Pd-catalyzed carboetherification ofβ,γ-unsaturated oximes: A novel approach to δ2-lsoxazolines

Article abstract of DOI:10.1021/ol8002173

A novel route to the synthesis of δ²-isoxazoline derivatives is described. Reaction of β,γ-unsaturated oximes with aryl bromides via palladium-catalyzed carboetherification affords 3,5-disubstituted δ²-isoxazollnes in good yields. The use of Xantphos as ligand Is crucial for the transformation. The carboetherification products can be further converted to β-hydroxy ketones in the presence of Fe powder and NH₄CI.

Full text of DOI:10.1021/ol8002173

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1695-1698
Pd-Catalyzed Carboetherification of
ꢀ,γ-Unsaturated Oximes: A Novel
Approach to ∆2-Isoxazolines
Dahong Jiang,†,‡ Jinsong Peng,§ and Yuanwei Chen*,†
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu 610041, P. R. China, Graduate School of Chinese Academy of Sciences,
Beijing 100049, P. R. China, and College of Science, Northeast Forestry UniVersity,
Haerbin 150040, P. R. China
chenyw@cioc.ac.cn
Received January 31, 2008
ABSTRACT
A novel route to the synthesis of ∆2-isoxazoline derivatives is described. Reaction of ꢀ,γ-unsaturated oximes with aryl bromides via palladium-
catalyzed carboetherification affords 3,5-disubstituted ∆2-isoxazolines in good yields. The use of Xantphos as ligand is crucial for the
transformation. The carboetherification products can be further converted to ꢀ-hydroxy ketones in the presence of Fe powder and NH4Cl.
∆2-Isoxazolines are frequently found in a diverse array of
compounds, including biologically active agents,1 chiral
ligands,2 and intermediates in organic synthesis.3 In particu-
lar, because of their easily cleaved N-O bond, ∆2-isoxazo-
lines also serve as precursors for ꢀ-hydroxy ketones,4
ꢀ-amino acids,5 and γ-amino alcohols.6 Therefore, the
construction of a ∆2-isoxazoline ring has received much
attention. The conventional method for their synthesis is via
cycloaddition of nitrile oxides and alkenes, which generates
the O-C5 and C3-C4 bond in one step (1).7,8 Although
† Chengdu Institute of Organic Chemistry.
(3) (a) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410. (b) Bode,
J. W.; Carreira, E. M. J. Org. Chem. 2001, 66, 6410. (c) Kim, D.; Lee, J.;
Shim, P. J.; Lim, J. I.; Jo, H.; Kim, S. J. Org. Chem. 2002, 67, 764. (d)
Smith, A. L.; Pitsinos, E. N.; Hwang, C. K.; Mizuno, Y.; Saimoto, H.;
Scarlato, G. R.; Suzuki, T.; Nicolaou, K. C. J. Am. Chem. Soc. 1993, 115,
7612. (e) Kambe, M.; Arai, E.; Suzuki, M.; Tokuyama, H.; Fukuyama, T.
Org. Lett. 2001, 3, 2575. (f) Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew.
Chem., Int. Ed. Engl. 1994, 33, 15.
‡ Graduate School of Chinese Academy of Sciences.
§ Northeast Forestry University.
(1) (a) Wityak, J.; Sielecki, T. M.; Pinto, D. J.; Emmett, G.; Sze, J. Y.;
Liu, J.; Tobin, E.; Wang, S.; Jiang, B.; Ma, P.; Mousa, S. A.; Wexler, R. R.;
Olson, R. E. J. Med. Chem. 1997, 40, 50. (b) Xue, C.-B.; Wityak, J.;
Sielecki, T. M.; Pinto, D. J.; Batt, D. G.; Cain, G. A.; Sworin, M.; Rockwell,
A. L.; Roderick, J. J.; Wang, S.; Orwat, M. J.; Frietze, W. E.; Bostrom,
L. L.; Liu, J.; Higley, C. A.; Rankin, F. W.; Tobin, A. E.; Emmett, G.;
Lalka, G. K.; Sze, J. Y.; Di Meo, S. V.; Mousa, S. A.; Thoolen, M. J.;
Racanelli, A. L.; Hausner, E. A.; Reilly, T. M.; DeGrado, W. F.; Wexler,
R. R.; Olson, R. E. J. Med. Chem. 1997, 40, 2064. (c) Olson, R. E.; Sielecki,
T. M.; Wityak, J.; Pinto, D. J.; Batt, D. G.; Frietze, W. E.; Liu, J.; Tobin,
A. E.; Orwat, M. J.; Di Meo, S. V.; Houghton, G. C.; Lalka, G. K.; Mousa,
S. A.; Racanelli, A. L.; Hausner, E. A.; Kapil, R. P.; Rabel, S. R.; Thoolen,
M. J.; Reilly, T. M.; Anderson, P. S.; Wexler, R. R. J. Med. Chem. 1999,
42, 1178. (d) Hwang, I. T.; Kim, H. R.; Jeon, D. J.; Hong, K. S.; Song,
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Chen, J.; Schinazi, R. F.; Zhao, K. Bioorg. Med. Chem. 1996, 6, 1051.
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40, 2082. (c) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826. (d) Curran,
D. P.; Scanga, S. A.; Fenk, C. J. J. Org. Chem. 1984, 49, 3474. (e) Andersen,
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10.1021/ol8002173 CCC: $40.75
Published on Web 04/08/2008
2008 American Chemical Society

