O-alkenyl hydroxylamines: A new concept for cyclofunctionalization

Article abstract of DOI:10.1021/ol026701d

(equation presented) Treatment of O-homoallylhydroxylamines with palladium(II) and copper(II) in the presence of a base, methanol, and carbon monoxide results in the formation of isooxazolidines. An electron-withdrawing group on the hydroxylamine nitrogen

Full text of DOI:10.1021/ol026701d

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4225-4227
O-Alkenyl Hydroxylamines: A New
Concept for Cyclofunctionalization
,†
Roderick W. Bates* and Kanicha Sa-Ei‡
Laboratory of Medicinal Chemistry, Chulabhorn Research Institute,
VibahaVadi-Rangsit Highway, Laksi, Bangkok 10210, Thailand, and Department of
Chemistry, Chulalongkorn UniVersity, Phaya Thai Road, Patumwan,
Bangkok 10330, Thailand
roderick@tubtim.cri.or.th
Received August 8, 2002
ABSTRACT
Treatment of O-homoallylhydroxylamines with palladium(II) and copper(II) in the presence of a base, methanol, and carbon monoxide results
in the formation of isooxazolidines. An electron-withdrawing group on the hydroxylamine nitrogen is essential. When carbamate groups are
used the products are formed exclusively as their cis isomers.
The cyclofunctionalization1 of tethered N-nucleophiles is a
valuable process for the stereo- and regiocontrolled formation
of C-N bonds, and it has found numerous uses in synthesis.2
Typical tethers require an sp2-hybridized carbon atom and
result in 1,2- or 1,3-stereocontrol via a five- or a six-
membered-ring heterocyclic intermediate.3
Mitsunobu reaction of the corresponding alcohols 16 using
N-hydroxyphthalimide.7 Without purification, the phthaloyl
group was cleaved by treatment with hydrazine hydrate at
room temperature, to give the hydroxylamines 3 in good yield
after chromatographic purification (Table 1).
Surprisingly, little work has been done concerning the use
of transition metal electrophiles as cyclofunctionalization
triggers4 for alkenes with tethered nitrogen despite the
potential for concurrent stereocontrolled C-N and C-C
bond formation.5
Table 1. Yields (%) for Preparation of Substrates
4
5
6
7
2
3
Z ) CO2Me
Z ) Ns
Z ) CBZ Z ) t-Boc
a
b
c
nda
nda
52
82b
49b
51
91
92
90
51
93
90
56
We sought to address these issues by employing O-,N-
functionalized hydroxylamines in which the tether would be
just an O-N single bond. In this way, a five-membered-
ring heterocyclic intermediate might result in 1,3-stereocon-
trol. With this aim, the hydroxylamines 3 were prepared by
a nd: not determined. b Over two steps.
The N-unsubstituted hydroxylamine 3a failed to cyclize
under typical conditions. The hydroxylamines were therefore
derivatized with a series of standard N-protecting groups
(Z1-Z4).8 With an electron-withdrawing group on nitrogen,
† Chulabhorn Research Institute.
‡ Chulalongkorn University.
(1) Frederickson, M.; Grigg, R. Org. Prepr. Proc. Int. 1997, 29, 33.
(2) For reviews, see: Cardillo, G.; Orena, M. Tetrahedron 1990, 46,
3321. Knapp, S. Chem. Soc. ReV. 1999, 28, 61.
(3) For example: Hirama, M.; Iwashita, M.; Yamazaki, Y.; Ito, S.
Tetrahedron Lett. 1984, 25, 4963. Snider, B. B.; Hawryluk, N. A. Org.
Lett. 2000, 2, 635. Kang, S. H.; Hwang, Y. S.; Youn, J.-H. Tetrahedron
Lett. 2001, 42, 7599.
(6) Pe´trier, C.; Luche, J.-L. J. Org. Chem. 1985, 50, 910.
(7) Totah, N. I.; Schreiber, S. L. J. Org. Chem. 1991, 56, 6255. Iwagami,
H.; Yatagai, M.; Nakazawa, M.; Orita, H.; Honda, Y.; Ohnuki, T.; Yukawa,
T. Bull. Chem. Soc. Jpn. 1991, 64, 175.
(4) For an example, see: Tamaru, Y.; Tanigawa, H.; Itoh, S.; Kimura,
M.; Tanaka, S.; Fugami, K.; Sekiyama, T.; Yoshida, Z.-I. Tetrahedron Lett.
1992, 33, 631.
(8) Standard methods for N-functionalization were used. Z ) CO2Me:
Corey, E. J.; Bock, M. G.; Kozikowski, A. P.; Rama Rao, A. V.; Floyd,
D.; Lipschutz, B. Tetrahedron Lett. 1978, 1051. Z ) t-Boc: Tarbell, D. S.;
Yamamoto, Y.; Pope, B. M. Proc. Natl. Acad. Sci. U.S.A. 1972, 69, 730.
(5) Frederickson, M.; Grigg, R. Org. Prepr. Proc. Int. 1997, 29, 65.
10.1021/ol026701d CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/06/2002

