Solvent-controlled oxidative cyclization for divergent synthesis of highly functionalized oxetanes and cyclopropanes

Article abstract of DOI:10.1021/ol9012102

An efficient solvent-controlled oxidative cyclization of Michael adducts of malonates with chalcones with the combination of iodosobenzene and tetrabutylammonium iodide is reported. Highly functionalized oxetanes and cyclopropanes were divergently synthes

Full text of DOI:10.1021/ol9012102

ORGANIC
LETTERS
2009
Vol. 11, No. 14
3156-3159
Solvent-Controlled Oxidative Cyclization
for Divergent Synthesis of Highly
Functionalized Oxetanes and
Cyclopropanes
Yang Ye, Chen Zheng, and Renhua Fan*
Department of Chemistry, Fudan UniVersity, 220 Handan Road, Shanghai, 200433, China, and
Shanghai Key Laboratory of Molecular Catalysts and InnoVatiVe Materials,
Department of Chemistry, Fudan UniVersity, Shanghai, 200433, China
rhfan@fudan.edu.cn
Received May 29, 2009
ABSTRACT
An efficient solvent-controlled oxidative cyclization of Michael adducts of malonates with chalcones with the combination of iodosobenzene
and tetrabutylammonium iodide is reported. Highly functionalized oxetanes and cyclopropanes were divergently synthesized in moderate to
excellent yields with high diastereoselectivity.
The efficient composition of highly strained compounds such
as three- or four-membered cycles is of significant synthetic
interest.1-4 Their rigid scaffolds not only appear as important
substructures in a large number of medicinally and biologi-
cally active natural and unnatural substances but also can
undergo a variety of transformations to afford other useful
synthetic building blocks.5 The Michael addition of mal-
onates to R,ꢀ-unsaturated ketones is one of the important
C-C bond forming reactions that offer access to synthetically
useful functionalized organic molecules.6 In the last decades,
(1) For reviews, see: (a) Suckling, C. J. Angew. Chem., Int. Ed. Engl.
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J.; Hudlicky, T. Chem. ReV. 1989, 89, 165. (d) Davies, H. M. L. Tetrahedron
1993, 49, 5203. (e) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911
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2251. (b) Donaldson, W. A. Tetrahedron 2001, 57, 8589. (c) Reissig, H.-
U.; Zimmer, R. Chem. ReV. 2003, 103, 1151. (d) Wessjohann, L. A.; Brandt,
W.; Thiemann, T. Chem. ReV. 2003, 103, 1625. (e) Lebel, H.; Marcoux,
J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977. (f) Fox,
J. M.; Yan, N. Curr. Org. Chem. 2005, 9, 719. (g) Reichelt, A.; Martin,
S. F. Acc. Chem. Res. 2006, 39, 433. (h) Doyle, M. P. AdV. Synth. Catal.
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Barnette, W. E.; Seitz, S. P. J. Am. Chem. Soc. 1979, 24, 3704. (b) Ehlinger,
E.; Magnus, P. J. Am. Chem. Soc. 1980, 102, 5004. (c) Arjona, O.; De la
Pradilla, R. F.; Plumet, J.; Viso, A. J. Org. Chem. 1992, 57, 772. (d) Galatsis,
P.; Millan, S. D.; Nechala, P.; Ferguson, G. J. Org. Chem. 1994, 59, 6643.
(e) Wempe, M. F.; Grunwell, J. R. J. Org. Chem. 1995, 60, 2714. (f)
Paquette, L. A.; Edmondson, S. D.; Monck, N.; Rogers, R. D. J. Org. Chem.
1999, 64, 3255. (g) Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2002, 3099.
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V. K. Chem. ReV. 1997, 97, 2341. (b) Aggarwal, V. K.; Alsono, E.; Fang,
G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem., Int. Ed. 2001,
40, 1433. (c) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 3240. (d) Zheng, J. C.; Liao, W. W.; Tang, Y.; Sun, X. L.; Dai, L. X.
J. Am. Chem. Soc. 2005, 127, 12222. (e) Johansson, C. C. C.; Bremeyer,
N.; Ley, S. V.; Owen, D. R.; Smith, S. C.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2006, 45, 6024. (f) Aggarwal, V. K.; Grange, E. Chem.sEur. J. 2006,
12, 568. (g) Deng, X.; Cai, P.; Ye, S.; Sun, X. L.; Liao, W. W.; Li, K.;
Tang, Y.; Wu, Y. D.; Dai, L. X. J. Am. Chem. Soc. 2006, 128, 9730. (h)
Kakei, H.; Sone, T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2007, 129, 13410. (i) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang,
(h) Brennan, N. K.; Guo, X.; Paquette, L. A. J. Org. Chem. 2005, 70, 732.
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Tetrahedron: Asymmetry 2000, 11, 645. (b) Davies, H. M. L.; Xiang, B.;
Kong, N.; Stafford, D. G. J. Am. Chem. Soc. 2000, 123, 7461. (c) Trost,
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.
10.1021/ol9012102 CCC: $40.75
Published on Web 06/17/2009
 2009 American Chemical Society

