Dicobalt Octacarbonyl Promoted Rearrangement of 4-Isoxazolines to Acylaziridines: Dramatic Rate Acceleration with Very High Substrate Tolerance

Article abstract of DOI:10.1021/ol025906j

(Matrix Presented) Dicobalt octacarbonyl [Co₂(CO)₈] in acetonitrile at 75 °C triggers the cleavage of the N-O bond of 4-isoxazolines (1) to bring about the valence rearrangement to 2-acylaziridines (2). The isoxazolines were stable a

Full text of DOI:10.1021/ol025906j

ORGANIC
LETTERS
2002
Vol. 4, No. 11
1907-1910
Dicobalt Octacarbonyl Promoted
Rearrangement of 4-Isoxazolines to
Acylaziridines: Dramatic Rate
Acceleration with Very High Substrate
Tolerance
Teruhiko Ishikawa,* Takayuki Kudoh, Juri Yoshida, Ayako Yasuhara,
Shinobu Manabe, and Seiki Saito*
Department of Bioscience and Biotechnology, Faculty of Engineering,
Okayama UniVersity, Tsushima, Okayama, Japan 700-8530
seisaito@biotech.okayama-u.ac.jp
Received March 21, 2002
ABSTRACT
Dicobalt octacarbonyl [Co2(CO)8] in acetonitrile at 75 °C triggers the cleavage of the N−O bond of 4-isoxazolines (1) to bring about the valence
rearrangement to 2-acylaziridines (2). The isoxazolines were stable at 75 °C in the absence of the cobalt complex.
The potential of 4-isoxazolines (1) as synthons for 2-acyl-
aziridines (2) through thermal valence rearrangements was
pointed out by Baldwin in 1969.1 However, this reaction has
not developed into a practical synthetic method because of
the severe limitations of the rearrangement.2 On the other
hand aziridines have been playing an important role as
precursors for diverse cyclic or acyclic nitrogen compounds.3
The significance of aziridines in organic synthesis has been
stimulating research to develop a number of synthetic
methods,4 although the substrate limitation problem has also
been addressed.
This situation directed our attention to the previous work
of Baldwin1 when we thought about almost free availability
of 4-isoxazolines through [3 + 2] cycloaddition reactions
between nitrones and alkynes2a or more promising addition-
cyclization processes between nitrones and metal acetylides.5
(3) For reviews on reactions of aziridines, see: (a) Mitunobu, O. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 6, Chapter 1.3. (b) Padwa, A. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; Vol. 4, Chapter 4.9. (c) Thompson, D. J. In ComprehensiVe
Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 3, Chapter 4.1. (d) Hudlicky, T.; Reed, J. W. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.
5, Chapter 8.1. (e) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599-
619.
(4) For leading references for aziridine synthesis, see: (a) Kemp, J. G.
In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I. Eds.;
Pergamon: Oxford, 1991; Vol. 7, Chapter 3.5. (b) Reference 3e. (c) Evans,
D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am. Chem. Soc.
1991, 113, 726-728. (d) Wulff, W. D.; Antilla, J. C. Angew. Chem., Int.
Ed. 2000, 39, 4518-4521. (e) Hada, K.; Watanabe, T.; Isobe, T.; Ishikawa,
T. J. Am. Chem. Soc. 2001, 123, 7705-7706. (f) Dauban, P.; Sanie´lie, L.;
Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc. 2001, 123, 7707-7708.
(5) Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2,
2331-2333.
(1) Baldwin, J. E.; Pudussery, R. G.; Qureshi, A. K.; Sklarz, B. J. Am.
Chem. Soc. 1968, 90, 5325-5326.
(2) (a) Freeman, J. P. Chem. ReV. 1983, 83, 241-261. (b) For N-methoxy-
4-isoxazoline to N-methoxyaziridine transformation, see: Gre¨e, R.; Carrie,
R. J. Am. Chem. Soc. 1977, 99, 6667-6672. (c) Shim, J.; Houk, K. N. J.
Am. Chem. Soc. 1973, 95, 5798-5800. (d) For isoxazolidinone to aziridine
transformation, see: Chidichimo, G.; Gum, G.; Lelj, F.; Uccella, N. J. Am.
Chem. Soc. 1980, 102, 1372-1377. The rearrangement took place, in
general, when a substituent on the nitrogen atom was a phenyl, tert-butyl,
or methoxy group except for the case in which X or Y was an electron-
withdrawing group.
10.1021/ol025906j CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/04/2002

