Transition metal-catalyzed synthesis and reactivity of N-alkenyl aziridines

Article abstract of DOI:10.1021/ol050094n

(Chemical Equation Presented) Straightforward methods for palladium-catalyzed alkenylation of aziridines with alkenyl halides and copper-catalyzed alkenylation of aziridines with alkenyl boronic acids have been developed. This methodology offers attractive alternatives to the known methods requiring activated alkenyl halides and acetylenes. A wide variety of N-alkenyl aziridines containing substituents other than electron-withdrawing substituants such as cyano groups and sulfones have been synthesized in good yields. Furthermore, these N-alkenyl aziridines exhibit quite a different reactivity from conventional enamines, as demonstrated by their reactivity.

Full text of DOI:10.1021/ol050094n

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1161-1164
Transition Metal-Catalyzed Synthesis
and Reactivity of N-Alkenyl Aziridines
Shadi Dalili and Andrei K. Yudin*
DaVenport Research Labs, Department of Chemistry, UniVersity of Toronto,
80 St. George St., Toronto, Ontario, M5S 3H6 Canada
ayudin@chem.utoronto.ca
Received January 17, 2005
ABSTRACT
Straightforward methods for palladium-catalyzed alkenylation of aziridines with alkenyl halides and copper-catalyzed alkenylation of aziridines
with alkenyl boronic acids have been developed. This methodology offers attractive alternatives to the known methods requiring activated
alkenyl halides and acetylenes. A wide variety of N-alkenyl aziridines containing substituents other than electron-withdrawing substituents
such as cyano groups and sulfones have been synthesized in good yields. Furthermore, these N-alkenyl aziridines exhibit quite a different
reactivity from conventional enamines, as demonstrated by their reactivity.
Enamines derived from secondary amines are among the
most versatile intermediates in organic synthesis.1 Known
as versatile enol synthons since the pioneering work of
Stork,2 enamines are typically prepared by reacting a given
secondary amine with an appropriate aldehyde or ketone in
a condensation process, often in the presence of an acid
catalyst and a water scavenger.3 This method is useful, but
it also has several drawbacks such as lack of regioselectivity
and low functional group tolerance. Other non-metal-
catalyzed methods for the synthesis of N-alkenylamines are
limited in scope due to the requirement for activated alkenyl
halides. Furthermore, all examples known to date contain
electron-withdrawing groups attached to the olefin moiety.4
Our ongoing program in synthetic applications of aziridines
required a general route to the enamines of type 1 (Scheme
1).
Scheme 1
(1) Rappoport, Z. In The Chemistry of Enamines; Wiley & Sons: New
York, 1994; Vol. 2.
(2) Stork, G.; Szmuszkovicz, J.; Terrell, R.; Brizzolara, A.; Landesman,
H. J. Am. Chem. Soc. 1963, 85, 207.
(3) Hickmott, P. W. Tetrahedron 1982, 38, 1975.
(4) For preparation of N-alkenylamines by nucleophilic substitution of
alkenyl halogen by amine nucleophiles, see: (a) de Ancos, B.; Maestro,
M. C.; Martin, M. R.; Farina, F. Synthesis 1988, 136. (b) Cebulska, Z.;
Laurent, A. J.; Laurent, E. G. J. Fluor. Chem. 1996, 76, 177. For reaction
of ketene S,N-acetals with ethyleneimine to yield 3-anilino-3-(1-aziridinyl)-
acrylnitriles, see: (c) Kumar, U.K.S.; Ila, H.; Junjappa, H. Org. Lett. 2001,
3, 4193. For aziridine addition to propiolates, see: (d) Expert, J.; Gelas-
Mialhe, Y.; Vessiere, R. J. Heterocycl. Chem. 1985, 22, 1285. (e) Gelas-
Mialhe, Y.; Touraud, E.; Vessiere, R. Can. J. Chem. 1982, 60, 2830. (f)
Dolfini, J. E. J. Org. Chem. 1965, 30, 1298. For N-alkenyl aziridine synthesis
via Peterson reaction, see: (g) Agawa, T.; Ishikawa, M.; Komatsu, M.;
Ohshiro, Y. Chem. Lett. 1980, 335. (h) Agawa, T.; Ishikawa, M.; Komatsu,
M.; Ohshiro, Y. Bull. Chem. Soc. Jpn. 1982, 55, 1205. For N-alkenyl
aziridine synthesis by pyrolysis of ∆2-triazolines, see: (i) Hassner, A.;
Belinka, B. A.; Haber, M.; Munger, P. Tetrahedron Lett. 1981, 22, 1863.
The chemical shift of the R proton in enamines derived
from simple amines is significantly upfield from the value
recorded for the ethyleneimine-derived enamine, in agree-
ment with the greater zwitterionic character in the ground
state of the former.5 One can therefore expect a deviation in
(5) Buist, G. J.; Lucas, H. S. J. Am. Chem. Soc. 1957, 79, 6157.
10.1021/ol050094n CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/19/2005

