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 isoxazolidine N-O bond 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 cycloaddition reactions between nitrones and alkenes,[4] which 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 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]
In this communication, we describe a new approach to the construction of substituted isoxazolidines that involves palladium-catalyzed carboetherification reactions of N-butenyl hydroxylamine derivatives with aryl bromides [Eq. (2)]. This method represents a new strategy for construction of the isoxazolidine ring, in which the O1-C5 bond and a C5′-Ar bond are formed in one step.[5] These transformations also provide access to isoxazolidine stereoisomers that cannot be generated with currently available methods. The reactions appear to proceed via intramolecular alkene insertion into previously unprecedented palladium alkoxyamine intermediates, which may be of utility in other Pd-catalyzed carbon-heteroatom bond-forming processes.
 |
(1) |
 |
(2) |
In preliminary experiments, we examined Pd-catalyzed reactions of N-butenyl hydroxylamines 1-3 with 4-bromobiphenyl using conditions that were employed in our prior studies on Pd-catalyzed carboetherification reactions of γ-hydroxyalkenes.[6-8] As shown below (Table 1), attempts to cyclize unprotected hydroxylamine substrate 1 or N-boc-protected derivative 2 were unsuccessful.[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% isolated yield.
Table 1.
Carboetherification of N-butenyl hydroxylamines[a]
Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 1.2 equiv NaOtBu, 2 mol % Pd(OAc)2, 2 mol% DPE-Phos, THF (0.125 M), 65 °C.
Yields represent average isolated yields for two or more experiments.
Heck arylation products were observed.
With viable reaction conditions and a suitable nitrogen protecting group identified, we examined Pd-catalyzed carboetherification reactions between several different substituted 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.
Table 2.
Pd-catalyzed synthesis of substituted isoxazolidines[a]
 | ||||
|---|---|---|---|---|
| Entry | Substrate | Isoxazolidine | dr[b] | Yield[b] |
| 1 |  |
 |
- | 85% |
| 2 |  |
 |
>20:1 (5:1) |
56% |
| 3 | 5 |  |
3:1 (3:1) |
70% |
| 4 | 5 |  |
>20:1 (3:1) |
57% |
| 5 |  |
 |
3:1 (3:1) |
77% |
| 6 | 6 |  |
3:1 (3:1) |
78% |
| 7 |  |
 |
3:1 (3:1) |
61% |
| 8 |  |
 |
>20:1 (10:1) |
82% |
| 9 | 8 |  |
>20:1 (10:1) |
85% |
| 10 |  |
 |
19:1 (9:1) |
94% |
| 11 | 9 |  |
>20:1 (9:1) |
89% |
| 12[d] |  |
 |
>20:1 (>20:1) |
78% |
| 13[d] | 10 |  |
>20:1 (>20:1) |
69% |
Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 1.2 equiv NaOtBu, 2 mol % Pd(OAc)2, 2 mol % DPE-Phos, THF (0.125 M), 65 °C.
dr = diastereomeric ratio of isolated material. Numbers in parentheses are the observed diastereomeric ratios for the crude reaction mixture.
Yields represent average isolated yields for two or more experiments.
The reaction was conducted at 110 °C in toluene solvent with Pd2(dba)3 (1 mol %) used in place of Pd(OAc)2.
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 cycloaddition methods. For example, Pd-catalyzed reactions of 10 with 4-bromobiphenyl or 3-bromobenzotrifluoride provide 22 and 23 in 78% and 69% isolated yields, with >20:1 diastereoselectivity and regioselectivity (Table 2, entries 12-13). In contrast, a 1,3-dipolar cycloaddition 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 dr to afford the 2R*,3aS*-hexahydropyrrolo[1,2b]isoxazole isomers 18-19 (entries 8-9). However, dipolar cycloadditions between 3,4-dihydropyrrole-1-oxide and allylbenzene derivatives instead generate stereoisomeric 2S*,3aS*-hexahydropyrrolo[1,2b]isoxazoles.[11] The hydroxylamine carboetherifications can also be used to prepare trans-4,5-disubstitued isoxazolidines 12-14 and cis-3,5-disubstituted isoxazolidines 15-17 in good yield with 3-5:1 diastereoselectivity.
