Stereoselective synthesis of isoxazolidines through Pd-catalyzed carboetherification of N-butenylhydroxylamines

Article abstract of DOI:10.1002/anie.200701386

(Chemical Equation Presented) Pd ploy to isoxazolidines: Carboetherification reactions of N-butenylhydroxylamines with aryl bromides afford substituted isoxazolidines in good yield with up to > 20:1 d.r. These transformations provide a new strategy for th

Full text of DOI:10.1002/anie.200701386

Communications
DOI: 10.1002/anie.200701386
Isoxazolidine Synthesis
Stereoselective Synthesis of Isoxazolidines through Pd-Catalyzed
Carboetherification of N-Butenylhydroxylamines**
Michael B. Hay and John P. Wolfe*
Isoxazolidines are frequently used as intermediates in the
synthesis of complex molecules[1] and are found in several
interesting biologically active compounds.[2] In addition, the
available methods. The reactions appear to proceed by
intramolecular alkene insertion into previously unprece-
dented palladium alkoxyamine intermediates, which may be
of utility in other Pd-catalyzed carbon–heteroatom bond-
forming processes.
In preliminary experiments, we examined Pd-catalyzed
reactions of N-butenyl hydroxylamines 1–3 with 4-bromobi-
phenyl under conditions that were employed in our prior
studies on Pd-catalyzed carboetherification reactions of g-
hydroxyalkenes.[6–8] As shown in Table 1, attempts to cyclize
À
isoxazolidine N Obond can be easily cleaved under reducing
conditions to afford 1,3-amino alcohols, which are also of
synthetic utility.[3] The most commonly employed method for
the construction of isoxazolidines involves 1,3-dipolar cyclo-
addition reactions between nitrones and alkenes,[4] which
À
À
generates the O1 C5 bond and the C3 C4 bond in one step
[Eq. (1)]. Although these transformations are very useful,
many intermolecular cycloadditions of unactivated alkenes
unprotected hydroxylamine substrate
1
and N-tert-
Table 1: Carboetherification of N-butenyl hydroxylamines.[a]
Hydroxylamine
R
Isoxazolidine
Yield [%][b]
generate mixtures of regioisomers.[4] Moreover, the major
stereoisomers typically result from endo addition on the less
hindered face of the alkene, and the selective preparation of
stereoisomers resulting from exo addition and/or addition to
the more substituted alkene face cannot be achieved in a
straightforward manner.[4]
Herein, we describe a new approach to the construction of
substituted isoxazolidines based on palladium-catalyzed car-
boetherification reactions of N-butenyl hydroxylamine deriv-
atives with aryl bromides [Eq. (2)]. This method represents a
new strategy for construction of the isoxazolidine ring, in
1
2
3
H
Boc
Bn
–
–
4
0[c]
0[c]
80
[a] Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 1.2 equiv NaOtBu,
2 mol% Pd(OAc)2, 2 mol% DPE-Phos, THF (0.125m), 658C. [b] Yields
represent average yields of isolated product for two or more experiments.
[c] Heck arylation products were observed.
butyloxycarbonyl(Boc)-protected derivative 2 were unsuc-
cessful.[9] However, we were gratified to find that treatment of
N-benzyl-protected substrate 3 with 4-bromobiphenyl and
NaOtBu in the presence of catalytic amounts of Pd(OAc)2
and DPE-Phos[10] afforded the desired product 4 in 80%
yield.
With viable reaction conditions and a suitable nitrogen
protecting group identified, we examined Pd-catalyzed car-
boetherification reactions between several different substi-
tuted hydroxylamines and a number of aryl bromides. As
shown in Table 2, this method is effective with electron-rich
(entry 10), electron-neutral (entries 4, 7, 8, and 12), electron-
poor (entries 1, 2, 11, and 13), o-substituted (entry 8), and
heterocyclic (entries 3, 5, 6, and 9) aryl bromides. In addition
to the N-benzyl-protected derivatives described above,
hydroxylamine substrates bearing N-methyl or N-tert-butyl
groups also undergo cyclization in good yield.
