The first example of 1,3-dipolar cycloaddition reactions of nitrones to vinylidenecyclopropanes

Article abstract of DOI:10.1016/j.tetlet.2011.08.116

The first example of 1,3-dipolar cycloaddition reactions of nitrones to vinylidenecyclopropanes is described. The nitrones react with the C10-C20 double bond of vinylidenecyclopropanes to give the corresponding 4-cyclopropylidene- isoxazolidines in modera

Full text of DOI:10.1016/j.tetlet.2011.08.116

Tetrahedron Letters 52 (2011) 5777–5781
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Tetrahedron Letters
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The first example of 1,3-dipolar cycloaddition reactions of nitrones
to vinylidenecyclopropanes
Anna G. Larina a, Alexander V. Stepakov a, , Vitaly M. Boitsov b, Alexander P. Molchanov a,
⇑
Vladislav V. Gurzhiy a, Galina L. Starova a, Anna N. Lykholay c
a Chemistry Department, Saint-Petersburg State University, Universitetsky prosp. 26, St.-Petersburg 198504, Russian Federation
b Saint-Petersburg Academic University, Nanotechnology Research and Education Centre RAS, Khlopin str. 8/3, St.-Petersburg, 195220, Russian Federation
c Biological Department, Saint-Petersburg State University, Universitetskaya nab. 7-9, St.-Petersburg 199034, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
The first example of 1,3-dipolar cycloaddition reactions of nitrones to vinylidenecyclopropanes is
described. The nitrones react with the C10–C20 double bond of vinylidenecyclopropanes to give the cor-
responding 4-cyclopropylidene-isoxazolidines in moderate yields.
Received 15 June 2011
Revised 6 August 2011
Accepted 19 August 2011
Available online 26 August 2011
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Keywords:
Vinylidenecyclopropanes
Nitrones
4-Cyclopropylidene-isoxazolidines
1,3-Dipolar cycloaddition
The 1,3-dipolar cycloaddition reaction has long been recognized
as an important strategy for the synthesis of heterocyclic rings.1
Nitrones are remarkably versatile building blocks in organic syn-
thesis, and are known to take part in 1,3-dipolar cycloaddition
reactions with a wide range of dipolarophiles. Cycloadditions of
nitrones to alkenes and allenes are well established reactions by
which isoxazolidines are formed, often with a high degree of ste-
reochemical control.2 These cycloadducts attracted considerable
attention due to the potential biological activities of isoxazoli-
dines.1a,b Isoxazolidines have also been used as precursors to b-
amino alcohols through reductive cleavage of the N–O bond, which
are potential precursors for the synthesis of such natural products
as alkaloids and b-lactam antibiotics.2a
propanes has been explored extensively. Novel intramolecular
rearrangements and cycloaddition reactions with compounds
Table 1
Reactions of vinylidenecyclopropanes 1 and 2 with nitrones 3a,b
R1
R2
R1
R4
Me
R2
R3
Me
O
O
Ph
Me
Me
toluene
110 oC, 24 h
N
R3
C
+
R4
Ar
N
Ar
Ph
1, 2
3a,b
4a-d
The groups of Brandi, de Meijere, and Molchanov have studied
the 1,3-dipolar cycloaddition of methylenecyclopropanes and
cyclopropenes with nitrones.3 Recently Shi reported the first
example of Yb(OTf)3-catalyzed formal [3+3] cycloaddition of viny-
lidenecyclopropane-dicarboxylates to nitrones with the formation
of 2-benzylidenepiperidin-3-ones in good yields.4 The 1,3-dipolar
cycloaddition reactions of vinylidenecyclopropanes with aromatic
diazomethanes generated in situ from the corresponding aromatic
aldehydes and tosylhydrazines, and also with a 1,3-dipole interme-
diate derived from phthalazine-1,4-dione were described in the
papers of Shi and co-workers.5 The chemistry of vinylidenecyclo-
Entry
R1
R2
R3
R4
Ar
Yield of 4a (%)
1
2
3
4
Me
Me
H
Me
Me
–(CH2)4–
–(CH2)4–
Me
Me
Me (1)
Me (1)
H (2)
Ph (3a)
4-ClC6H4 (3b)
Ph (3a)
29 (4a)b
34 (4b)c
23 (4c)d,e
28 (4d)f,g
H
H (2)
4-ClC6H4 (3b)
a
b
c
Isolated yield.