Table 1. Pd-Catalyzed N-Alkenylation of Aziridines
entry
1
R1
R2
alkenyl bromide
R-bromostyrene
product
yield (%)
-(CH2)4-
-(CH2)4-
1a
22a
69b
25a
65b
75b
67c
2
â-bromostyrene (E/Z mixture)
(E)-1b
3
4
5
6
7
Me
Me
Me
Me
COOMe
COOMe
(R)-Me
(R)-Me
(R)-Me
(R)-Me
(R)-Me
H
H
H
H
H
H
R-bromostyrene
2a
â-bromostyrene (E/Z mixture)
N,N-dibenzyl-2-bromoallylamine
2-bromo-1-decene
R-bromostyrene
â-bromostyrene (E/Z mixture)
R-bromostyrene
â-bromostyrene (E/Z mixture)
1-bromo-2-methyl propene
1-bromopropene
2-bromo-2-butene
R-bromostyrene
(E)-2b
N/Ad
N/Ae
3a
(E)-3b
4a
(E)-4b
4c
(E)-4d
4e
65b
60c
64c
68c
70c
65c
85c
8
9
(S)-Ph
(S)-Ph
(S)-Ph
(S)-Ph
(S)-Ph
PhCO-
PhCO-
10
11
12
13
14
15
CH2dCHCH2CH2-
CH2dCHCH2CH2-
NR
N/Ae
2-bromopropene
a Purification on a silica gel column (4:1 hexanes/ethyl acetate). b Purification by Kugelrohr distillation. c Purification on alumina column (4:1 hexanes/
ethyl acetate). d Unidentified byproducts/polymerization. e Decomposition of products.
chemistry of the aziridine-containing enamines compared to
the conventional systems (Figure 1). We opted to investigate
the N-nucleophilic character of these unusual intermediates,
complementary to the more rigid bicyclic systems disclosed
in our earlier work.6
trans isomers), which gave a similar yield as in the previous
reaction (Table 1, entry 2). The product obtained had
exclusively trans geometry. The relatively low yields are due
to the sensitivity of the products to aziridine ring opening
on silica gel and can be augmented by purification of the
crude product using distillation. Thus, when the crude
(6) Sasaki, M.; Yudin, A. K. J. Am. Chem. Soc. 2003, 125, 14242.
(7) For recent reviews, see: (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.
F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (b) Hartwtig, J. F. Acc.
Chem. Res. 1998, 31, 852. (c) Hartwig, J. F. In Modern Amination Methods;
Ricci, A., Ed.; Wiley-VCH: Weinheim, Germany, 2000. (d) Muci, A. R.;
Buchwald, S. L. Top. Curr. Chem. 2002, 219, 133. (e) Hartwig, J. F. Angew.
Chem., Int. Ed. 1998, 37, 2046.
(8) For intermolecular palladium-catalyzed cross-coupling of amines with
alkenyl bromides, see: (a) Barluenga, J.; Fernandez, M. A.; Aznar, F.;
Valdes, C. Chem. Commun. 2002, 2362. (b) Barluenga, J.; Fernandez, M.
A.; Aznar, F.; Valdes, C. Chem. Eur. J. 2004, 10, 494. For intramolecular
palladium-catalyzed cross-coupling of alkenyl halide and â-lactam nitrogen,
leading to a carbapenem skeleton, see: (c) Kozawa, Y.; Mori, M.
Tetrahedron Lett. 2002, 43, 111. (d) Kozawa, Y.; Mori, M. J. Org. Chem.
2003, 68, 3064. For palladium-catalyzed cross-coupling of azoles with
alkenyl bromides, see: (e) Lebedev, A. Y.; Izmer, V. V.; Kazyul’kin, D.
N.; Beletskaya, I. P.; Voskoboynikov, A. Z. Org. Lett. 2002, 4, 623.
(9) General Procedure for Palladium-Catalyzed N-Alkenylation of
Aziridines. A flame-dried Schlenk flask under an argon atmosphere was
charged with (()-BINAP (6 mol %), Pd2(dba)3 (2 mol %), NaOtBu (1.4
equiv), and dry, degassed toluene. After the mixture was stirred at room
temperature for about 10 min, the alkenyl bromide (1 equiv) and the aziridine
(1.1 equiv) were added under argon, and the flask was immersed in an oil
bath and heated to 90 °C with stirring until the starting alkenyl bromide
had been completely consumed as judged by GC and TLC analysis. All
reactions were generally complete after overnight stirring. The mixture was
then allowed to cool to room temperature, diluted with hexanes, and filtered
through Celite. The solvent was evaporated in vacuo, and the residue was
redissolved in hexanes, filtered through Celite, concentrated under reduced
pressure, and dried under high vacuum to remove any excess aziridine.
This afforded a residue that consisted of the crude N-alkenyl aziridine, which
was purified further by Kugelrohr distillation under high vacuum (dependent
on the boiling point and amount of product obtained) or by column
chromatography on alumina.
Figure 1.
Clearly, the use of an aziridine nucleophile as the
secondary amine under standard conditions for enamine
synthesis would lead to highly strained iminium intermedi-
ates, making the prospects of condensation chemistry prob-
lematic. We therefore turned to transition metal catalysis.
The transition metal-catalyzed cross-coupling reaction of aryl
halides with amines, known as the Buchwald-Hartwig
reaction, has emerged as a powerful procedure for the
creation of C-N bonds.7,8 When a mixture of 7-azabicyclo-
[4.1.0]heptane and R-bromostyrene was heated to 90 °C
overnight in the presence of Pd2(dba)3, rac-BINAP, and
NaOtBu (Table 1, entry 1),9 a 22% yield of the enamine was
obtained with no evidence for aziridine ring opening in the
course of the reaction. The same reaction condition was
applied to â-bromostyrene (supplied as a mixture of cis and
1162
Org. Lett., Vol. 7, No. 6, 2005

