Synthesis of 2,3-dihydroisoxazoles from propargylic N-hydroxylamines via Zn(II)-catalyzed ring-closure reaction

Article abstract of DOI:10.1021/ol006095r

(equation presented) A novel cyclization reaction of propargylic N-hydroxylamines to 2,3,5-trisubstituted 2,3-dihydroisoxazoles in the presence of catalytic amounts (10 mol %) of ZnI₂ and DMAP is reported. The methodology provides a mild new approach to this useful class of substituted heterocycles that complements extant methods. The unique reactivity of the propargylic N-hydroxylamine substrates in the presence of Zn(II) and DMAP may have additional applications in other, related alkyne cyclization reactions.

Full text of DOI:10.1021/ol006095r

ORGANIC
LETTERS
2000
Vol. 2, No. 15
2331-2333
Synthesis of 2,3-Dihydroisoxazoles from
Propargylic N-Hydroxylamines via
Zn(II)-Catalyzed Ring-Closure Reaction
Patrick Aschwanden, Doug E. Frantz, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH-Zentrum, UniVersita¨trasse 16,
CH-8092 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received May 23, 2000
ABSTRACT
A novel cyclization reaction of propargylic N-hydroxylamines to 2,3,5-trisubstituted 2,3-dihydroisoxazoles in the presence of catalytic amounts
(10 mol %) of ZnI2 and DMAP is reported. The methodology provides a mild new approach to this useful class of substituted heterocycles that
complements extant methods. The unique reactivity of the propargylic N-hydroxylamine substrates in the presence of Zn(II) and DMAP may
have additional applications in other, related alkyne cyclization reactions.
2,3-Dihydroisoxazoles represent a class of heterocycles that
may be employed as useful building blocks for synthesis.1
Most commonly they are prepared in the laboratory through
either the 1,3-dipolar cycloaddition reaction of nitrones and
alkynes or the condensation reaction of N-hydroxylamines
and R,â-unsaturated ketones. Although cycloaddition reac-
tions can provide ready access to 2,3-dihydroisoxazoles, they
typically furnish regioisomeric mixtures of adducts.1f In
principle, the intramolecular cyclization of propargylic
N-hydroxylamines can also provide direct access to 2,3,5-
trisubstituted 2,3-dihydroisoxazoles. Surprisingly, such a
transformation has not been investigated and, to the best of
our knowledge, lacks precedence. Nevertheless, the develop-
ment of such a cyclization reaction under mild, catalytic
conditions would considerably facilitate access to this
synthetically useful class of dihydroisoxazoles. We have
recently reported a novel, mild, catalytic method for the
preparation of propargylic N-hydroxylamines from nitrones
and terminal acetylenes.2 Key to this method is the in situ
generation of a Zn-alkynilide under mild conditions (23 °C;
toluene, MeCN, or Et2O). Thus, in the presence of catalytic
Zn(OTf)2 and Et3N, terminal alkynes undergo addition to
nitrones at room temperature in high yields to give propar-
gylic N-hydroxylamines. In optimizing and studying these
addition reactions, we had observed the formation of 2,3-
dihydroisoxazoles as minor side products under certain
conditions. In the context of our interest in developing
methods for heterocycle synthesis,3 herein we document that
in the presence of catalytic ZnI2 and DMAP (10 mol % each),
propargylic N-hydroxylamines undergo 5-endo-dig cycliza-
tion to the corresponding 2,3-dihydroisoxazoles in good
yields (Scheme 1).4 The cyclization is demonstrated to be
general for a wide range of propargylic N-hydroxylamines.
Scheme 1. Cyclization of the Propargylic N-Hydroxylamines
to 2,3-Dihydroisoxazoles
(1) (a) Freeman, J. P. Chem. ReV. 1983, 83, 241. (b) Adachi, I.; Miyazaki,
R.; Kano, H. Chem. Pharm. Bull. 1974, 22, 70. (c) Liguori, A.; Ottana, R.;
Romeo, G.; Sindona, G.; Uccella, N. Tetrahedron 1988, 44, 1255. (d) Padwa,
A.; Chiachio, U.; Line, D. N.; Perumattan, J. J. Org. Chem. 1988, 53, 2238.
