Sequential [3+2] cycloaddition/rearrangement reaction of imidazolone nitrones and allenoates for the efficient synthesis of functionalized imidazolidinone

Article abstract of DOI:10.1016/j.tetlet.2011.11.049

Sequential [3+2] cycloaddition/rearrangement reaction of imidazolone nitrones and allenoates is described. The reaction was carried out in refluxing toluene to provide the methylene imidazolidinone derivatives in high yield. It provides a simple and conve

Full text of DOI:10.1016/j.tetlet.2011.11.049

Tetrahedron Letters 53 (2012) 342–344
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Tetrahedron Letters
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Sequential [3+2] cycloaddition/rearrangement reaction of imidazolone
nitrones and allenoates for the efficient synthesis of functionalized
imidazolidinone
Xi Wu a, Risong Na a, Honglei Liu a, Jun Liu a,b, Min Wang a, Jiangchun Zhong a, , Hongchao Guo a,
⇑
⇑
a Department of Applied Chemistry, China Agricultural University, Beijing 100193, PR China
b Chemical Industry Press, 13 Qingnianhu South St., Beijing 100011, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2011
Revised 7 November 2011
Accepted 10 November 2011
Available online 18 November 2011
Sequential [3+2] cycloaddition/rearrangement reaction of imidazolone nitrones and allenoates is
described. The reaction was carried out in refluxing toluene to provide the methylene imidazolidinone
derivatives in high yield. It provides a simple and convenient strategy for the synthesis of functionalized
imidazolidinones.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cycloaddition
Rearrangement
Sequential reaction
Nitrone
Allenoate
1,3-Dipolar cycloaddition reaction is one of the most important
methodologies and provides powerful tools for the synthesis of het-
erocycles from simpler starting materials.1 Various 1,3-dipoles such
as nitrone, azomethine ylide, azomethine imine, nitrile oxide, car-
bonyl ylide, azide, nitrile imine, carbonyl oxide, diazoalkane, and
diazoacetate have been used for all kinds of target heterocycles.1
Among these 1,3-dipoles, nitrone is a highly attractive one due to
the extensive application of the corresponding cycloadduct.2 Vari-
ous dipolarophiles such as alkenes, alkynes, and allenes could un-
dergo [3+2] cycloaddition with nitrones to furnish the useful
heterocycles (Scheme 1).2 The alkenes react with nitrones to give
isoxazolidines. The alkynes undergo cycloaddition with nitrones
to provide isoxazolines. The allenes have similar reaction mode as
alkenes, leading to methylene isoxazolidine derivatives. While the
cycloadditions of alkenes or alkynes and nitrones are widely used
in organic synthesis, only a few examples of 1,3-dipolar cycloaddi-
tion of nitrones and allenoates have been reported to date.3 Allenes
contain highly valuable 1,2-propadiene system and are extremely
versatile synthetic building blocks in modern synthetic chemistry.4
Both C@C bonds are active positions for dipolar attack which can
proceed with two opposite orientations, especially, allenes possess-
ing electron-withdrawing substituents are very active to undergo
dipolar cycloaddition. Generally, one of two C@C bonds in the
functionalized allenes conducts the [3+2] cycloaddition to afford
methylene isoxazoline derivatives, which can carry out rearrange-
ment to provide new heterocyclic skeleton. By using this sequential
reaction strategy, some very interesting heterocycles could be syn-
thesized. For example, Padwa has used several electron-deficient
allenes such as (phenylsulfonyl) allene to perform the [3+2] cyclo-
addition with nitrone, giving rise to the desired 5-exo-methylene
substituted isoxazolidines, which underwent smooth rearrange-
ment on thermolysis to produce 3-pyrrolidinones in high yield.5
In order to develop this kind of sequential reaction to synthesize
useful heterocycle molecules, we have explored the reactions be-
tween nitrones and allenes. Herein, we describe sequential [3+2]
cycloaddition/rearrangement reaction of imidazolone nitrones with
allenoates to furnish functionalized imidazolidinone (Scheme 2).
The imidazolone nitrones have extensively been utilized as 1,
3-dipoles in the cycloaddition reaction for the synthesis of various
O
N
O
O
N
N
O
N
⇑
Corresponding authors. Tel.: +86 10 62731356; fax: +86 10 62820325.
E-mail address: hchguo@gmail.com (H. Guo).