Thus, we made extensive efforts to accelerate the valence
rearrangement of 1 to the aziridines.
from benzalacetone, 2-methylpropanal, and isoxazolidinone,
respectively, and converted to the corresponding arizidino
ketones 2f, 2h, and 2j (Scheme 1).
It is well-known that Mo(CO)6 can cleave a N-O bond.6
However, heating a solution of 1h, for example, in aqueous
acetonitrile in the presence of Mo(CO)6 under reflux afforded
not the aziridine but the acylsilane derivative.7 We also tried
dicobalt octacarbonyl [Co2(CO)8] in vain. However, it was
found that Co2(CO)8 in anhydrous acetonitrile (or propioni-
trile) provides a practical solution to this longstanding
problem. Established synthetic procedure is as follows: to
a solution of 1 in CH3CN (20 mL/1 mmol of 1) was added
powdered Co2(CO)8 (50 mol %) at ambient temperature
under stirring, and the resulting mixture was immediately
heated at 75 °C for 0.5-1 h under nitrogen atmosphere until
the disappearance of 1 on TLC.8 Then, the mixture was kept
in contact with air for a few hours to facilitate the
decomposition of the cobalt complex through oxidation to
form precipitates, which were removed by filtration. The
filter cake was rinsed with ethyl acetate. The combined
organic solutions were dried and concentrated to give an oil,
which was purified by column chromatography (silica gel).
The diastereoisomers, if any, were able to be separated, and
the stereochemistry was determined by means of both NOE
and J-values. In Table 1 are summarized the results of the
Scheme 1a
a (i) BnNHOH/THF/rt, 6 h; (ii) MsCl/Et3N/THF/0 °C, 0.5 h; (iii)
see Table 1; (iv) (1) BnNHOH/THF/rt, 2 h, (2) TMSCCTMS (5
equiv)/100 °C, 4 h; (v) DIBALH/PhMe/-78 °C, 0.5 h; (vi) MsCl/
Et3N/THF/0 °C f rt, 1 h.
It should be noted that 1a-j was recovered unchanged
when solutions in acetonitrile, DMF, DMSO, THF, or toluene
were heated at 75 °C for 26 h without Co2(CO)8, and these
solvents other than acetonitrile were totally ineffective even
if used with Co2(CO)8.
Table 1. Co2(CO)8-Promoted Rearrangements of
4-Isoxazolines 1 to Isomeric 2-Acylaziridines 2 and 3a
It turned out that the rearrangement proceeded with
exclusive diastereoselectivity when a stereogenic center
existed in the substituent on the nitrogen atom, such as 1k
prepared from optically pure isoxazolidinone 410 to give
aziridino ketone 2k as a single isomer (Scheme 2).11 The
fully substituted 4-isoxazoline 1l, obtained through 1,3-
dipolar cycloaddition between nitrone-A and methyl 3-phe-
nylpropiolate followed by reduction and protection, afforded
2,2-disubstituted aziridine 2l in an excellent yield with a high
diastereomeric ratio (10:1). Furthermore, the rearrangement
of diastereomerically pure 4-isoxazoline 1m, prepared like-
wise employing (S)-lactate-based nitrone-B, afforded 2m,
which is otherwise difficult to access, albeit in low yield.12
1
yield,
%b (2: 3)
entry
R1
R2
X
Y
1
2
1a
1b
1c
1d
1e
1f
1g
1h
1i
isopropyl
Ph
H
H
H
H
H
H
H
Ph
51 (4:1)
61 (2.8:1)c
75 (2.3:1)
86 (2.5:1)
66d
47d,e
56f
H
Ph
3
4-MeOPh
heptyl
CH3
H
Ph
4
H
Ph
5
CH3
H
Ph
6
Ph
CH3
SiMe3
SiMe3
butyl
H
7
Ph
H
SiMe3
SiMe3
H
8
isopropyl
isopropyl
isopropy
H
92f
9
H
67 (17:1)
39d
10
1j
H
H
(6) Nitta, M.; Kobayashi, T. J. Chem. Soc., Perkin Trans. 1 1985, 1401-
1406.
(7)
a Neither 4-isoxazolines nor cobalt complex was recovered. Structures
were determined by 1H and 13C NMR spectroscopy including NOE and
two-dimensional correlation techniques. b Isomers, separated by flash
column chromatography (silica gel). Yields are for combined products. No
other identifiable products were isolated. c Padwa, A.; Hamilton, L.
Tetrahedron Lett. 1967, 20, 1861-1864. d Isomeric aziridines 3 not detected.
e Davoli, P.; Forni, A.; Moretti, I.; Prati, F.; Torre, G. Tetrahedron 2001,
57, 1801-1812. f Single diastereomer; relative configurations, not deter-
mined.
(8) No reaction occurred below 70 °C.
(9) Synthetic procedures of 1 are provided in Supporting Information.
(10) For the preparation of 4, see: Ishikawa, T.; Nagai, K.; Kudoh, T.;
Saito, S. Synlett 1995, 1171-1173.
(11) This process opens a general strategy for the synthesis of chiral
aziridines from chiral isoxazolidinones. For the asymmetric synthesis of
isoxazolidinones, see: (a) Ishikawa, T.; Nagai, K.; Kudoh, T.; Saito, S.
Synlett 1998, 1291-1293. (b) Sibi, M. P.; Liu, M. Org. Lett. 2000, 2, 3393-
3396 and references therein.
rearrangement of isoxazolines 1a-j9 to predominantly 2-
acylaziridines 2a-j. The following three representative cases
illustrate how 4-isoxazolines 1f, 1h, and 1j, were formed
1908
Org. Lett., Vol. 4, No. 11, 2002

