Unprecedented carbon-carbon bond cleavage in nucleophilic aziridine ring opening reaction, efficient ring transformation of aziridines to imidazolidin-4-ones

Article abstract of DOI:10.1039/b816007d

N-Styryl-3-aryl-1-methylaziridine-2-carboxamides, which were readily obtained from the cross coupling reaction between 3-aryl-1-methylaziridine-2- carboxamides and 1-aryl-2-bromoethenes catalyzed by CuI/N,N-dimethylglycine in the presence of Cs₂

Full text of DOI:10.1039/b816007d

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Unprecedented carbon–carbon bond cleavage in nucleophilic aziridine
ring opening reaction, efficient ring transformation of aziridines to
imidazolidin-4-onesw
Jin-Yuan Wang, Yuan Hu, De-Xian Wang, Jie Pan, Zhi-Tang Huang and Mei-Xiang Wang*
Received (in Cambridge, UK) 12th September 2008, Accepted 20th October 2008
First published as an Advance Article on the web 18th November 2008
DOI: 10.1039/b816007d
N-Styryl-3-aryl-1-methylaziridine-2-carboxamides, which were
readily obtained from the cross coupling reaction between
3-aryl-1-methylaziridine-2-carboxamides and 1-aryl-2-bromo-
ethenes catalyzed by CuI/N,N-dimethylglycine in the presence
of Cs2CO3, underwent a base-mediated intramolecular nucleo-
philic aziridine ring opening reaction effectively via the carbon–
carbon bond cleavage of aziridine to afford the ring expanded
Scheme 1 Carbon–nitrogen bond cleavages in nucleophilic aziridine
imidazolidin-4-one products in good yields.
ring opening reactions.
Owning to the ring strain and the electronegativity of nitrogen,
8-, 6- and 5-membered lactam-containing alkaloids that were
aziridines, the smallest N-heterocyclic compounds, exhibit
isolated from the leaf extract of Rutaceae Clausena lansium
intriguing and diverse reactivity, and have thus become unique
(Lour.) Skeels (Scheme 2). It was envisaged that if the oxirane
and versatile synthons in organic synthesis.1–4 The ring open-
ring is replaced by an aziridine ring, the analogous intra-
ing reactions of aziridines, widely investigated reactions, for
molecular aziridine ring opening reactions would give rise to
example, have been used to generate a large number of
amino substituted natural product-like lactam derivatives.
functionalized organic molecules that are not easily accessible
by other means. Noticeably, however, the regioselectivity and
We initially examined the cross coupling reaction between
trans-1-methyl-3-phenylaziridine-2-carboxamide
1a with
the efficiency of the ring opening reactions of aziridines are
heavily dependent upon the nature of the substituents on the
three-membered heterocyclic ring, the nucleophiles, and the
reaction conditions employed.1–4 To the best of our know-
ledge, all nucleophilic ring opening reactions of aziridines
reported to date occur on the C-2 and C-3 positions of the
aziridine ring with the cleavage of the carbon–nitrogen
bond1–4 (Scheme 1). Only under pyrolysis conditions such as
at 280 1C does the carbon–carbon bond cleavage proceed to
form azomethine ylide 1,3-dipolar intermediates that can be
trapped by alkenes, yielding five-membered pyrrolidine pro-
ducts.5–9 We report herein an unprecedented example of
carbon–carbon bond cleavage in the nucleophilic ring opening
reaction of aziridine under mild conditions. Mediated by a
base, intramolecular nucleophilic ring opening reaction of
N-styryl-3-aryl-1-methylaziridine-2-carboxamides led to the
formation of the ring expansion imidazolidin-4-one products.
We6,7 have recently reported the cross coupling reaction of
3-aryloxirane-2-carboxamides with 1-bromovinyl benzene.
The resulting oxirane-containing enamides were found to
undergo divergent intramolecular nucleophilic oxirane ring
opening reactions under different conditions to produce
z-clausenamide,10 homoclausenamide and neoclausenamide,11
(Z)-(2-bromovinyl)benzene 2a. Catalyzed by CuI/N,N-dimethyl-
glycine (DMGC) in the presence of Cs2CO3, the reaction
conditions successfully used for the cross coupling reaction
between 3-aryloxirane-2-carboxamides with (Z)-(2-bromovinyl)
benzene 2a,10,11 we found the reaction of 1a with 2a proceeded
smoothly in refluxing 1,4-dioxane. After 3.5 h, the expected
N-(Z)-styryl-1-methyl-3-phenylaziridine-2-carboxamide 3 was
obtained in 60% yield. Surprisingly, in addition to enamide
Beijing National Laboratory for Molecular Sciences, Laboratory of
Chemical Biology, Institute of Chemistry, Chinese Academy of
Sciences, Beijing, 100190, China. E-mail: mxwang@iccas.ac.cn;
Fax: +86 10-6256-4723; Tel: +86 10-6256-5610
w Electronic supplementary information (ESI) available: Synthesis and
characterization of compounds 3, 4, 6, 8, 9. See DOI: 10.1039/b816007d
Scheme 2 Diverse intramolecular oxirane ring opening reactions of
oxirane-containing enamides for the synthesis of Clausena alkaloids.