compounds were purified by Kugelrohr distillation (Table
1, entries 1 and 2), 69 and 65% respective yields were
obtained. Likewise, 2-methyl aziridine led to enamines 2a
and (E)-2b in 75 and 67% yields, respectively (Table 1,
entries 3 and 4). N,N-Dibenzyl-2-bromoallylamine and
2-bromo-1-decene10 did not give any isolable products (Table
1, entries 5 and 6). Aziridine-2-carboxylic acid methyl ester
gave the coupling products 3a and (E)-3b in 65 and 60%
yields, respectively (Table 1, entries 7 and 8). The reaction
was extended to N-H aziridines containing aromatic rings.11
(2S,3R)-3-methyl-2-phenylaziridine (4) was used in the
N-alkenylation process with various alkenyl bromides to
obtain aryl-containing N-alkenyl aziridines in good yields.
For example, the aziridine 4 was reacted with R-bromo-
styrene as well as a mixture of cis- and trans-â-bromostyrene
to give N-alkenyl aziridine 4a and (E)-4b in 64 and 68%
yields, respectively (Table 1, entries 9 and 10).12 Nonaromatic
alkenyl bromides provided the N-alkenyl aziridines in high
yields (Table 1, entries 11-13). The (3-but-3-enyl-trans-
aziridin-2-yl)phenylmethanone (5), synthesized according to
literature procedure,13 was found to be unreactive with
R-bromostyrene (Table 1, entry 14). The reaction of 5 with
2-bromopropene under optimal reaction conditions, as well
as with a higher loading of the palladium catalyst, did not
lead to any conversion to N-alkenyl aziridine. Inseparable
byproducts, thought to be the result of polymerization, were
detected by NMR of the crude product along with unreacted
starting material (Table 1, entry 15). The sluggish reactivity
of 5 toward N-alkenylation of the aziridine nitrogen is likely
due to chelation of the palladium center between the aziridine
nitrogen and the carbonyl side chain oxygen (Figure 2), a
process that is a likely impediment to catalysis.14
Table 2. Cu-Catalyzed N-Alkenylation of Aziridines
entry
R1
R2
R3
product
yield (%)
1
2
3
4
-(CH2)4-
p-MeC6H4
1c
4f
4g
NR
40
50
30
(R)-Me
(R)-Me
b
(S)-Ph
(S)-Ph
nBu
a
a
a 2,4,6-Trivinylcyclotriboroxane-pyridine was used as a boronic acid
equivalent. b (3-But-3-enyl-trans-aziridin-2-yl)phenylmethanone was used
as a substrate.
compound 4f in 50% yield (Table 2, entry 2). The yields of
the final products are lower using the copper-catalyzed
procedure. However, the reactions with lower boiling alkenyl
bromides do not proceed well with palladium. On the other
hand, 2,4,6-trivinylcyclotriboroxane-pyridine complex, which
serves as the boronic acid equivalent of vinyl bromide,17
provided the N-vinyl product in 30% yield upon reaction
with aziridine 4 (Table 2, entry 3). The coupling of 2,4,6-
trivinylcyclotriboroxane-pyridine with aziridine 5 was un-
successful even after prolonged reaction time (Table 2, entry
4).
To test the extent of N-nucleophilicity and possible
synthetic application of N-alkenyl aziridines, we explored
their reactivity with electron-deficient acceptor molecules.
When N-alkenyl aziridine 2a was reacted with dimethyl-
acetylene dicarboxylate (DMAD), the starting material
disappeared within 24 h and a new product was generated
in 80% yield.
Upon analysis of the g-COSY NMR, the product was
assigned to a 1:1 mixture of regioisomeric pyrrolines obtained
via formal [3 + 2] cycloaddition (Table 3, entry 1).18 This
reaction was also applied to N-alkenyl aziridines 3a, 1a, and
Figure 2.
Table 3. N-Alkenyl Aziridine Reaction with DMAD
Selected examples of the copper-based synthesis of N-aryl
aziridines were reported by us earlier.15,16 In the present case,
the copper-catalyzed coupling of 7-azabicyclo[4.1.0]heptane
with trans-2-tolylvinylboronic acid gave the N-alkenyl aziri-
dine 1c in 40% yield (Table 2, entry 1), and coupling of
aziridine 4 with hexenyl vinyl boronic acid provided
(10) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett. 1983,
24, 731.
(11) S,3R)-(+)-3-Methyl-2-phenylaziridine was synthesized according to
published procedure; see: Galindo, A.; Orea, L. F.; Gnecco, D.; Enriquez,
R. G.; Toscano, R. A.; Reynolds, W. F. Tetrahedron: Asymmetry 1997, 8,
2877.
(12) For Pd-catalyzed isomerization of cis-olefins, see: Yu, J.; Gaunt,
M. J.; Spencer, J. B. J. Org. Chem. 2002, 67, 4627.
(13) Seko, S.; Tani, N. Tetrahedron Lett. 1998, 39, 8117.
(14) We have observed lack of reactivity of carbonyl-containing aziridines
in other transition metal-catalyzed processes: Chen, G.; Yudin, A. K.
Unpublished results.
Org. Lett., Vol. 7, No. 6, 2005
1163