these transformations are widely used, some challenges still
remain especially for the issue of the regioselectivity.8
Table 1. Effect of Ligand on the Pd(0)-Catalyzed
Carboetherification of ꢀ,γ-Unsaturated Oxime 1a and
p-Bromotoluenea
(1)
Recently, Pd-catalyzed inter- and intramolecular carboet-
herification of olefins has been proved to be a very efficient
way to produce elaborate and important heterocyclic struc-
tures.9 We felt that the formation of substituted ∆2-isoxazo-
lines could be achieved by this method with a judicious
choice of palladium catalyst (2). However, Mosher et al.
reported that ꢀ,γ-unsaturated oximes were easily rearranged
to R,ꢀ-unsaturated oximes when a strong base was em-
ployed.10 Furthermore, the annulations of oximes were
dependent on the geometry of the hydroxyimino moiety in
the oxime precursors.11 On the basis of these observations,
we envisioned that this transformation may form several
undesired byproducts. In this paper, we report a novel, highly
chemoselective formation of ∆2-isoxazolines from ꢀ,γ-
unsaturated oximes and aryl halides via palladium-catalyzed
carboetherification reactions, in which the intramolecular
C-O bond and intermolecular C-Ar bond are formed in
one step.
entry
ligand
PPh3
P(o-tol)3
DPPF
DPE-Phos
Xantphos
isolated yield of 2a (%) isolated yield of 3 (%)
1
2
3
0
95
32
60
<5
28
92
48
4
5b
80(92)
12(<5)
a Reaction conditions: 1.0 equiv substrate 1a, 1.2 equiv ArBr, 1.2 equiv
NaOt-Bu, 1 mol % Pd2(dba)3, 2 mol % bidentate phosphine or 4 mol %
monodentate phosphine, toluene (0.1 M), 90 °C. b Numbers in parentheses
are the yield conducted at 105 °C.
rearrangement reaction. We were gratified to find that P(o-
tol)3 as ligand was effective in the carboetherification process
although the yield was relatively low (entry 2, Table 1). To
improve the yield, different supporting ligands were exam-
ined for the transformation of 1a with p-bromotoluene to
2a in toluene (Table 1). The use of a DPPF-derived catalyst
was unsuccessful under similar reaction conditions (entry 3,
Table 1). With the addition of DPE-Phos,14 the reaction
afforded 2a in a similar low yield (entry 4, Table 1).
However, the use of the ligand Xantphos14 at 90 °C provided
∆2-isoxazoline 2a in 80% yield (entry 5, Table 1).
(2)
During the course of our studies on palladium-catalyzed
cascade reactions of aryl bromides with N-homoallylhy-
droxylamines, we found that use of Pd2(dba)3/PPh3 as catalyst
could lead to the formation of 5-arylmethylisoxazolidines.12
Hence, in our preliminary experiments we first examined the
reaction of ꢀ,γ-unsaturated oxime 1a13 with 1.2 equiv of
p-bromotoluene in the presence of NaOt-Bu (1.2 equiv) and
catalytic amounts of Pd2(dba)3 (1 mol %) and PPh3 (4 mol
%). To our disappointment, no detectable ∆2-isoxazoline 2a
was observed, while only the rearranged R,ꢀ-unsaturated
oxime 3 was obtained (entry 1, Table 1). This is likely