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product 3, a five-membered heterocyclic product 1-methyl-2-
phenyl-3-(Z)-styrylimidazolidin-4-one 4a was also isolated in
15% yield. The ring expansion product 4a was obtained as the
sole isolable product in 65% when the reaction mixture was
refluxed for an elongated period of time (12 h), implying the
conversion of aziridine-bearing enamide 3 into the five-
membered heterocycle 4a under the reaction conditions. To shed
light on the formation of imidazolidin-4-one 4a, the reaction
of the isolated aziridine intermediate 3 was tested. N-(Z)-
styryl-1-methyl-3-phenylaziridine-2-carboxamide 3 was found
Table 1 Ring transformation of aziridine to imidazolin-4-one
Entry
1
Ar1
2
Ar2
4 (%)a
to undergo efficiently
a Cs2CO3-mediated intramolecular
1
2
3
4
5
1a
1a
1a
1b
1c
C6H5
C6H5
C6H5
4-F-C6H4
4-Cl-C6H4
2a
2b
2c
2a
2a
C6H5
4a (65)
4b (85)
4c (74)
4d (71)
4e (80)
nucleophilic aziridine ring opening reaction with the cleavage
of the carbon–carbon bond to furnish the ring expanded product
4a in 61% yield (Scheme 3).
4-Cl-C6H4
4-Me-C6H4
C6H5
C6H5
The tandem CuI/DMGC-catalyzed cross coupling reaction
and the base-mediated intramolecular nucleophilic aziridine ring
opening reaction appeared general. Summarized in Table 1 are
the results of the reaction between trans-3-aryl-1-methyl-
aziridine-2-carboxamides 1 and (Z)-1-aryl-2-bromoethenes 2.
In all cases, imidazolidin-4-one products 4 were obtained in
good yield after 12 h regardless of the substituent on the benzene
rings of both reactants. When (E)-(2-bromovinyl)benzene 5
was used instead of its Z-isomer 2a, the same tandem
CuI/DMGC-catalyzed cross coupling reaction and the base-
mediated intramolecular nucleophilic aziridine ring opening
reaction proceeded equally well. As exemplified in Scheme 4,
2-aryl-1-methyl-3-(E)-styrylimidazolidin-4-ones 6a–c, were
produced in 71–84% yield from the corresponding substrates.
We finally studied the reaction of cis-1-methyl-3-phenyl-
aziridine-2-carboxamide 7 with (Z)-(2-bromovinyl)benzene 2a
and (E)-(2-bromovinyl)benzene 5 (Scheme 5). Under the iden-
tical CuI/DMGC catalytic conditions for the reaction of 1,
cis-1-methyl-3-phenylaziridine-2-carboxamide 7 was converted
efficiently into enamide products 8 and 9 in 78% and 70%,
respectively. No further ring transformation was evidenced
under the reaction conditions, however. Treatment of 8 with
Cs2CO3 in DMSO solution at 70 1C led to the isomerization of
carbon–carbon double bond, affording enamide product 9 in
77% yield. Among the bases such as NaOH, K2CO3, Cs2CO3
and NaH examined, only the combination of NaH in
DMF at 70 1C effected the efficient intramolecular nucleophilic
a
Isolated yield.
Scheme
4 Reaction of trans-3-aryl-1-methylaziridine-2-carbox-
amides 1 with (E)-(2-bromovinyl)benzene 5.
Scheme 5 Reaction of cis-1-methyl-3-phenylaziridine-2-carboxamide
7 with 2 and 5.
aziridine ring opening reaction of 9 to give imidazolidin-4-one
6a (Scheme 5).
The unusual nucleophilic ring opening reaction of aziridine
with the cleavage of carbon–carbon bond is intriguing.
