You are on page 1of 4


Tetrahedron Letters 47 (2006) 927–930

Palladium(0)-catalyzed cascade one-pot synthesis of isoxazolidines
Krishna Gopal Dongol* and Boon Ying Tay
Institute of Chemical and Engineering Sciences, 1 Pesek Road, Jurong Island, Singapore 627833, Singapore
Received 29 September 2005; revised 25 November 2005; accepted 30 November 2005
Available online 20 December 2005

Abstract—A highly diastereoselective cascade reaction protocol has been developed for the synthesis of isoxazolidine derivatives
utilizing aryl halides, O-homoallyl hydroxylamine and palladium(0) in a one-pot reaction.
Ó 2005 Elsevier Ltd. All rights reserved.

The use of palladium-catalyzed cascade reactions in the cess. This chemistry could potentially offer a convenient
synthesis of heterocyclic compounds of biological inter- entry to 3,5-disubstituted isoxazolidines, which serve as
est continues to receive widespread attention.1 Recently, valuable synthetic building blocks for the construction
heterocyclic rings such as tetrahydrofurans2 and pyrrol- of bioactive natural products5,6 and as precursors for
idines3 were synthesized with good to excellent stereo- b-amino ketones.7
selectivity by the cascade method, employing a suitable
Pd0 catalyst and the requisite aryl halides and alkenes. To examine this hypothesis, a series of N-Boc protected
There are no reports, however, describing the use of a hydroxylamines 4 were prepared from the correspond-
palladium-mediated cascade sequence for substrates ing alcohols 18 via the Mitsunobu protocol.9 O-Homo-
containing an alkene with tethered nitrogen, in which allylic alcohol 1 was treated with N-hydroxyphthalimide,
the construction of both C–N and C–C bonds could triphenylphosphine (PPh3) and diethyl azodicarboxylate
conceivably be achieved in a one-pot event.4 We decided (DEAD) in THF furnishing hydroxylamine ether 2. The
to investigate this area using functionalized O-homoallyl phthaloyl moiety (Phth) was then cleaved by treatment
hydroxylamines such as 4 where the N–O bond would with hydrazine hydrate at 0 °C to room temperature,
serve as a tether in facilitating an intramolecular pro- leading to O-homoallyl hydroxylamine 3.10 Protection

NPhth NH2
OH N-hydroxylphthalimide O hydrazine hydrate O

DEAD, PPh3, 0 °C - rt, DCM
1 THF, 0 °C - rt 2 3

di-tert-butyl dicarbonate

R Yield Boc ArI, Boc
Pd2(dba)3 NH
N Ph
5a Ph, 80% O NaOtBu O
5b p-MeOC6H4, 84%
5c 2-furyl 76% R R
dppe, toluene
5 reflux 4

Scheme 1.

Keywords: Cascade reaction; Palladium(0); Isoxazolidine; O-Homoallyl hydroxylamine.
* Corresponding author. Tel.: +65 6796 3917; fax: +65 6316 6184; e-mail:

0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.

