Tetrahedron

Letters
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

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

di-tert-butyl dicarbonate
NaOH/DCM

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: [email protected]

0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.148
928 K. G. Dongol, B. Y. Tay / Tetrahedron Letters 47 (2006) 927–930

Boc R'I, Boc

Pd2(dba)3, Boc
NH NH
O P-ligand O N O
R'
+ R'
R R R
Cs2CO3
4 toluene, 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. Substituent effects.

Table 1. 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.
b
The cis/trans ratio of 6 was based on 1H NMR analysis. In the case of entries 4 and 5, we are unable to isolate pure cyclized compounds 6.

of 3 as its N-Boc carbamate then completed the synthe- Unfortunately, no improvement in product distribution
sis of 4, setting the stage for the investigation of palla- was observed when the catalyst loading was varied from
dium-mediated isoxazolidine formation (Scheme 1). 1 to 20 mol %.

In the initial studies, an attempted Pd2(dba)3-catalyzed However, the choice of the phosphine ligand does play a
reaction between N-Boc hydroxylamine ether 4 and iodo- role in the observed product ratio. In the presence of
benzene in the presence of NaOtBu failed to provide P(Cy)3 or P(o-Tol)3, an approximately 3:1 ratio in
the desired isoxazolidine 6. Instead, amide 5 resulting favour of isoxazolidine 6b was observed. In contrast, a
from direct amination of iodobenzene with 4 was reversed product distribution favouring the Heck adduct
observed as the sole product. A possible explanation is 7b was found when P(tBu)3 was employed. These results
that the strong base, NaOtBu, abstracts the amide are summarized in Table 2 in reference to the reaction in
N-hydrogen and thus facilitates N-arylation.11 To Scheme 2. The best result for the isoxazolidine 6b over
circumvent the formation of this undesired product, Heck type product 7b was obtained when 1 mol% P(o-
Cs2CO3 was employed as an alternative,12 and under Tol)3 was used.
this modified procedure, isoxazolidine 6b, for example,
was obtained in 60% isolated yield, together with the A mechanistic rationale for the observed products is
Heck coupling adduct 7b, 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, 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- across the terminal olefin to afford intermediate 9.
tuted N-Boc-hydroxylamine ethers (Ph, p-MeOC6H4,
Me, 2-furyl) and aryl iodides (R 0 = p-MeOC6H4, Ph, The relative rates of the subsequent b-hydride elimina-
p-O2NC6H4). tion versus nitrogen coordination in intermediate 9

The product distribution is summarized in Table 1 in Table 2. Ligand effects

reference to Scheme 2.
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. In gen- 1 dppe 52 48
eral, when R was electron donating in nature, the cyclic 2 P(Cy)3 72 28
product 6 was favoured, while if R 0 was an electron 3 P(o-Tol)3 79 21
donating group the Heck type product 7 was preferred. 4 P(tBu)3 30 70
R = p-MeOC6H4 and R 0 = Ph.
In order to suppress the formation of the undesired Heck a
The product ratio and conversion was based on gas chromatographic
product 7, the effect of catalyst loading was examined. (GC) analysis based on 100% conversion.
 K. G. Dongol, B. Y. Tay / Tetrahedron Letters 47 (2006) 927–930 929

Boc Acknowledgements
N
O R'
R'X The authors thank the Agency for Science, Technology
R Pd0 and Research (A*STAR) of Singapore under project
6
code ICES 03-142001, for financial support. The authors
HX Pd-N insertion/
also wish to thank Prof. Holger Butenschoen, University
reductive oxidative of Hannover, Germany, for his helpful suggestions and
elimination addition Dr. Felicity K. Moore, for checking the English in this
H Boc manuscript.
N Pd
O R'PdIIX
R'
R 8
9 References and notes
β -elimination
Boc 1. Balme, G.; Bossharth, E.; Monteiro, N. Eur. J. Org.
NH
O Chem. 2003, 4101–4111.
R' Boc 2. Wolfe, J. P.; Rossi, M. A. J. Am. Chem. Soc 2004, 126,
R NH 1620–1621.
7 O
3. Ney, J. E.; Wolfe, J. P. Angew. Chem., Int. Ed. 2004, 43,
R 3605–3608.
4 4. (a) Hosokawa, T.; Murahashi, S.-I. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negi-
R' = p-MeOC6H4, p-O2NC6H4, Ph shi, E.-I., Ed.; Wiley and Sons, 2002; pp 2129–2169, 2211–
2225; (b) Tsuji, J. Palladium Reagents and Catalysts:
Figure 1. Proposed catalytic cycle leading to 6 and 7.
Innovations in Organic Synthesis; Wiley and Sons: Chich-
ester, 1995, pp 510–527; (c) Aftab, T.; Grigg, R.; Ladlow,
M.; Sridharan, V.; Thornton-Pett, M. Chem. Commun.
determine the observed product distribution. Moreover, 2002, 1754–1755; (d) Grigg, R.; Markandu, J. Tetrahedron
the carbonyl oxygen of the N-Boc group may also offer Lett. 1991, 32, 279–282; (e) Frederickson, M.; Grigg, R.;
additional stabilization through its participation via Markandu, J.; Thornton-Pett, M.; Redpath, J. Tetra-
hedron 1997, 53, 15051–15060.
intramolecular chelation, thereby stabilizing intermedi-
5. (a) Ravi Kumar, R. K.; Mallesha, H.; Ranagappa, B. K.
ate 9 and suppressing b-hydride elimination. The pres- S. Eur. J. Med. Chem. 2003, 1–7; (b) Haken, P. T.; Webb,
ence of electron-donating phosphine ligands on the Pd S. B. GB Pat. 2024218, 1980; Chem. Abstr. 1980, 93,
will accelerate C–N bond formation by accelerating 132471; Saber, S. H.; Zhang, L. Szapacs, E. M.; Quinn,
the reductive elimination,13 hence, the use of P(Cy)3 or J. A. EU Pat. 1035122 A1, 2000; Chem. Abstr. 2000, 133,
P(o-Tol)3 favours product 6 over b-hydride elimination 222723.
product 7. 6. Kasahara, K.; Iida, H.; Kibayashi, C. J. Org. Chem. 1989,
54, 2225–2233.
A 10:1 the cis/trans ratio14 of the 3,5-substituents in 7. Murahashi, S.-I.; Kodera, Y.; Hosomi, T. Tetrahedron
isoxazolidine 6b was established by integration of the Lett. 1988, 29, 5949–5952.
1 8. Petrier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910–912.
H NMR spectrum. The stereochemistry of the major
9. Bates, R. W.; Sa-Ei, K. Org. Lett. 2002, 4, 4225–4227.
isomer of 6b was determined by NOE and NOESY15 10. Janza, B.; Studer, A. Synthesis 2002, 2117–2123.
studies, and is believed to arise from transition state A 11. Louie, J.; Hartwig, J. Tetrahedron Lett. 1995, 36, 3609–
as depicted in Figure 2. 3612.
12. Representative experimental procedure: A 50 mL Schlenk
A rationale for the cis selectivity can be gained by exam- flask was charged with 3.1 mg Pd2(dba)3 (1 mol %,
ining the reactive conformations (Fig. 2). Chelation of 0.003 mmol), 145 mg Cs2CO3 (1.3 equiv, 0.44 mmol),
PdII with the nitrogen lone pair is favoured in conforma- 1.4 mg (1 mol %, 0.0034 mmol) 1,2-bis(diphenylphosph-
tion A as compared to conformation B, leading to the ino)ethane (dppe) using a glove box. The Schlenk flask
formation of the cis-diastereomer as the major product. was then evacuated and back filled with argon three times.
Toluene (5 mL) and 100 mg of N-Boc hydroxylamine 4b
(0.34 mmol) and 90 mg (1.3 equiv, 0.44 mmol) iodoben-
In summary, a novel, cascade sequence leading to the zene were added to the flask under argon, then the
formation of isoxazolidines 6 has been developed. A sys- reaction mixture was refluxed for 20 h. 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. Evaporation of the solvent provided the crude
underway. 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. Conformations leading to the cis selectivity.