(e) Padwa, A.; Norman, B. H.; Perumattam, J. Tetrahedron Lett. 1988, 29,
663. (f) DeShong, P.; Li, W.; Kennington, J. W.; Ammon, H. L. J. Org.
Chem. 1991, 56, 1364.
In a series of studies by McDonald, homopropargylic
alcohols have been shown to participate in metal-mediated
10.1021/ol006095r CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/06/2000

(Mo and Cr) cyclization reactions to furnish 2,3-dihydro-
furans.5 The cyclization reactions of alkynyl allylic alcohols
to the corresponding furans under basic conditions have been
the subject of investigations by Marshall in the context of
synthetic studies aimed at 2,5-furanocyclic natural products.6
Additionally, Marshall has documented the Ag(I)-catalyzed
isomerization of allenones to furans along with allenyl
carbinols to 2,5-dihydrofurans.7 The 5-exo-trig iodocycliza-
tion reaction of allylic O-silylated N-hydroxylamines using
NIS has been reported to give iodo-substituted isoxazolidines
in 55-91% yields.8,9 By contrast, the direct cyclization
reaction of propargylic N-hydroxylamines to 2,3-dihydro-
isoxazoles, however, has not been examined.
Table 1. Cyclization Reaction of Propargylic
N-Hydroxylaminesa
In the context our investigations of the Zn(II)- and amine-
catalyzed addition reaction of terminal acetylenes to nitrones,
we carried out a series of investigations in which the structure
of the amine base was systematically varied. As we have
previously noted, the use of Et3N or Hu¨nig’s base leads to
generation of a putative Zn-acetylide that subsequently
participates in additions to nitrones and imines. When
pyridine was employed under otherwise identical conditions
(Zn(OTf)2, 23 °C, CH2Cl2), the starting nitrone and terminal
acetylene could be recovered quantitatively. This observation
suggested that pyridine is insufficiently basic to effect
deprotonation of terminal alkyne‚Zn(II) complex. Interest-
ingly, however, when this same mixture of Zn(OTf)2,
pyridine, acetylene, and nitrone was treated with Hu¨nig’s
base, rapid formation of a product (91%) was observed that
was subsequently shown to correspond to a 2,3-dihydroisox-
azole. In subsequent studies (vide infra), we established that
the 2,3-dihydroisoxazoles isolated from these test reactions
were generated as secondary products from the first-formed
propargylic N-hydroxylamines. We have subsequently in-
vestigated a one-pot procedure for acetylide addition to
nitrones to give propargylic N-hydroxylamines with cycliza-
tion to give 2,3-dihydroisoxazoles; however, at the current
(2) (a) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999,
121, 11245. (b) For additions to aldehydes, see: Frantz, D. E.; Fa¨ssler, R.;
Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806.
(3) (a) Alper, P. B.; Meyers, C.; Siegel, D. R.; Carreira, E. M. Angew.
Chem., Int. Ed. Engl. 1999, 38, 3186. (b) Frantz, D. E.; Fa¨ssler, R.; Carreira,
E. M. J. Am. Chem. Soc. 1999, 121, 11245. (c) Muri, D.; Bode, J. W.;
Carreira, E. M. Org. Lett. 2000, 2, 539. (d) Tomooka, C. S.; LeCloux, D.
D.; Sasaki, H.; Carreira, E. M. Org. Lett. 1999, 1, 149. (e) Carreira, E. M.;
Hong, J.; Du Bois, J.; Tomooka, C. S. Pure Appl. Chem. 1998, 70, 1097.
(f) Du Bois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M. Acc. Chem. Res.
1997, 30, 364. (g) Du Bois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M.;
Day, M. W. Angew. Chem. 1997, 36, 1645. (h) Du Bois, J.; Tomooka, C.
S.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 3179. (i) Du
Bois, J.; Hong, J.; Carreira, E. M. J. Am. Chem. Soc. 1996, 118, 915.