because the rearrangement of the alkene into conjugation
may be much faster than the cyclization of ꢀ,γ-unsaturated
oxime 1a. We reasoned that a proper phosphine ligand might
accelerate the cyclization reaction and thus suppress the
To optimize the present reaction, various palladium
complexes, bases, and reaction temperatures were screened
for the carboetherification reaction (see Supporting Informa-
tion). PdCl2/Xantphos was active for the reaction but gave
2a in only 30% yield, while Pd(PPh3)4 and PdCl2/PPh3 were
completely inactive. Lowering the reaction temperature
resulted in poorer yield due to the rising byproduct 3, whereas
by increasing the reaction temperature to 105 °C, a 92%
isolated yield of 2a was obtained (entry 6, Table 1). NaOt-
Bu was proved to be clearly superior to other bases, such as
Na2CO3, K2CO3, K3PO4, and KOt-Bu, which gave 2a in 0%,
12%, 20%, and 72% yields, respectively.
With the optimized reaction conditions secured, we studied
the synthesis of a wide range of substituted ∆2-isoxazolines
2a-p from ꢀ,γ-unsaturated oximes 1a-i and different aryl
halides. The results are summarized in Table 2. From the
results in the Table, this method is effective for the
conversion of a variety of 1-substituted ꢀ,γ-unsaturated
oximes 1 such as aryl (entries 1-10, Table 2), heteroaryl
(entries 11 and 12, Table 2), alkenyl (entries 13 and 14, Table
2), and alkyl (entries 15 and 16, Table 2) to 3,5-disubstituted
∆2-isoxazoline derivatives. The electronic and steric effects
of the aryl substituents on the reaction were also examined.
The electron-neutral (entries 1 and 2, Table 2), electron-rich
(entries 3, 7 and 8, Table 2), electron-poor (entries 4-6, 9,
(7) (a) Torssell, K. B. G. Nitrile Oxides, Nitrones, and Nitronates in
Organic Chemistry; VCH: Stuttgart, Germany, 1988. (b) Caramella, P.;
Grunanger, P. In 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, 1984; Vol. 1, p , 177. (c) Kanemasa, S.; Tsuge, O.
Heterocycles 1990, 30, 719. (d) Yeh, M. P.; Jou, C.; Yeh, W.; Chiu, D.;
Reddy, N. R. K. Tetrahedron 2005, 61, 493.
(8) Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863.
(9) (a) Wolfe, J. P. Eur. J. Org. Chem. 2007, 571. (b) Wolfe, J. P.;
Rossi, M. A. J. Am. Chem. Soc. 2004, 126, 1620. (c) Hay, M. B.; Wolfe,
J. P. Angew. Chem., Int. Ed. 2007, 46, 6492.
(10) Norman, A. L.; Shurrush, K. A.; Calleroz, A. T.; Mosher, M. D.
Tetrahedron Lett. 2007, 48, 6849.
(11) Kai, H.; Nakai, T. Tetrahedron Lett. 2001, 42, 6895.
(12) Jiang, D.; Peng, J.; Chen, Y. Tetrahedron, published online: 2008.
DOI:10.1016/j.tet.2007.12.014.
(13) A mixture containing both Z and E isomers of ꢀ, γ-unsaturated
oxime 1a in the hydroxyimino moiety was used.
(14) DPE-Phos ) 1,1-bis(diphenylphosphinophenyl)ether, Xantphos )
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene.
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Org. Lett., Vol. 10, No. 9, 2008