Scheme 1. Classic [3+2] cycloaddition of nitrones with alkenes, alkynes, and
allenes.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.049

X. Wu et al. / Tetrahedron Letters 53 (2012) 342–344
343
48 h.7 To our delight, the new product was obtained in a 58% yield.
In order to improve the yield, 3, 4, 5, and 6 equiv of allenoate (2a)
were used respectively, the corresponding 63%, 80%, 89%, and 90%
yield was obtained. Obviously, the reaction yield was significantly
improved with increased amount of allenoate. The excess allenoate
probably drives first step of [3+2] cycloaddition to completion.
However, 4–6 equiv of allenoate is too much for a practical reac-
tion. Fortunately, the excess allenoate could be recovered in about
an 80% yield by flash column chromatography and reused in the
next case. Therefore, in next experiments, all reactions of imidazo-
lone nitrones were carried out in refluxing toluene in the presence
of 5 equiv of allenoates. By using 1H NMR, 13C NMR, and 2D NMR,
the structure of new product was determined to be (Z)-methylene
imidazolidinone (3aa), which was formed from the sequential
cycloaddition/rearrangement reaction of imidazolone nitrone (1a)
and allenoate (2a). The hydrogen-bond between hydroxyl and
amine group stabilizes the product, favoring the (Z)-configuration
of alkene.
Ph
NH OH
O
O
BnN
O
N
BnN
+
OEt
CO2Et
O
Ph
1a
2a
3aa
Scheme 2. The reaction was performed for screening reaction conditions.
Table 1
Sequential cycloaddition/rearrangement of imidazolone nitrones (1) and allenoates
(2)a
R1
R1
R1 R1
R2
NH OH
O
toluene
BnN
O
N
BnN
+
OEt
reflux, 48h
CO2Et
O
R2
O
A range of allenoates and three imidazolone nitrones were
examined in the sequential cycloaddition/rearrangement reaction
under the optimized reaction conditions (Table 1). A variety of
allenoates underwent the sequential reaction with imidazolone
nitrone (1a), providing the anticipated functionalized imidazolidi-
none in good to excellent yields (entries 1–16). Since the R2 in
allenoate is far away from the reacted double bond, the electron-
donating or withdrawing substituent on benzene ring of aryl did
not exert much influence on the course of the reaction. A variety
of aryl-substituted allenoates underwent the reaction at reason-
able rates (entries 1–13). After successful evaluation of the sequen-
tial reaction of aromatic allenoates with nitrone (1a), we were
delighted to find out that aliphatic allenoates could also carry
out the reaction in the refluxing toluene (entries 14–16). The
sequential reaction of the aliphatic allenoate provided the corre-
sponding products in comparable yields as aromatic allenoates.
Two variants (1b and 1c) of imidazolone nitrone (1a) worked well
too, affording the corresponding products in satisfactory yields
(entries 17–18). Since (Z)-methylene imidazolidinone products
could be further functionalized, the sequential cycloaddition/rear-
rangement reaction would provide a generally applicable proce-
dure for the synthesis of imidazolidinone derivatives, which are
the key units of natural products and drug candidates.8
1
2
3
Entry
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Me (1a)
Me(1a)
Me(1a)
Me(1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Et (1b)
Ph (2a)
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
3ba
3ca
89
81
74
81
73
72
77
82
74
80
71
75
84
80
76
74
70
66
2-MeC6H4 (2b)
3-MeC6H4 (2c)
4-MeC6H4 (2d)
2-FC6H4 (2e)
3-FC6H4 (2f)
4-FC6H4 (2g)
2-ClC6H4 (2h)
3-ClC6H4 (2i)
4-ClC6H4 (2j)
2-BrC6H4 (2k)
3-BrC6H4 (2l)
4-BrC6H4 (2m)
H (2n)
Me (2o)
Et (2p)
Ph (2a)
Ph (2a)
n-Pr (1c)
a
5 equiv of allenoate were used. The excess allenoate was recovered by flash
column chromatography.
b
Isolated yield.
heterocyclic compounds.6 Our initial attempts at the reaction of
imidazolone nitrones with allenoates commenced with the reac-
tions of 1-benzyl-2,2-dimethyl-5-oxo-2,5-dihydro-1H-imidazole
3-oxide (1a) (Scheme 2). The imidazolone nitrone (1a) was treated
with 2 equiv of ethyl 2-benzylbuta-2,3-dienoate (2a) in dichloro-
methane at room temperature. No new product was observed.
