Copper-catalyzed cascade approach to 1,3-diazabicyclo[3.1.0]hex-3-enes from aziridines and ethyl diazoacetate

Article abstract of DOI:10.1016/j.tetlet.2010.07.026

An efficient and general synthesis of 1,3-diazabicyclo[3.1.0]hex-3-enes via the copper-catalyzed cascade reaction of aziridines with ethyl diazoacetate is described.

Full text of DOI:10.1016/j.tetlet.2010.07.026

Tetrahedron Letters 51 (2010) 4763–4766
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper-catalyzed cascade approach to 1,3-diazabicyclo[3.1.0]hex-3-enes
from aziridines and ethyl diazoacetate
*
*
Yuanxun Zhu, Shaoyin Wang, Shan Wen, Ping Lu , Yanguang Wang
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and general synthesis of 1,3-diazabicyclo[3.1.0]hex-3-enes via the copper-catalyzed cascade
reaction of aziridines with ethyl diazoacetate is described.
Received 26 May 2010
Revised 1 July 2010
Accepted 6 July 2010
Available online 8 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Henry N. C. Wong on
the occasion of his 60th birthday
Functionalized aziridines, with relatively reactive three-mem-
bered heterocycles, are potential precursors of many new biologi-
cally active compounds. They exist as substructures in a number of
natural products and can be employed as efficient intermediates in
the synthesis of other heterocyclic entities.1 Zhu and Wu recently
elegantly used aziridine as a lynchpin to construct antitumor anti-
biotic renieramycins M and G.2 Promoted by active manganese,
aromatic aziridine 2-carboxamides could be regioselectively trans-
ferred into 2-aminoamides.3 With the ring opening of aziridines, a
cascade reaction could thus be rationally designed and practically
approached.4 Aziridine-fused bicyclo compounds were also devel-
oped for the synthesis of pharmaceutical and natural products.
However, most of these bicyclo compounds published in literature
hitherto were 2,3-fused aziridines.5 1,2-Fused aziridines were sel-
dom reported due to their unstability,6 especially those aziridines
fused to another heterocyclic ring, such as 1,3-diazabicy-
clo[3,1,0]hex-3-enes, which were ever synthesized by reaction of
trans-2-aryl-3-aroylaziridines with aldehydes/ketones in alcoholic
solutions saturated with ammonia in the presence of a small
amount of ammonium bromide and found to be unstable to base
and sensitive to sunlight.7,8 As an improved approach leading to
research using aziridine as a lynchpin in cascade reactions,6,11 we
herein report a copper-catalyzed reaction between 2-aryl-3-aroy-
laziridines and EDA, which efficiently furnished 1,3-diazabicyclo-
[3,1,0]hex-3-ene.
H
N
N
2,3-fused aziridines 1,2-fused aziridines
N
N
1,3-diazabicyclo[3.1.0]hex-3-ene
Initially, we examined the reaction between aziridine 1a and
EDA (2) using 10 mol % CuI as catalyst. As shown in Scheme 1,
the reaction gave 1,3-diazabicyclo[3,1,0]hex-3-ene 3a along with
chalcone when an excess amount of EDA was used. We then opti-
1,3-diazabicyclo[3,1,0]hex-3-enes, Risitano et al. developed
a
three-component reaction of phenacyl chloride, aldehyde and
ammonium acetate under microwave irradiation.9
As more aziridines and fused aziridines were identified with
multipurpose applications, the development of a new methodology
to construct aziridines and their derivatives has attracted more
attention. As a remarkable contribution, fluoronium (F+) was used
as an organocatalyst for triggering the reaction between N-substi-
tuted imines and ethyl diazoacetate (EDA) to successfully afford
aziridines.10 Illuminated by this work and as a part of our ongoing
H
N
EtO2C
N
N
Ph
Ph
CuI
DCE
3a
1a
+
Ph
Ph
O
Ph
+
rt, N2
24 h
CO2Et
N2
Ph
H
O
2
* Corresponding authors. Tel./fax: +86 571 87951512 (Y.W.).
E-mail addresses: pinglu@zju.edu.cn (P. Lu), orgwyg@zju.edu.cn (Y. Wang).
Scheme 1. Reaction between aziridine 1a and EDA (2).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.026