Ph. we are unable to isolate pure cyclized compounds 6. A possible explanation is 7b was found when P(tBu)3 was employed. B. Substituent effects Entry R R0 GC yielda (%) Cis/transb ratio of 6 6 7 a Ph Ph 52 48 6:1 b p-MeOC6H4 Ph 64 36 10:1 c 2-Furyl Ph 74 26 3:1 d CH3 Ph 11 89 — e p-MeOC6H4 p-MeOC6H4 8 92 — f p-MeOC6H4 p-O2NC6H4 61 39 2:1 a The ratio (%) was based on gas chromatographic analysis. Entry P-ligands GC yielda (%) It was evident that the substituents R and R 0 influenced 6b 7b the ratio of products obtained to some degree. Unfortunately. the effect of catalyst loading was examined. role in the observed product ratio. Dongol. 2-furyl) and aryl iodides (R 0 = p-MeOC6H4.11 To Scheme 2. setting the stage for the investigation of palla. (GC) analysis based on 100% conversion. . an attempted Pd2(dba)3-catalyzed However. NaOtBu. of 3 as its N-Boc carbamate then completed the synthe. a from direct amination of iodobenzene with 4 was reversed product distribution favouring the Heck adduct observed as the sole product. p-MeOC6H4. this modified procedure. In the initial studies. tuted N-Boc-hydroxylamine ethers (Ph. across the terminal olefin to afford intermediate 9. Substituent effects. an approximately 3:1 ratio in the desired isoxazolidine 6. the choice of the phosphine ligand does play a reaction between N-Boc hydroxylamine ether 4 and iodo. The relative rates of the subsequent b-hydride elimina- p-O2NC6H4). Boc Pd2(dba)3. while if R 0 was an electron 3 P(o-Tol)3 79 21 donating group the Heck type product 7 was preferred. 20 h 6 7 reflux a R = Ph R' = Ph c R = 2-furyl R' = Ph b R = p-MeOC6H4 R' = Ph d R = Me R' = Ph Scheme 2. Y. for example. b The cis/trans ratio of 6 was based on 1H NMR analysis.928 K. abstracts the amide are summarized in Table 2 in reference to the reaction in N-hydrogen and thus facilitates N-arylation. no improvement in product distribution sis of 4. 1 to 20 mol %. amide 5 resulting favour of isoxazolidine 6b was observed. In the case of entries 4 and 5. In order to suppress the formation of the undesired Heck a The product ratio and conversion was based on gas chromatographic product 7. was obtained in 60% isolated yield. where an initial oxidative insertion of Pd0 into To determine the scope of this reaction. a series of the aryl halide R 0 X is followed by syn carbopalladation reactions were carried out with a variety of R-substi. was observed when the catalyst loading was varied from dium-mediated isoxazolidine formation (Scheme 1). The best result for the isoxazolidine 6b over circumvent the formation of this undesired product. Tay / Tetrahedron Letters 47 (2006) 927–930 Boc R'I. In the presence of benzene in the presence of NaOtBu failed to provide P(Cy)3 or P(o-Tol)3. In contrast. when R was electron donating in nature. In gen. Heck type product 7b was obtained when 1 mol% P(o- Cs2CO3 was employed as an alternative. Ligand effects reference to Scheme 2. Table 1. isoxazolidine 6b. G. Boc NH NH O P-ligand O N O R' + R' R R R Cs2CO3 4 toluene. These results that the strong base. in 21% yield as shown in summarized in Figure 1. The first part of the catalytic Scheme 2. cycle is believed to proceed through the standard Heck pathway. the cyclic 2 P(Cy)3 72 28 product 6 was favoured. together with the A mechanistic rationale for the observed products is Heck coupling adduct 7b. 1 dppe 52 48 eral. tion versus nitrogen coordination in intermediate 9 The product distribution is summarized in Table 1 in Table 2.12 and under Tol)3 was used. 4 P(tBu)3 30 70 R = p-MeOC6H4 and R 0 = Ph. Me. Instead.