The reaction was carried out in ethanol and benzene respectively,
although the reaction mixture had been stirred at 80 °C for 120 h,
the nitrone could not be consumed and no product was obtained.
Considering that the reaction might need higher temperature to
complete, the reaction was carried out in refluxing toluene for
On the basis of the reported mechanistic studies,5 the methy-
lene isoxazoline derivatives from the reaction of nitrone and allene
often underwent radical rearrangement under heated conditions.
However, when the radical scavenger (1,4-dinitrobenzene) or rad-
ical inhibitor (hydroquinone) was used in the reaction, the sequen-
tial cycloaddition/rearrangement reaction could not be inhibited
and the corresponding product was obtained in the nearly same
yield as that in the absence of radical scavenger or inhibitor.
According to this observation, a plausible pathway for the sequen-
tial reactions of the nitrone 1 and the allenoates 2 was presented in
R
BnN
N
O
BnN
O
N
O
O
toluene
reflux
BnN
O
N
CO2Et
R
+
CO2Et
R
CO2Et
O
1
2
A
B
H
BnN
O
N
OH
O
N
OH
BnN
CO2Et
R
OEt
O
R
C
3
Scheme 3. Postulated mechanism for sequential cycloaddition/rearrangement reaction.

344
X. Wu et al. / Tetrahedron Letters 53 (2012) 342–344
Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, The
Chemistry of Heterocyclic Compounds; Wiley: New York, 2002; Vol. 59, pp 1–81;
(b) Feuer, H. Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis, 2nd ed.;
John Wiley & Sons: Hoboken, NJ, 2008; For reviews on nucleophilic additions to
nitrones see: (c) Merino, P.; Franco, S.; Merchán, F. L.; Tejero, T. Synlett 2000, 442–
454; (d) Cardona, F.; Goti, A. Angew. Chem., Int. Ed. 2005, 44, 7832–7835; (e) Brandi,
A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur. J. 2009, 15, 7808–7821.
3. For a review, see: Pinho e Melo, T. M. V. D. Curr. Org. Chem. 2009, 13, 1406–1431.
4. For reviews on the synthetic applications of allenes, see: (a) Lu, X.; Zhang, C.; Xu,
Z. Acc. Chem. Res. 2001, 34, 535–544; (b) Methot, J. L.; Roush, W. R. Adv. Synth.
Catal. 2004, 346, 1035–1050; (c) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008,
37, 1140–1152; (d) Cowen, B. J.; Miller, S. J. Chem. Soc. Rev. 2009, 38, 3102–3116;
(e) Marinetti, A.; Voituriez, A. Synlett 2010, 2005, 174–194; (f) Ma, S. M. Chem.
Rev. 2005, 105, 2829–2871.
5. For selected examples, see: (a) Padwa, A.; Carter, S. P.; Chiacchio, U.; Kline, D. N.
Tetrahedron Lett. 1986, 27, 2683–2686; (b) Padwa, A.; Kline, D. N.; Koehler, K. F.;
Matzinger, M.; Venkatramanan, M. K. J. Org. Chem. 1987, 52, 3909–3917; (c)
Padwa, A.; Matzinger, M.; Tomioka, Y.; Venkatramanan, M. K. J. Org. Chem. 1988,
53, 955–963; (d) Padwa, A.; Craig, S. P.; Chiacchio, U.; Kline, D. N. J. Org. Chem.
1988, 53, 2232–2238; (e) Padwa, A.; Kline, D. N.; Norman, B. H. J. Org. Chem.
1989, 54, 810–817; (f) Padwa, A.; Bullock, W. H.; Kline, D. N.; Perumattam, J. J.
Org. Chem. 1989, 54, 2862–2869; (g) Padwa, A.; Norman, B. H.; Perumattam, J.
Tetrahedron Lett. 1989, 30, 663–666.
Scheme 3. At high temperature, the allenoate and nitrone carry out
[3+2] cycloaddition to give methylene tetrahydroimidazo
[1,5-b]isoxazol-4(2H)-one A. Due to the thermal instability of A, a
heterolytic cleavage of the N–O bond of A generates a zwitterionic
intermediate B. Subsequent isomerization gives rise to the inter-
mediate C. It undergoes rearrangement to lead to the formation
of the final product 3, which was stabilized by the hydrogen bond
between amine and hydroxyl.