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Y. Zhu et al. / Tetrahedron Letters 51 (2010) 4763–4766
Table 1
Effect of reaction conditions on the copper-catalyzed reaction of 1a and 2a
Entry
Catalyst (equiv)
1a/2
Reaction temperature (°C)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
CuCl (0.1)
CuBr (0.1)
CuCN (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.1)
CuI (0.05)
CuI (0.2)
CuI (0.1)
CuI (0.1)
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:1.5
25
25
25
25
25
25
25
0
50
25
25
25
25
DCE
DCE
DCE
DCE
46
49
44
58
53
0
THF
CH3CN
Toluene
DCE
DCE
DCE
DCE
DCE
DCE
42
0
50
48
55
42
56
a
Reaction conditions: 1a (0.5 mmol), 2 (0.5, 0.75 or 1.0 mmol), solvent (5 mL), 24 h.
Isolated yield refers to aziridine 1a.
b
Table 2
Scope for the copper-catalyzed reaction of aziridines with EDAa
CO2Et
N
H
N
CuI
CO2Et
N2
N
DCE
R1
R2
H
+
R1
rt, N2
24 h
R2
O
1
2
3
Entry
R1/R2
C6H5/C6H5 (1a)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
58
54
56
78
76
70
72
61
65
55
41
NR
4-ClC6H4/C6H5 (1b)
4-BrC6H4/C6H5 (1c)
4-PhC6H4/C6H5 (1d)
3-MeOC6H4/C6H5 (1e)
4-MeOC6H4/C6H5 (1f)
C6H5/4-MeOC6H4 (1g)
3-MeOC6H4/4-MeOC6H4 (1h)
4-ClC6H4/4-MeOC6H4 (1i)
1-Naphthyl/C6H5 (1j)
2-Furyl/C6H5 (1k)
10
11
12
3j
3k
C6H5/t-Bu (1l)
a
Reaction conditions: 1 (0.5 mmol), 2 (1.0 mmol), CuI (0.05 mmol), DCE (5 mL),
24 h.
b
Isolated yield refers to aziridine 1.
Figure 1. X-ray structure of compound 3a.
mized the reaction conditions and the results are summarized in
Table 1. CuI was observed to be the best copper (I) source in com-
parison with others, such as CuCl, CuBr, and CuCN (Table 1, entries
1–4), whereas dichloroethane (DCE) was found to be a suitable sol-
vent (Table 1, entries 4–7). Besides these two key factors, the yield
also depended on the reaction temperature (Table 1, entries 4, 8
and 9) and the amount of catalyst (Table 1, entries 4, 10 and 11)
as well. Decreasing the amount of EDA led to relatively lower
yields (Table 1, entries 12 and 13). Thus, we selected CuI as the cat-
alyst, dichloroethane as the solvent and ran the reaction mixture at
25 °C for 24 h. Under this condition, the highest yield of 3a (58%
yield) was obtained (Table 1, entry 4). It must be indicated that
the vice-product chalcone was also obtained in almost similar yield
with the desired product 3a. For entry 4 in Table 1, chalcone was
isolated in 51% yield (58% yield for 3a). This vice-product could
be recycled for preparation of the starting material 1a.12
With the optimized reaction conditions in hand, we next fo-
cused our attention on the diversity of aziridines1.12 As shown in
Table 2, both phenyl-substituted aziridines 1a–i (Table 2, entries
1–9) and 1-naphthyl-substituted aziridine 1j (Table 2, entry 10)
gave the desired 1,3-diazabicyclo[3,1,0]hex-3-enes 3a–j in moder-
ate to good yields (54–78%), while furyl-substituted aziridine 1k
afforded 3k in a relatively lower yield (41%) (Table 2, entry 11).13
For the electronic effect of R1 and R2 groups in aziridines 1, it
Table 3
Formation of substituted pyrimidinesa
CO2Et
N
O
CO2Et
N2
H
N
CuI
N
+
H
R2
80ºC, DCE
R1
R2
R1
2
1
4
Entry
R1/R2
Product
Yieldb (%)
1
2
3
C6H5/C6H5 (1a)
C6H5/4-MeOC6H4 (1g)
C6H5/4-BrC6H5 (1m)
4a
4b
4c
53
68
42
a
Reaction conditions: 1 (0.5 mmol), 2 (2.0 mmol), CuI (0.05 mmol), DCE (5 mL),
3 days.
b
Isolated yield refers to aziridine 1.
was found that the electron-rich substitution on the phenyl ring
of R1 (Table 2, entries 4–6) and R2 (Table 2, entries 7 and 9) gave
better yields than the electron-deficient substitution (Table 2,
entries 1–3). 2-Phenyl-3-pivaloyl aziridine (1l) did not work for