(4) 5-Endo-dig cyclizations were discussed in the original formulation
of Baldwin’s rules and constitute an allowed process, see: (a) Baldwin,J.
E. J. Chem. Soc., Chem. Commun. 1976, 734. (b) Baldwin, J. E. J. Chem.
Soc., Chem. Commun. 1976, 738. (c) Baldwin, J. E.; Cutting, J.; Dupont,
W.; Kruse, L.; Silbermann, L.; Thomas, R. C. J. Chem. Soc., Chem.
Commun. 1976, 736. (c) Baldwin, J. Rules for Ring Closure, Ciba
Foundation Symposium 53, Furhter Perspectives in Organic Chemistry;
Elsevier: New York, 1978; p 85.
a Conditions: 10 mol % of ZnI2 and 10 mol % of DMAP were added to
a solution of propargylic N-hydroxylamine in CH2Cl2 at 23 °C. The reaction
mixture was stirred for the time indicated above before it was quenched by
partitioning between CH2Cl2 and an aqueous ammonium chloride solution.
Yields are of the pure isolated compounds.
level of development this has not been possible. Nonetheless,
we have found that treatment of propargylic N-hydroxyl-
amines with ZnI2 and DMAP in CH2Cl2 at 23 °C afforded
clean conversion to 2,3-dihydroisoxazoles.
As shown in Table 1, a wide range of propargylic
N-hydroxylamines participate in this transformation to afford
heterocyclic products in good yields. The workup of the
(5) (a) Bowman, J. L.; McDonald, F. E J. Org. Chem. 1998, 60, 3680.
(b) McDonald, F. E.; Bowman, J. L Tetrahedron Lett. 1996, 4675. (c)
McDonald, F. E.; Connolly, C. B.; Gleason, G. G. J. Org. Chem. 1993, 58,
6952.
(6) (a) Marshall, J. A.; Sehon, C. A J. Org. Chem. 1995, 60, 5966. (b)
Marshall, J. A.; Bennett, C. E. J. Org. Chem. 1995, 60, 2644. (c) Marshall,
J. A.; Bennett, C. E. J. Org. Chem. 1994, 59, 6110. (d) Marshall, J. A.;
DuBay, W. J. J. Org. Chem. 1993, 58, 3435.
(7) (a) Marshalll, J. A.; Yu, B. C. J. Org. Chem. 1994, 59, 324. (b)
Marshall, J. A. Bartley, G. S. J. Org. Chem. 1994, 59, 7169.
(8) (a) Fiumana, A.; Lombardo, M.; Trombini, C. J. Org. Chem. 1997,
62, 5623.
(9) For a recently reported example involving the intramolecular 5-endo-
trig cyclization reaction of 2-alkynyl anilides to indoles, see: Ma, C.; He,
X.; Liu, X.; Cook, J. M. Tetrahedron Lett. 2000, 41, 2781.
2332
Org. Lett., Vol. 2, No. 15, 2000

reaction is experimentally straightforward, as a simple acidic
aqueous workup allows for the separation of the reactants
(Zn(II) and DMAP) from the product. With the exception
of those substrates incorporating propargylic silyl ethers
(entries 2, 5, and 8) the cyclization reactions are observed
to proceed in 1-4 h (Table 1).