930 K. G. Dongol, B. Y. Tay / Tetrahedron Letters 47 (2006) 927–930

chromatography which afforded isoxazolidine 6b (73 mg, 128.7, 128.4, 127.1, 126.1, 125.4, 113.9, 86.7, 81.6, 55.3,
0.2 mmol, 60%) as a colourless oil and Heck product 7b 38.6, 28.2. EI MS: m/z (70 eV) 369 (2), 279 (2), 252 (13),
(27 mg, 0.07 mmol, 21%) as a colourless oil. 236 (89), 205 (57), 178 (63), 152 (42), 135 (100, M+1), 121
Compound 6b: IR (neat): m 3314, 2977, 2934, 1732, 1683, (77), 91 (67), 56 (33), 41 (57). HRMS: C22H27NO4: calcd
1615, 1515, 1440, 1367, 1305, 1250, 1173, 1035, 830 cm
1. 369.1943, found 369.1947.
1
H NMR (400 MHz, CDCl3): d 7.17 (m, 7H), 6.80 (d, 2H, 13. (a) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1995,
J 8.4 Hz) 4.74 (dd, 1H, J 6.4, 3.6 Hz), 4.44 (m, 1H), 3.73 (s, 117, 4708–4709; (b) Driver, M. S.; Hartwig, J. J. F. J. Am.
3H, OCH3), 3.11 (dd, 1H, J 6.4, 7.2 Hz), 2.77 (dd, 1H, J Chem. Soc. 1997, 119, 8232–8245.
7.6, 6.0 Hz), 2.54 (m, 1H), 1.94 (m, 1H), 1.37 (s, 9H). 13C 14. The cis/trans ratio of isoxazolidine 6b was determined as
NMR (100.4 MHz, CDCl3): d 159.7, 156.5, 137.1, 128.5, 10:1 from 1H NMR integration of the OMe resonance at
128.1, 127.5, 127.1, 125.4, 112.9, 81.8, 80.7, 60.9, 54.3, d = 3.73 ppm for major isomer and d = 3.79 ppm for
41.5, 41.2, 27.2. EIMS: m/z (70 eV) 369 (2), 252 (11), 236 minor isomer.
(39), 205 (15), 178 (78), 162 (37), 135 (100), 119 (80), 91 15. The NOESY experimental data showed a distinct corre-
(79), 57 (47), 41 (61). HRMS C22H27NO4: calcd 369.1943, lation between the protons H-3 and H-5.
found 369.1943.
Compound 7b: IR (neat): m 3307, 2978, 2933, 1760, 1612,
Boc
1367, 1248, 1172, 1033, 830 cm
1. 1H NMR (400 MHz, Boc
O N O N
CDCl3): d 7.20–7.13 (m, 7H), 6.84 (br s, 1H, NH) 6.83 (d,
2H, J 8.2 Hz), 6.37 (d, 1H, J 15.8 Hz), 6.05 (dt, 1H, J 15.8, H HH
H H HH
7.2 Hz ), 4.74 (t, 1H, J 6.9 Hz), 3.70 (s, 3H, OCH3), 2.83 H H H
H H
(m, 1H), 2.59 (m, 1H), 1.37 (s, 9H). 13C NMR O
O
1
(100.4 MHz, CDCl3): d 159.6, 156.5, 137.4, 132.5, 131.6, H-noesy noe