Pd black) prior to completion (entries 1, 4, and 8). We
attributed this to premature reduction of the active palladium-
(II) species to palladium(0) by carbon monoxide10 and
inefficient reoxidation by the (only slightly soluble) cupric
complexes. Use of a stronger base, a more soluble copper
salt (copper acetate: compare entries 5 and 6), a good
coordinating solvent, acetonitrile,11 and a lower temperature
improved matters. Tetramethylguanidine (TMG) was selected
as the base due to its relative strength compared to other
organic bases and the absence of copious precipitates when
added to methanol solutions of cupric chloride. Sodium
methoxide could give similar yields to TMG in certain cases
(entries 10-12). Potassium carbonate proved to be only
moderately effective (entries 5 and 6). Despite these im-
provements, starting material was still recovered in most
experiments.
Scheme 1. Preparation and Cyclization of Hydroxylaminesa
In all cases with carbamate groups on nitrogen, a single
diastereoisomer was obtained. In the case of isoxazolidine
8a, this was shown to be the cis isomer by nOe experiments
(Figure 1). Irradiation of one of the H4 protons led to no
a Reagents and conditions: (a) PhthNOH, PPh3, DEAD, THF, 0
°C to rt; (b) H2NNH2‚xH2O, CH2Cl2, rt; (c) MeOCOCl, K2CO3,
CH2Cl2, reflux or NsCl, Na2CO3, CH2Cl2, H2O, rt or CBZOSuc,
NaHCO3, CH2Cl2, H2O or Boc2O, NaOH, CH2Cl2, H2O.
cyclization-carbonylation proceeded to give the isoxazo-
lidines 8-11 (Table 2).
Figure 1. Significant nOe interactions for isoxazolidine 8a.
Table 2. Cyclofunctionalization Reactions
entry
substrate
conditionsa
yield, %
RSM,c %
enhancement of either proton R to a heteroatom (H3, H5).
Irradiation of the other H4 proton led to clear enhancement
of both protons R to heteroatoms. This experiment is slightly
complicated by the fact that this H4 proton signal is very
close to the signal for a side chain methylene proton,
preventing selective irradiation. The assignment is, however,
comfirmed by irradiation of either H3 or H5. In both cases
the same H4 proton is enhanced. The sulfonamide 5a was
less selective leading to an approximately 5:1 mixture of
separable diastereoisomers.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4a
4a
5a
6a
6a
6a
6a
7a
7a
7a
7a
7a
7b
6b
6c
A
D
A
A
B
C
D
A
37
43
61 + 12b
31
32
1
35
59
19
49
28
48
63
0
79
75
0
51
30
41
38
D
E1
E2
E3
D
D
D
The predominant formation of the cis isomer can be
explained by appeal to an envelope-like reactive conforma-
tion, in which A is favored over B due to the lesser crowding
of the alkene moiety (Figure 2). The stereochemical outcome
can be compared to the nitrone-alkene cycloaddition, which
can be used to form similar isoxazolidines. The cycloaddition,
however, results in the trans isomer as the major product,
usually as a mixture when acyclic nitrones are employed.12
An isomerically pure trans isoxazolidine has been prepared
by Michael addition.13 The reaction may not be extended to
24
42
16
8
a Conditions (all using 1:1 CH3CN/MeOH unless otherwise indicated
and 10 mol % of PdCl2): AsPdCl2, CuCl2‚2H2O, NaOAc, MeOH, CO;
BsPdCl2, CuCl2‚2H2O, K2CO3, CO; CsPdCl2, Cu(OAc) 2‚2H2O, K2CO3,
CO; DsPdCl2, Cu(OAc) ‚2H2O, TMG, CO; E1saddition of NaOMe to
2
PdCl2, Cu(OAc) 2‚2H2O, CO; E2sas E1, but using CuCl2‚2H2O; E3saddition
of PdCl2, Cu(OAc) 2‚2H2O to NaOMe, CO. b Cis + trans isomers. Isolated
yields of chromatographically separated compounds. c Recovered starting
material.
(10) Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation;
Plenum Press: New York, 1991; pp 139-140.
Under the original conditions employed with sodium
acetate as the base,9 the reactions terminated (formation of
(11) Acetonitrile improves the oxidizing ability of Cu(II) by stabilizing
Cu(I): AdVanced Inorganic Chemistry, 4th ed.; Cotton, F. A., Wilkinson,
G., Eds.; John Wiley & Sons: New York, 1980; pp 801-802.
(12) Kasahara, K.; Iida, H.; Kibayashi, C. J. Org. Chem. 1989, 54, 2225.
(13) Socha, D.; Jurczak, M.; Chmielewski, M. Tetrahedron Lett. 1995,
36, 135.
(9) Tamaru, Y.; Higashimura, H.; Naka, K.; Hojo, M.; Yoshida, Z.
Angew. Chem., Int. Ed. Engl. 1985, 24, 1045. Gracza, T.; Ja¨ger, V. Synlett
1992, 191.
4226
Org. Lett., Vol. 4, No. 24, 2002