À
À
which the O1 C5 bond and a C5’ Ar bond are formed in one
step.[5] These transformations also provide access to isoxazo-
lidine stereoisomers that cannot be generated with currently
[*] M. B. Hay, Prof. J. P. Wolfe
University of Michigan
Department of Chemistry
Ann Arbor, MI 48109-1055 (USA)
Fax: (+1)734-763-2307
E-mail: jpwolfe@umich.edu
The carboetherification reactions are also effective with
substrates bearing substituents along the tether between the
hydroxylamine moiety and the alkene. Transformations of
these substrates provide access to disubstituted isoxazolidines
with moderate to excellent stereocontrol. Importantly, in
many cases these cyclizations provide a means to generate
isoxazolidines that could not be prepared using 1,3-dipolar
[**] This research was supported by the NIH-NIGMS (GM-071650).
J.P.W. thanks The Camille and Henry Dreyfus Foundation (New
Faculty Award, Teacher Scholar Award) and Research Corporation
for an Innovation Award. Additional unrestricted support was
provided by Eli Lilly, 3M, and Amgen.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or fromthe author.
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Chemie
Table 2: Pd-catalyzed synthesis of substituted isoxazolidines.[a]
reaction between a nitrone and a 3-arylcyclopentene would
be expected to occur on the less hindered face of the alkene to
afford a different stereoisomer and would likely generate
mixtures of regioisomers.[4] In addition, reactions of 8 with
aryl bromides proceed in 82–85% yield and 10:1 d.r. to afford
the (2R*,3aS*)-hexahydropyrrolo[1,2b]isoxazole isomers 18
and 19 (Table 2, entries 8 and 9). However, dipolar cyclo-
additions between 3,4-dihydropyrrole-1-oxide and allylben-
zene derivatives instead generate stereoisomeric (2S*,3aS*)-
hexahydropyrrolo[1,2b]isoxazoles.[11] The hydroxylamine car-
boetherifications can also be used to prepare trans-4,5-
disubstituted isoxazolidines 12–14 and cis-3,5-disubstituted
isoxazolidines 15–17 in good yield with 3:1 to 5:1 diastereo-
selectivity.
Entry Substrate
1
Isoxazolidine
d.r.[b]
–
Yield [%][c]
85
2
>20:1 (5:1)
56
70
3
5
5
3:1 (3:1)
A plausible mechanism for the isoxazolidine-forming
reactions is shown in Scheme 1. These transformations
appear to be mechanistically related to Pd-catalyzed carbo-
4
5
6
7
>20:1 (3:1)
3:1 (3:1)
3:1 (3:1)
3:1 (3:1)
57
77
78
61
6
8
9
>20:1 (10:1)
>20:1 (10:1)
82
85
8
9
10
11
19:1 (9:1)
94
89
Scheme 1. Catalytic cycle of the Pd-catalyzed carboetherification reac-
tion of N-butenylhydroxylamines.
>20:1 (9:1)
etherification reactions of g-hydroxy alkenes with aryl
bromides[6] and are likely initiated by oxidative addition of
the aryl bromide to Pd0 to afford 24. The [LnPd(Ar)(Br)]
complex can then be transformed to intermediate 25 by
reaction with the hydroxylamine substrate and NaOtBu.
Intramolecular syn oxypalladation[6,12] of the tethered alkene
12[d]
>20:1 (>20:1)
>20:1 (>20:1)
78
69
13[d]
10
À
moiety of 25 would generate 26, which can undergo C C
bond-forming reductive elimination[13] to afford the observed
isoxazolidine products. The conversion of 10 to syn-addition
products 22 and 23 is consistent with this hypothesis. More-
over, this model also accounts for the observed stereochem-
istry of 12–21, as the syn oxypalladation likely occurs from an
organized cyclic transition state in which nonbonding inter-
actions are minimized by pseudoequatorial orientation of the
substrate R1 and R2 groups. This transition state arrangement
would provide cis-3,5-disubstituted products (R2 = H) and
trans-4,5-disubstituted compounds (R1 = H).
[a] Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 1.2 equiv NaOtBu,
2 mol% Pd(OAc)2, 2 mol% DPE-Phos, THF (0.125m), 658C. [b] d.r.=
diastereomeric ratio of isolated material. Numbers in parentheses are
the observed diastereomeric ratios for the crude reaction mixture.