many methods have been developed for the stereoselective
reaction.7 As a result, this transformation is practical for use
in organic synthesis. In this communication, we present a
solvent-controlled stereoselective oxidative cyclization of
Michael adducts of malonates with chalcones for the
divergent synthesis of highly functionalized oxetanes and
cyclopropanes.
iodosobenzene (PhIO) instead of PhI(OAc)2, the desired
cyclopropane 3a was obtained in 20% yield, and an
unexpected product, which was identified as the oxetane 2a,
was isolated in 38% yield (Scheme 1).
Scheme 2
Polyvalent iodine derivatives have been used extensively
in organic synthesis as a result of their benign environmental
character, ready availability and versatility.8 Some of our
recent efforts9 have been addressed in the development of
synthetic application of iodobenzene diacetate, PhI(OAc)2,
to construct aziridines9b and nitrocyclopropanes.9d With the
aim of extending this approach, we investigated the oxidative
cyclization of Michael adduct of ethyl malonate with
chalcone.
Scheme 1
Due to Dunitz-Schomaker strain (1,3-carbon-carbon
interaction),10 which is significant in four-membered sys-
tems,11 the efficient synthesis of oxetanes remains a challenge
for organic chemists.4 Motivated by the synthetic potential
of the possible method, the reaction was further optimized
by examining various reaction conditions, and some of the
results are shown in Table 1. Compared with the reactions
in polar or nonpolar aprotic solvents, the reactions in alcohols
completed in the shorter time. A satisfactory selectivity and
isolated yield of cyclopropane 3a (90% yield) was achieved
when methanol was utilized (Table 1, entry 6). When the
reaction was carried out in an air-open system with water as
the solvent, the reaction gave rise to oxetane 2a as the major
product in 60% yield, albeit in a longer time (Table 1, entry
7). Higher temperature accelerated the reaction but resulted
in an inferior result (Table 1, entry 8). Addition of a
surfactant or ultrasonic treatment resulted in complicated
reactions, and no oxetane 2a was obtained (Table 1, entries
9 and 10). Moreover, when SiO2 and Na2CO3 (0.5 equiv)
were used as the additives, the reaction was accelerated and
No cyclopropanation was observed with PhI(OAc)2 as the
oxidant under the typical conditions. Interestingly, with
Table 1. Evaluation of Reaction Conditionsa
3a
2a
entry
conditions
Toluene, 30 °C, 28 h
(%)b (%)b
1
25
28
47
28
59
90
4
17
7
6
32
27
30
26
7
(6) (a) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem., Int.
Ed. 1993, 32, 1176. (b) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org.
Chem. 1996, 61, 3520. (c) Halland, N.; Abured, P. S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2003, 42, 661. (d) Wang, Z.; Wang, Q.; Zhang, Y.;
Bao, W. Tetrahedron Lett. 2005, 46, 4657. (e) Chen, C.; Zhu, S.-F.; Wu,
X.-Y.; Zhou, Q.-L. Tetrahedron: Asymmetry 2006, 17, 2761. (f) Park, S.-
Y.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Tetrahedron Lett. 2007,
48, 2815. (g) Wascholowski, V.; Knudsen, K. R.; Mitchell, C. E. T.; Ley,
S. V. Chem.sEur. J. 2008, 14, 6155.
2
3
4
5
6
7
8
CH2Cl2, 30 °C, 36 h
DMF, 30 °C, 30 h
t-BuOH, 30 °C, 10 h
EtOH, 30 °C, 10 h
MeOH, 30 °C, 3 h
H2O, 30 °C, 128 h
H2O, 50 °C, 30 h
C12H25C6H4SO3Na, H2O, 30 °C, 128 h
Ultrasonic, H2O, 30 °C, 128 h
SiO2, Na2CO3 (0.5 equiv), H2O, 30 °C, 96 h
MeOH, 30 °C, 3 h
0
60
40
0
0
63
0
9c
10
11d
12e
13f
(7) (a) Kim, D. Y.; Hunh, S. C.; Kim, S. M. Tetrahedron Lett. 2001,
42, 6299. (b) Dere, R. T.; Pal, R. R.; Patil, P. S.; Salunkhe, M. M.
Tetrahedron Lett. 2003, 44, 5351. (c) Ooi, T.; Ohara, D.; Fukumoto, K.;
Maruoka, K. Org. Lett. 2005, 7, 3195. (d) Wang, J.; Li, H.; Zu, L.; Xie,
H.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128, 12652. (e)
Agostinho, M.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 2430. (f) Yang,
Y.-Q.; Zhao, G. Chem.sEur. J. 2008, 14, 10888.
2
92
2
SiO2, Na2CO3 (0.5 equiv), H2O, 30 °C, 96 h
68
a Reaction conditions: substrate 1a (0.5 mmol), PhIO (1 mmol), and
Bu4NI (1 mmol), solvent (2 mL), unless noted. b Isolated yield based on
substrate 1a. c C12H25C6H4SO3Na (100 mg) was added. d Na2CO3 (0.5 equiv,
0.25 mmol) and silica gel (100 mg) were added. e Bu4NI (1.5 equiv, 0.75
mmol) was used. f PhIO (3 equiv, 1.5 mmol) and 1.2 equivalents of Bu4NI
(0.6 mmol), 0.5 equivalents of Na2CO3 (0.25 mmol), and silica gel (100
mg) were used.
(8) For selected reviews: (a) Moriarty, R. M.; Vaid, R. K. Synthesis
1990, 431. (b) Stang, P. J.; Zhdankin, V. V. Chem. ReV. 1996, 96, 1123.
(c) Zhdankin, V. V.; Stang, P. J. Chemistry of HyperValent Compounds;
Akiba, K., Ed.; VCH Publishers: New York, 1999; Vol. 11, p 327. (d)
Grushin, V. V. Chem. Soc. ReV. 2000, 29, 315. (e) Zhdankin, V. V.; Stang,
P. J. Chem. ReV. 2002, 102, 2523. (f) Stang, P. J. J. Org. Chem. 2003, 68,
2997. (g) Moriarty, R. M. J. Org. Chem. 2005, 70, 2893. (h) Zhdankin,
V. V.; Stang, P. J. Chem. ReV. 2008, 108, 5299.
Org. Lett., Vol. 11, No. 14, 2009
3157