of the reactive species involved. In our working hypothesis,
we speculate that the resting state of the Zn(II) is a
coordination complex that results from association of the
N-hydroxylamine and the Zn(II) (Scheme 2, cf. 3 and 4).10
We have carried out a number of control experiments that
provide insight into the mechanistic aspects of the novel
cyclization reaction and highlight the unique aspects of the
combination of ZnI2 and DMAP as catalysts. As highlighted
above, although the combination of Hu¨nig’s base and
Zn(OTf)2 leads to the addition reaction of terminal acetylenes
and nitrones, this reagent combination does not lead to
cyclization of the propargylic N-hydroxylamine during the
reaction times (4-8 h) that have been employed for the
nitrone addition reactions. Only in the presence of Zn(OTf)2
and pyridine, with the latter present either at the outset of
the reaction or after formation of the propargylic N-
hydroxylamine adducts, could the formation of heterocyclic
adduct be observed. This led us to suspect that a complex
formed between DMAP and Zn(II) has the special ability to
activate both the N-hydroxylamine and the C-C triple bond
toward the cyclization reaction. Indeed, only upon prolonged
stirring (>28 h) could any 2,3-dihydroisoxazole be observed
(5%) upon treatment of starting propargylic N-hydroxylamine
with Hu¨nig’s base and Zn(OTf)2. Although our initial studies
employed Zn(OTf)2 in the cyclization reaction, we have
observed that ZnCl2, ZnBr2, and ZnI2 promote heterocycle
formation from propargylic N-hydroxylamines, with ZnI2
affording product at the fastest rate.
Scheme 2. Working Model for the Cyclization Reaction
In either form, however, we speculate the Zn(II) is precluded
from participating in the necessary complexation and activa-
tion of the alkyne CtC for subsequent cyclization (5). It
would seem reasonable that the nature of amine and
counterions affects the equilibrium between free and coor-
dinated Zn(II), thereby influencing the rate of cyclization.
In summary, we have developed a novel cyclization
reaction of propargylic N-hydroxylamines to 2,3-dihydro-
isoxazoles under mild conditions in the presence of catalytic
amounts (10 mol %) of ZnI2 and DMAP. The method
described provides a new approach to this useful class of
substituted heterocycles that complements extant methods.
The intriguing reactivity of the substrates in the presence of
Zn(II) and DMAP may have additional applications in related
alkene or alkyne cyclization reactions. Further investigations
of this process are ongoing and will be reported as results
are forthcoming.
A series of control experiments were conducted to examine
and preclude proton-catalyzed processes. In this regard, we
were unable to induce the cyclization of propargylic N-
hydroxylamines in the presence of triflic acid. Additionally,
the combination of other Lewis acids (BF3‚OEt2, AlCl3,
Cu(OTf)2, Mg(OTf)2, and Sn(OTf)2) along with DMAP or
Hu¨nig’s base did not lead to the formation of 2,3-dihydro-
isoxazoles. Heating a solution of the propargylic N-hydroxyl-
amines in toluene or CH2Cl2 returned starting material. To
establish that the reaction was not proceeding through a
mechanism in which the propargylic N-hydroxylamine
Acknowledgment. Support has been provided by gener-
ous funds from the ETH, the Kontaktgruppe fu¨r Forschungs-
fragen (KGF), Hoffman-La Roche, and Merck. We are
grateful to Mr. Roger Fa¨ssler for assistance and useful
discussions throughout the studies described.
3
undergoes Csp-Csp bond cleavage to give the corresponding
terminal acetylene and nitrone followed by a recombination
through a dipolar cycloaddition reaction to give 2,3-di-
hydroisoxazoles directly, a crossover experiment was con-
ducted. Thus, treatment of a 1:1 mixture of the N-hydroxyl-
amines from entries 6 and 7 (Table 1) under the reaction
conditions we have described (10 mol % of ZnI2, and DMAP,
CH2Cl2, 23 °C) gave a 1:1 mixture of 2,3-dihydroisoxazoles
expected from intramolecular cyclization and none resulting
from cross-reactivity.
Supporting Information Available: Full characterization
and experimental procedures for the synthesis of the prop-
argylic N-hydroxylamines, the 2,3-dihydroisoxazoles prod-
ucts, and control experiments. This material is available free
of charge via the Internet at http://pubs.acs.org/.
OL006095R
(10) The coordination chemistry of N-hydroxylamines has been inves-
tigated by Wiegardt, see: Wiedgardt, K.; Hofer, E.; Holzbach, W.; Nuber,
B.; Weiss, J. Inorg. Chem. 1980, 19, 2927.
The mechanistic details of the process we have described
are currently under scrutiny in order to determine the nature
Org. Lett., Vol. 2, No. 15, 2000
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