[c] Yields represent average yields of product isolated in two or more
experiments. [d] The reaction was conducted at 1108C in toluene solvent
with [Pd2(dba)3] (1 mol%) used in place of Pd(OAc)2 (dba=dibenzyl-
ideneacetone).
cycloaddition methods. For example, Pd-catalyzed reactions
of 10 with 4-bromobiphenyl and 3-bromobenzotrifluoride
provide 22 and 23, respectively, in 78% and 69% yields, with
> 20:1 diastereoselectivity and regioselectivity (Table 2,
entries 12 and 13). In contrast, a 1,3-dipolar cycloaddition
Although palladium(aryl)alkoxides have been shown to
be important intermediates in a number of catalytic process-
es,[6,14,15] the analogous complexes derived from hydroxyl-
amines (e.g. 25) are unknown. The reactions described in this
paper represent the first examples of catalytic transforma-
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activation followed by outer-sphere anti-oxypalladation. No
evidence exists for the intermediacy of [LnPd(ONR2)(allyl)]
tions involving [Pd(Ar)(ONRR’)] species. These previously
unknown intermediates will likely find additional applications
in other metal-catalyzed carbon–heteroatom bond-forming
reactions.[15]
À
complexes that bear a Pd Obond. See: a) P. Merino, T. Tejero,
V. Mannucci, G. Prestat, D. Madec, G. Poli, Synlett 2007, 944 –
948. For additional discussion of Pd-catalyzed allylations of
In conclusion, we have developed a new stereoselective
method for the construction of substituted isoxazolidines
through Pd-catalyzed carboetherification reactions of unsa-
turated hydroxylamine substrates. In many cases the stereo-
chemical outcome of these transformations is complementary
to that of nitrone cycloadditions, and this method provides a
new strategic disconnection that can be used for retrosyn-
thetic analysis of substituted isoxazolidines.
À
nucleophiles containing an N Obond, see: b) H. Miyabe, K.
Yoshida, V. K. Reddy, A. Matsumura, Y. Takemoto, J. Org.
Chem. 2005, 70, 5630 – 5635.
[6] a) J. P. Wolfe, M. A. Rossi, J. Am. Chem. Soc. 2004, 126, 1620 –
1621; b) M. B. Hay, A. R. Hardin, J. P. Wolfe, J. Org. Chem. 2005,
70, 3099 – 3107; c) M. B. Hay, J. P. Wolfe, J. Am. Chem. Soc. 2005,
127, 16468 – 16476; d) M. B. Hay, J. P. Wolfe, Tetrahedron Lett.
2006, 47, 2793 – 2796.
[7] For a review on Pd-catalyzed carboetherification and carboami-
nation reactions of g-hydroxy and g-amino alkenes, see: J. P.
Wolfe, Eur. J. Org. Chem. 2007, 571 – 582.
Received: March 30, 2007
Published online: July 26, 2007
[8] Two recent reports have described a related approach to the
À
synthesis of cis-3,5-disubstituted isoxazolidines in which the N
C3 bond is generated by Pd-catalyzed carboamination of O-
homoallyl hydroxylamines. The scope of these transformations
has not been fully explored. See: a) K. G. Dongol, B. Y. Tay,
Tetrahedron Lett. 2006, 47, 927 – 930; b) J. Peng, W. Lin, S. Yuan,
Y. Chen, J. Org. Chem. 2007, 72, 3145 – 3148.
Keywords: aryl halides · homogeneous catalysis ·
nitrogen heterocycles · olefin insertion · palladium
.
[1] For a review on the use of isoxazolidines as intermediates in
complex molecule synthesis, see: M. Frederickson, Tetrahedron
1997, 53, 403 – 425.
[9] The major products observed in these reactions resulted from
Heck arylation of the alkene.
[10] DPE-Phos = bis(diphenylphosphinophenyl)ether.
[11] H. Iida, Y. Watanabe, C. Kibayashi, J. Chem. Soc. Perkin Trans. 1
1985, 261 – 266.
[2] a) H. Ishiyama, M. Tsuda, T. Endo, J. Kobayashi, Molecules
2005, 10, 312 – 316; b) A. R. Minter, B. B. Brennan, A. K. Mapp,
J. Am. Chem. Soc. 2004, 126, 10504 – 10505; c) G. C. Palmer,
M. J. Ordy, R. D. Simmons, J. C. Strand, L. A. Radov, G. B.
Mullen, C. R. Kinsolving, V. St. Georgiev, J. T. Mitchell, S. D.
Allen, Antimicrob. Agents Chemother. 1989, 33, 895 – 905.