in H2O was 1:3:1.2, with which the yield of 2a increased to
68% (Table 1, entries 12 and 13).
Scheme 3
.
Plausible Reaction Pathway for the Oxidative
Cyclization
To understand the reaction pathway, several control
experiments were conducted (Scheme 2). While no reaction
occurred in the absence of Bu4NI, cyclopropane 3a was
obtained in 48% yield with the combination of PhIO with a
base (t-BuOK). Although the generation of iodine was
observed during the reactions, no cyclopropane or oxetane
was formed with I2 instead of Bu4NI. The above results
indicated that the reaction might not be mediated by I+. A
small amount of 2-hydroxy substituted Michael adduct 4 was
detected from the reaction in water. After the purification
and identification, compound 4 was treated with PhIO and
Bu4NI in water. The reaction was completed in 24 h and
gave rise to oxetane 2a in 82% yield.
A plausible reaction pathway, which involves the ligand
exchange reaction and reductive elimination reaction of
organic iodine(III) compounds,8,12 is outlined in Scheme 3.
In the presence of Bu4NI, polymeric iodosobenzene is
depolymerized and generates an oxidizing monomeric species
A,13 which can be transformed into an intermediate B in
MeOH. Michael adduct 1a reacts with the highly reactive
speciesA orB via a ligand exchange reaction to form an
intermediate C, which undergoes an intramolecular reductive
elimination to afford cyclopropane 3a. When the reaction is
carried out in water, the intermediate C reacts with water to
gave rise to a better selectivity and a higher isolated yield
of oxetane 2a (Table 1, entry 11). In the further investigation,
we found that the best ratio of substrate, PhIO, and Bu4NI
for the reaction in MeOH was 1:2:1.5, with which the yield
of 3a increased to 92%, while the best ratio for the reaction
Table 2. Solvent-Controlled Oxidative Cyclization of Michael Adducts of Malonates with Chalcones
condition Aa
condition Bb
entry
R1
R2
R3
Et
2
yield (%)c
3
yield (%)c
2
yield (%)c
3
yield (%)c
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
68
83
70
60
61
0
41
73
70
63
0
66
71
60
0
0
0
3a
3b
3c
3d
3e
3f
3g
3h
3i
2
3
3
12
28
0
21
trace
trace
21
68
trace
11
trace
0
2a
2b
2c
2d
2e
2f
2g
2h
2i
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
95
96
96
92
92
95
98
98
94
75
95
96
94
89
0
4-MeO-C6H4
4-Me-C6H4
4-Cl-C6H4
2-Cl-C6H4
4-NO2-C6H4
3-NO2-C6H4
Ph
4-MeO-C6H4
4-Me-C6H4
4-Cl-C6H4
4-NO2-C6H4
4-Me-C6H4
4-Cl-C6H4
Ph
9
Ph
Ph
Ph
10
11
12
13
14
15
16
17
2j
3j
2j
3j
2k
2L
2m
2n
2o
2p
2q
3k
3L
3m
3n
3o
3p
3q
2k
2L
2m
2n
2o
2p
2q
3k
3L
3m
3n
3o
3p
3q
4-MeO-C6H4
4-MeO-C6H4
Ph
Me
tBu
Et
Ph
t-Bu
Ph
Ph
Ph
CH3
0
0
Et
0
a Reaction conditions A: substrate 1 (0.5 mmol), PhIO (1.5 mmol), Bu4NI (0.6 mmol), silica gel (100 mg) and Na2CO3 (0.25 mmol), H2O (2 mL).
b Reaction conditions B: substrate 1 (0.5 mmol), PhIO (1 mmol), Bu4NI (0.75 mmol), MeOH (2 mL). c Isolated yield based on substrate 1.
3158
Org. Lett., Vol. 11, No. 14, 2009