(E)-1b. In the case of 3a, the same type of reaction occurred
as with 2a, leading to two regioisomeric products in a 1:3
ratio and 65% yield (Table 3, entry 2). For the more sterically
congested compounds 1a and (E)-1b, no reaction occurred
and the starting materials were recovered (Table 3, entries 3
and 4). Interestingly, a thermal [1,5] hydrogen shift was
observed upon heating the N-alkenyl aziridine 2a in the
absence of DMAD at a higher temperature (Scheme 2).19
Mechanistic investigation and synthetic application of these
interesting reactions are in progress.
these N-alkenyl aziridines exhibit quite a different reactivity
from conventional enamines. Future work will focus on
expanding the scope of their applications in complex
heterocycle construction.
Acknowledgment. We thank the Natural Science and
Engineering Research Council (NSERC), Canada Foundation
for Innovation, ORDCF, Affinium Pharmaceuticals, Amgen,
and the University of Toronto for financial support.
Supporting Information Available: Experimental pro-
cedures, characterization data, and spectra for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 2
OL050094N
(15) For some recent examples of amination of aryl halides, see: (a)
Gajare, A. S.; Toyota, K.; Yoshifuji, M.; Ozawa, F. Chem. Commun. 2004,
17, 1994. (b) Lu, Z.; Twilg, R. J.; Huang, S. D. Tetrahedron Lett. 2003,
44, 628. (c) Enguehard, C.; Allouchi, H.; Guieffer, A.; Buchwald, S. L. J.
Org. Chem. 2003, 68, 4367. (d) Kwong, F. Y.; Buchwald, S. L. Org. Lett.
2003, 5, 793. (e) Kelkar, A. A.; Patil, N. M.; Chaudhari, R. V. Tetrahedron
Lett. 2002, 58, 7943. (f) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org.
Lett. 2002, 4, 581. (g) Clement, J. B.; Hayes, J. F.; Sheldrake, H. M.;
Sheldrake, P. W.; Wells, A. S. Synlett, 2001, 9, 1423. (h) Satoh, T.; Matsue,
R.; Fujii, T.; Morikawa, S. Tetrahedron, 2001, 57, 3891.
(16) Sasaki, M.; Dalili, S.; Yudin, A. K. J. Org. Chem. 2003, 68, 2045.
(17) Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968.
(18) Gaebert, C.; Mattay, J. Tetrahedron 1997, 53, 14297.
(19) For [1,5] hydrogen shifts in C-vinyl aziridines, see: Åhman, J.;
Somfai, P. Tetrahedron 1999, 55, 11595.
In summary, straightforward methods for palladium-
catalyzed alkenylation of aziridines with alkenyl halides and
Cu-catalyzed alkenylation of aziridines with alkenyl boronic
acids are attractive alternatives to the known methods
requiring activated alkenyl halides and acetylenes. A wide
variety of N-alkenyl aziridines containing substituents other
than electron-withdrawing groups such as cyano groups and
sulfones have been synthesized in good yields. Furthermore,
1164
Org. Lett., Vol. 7, No. 6, 2005