[3] a) S. M. Lait, D. A. Rankic, B. A. Keay, Chem. Rev. 2007, 107,
767 – 796; b) J. Revuelta, S. Cicchi, A. Brandi, Tetrahedron Lett.
2004, 45, 8375 – 8377; c) N. A. LeBel, N. Balasubramanian, J.
Am. Chem. Soc. 1989, 111, 3363 – 3368; d) H. Iida, K. Kasahara,
C. Kibayashi, J. Am. Chem. Soc. 1986, 108, 4647 – 4648.
[4] For reviews on 1,3-dipolar cycloaddition reactions, see: a) P. N.
Confalone, E. M. Huie, Org. React. 1988, 36, 1 – 173; b) K. V.
Gothelf, K. A. Jorgensen, Chem. Commun. 2000, 1449 – 1458;
c) S. Kanemasa, Synlett 2002, 1371 – 1387; d) A. E. Koumbis,
J. K. Gallos, Curr. Org. Chem. 2003, 7, 585 – 628; e) P. Merino in
Science of Synthesis (Houben-Weyl Methods of Molecular
Transformations), Vol 27 (Ed.: A. Padwa), Thieme, Stuttgart,
2004, pp. 511 – 580; f) G. Pandey, P, Banerjee, S. R. Gadre,
Chem. Rev. 2006, 106, 4484 – 4517; g) G. Molteni, Heterocycles
2006, 68, 2177 – 2202.
[12] For other recent studies on syn alkene insertions into late-
transition-metal oxygen bonds, see: a) H. E. Bryndza, J. C.
Calabrese, S. S. Wreford, Organometallics 1984, 3, 1603 – 1604;
b) M. A. Bennett, H. Jin, S. Li, L. M. Rendina, A. C. Willis, J.
Am. Chem. Soc. 1995, 117, 8335 – 8340; c) O. Hamed, C.
Thompson, P. M. Henry, J. Org. Chem. 1997, 62, 7082 – 7083;
d) T. Hayashi, K. Yamasaki, M. Mimura, Y. Uozumi, J. Am.
Chem. Soc. 2004, 126, 3036 – 3037; e) R. M. Trend, Y. K.
Ramtohul, B. M. Stoltz, J. Am. Chem. Soc. 2005, 127, 17778 –
17788; f) P. Zhao, C. D. Incarvito, J. F. Hartwig, J. Am. Chem.
Soc. 2006, 128, 9642 – 9643.
[13] a) D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1979, 101, 4981 –
4991; b) J. F. Hartwig, Inorg. Chem. 2007, 46, 1936 – 1947.
[14] For examples of well-characterized [LnPd(Ar)(OR)] complexes,
see: a) G. Mann, J. F. Hartwig, J. Am. Chem. Soc. 1996, 118,
13109 – 13110; b) R. A. Widenhoefer, H. A. Zhong, S. L. Buch-
wald, J. Am. Chem. Soc. 1997, 119, 6787 – 6795.
[15] In addition to carboetherification reactions of g-hydroxyalkenes,
synthetically useful reactions that are believed to proceed via
[LnPd(Ar)(OR)] complexes include Pd-catalyzed O-arylation
reactions and oxidation reactions. It is likely that the analogous
hydroxylamine complexes [LnPd(Ar)(ONRR’)] will find similar
applications. For lead references on useful catalytic transforma-
tions involving [LnPd(Ar)(OR)] intermediates, see: a) A. V.
Vorogushin, X. Huang, S. L. Buchwald, J. Am. Chem. Soc. 2005,
127, 8146 – 8149; b) N. Kataoka, Q. Shelby, J. P. Stambuli, J. F.
Hartwig, J. Org. Chem. 2002, 67, 5553 – 5566; c) A. S. Guram, X.
Bei, H. W. Turner, Org. Lett. 2003, 5, 2485 – 2487.
[5] A recent report described Pd0- and PdII-catalyzed syntheses of 2-
vinyl isoxazolidines by cyclizations of hydroxylamines bearing
tethered allylic acetate groups. In contrast to the reactions
described in this paper, the cyclizations of the allyl acetate
À
derivatives do not lead to C C bond formation concomitant with
ring closure. The cyclizations of the allylic acetate derivatives are
also mechanistically distinct, as the Pd0-catalyzed transformation
proceeds via a p-allylpalladium intermediate which is likely
captured by an outer-sphere nucleophilic attack on the allyl
ligand, and the PdII-catalyzed transformation proceeds by alkene
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