A plausible mechanism for the isoxazolidine-forming reactions is shown in Scheme 1. These transformations appear to be mechanistically related to Pd-catalyzed carboetherification reactions of γ-hydroxy alkenes with aryl bromides,[6] and are likely initiated by oxidative addition of the aryl bromide to Pd(0) to afford 24. The LnPd(Ar)(Br) complex can then be transformed to intermediate 25 via reaction with the hydroxylamine substrate and NaOtBu. Intramolecular syn-oxypalladation[6,12] of the tethered alkene 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. Moreover, this model also accounts for the observed stereochemistry of 12-21, as the syn-oxypalladation likely occurs from an organized cyclic transition state in which nonbonding interactions 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).
Although palladium(aryl)alkoxides have been shown to be important intermediates in a number of catalytic processes,[6,14-15] the analogous complexes derived from hydroxylamines (e.g. 25) are unknown. The reactions described in this paper represent the first examples of catalytic transformations involving Pd(Ar)(ONRR’) species. These previously unknown intermediates will likely find additional applications in other metal-catalyzed carbon-heteroatom bond-forming reactions.[15]
In conclusion, we have developed a new stereoselective method for the construction of substituted isoxazolidines via Pd-catalyzed carboetherification reactions of unsaturated hydroxylamine substrates. In many cases the stereochemical outcome of these transformations is complementary to nitrone cycloadditions, and this method provides a new strategic disconnection that can be used for retrosynthetic analysis of substituted isoxazolidines.
Supplementary Material
Footnotes
This research was supported by the NIH-NIGMS (GM-071650). JPW 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.
References
- [1].For a review on the use of isoxazolidines as intermediates in complex molecule synthesis, see:Frederickson M. Tetrahedron. 1997;53:403–425.
- [2].a) Ishiyama H, Tsuda M, Endo T, Kobayashi J. Molecules. 2005;10:312–316. doi: 10.3390/10010312. [DOI] [PMC free article] [PubMed] [Google Scholar]; b) Minter AR, Brennan BB, Mapp AK. J. Am. Chem. Soc. 2004;126:10504–10505. doi: 10.1021/ja0473889. [DOI] [PubMed] [Google Scholar]; c) Palmer GC, Ordy MJ, Simmons RD, Strand JC, Radov LA, Mullen GB, Kinsolving CR, St. Georgiev V, Mitchell JT, Allen SD. Antimicrob. Agents. Chemother. 1989;33:895–905. doi: 10.1128/aac.33.6.895. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].a) Lait SM, Rankic DA, Keay BA. Chem. Rev. 2007;107:767–796. doi: 10.1021/cr050065q. [DOI] [PubMed] [Google Scholar]; b) Revuelta J, Cicchi S, Brandi A. Tetrahedron Lett. 2004;45:8375–8377. [Google Scholar]; c) LeBel NA, Balasubramanian N. J. Am. Chem. Soc. 1989;111:3363–3368. [Google Scholar]; d) Iida H, Kasahara K, Kibayashi C. J. Am. Chem. Soc. 1986;108:4647–4648. [Google Scholar]
- [4].For reviews on 1,3-dipolar cycloaddition reactions, see:Confalone PN, Huie EM. Org. React. 1988;36:1–173.Gothelf KV, Jorgensen KA. Chem. Commun. 2000:1449–1458.Kanemasa S. Synlett. 2002:1371–1387.Koumbis AE, Gallos JK. Curr. Org. Chem. 2003;7:585–628.Merino P. In: Science of Synthesis (Houben-Weyl Methods of Molecular Transformations) Padwa A, editor. Vol. 27. Thieme; Stuttgart: 2004. pp. 511–580.Pandey G, Banerjee P, Gadre SR. Chem. Rev. 2006;106:4484–4517. doi: 10.1021/cr050011g.Molteni G. Heterocycles. 2006;68:2177–2202.
- [5].A recent report described Pd(0)- and Pd(II)-catalyzed syntheses of 2-vinyl isoxazolidines via cyclizations of hydroxylamines bearing tethered allylic acetate groups. In contrast to the reactions described in this paper, the cyclizations of the allyl acetate 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 Pd(0)-catalyzed transformation proceeds via a π-allylpalladium intermediate which is likely captured via an outer-sphere nucleophilic attack on the allyl ligand, and the Pd(II)-catalyzed transformation proceeds via alkene activation followed by outer-sphere anti-oxypalladation. No evidence exists for the intermediacy of LnPd(ONR2)(allyl) complexes that bear a Pd-O bond. See:Merino P, Tejero T, Mannucci V, Prestat G, Madec D, Poli G. Synlett. 2007:944–948.For additional discussion of Pd-catalyzed allylations of nucleophiles containing an N-O bond, see:Miyabe H, Yoshida K, Reddy VK, Matsumura A, Takemoto Y. J. Org. Chem. 2005;70:5630–5635. doi: 10.1021/jo050632+.