17% of starting material 1 was recovered.
14% of starting material 1 was recovered.
Chromatographically inseparable mixture of two diastereomers (7.3:1 by 1H
d
NMR data).
e
15% of starting material 2 was recovered.
Chromatographically inseparable mixture of two diastereomers (7.0:1 by 1H
f
⇑
Corresponding author. Fax: +7 812 4286939.
E-mail address: alstepakov@yandex.ru (A.V. Stepakov).
NMR data).
g
12% of starting material 2 was recovered.
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All
rights reserved.

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A. G. Larina et al. / Tetrahedron Letters 52 (2011) 5777–5781
Figure 2. ORTEP representation of 6c.
diffraction analysis (Fig. 1).10 A similar reaction occurred on treat-
ment of vinylidenecyclopropane 2 with nitrones 3a,b giving isox-
azolidines 4c,d as inseparable mixtures of two diastereomers
(Table 1, entries 3 and 4, the diastereomeric ratio were determined
from 1H NMR spectra by integration of the C3–H signal). Increasing
the nitrone concentration in the reaction mixture and the reaction
time (36–48 h) did not lead to a significant increase in the yield of
the isoxazolidines. At the same time increased amounts of uniden-
tified products were observed in these cases, which made product
separation difficult. Regioisomeric products and products of nit-
rone addition to the C1–C10 double bond were not observed in
the reaction mixtures.
The 1,3-dipolar cycloaddition of nitrones 3c–e with 1-phenyl-2-
(2-methylprop-1-enylidene)cyclopropane (5) was then attempted
(toluene, 110 °C, 6 h). The reaction gave inseparable mixtures of four
diastereomers 60a–c. Separation of the crude mixtures on silica gel
and subsequent crystallization from methanol gave pure samples
of isoxazolidines 6a–c as single diastereomers in 11–16% yields
(Table 2). The other diastereomers were not isolated in pure form
(the 1H NMR spectra mixture of isomers 60a–c were too complicated
and it was impossible to identify the single diastereomers). The
compositions and structures of products 6a–c were established by
elemental and spectral analyses.11 The structure of compound 6c
was confirmed additionally by X-ray diffraction analysis (Fig. 2).12
Figure 1. ORTEP representation of 4a.
containing carbon–carbon or carbon–heteroatom multiple bonds,
such as imines, aldehydes, nitriles, and ,b-unsaturated ketones
a
have been studied.6,7 However, 1,3-dipolar cycloaddition reactions
of vinylidenecyclopropanes with nitrones have not been studied as
yet. In continuation of our earlier work,8 we have studied the reac-
tion of non-activated vinylidenecyclopropanes with nitrones. In
the present work we show for the first time that nitrones react
with the C10–C20 double bond of vinylidenecyclopropanes to give
the corresponding 4-cyclopropylidene-isoxazolidines in moderate
yields.
As a model study, we investigated the cycloaddition of C,N-
diarylnitrones
with
1,1,2,2-tetramethyl-3-(2-methylprop-1
-enylidene)cyclopropane (1). Heating vinylidenecyclopropane 1
and nitrones 3a,b in toluene (110 °C, 24 h) led to the formation
of 4-cyclopropylidene-isoxazolidines 4a,b in 29% and 34% yields
(Table 1, entries 1 and 2). Running the reaction in benzene at
80 °C for 36 h gave the corresponding isoxazolidines in yields less
than 10%. The reaction products were isolated by preparative thin
layer chromatography on silica. The compositions and structures of
the products were established by elemental and spectral analyses.9
The structure of compound 4a was confirmed additionally by X-ray
Table 2
Reactions of vinylidenecyclopropane 5 with nitrones 3c–e
Me
Me
Ph
Me
Me
Ph
O
Ar1
Me
Me
Recrystallization
from EtOH
Ph
toluene
N
O
O
C
+
110 oC, 6 h
N
N
Ar2
Ar2
Ar2
Ar1
Ar1
5
3c-e
6'a-c
6a-c
Chromatographically inseparable
mixture of four isomers
a
Entry
Ar1
Ar2
Yield of 60 (%)
Yield of 6a (%)
1
2
3
Ph
Ph
3-BrC6H4
4-FC6H4 (3c)
4-MeC6H4 (3d)
4-ClC6H4 (3e)
49 (60a)b,c
41 (60b)d,e
57 (60c)f,g
14 (6a)
11 (6b)
16 (6c)
a
b
c
d
e
f
Isolated yield.