In Handbook of Organopalladium Chemistry for Organic Synthesis..44 mmol) iodoben- In summary. Webb. Chem. H. B. The stereochemistry of the major 9. isomer of 6b was determined by NOE and NOESY15 10. N Pd O R'PdIIX R' R 8 9 References and notes β -elimination Boc 1. Org. J. Toluene (5 mL) and 100 mg of N-Boc hydroxylamine 4b (0. R. Iida. Tetrahedron the carbonyl oxygen of the N-Boc group may also offer Lett. Conformations leading to the cis selectivity. 1 8. 6. Monteiro.5-substituents in 7. E. Bossharth. Innovations in Organic Synthesis. Eur. Commun. Ranagappa. 2003. 36. 0. H NMR spectrum. 4225–4227. for his helpful suggestions and elimination addition Dr. 2002. Janza. Grigg. 5949–5952. M. P(o-Tol)3 favours product 6 over b-hydride elimination 222723. J. M. J. Representative experimental procedure: A 50 mL Schlenk A rationale for the cis selectivity can be gained by exam. J.003 mmol). 1988. 2002. A. then the formation of isoxazolidines 6 has been developed. M..3 equiv. the use of P(Cy)3 or J. Ed.. Chem. Thornton-Pett. Rossi. 43. Louie. Moreover. Eur. The Schlenk flask formation of the cis-diastereomer as the major product. Hosomi.. 50. 1980. intramolecular chelation. Wiley and Sons. Ladlow. 54.0034 mmol) 1. ining the reactive conformations (Fig. Chelation of 0. Y. Germany. T. 12. 2225–2233. J... S. P. A 10:1 the cis/trans ratio14 of the 3. ate 9 and suppressing b-hydride elimination. 93. Abstr. 2003. thereby stabilizing intermedi- 5. M. Technology R Pd0 and Research (A*STAR) of Singapore under project 6 code ICES 03-142001. J. (e) Frederickson. Wiley and Sons: Chich- ester.. Petrier. 2004. Synthesis 2002. T. 2211– 2225. K. B. . C. S. Murahashi. A. Studer. Quinn. Balme. N. Tetrahedron isoxazolidine 6b was established by integration of the Lett. K. R 3605–3608. 1754–1755. 2000. (b) Haken.. Tetrahedron Lett. Szapacs. 279–282. 126. 1–7. Ney. Dongol. p-O2NC6H4. 4. E. Negi- R' = p-MeOC6H4... Wolfe. product 7. 1991. Chem. 1995.. Angew. G. 133.-I. Kasahara. Chem. 1035122 A1. a novel. R. studies. pp 2129–2169. Proposed catalytic cycle leading to 6 and 7. 2024218. A. T. 0... ence of electron-donating phosphine ligands on the Pd S. A sys. Grigg. 1980. Abstr. 3612. Evaporation of the solvent provided the crude underway. for checking the English in this H Boc manuscript. cascade sequence leading to the zene were added to the flask under argon. Chem.. R' Boc 2. Bates. 2000. Sa-Ei.. M. 32. GB Pat. Redpath. Palladium Reagents and Catalysts: Figure 1.. P. S. Ed.-I. 7 O 3. P. The pres. K.. Y. 0. and is believed to arise from transition state A 11. pp 510–527..44 mmol).. Org. 29. (a) Ravi Kumar. 2002.4 mg (1 mol %. The authors HX Pd-N insertion/ also wish to thank Prof. M.-I.. leading to the ino)ethane (dppe) using a glove box. J. Sridharan. R. K. 1995. product which was further purified by flash column Ar' Boc PdII Boc Ar' II O N Ar O N Ar Pd Ar' O N Ar' O N H Boc H Boc Ar Ar A B Figure 2.. (a) Hosokawa. L. Org. Murahashi. J. 1. additional stabilization through its participation via Markandu. PdII with the nitrogen lone pair is favoured in conforma. C. 4 4. Wolfe. reaction mixture was refluxed for 20 h. Saber. flask was charged with 3. determine the observed product distribution. The mixture was tematic study of substituent effects and the application filtered through a pad of silica gel and washed with ethyl of this route to natural product synthesis is currently acetate. Tay / Tetrahedron Letters 47 (2006) 927–930 929 Boc Acknowledgements N O R' R'X The authors thank the Agency for Science.. (d) Grigg.-L. R NH 1620–1621.2-bis(diphenylphosph- tion A as compared to conformation B. Int. Luche.. B. for financial support. NH O Chem. J. 3609– as depicted in Figure 2. T. J.13 hence. 15051–15060.. Moore. Tetra- hedron 1997. 145 mg Cs2CO3 (1. G. J. Chem. Ph shi. 1989. J. EU Pat. K. Mallesha. 910–912. Am. (c) Aftab. Chem.. B.3 equiv.. H. S. Chem. Lett. J. 2117–2123. H. 4101–4111. (b) Tsuji.. Felicity K. V. Markandu.34 mmol) and 90 mg (1. Hartwig. Zhang. E.. 2). J. R. 1985. University reductive oxidative of Hannover... 53. was then evacuated and back filled with argon three times. Med. J. Holger Butenschoen. Soc 2004. R. E. Thornton-Pett. will accelerate C–N bond formation by accelerating 132471. W. Kibayashi.1 mg Pd2(dba)3 (1 mol %. Org. the reductive elimination. Kodera.