Although oximes have been previously employed in
palladium-catalyzed cyclizations as both N-nucleophiles5,15
and O-nucleophiles,16 this is the first example to our
knowledge of the use of O-substituted hydroxylamines.
Isoxazolidines have been found to be valuable synthetic
intermediates.12,13,17 The clean, diastereoselective formation
of isoxazolidines by the novel cyclofunctionalization reported
here is a potentially useful procedure and its application in
synthesis is in hand. Other modes of cyclization of these
and related compounds are being examined.
Acknowledgment. We thank the Thailand Research Fund
Figure 2. Reaction intermediate conformations.
for partial support of this work.
the formation of six-membered rings, as the hydroxylamine
12, prepared in the standard way in overall 46% yield from
the corresponding alcohol,14 was recovered unchanged
(conditions D).
Supporting Information Available: Spectroscopic data
for hydroxylamines and isoxazolidines, nOe experiments for
compound 8a, and experimental procedures for the prepara-
tion and cyclization of hydroxylamines. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL026701D
(14) Lansbury, P. T.; Pattison, V. A. J. Org. Chem. 1962, 20, 4295.
(15) Bates, R. W.; Satcharoen, V. Chem. Soc. ReV. 2002, 12.
(16) Maeda, K.; Hosokawa, T.; Murahashi, S.-I.; Moritani, I. Tetrahedron
Lett. 1973, 5075.
(17) For examples, see: Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58,
5957.
Figure 3. Hydroxylamine (12).
Org. Lett., Vol. 4, No. 24, 2002
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