Chromatographically inseparable mixture of four isomers (0.6:0.5:0.2:1.0 by 1H NMR data).
12% of starting material 5 was recovered.
Chromatographically inseparable mixture of four isomers (0.6:0.4:0.2:1.0 by 1H NMR data).
13% of starting material 5 was recovered.
Chromatographically inseparable mixture of four isomers (0.6:0.5:0.1:1.0 by 1H NMR data).
9% of starting material 5 was recovered.
g

A. G. Larina et al. / Tetrahedron Letters 52 (2011) 5777–5781
5779
Table 3
Reactions of vinylidenecyclopropanes 7,8, and 9a with nitrones 3a,b
R1
R2
R1
Ph
R2
R3
Ph
O
O
Ph
Ph
Ph
toluene
N
R3
C
+
110 o
C
R4
Ar
3a,b
N
R4
Ar
Ph
10a-d
7, 8, 9a
Entry R1
R2
R3
R4
Ar
Time
(h)
Yield of 10a (%)
1
2
Me Me Me Me
Ph (3a)
24
24
41 (10a)b
36 (10b)c
(7)
Me Me Me Me
(7)
4-ClC6H4
(3b)
Ph (3a)
d
3
4
5
Ph
H
H
Ph
H
H (8)
48
24
24
0
–(CH2)4– H (9a) Ph (3a)
–(CH2)4– H (9a) 4-ClC6H4
(3b)
48 (10c)e,f
43 (10d)g,h
a
b
c
Isolated yield.
0% of starting material 7 was recovered.
9% of starting material 7 was recovered.
Figure 3. ORTEP representation of 12a.
d
73% of starting material 8 was recovered. Product 10 was not present in the
reaction mixture.
e
Chromatographically inseparable mixture of two diastereomers (2.7:1 by 1H
data.13 The formation of a cycloaddition product was not observed
in the reaction of nitrone 3a with vinylidenecyclopropane 8 (Table
3, entry 3). This is possibly the result of steric hindrance in the tran-
sition state. Heating nitrones 3a,b and vinylidenecyclopropane 9a in
boiling toluene led to the formation of isoxazolidines 10c,d as mix-
tures of two diastereomers which could not be separated by silica gel
chromatography (Table 3, entries 4 and 5). Compound 10d, in a dia-
stereomeric ratio of 12:1, was isolated by recrystallization from
MeOH.
We also examined the reaction of amidonitrones 11a,b with
vinylidenecyclopropanes 8a,b. In this case chromatographically
inseparable mixtures of two diastereomers 120a–c were produced.
The products of the reactions were isolated by preparative thin
layer chromatography on silica gel. Crystallization of the mixture
of 120a from ethanol resulted in pure 12a in 21% yield (Table 4,
NMR data).
f
12% of starting material 9a was recovered.
g
Chromatographically inseparable mixture of two diastereomers (3.2:1 by 1H
NMR data).
h
14% of starting material 9a was recovered.
Next, the reactions of vinylidenecyclopropanes 7, 8, and 9a, con-
taining aryl groups on the double bond, with nitrones were investi-
gated. The reaction of vinylidenecyclopropane 7 with nitrones 3a,b
at 110 °C for 24 h gave 5,5-diphenyl-4-(tetramethylcyclopropylid-
ene)isoxazolidines 10a,b in 41% and 36% isolated yields (Table 3,
entries 1 and 2). The products of the reactions were isolated by pre-
parative thin layer chromatography on silica gel. The structures of
isoxazolidines 10a,b were assigned on the basis of their spectral
Table 4
Reactions of vinylidenecyclopropanes 8a,b with nitrones 11a,b
Ar1
Ar1
O
Ar2
Ar1
Ar1
Ar1
Ar1
N
Recrystallization
from EtOH
toluene
C
+
O
O
O
110 oC, 8 h
N
N
O
O
NHPh
11a,b
Ar2
Ar2
8a,b
NHPh
NHPh
12'a-c
12a
(major diastereomer)
Chromatographically inseparable
mixture of two diastereomers
a
Entry
Ar1
Ph (8a)
4-MeC6H4 (8b)
4-MeC6H4 (8b)
Ar2
Yield of 120 (%)
Yield of 12a (%)
1
2
3
4-MeC6H4 (11a)
4-MeC6H4 (11a)
Ph (11b)
63 (120a)b,c
60 (120b)d,e
56 (120c)f,g
21 (12a)
—
—
a
b
c
d
e
f
Isolated yield.