yield 2-hydroxy compound 4. After the second ligand
exchange reaction with A to generate an intermediate D and
its subsequent reductive elimination, oxetane 2a is formed.
The generality of the present PhIO/Bu4NI induced diver-
gent oxidative cyclization of Michael adducts of malonates
with chalcones was then investigated under the established
conditions (Table 2). When the reactions were carried out
in water, a moderate electronic substrate effect was observed.
Compounds with an electron-donating substituent were better
substrates than those with an electron-withdrawing substitu-
ent, and their reactions afforded the corresponding oxetanes
in better selectivities and yields. This electronic substrate
effect accorded with the proposed mechanism. Oxetanes and
cyclopropanes are derived from the same intermediate C.
Due to the higher reactivity of the proton on the carbon alpha
to the electron-poor aryl ketone, the intramolecular reductive
elimination reaction of the intermediate C is preferred to yield
cyclopropane. For the electron-rich aryl ketone substrates,
the lower reactivity of the corresponding proton leads the
intermediate C to be readier to undergo the intermolecular
reaction with water to yield 2-hydroxy compound and to
afford oxtane. No oxetane was obtained from the reactions
of p-nitro substrates or ditert-butyl malonate derivative. When
the reactions were carried out in MeOH, all substrates
showed a good reactivity. The corresponding cyclopropanes
were generated in good to excellent yields, while no oxetane
was detected from the reactions. Aliphatic substrates were
unreactive under the same conditions, and no oxetane or
cyclopropane was isolated from the reactions (Table 2, entries
16 and 17). All oxetanes and cyclopropanes were formed
with a high diastereoselectivity (anti:syn >95:5, determined
1
by H NMR). The anti relative stereochemistry was con-
firmed by 1H NMR and the single-crystal diffraction analysis
of 2d (Figure 1).
Figure 1. X-ray diffraction structure of 2d.
In conclusion, we report here an efficient solvent-
controlled oxidative cyclization of Michael adducts of
malonates with chalcones with the combination of
iodosobenzene and tetrabutylammonium iodide. Highly func-
tionalized oxetanes and cyclopropanes are divergently syn-
thesized in moderate to excellent yields with high diastereo-
selectivity. Current dedication has been made to extend its
scope, asymmetric transformations, and possible synthetic
applications.
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Acknowledgment. Financial support from National Natu-
ral Science Foundation of China (20702006), the Shanghai
Rising-Star program (07QA14007), and Shanghai Key
Laboratory of Molecular Catalysts and Innovative Materials,
Department of Chemistry, Fudan University (2009KF02) are
gratefully acknowledged.
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Supporting Information Available: Experimental details
and spectral data for the major products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL9012102
Org. Lett., Vol. 11, No. 14, 2009
3159