Table 2. Pd-Catalyzed Carboetherification of ꢀ,γ-Unsaturated Oximes with Aryl Bromides to ∆2-Isoxazolinesa
a Unless noted, all reactions were carried out using 1 (0.2 mmol), ArBr (0.24 mmol), Pd2(dba)3 (1 mol %), Xantphos (2 mol %), and NaOt-Bu (0.24
mmol) in toluene at 105 °C for 3 h. b The geometries of 1a-c were unclear and a mixture of E/Z isomers in hydroxyimino moiety was used in the cases
of 1d-i. c Isolated yield.
and 10, Table 2), o-substituted (entries 7 and 8, Table 2),
and m-substituted (entries 9 and 10, Table 2) aryl substituents
are well tolerated.
oximes were the mixture of E/Z isomers in hydroxyimino
moiety, we presumed that the E isomer (relative to allyl
moiety) can be quickly converted to the Z isomer under the
reaction conditions. Then cyclization of the Z isomer with
aryl bromide affords the desired ∆2-isoxazoline product.
Additional evidence of this conversion was obtained by
subjecting both the Z and E isomers of (N-Boc-3-indolyl)
ꢀ,γ-unsaturated oxime 1g to the reaction conditions with
2-bromothiophene (Scheme 1).15 The product isoxazoline,
2k, was obtained in 52% and 41%, yield respectively.
Although the substituted ∆2-isoxazolines are in themselves
useful compounds, we have carried out their conversion to
the corresponding ꢀ-hydroxy ketones. For example, the ∆2-
isoxazoline 2a undergoes reductive N-O bond cleavage and
imine hydrolysis in the presence of Fe (5 equiv) and NH4Cl
(5 equiv) in EtOH/H2O at 80 °C for 3 h, providing ꢀ-hydroxy
ketone 4 in 90% yield (Scheme 2).
On the other hand, a variety of electron-neutral (entries
1, 3, 5, 6, and 15, Table 2), electron-rich (entries 12 and 13,
Table 2) and electron-deficient (entries 2, 8, 10, 14, and 16,
Table 2) aryl bromides are effectively transformed under
these conditions. Several functional groups are tolerated
(entries 2, 8, 10, 14, and 16, Table 2), and heteroaryl
bromides also afford the desired products in good yields
(entries 4, 7, and 9, Table 2), indicating the generality of
the above method. However, for 2-bromothiophene (entry
11, Table 2), the expected ∆2-isoxazoline 2k was obtained
only in 48% yield, probably due to the decomposition of
2-bromothiophene. Some o-substituted aryl bromides resulted
in modest yields of the desired products (entries 6 and 13,
Table 2).
On the basis of the observation that some transformations
can afford high yields though the starting ꢀ,γ-unsaturated
In summary, we have shown a novel protocol for the
construction of 3,5-disubstituted ∆2-isoxazolines through Pd-
Org. Lett., Vol. 10, No. 9, 2008
1697

Scheme 1
.
Reactions of Z and E Isomers of (N-Boc-3-indolyl)
Scheme 2. Synthesis of ꢀ-Hydroxy Ketones
ꢀ,γ-Unsaturated Oxime 1g and 2-Bromothiophenea
stereoselective preparation of 3,4,5-polysubstituted ∆2-isox-
azolines is currently being carried out in our laboratory.
Acknowledgment. We thank the 100-talent program of
Chinese Academy of Sciences and Chengdu Institute of
Organic Chemistry, Chinese Academy of Sciences, for
generous financial support of this work.
a The geometry of Z and E is relative to the allyl moiety.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
catalyzed carboetherification reactions of ꢀ,γ-unsaturated
oximes, which is complementary to that of nitrile oxide
cycloadditions. Both isomers of the oxime substrates have
proven to be effective for this transformation. The resulting
∆2-isoxazolines can be reductively cleaved to ꢀ-hydroxy
ketones. A study of the application of this method in the
OL8002173
(15) The geometries of Z and E of 1g were determined by 1H NMR
analysis. See Supporting Information for further details.
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Org. Lett., Vol. 10, No. 9, 2008