Chromatographically inseparable mixture of two diastereomers (1.6:1 by 1H NMR data).
7% of starting material 8a was recovered.
Chromatographically inseparable mixture of two diastereomers (1.5:1 by 1H NMR data).
9% of starting material 8b was recovered.
Chromatographically inseparable mixture of two diastereomers (1.7:1 by 1H NMR data).
12% of starting material 8b was recovered.
g

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A. G. Larina et al. / Tetrahedron Letters 52 (2011) 5777–5781
Ar1
Ar1
O
Ar1
Ar1
C
Ar1
O
N
C
Ar2
O
Ar1
PhHN
A
B
N
PhHN
+
Ar2
H
O
O
major diastereomer
PhHN
O
Ar1
Ar1
O
Ar1
Ar1
N
Ar2
C
O
N
Ar2
O
PhHN
N
PhHN
Ar2
H
O
minor diastereomer
Scheme 1. Possible pathways for the reaction of nitrones 11a,b with vinylidenecyclopropanes 8a,b.
entry 1).14 It was not possible to isolate the major diastereomers
from the mixtures of 120b,c. The structure of 12a was established
unequivocally by X-ray diffraction analysis (Fig. 3).15 The stereo-
chemical outcome of the reaction between 8a,b and 11a,b is out-
lined in Scheme 1. Formation of the major diastereomer occurs
by approach of the nitrone dipole from the least hindered side of
the cyclopropane ring (Scheme 1, path A).
In conclusion, the first examples of 1,3-dipolar cycloaddition
reactions of nitrones to non-activated vinylidenecyclopropanes
have been described. The nitrones react with the C10–C20 double
bond of the vinylidenecyclopropanes to give the corresponding
4-cyclopropylidene-isoxazolidines in moderate yields. Regioiso-
meric products and products of nitrone addition to the C1–C10 dou-
ble bond were not observed. It is clear from the data that the
cycloaddition occurs with high regioselectivity. The high regiose-
lectivity observed in these 1,3-dipolar cycloadditions can be ex-
plained from two point of views: (1) steric interactions between
the substituents on the reactants, and (2) atomic orbital coeffi-
cients of the HOMO (nitrone)–LUMO (vinylidenecyclopropane) fa-
vour the expected interaction for this type of cycloaddition, which
is in accordance with previous literature on cycloadditions of nitro-
nes to allenes.2
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Supplementary data associated with this Letter can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.116.
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CCDC 825729. Copies of these data can be obtained on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (email: deposit@ccdc.cam.ac.uk).
13. 1H NMR data for 10a: dH (300 MHz, CDCl3) 0.18 (s, 3H, Me), 0.32 (s, 3H, Me),
0.82 (s, 3H, Me), 1.05 (s, 3H, Me), 5.14 (s, 1H, CH), 6.90 (t, 1H, Ph, J = 7.3 Hz),
7.03 (d, 2H, Ph, J = 8.0 Hz), 7.16 (t, 2H, Ph, J = 7.3 Hz), 7.22–7.34 (m, Ph, 10H),
7.38–7.43 (m, 3H, Ph), 7.6 (d, 2H, Ph, J = 7.3 Hz). 13C NMR data for 10a: dc
(75 MHz, CDCl3) 19.8 (Me), 19.9 (Me), 20.6 (Me), 20.7 (Me), 21.7 (Ccycloprop),
23.3 (Ccycloprop), 74.6 (C3), 89.9 (C5), 116.7 (2CArH), 122.3 (CArH), 127.9 (2CArH),
128.0 (2CArH), 128.2 (2CArH), 128.3 (2CArH), 128.7 (2CArH), 128.9 (4CArH), 129.1
(2CArH), 129.2 (2CArH), 138.8 (@Ccycloprop), 139.6 (CAr), 141.5 (@C4), 143.3 (CAr),
156.7 (CAr).
8. (a) Stepakov, A. V.; Larina, A. G.; Molchanov, A. P.; Stepakova, L. V.; Starova, G.
