
filtration of the drying agent and evaporation of the solvent. The residue
was dissolved in dry dichloromethane (80 mL), K2CO3 (10 g) was added
and the mixture was heated under reflux for 30 minutes. After filtration
and evaporation of the solvent in vacuo, distillation of the crude reaction
mixture yielded the anticipated aziridines 8. Spectroscopic data of 3-(1-
cyclohexylaziridin-2-yl)-2,2-dimethylpropanal 8a. Yield 53%. Bp. 75–
1
85 uC/0.2 mmHg. H NMR (270 MHz, CDCl3): d 0.95 (9H, s, Me3);
1.14 and 1.17 (2 6 3H, 2 6 s, Me2); 1.08–1.90 (9H, m,
NCH(CH2)3CHCH); 9.67 ppm (1H, s, HCLO). 13C NMR (68 MHz,
CDCl3): d 19.53, 20.24 (Me2); 20.99, 22.91, 24.37 ((CH2)3); 27.03 (Me3);
28.20 (CH); 32.78 and 42.18 (2 6 NCH); 48.81 (CMe2); 53.48 (CMe3);
206.95 ppm (HCLO). IR (NaCl, cm21): nCLO = 1718. MS (70 eV) m/z
(%): no M+; 195 (11); 194 (8); 152 (23); 138 (13); 96 (100); 67 (12); 58
(19); 57 (19); 56 (14); 55 (12). Anal. Calcd for C14H25NO: C 75.28%; H
11.28%. Found: C 75.17%; H 11.40%.
1
77 uC/0.075 mmHg. H NMR (60 MHz, CDCl3): d 1.10 (3H, s, Me);
1.13 (3H, s, Me); 1.0–2.0 (16H, m, C6H11, NCH2, CH2); 9.40 ppm (1H,
s, HCLO). 13C NMR (20 MHz, CDCl3): d 21.36, 22.13 (Me2); 24.90
(CH2); 26.19 (CH2); 32.49 (NCH2); 33.00 (NCH); 41.52 (CH2CMe2);
45.78 (CMe2); 69.24 (NCH); 204.63 ppm (HCLO). IR (NaCl, cm21):
16 M. D’hooghe, V. Van Speybroeck, M. Waroquier and N. De Kimpe,
Chem. Commun., 2006, 1554.
n
CLO = 1718. MS (70 eV) m/z (%): 209 (M+, 3); 191 (32); 166 (18); 138
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Chem. Commun., 2007, 1927–1929 | 1929