Scheme 2a
Scheme 3
one Co2(CO)8 molecule can generate two of the active
species. Therefore, although the elucidation of this active
species must await future study, it might be a cobalt radical
species.14,15 If this is the case, the cobalt radical could
promote the fragmentation of the N-O bond6,16 probably as
shown in Scheme 3. We can expect that A might initiate the
valence rearrangement of 1 through a series of reactions
involving one-electron reduction to trigger N-O bond
cleavage, generation of intermediate B, and final one-electron
oxidation to complete the formation of aziridino ketones 2
(or 3).
The selective formation of aziridines 2 can be explained
on this basis by assuming the preferential formation of
chelated aza-radical intermediates IA over IB. The electron
reorganization from IA or IB may lead to 2-acylaziridines 2
or the isomers 3 (Scheme 4).
a (i) (1) BuLi/THF, (2) MsCl, Et3N/THF; (ii) Co2(CO)8/aceto-
nitrile, 75 °C, 0.5 h; (iii) PhCCCO2Me/PhCH3/75 °C, 2 h; (iv) LAH/
THF/rt, 1 h; (v) (1) LAH/THF/rt, 1 h/separation of diastereoisomers
(81%), (2) TBDMSCl/ imidazole/THF/0 °C f rt, 2.5 h (46%), (3)
DIPEA/MOMCl/THF/40 °C, 24 h (73%).
Scheme 4
When 1 was added to a solution of Co2(CO)8 in acetonitrile
that had been standing at room temperature for 5 min or
more, no rearrangements occurred at all.13 Thus, it is
important to use an active species (A, Scheme 2) as soon as
it is generated. The complete consumption of substrates 1
required 50 mol % of Co2(CO)8, which probably means that
(12) The generation of azomethine ylide intermediates from 2 or 3 under
the given conditions might be responsible for the low yield of 2 (or 3)
(entries 1, 6, and 10 in Table 1 and 2m in Scheme 1). In fact a solution of
2f in benzene at 80 °C for 12 h in the presence of ethyl propiolate afforded
substituted pyrrole 5 apparently through regioselective [1,3]-dipolar cy-
cloaddition of azomethine ylide (C) followed by oxidation.
In conclusion, we have developed the valence rearrange-
ment of 4-isoxazolines to 2-acylaziridines promoted by Co2-
(14) For the mechanism of the thermal rearrangement of 1 with an N-aryl
or N-methoxy substituent to 2-acylaziridines, three possibilities have been
proposed involving concerted, zwitterionic, or biradical processes. See ref
2.
(15) For radical generation from Co2(CO)8, see: (a) Absi-Halabi, M.;
Atwood, J. D.; Forbus, N. P.; Brown, T. L. J. Am. Chem. Soc. 1980, 102,
6248-6254. See also: (b) Collman, J. P.; Hegedus, L. S.; Norton, J. R.;
Finke, R. G. Principles and Applications of Organotransition Metal
Chemistry; University Science Books: Mill Valley, CA, 1987; pp 266-
267 and (c) Hosokawa, S.; Isobe, M. Tetrahedron Lett. 1998, 39, 2609-
2612. However, we cannot completely rule out an anionic mechanism
because cobalt carbonyl anion [Co(CO)4]- can be generated from Co2(CO)8
on treatment with a weak base. See: Hinterding, K.; Jacobsen, E. N. J.
Org. Chem. 1999, 64, 2164-2165.
For azomethine ylide formation, see: (a) Wenkert, D.; Ferguson, S. B.;
Porter, B.; Qvarnstrom, A.; McPhail, A. T. J. Org. Chem. 1985, 50, 4114-
4119. (b) Vedejs, E.; Grissom, J. W. J. Am. Chem. Soc. 1988, 110, 3238-
3246 and references therein. See also: (c) L.-Calle, E.; Eberbach, W. J.
Chem. Soc., Chem. Commun. 1994, 301-302.
(13) Evolution of CO was observed on mixing Co2(CO)8 with acetonitrile.
When the evolution of CO ceased, the mixture turned out to be useless for
the rearrangement. Therefore, the cobalt complex should be added to a
solution of 1 in acetonitrile.
Org. Lett., Vol. 4, No. 11, 2002
1909

(CO)8 in acetonitrile with very high substrate tolerance, which
occurs under mild conditions and, in some cases, is diaste-
reoselective. We have also proposed the role of Co2(CO)8
in the rearrangement of this class, which in general may
provide a concept for activating heteroatom bonds.
discussion and also to the SC-NMR Laboratory of Okayama
University for high-field NMR experiments.
Supporting Information Available: Synthesis and spec-
1
troscopic data for 1a-m, 2a-m, and 5 and copies of H
and 13C NMR spectra of 2a-m.nts. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules” from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan. We are grateful to Dr. T. Sugihara for his helpful
OL025906J
(16) For other examples of the rearrangement involving N-O bond
cleavage processes, see: (a) Hutchins, C. W.; Coates, R. M. J. Org. Chem.
1979, 44, 4742-4744. (b) Padwa, A.; Wong, G. S. K. J. Org. Chem. 1986,
51, 3125-3133.
1910
Org. Lett., Vol. 4, No. 11, 2002