L.; Kostikov, R. R. Russ. J. Org. Chem. 2007, 43, 41; (b) Stepakov, A. V.; Larina, A.
G.; Radina, O. V.; Boitsov, V. M.; Molchanov, A. P. Chem. Heterocycl. Compd.
2008, 44, 430; (c) Stepakov, A. V.; Larina, A. G.; Radina, O. V.; Molchanov, A. P.;
Kostikov, R. R. Vestnik SPbGU 2009, 1(4), 110.
9. 1H NMR data for 4a: dH (300 MHz, CDCl3) 0.17 (s, 3H, Me), 0.99 (s, 3H, Me), 1.11
(s, 3H, Me), 1.15 (s, 3H, Me), 1.46 (s, 3H, Me), 1.65 (s, 3H, Me), 4.89 (s, 1H, CH),
6.91 (t, 1H, Ph, J = 7.3 Hz), 7.00 (d, 2H, Ph, J = 8.1 Hz), 7.17 (t, 2H, Ph, J = 7.3 Hz),
7.28 (t, 1H, Ph, J = 7.3 Hz), 7.36 (t, 2H, J = 8.1 Hz), 7.48 (d, 2H, Ph, J = 7.3). 13C
NMR data for 4a: dc (75 MHz, CDCl3) 19.5 (Me), 21.0 (Me), 21.4 (Ccycloprop), 21.7
(Ccycloprop), 21.8 (Me), 22.4 (Me), 26.8 (Me), 27.8 (Me), 74.1 (C3), 82.2 (C5),
116.8 (2CArH), 122.3 (CArH), 128.0 (CArH), 128.8 (2CArH), 129.0 (4CArH), 134.3
(@Ccycloprop), 141.5 (@C4), 141.9 (CAr), 151.3 (CAr).
14. 1H NMR data for 12a: dH (300 MHz, CDCl3) ꢀ0.14 to ꢀ0.12 (m, 1H, CH), 0.68–
0.77 (m, 1H, CH), 0.95–1.23 (m, 4H, 2CH2), 1.47–1.80 (m, 4H, 2CH2), 2.30 (s, 3H,
Me), 4.76 (s, 1H, CH), 6.94–7.22 (m, 15H, Ar), 7.36–7.39 (m, 3H, Ar), 7.62 (m,
1H, Ar), 7.67 (s, 1H, NH). 13C NMR data for 12a: dc (75 MHz, CDCl3) 13.3 (CH),
14.9 (CH), 20.8 (CH2), 21.0 (Me), 21.3 (CH2), 21.5 (CH2), 21.8 (CH2), 72.8 (C3),
89.7 (C5), 116.1 (2CArH), 119.7 (2CArH), 124.3 (CArH), 127.9 (CArH), 128.2
(2CArH), 128.3 (2CArH), 128.4 (CArH), 128.5 (2CArH), 128.8 (2CArH), 129.0
(2CArH), 129.9 (2CArH), 130.8 (CAr), 132.6 (CAr), 132.8 (@Ccycloprop), 137.7 (CAr),
141.4 (@C4), 142.6 (CAr), 146.8 (CAr), 166.7 (C@O).
15. Crystallographic data for the structure 12a have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication number
CCDC 825730. Copies of these data can be obtained on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (email: deposit@ccdc.cam.ac.uk).
10. Crystallographic data for the structure 4a have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 825728. Copies of these data can be obtained on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (email: deposit@ccdc.cam.
ac.uk).
11. 1H NMR data for 6c: dH (300 MHz, CDCl3) 1.21–1.29 (m, 1H, CH2), 1.64 (s, 3H,
Me), 1.65 (s, 3H, Me), 1.63–1.72 (m, 1H, CH2, overlapped with the Me group
signal), 2.07–2.11 (m, 1H, CH), 4.90 (s, 1H, CH), 6.68 (d, 1H, Ar, J = 8.1 Hz), 6.93–
7.02 (m, 4H, Ar), 7.15–7.29 (m, 8H, Ar). 13C NMR data for 6c: dc (75 MHz, CDCl3)
13.3 (CH2), 18.2 (CH), 26.5 (Me), 26.7 (Me), 72.1 (C3), 82.9 (C5), 114.7 (CArH),
118.3 (CAr), 119.4 (CArH), 123.0 (CAr), 125.1 (CArH), 126.2 (2CArH), 126.5 (CArH),