In conclusion, a simple and convenient strategy for the synthe-
sis of functionalized imidazolidinones via sequential [3+2] cycload-
dition/rearrangement reaction of imidazolone nitrones and
allenoates has been developed. Using this method a range of func-
tionalized imidazolidinones have been prepared from readily avail-
able starting materials. A variety of allenoates with various
substituents are tolerated under the reaction conditions.
Acknowledgments
6. See recent example of 1,3-dipolar cycloaddition of imidazolone nitrones: (a)
Baldwin, S. W.; Long, A. Org. Lett. 2004, 6, 1653–1656; (b) Aouadi, K.; Vidal, S.;
Msaddek, M.; Praly, J.-P. Synlett 2006, 3299–3303; (c) Pernet-Poil-Chevrier, A.;
Cantagrel, F.; Le Jeune, K.; Philouze, C.; Chavant, P. Y. Tetrahedron: Asymmetry
2006, 17, 1969–1974; (d) Aouadi, K.; Jeanneau, E.; Msaddek, M.; Praly, J.-P.
Synthesis 2007, 3399–3405; (e) Aouadi, K.; Jeanneau, E.; Msaddek, M.; Praly, J.-P.
Tetrahedron: Asymmetry 2008, 19, 1145–1152; (f) Dai, X.; Miller, M. W.;
Stamford, A. W. Org. Lett. 2010, 12, 2718–2721.
This work was financially supported by the startup research
funding of China Agricultural University, Chinese Universities Sci-
entific Fund (Nos. 2011JS029 and 2011JS031), the National Scien-
tific and Technology Supporting Program of China (No.
2011BAE06B05-5), the National Natural Science Foundation of Chi-
na (No. 21172253), the Key Technologies R&D Program of China,
and Nutriechem Company.
7. General procedure for sequential [3+2] cycloaddition/rearrangement: The nitrone
1a (0.125 mmol, 1 equiv) was added to a solution of allenoate 2a (0.625 mmol,
5 equiv) in 2 mL of toluene at room temperature, then the resulting mixture was
stirred in the refluxing toluene for 48 h. The reaction mixture was concentrated
under reduced pressure. The residue was purified by flash column
chromatography (ethyl acetate/hexanes = 1:2) to give the corresponding
product 3aa as a colorless oil. IR (film) mmax 2962, 2930, 2873, 1736, 1701,
1585, 1456, 1401, 1365, 1298, 1260, 1221, 1181, 1149, 1095, 1029, 956, 921,
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.049.
801, 708, 623, 582, 553, 496 cmÀ1 1H NMR (300 MHz, CDCl3) d 7.36–7.17 (m,
;
10H), 6.24 (s, 1H), 5.03 (d, J = 1.0 Hz, 1H), 4.68–4.51 (m, 2H), 4.12–3.93 (m, 2H),
3.45–3.29 (m, 2H), 1.22 (d, J = 3.3 Hz, 6H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3) d 172.9, 162.2, 160.2, 140.5, 136.6, 135.6, 130.6, 128.7, 128.0,
127.9, 127.8, 126.8, 126.0, 83.5, 78.7, 61.5, 44.3, 42.4, 25.6, 25.5, 14.0; HRMS
References and notes
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Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John Wiley
and Sons: Hoboken, NJ, 2003; (c) Hashimoto, T.; Maruoka, K. In Handbook of
Cyclization Reactions; Ma, S., Ed.; Wiley-VCH: Weinheim, Germany, 2009; pp 87–
168.
(ESI) calcd for C25H28N2O4 [M]+ 420.2044, found 420.2040.
+
8. For a highly bioactive 2,3,5-substituted imidazolidin-4-one, which is b-secretase
inhibitor, see: Barrow, J. C.; Rittle, K. E.; Ngo, P. L.; Selnick, H. G.; Graham, S. L.;
Pitzenberger, S. M.; McGaughey, G. B.; Colussi, D.; Lai, M.-T.; Huang, Q.;
Tugusheva, K.; Espeseth, A. S.; Simon, A. J.; Munshi, S. K.; Vacca Jo, P.
ChemMedChem 2007, 2, 995–999.
2. For reviews on 1,3-dipolar cycloadditions of nitrones, see: (a) Jones, R. C. F.;
Martin, J. N. In Padwa, A., Pearson, W. H., Eds.; Synthetic Applications of 1,3-