found 369. 1H. 9H).05 (dt. 156. Hartwig. 4. J 15. J 6.1. 1H). CDCl3): d 159. 3. 236 (89). 1H. 126. CDCl3): d 159.4 MHz. 1H). 6.9. 152 (42). 0. 1H.83 H H H H H (m. 127. 1612.9. d = 3. H HH H H HH 7.2 Hz). The cis/trans ratio of isoxazolidine 6b was determined as NMR (100. EIMS: m/z (70 eV) 369 (2).7. 135 (100. S.4 MHz.17 (m. 127. J. 3.13 (m.1.73 ppm for major isomer and d = 3. 56 (33). 1248. 0. J 8. 1033.2. Dongol. 27.20–7. 2977. 10:1 from 1H NMR integration of the OMe resonance at 128. 3H. S.6. HRMS C22H27NO4: calcd 369. 4708–4709. 1515.7. Hartwig. 60%) as a colourless oil and Heck product 7b 38. found 369. 28.7.54 (m.84 (br s. (a) Driver.6.1. 2.1. Soc. 830 cm1. G. 86. 1250. J. 1. Tay / Tetrahedron Letters 47 (2006) 927–930 chromatography which afforded isoxazolidine 6b (73 mg.73 (s. 41 (61). J 15. 128. 1035. 127.8.0 Hz).4. 1H. 3. 57 (47). 113.5. (39).2 Hz ). Boc 1367.83 (d. F. OCH3). 1367.79 ppm for 41.70 (s.5. 91 15. 2H. Boc O N O N CDCl3): d 7.59 (m. 131.6. 1760. 1H. 21%) as a colourless oil. J.6 Hz). 121 Compound 6b: IR (neat): m 3314.2. M.37 (d. M. The NOESY experimental data showed a distinct corre- (79).5. Soc. J. 1H.4. 205 (57). (b) Driver.5. EI MS: m/z (70 eV) 369 (2).1943. 1305.1. 119.8 Hz). F. HRMS: C22H27NO4: calcd 1615. 1H). 178 (78). 6. J 8.4.94 (m.1943. 252 (11). Am. 6. CDCl3): d 7. 119 (80). 830 cm1. 1732. OCH3). 41 (57). Am. 1172. 91 (67).11 (dd. 60. 7. 54. J 6. 8232–8245.4 Hz) 4. 7H).9 Hz). 125.37 (s. 2.2 mmol. 1H.6. 2. Compound 7b: IR (neat): m 3307. 7. 125.4. 13C NMR O O 1 (100.1947..1943.44 (m.4. 369. 81. B. 252 (13). 1H). 1. 13C 14. 80. 137.80 (d.9. 1683. lation between the protons H-3 and H-5. 236 minor isomer. 128. 1995. 132. 1440. 41. J 6.3. 13.. (27 mg. 1173. 135 (100). 2978. 2933. 137. 55.07 mmol.5. 156. Chem. 1 H NMR (400 MHz.2.6. 279 (2). 3H.8.74 (t. 2. 6. 2H.77 (dd. 1. (77). 4. H-noesy noe .5. Y.930 K. 117.2 Hz). 9H). 6.74 (dd. 162 (37). 7H).3. 1H NMR (400 MHz. NH) 6.7. 178 (63). 205 (15). M+1). 1997. 128.4. 2934. J Chem. 3.37 (s. 112. J. 1H). 81.