To account for the ring transformation of N-styryl-3-aryl-1-
methylaziridine-2-carboxamides, a plausible reaction mechanism
Scheme 3 Cross coupling reaction of 1a with 2a and the conversion
of 3 into 4a.
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to form azomethine ylide E5–9,14 followed by ring closure
reaction (Scheme 6). Both reaction pathways would also
give oxazoline products. However, no oxazoline products were
observed experimentally in our study.
In conclusion, we have shown the first example of carbon–
carbon bond cleavage of the aziridine ring in a nucleophilic
aziridine ring opening reaction. N-Styryl-3-aryl-1-methylazaridine-
2-carboxamides, which are readily obtained from the CuI/
DMGC-catalyzed cross coupling reaction of 3-aryl-1-methyl-
aziridine-2-carboxamides with 1-aryl-2-bromoethenes, are able to
undergo efficiently a base-mediated intramolecular aziridine ring
opening reaction via carbon–carbon bond cleavage to afford the
ring expanded imidazolidin-4-one products. The carbon–carbon
bond cleavage of the aziridine ring should open a new avenue for
the exploration of new applications of aziridine compounds in
organic synthesis.
We thank the National Natural Science Foundation of
China, Ministry of Science and Technology, and Chinese
Academy of Sciences for financial support.
Notes and references
1 For a recent monograph about aziridine chemistry, see: Aziridines
and Epoxides in Organic Synthesis, ed. A. K. Yudin, Wiley-VCH,
2006.
Scheme 6 Plausible pathway for the tandem cross coupling reaction
and ring transformation.
2 For recent reviews on aziridine chemistry, see: (a) H. M. Osborn
and J. Sweeney, Tetrahedron: Asymmetry, 1997, 8, 1693;
(b) X. E. Xu, Tetrahedron, 2004, 60, 2701; (c) W. McCoull and
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3 For recent examples, see: (a) C. S. Park, H. G. Choi, H. Lee,
W. K. Lee and H.-J. Ha, Tetrahedron: Asymmetry, 2000, 11, 3283;
(b) T. B. Sim, S. H. Kang, K. S. Lee and W. K. Lee, J. Org. Chem.,
2003, 68, 104; (c) J. M. Yun, T. B. Sim, H. S. Hahm and W. K. Lee,
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S. W. Ko, H. Yun, H. J. Yoon, M. S. Kim and W. K. Lee,
Tetrahedron Lett., 2005, 46, 4407; (e) B. K. Lee, M. S. Kim,
H. S. Hahm, D. S. Kim, W. K. Lee and H.-J. Ha, Tetrahedron,
was proposed. As depicted in Scheme 6, CuI/DMGC-catalyzed
cross coupling reaction of amides and 1-aryl-2-bromoethenes
results in the formation of aziridine-containing enamides. Under
the basic conditions, deprotonation of enamides occurs to form
amide anion intermediate A, which can be stabilized by the styryl
group. Intramolecular nucleophilic attack of the amide nitrogen
at the C-3 of the aziridine ring leads to carbon–carbon bond
cleavage to form intermediate B. Subsequent O-protonation and
tautomerization furnish the imidazolidin-4-one products. It is
worth addressing the regiospecific nucleophilic attack of amide
nitrogen on the C-3 of aziridine ring, which might be regarded as
a disfavored process according to Baldwin’s rules,12 is probably
due to its close proximity to the C-3 position. More likely, it is
the electrophilic nature of the benzylic C-3 that determines the
regiospecific nucleophilic aziridine ring opening reaction. The
cleavage of the carbon–carbon bond rather than carbon–
nitrogen bond of the aziridine ring is most probably attributed
to the release of the ring strain by forming a more stable
five-membered imidazoline intermediate B. The stabilization
energy gained from the formation of conjugation in B may also
contribute to the ring transformation pathway. It should also be
noted that, due to the weaker electrophilicity of the aziridine ring
in comparison to the oxirane ring, and because of the weaker
reactivity of enamide than enamine, neither intramolecular
aryl–aziridine cyclization nor enamine–aziridine cyclization
took place. A similar intramolecular aryl–epoxide cyclization10
and intramolecular enamine–epoxide cyclization11 in the
analogous oxirane-containing enamide derivatives were reported
(Scheme 2). Alternatively, imidazolin-4-one products 4 and 6
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14 The authors are grateful to a referee for have their attention to
alternative mechanisms describing the observed conversion.
might also be formed from electrocyclization of C,13,14
a
tautomer of 3, and from spontaneous ring opening of aziridine
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This journal is The Royal Society of Chemistry 2009
424 | Chem. Commun., 2009, 422–424