Y. Zhu et al. / Tetrahedron Letters 51 (2010) 4763–4766
4765
O
H
CO2Et
CuI
Ph
H
Ph
N2
N
H
H
1a
A
H
EtO2C
H
CO2Et
EtO2C
Ph
H
N
N2
N
Ph
Ph
CuI
2
Ph
O
B
O
H
N
EtO2C
N
EtO2C
Ph
NH2
Ph
NH
HN CHCO2Et
Ph
C
O
Ph
H
N
OH
E
O
D
Ph
Ph
Ph
Ph
−H2O
1a
O
CO2Et
H
CO2Et
N
CO2Et
N
[O]
N
N
N
N
CuI
Ph
Ph
Ph
Ph
Ph
Ph
F
3a
4a
Scheme 2. Possible mechanism for the cascade reaction.
this reaction (Table 2, entry 12). Structures of 1,3-diazabicy-
for the Central Universities (2009QNA3011) for financial support
of this research.
1
clo[3.1.0]-hex-3-enes 3a–k were confirmed by H and 13C NMR
spectroscopy, HRMS and comparative analysis of the X-ray struc-
ture of 3a (Fig. 1).14
Supplementary data
1,3-Diazabicyclo[3.1.0]hex-3-enes 3 were relatively unstable
when they were exposed to UV light.8 It might undergo rearrange-
ment and subsequent oxidation in the presence of sodium methox-
ide and result in the formation of the more stable pyrimidine.7 By
raising the reaction temperature to 80 °C and prolonging the reac-
tion time to 72 h, pyrimidine skeletons were also formed in our
cases(Table 3).
A proposed mechanism for this cascade reaction is shown in
Scheme 2. Firstly, copper-stabilized carbene complex A is gener-
ated in situ by the reaction of EDA and CuI. Insertion of A to N–H
bond of 1a leads to the formation of intermediate B.15 The ring
opening of active aziridine B, assisted by the electron-withdrawing
nature of carbonyl, results in the formation of stable chalcone and
imine C.16 Sequentially nucleophilic addition of 1a to imine C gives
multi-functionalized intermediate D. After intramolecular addition
of amino group to the carbonyl of D, followed by dehydration, the
final 1,3-diazabicyclo[3.1.0]hex-3-ene skeleton 3a was obtained.
Further ring-expansion of 3a, due to the strain of fused rings as
well as the acidity of the proton adjacent to the ester group, gener-
ates the dihydropyrimidine F, which is aromatized to pyrimidine
4a if a harsh reaction condition is employed.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.026.
References and notes
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13. General procedure for the synthesis of 1,3-diazabicyclo[3.1.0]hex-3-enes 3: To
a solution of aziridine 1 (0.5 mmol), and the CuI (0.05 mmol) in DCE (5 mL),
was added ethyl diazoacetate (2, 1 mmol). The reaction mixture was stirred
under N2 atmosphere at 25 °C for 24 h. The mixture was diluted with ethyl
acetate (10 mL) and then washed with saturated NaCl solution (10 mL) and
dried over anhydrous Na2SO4. The solvent was evaporated and the crude
product was purified by silica gel column chromatography with hexane–EtOAc.
Characterization data for the selected products: 3a: White solid, mp 134–
In conclusion, a novel synthesis of 1,3-diazabicyclo[3.1.0]hex-3-
enes was developed via a copper (I)-catalyzed reaction between
aziridines and ethyl diazoacetate. A possible mechanism for this
cascade reaction was proposed. This example proved aziridines
as useful starting materials in the construction of more compli-
cated heterocyclic compounds.
Acknowledgment
We thank the National Natural Science Foundation of China
(Nos. 20872128; J0830413) and the Fundamental Research Funds

4766
Y. Zhu et al. / Tetrahedron Letters 51 (2010) 4763–4766
136 °C; 1H NMR (400 MHz, CDCl3): d 7.97–7.95 (2H, m), 7.56–7.52 (1H, m),
93.5, 61.9, 56.7, 43.8, 14.2 ppm; IR (KBr): 2983, 1747, 1605, 1494, 1193, 1060,
797, 698 cmÀ1 MS (ESI): m/z 363 ([M+Na]+); HRMS (ESI) m/z calcd for
19H17ClN2O2 + Na+: 363.0871; found: 363.0877.
7.50–7.45 (2H, m), 7.36–7.30 (5H, m), 5.70 (1H, d, J = 2.8 Hz), 4.38–4.27 (2H,
m), 3.79 (1H, t, J = 2.4 Hz), 2.56 (1H, d, J = 2.4 Hz), 1.37(3H, t, J = 7.2 Hz) ppm;
13C NMR (100 MHz, CDCl3): d: 173.8, 168.7, 137.1, 131.9, 131.2,128.8, 128.7,
128.5, 127.9, 126.5, 94.9, 61.7, 56. 6, 47.9, 14.1 ppm; IR (KBr) 2985, 1747, 1603,
1454, 1194, 1054, 753, 692 cmÀ1; MS (ESI): m/z 329 ([M+Na]+); HRMS (ESI) m/z
calcd for C19H18N2O2 + Na+: 329.1260; found: 329.1249. 3b: White solid, mp
138–140 °C; 1H NMR (400 MHz, CDCl3): d 7.94–7.92 (2H, m), 7.55–7.52 (1H,
m), 7.48–7.44 (2H, m), 7.34–7.26 (4H, m), 6.00 (1H, s), 4.36–4.23 (2H, m), 3.68
(1H, t, J = 2.0 Hz), 3.04 (1H, s), 1.32 (3H, t, J = 7.2 Hz) ppm; 13C NMR (100 MHz,
CDCl3): d: 173.3, 168.1, 135.9, 133.6, 132.0, 131.0, 128.8, 128.7, 128.6, 127.9,
;
C
14. CCDC 777087 contains the supplementary crystallographic data for
compounds 3a. These data can be obtained free of charge via www.ccdc.
cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by
contacting The Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
15. (a) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091; (b) Zhang, Z.; Wang, J.
Tetrahedron 2008, 64, 6577.
16. Webster, O. W. J. Am. Chem. Soc. 1965, 87, 1821.