- [6].a) Wolfe JP, Rossi MA. J. Am. Chem. Soc. 2004;126:1620–1621. doi: 10.1021/ja0394838. [DOI] [PubMed] [Google Scholar]; b) Hay MB, Hardin AR, Wolfe JP. J. Org. Chem. 2005;70:3099–3107. doi: 10.1021/jo050022+. [DOI] [PMC free article] [PubMed] [Google Scholar]; c) Hay MB, Wolfe JP. J. Am. Chem. Soc. 2005;127:16468–16476. doi: 10.1021/ja054754v. [DOI] [PMC free article] [PubMed] [Google Scholar]; d) Hay MB, Wolfe JP. Tetrahedron Lett. 2006;47:2793–2796. doi: 10.1016/j.tetlet.2006.02.066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].For a review on Pd-catalyzed carboetherification and carboamination reactions of γ-hydroxy- or γ-amino alkenes, see:Wolfe JP. Eur. J. Org. Chem. 2007:571–582.
- [8].Two recent reports have described a related approach to the synthesis of cis-3,5-disubstituted isoxazolidines in which the N-C3 bond is generated via Pd-catalyzed carboamination of O-homoallyl hydroxylamines. The scope of these transformations has not been fully explored. See:Dongol KG, Tay BY. Tetrahedron Lett. 2006;47:927–930.Peng J, Lin W, Yuan S, Chen Y. J. Org. Chem. 2007;72:3145–3148. doi: 10.1021/jo0625958.
- [9].The major products observed in these reactions resulted from Heck-arylation of the alkene.
- [10].DPE-Phos = bis(diphenylphosphinophenyl)ether.
- [11].Iida H, Watanabe Y, Kibayashi C. J. Chem. Soc., Perkin Trans. 1. 1985:261–266. [Google Scholar]
- [12].For other recent studies on syn-alkene insertions into late transition metal-oxygen bonds, see:Bryndza HE, Calabrese JC, Wreford SS. Organometallics. 1984;3:1603–1604.Bennett MA, Jin H, Li S, Rendina LM, Willis AC. J. Am. Chem. Soc. 1995;117:8335–8340.Hamed O, Thompson C, Henry PM. J. Org. Chem. 1997;62:7082–7083. doi: 10.1021/jo971051q.Hayashi T, Yamasaki K, Mimura M, Uozumi Y. J. Am. Chem. Soc. 2004;126:3036–3037. doi: 10.1021/ja031946m.Trend RM, Ramtohul YK, Stoltz BM. J. Am. Chem. Soc. 2005;127:17778–17788. doi: 10.1021/ja055534k.Zhao P, Incarvito CD, Hartwig JF. J. Am. Chem. Soc. 2006;128:9642–9643. doi: 10.1021/ja063347w.
- [13].a) Milstein D, Stille JK. J. Am. Chem. Soc. 1979;101:4981–4991. [Google Scholar]; b) Hartwig JF. Inorg. Chem. 2007;46:1936–1947. doi: 10.1021/ic061926w. [DOI] [PubMed] [Google Scholar]
- [14].For examples of well-characterized LnPd(Ar)(OR) complexes, see:Mann G, Hartwig JF. J. Am. Chem. Soc. 1996;118:13109–13110.Widenhoefer RA, Zhong HA, Buchwald SL. J. Am. Chem. Soc. 1997;119:6787–6795.
- [15].In addition to carboetherification reactions of γ-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 transformations involving LnPd(Ar)(OR) intermediates, see:Vorogushin AV, Huang X, Buchwald SL. J. Am. Chem. Soc. 2005;127:8146–8149. doi: 10.1021/ja050471r.Kataoka N, Shelby Q, Stambuli JP, Hartwig JF. J. Org. Chem. 2002;67:5553–5566. doi: 10.1021/jo025732j.Guram AS, Bei X, Turner HW. Org. Lett. 2003;5:2485–2487. doi: 10.1021/ol0347287.
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